2024 NOGG临床指南：骨质疏松的预防和治疗

Abstract

Summary The National Osteoporosis Guideline Group (NOGG) has updated the revised UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. This guideline is relevant for all healthcare professionals involved in osteoporosis management.

Introduction The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013, 2017 and 2021. This paper presents a minor update of the 2021 guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men aged 50 years and older.

Methods Where available, systematic reviews, meta-analyses and randomised controlled trials have been used to provide the evi-dence base. Conclusions and recommendations have been systematically graded according to the strength of the available evidence.Results Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assess-ment and intervention thresholds, management of vertebral fractures, non-pharmacological and pharmacological treatments,including duration and monitoring of anti-resorptive therapy, glucocorticoid-induced osteoporosis, as well as models of care for fracture prevention. Recommendations are made for training, service leads and commissioners of healthcare, and for review criteria for audit and quality improvement. Specific 2024 updates include guidance on fracture risk assessment by ethnicity, Parkinson's disease, Down's syndrome and lower-limb amputation; furthermore, the definition of very high fracture risk has been clarified. Hormone replacement therapy(HRT) is now recommended as a first-line treatment option in younger postmenopausal women with high fracture risk and low baseline risk for adverse events; recommendations regarding abaloparate are included; additional training resources have been added.

Conclusion The guideline provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals involved in its management. This position paper has been endorsed by the International Osteoporosis Foundation and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases(ESCEO).

Keywords Osteoporosis·Fracture·NOGG·Guideline

Introduction

This guideline was prepared in 2021 with the support of the societies listed to provide guidance on prevention and treatment of osteoporosis with the overarching aim of reduc-ing fragility fracture risk, and updated in 2024, replacing previous National Osteoporosis Guideline Group (NOGG)

<EndOfPara>guidance [1-4]. The scope of the guideline is to review the assessment and diagnosis of osteoporosis, the therapeutic interventions available and the approaches for the preven-tion of fragility fractures, in postmenopausal women, and in men aged 50 years or older. This focus is chosen as fragility fractures and osteoporosis are uncommon in premenopau-sal women and men younger than 50 years, and therefore,when these occur, patients need thorough investigation for secondary causes of osteoporosis, and careful consideration of treatment options. Specialist referral is usually required.

Extended author information available on the last page of the article

119 Page 2 of 50

Archives of Osteoporosis

This NOGG guidance has appraised the current evidence base to inform these updated recommendations. The aim of the guideline is to provide clinically appropriate recommen-dations that integrate available evidence on clinical efficacy,effectiveness, and safety.This contrasts with, but complements, the remit of the National Institute for Health and Care Excel-lence(NICE), which focuses principally on establishing criteria for cost effectiveness. Cost effectiveness analyses are generally supportive for treatment guided by clinical effectiveness thresh-olds, rather than defining intervention thresholds per se[5]. The guideline has been prepared by a writing group and has been approved after consultation with stakeholders(Appendix 1).

The guideline is intended for all healthcare professionals involved in the prevention and treatment of osteoporosis and fragility fractures. This includes primary care practitioners,allied health professionals and relevant specialists in second-ary care including rheumatologists, gerontologists, gynaecol-ogists, endocrinologists, clinical biochemists, and orthopae-dic surgeons. The guideline includes recommendations for training in osteoporosis care. The guideline is supported by a series of Frequently Asked Questions(FAQs) available on the NOGG website(https://www.nogg.org.uk/). The conclusions and recommendations in the document are systematically graded, according to the quality of information available, to indicate the level of evidence on which recommendations are based. The grading methodology is summarised in Appen-dix 2. Where available, systematic reviews, meta-analyses and randomised controlled trials have been used to provide the evidence base. The evidence base comprises systematic reviews and meta-analyses identified in PubMed from July 2016 to Sept 2020, with additional evidence added based on expertise and knowledge of the advances in the field, from within the group. The quality of systematic reviews and meta-analyses used in the formulation of recommendations was assessed using AMSTAR2(Appendix 3). The updates to rec-ommendations in this guideline were agreed by the National Osteoporosis Guideline Development Group.

This guideline provides a framework from which local management protocols should be developed to provide advice for healthcare professionals. Implementation of this guideline should be audited at a local and national level. The recom-mendations in the guideline should be used to aid manage-ment decisions but do not replace the need for clinical judg-ment in the care of individual patients in clinical practice.

# Summary of the 2024 update to the 2021 guideline

This revised guideline now includes clarification that quan-titative ultrasound, IBEX bone health, and Radiofrequency Echographic Multi Spectrometry are not recommended for the diagnosis of osteoporosis; advice on the use of FRAX

in non-white ethnic groups and those who have migrated to the UK; advice on FRAX adjustment when assessing patients with Parkinson's disease; addition of clinical risk factors that increase fracture risk, specifically lower limb amputation and adult learning disabilities: e.g., Down's Syndrome; the definition of very high fracture risk has been clarified; the intervention threshold has been defined and the associated NOGG graphs updated; vaping with e-cig-arettes has been added as a possible risk factor for fragil-ity fracture; hormone replacement therapy(HRT) is now recommended as a first-line treatment option in younger postmenopausal women(age≤ 60 years) with high frac-ture risk and low baseline risk for adverse malignant and thromboembolic events; recommendations pertaining to the use of abapolarate have been added; considerations when choosing which anabolic agent to use have been outlined;and additional training resources have been added.

Background

The conceptual definition of osteoporosis was made by the World Health Organization(WHO) in 1994 as a‘progres-sive systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture'[6]. Since microarchitectural deterioration could not be measured clinically, the operational description was based on a bone mineral density(BMD) T-score of≤-2.5. Over the years this was adopted as a clinical definition; however,the limitations of focusing on a BMD-based definition alone have since become clear. BMD is now viewed as one, albeit very important, risk factor to be considered when assessing fracture risk, which is now viewed as the principal necessity.

The clinical significance of osteoporosis lies in the fractures that arise. In adults, approximately one in two women and one in five men will sustain one or more fra-gility fractures(a low trauma fracture sustained from a fall from standing height or less) in their lifetime[7]. In the UK, the prevalence of femoral neck BMD T-score≤-2.5, in those aged 50 years and older, is 6.8% in men and 21.8% in women[8]. However, the majority of people who sustain a fragility fracture will have a femoral neck BMD T-score above-2.5, reflecting the contribution of many other factors, besides BMD, to fracture risk[9-11]. Fall-related risk factors add significantly to fracture risk and often overlap with risk factors for osteoporosis, hence the need for integrated fall and fracture services.

Currently in the UK, approximately 549,000 new fragil-ity fractures occur each year, including 105,000 hip frac-tures, 86,000 vertebral fractures, and 358,000 other frac-tures(i.e., fractures of the pelvis, ribs, humerus, forearm,

Archives of Osteoporosis(2025) 20:119

Page 3 of 50 119

119

tibia, fibula, clavicle, scapula, sternum, and other femoral fractures); 33% are sustained by men[8, 12, 13]. Such fractures cause severe pain, disability, reduction in qual-ity of life, and in some cases increased mortality[14, 15].In the UK, fragility fractures are estimated to account for 579,722 DALYs(Disability Adjusted Life Years) lost,largely driven by years lived with disability. This equates to 24 DALYs per 1000 people aged over 50 years, which is comparable to the DALYs lost from dementia[8]. Costs of fragility fractures to the National Health Service(NHS)exceed£4.7 billion per annum, of which£2.6 billion is directly incurred after an incident fracture(£1.1 billion for hip fractures alone[16]), with more than£1.7 billion attributable to institutional care costs post-fracture(esti-mated for 2017)[8]. Total direct costs for 2019 were£5.4 billion, accounting for 2.4% of healthcare spending[17].

Common sites of fragility fracture include the vertebral bodies, hip, distal radius, proximal humerus, and pelvis.Hip fracture is the most common reason for emergency anaes-thesia and surgery in older people. It is also the most com-mon cause of death following a fall. After hip fracture, the mean hospital length of stay is 20 days, accounting for half a million hospital bed days used each year, with 3600 hospital beds(3159 in England, 325 in Wales and 133 in Northern Ireland) occupied at any one time by patients recovering from hip fracture[18, 19]. Loss of independence is common following a hip fracture, with only 52% living in their own home after 120 days[12] and 26% will die within 12 months of their fracture[20]. Most major osteoporotic fractures are associated with reduced relative survival, part causally related and part due to associated co-morbidity[21-23].

In the UK, fracture rates vary by geographic location,race and levels of socioeconomic deprivation[24-26]. As in many higher income countries, age- and sex-adjusted fracture rates appear relatively stable, although increases in hip fractures amongst men in the UK have been reported[24,27]. Changes in vertebral fracture rates potentially reflect secular alterations to reporting of cases. Impor-tantly, the ageing of the UK population is predicted to give rise to a 19.6% increase in the number of fragility fractures by 2030 if changes are not made to current practice[8].

Fracture risk assessment and case finding

Recommendations

1. A FRAX assessment should be performed in any postmenopausal woman or man age≥50 years, with a clinical risk factor for fragility fracture to guide BMD measurement and prompt timely referral and/or drug treatment where indicated(Strong recommendation).

2.When using FRAX to calculate the probability of frac-ture, clinical judgement is needed when clinical risk exceeds those factors able to be entered into FRAX(Strong recommendation).

3.Arithmetic adjustments to FRAX probabilities of major osteoporotic fracture(MOF: clinical spine, hip, forearm or humerus) and hip fracture(see Table 1) can be used in clinical practice to take account of additional clini-cal risk factors, such as high dose glucocorticoid use,discordantly low lumbar spine BMD, type 2 diabetes,and a history of falls(Conditional recommendation).

4. Vertebral fracture assessment (VFA) is indicated in postmenopausal women and men age≥50 years if there is a history of≥4 cm height loss, kyphosis,recent or current long-term oral glucocorticoid therapy,a BMD T-score ≤-2.5 at either the spine or hip, or in cases of acute onset back pain with risk factors for osteoporosis (Strong recommendation).

5.T-scores in men and women derived from femoral neck BMD should use normative values for BMD derived from young healthy women from NHANES III(Strong recommendation).

6.DXA scan results should be reported within 3 weeks of the scan, by healthcare professionals with specific training in DXA interpretation, and in accordance with national and international reporting standards(Strong recommendation).

7. Patients with osteoporosis and/or a fragility fracture should be investigated for underlying causes, including the need for routine blood tests(Strong recommendation).

8.The use of quantitative ultrasound, IBEX bone health,and Radiofrequency Echographic Multi-Spectrometry are not recommended for the diagnosis of osteoporosis(Strong recommendation).

9.QCT-measured femoral neck areal BMD in postmeno-pausal women and men aged≥50 years can be used for opportunistic diagnosis of osteoporosis and to inform individual treatment decisions using FRAX(Condi-tional recommendation).

10. Computer Aided Diagnostics(CAD) may be consid-ered to improve standard reporting of CTs performed on postmenopausal women and men aged≥50 years to improve opportunistic identification of vertebral frac-tures(Conditional recommendation).

Measurement of bone mineral density

The risk of fracture increases progressively with decreas-ing bone mineral density(BMD). Systematic reviews and

119 Page 4 of 50

Archives of Osteoporosis

Table 1 Approximate adjustments and considerations to probabilities of hip fracture and major osteoporotic fracture to aid the interpretation of FRAX

|Risk variable|Adjustment to FRAX*|Access| |---|---|---| |Medium and high dose exposure to oral gluco- corticoids|Medium doses(2.5-7.5 mg daily) are the assumed minimum requirement for FRAX calculation, and the unadjusted FRAX value is used. For high doses (>7.5 mg daily), MOF probabilities are upward revised by about 15% and hip fracture probabilities by 20%¥|Automatic adjustment available on FRAX website: http://www.nogg.org.uk/manual-data-entry. Kanis et al.(2011)[28]| |Concurrent data on lumbar spine (LS) BMD|Increase or decrease the MOF probability by 10% of each rounded T-score differ- ence between LS and FN (see Frequently Asked Questions | NOGG no.4 for worked example)*|Leslie et al.(2011); Johansson et al.(2014) [29,30]| |Trabecular bone score (TBS)|Increase MOF probability by 30% for each standard deviation (SD) decrease in TBS|TBS adjustment can be accessed from the UK FRAX website. McCloskey et al.(2016) [31]| |Hip axis length (HAL)|Increase or decrease hip fracture probability by 30% for each SD difference in HAL|Leslie et al.(2016) [32]| |Falls history|Increase MOF and hip fracture probability by 30% for a history of recurrent falls (≥2 falls in the last year)|Masud et al.(2011)[33]; Vandenput et al.[34]| |Country of birth|Use FRAX model for country of birth since individuals retain the risk characteristics of their country of origin|Johansson et al.(2015)[35]; Wandell et al. (2021)[36]| |Type 1 and 2 diabetes mellitus|Enter ‘yes’ in the rheumatoid arthritis input to FRAX|Other adjustments in Leslie et al.(2018)[37]| |Parkinson's disease, and related movement disorders|Enter‘yes’ in the rheumatoid arthritis input to FRAX|Schini et al.(2023)[38]| |Recent MOF|Marked uplift to fracture probabilities|Kanis et al.(2020)[39]|

${}^{*}$ Downward adjustment to FRAX probabilities should only be made in the context of a very reliable high lumbar spine BMD measurement and not on the basis of a discordant result due to artefact,e.g.,from degenerative change

${}^{*}$ See ${}^{*}$ glucocorticoid-induced osteoporosis' for further details on glucocorticoid doses and recommendations

meta-analyses of observational population-based studies using absorptiometric techniques indicate that the risk of fracture increases approximately two-fold for each standard deviation(SD) decrease in BMD[40, 41];(Evidence level Ia). The gradient of fracture risk varies according to the site and technique used, the person's age, and the fracture type[41];(Evidence level Ia). The predictive value of BMD for hip fracture is at least as good as that of blood pressure for stroke[42];(Evidence level IV).

The WHO and the International Osteoporosis Founda-tion(IOF) recommend that the reference technology for the measurement of BMD is dual-energy X-ray absorpti-ometry(DXA) applied to the femoral neck, because of its higher predictive value for fracture[43, 44];(Evidence level Ia). DXA measurements of femoral neck BMD are used in FRAX®. The spine is not always a reliable site for risk assessment or for the diagnosis of osteoporosis in older people because of the high prevalence of degenera-tive changes, which artefactually increase the BMD value.However, a result in an older person showing low BMD

<EndOfPara>is almost always valid and clinically useful, particularly in those people with disproportionately low spine BMD compared to the hip, but may not always relate to osteo-porosis(e.g. osteomalacia can also cause low BMD). At the same DXA-measured femoral neck BMD, men and women are at approximately the same fracture risk[45,46];(Evidence level IIa). Therefore, the recommended reference range, from which femoral neck and total hip T-scores are calculated for men, women and transgender individuals in the US, is that derived from the NHANES III survey for white women aged 20 to 29 years[44, 47].The reference ranges, from which lumbar spine and distal forearm T-scores are calculated, for both men and women of all ethnicities, are usually those of the manufacturer of the DXA scanner[47].

Osteoporosis can be diagnosed on the basis of the BMD T-score measured at the total hip, femoral neck, or lumbar spine. However, fracture risk prediction is not improved by the use of measurements from multiple sites[48, 49];(Evidence level IIa). Where hip BMD measurement is not

Archives of Osteoporosis(2025) 20:119

Page 5 of 50119

possible for technical reasons, or if the spine is differentially affected, then spine BMD measurements can be used for diagnosis. A diagnosis of osteoporosis can be made based on distal forearm(1/3 radius) T-score if neither spine nor hip can be reliably measured or interpreted, or if a patient exceeds the weight limit for the DXA table[47];(Evidence level IV). Serial BMD measurement can be used to moni-tor response to treatment[50]. Lumbar spine BMD shows the largest treatment-related changes and is the preferred site, although if spinal degenerative changes are marked,BMD at the hip is a better site for monitoring. The validity of BMD measurements depends on good quality control and national(Royal Osteoporosis Society) and international(International Society for Clinical Densitometry) bodies have published standards for the reporting of DXA scans[47, 51]. Derivation of DXA-measured BMD Z-Scores,which compare a BMD measure with average BMD of people of the same age, sex, and ethnicity, is recommended in men< 50 years and pre-menopausal women[47]. A low Z-Score can indicate the need for further investigation(see Table 2).

QCT-measured femoral neck areal BMD predicts osteo-porotic fractures in men and women and is equivalent to DXA-derived areal BMD[53-55]. Femoral neck and total hip T-scores calculated from two-dimensional projections of quantitative computed tomography(QCT) data are equiva-lent to the corresponding DXA-derived T-scores. Thus,femoral neck CT X-ray absorptiometry(CTXA) BMD meas-urements can be included in FRAX[47, 56-58];(Evidence level IIa). Other techniques for assessing skeletal BMD,

including quantitative ultrasound, have been less well vali-dated than absorptiometric techniques.

Assessment of clinical risk factors

The performance characteristics of BMD assessment can be improved by the concurrent consideration of clinical risk factors that operate independently of BMD. Of particular importance is age, which contributes to risk independently of BMD[11, 59];(Evidence level Ia). Additional clinical risk factors have been identified that provide information on fracture risk independently of both age and BMD:

i. Low body mass index(BMI) is a significant risk fac-tor for hip fracture, but the value of BMI in predicting other fractures is very much diminished when adjusted for BMD[60];(Evidence level Ia).

ii. A history of a prior fracture, particularly if sustained from low trauma and at a site characteristic for oste-oporosis, is an important risk factor for further frac-ture[61]. The risks are in part independent of BMD[62]. Fracture risk is approximately doubled in the presence of a prior fracture, including asymptomatic moderate or severe(Grade 2 or 3) morphometric vertebral fractures[62, 63]; (Evidence level Ia).The increase in risk is even more marked for more than one vertebral fracture. After a fracture, the risk of subsequent fracture is highest in the immediate post-fracture interval (imminent risk) with more than one-third of subsequent fractures over a ten-

Table 2 Proposed clinical investigations to consider for the investigation of osteoporosis/fragility fractures

|Routine|Other procedures, if indicated| |---|---| |Clinical history|Serum electrophoresis, serum immunoglobulins and serum free light chain assay| |Physical examination including measurement of height and assessment of thoracic kyphosis|Plasma parathyroid hormone (PTH)b| |Full blood cell count|Serum testosterone, sex hormone binding globulin, follicle stimulating hormone, lutein-izing hormone| |Erythrocyte sedimentation rate or C-reactive protein|24-h urinary free cortisol/overnight dexamethasone suppression test| |Renal function|Serum prolactin| |Serum calcium, albumin, creatinine, phosphate ${}^{a}$,|Serum magnesium if hypocalcaemicTissue transglutaminase antibodies,+/-endomysial antibodies(coeliac disease screen)| |serum 25-hydroxyvitamin D|Urinary calcium excretion| |Thyroid function tests|Markers of bone turnover(e.g.,CTX, $P1$ NP ${}^{c}$ ) Lateral radiographs of lumbar and thoracic spine or DXA based lateral vertebral imagingBone densitometry(DXA) if indicated by FRAX assessment and/or required for BMD monitoringIsotope bone scan|

aPersistent low phosphate or alkaline phosphatase should not be overlooked as this can indicate underlying metabolic bone disease

${}^{b}$ Measure PTH if albumin-adjusted serum calcium≥2.6 mmol/l twice, or if≥2.5 mmol/l twice if primary hyperparathyroidism is suspected[52]}${}^{c}$ Principally measured to monitor bone turnover in response to anti-resorptive treatment, CTX reflects bone resorption, P1NP reflects bone for-mation. CTX is best measured in the morning after an overnight fast. Other investigations-for example, bone biopsy and genetic testing for osteogenesis imperfecta-are largely restricted to specialist centres

119 Page 6 of 50

Archives of Osteoporosis

year time frame occurring within the first year[39,64];(Evidence level Ic).

iii. A parental history of hip fracture is a significant risk factor that is largely independent of BMD[65];(Evi-dence level Ia).

iv.Smoking is a risk factor that is in part dependent on BMD[66];(Evidence level Ia).

v.Oral glucocorticoid therapy increases fracture risk in a dose-dependent manner. The fracture risk conferred by the use of glucocorticoids is, however, not solely dependent upon bone loss and BMD-independent risks have been identified[67, 68];(Evidence level Ia).

vi. Alcohol intake shows a dose-dependent relationship with fracture risk. Where alcohol intake is on average two units or less daily, no increase in risk has been identified. Intakes of 3 or more units daily are associ-ated with a dose-dependent increase in fracture risk[69]; (Evidence level Ia).

vii. There are many secondary causes of osteoporosis(e.g.,inflammatory bowel disease, endocrine disorders),but in most instances it is uncertain to what extent an increase in fracture risk is dependent on low BMD or other factors such as the use of glucocorticoids. By contrast, rheumatoid arthritis increases fracture risk independently of BMD and the use of glucocorticoids[68];(Evidence level Ia).

viii. Diabetes mellitus(both type 1 and type 2) is associ-ated with an increase in risk of hip and non-vertebral fracture. In type 2 diabetes, a longer duration of dis-ease and insulin use are associated with an increased risk[70, 71];(Evidence level Ia), which is partly inde-pendent of BMD[72, 73].

The use of combined clinical risk factors alone to predict fracture risk performs very similarly to that of BMD alone[74]. The use of clinical risk factors with the addition of BMD is optimal, but BMD measurement can be targeted to those close to the threshold of low/high risk or close to the threshold of high/very high risk. There are many addi-tional clinical risk factors for fracture not included in FRAX,including risks that either act solely by reducing BMD or have been less well validated or identify a risk that may not be amenable to particular treatments[11, 75]. Liability to falls is an example of the latter, where the risk of fracture is high, and treatment with drugs affecting bone metabolism alone may not fully address this risk[76].

In addition to glucocorticoids, several medications are known to increase hip fracture risk, including thyroid hor-mone excess, aromatase inhibitors for the treatment of breast cancer, and androgen deprivation for the treatment of pros-tate cancer[77-81];(Evidence level Ia). Thazolidinediones,

used in the treatment of type 2 diabetes, also increase frac-ture risk[82, 83].

Several other drugs have been associated with increased fracture risk including antidepressants, antipar-kinsonian drugs, antipsychotic drugs, anxiolytic drugs,benzodiazepines, sedatives, H2 receptor antagonists, and proton pump inhibitors[77-81]. The extent to which frac-ture risk is mediated by low BMD, fall risks, or other factors, or indeed is definitely causal in each case, is not known and therefore no specific recommendation is made regarding cessation. The impact of sex steroids on bone health in transgender individuals is unclear[84]. Bio-chemical indices of skeletal turnover have the potential to aid risk assessment but probably play a more immedi-ate role in the monitoring of treatment[85-87];(Evidence level Ia).

Fracture risk assessment tools

The IOF and the WHO recommend that the risk of frac-ture is expressed as an absolute risk, i.e., probability over a ten-year interval[11]. The absolute risk of fracture depends upon age and life expectancy as well as the current relative risk. The period of 10 years covers the likely initial duration of treatment and the benefits that may continue if treatment is stopped. Shorter time horizons do not aid the categori-sation of risk[88, 89]. Where life expectancy is less than 10 years, FRAX provides the remaining lifetime probability of fracture. Algorithms that integrate the weight of clinical risk factors for fracture risk, with or without information on BMD, were developed in 2008 by the then WHO Col-laborating Centre for Metabolic Bone Diseases at Sheffield.The FRAX tool(https://www.fraxplus.org/calculation-tool/)computes the 10-year probability of hip fracture and/or of major osteoporotic fracture. A major osteoporotic fracture is a clinical spine, hip, forearm or humerus fracture. The tool has been externally validated in independent cohorts[59,90];(Evidence level Ia).

QFracture is based on a UK prospective open cohort study of routinely collected data from general practices that takes into account numerous clinical risk factors and estimates the 1 to 10 year cumulative incidence of hip and/or major osteoporotic fracture(http://www.qfracture.org[91]). The NICE has recommended the use of fracture risk assessment tools(FRAX or QFracture) in the assessment of patients[92]. Since FRAX and QFracture yield different outputs(probability of fracture accounting for mortality risk in the case of FRAX, and a cumulative risk of fracture in the case of QFracture), the two calculators cannot be used interchangeably. In addition, BMD cannot be incorporated into QFracture estimations. Finally, the NOGG intervention

Archives of Osteoporosis(2025) 20:119

Page 7 of 50119

thresholds, recommended by NICE Quality Standards, are based on FRAX probability and thus cannot be used with fracture risk derived from QFracture or other calculators[90,93].

Whilst QFracture takes account of several ethnicities, the FRAX tool takes a different approach. Importantly, the UK FRAX is calibrated to a majority white population, with a small minority of other ethnic groups included, so that the generated probabilities reflect a predominantly white popu-lation. When using FRAX in individuals who have moved from another country to the UK, regardless of ethnicity, the use of the FRAX model for their country of birth, if it exists,is appropriate since individuals retain the risk characteristics of their country of birth[35][36]. While fracture risk in sec-ond and subsequent generations might move towards that in the general UK population, the accuracy of this assumption and speed of transition is not known for either QFracture or FRAX[94].

The input into FRAX includes, with age and sex, BMD independent clinical risk factors including: Body mass index(calculated from weight and height in kg/m2), pre-vious fragility fracture(including morphometric vertebral fracture), parental history of hip fracture, current glucocor-ticoid treatment(any dose, by mouth for 3 months or more),current smoking, alcohol intake of 3 or more units daily,rheumatoid arthritis, secondary causes of osteoporosis(including: type 1 diabetes, long-standing untreated hyper-thyroidism, untreated hypogonadism/premature menopause(<45 years), chronic malnutrition/malabsorption, chronic liver disease, non-dialysis chronic renal failure(i.e., CKD 3a-5). Femoral neck BMD is an optional input. The listed secondary causes are conservatively assumed to be medi-ated through low BMD and carry no weight when femoral neck BMD is entered into FRAX. Femoral neck BMD is an optional input. The listed secondary causes are conserva-tively assumed to be mediated through low BMD and carry no weight when femoral Tically assumed to be mediated through low BMD and carry no weight when femoral Tically assumed to be mediated through low BMD and carry

FRAX assessment takes no account of prior osteoporosis drug treatment, or of the dose of several clinical risk fac-tors. For example, a history of two prior fractures carries a higher risk than a single prior fracture. A prior clinical vertebral fracture carries an approximately two-fold higher risk than other prior fracture types. Dose responses are also evident for glucocorticoid use and are partially addressed in the NOGG guideline. Since it is not possible to model all such scenarios within the FRAX algorithm, clinical judge-ment is needed to interpret FRAX outputs.

High and low impact injuries exist on a continuum and the clinical significance of high and low impact frac-tures is blurred in the context of osteoporosis. Indeed,prior high-trauma fractures are associated with low BMD and future fracture risk to the same extent as fractures

without high-trauma[61]. Although FRAX has a limited input of variables, relatively simple arithmetic proce-dures are available(Table 1) which can be applied to conventional FRAX estimates of probabilities of hip frac-ture and major osteoporotic fracture to adjust the prob-ability assessment with knowledge of: high, moderate and low exposure to oral glucocorticoids[28];(Evidence level IIa), concurrent data on lumbar spine BMD[29,30];(Evidence level Ia), information on trabecular bone score(TBS)[31];(Evidence level Ia). TBS values can be entered on the UK FRAX website, hip axis length[32];(Evidence level Ib), falls history[33];(Evidence level IIa), country of birth[35];(Evidence level Ib), type 2 diabetes mellitus[37];(Evidence level Ib), Parkinson's disease[38];(Evidence level Ic), and recent major osteo-porotic fracture(MOF)[39];(Evidence level Ib). When applying these FRAX adjustments, a suggested increase of x% should be applied as a proportion of the original FRAX score. For example, uplifting the FRAX prob-ability of 30% by 10% gives an adjusted probability of 30x1.10=33%. There is no evidence base available to inform on the accuracy of multiple adjustments. Prag-matically, the adjustment should be made for the most dominant factor, i.e. that which will have the greater impact on the estimated probability;(Evidence level IV). Although type 1 diabetes carries a risk of fracture over and above that provided by FRAX, there are yet no empirical data from which to recommend adjustment.In the meanwhile, adjustment can be used as for type 2 diabetes:(Evidence level IV). Parkinson's disease(PD),and related movement disorders substantially increase both hip and non-terbral fracture risk, independent of BMD[38, 95]. Entering PD as a risk variable using the rheumatoid arthritis input as a surrogate only partly accounts for this increased fracture risk[38];(Evidence level Ib). Additionally, FRAX values have been shown to be largely unaffected by socioeconomic status[96], vari-ation in body composition[97], cancer[98] and chronic renal disease[99];(Evidence level Ib). Adjustments to FRAX probabilities which take into account severity and/or number of vertebral fractures can be made using the https://www.fraxplus.org/calculation-tool; however, cur-rently payment is needed for each calculation.

Risk is best presented to patients numerically using sim-ple frequencies and positive and negative framing e.g., for a 23% risk say‘100 people like you, over the next 10 years,23 will break a bone and 77 will not'. Describing risks solely with words, such as‘You have a high chance of experiencing a fracture' is ineffective and does not provide patients with the details needed to make an informed decision; it increases risk perceptions, and patients vary in their interpretations of what are low and high risks. It is easier for patients to

119

Page 8 of 50

Archives of Osteoporosis

2025) 20:119

understand whole numbers and simple frequencies(e.g., 1 in 100) rather than percentages. Graphs and pictograms make numeric information easier to understand and should be used where available [100]; (Evidence level IV).

Investigation of osteoporosis and fragility fractures

Diagnostic assessment of individuals with osteoporosis should exclude diseases that mimic osteoporosis, identify the cause(s) of the osteoporosis, and include the manage-ment of any associated comorbidity. Common investigations are given in Table 2.

Vertebral fracture assessment

The majority of vertebral fractures do not currently come to medical attention and thus remain undiagnosed[101]. Mod-erate or severe vertebral fractures, even when asymptomatic,are strong risk factors for subsequent fracture at the spine and other skeletal sites[63, 102, 103]; (Evidence level Ia).Vertebral fracture assessment (VFA) should therefore be con-sidered in high-risk individuals, using either lateral lumbar and thoracic spine radiographs or lateral spine DXA imaging[104]; (Evidence level Ia). The latter delivers a significantly lower radiation dose whilst performing comparably to tradi-tional radiographs [105]. Identification of vertebral fractures on routine radiological images, such as plain abdominal and chest radiographs, performed for other indications, offers the opportunity to detect clinically important osteoporotic fractures. Opportunistic diagnosis of osteoporosis and verte-bral fractures is feasible using CT scans acquired for various clinical reasons, since the hip and spine are frequently in the scan field [106]; (Evidence level Ia). Vertebral fracture identification from CT using Computer Aided Diagnostics(CAD) can augment and improve standard reporting meth-ods [107-110]; (Evidence level IIb). Reliable CAD methods have high sensitivity, specificity, and accuracy for vertebral fracture detection; (Evidence level IV).

Screening and case finding

At present, there is no universally accepted policy for popu-lation-based screening to identify people with osteoporosis.With the recognition that factors in addition to BMD can improve fracture risk prediction, it is possible that screen-ing strategies might be implemented in the future. A trial of screening in the UK used FRAX to target osteoporosis drug treatment to women at high risk of hip fracture. The risk assessment, with subsequent femoral neck BMD measure-ment and input to FRAX in intermediate/high risk individu-als, was conducted in a primary care setting and involved

<EndOfPara>almost 12,500 women aged 70-85 years. Over 5 years, com-pared to standard clinical care, the screening programme reduced the number of hip fractures by 28%. Similar results were observed in a study from Denmark [111], but with lesser effects observed in a further study in the Netherlands[112]. A meta-analysis of the three trials showed that screen-ing reduced hip fracture risk by $20\%$ [113]; (Evidence level Ia).

In the absence of a screening policy, a case-finding strat-egy is appropriate where patients are identified because of a fragility fracture or by the presence of other clinical risk factors. There are many clinical risk factors for fracture in addition to those included in FRAX which can be used to trigger fracture risk assessment (see Table 3), including thoracic kyphosis and height loss ( $\geq$ 4 cm), either in com-parison with recalled young adult height or a documented loss on serial measurements [114]; (Evidence level IIa),and bariatic surgery resulting in malabsorption [115];(Evidence level Ia).

Intervention thresholds and strategy

Recommendations

1.An initial FRAX assessment, which provides the ten-year probability of a major osteoporotic fracture(MOF; clinical spine, hip, forearm or humerus) and/or hip fracture, can be used to identify patients at low,intermediate, high or very high risk of fracture(Strong recommendation).

2.Consider, particularly in older people, drug treatment in those with a prior and/or recent fragility fracture,with fracture risk assessment informing the choice of drug treatment(Strong recommendation).

3.Men and women with high and very high fracture risk(see Fig. 1) should have a DXA if a baseline measure-ment is needed against which to compare future BMD measurements(Strong recommendation).

4.Men and women with intermediate fracture risk (i.e.,between the upper and lower assessment thresh-olds) should be referred for BMD measurement, if practical.Thereafter, fracture probability should be reassessed using FRAX (Strong recommenda-tion).

5.When BMD is included in a FRAX assessment, the patient's risk(high, very high or low) is determined by the higher of the two(MOF and hip fracture) risk assessments(Strong recommendation).

6.In men and women with intermediate fracture risk,if BMD measurement is unavailable, contraindicated,

Archives of Osteoporosis(2025) 20:119

Page 9 of 50 119

119

Table 3 Clinical risk factors for osteoporosis/fractures, not accommodated in FRAX, which should trigger fracture risk assessment

Thoracic kyphosis

Height loss(≥4cm)

Falls and frailty

Inflammatory disease: e.g., ankylosing spondylitis, other inflammatory arthritis, connective tissue diseases, systemic lupus erythematosus Endocrine disease: e.g., Type 1 and 2 diabetes mellitusa, hyperparathyroidism, hyperthyroidism, hypogonadism, Cushing's disease/syndrome

Haematological disorders/malignancy e.g., multiple myeloma, thalassaemia

Muscle disease: e.g., myositis, myopathies and dystrophies, sarcopenia

Lower limb amputation

Lung disease: e.g., asthma, cystic fibrosis, chronic obstructive pulmonary disease

HIV

Neurological/psychiatric disease e.g., Parkinson's disease and associated syndromes ${}^{a}$ , multiple sclerosis, epilepsy, stroke, depression, dementia

Adult learning disabilities: e.g., Down's Syndrome

Nutritional deficiencies: calcium, vitamin D[note that vitamin D deficiency may contribute to fracture risk through undermineralisation of bone(osteomalacia) rather than osteoporosis]

Bariatric surgery and other conditions associated with intestinal malabsorption; e.g., inflammatory bowel disease, celiac disease

Medications, e.g.:

Some immunosuppressants(calmodulin/calcineurine phosphatase inhibitors)

(Excess) thyroid hormone treatment(levothyroxine and/or liothyronine). Patients with thyroid cancer with suppressed TSH are at particular risk Drugs affecting gonadal hormone production(aromatase inhibitors, androgen deprivation therapy, medroxyprogesterone acetate, gonadotrophin hormone releasing agonists, gonadotrophin hormone receptor antagonists)

Some diabetes drugs(e.g., thiazolidinediones)

Some antileptieeps(e.g., phenytoin and carbamazepine)

${}^{a}$ Able to be accommodated in FRAX by proxy, by entering‘yes’ in the rheumatoid arthritis input(see Table 2)

or impractical (e.g., in frail individuals), drug treat-ment should be offered if there is a history of fragility fracture and/or if fracture risk exceeds the intervention threshold (Strong recommendation).

$\text{7. Men and women with low fracture risk, without a prior}$fragility fracture, can be reassured that their fracture risk is low and offered lifestyle advice as appropriate(Strong recommendation).

8.Consider referral of very high-risk patients to an oste-oporosis specialist in secondary care for assessment and consideration of parenteral treatment(some may need first-line anabolic drug treatment, espe-cially those with multiple vertebral fractures). Indi-cations of very high risk, where specialist referral should be considered, include(Conditional recom-mendation):

The presence of single but important clinical risk factors, such as

● A recent vertebral fracture(within the last 2 years)

● $\geq$ 2 vertebral fractures (whenever they have occurred)

● BMD T-score $\leq-3.5$

● Treatment with high-dose glucocorticoids(≥7.5 mg/day of prednisolone or equivalent over 3 months)(refer urgently given rapid loss in bone post initiation of glucocorticoids; if any delay is antici-pated, start an oral bisphosphonate in the meantime)

The presence of multiple clinical risk factors, particu-larly with a recent fragility fracture indicating high imminent risk of re-fracture,

Or other indicators of very high fracture risk, including as defined by FRAX.

9.The choice of drug treatment should be informed by the level of fracture risk, additional clinical risk fac-tors, cost-effectiveness of treatment, and patient prefer-ences(Strong recommendation).

10.FRAX and the link to the NOGG website should be incorporated into electronic patient health record sys-tems(Strong recommendation).

119

Page 10 of 50

Archives of Osteoporosis

(%) 10-year probability of Major Osteoporotic Fracture

 Fig.1 NOGG assessment, interventions, and risk thresholds for major osteoporotic fracture probability(MOF) in the UK with the use of FRAX. Individuals with probabilities below the lower assessment threshold(LAT) are considered for lifestyle advice. Those at inter-mediate risk(probabilities between the upper assessment threshold(UAT) and lower assessment threshold(LAT) are further assessed with BMD measurement. Where probabilities calculated using BMD lie above or below the intervention threshold(IT), treatment or life-

FRAX assessment thresholds for 10-year probability of fracture

The approach recommended for decision-making is based on fracture probabilities derived from FRAX and can be applied to men and women[90]. This approach is underpinned by cost-effectiveness analysis with oral or intravenous bisphosphonates as the intervention[116,117];(Evidence level Ib). FRAX assessment thresholds for 10-year probability of a major osteoporotic fracture(MOF) are shown in Fig. 1. An intervention thresh-old denotes a probability of fracture above which it is expected that a patient is offered anti-osteoporosis treat-ment. The fracture probability can be refined by DXA measurement of BMD and hence its relation to the inter-vention threshold. The use of FRAX without BMD has approximately the same performance as BMD without FRAX[11];(Evidence level Ia). Thus, the same interven-tion threshold can be used when fracture risk is assessed with or without BMD(see Fig. 1). For men and women,the intervention threshold up to age 70 years is set at a risk equivalent to that of a woman of the same age with a

style advice, respectively, is recommended[3, 90]. Patients with probabilities above the upper assessment threshold(UAT) are con-sidered for treatment. Those with probabilities above the very high-risk threshold(VHRT) should be considered for specialist referral.Where BMD measurement is not practical(e.g., when individuals are frail and unable to get onto a DXA table, or lie flat on a DXA table),patients with probabilities above the IT are considered for treatment

prior fracture, in line with current clinical practice, and therefore rises with age. At age 70 years and above, fixed thresholds are applied[118];(Evidence level Ib). The pro-portion of women potentially eligible for treatment rises from approximately 30 to 50% with age, largely driven by the prevalence of prior fracture[118];(Evidence level Ib). When FRAX is calculated with BMD included, the NOGG website also provides intervention thresholds based on the 10-year probability of hip fracture, in addi-tion to the 10-year probability of a MOF(Fig. 2). If there is discordance between the risk categories identified by the two probabilities, the highest risk category can be used to guide intervention. Of note, in the SCOOP study of screening for high fracture risk, treatment was targeted on the basis of risk assessed by hip fracture probability,with or without BMD[119].

Indications for specialist referral in those at very high fracture risk

Individuals at very high fracture risk have the most to gain from thorough investigation of osteoporosis, falls

Archives of Osteoporosis(2025) 20:119

Page 11 of 50 119

119

 Age (years)

(%) 10-year probability of Hip Fracture

  Fig.2 NOGG thresholds for intervention and/or referral using major osteoporotic fracture(MOF) and hip fracture(HF) probabilities in the UK. The panels show the thresholds following the recalculation of FRAX after the input of BMD; the same thresholds are used when

assessment, and development and delivery of a personal-ised treatment plan for a chronic, life-long condition. A range of treatments now available to treat osteoporosis are mostly(but exclusively) initiated through secondary care and the sequence in which they are used is important.Three anabolic agents(teriparatide, abaloparatide and romo-sozumab) are now available, with teriparatide licensed for a once-only treatment course. Within the licensing permis-sions, all anabolic agents might be used at different stages within the course of a lifetime of osteoporosis; however,there is currently no evidence to support a specific sequence,and input from an osteoporosis specialist is essential to inform a personalised care plan. Treatment with teripara-tide or abaloparatide, which are anabolic skeletal agents, or romosozumab, which has a dual anabolic and antiresorp-tive action, results in rapid and greater fracture risk reduc-tions than some antiresorptive treatments $[120-122]$ [123]; (Evidence level Ib). This has led to the need to identify the

BMD is unavailable. The intervention threshold(IT) and very high-risk threshold(VHRT) denote the thresholds for high and very high risk, respectively

sub-group of patients at very high fracture risk who would potentially benefit from clinical review by an osteoporosis specialist and who may benefit from anabolic drug treat-ment[124]. Indications for referral to an osteoporosis spe-cialist may arise through several routes, for example, in the presence of single but important clinical risk factors, such as a recent vertebral fracture(within the last 2 years),≥ 2 vertebral fractures,(whenever they have occurred), a BMD T-score $\leq$ -3.5, high-dose glucocorticoids use $(\geq 7.5 mg /$ day of prednisolone or equivalent over 3 months) [67, 125];(Evidence levels IIb and IV), or via a combination of clini-cal risk factors, resulting in very high fracture risk [126];(Evidence level IIb).

Prior fragility fracture is a well-established risk factor for a future fracture. This risk of subsequent osteoporotic frac-ture is particularly acute immediately after an index fracture and wanes progressive over the next 2 years, but thereaf-ter remains higher than that of the general population $[103,$

119 Page 12 of 50

Archives of Osteoporosis(2025) 20:119

127-134]. This effect of recency of fracture, sometimes termed imminent risk[133], is also dependent on age, sex,and site of fracture[39];(Evidence level Ic). This complex-ity is being addressed by the development of optional post-FRAX algorithms to allow clinicians to explore the potential impact of fracture recency on the calculated probability of MOF and hip fracture(see Table 1)[39]. The mechanism underlying imminent risk is not yet fully understood and no clinical risk factors have yet been identified for short-term recurrent fractures that differ from those identified for frac-ture over a longer time horizon[89]. Few therapeutic studies have reported the recency of fracture in those patients whom they have recruited, though rapid clinical efficacy has been demonstrated within studies of zoledronate, risedronate, teri-paratide, abaloparatide, and romosozumab[121, 135, 136][123];(Evidence level Ib).

A NOGG threshold that characterises men and women at high and very high fracture risk has also been established using FRAX probabilities; very high risk is identified as a FRAX-based fracture probability that exceeds the inter-vention threshold by 60%(Figs. 1 and 2)[137]. It can be used to identify patients who likely require specialist referral for assessment of their osteoporosis(which should include DXA measurement of BMD), and further consideration of appropriate treatment strategies[124, 138]. The proportion of postmenopausal women at very high risk defined in this way rises from approximately 6% at age 50-54 to 36% at age 90 years or older. Numerical values for the probability thresholds are given in Table 4 for MOF and for hip fracture.An assessment algorithm is shown in Fig. 3. In patients with FRAX probabilities in the high-risk category, consideration of additional clinical risk factors(e.g., frequent falls, very

Table 4 Numerical values for NOGG thresholds for major osteoporo-tic fracture and hip fracture probabilities based on FRAX

|Age(years)|LAT|IT|UAT|VHRT| |---|---|---|---|---| |Major osteoporotic fracture||||| |50|3.4|7.3|8.8|11.7| |55|4.5|9.5|11.4|15.2| |60|6.0|12.2|14.6|19.4| |65|8.6|16.5|19.8|26.4| |70|11.1|20.3|24.4|32.5| |Hip fracture||||| |50|0.23|0.91|1.1|1.5| |55|0.43|1.5|1.7|2.3| |60|0.80|2.3|2.8|3.7| |65|1.4|3.5|4.2|5.6| |70|2.6|5.4|6.5|8.6|

LAT and UAT refer to the lower and upper assessment thresholds,respectively, between which a BMD is indicated. The interven-tion threshold(IT) and very high-risk threshold(VHRT) denote the thresholds for high and very high risk

low spine BMD; see Table 1) can also lead to redesignation from high to very high risk of fracture.

FRAX-practical considerations

The FRAX MOF probabilities are transferred automati-cally to the NOGG website by clicking on the specified button on the FRAX results box. Where practitioners receive the results of a FRAX risk assessment for an individual patient without treatment guidance, the FRAX probabilities can also be entered manually onto the NOGG website(https://www.nogg.org.uk/manual-data-entry);this page also captures additional information(age, sex,glucocorticoid exposure and finally, whether a femoral neck BMD has been included, in the FRAX estimates)so that the result can be automatically compared to the NOGG thresholds with appropriate guidance on treatment.In the case of a patient born in another country, now living in the UK, FRAX-derived probabilities from a non-UK FRAX tool can be entered manually onto the NOGG web-site(https://www.nogg.org.uk/manual-data-entry) to deter-mine where risk lies in relation to intervention thresholds.Lack of integration of FRAX assessments and links to NOGG guidance in existing patient health record systems represents a barrier to effective fracture risk assessment(Evidence IV).

The targeted use of BMD assessments with the NOGG strategy makes more efficient use of often limited resources than would DXA scanning of all individuals with risk fac-tors[139];(Evidence level Ib). Historically it was thought that treatment should not be undertaken in women without initial BMD measurement, except in those with hip or ver-tebral fractures. This view arose after a post-hoc analysis in 1998 suggested reduced efficacy of alendronate in patients with BMD T-scores above-2.5[140];(Evidence level Ib).However, this approach is now outdated as many studies have since shown little or no interaction of BMD on the effectiveness of several agents, including bisphosphonates(e.g., zoledronate, denosumab, raloxifene, abaloparatide and teriparatide)[75, 141-144][145][146];(Evidence level Ib). Moreover, clinical risk factors are not totally independent of BMD and, when clinical risk factors alone are used in women age 70 years or more to identify patients at high fracture risk, BMD is approximately 1 SD lower in the high-risk group compared with a low-risk group[147,148];(Evidence level Ib). These findings indicate that the categorisation of patients at high fracture risk on the basis of FRAX without BMD mostly selects patients with low BMD and that the higher the fracture probability, the lower the BMD. Note that this does not preclude the use of DXA scanning if more widely available; in addition to provid-ing the most accurate risk assessment, DXA provides a baseline measurement for treatment monitoring and also

Archives of Osteoporosis(2025) 20:119

Page 13 of 50 119

 Fig.3 Management algorithm for the assessment of individuals at risk of fracture[137]. Those at very high risk should be treated and considered for referral to an osteoporosis specialist in secondary care;

permits, again if available and indicated, detection of ver-tebral fractures using VFA. FRAX is not recommended as a tool to monitor treatment[149]; (Evidence level IIb).However, the use of FRAX is appropriate to re-evaluate current fracture probabilities when considering a change in patient management; (Evidence level IV).

Non-pharmacological management of osteoporosis

Recommendations

Postmenopausal women and men, age≥50 years,with osteoporosis or who are at risk of fragility fracture are recommended:

1. A healthy, nutrient-rich balanced diet(Strong recom-mendation).

2.An adequate intake of calcium(minimum 700mg daily)preferably achieved through dietary intake or otherwise by supplementation(Strong recommendation).

3.To consume vitamin D from foods or be prescribed vita-min D supplements of at least 800 IU/day if they have identified vitamin D insufficiency or risk factors for vita-

some may benefit from parenteral treatment(including first-line ana-bolic drug treatment, especially if multiple vertebral fractures). All individuals should be offered lifestyle advice. CRF, clinical risk factor

min D insufficiency. Those who are either housebound or living in residential or nursing care are more likely to require calcium and vitamin D supplementation to achieve recommended levels of intake(Strong recom-mendation).

4. A combination of regular weight-bearing and muscle strengthening exercise, tailored according to the indi-vidual patient's needs and ability(Strong recommenda-tion).

$\underline{5}$ Advice about smoking cessation if an individual is a smoker(Strong recommendation).

$\text{6.}$ Advice to restrict alcohol intake to $\leq 2$ units/day/day(Strong recommendation).

7.A falls assessment should be undertaken in all patients with osteoporosis and fragility fractures; those at risk should be offered exercise programmes to improve bal-ance and/or that contain a combined exercise protocol(Strong recommendation).

Dietary modification

A meta-analysis of observational studies examining different dietary patterns found a modest reduction in the risk of low BMD and of hip fractures in subjects adhering to‘healthy’(high in fruit and vegetables, fish, poultry and whole grains)

119

Page 14 of 50

Archives of Osteoporosis

diets and a reduction in the risk of low BMD in those with‘milk/dairy’ diets. By contrast, those with a‘meat/Western’dietary pattern(high in processed and red meat, animal fat,refined sugar and soft drinks) saw a modest increase in the risk of low BMD and of hip fractures. However, popula-tion heterogeneity with the inclusion of subjects aged under 25 years in many dietary studies reduces generalisability[150];(Evidence level IIa). A randomised controlled trial of a‘healthy diet’ consumed for 30 days, specifically a cal-cium-rich diet that emphasises fruits, vegetables and low-fat dairy products(Dietary Approaches to Stop Hypertension(DASH)), resulted in a reduction in a reduction in bone turnover[151];(Evidence level Ib).

Protein is an important constituent of bone and muscle tissue, and good dietary intake is necessary to maintain the health of the musculoskeletal system. Protein intakes higher than the recommended daily allowance(RDA) of 0.75 g/kg body weight/day are associated with higher BMD at the neck of femur and total hip in one RCT, and in observational studies, has been associated with a reduced risk of hip frac-tures[152, 153];(Evidence levels Ib and IIa); however, in a meta-analysis of 30 interventional studies, no significant effects of protein supplementation on BMD were seen[153];(Evidence level Ia). Post-operative protein supplementation in patients with a recent hip fracture has been shown to improve the subsequent clinical course by significantly low-ering rates of infection and duration of hospital stay[154];(Evidence level Ib).

Whilst there are inconsistencies in the evidence base for the associations between vegetarian and genetic diets and musculoskeletal health, consumption of a vegetarian or vegan diet has been associated with lower BMD at the lumbar spine and hip than an omnivore diet, and a vegan diet has been associated with higher fracture risk[155];(Evidence level IIa). A subsequent prospective cohort study of 65,000 people in the UK also identified lower BMD at the spine and hip in veg withs and vegetarians, and higher hip fracture risk in vegans, attenuated in part by adjustment for calcium and/or protein intake[156];(Evi-dence level IIb).

Calcium and vitamin D

At every stage of life, adequate dietary intakes of key bone nutrients such as calcium and vitamin D contribute to bone health. The UK Reference Nutrient Intake per day of cal-cium is 700 mg for adults aged 19 years and older[157].Dietary calcium calculators are available to assess intake,e.g.,https://www.cgem.ed.ac.uk/research/reumatological/calcium-calculator/. Whilst the Scientific Advisory Com-mittee on Nutrition(SACN) recommends a reference nutri-ent intake(RNI) of 400 IU daily of vitamin D for adults of all ages[158], in the context of osteoporosis, higher

levels-specifically 800 up to 2000 IU daily may-be appro-priate[159];(Evidence level IV).

Most randomised controlled trials of anti-resorptive and anabolic drugs have included co-administration of calcium and vitamin D supplements. There have been many ran-domised controlled trials of either calcium alone, vitamin D alone, or both in combinations to examine whether use of these supplements alone reduces fracture risk. With respect to combined calcium and vitamin D supplements, meta-analyses have reported a reduction in hip and non-vertebral fractures, and possibly also in vertebral fractures[160-162];(Evidence level Ia). Overall, there is little evidence that vita-min D supplementation alone reduces fracture incidence,although it may reduce falls risk[162, 163];(Evidence level Ib). However, it is important for patients taking anti-resorptive and anabolic osteoporosis drug therapies to be vitamin D replete. In clinical practice, dietary sources of calcium are the preferred option, and calcium(combined with vitamin D) supplementation should be targeted to those who do not get sufficient calcium from their diet and who are at risk of osteoporosis and/or fragility fracture, such as older adults who are housebound or living in residential or nursing care[161], and those with intestinal malabsorption,e.g., due to chronic inflammatory bowel disease or following bariatric surgery. Calcium and vitamin D supplements may increase the risk of kidney stones but not the incidence of cardiovascular disease or cancer[164];(Evidence level Ia).(Evidence level Ia).

Exercise to improve or maintain bone density

Exercise has beneficial effects on BMD[167](Evidence level Ia); however, clear evidence for a reduction in frac-ture risk is wanted. The effect of exercise on different skel-etal sites varies. Combination exercise programmes, which include weight-bearing and resistance strengthening exer-cise, are effective at reducing bone loss in the femoral neck and lumbar spine in post-menopausal women[167, 168];(Evidence level Ia). Similarly, upper body resistance exer-cise increases forearm bone mass[169];(Evidence level Ia).A meta-analysis of the effects of exercise interventions on BMD in men found only three studies and identified a sig-nificant but moderate improvement in BMD at the femoral neck and a trend towards increased BMD at the lumbar spine[170];(Evidence level Ia).

The effect of exercise varies with intensity and duration.Strengthening(resistance) exercise may be more effective if supervised. People at risk of falls, or with vertebral frac-tures, may need more specific advice and assessment before increasing exercise intensity[171]. The NOGG supports

Archives of Osteoporosis(2025) 20:119

Page 15 of 50 119

119

the Royal Osteoporosis Society Strong, Steady and Straight Expert Consensus Statement, which offers advice on inten-sity and duration and linked patient information videos and factsheets[171]. In people with osteoporosis, repetitive forced spinal forward flexion exercises should be undertaken with care as this specific movement may be associated with an increased risk of new vertebral fractures[172]; (Evidence level Ia). However, in general, people with osteoporosis can safely participate in exercise because the risk of serious adverse events is very low [172]; (Evidence level Ia).

Falls interventions

The majority of non-vertebral fractures are preceded by a fall. Exercise can significantly reduce the risk of falls and,perhaps, the risk of subsequent fractures, by maintaining or restoring muscle strength, balance and posture, improving confidence and reaction times. However, two recent large randomised controlled trials have not demonstrated an effect of multi-disciplinary interventions, targeted at falls, on frac-ture reduction when combined with screening for falls risk in primary care[173, 174];(Evidence level Ib), a recent Cochrane review of falls prevention exercise programmes,and two previous meta-analyses demonstrated, albeit with low certainty, evidence of a reduction in fall-related frac-tures(or falls resulting in fractures) in those living in the community[168, 175, 176];(Evidence level Ia). Exercise interventions to reduce falls in people with osteoporosis and/or at high risk of falling have been found to be safe[177];(Evidence level Ia). Programmes that involve balance train-ing and/or a combined exercise protocol are more effective in those who have risk factors for falling[175, 177];(Evi-dence level Ia). Combined exercise protocols may include resistance training, balance challenging, aerobic exercise and impact exercise. Interventions of 3 h per week or more are most effective[178];(Evidence level Ia). Interventions of short duration(less than 6 months) have been found to be effective, and good compliance with exercise interventions has been reported[177];(Evidence level Ia). Home safety interventions(best delivered by an occupational therapist) have been shown to reduce the risk of falls in people living in the community[179];(Evidence level Ia). Furthermore,whole body vibration has been demonstrated to reduce fall rate but does not increase BMD[180];(Evidence level Ia).

Lifestyle measures

Other measures to improve bone health include optimisa-tion of body mass index if underweight or overweight, stop-ping smoking, and reducing alcohol intake. Smoking cessa-tion has been demonstrated to reduce the risk of vertebral and hip fractures in women[181,182]; (Evidence levels

Ilb and IIa). However, the risk of hip fracture was reduced in those who had stopped smoking, compared with cur-rent smokers, only after 5 years.Furthermore, pre-operative smoking cessation is associated with fewer post-operative complications[183];(Evidence level Ia). Currently, mini-mal evidence is available on the fracture risk associated with vaping/e-cigarette use; one cross-sectional study has identified elevated risk of self-reported fragility fracture in electronic cigarette users[184];(Evidence level Ic). In men with previous alcohol dependence, BMD is significantly lower than controls, but improves following 3-4 years of abstinence[185];(Evidence level IIa). National guidelines recommend alcohol intake is limited to $\leq$ 2 units/day for women and men[186].

Pharmacological treatment options

Recommendations

1.Fracture risk assessment, patient suitability and pref-erence should inform the choice of drug treatment. In most people at risk of fragility fracture, anti-resorptive therapy is the first-line option(Strong recommendation).

Antiresorptive drug treatment

2. Offer oral bisphosphonates(alendronate or rise-dronate) or intravenous zoledronate as the most cost-effective interventions. Alternative options include denosumab,ibandronate, hormone replacement ther-apy,raloxifene, and strontium ranelate(Strong Recom-mendation).

3. Offer intravenous zoledronate as a first-line treatment option following a hip fracture(Strong Recomma-tion).

4.Consider offering younger postmenopausal women(age≤60 years) with high fracture risk and low baseline risk for adverse malignant and thromboembolic events HRT as a first-line treatment option(Conditional recom-mendation).

5. Discuss continued use of HRT after the age of 60 years with the patient, with treatment based on an individual risk-benefit analysis(Conditional recommendation).

6.When HRT is discontinued, reassess fracture risk and consider an alternative treatment if indicated(Condi-tional recommendation).

7.Before starting denosumab, ensure that a long-term per-sonalised osteoporosis management plan is in place and that both the patient and the primary care practitioner are made aware that denosumab treatment should not be stopped or delayed without discussion with a healthcare professional(Strong recommendation).

119

Page 16 of 50

Archives of Osteoporosis(2025) 20:119

(2025)20:119

8.Avoid unplanned cessation of denosumab because it can lead to increased vertebral fracture risk; hence, it must not be stopped without considering an alternative therapy (Strong recommendation).

9.If denosumab therapy is stopped, intravenous infusion of zoledronate is recommended 6 months after the last injection of denosumab, with subsequent monitoring of serum CTX guiding the timing of further treatment(Strong Recommendation). Where monitoring of serum CTX is not possible, consider a further intravenous infu-sion of zoledronate 6 months after the first dose of zole-dronate (Conditional Recommendation).

Anabolic drug treatment

10. Consider teriparatide, abaloparatide or romozozumab as first-line treatment options in postmenopausal women at very high fracture risk, particularly in those with vertebral fractures (Conditional Recommenda-tion).

11.Consider teriparatide as a first-line treatment option in men aged 50 years and older who are at very high frac-ture risk, particularly in those with vertebral fractures (Conditional Recommendations).

12.Consider as second-line treatment options, teriparatide in postmenopausal women and men age 50 years and older, and abaloparite or romozosumab in postmeno-pausal women who are intolerant of bisphosphonate treatment, particularly in those with vertebral fractures(Conditional recommendation).

13. Following the approved duration of treatment with teriparatide, abaloparatide, or romozosumab(24, 18 or 12 months respectively), initiate treatment with alendronate,zoledronate, or denosumab without delay(Strong Recommendation).

14.Consider raloxifene as an option for follow-on treat-ment after an anabolic drug in women(Conditional recommendation).

Other treatments

15.When other antiresorptive and anabolic treatments are contraindicated or not tolerated, strontium ranaelate can be used to treat postmenopausal osteoporosis and men with severe osteoporosis, provided the risk-benefit in relation to cardiovascular and thromboembolic events is considered. Initiation by a specialist who is an expert in osteoporosis management is advised (Strong recom-mendation).

<BeginOfPara>16. Offer calcium and/or vitamin D supplementation as an adjunct to anti-osteoporosis drug treatment, if dietary

<EndOfPara>calcium is low and/or vitamin D insufficiency is a risk,respectively(Strong recommendation).

17.Treat vitamin D deficiency and insufficiency prior to initiation of parental anti-osteoporosis drug treat-ment, and alongside initiation of oral anti-osteoporosis drug treatment(Strong recommendation).

Overview of treatment options

Drugs used in the management of osteoporosis can be con-sidered under two broad headings based on their primary mode of action. Anti-resorptive drugs primarily inhibit osteoclastic bone resorption with later secondary effects on bone formation. Anabolic drugs primarily stimulate osteoblastic bone formation with variable effects on bone resorption to increase bone density and strength. Most drugs fit into one or other category, but romosozumab has a dual action, both stimulating bone formation and inhibiting bone resorption.Teriparatide and abaloparate both promote bone remod-elling, increasing bone formation and, in response, bone resorption. Anti-resorptive drugs are much less expensive than anabolic drugs. It is important to consider the long-term management strategy for each patient initiated on osteoporosis treatment, as the timing of use of certain drugs is important. For example, teriparatide can only be used once as a full course of treatment in a lifetime(abalopara-tide and romosozumab do not have this restriction), whilst denosumab requires careful consideration before initiation given the difficulties in stopping treatment once it is started.

The drugs listed in Table 5 have been shown to reduce fragility fractures in postmenopausal women, and men where indicated, with osteoporosis[187](Evidence levels Ia and Ib). The efficacy of the drugs listed in Table 5 is well established for the prevention of vertebral fractures. Teri-paratide and romozumab are superior to risedronate and alendronate respectively at reducing vertebral fractures in high-risk postmenopausal women with osteoporosis. Most drugs listed in Table 5 have been shown to reduce hip frac-ture incidence, with the exception of ibandronate, calcitriol,raloxifene, and abaloparatide. Drugs listed in Table 5(except calcitriol and raloxifene) have been shown to reduce the inci-dence of non-vertebral fractures.

Primary and secondary care drug initiation

Oral and intravenous bisphosphonates, denosumab, ralox-ifene, calcitriol, and RT can be initiated by primary or sec-ondary care clinicians. If denosumab is initiated in primary care, consultation with secondary care colleagues is advised given the need to have a long-term personalised osteoporo-sis management plan in place before denosumab is started

Archives of Osteoporosis (2025) 20:119

Page 17 of 50 119

Table 5 Anti-fracture efficacy of approved drug treatments for postmenopausal women and men with osteoporosis when given with calcium and vitamin D

|Intervention|Vs. placebo|Vs. placebo|Vs. placebo|Vs. placebo|Vs. another drug treatment|||| |---|---|---|---|---|---|---|---|---| |Intervention|Ver-tebral fracture|Non-vertebral fracture|Hip fracture|Vertebral fracture|Non-vertebral fracture|Hip fracture|Licenced for use in men|| |Romosozumab|lb|IIb|IIb|Superior to Alen-dronate (Ib)*|Superior to Alen-dronate (Ib)*|Superior to Alen-dronate (Ib)*|No|| |Teriparatide|Ia|Ia|Ia|Superior to Alen-dronate (Ia) Risedronate (Ia) Denosumab (Ia)|Superior to Alen-dronate (Ia)|NAE|Yes|| |Abaloparatide|Ia|Ia|IIb|Superior to Raloxifene (Ia)|Superior to Teripara-tide (Ia)|NAE|No|| |Alendronate|Ia|Ia|Ia|Inferior to Teripara-tide (Ia) & Romo-sozumab (Ib)|Inferior to Teriparatide (Ia)|Inferior to Romo-sozumab (Ib)|Yes|| |Ibandronate|lb|lb|NA|NAE|NAE|NAE|No|| |Risedronate|Ia|Ia|Ia|Inferior to Teriparatide (Ia)|Inferior to Abolopara-tide (Ia)|NAE|Yes|| |Zoledronate|Ia|Ia|Ia|NAE|NAE|NAE|Yes|| |Calcitriol|IIa|NAE|NAE|NAE|NAE|NAE|Yes|| |Denosumab|Ia|Ia|Ia|Inferior to Teriparatide (Ia)|NAE|NAE|Yes|| |HRT|Ia|Ia|Ia|NAE|NAE|NAE|No|| |Raloxifene|Ia|NAE|NAE|Inferior to Teriparatide & Abaloparate(Ia)|NAE|NAE|No|| |Strontium Ranelate|Ia|Ia|IIb|NAE|NAE|NAE|Yes||

Evidence levels are shown in Appendix 2

HRT hormone replacement therapy, NAE no available evidence from clinical trials

${}^{*}$ When 12 months of Romosozumab is followed by an antiresorptive

to enable denosumab to be stopped in a managed way as necessary. As calcitriol use is only supported by a grade IIa evidence base, its use is generally restricted to a select sub-group managed through secondary care. Strontium ranelate can be initiated by primary or secondary care clinicians, but if started in primary care should involve consultation with secondary care.

Secondary care drug initiation

Teriparatide, abaloparatide and romozosumab should be initiated by secondary care clinicians. In the UK teripara-tide and romozosumab are provided via‘home healthcare’services, which also provide patient education.

Considerations when choosing which anabolic agent to use

i. Teriparatide and romosozumab have been shown to reduce hip fracture risk, whereas this has not been demonstrated for abaloparatide in the setting of a ran-domised controlled trial.

<EndOfPara>ii. There are no consistent randomised controlled trials showing superiority or otherwise of abaloparatide against anti-resorptives for any fracture type. How-ever, a systematic review and network meta-analysis of randomised controlled trials and real-world evi-dence has suggested that whilst abaloparatide is equiv-alent to teriparatide at reducing vertebral fracture risk,abaloparatide is superior to teriparatide at reducing non-vertebral fracture risk [188].

iii.There is no evidence for superiority or otherwise of abaloparatide or teriparatide against romozozumab.

iv.All three anabolic agents are approved for the treat-ment of osteoporosis in postmenopausal women at increased risk of fracture; however, only teriparatide is approved for use in men. NICE additionally recom-mends abaloparatide for people who identify as non-binary and trans men, registered female at birth, and romozumab for people who are post-menopausal,not specifying sex.

v.Teriparatide is given for 24 months, abaloparatide for 18 months, and romosozumab for 12 months.

119

Page 18 of 50

Archives of Osteoporosis(2025) 20:119

vi. Teriparatide and abaloparatide are injected once daily;romosozumab is injected once monthly.

vii. Teriparatide pens must be stored in the fridge.Unopened abaloparatide pens must be stored in the fridge before use; after opening they can be stored at room temperature for 30 days, after which they must be discarded.

viii.Unlike teriparatide and abaloparatide, which are sin-gle-effect anabolic agents, romozozumab has a dual action, conferring both anabolic and antiresorptive effects.

Treatment sequence

Any patient stopping denosumab, romosozumab, teripara-tide, or abaloparatide requires a sequential therapy strategy usually involving an anti-resorptive drug, which should be planned at the time the initial anabolic therapy is instigated to avoid a gap in treatment.

Specific drug options

Anti-resorptive drugs: bisphosphonates

Alendronate 70 mg once weekly by mouth is recommended for the treatment of women with postmenopausal osteoporosis(PMO), men with osteoporosis, glucocorticoid-induced osteoporosis(GIO) and the prevention of PMO and GIO.The 70 mg weekly dose is considered equivalent to the pre-viously approved dose of 10 mg daily. In postmenopausal women with osteoporosis, alendronate has been shown to reduce vertebral, non-vertebral, and hip fractures[189];(Evidence level Ib). Approval for the use of alendronate in men with osteoporosis, and in men and women taking glu-cocorticoids, was granted on the basis of BMD bridging studies[190, 191];(Evidence level Ib). Although the daily dose of alendronate(10 mg) is licensed for use in men, this is considered equivalent to the weekly dose(70 mg) which is commonly prescribed off-licence; (Evidence level IV).

Common side-effects of alendronate include upper gas-trointestinal symptoms, bowel disturbance, headaches, and musculoskeletal pain. Alendronate should be taken after an overnight fast and at least 30 min before the first food or drink(other than water) of the day or any other oral medici-nal products or supplementation(including calcium). Tab-lets should be swallowed whole with a glass of plain water(~200 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 30 min after taking the tablet. Alendronate is also available as 70 mg effervescent or soluble tablets, to be dissolved in a glass of plain water(≥120 ml).

Risedronate 35 mg once weekly by mouth is recom-mended for the treatment of PMO, men with osteoporo-sis, GIO, and the prevention of GIO in women. The 35 mg weekly dose is considered equivalent to the previously approved dose of 5 mg daily. In postmenopausal women with osteoporosis, risedronate has been shown to reduce vertebral and non-vertebral fractures[192, 193]; (Evidence level Ib). In a large population of older women, risedronate significantly decreased the risk of hip fractures, an effect that was greater in osteoporotic women[76]; (Evidence level Ib).Approval for use of risedronate in men with osteoporosis and in postmenopausal women taking glucocorticoids was granted on the basis of BMD bridging studies [194-196];(Evidence levels Ib).

Common side-effects include upper gastrointestinal symp-toms, bowel disturbance, headache and musculoskeletal pain.Risedronate should be taken after an overnight fast and at least 30 min before the first food or drink(other than water)of the day or any other oral medicinal products or supple-mentation(including calcium). Tablets should be swallowed whole with a glass of plain water(≥120 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 30 min after taking the tablet.

IBandronate 150 mg once monthly by mouth or 3 mg as a prefilled intravenous injection(usually given as a 15- to 30-s push via butterfly cannula) every 3 months is recommended for the treatment of postmenopausal women with osteopo-rosis.The 150 mg monthly dose and 3 mg 3-monthly intra-venous dose are considered equivalent to 2.5 mg daily by mouth for the treatment of PMO. In postmenopausal women with osteoporosis, ibandronate 2.5 mg daily has been shown to reduce vertebral fracture incidence[197];(Evidence level Ib). In a post-hoc analysis of women at high fracture risk(with a femoral neck BMD T-score below-3.0), a signifi-cant reduction in non-vertebral fractures was shown[198]; (Evidence level Ib). No data are available to show efficacy of hip fracture risk reduction. Approval for the oral 150 mg once monthly and 3 mg intravenously every 3 months for-mulations was granted on the basis of BMD bridging studies[199,200];(Evidence levels Ib).

Common side-effects with the oral preparation include upper gastrointestinal side-effects and bowel disturbance.Intravenous administration may be associated with an acute phase reaction, characterised by an influenza-like illness;this is generally short-lived and typically occurs only after the first injection. Oral bandronate should be taken after an overnight fast and 1 h before the first food or drink (other than water) of the day, or any other oral medicinal products or supplementation(including calcium). Tablets should be swallowed whole with a glass of plain water(180 to 240 ml)while the patient is sitting or standing in an upright position.Patients should not lie down for 1 h after taking the tablet.

Archives of Osteoporosis(2025) 20:119

Page 19 of 50119

119

Zoledronate 5 mg once yearly by intravenous infusion(as 5 mg/100 ml infusion given over a minimum of 15 min via an intravenous cannula) is recommended for the treat-ment of PMO, men with osteoporosis, and men and post-menopausal women with GIO. In postmenopausal women with osteoporosis, zoledronate 5 mg once yearly has been shown to reduce the incidence of vertebral, non-vertebral,and hip fractures[201]; (Evidence level Ib). Approval for use of zoledronate in men with osteoporosis and in men and women taking glucocorticoids was granted on the basis of BMD bridging studies[202, 203];(Evidence levels Ib).When given shortly after hip fracture, men and women given zoledronate 5 mg annually had fewer clinical frac-tures and lower mortality 3 years later[136];(Evidence level Ib). When given(without calcium supplementation) every 18 months to women with osteopenia, there were fewer vertebral and non-vertebral fractures[144, 204];(Evidence level lb). A lower, although non-significant, decrease in mortality in fracture-free women, fewer breast cancers, and fewer non-breast cancers were also reported as secondary outcomes by the end of the 6-year study.

Common side-effects include an acute phase reaction usu-ally only after the first infusion[205], which can be ame-liorated by co-administration of paracetamol. Glomerular filtration rate(eGFR) should be calculated prior to initiation of treatment and caution advised for recipients at risk of kid-ney failure, with monitoring for any increase in serum cre-atinine or reduction in eGFR. The MHRA recommends use of creatinine clearance instead of eGFR to inform treatment decisions in those aged over 75 years and/or with BMI<18 or>40 kg/m2. An increase in symptomatic atrial fibrillation,reported as a serious adverse event, was seen in the main phase III trial[201];(Evidence level Ib).

Contraindications and special precautions for the use of bisphosphonates

Oral and intravenous bisphosphonates are contraindicated in patients with hypocalcaemia, hypersensitivity to bispho-sphonates, and in women who are pregnant or lactating. Oral bisphosphonates are contraindicated in people with abnor-malities of the oesophagus that delay oesophageal emptying,such as stricture or achalasia, and inability to stand or sit upright for at least 30-60 min. They should be used with caution in patients with other upper gastrointestinal disor-ders. Zoledronate and risedronate are contraindicated in severe renal impairment(GFR $\leq 35$ ml/min for zoledronate and $\leq 30$ ml/min for risedronate), whilst alendronate and ibandronate are cautioned against(GFR $\leq 35$ ml/min for alendronate and $\leq 30$ ml/min for ibandronate). Pre-existing hypocalcaemia must be investigated and, where due to vita-min D deficiency, treated with vitamin D(e.g., 100,000 to

300,000 IU orally as a loading dose in divided doses) before zoledronate treatment is initiated.

Anti-resorptive drugs: denosumab

Denosumab is a fully humanised monoclonal antibody against the Receptor Activator of Nuclear factor Kappa B Ligand(RANKL), a major regulator of osteoclast develop-ment and activity. It is approved for the treatment of PMO and men at increased fracture risk, for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased fracture risk, and for the treatment of bone loss associated with long-term systemic glucocorticoid therapy in adults at risk of fragility fracture[206];(Evidence level lb). Denosumab is given as a subcutaneous injection of 60 mg once every 6 months. It has been shown to reduce the incidence of vertebral, non-vertebral, and hip fractures in postmenopausal women with osteoporosis[207] and safety and efficacy are maintained over 10 years of treatment[208];(Evidence level Ib). Approval for its use in men with osteo-porosis was granted on the basis of a BMD bridging study[209];(Evidence level Ib).

Denosumab is contraindicated in patients with hypocal-caemia or with hypersensitivity to any of the constituents of the formulation. Its use is not recommended in pregnancy or in those aged<18 years. Hypocalcaemia, as a side-effect of denosumab treatment, increases with the degree of renal impairment; patients should be advised to report symp-toms of hypocalcaemia. Pre-existing hypocalcaemia must be investigated and, where due to vitamin D deficiency,treated with vitamin D(e.g., 100,000 to 300,000 IU orally as a loading dose in divided doses) before denosumab treat-ment is initiated. Adequate intake of calcium and vitamin D is important in all patients, especially those with severe renal impairment. The SPC states all patients should have calcium checked prior to each dose. In patients predisposed to hypoc-alcaemia(e.g. patients with a creatinine clearance<35 ml/min), serum calcium levels should also be checked within 2 weeks after the initial dose[210]. Side-effects include skin infection, predominantly cellulitis, eczema, hypocalcaemia,and flatulence.

Denosumab cessation leads to rapid reductions in BMD and elevations in bone turnover to levels above those seen before treatment initiation[211-213];(Evidence level Ib).Patients who discontinue denosumab have an increased risk of sustaining multiple vertebral fractures. In a post hoc analysis of the FREEDOM study and its extension, women discontinuing denosumab had an increased rate of vertebral fracture over an average of 3-6 months since the last deno-sumab injection was due. Of those patients who sustained vertebral fractures, 60.7% sustained multiple fractures com-pared to 38.7% of those discontinuing placebo[214, 215];

119 Page 20 of 50

Archives of Osteoporosis(2025) 20:119

(Evidence level Ib). The increase in vertebral fracture risk following cessation of denosumab therapy emphasises the need to continue treatment with an alternative anti-resorp-tive drug following denosumab withdrawal. An intravenous infusion of 5 mg of zoledronate, 6 months after the last den-osumab injection, reduces subsequent bone loss[216-220],although this effect is not seen in all patients and may not be maintained beyond 1 year, particularly in those who have had more than 3 years of denosumab treatment[221](Evi-dence levels IIa and IIb). Monitoring bone turnover markers at 3 and 6 months post zoledronate infusion can help guide the timing of subsequent infusions. Where bone turnover markers are not available, a second infusion of zoledronate after 6 months has been proposed[222];(Evidence level IV). Oral alendronate 70 mg once weekly was shown to maintain BMD for 12 months in most patients following 1 year of denosumab therapy, although significant bone loss occurred in a minority[223];(Evidence level IIa). Given the difficulties in stopping denosumab treatment, particularly careful consideration is needed before starting denosumab in younger postmenopausal women and men.

Anti-resorptive drugs: hormone replacement therapy(HRT)

HRT comprises a large number of oestrogen or combined oestrogen plus progestogen formulations(including syn-thetic progestins or body identical progesterone, some of which are approved for the prevention of osteoporosis in postmenopausal women at risk of fragility fracture. Con-jugated equine oestogens 0.625 mg daily±2.5 mg/day of medroxyprogesterone acetate has been shown to reduce ver-tebral, non-vertebral and hip fracture risk in postmenopausal women not selected on the basis of low bone density or high fracture risk[224, 225];(Evidence level Ib). The 2019 evi-dence review from NICE identified that HRT was associated with lower fracture risk or increased BMD in nine out of 10 analyses, summarised from two cohort studies, one RCT,a Cochrane review and one other systematic review[226].The risk of venous thromboembolism(VTE) is increased by oral oestrogen containing HRT compared with baseline population risk, but not with transdermal HRT(at standard doses)[226]. HRT does not increase cardiovascular disease risk when started in women aged under 60 years[226]; when started within 10 years of menopause it appears to lower risk[227].

Some HRT preparations, particularly those containing synthetic progestins, are associated with a small excess incidence of breast cancer[228]. However, this risk appears less than that associated with adverse lifestyle factors such as reduced physical activity, obesity and high alcohol intake[229]. In women with a low underlying risk of breast cancer(i.e., most women), the benefits of HRT for up to 5 years',

when used for symptom relief alone without consideration of the added bone benefits, exceed potential harm[229].

Anti-resorptive drugs: calcitriol

Calcitriol(1,25-dihydroxyvitamin D3) is the active form of vitamin D and, although rarely used now, is approved for the treatment of established postmenopausal osteoporosis in an oral dose of 0.25μg twice daily. It acts mainly by inhibit-ing bone resorption. It has been shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis,but effects on non-vertebral and hip fractures have not been demonstrated[230];(Evidence level IIb). It is contraindi-cated in patients with hypercalcaemia or with metastatic calcification. Because calcitriol can cause hypercalcaemia and/or hypercalciuria, serum calcium and creatinine levels should be monitored at 1, 3, and 6 months after starting treatment and at 6-monthly intervals thereafter.

Anti-resorptive drugs: raloxifene

Raloxifene is a selective oestrogen receptor modulator and inhibits bone resorption. It is approved for the treatment and prevention of osteoporosis in postmenopausal women.Raloxifene has been shown to reduce vertebral fracture risk,but reduction in non-vertebral and hip fractures has not been demonstrated[231];(Evidence level Ib). Raloxifene is taken orally as a single daily 60 mg dose and may be taken at any time without regard to meals. Raloxifene is contraindicated in women with child-bearing potential, unexplained uterine bleeding, severe hepatic or renal impairment, and in women with a history of venous thromboembolism. Side effects include leg cramps, oedema, and vasomotor symptoms.There is a small increase in the risk of venous thromboem-bolism, mostly within the first few months of treatment, and a small increase in the risk of fatal stroke has been reported[232],(Evidence level IIa) such that it should be used with caution in women with a history of stroke or with risk factors for stroke disease. In the phase III trials, women treated with raloxifene had a significantly decreased risk of developing breast cancer[233];(Evidence level Ib).

Other drugs: strontium ranelate

Strontium ranelate is taken in a dose of 2 g once at night by mouth as a suspension of granules stirred in water, at least 2 h after food and/or consumption of calcium-containing products. As an alkaline earth metal(closely related to calcium) it substitutes for calcium within hydroxyapatite.Its mode of action is not completely understood, but the evidence suggests it has weak anti-resorptive effects whilst maintaining bone formation. In postmenopausal women with osteoporosis, strontium ranelate 2 g daily has been shown to

Archives of Osteoporosis(2025) 20:119

Page 21 of 50119

119

reduce the incidence of vertebral and non-vertebral fractures[234, 235];(Evidence levels Ib). Fewer hip fractures were reported in a post-hoc analysis of women at high risk of hip fracture(i.e., age≥74 years with a femoral neck BMD T-score≤-2.5). Approval for its use in men use in men use is trans-sis was granted on the basis of a BMD bridging study[236];(Evidence level Ib).

Common side effects include nausea and diarrhoea. There was a significant increase in venous thromboembolism in the Phase III trials[237]. Contraindications include previ-ous myocardial infarction, stroke, or venous thromboembo-lism, as a post-hoc pooled safety analysis showed signifi-cant increases in myocardial infarction and‘nervous system disorders' including cerebrovascular disease, which was observed in patients taking strontium ranaelate compared to placebo[238]. The manufacturer advises against use when the eGFR is<30 ml/ml. The higher atomic number of stron-tium compared with calcium artefactually increases BMD when incorporated into the bone matrix[239]. When stron-tium ranaelate is stopped, this effect is slow to resolve, with implications for future BMD monitoring.

Anabolic drugs: teriparatide(recombinant human parathyroid hormone(PTH) 1-34)

When administered intermittently, teriparatide has anabolic skeletal effects which are most marked in trabecular bone.Teriparatide is approved for the treatment of osteoporosis in postmenopausal women and in men at risk of fragility frac-ture, and osteoporosis associated with systemic glucocorti-coid therapy in women and men at risk of fragility fracture.Teriparatide is given as a subcutaneous injection in a dose of 20μg/day. The duration of treatment is limited to 24 months.

Teriparatide is contraindicated in patients with hypercal-caemia, severe renal impairment, malignant disease affect-ing the skeleton, prior radiation to the skeleton, in women who are pregnant or lactating, and in metabolic bone dis-eases other than osteoporosis and osteogenesis imperfecta.Teriparatide should be used with caution in patients with moderate renal impairment. PTH levels need to be normal to initiate teriparatide; hence, levels should be checked even with normocalcaemia. Side effects include headache, nanu-sea, dizziness, postural hypotension, and leg pain. Slight and transient elevations of serum calcium may occur following teriparatide injection.

Teriparatide has been shown to reduce vertebral and non-vertebral fractures in postmenopausal women with osteoporosis[240];(Evidence level Ib). No primary effi-cacy end-point data are available for hip fracture incidence,but systematic review and meta-analysis level evidence has shown an OR for hip fracture risk of 0.44(95% CI: 0.22,0.87;p=0.019) in patients treated with teriparatide com-pared with placebo, when considering hip fracture as a

safety end point. No significant benefit was seen on upper limb fractures[241];(Evidence level Ia). These findings were further supported by a network meta-analysis of a simi-lar list of RCTs, which reported a HR of 0.35(95% CI: 0.15,0.73) for hip fracture in patients treated with teriparatide compared with placebo[242];(Evidence level Ia). Approval for teriparatide use in men with osteoporosis and in men and women with glucocorticoid-induced osteoporosis was granted on the basis of BMD bridging studies[243, 244];(Evidence level Ib). Teriparatide biosimilars are available which may improve the cost-effectiveness of teriparatide.

Anabolic drugs: abaloparatide

Abaloparatide is a synthetic peptide analogue of the first 34 amino acids of the human parathyroid hormone-related peptide(PTHrP). It has anabolic skeletal effects and is approved for the treatment of osteoporosis in postmenopau-sal women at increased risk of fracture. Abaloparatide is given as a subcutaneous injection of 80μg once daily. The duration of treatment is limited to 18 months. Abalopara-tide is contraindicated in people with hypersensitivity to the active substance or to any of the excipients, pregnancy and breast-feeding, women of childbearing potential, pre-existing hypercalaemia, severe renal impairment, unex-plained elevations of serum alkaline phosphatase, patients with known risks for osteosarcoma such as those who have received prior external beam or implant radiation therapy involving the skeleton, and patients with skeletal malignan-cies or bone metastases. The European Medicines Agency SmPC specifies that patients should receive supplemental calcium and vitamin D if dietary intake is inadequate, and that no dosage adjustment is required in renal impairment;however, abaloparate must not be used in people with severe renal impairment including patients with end-stage renal disease. Blood pressure, cardiac status and ECG should be assessed prior to beginning treatment with abalopara-tide. Patients with cardiac disease should be monitored for worsening of their disease. Side-effects include hypercal-caemia and hypercalciuria, dizziness, back pain, nausea,headache, arthralgia, hypertension, injection site reaction,and palpitations.

Abaloparatide has been shown to reduce vertebral frac-tures in postmenopausal women with osteoporosis. There was no statistically significant reduction in non-vertebral fractures[123]; (Evidence level 1b). Two network meta-analyses have shown a reduction in both vertebral and non-vertebral fractures when compared to placebo, with RRs for vertebral fracture of 0.14(95% CI 0.05, 0.42)[245] and 0.13(95% credible interval(CrI) 0.04, 0.34)[246], and RRs for non-vertebral fracture of 0.51(95% CI 0.29, 0.87)[245]and 0.50(95% CrI 0.28, 0.85)[246];(Evidence level Ia). A significant reduction in wrist fracture compared to placebo

119 Page 22 of 50

Archives of Osteoporosis(2025) 20:119

was also shown in one network meta-analysis(YRR 0.39;95% Cri 0.15, 0.90)[246](Evidence level Ia). A further network meta-analysis of nine randomized controlled trials and two real-world evidence observational studies showed abaloparotide to be superior to teriparate for non-vertebral fracture risk reduction(OR, 0.87; 95% CI, 0.80-0.95)[188];(Evidence level Ia). There are insufficient trial data to assess efficacy against hip fracture.

Anabolic drugs with additional antiresorptive effect:romosozumab

Romosozumab is a humanised monoclonal antibody that binds to and inhibits sclerostin. It has a dual action, stimu-lating bone formation and inhibiting bone resorption and is approved for the treatment of severe osteoporosis in post-menopausal women at very high risk of fracture. It is cur-rently not approved for use in men, although it has been used successfully to increase BMD in men in[24];(Evidence level Ib). It is given as a subcutaneous injection in a dose of 210 mg(administered as two subcutaneous injections of 105 mg each) once monthly. The duration of treatment is limited to 12 months.

In postmenopausal women with osteoporosis who received romozozumab 210 mg or placebo subcutane-ously once monthly for 12 months, followed by denosumab 60 mg subcutaneously in both groups for 12 months, new vertebral fractures and clinical fractures were significantly reduced in women treated with romozozumab when com-pared to placebo at 12 months, and at 24 months vertebral fracture rates were significantly lower in women treated with romozozumab during the first 12 months[120];(Evidence Level Ib). In a comparator-controlled study in postmenopau-sal women with severe osteoporosis, subcutaneous romo-sozumab 210 mg once monthly for 12 months followed by oral alendronate 70 mg once weekly for 12 months was com-pared against alendronate 70 mg once weekly for 24 months[121]. New vertebral, non-vertebral, clinical, and hip frac-tures were all significantly lower in women treated with romozozumab followed by alendronate than in those treated with alendronate alone(Evidence level Ib). Significantly greater risk reduction in new vertebral and clinical fractures was seen for romozozumab vs alendronate at 12 months. A significantly higher incidence of cardiovascular events was seen in the romozozumab group compared to the alendronate group[120];(Evidence level Ib).

Romosozumab is contraindicated in patients with hypoc-alcaemia, hypersensitivity to any of the constituents of the formulation, or a history of myocardial infarction or stroke.When determining whether to use romosozumab for an indi-vidual patient, both fracture and cardiovascular risk(based on risk factors) over the next year need to be considered.

Transient hypocalcaemia has been observed in patients receiving romozozumab. Hypocalcaemia should be cor-rected prior to initiation of treatment, and patients should be adequately supplemented with calcium and vitamin D.Patients with severe renal impairment or on dialysis are at increased risk of developing hypocalcaemia. Osteonecrosis of the jaw and atypical femoral fractures have been very rarely reported with romozozumab use.

Drug treatment for patients with very high fracture risk

Two randomised comparator-controlled studies in postmen-opausal women with severe osteoporosis have demonstrated superior anti-fracture efficacy of skeletal anabolic agents versus anti-resorptive drugs. Subcutaneous romozumab 210 mg once monthly resulted in significantly greater reduc-tion of vertebral, non-vertebral, clinical, and hip fractures at 24 months(risk reduction of 48%, 19%, 27% and 38%respectively) and significantly greater risk reduction in new vertebral and clinical fractures at 12 months when com-pared to oral alendronate 70 mg once weekly. In the VERte-bral fracture treatment comparisons in Osteoporotic women(VERO) study, subcutaneous teriparatide, 20μg once daily,was associated with significantly fewer new vertebral and clinical fractures than oral risedronate, 35 mg once weekly(56% and 52% respectively) after 2 years of treatment[248];(Evidence level Ib). These studies provide the rationale for considering teriparatide or romosozumab as a first-line treatment option in postmenopausal women at very high risk of fracture. Comparator studies of anti-resorptive and anabolic agents have not been reported in men.

Following discontinuation of treatment with teriparatide or romosozumab, bone turnover increases and there is a fall in BMD. Although not specifically studied for abaloparatide,similar changes would be expected. Since the maximum per-mitted duration of treatment with teriparatide is 24 months,with abaloparatide 18 months, and with romosozumab 12 months, sequential therapy with anti-resorptive drugs is required to maintain their beneficial skeletal effects. Both alendronate and denosumab have been shown to maintain and increase BMD at the spine and hip following teriparatide or romosozumab therapy[121, 249-252]. In the FRAME extension study, the beneficial effects of 12 months romo-sozumab therapy on vertebral and non-vertebral fracture risk were maintained when followed by 24 months of denosumab treatment[253];(Evidence level IIb). Sequential therapy with alendronate following 18 months treatment with aba-loparatide results in further gains in BMD and sustained reductions in vertebral and non-vertebral fracture rates[254];(Evidence level IIb).

Archives of Osteoporosis(2025) 20:119

Page 23 of 50119

119

When women are switched from oral bisphosphonates to teriparatide or romosozumab, there is attenuation of the increase in spine and hip BMD compared to when these agents are used in treatment-naive individuals. This blunt-ing effect is greater for teriparatide from romosozumab,especially at the hip[255, 256];(Evidence level IIb). The impact of these effects, if any, on fracture risk is unknown.The effect of switching from oral bisphosphonates to aba-loparatide on the efficacy or effectiveness of abaloparatite treatment is unknown. In women previously treated with denosumab, switching to teriparatide is associated with tran-sient bone loss in the spine and greater and longer lasting bone loss in the hip[250]. When romosozumab is given following denosumab therapy, there is attenuation of the BMD increase at the spine and hip[248, 257];(Evidence level IIb). The impact of these effects, if any, on fracture risk is unknown.

Duration and monitoring of bisphosphonate treatment

Osteoporosis is a long-term condition for which there is cur-rently no cure; therefore, life-long treatment and monitoring to prevent fractures is often required.

Recommendations

1. Plan to prescribe oral bisphosphonates(alendronate,ibandronate and risedronate) for at least 5 years and then re-assess fracture risk. Longer durations of treatment, for at least 10 years, are recommended in the following men and women (Strong recommendation) (see Fig. 4):

o Age≥70 years at the time that the bisphosphonate is started

Fig.4 Oral bisphosphonates:clinical flowchart for long-term treatment and monitoring. GC,glucocorticoids(oral≥7.5 mg prednisolone/day or equivalent);BP, bisphosphonate

 119

Page 24 of 50

Archives of Osteoporosis

(2025) 20:119

Fig.5 Intravenous bisphos-phonates: clinical flowchart for long-term treatment and monitoring. GC, glucocorti-coids(oral≥7.5 mg predniso-lone/day or equivalent); BP,bisphosphonate

 o Who has a previous history of a hip or vertebral fracture(s)

o Treated with oral glucocorticoids≥7.5 mg predni-solone/day or equivalent

o Who experiences one or more fragility fractures dur-ing the first 5 years of treatment(if treatment is not changed).

2. Plan to prescribe an annual intravenous bisphosphonate(i.e., zoledronate) for at least 3 years and then re-assess fracture risk. Longer durations of treatment, for at least 6 years, are recommended in the following men and women (Strong recommendation)(see Fig. 5):

o Age≥70 years at the time that the bisphosphonate is started

o Who has a previous history of a hip or vertebral fracture(s)

o Treated with oral glucocorticoids≥7.5 mg predni-solone/day or equivalent

o Who experiences one or more fragility fractures dur-ing the first 3 years of treatment(if treatment is not changed).

3.If a new fracture occurs after bisphosphonate treatment is discontinued, reassess using FRAX and restart treat-ment(Strong recommendation).

4. If bisphosphonate treatment is discontinued and no new fracture occurs, reassess using FRAX after 18 months for risedronate and ibandronate, 2 years for alendronate,and 3 years for zoledronate to inform whether treatment should be restarted(Strong recommendation).

Archives of Osteoporosis(2025) 20:119

Page 25 of 50119

119

Bisphosphonate therapy is associated with rare but serious adverse events, notably atypical femoral fractures(AFFs) and osteonecrosis of the jaw(ONJ). Defining the optimal duration of bisphosphonate therapy attempts to ensure that the benefit in fracture risk reduction outweighs the small risk of AFFs and ONJ at all time points through patient management. Bisphosphonates are retained long term in bone, allowing the beneficial effects to persist for some time after cessation of treatment administration. This has raised the possibility that some patients may benefit from a period of treatment to restore the benefit/risk balance[258];(Evidence level IIa), in which treatment is stopped after some years and the need for reinstitution of therapy is subsequently reassessed. Treatment review in patients tak-ing bisphosphonates is, therefore, critical[259] and each patient must be assessed individually to assess relative risks and benefits; there is no standard policy for‘all patients’[215];(Evidence level IIa). Because pivotal clinical trials have mostly been limited to a duration of 3 years, recom-mendations for longer term use and for pauses in treatment are based on limited evidence from extension studies in post-menopausal women[260, 261];(Evidence level IIa). There is currently no evidence on which to base specific recom-mendations for men.

Withdrawal of bisphosphonate treatment is associated with decreases in BMD and increased bone turnover after 2-3 years for alendronate[262, 263];(Evidence level Ib),and 1-2 years for ibandronate and risedronate[264, 265];(Evidence level Ib). In the case of zoledronate, withdrawal after 3 years' treatment is associated with only a small decrease in BMD after a further 3 years without treatment[266];(Evidence level Ib). Comparison between offset of alendronate and zoledronate at 3 years showed alendronate-treated patients had greater reductions in total hip BMD and greater rises in PINP, despite a longer treatment exposure with alendronate, supporting a more rapid offset of drug effect than with zoledronate[267];(Evidence level IIb).

In the Fracture Intervention Trial Long-term exten-sion study of alendronate(FLEX), there were signifi-cantly fewer clinical vertebral fractures in women previ-ously treated with alendronate for 5 years who continued with alendronate for 5 more years than in those assigned to placebo after 5 years of alendronate[263];(Evidence level Ib). In the Health Outcomes and Reduced Incidence with Zoledronate once yearly(HORIZON) study exten-sion, the risk of morphometric vertebral fractures was sig-nificantly lower in women continuing on zoledronate for 3 years after the initial 3 years of therapy when compared to those switched to placebo[266];(Evidence level Ib).Post-hoc analyses from the alendronate and zoledronate extension studies suggest that women most likely to benefit from long-term bisphosphonate therapy are those with low

hip BMD(T-score<-2.0 in FLEX and≤-2.5 in HORI-ZON), those with a prevalent vertebral fracture, and those who sustained one or more incident fractures during the initial 3 or 5 years of 4 treatment[82];(Evidence level Ib).Older age was also associated with increased fracture risk after discontinuation of alendronate therapy[268];(Evi-dence level Ib).

Reassessment of fracture risk in individuals on osteoporosis drug treatment

Recommendations

5. Review treatment adherence in men and women who sustain a fragility fracture whilst on drug treatment,(poor adherence is when less than 80% of treatment has been taken correctly) and investigate for secondary causes of osteoporosis(Strong recommendation).

6.Fracture risk assessment in patients receiving drug treat-ment should be performed using FRAX with BMD, with arithmetic adjustments to FRAX probabilities to take account of additional clinical risk factors. If the FRAX-derived fracture probability exceeds the intervention threshold, drug treatment should be continued(Strong recommendation).

7. If biochemical markers of bone turnover indicate relapse from suppressed bone turnover and/or BMD has decreased following bisphosphonate withdrawal, con-sider resumption of drug treatment(Conditional recom-mendation).

8. After 10 years of bisphonate treatment, patient man-agement should be considered on an individual basis(Conditional recommendation).

Stopping osteoporosis treatment, be it with bisphospho-nate or denosumab, is associated with an increased risk of fragility fracture, such that routine cessation of anti-resorp-tive therapy(so called‘drug holidays’) is not supported by a review of the evidence[215];(Evidence level IIa). Reassess-ment of fracture risk in treated individuals can be performed using FRAX with femoral neck BMD[149];(Evidence level IIb). The NOGG intervention thresholds can then be used to guide the decision as to whether treatment can be stopped for a period of time(Figs. 4 and 5). Whereas FRAX cannot be used to assess treatment response[149];(Evidence level IIb) it does have a role in reassessing current fracture risk to determine the need to continue or to discontinue treatment.Detection of the offset of drug effect, using BMD and bone turnover changes, potentially provides information to influ-ence clinical management. However, there are presently no definitive data that link a potential threshold change in BMD

119

Page 26 of 50

Archives of Osteoporosis(2025) 20:119

or bone turnover markers during drug offset to clinically meaningful changes in fracture risk.

Rare adverse effects of long-term bisphosphonate and denosumab treatment

Recommendations

9. During bisphosphonate or denosumab therapy, encour-age all patients to maintain good oral hygiene, receive routine dental check-ups, and report any oral symptoms such as dental mobility, pain, or swelling(Strong rec-ommendation).

10.In those with severe dental disease who require bis-phosphonate or denosumab treatment, timely dental review and dental treatment by an appropriately expe-rienced dental surgeon should be pursued before drug administration, bearing in mind drug treatment should be initiated as soon as possible after a fragility fracture;a multi-disciplinary team(MDT) approach to discuss individual needs is encouraged(Conditional recom-mendation).

11. During bisphosphonate or denosumab treatment,although ideally patients should minimise invasive dental procedures where possible, if indicated they can be carried out safely and successfully in most patients.When dental procedures are required, there are no data available to show whether treatment discontinuation reduces the risk of ONJ. Clinical judgment of the treat-ing physician should guide the management plan of each patient based on individual benefit/risk assess-ment,ensuring patients continue to access routine den-tal care(Conditional recommendation).

12. During bisphosphonate or denosumab therapy, advise patients to report any unexplained thigh, grain, or hip pain, and if such symptoms develop, the femur should be imaged (by full length femur X-ray, isotope scan-ning or MRI) (Strong recommendation).

13.If an AFF is identified, image the contralateral femur(Strong recommendation).

14.All patients who develop an AFF should be referred to an osteoporosis specialist to guide management of future bone health(Strong recommendation).

15.In patients who develop an AFF, discontinue bisphos-phonate or denosumab treatment(Conditional recom-mendation).

Osteonecrosis of the jaw(ONJ)

Osteonecrosis occurs only very rarely in patients receiving bisphosphonate or denosumab therapy for osteoporosis. The estimated incidence in those receiving bisphosphonates is

10-100/100,000 person-years of exposure in clinical trials.Risk factors for ONJ include poor oral hygiene, dental dis-ease, dental interventions, smoking, cancer, chemotherapy and/or glucocorticoid therapy[269, 270];(Evidence level IIa). The incidence of ONJ is substantially greater with the higher doses of bisphosphonates or denosumab that are used to treat patients with skeletal metastases. The Scottish Den-tal Clinical Effectiveness Programme has produced guidance on oral health management in patients taking anti-resorptive medication[271]. Osteonecrosis of the external auditory canal after bisphosphonate treatment has been described very rarely in case reports, with patients presenting with ear symptoms including chronic ear infections. Possible risk factors include steroid use and chemotherapy and/or local risk factors such as infection or trauma[272];(Evidence level IV).

Atypical femoral fractures (AFF)

Atypical femoral fractures, mainly of the subtrochanteric and diaphyseal regions of the femoral shaft, have been reported rarely in patients taking bisphosphonates or denosumab for osteoporosis. Asian race, femoral bowing,and glucocorticoid use have been identified as risk factors[273]. In a recent review by the ASBMR Task Force on the management of osteoporosis in patients on long-term bis-phosphonates, a systematic search of the literature revealed that the absolute risk was consistently low, ranging between 3.2 and 50 cases/100,000 person-years of exposure[274,275];(Evidence level IV). This estimate appeared to dou-ble with prolonged duration of BP use(> 3 years, median duration 7 years), and declined with discontinuation[274,275];(Evidence level IV),[276];(Evidence level IIa). In a nationwide cohort study from Denmark, use of alendronate in excess of 10 years was associated with a 30% lower risk of hip fracture and no increase in the risk of fractures of the subrochanteric femur and femoral shaft, support-ing an acceptable risk-benefit balance in terms of fracture outcomes[277];(Evidence level IIb). Atypical femoral fractures are often bilateral, associated with prodromal pain, and tend to heal poorly. Prodromal pain can be felt in the thigh, grain, or hip for days, weeks, or months before fracture. Discontinuation of bisphosphonate or denosumab therapy is advised in patients who develop an atypical frac-ture; weight-bearing activity should be restricted, adequate calcium and vitamin D should be ensured, and alternative treatment options considered where appropriate. Surgi-cal treatment with intramedullary nailing is often recom-mended[274, 275];(Evidence level IV).

There is a lack of good quality evidence on the medical management of bone health following an AFF. However, a recent international expert consensus document supported by a systematic review proposed practical measures to help

Archives of Osteoporosis(2025) 20:119

Page 27 of 50 119

119

in patient management [278]; (Evidence level IV). Follow-ing an AFF, if the risk of fragility fracture is low, further pharmacological bone treatments can be avoided. If fracture risk is high and bilateral surgical fixation of fractures has been performed, consider the use of teriparatide. If unilateral or no surgical intervention has taken place, consider teri-paratide, romozozumab, raloxifene, or HRT. The potential utility of teriparatide as an adjunct to healing following AFF has been examined. There is no evidence that teriparatide enhances healing of AFFs, but limited data show a tendency towards faster healing in surgically managed AFFs (com-plete and incomplete). However, in AFFs managed conserv-atively, there was no suggestion of improved fracture healing with teriparatide [278]; (Evidence level IV). The benefits versus risks of using bisphosphonates or denosumab after AFF should be carefully examined if these options are con-sidered, taking into consideration prior unilateral or bilateral nailing, the use of an anabolic agent post AFF, together with the overall clinical situation and fracture risk (Evidence level IV).

Glucocorticoid-induced osteoporosis

Recommendations

15. Because bone loss and increased fracture risk occur early after initiation of oral glucocorticoids, bone-protective treatment should be started in the fol-lowing people, at the same time as glucocorticoid therapy without waiting for bone density assess-ment, which should follow later(Strong recommen-dations):

a) anyone with a prior fragility fracture,

b) women age≥70 years,

c)postmenopausal women, and men age≥50 years,prescribed high doses of glucocorticoids, i.e.,≥7.5 mg/day of prednisolone or equivalent over 3 months(N.B., this is equivalent to≥30 mg/day of prednisone for 4 weeks over 3 months).

d)postmenopausal women, and men age $\geq$ 50 years,with a FRAX probability of major osteoporotic frac-ture or of hip fracture exceeding the intervention threshold.

16.Oral bisphosphonates(alendronate or risedronate) or intravenous zoonedronate are the most cost-effective first-line drug options for bone protection. Denosumab is an alternative option. Teriparatide can be a first-line drug option in those at very high fracture risk (Strong Recommendation).

17.Adequate calcium intake should be achieved through dietary intake if possible, with the use of supplements if necessary. An adequate vitamin D status should be maintained, using supplements if required(Strong Rec-ommendation).

18.If glucocorticoid therapy is stopped, withdrawal of bone-protective therapy may be considered at the same time, provided on re-assessment of fracture risk using FRAX, the probabilities of both major osteoporotic fracture and of hip fracture lie below the intervention threshold(Strong Recommendation).

19.If glucocorticoids are continued long term, bone pro-tection should be maintained in the majority of cases(Strong Recommendation).

20. Patients starting medium or low dose oral glucocorti-coid therapy who have a FRAX probability near to, but below the intervention threshold, should have FRAX with BMD reassessed 12-18 months after starting glu-cocorticoid therapy(Conditional recommendation).

Abaloparatide and romosozumab are further options for treatment if their therapeutic indication is fulfilled, i.e., in postmenopausal women at very high fracture risk. Bone pro-tective therapy may be appropriate in some premenopausal women and younger men, particularly in individuals with a previous history of fracture, or those receiving high doses of glucocorticoids(≥7.5 mg/day of prednisolone or equivalent over 3 months). Caution is advised when prescribing drug treatment in women of childbearing age. Referral of com-plex cases to secondary care is often necessary. Although

Table 6 Effect of approved interventions for glucocorticoid-induced osteoporosis on BMD and fracture risk

|Bone protective therapy|Spine BMD|Hip BMD|Vertebral fracture|Non-vertebral fracture|Evidence of superiority for spine and/or hip BMD| |---|---|---|---|---|---| |Alendronate|Ib|Ia|Ia|Ia|Inferior to teriparatide (Ib)| |Risedronate|Ib|Ia|Ia|NAE|Inferior to zoledronate (Ia)| |Zoledronate|Ib|Ib|Ia|NAE|Superior to risedronate (Ib)| |Denosumab|Ib|Ia|Ia|NAE|Superior to bisphosphonates (IIa)| |Teriparate|Ib|Ib|Ia|Ia|Superior to alendronate (Ib)|

NAE no available evidence

119 Page 28 of 50

Archives of Osteoporosis(2025) 20:119

guidance on the prevention and management of glucocor-ticoid-induced osteoporosis has been developed in many countries, there is evidence that in the UK osteoporosis risk assessment and management are still inadequate in long-term users of oral glucocorticoids[279];(Evidence level IIIb). Bone loss and increased fracture risk occur rapidly after initiation of oral glucocorticoid therapy and increase with the dose of glucocorticoids[67, 280]. The increase in fracture risk is seen for vertebral and non-vertebral fractures,including hip fractures, and is partially independent of BMD[68];(Evidence level Ia).

Approval for the use of bone protective therapy to pre-vent osteoporosis in people receiving oral glucocorticoids was based mainly on BMD bridging studies carried out as part of Phase III randomised controlled trials with bisphos-phonates[191,196,203,281,282]. Subsequently, approval has been given for denosumab using the same methodology[206]. Fracture prevention has not been considered as an efficacy end-point in most trials. However, although not a primary end-point, in an 18-month randomised controlled trial extended to 36 months comparing teriparatide with alendronate, significantly fewer subjects in the teriparatide group had vertebral fractures compared with the alendronate arm[244], but with no benefit on non-vertebral fractures.This protection against vertebral fractures was confirmed in a recent meta-analysis, which showed that co-prescription of teriparatide, alendronate, risedronate, or denosumab with glucocorticoids could reduce the incidence of vertebral frac-tures, with further evidence of a reduction in non-vertebral fracture rates with alendronate or teriparatite(Table 6)[283];(Evidence levels Ia& Ib).

Considering the increased fracture risk associated with higher glucocorticoid doses, FRAX assessment provides fracture probabilities based on both an average dose of oral prednisolone(2.5-7.5 mg/day or its equivalent) and a higher dose(≥7.5 mg/day or its equivalent). Individu-als taking an average dose of prednisolone<2.5 mg/day will have lower fracture risk, and the average adjust-ments over all ages in postmenopausal women and men aged≥50 years are shown in Table 7[28];(Evidence level IIb). For very high doses of glucocorticoids, i.e.,> 20 mg/day prednisolone or its equivalent, greater upward adjust-ment of fracture probability is required[67];(Evidence level IIa).

When the UK FRAX model is used and the glucocor-ticoid box is filled, 2 points appear on the NOGG graphs,one for medium dose and one for high dose(all defined as above). The assessment thresholds(fracture probabilities for BMD testing) and intervention thresholds(fracture probabil-ities for therapeutic intervention) are then used in the same way as described for postmenopausal women and older men.

Men receiving androgen-deprivation therapy

Recommendations

The NOGG supports the guideline published by Brown et al.2020[284].

21. All men starting androgen deprivation therapy(ADT)should have their fracture risk assessed using FRAX,considering ADT use as a secondary cause of osteo-porosis, with BMD measured where available(Strong recommendation).

22.Consider referring men, with high fracture risk requir-ing drug treatment, to secondary care for assessment and initiation of treatment with bisphosphonates or denosumab(Conditional recommendation).

23.Men with FRAX probability near to, but below the intervention threshold, and patients going on to addi-tional systemic therapies(particularly those requiring glucocorticoids), should have FRAX with BMD reas-sessed 12-18 months after starting ADT(Conditional recommendation).

There is no evidence that skeletal metabolism in men differs fundamentally from that of women[285]. However,secondary causes of osteoporosis are common in men and amongst these hypogonadism is prominent[286]. Androgen deprivation therapy(ADT), used primarily in the treatment of older men with prostate cancer, is frequently associated with hypogonadism. Osteoporosis caused by ADT is associ-ated with rapid loss of BMD within 6-12 months of initia-tion of ADT[287];(Evidence level Ic). There is a significant increase in fracture risk in men with prostate cancer in the 5 years following the initiation of ADT when compared to

Table 7 Adjustment of FRAX derived fracture probability estimates according to daily dose of prednisolone

|Dose|Prednisolone equivalent dose(mg/day)|Average adjustment to hip fracture probability|Average adjustment to major osteoporotic fracture(MOF) prob- ability| |---|---|---|---| |Low|<2.5|-35%|-20%| |Medium|2.5-7.5|None|None| |High|≥7.5|+20%|+15%|

Archives of Osteoporosis(2025) 20:119

Page 29 of 50119

119

those not receiving ADT[288];(Evidence level Ic). Bis-phosphonates and denosumab are effective drug treatments for preventing BMD loss in men with prostate cancer taking ADT, although effects on fracture risk have not been demon-strated. Exercise programmes are a less effective alternative which are insufficient in isolation[289];(Evidence level Ib).

In a systematic review and network meta-analysis, all evaluated treatments for ADT-induced bone loss, which included bisphosphonates and selective oestrogen recep-tor modulators(SERMs), were effective in improving BMD compared to placebo. However, zoledration gener-ated greater improvements in BMD compared to other drug treatments at all bone density sites, except for risedronate,which had better BMD improvement compared to zole-dronate at the femoral neck site in one small study[290];(Evidence level IIa). A recent UK consensus statement on prostate cancer treatment-induced bone loss concluded that fracture risk should be calculated using FRAX, considering ADT use as a secondary cause of osteoporosis and including BMD where available and practical. BMD should always be assessed where calculated fracture risk is close to the NOGG intervention threshold. Those with FRAX probability near to but below the intervention threshold and patients going on to additional systemic therapies should have FRAX with BMD repeated after 12 to 18 months[284];(Evidence level IIa).

Women receiving aromatase inhibitor therapy

Recommendations

24. All women starting aromatase inhibitor(AI) therapy should have their fracture risk assessed using FRAX,considering AI use as a secondary cause of osteopo-rosis, including BMD measurement where practical(Strong recommendation).

25. Women with high fracture risk should be commenced on drug treatment to prevent osteoporosis and fracture,with bisphosphonates or denosumab(Strong recom-mendation).

26.Women with a FRAX probability near to, but below the intervention threshold, and patients going on to addi-tional systemic therapies(particularly those requiring glucocorticoids), should have FRAX with BMD reas-sessed 12-24 months after starting AI therapy(Con-ditional recommendation).

27.If adjuvant high-dose bisphosphonate therapy is used as part of breast cancer management, consider assess-ing fracture risk at the end of this bisphosphonate ther-apy, particularly if AI therapy continues(Conditional Recommendation).

The use of aromatase inhibitors(AI) in postmenopausal women induces bone loss at an average rate of 1-3% per year at sites rich in trabecular bone. Bone loss is more marked in young women with treatment-induced ovarian suppres-sion, losing an average of 7-8% per annum[291];(Evidence level IIa). In case-control studies, the incidence of fracture in women with breast cancer treated with AIs is reported to be around 18-20% after 5 years follow-up[292]. NICE guid-ance on the management of early breast cancer, which rec-ognises the excess risk of osteoporosis with the use of AIs,recommends a baseline DXA scan to assess BMD at the time of initiation of AI therapy[293];(Evidence level IV). Inter-national Consensus Position Statements suggest that fracture risk should be assessed, although the consideration of AI use as a secondary cause of osteoporosis in FRAX may not adequately estimate fracture risk[292, 294];(Evidence level IIa) with drug treatment to prevent bone loss and fractures recommended in those with a T-score of less than-2, or less than-1.5 with 1 additional risk factor, or in those with 2 or more risk factors(without BMD). Drug treatment should be a bisphosphonate(oral or parenteral) or denosumab, used in the doses as for postmenopausal osteoporosis. Denosumab and zoledorate both lead to significant gains in BMD at the spine and hip in postmenopausal women with breast cancer receiving Als, and both denosumab and risedronate have been shown to reduce fracture risk[295];(Evidence level Ia).

Management of symptomatic osteoporotic vertebral fractures

Recommendations

1. Administer analgesia orally rather than parenterally whenever possible. Pain should be regularly reviewed,and analgesia titrated up or down according to pain intensity and side effects, with use of the weakest effec-tive agent for the shortest possible time(Strong recom-mendation).

2.Avoid use of non-steroidal anti-inflammatory drugs(NSAIDs) in older people, but, if used, co-prescribe a proton-pump inhibitor, and monitor for gastrointestinal,renal and cardiovascular side-effects(Strong recommen-dation).

3.Prescribe appropriate laxative therapy, such as the com-bination of a stool softener and a stimulant laxative,whenever opioid therapy is used in older people(Strong recommendation).

4. It is recommended that exercise programmes following vertebral fracture include progressive muscle strength-

119

Page 30 of 50

Archives of Osteoporosis(2025) 20:119

ening activity, including back extensor muscle strength-ening and/or endurance exercise(Strong recommenda-tion).

5.When a patient is in pain, it may be advisable to initially perform exercise for back extensors in an unloaded posi-tion(Conditional recommendation).

6.Provide clear and prompt guidance on how to adapt movements involved in day-to-day living, including how exercises can help with posture and pain, to patients with painful vertebral fractures (Strong recommendation).

<BeginOfPara>7. Ensure prompt secondary fracture prevention is started following a fracture, with follow-up through fracture liaison services for all postmenopausal women, and men aged 50 years and older, with a newly diagnosed vertebral fracture(Strong recommendation).

Vertebral fractures can cause acute and chronic pain,height loss, spinal deformity and altered body shape, func-tional impairment, and reduced health-related quality of life[14]; (Evidence level Ila). Analgesia for acute pain is important to allow restoration of function and mobility but must be used safely [296-298]; (Evidence level IIla). In patients admitted to hospital, salmon calcitonin given for up to 4 weeks (50-100 IU daily given subcutaneously or intramuscularly) has been shown to be an effective adjunc-tive analgesic for pain experienced at rest or when walking,associated with acute (within 10 days of) vertebral fracture[299]; (Evidence level IIa). However, side effects (mainly flushing and gastro-intestinal disturbance) are common.Long-term use may be associated with an increased risk of cancer [300]. There is no evidence that salmon calcitonin is an effective treatment for chronic pain associated with vertebral fractures [299]; (Evidence level Ila). Of note, in the SPC, calcitonin is indicated for the prevention of acute bone loss due to sudden immobilisation such as in patients with recent osteoporotic fractures, rather than for the management of pain. A single, small, randomised double-blind, controlled trial found 30 mg intravenous pamidronate, given within 21 days of acute vertebral fracture, to be more effective than placebo in reducing pain [301]; (Evidence level IIb). Of note in the SPC, pamidronate is indicated for the treatment of conditions associated with increased osteoclast activity,rather than for the management of pain. Physiotherapist supervised exercise following vertebral fracture improves pain and physical performance [302]; (Evidence level Ib). In the presence of pain, it may be advisable to initially perform exercise for back extensors in an unloaded position, such as supine [303]; (Evidence level Ila).

Combining exercise with physiotherapy-delivered edu-cation and guidance can reduce fear of falling and improve psychological symptoms associated with vertebral fractures in[171, 304]; (Evidence level Ia). For patients with painful vertebral fractures, there is low quality evidence suggesting

that spinal bracing using soft or rigid external orthoses for 2 h a day over 6 months may improve pain and trunk muscle strength[303]. There is currently no evidence that bracing with soft or rigid external orthoses improves fracture heal-ing[305]. Hence, routine use of bracing for the treatment of acute or subacute vertebral fractures cannot be recom-mended(Evidence level Ia). The current evidence does not support the routine use of percutaneous vertebroplasty or balloon kyphoplasty for the treatment of painful osteoporotic vertebral fractures, as these procedures do not show consist-ent patient benefit[303, 306];(Evidence level Ia). In older women with vertebral fractures and chronic back pain sta-ble for 6 months or more, a small randomised controlled trial has shown electrical nerve stimulation, administered as inferential therapy or horizontal therapy 5 days a week for 2 weeks, can improve pain over 14 weeks[307];(Evidence level IIb). Patients with a recent vertebral fracture have a high imminent risk of further fragility fracture[64];(Evi-dence level IIb). If a vertebral fracture is associated with impending or existing neurological deficits, urgent referral to spinal surgical services is indicated.

Models of care for fracture prevention

Recommendations

1. Multidisciplinary, coordinator-based FLS are recom-mended to systematically identify men and women with fragility fractures, facilitating timely assessment of fracture and falls risk, and where appropriate, tests to exclude secondary causes of osteoporosis, radiological investigation including BMD testing, and initiation of pharmacological and non-pharmacological interventions to reduce risk of falls and fractures(Strong recommen-dation).

2. FLSs should include embedded local audit systems sup-ported by a clinical fracture database to enable moni-toring of care provided to fracture patients [e.g., Royal College of Physicians FLS-Database]; (Strong recom-mendation).

3.FLSs should employ a range of case-finding strategies to identify all inpatients and outpatients with fragility fractures (Strong recommendation).

4.Diagnostic imaging services should routinely evaluate the spine in all imaging of postmenopausal women, and men aged $\geq 50$ years, in which the spine is visualised,and report vertebral fractures using standardised meth-ods(Strong recommendation).

5. Patients recommended drug treatment for osteoporosis should be offered tailored information about osteoporo-sis and its treatments, and further medication reviews to

Archives of Osteoporosis(2025) 20:119

Page 31 of 50119

119

support adherence and to discuss alternative treatments if unacceptable adverse events arise or adherence is dif-ficult(Strong recommendation).

6. Primary care clinicians should always have in mind the possibility of vertebral fracture in postmenopausal women and men aged≥50 years who present with acute onset back pain, especially thoracic pain, if they have risk factors for osteoporosis(Strong recommendation).

FLS models of care

Collaboration between primary care clinicians, secondary care physicians, orthopaedic surgeons, radiologists, and pharmacists, and between the medical and non-medical disciplines concerned, should underpin secondary fracture prevention programmes. Fracture Liaison Service(FLS)programmes reduce re-fracture rates and improve survival[308, 309](Evidence levels Ia and IIb). The Department of Health and NHS RightCare both state that FLS should be provided for all patients sustaining a fragility fracture[310,311], which aligns with the International Osteoporo-sis Foundation's global Capture the Fracture® programme[312] and the Royal Osteoporosis Society(ROS) FLS Clini-cal Standards[313].

FLS should provide fully coordinated, intensive mod-els of care for secondary fracture prevention. FLS models which provide identification, assessment and treatment initiation, or a treatment recommendation to primary care,are more clinically effective and cost-effective in improving patient outcomes than approaches that provide identifica-tion and/or patient alerts, and/or patient education only[314];(Evidence Level Ia). The required approach is a FLS in which identification, assessment and osteoporosis treatment are all conducted within an integrated electronic health care network, overseen by a coordinator and uti-lising a dedicated database measuring performance[312,314-316];(Evidence level Ia). FLS that initiate pharma-cological treatment, rather than making a treatment recom-mendation for primary care initiation, have higher rates of treatment initiation[315];(Evidence level Ia). FLS should also initiate appropriate non-pharmacological interventions and communicate ongoing care effectively with primary care practitioners[313]. FLS should provide a coordinated programme with an integrated approach for falls and frac-ture prevention; all individuals with a fracture should be fully assessed for falls risk and appropriate interventions to reduce falls should be undertaken[317]. As risk of re-fracture is highest immediately after a fragility fracture,secondary fracture prevention assessment and interven-tion should be initiated as soon as possible and no later than 16 weeks post-fracture, as recommended by the Royal Osteoporosis Society[64, 313].

FLS patient identification

FLS need to employ a range of case finding strategies to identify both inpatients and outpatients with fragility frac-tures and people with vertebral fractures who are often undiagnosed. Reasons for non-identification of vertebral fractures include the absence of a fall as a trigger for inves-tigation, absence of symptoms or attribution of symptoms to other causes. Furthermore, in patients who do have spi-nal imaging, use of ambiguous non-standardised terminol-ogy in imaging reports and failure to routinely evaluate the vertebrae captured in imaging of other body systems can both contribute to non-identification of vertebral fractures.The Royal Osteoporosis Society recommends that radiol-ogy services should establish local processes to ensure that the spine is routinely evaluated for the presence of vertebral fracture in all available imaging and that reports identifying vertebral fractures should be standardised, using the words‘vertebral fracture’, are actionable and indicate future man-agement[318];(Evidence level IV).

Primary care plays an important role in case finding for osteoporotic fractures, particularly vertebral frac-tures, as acute onset back pain, especially thoracic pain,is a common presenting complaint. Targeted use of spinal imaging can help increase case identification, appropri-ate symptom management, and prompt secondary frac-ture prevention.

Providing patient information and adherence support

Patients identified by any clinical service, to be in need of further intervention, should be offered an explanation of osteoporosis, the causes, consequences and how it can be managed with pharmacological and non-pharmacological interventions. When discussing pharmacological treatment,explanations should be offered for why drug treatment is recommended, the aims and benefits, common and/or severe side effects, the practicalities of taking the medicine and for how long it should be taken[319];(Evidence level IV).The use of decision aids in osteoporosis to support com-munication of medicine risk-benefit has been shown to improve shared decision making, reduce decisional conflict and improve the accuracy of patient perceived fracture risk[320];(Evidence level Ib). Information should be tailored to the needs of the patient to make it accessible and under-standable, including the provision of written information[321].

To promote treatment adherence, healthcare profession-als should elicit and address any beliefs and concerns asso-ciated with reduced adherence and establish realistic treat-ment expectations with the patient[319, 321]. No one type

119

Page 32 of 50

Archives of Osteoporosis (2025) 20:119

Archives of Osteoporosis

of intervention has been demonstrated to enhance medicines adherence in osteoporosis care, but multi-component models with active patient engagement have the most positive effects[322, 323]; (Evidence level Ia). FLS models with a greater number of patient interactions have demonstrated greater clinical effectiveness [316]; (Evidence level Ia). The NOGG supports the Royal Osteoporosis Society recommendation to follow up within 16 weeks and 52 weeks post-fracture, to review use of medications that increase the risk of falls and/or fracture, to ensure co-prescription of calcium and vitamin D with bone protective interventions where indicated, to review adverse effects and monitor adherence to therapy [313].

Recommendations for training

Recommendations

It is recommended that:

1.Training in personalised care, including shared decision making, is provided within all higher professional train-ing curricula in relevant medicine and surgical speciali-ties (Strong recommendation).

2.Training in osteoporosis and metabolic bone diseases is a clearly articulated component of each of the relevant medical and surgical specialities' higher professional training curricula set out by the applicable medical and surgical Royal Colleges (Strong recommendation).

3.Primary care physicians have sufficient training in this area with efficient access to up-to-date evidence-based resources and guidelines, and continual professional development(CPD) opportunities to maintain and refine knowledge(Strong recommendation).

4.The management of osteoporosis is a component of training in all relevant allied health disciplines (Strong recommendation).

5.Training should be provided to Fracture Liaison Service personnel to achieve high-quality DXA performance and reporting (Strong recommendation).

<BeginOfPara>6. Quality improvement training should be provided to healthcare personnel responsible for the delivery of Fracture Liaison and/or Osteoporosis Services(Strong recommendation).

<BeginOfPara>The management of osteoporosis and fragility fracture risk is not subserved by any one specialty. The relevant medical and surgical specialties include general prac-tice,rheumatology,orthopaedic surgery,endocrinology,metabolic medicine, renal medicine, geriatric medicine,and obstetrics and gynaecology. Furthermore, the care of

<EndOfPara>patients with osteoporosis is the responsibility of mul-tiple healthcare professionals, including nurses, physio-therapists, occupational therapists, pharmacists, and DXA operators. The multi-disciplinary nature of osteoporosis care offers opportunities for cross-speciality training. It is recognised that primary care is pivotal to the identification of the population at risk of fragility fractures as well as to the long-term management of patients with osteoporosis.It is important that primary care physicians have suffi-cient training in this area, with access to resources such as updated guidelines and online learning modules to refresh their knowledge.

Common to all healthcare roles is a need to provide per-sonalised patient-centred care, a key commitment outlined by the NHS to be achieved by 2023/24. Personalised care is a partnership approach that helps people make informed decisions and choices about their health and wellbeing,working alongside clinical information[Personalised Care Institute 2020]. There is significant variability in the access to and quality of DXA services for established FLS worldwide. Despite two decades of training initiatives in osteoporosis densitymetry, many centres are falling short of the standards of the IOF-ISCD Osteoporosis Essentials criteria[324].

Improving the quality of osteoporosis and fracture lia-son services is about making health care delivery safe,effective, patient-centred, timely, efficient, and equitable.Quality improvement involves the use of a systematic and coordinated approach to solving a problem using specific methods and tools with the aim of bringing about a measur-able improvement within a health care setting [325], and can be aided by the use of appropriate Toolkits (e.g. the Royal Osteoporosis Society Fracture Liaison Service Implementa-tion Toolkit).

Examples of appropriate training

i. Training in Personalised Care. Training in enhanced consultation skills including risk communication,shared decision making, applying principles of health literacy and how to communicate about osteoporosis is available at http://www.ifaprtraining.co.uk.The Personalised Care Institute is a virtual organisation,accountable for setting the standards for evidence-based training in personalised care in England. The Personalised Care Institute Curriculum sets out the standards for training programmes to become accred-ited with the Personalised Care Institute. The Person-alised Care Institute provides eLearning modules, for example, on Shared Decision Making. The curriculum is designed for health care personnel within primary

Archives of Osteoporosis

(2025) 20:119

Page 33 of 50 119

119

and secondary care and community teams https://www.personalisedcareinstance.org.uk.

Ⅱ. Training in Osteoporosis Management. The Royal Osteoporosis Society Fracture Prevention Practitioner Training is accredited for CPD by RCGP, RCP and RCN. The online training includes five foundation modules and then three advanced modules https://theros.org.uk/healthcare-professionals/courses-and-cpd/fracture-prevention-practitioner-training/. The Royal College of General Practice also provides a short e-Learning module on the diagnosis and man-agement of osteoporosis https://learning.rcg.org.uk/course/info.php?id=233. Evidenced-based resources to support osteoporosis care are available at www.erohub.co.uk.

iii.Training in Musculoskeletal Pain Management.The Health Education England e-Learning for Health-care Pain Management programme includes train-ing on musculoskeletal pain which encompasses the assessment and management of osteoporic vertebrael fractures https://www.e-lfh.org.uk/programmes/pain-management/.

iv. Training in DXA conduct. The Royal Osteoporosis Society runs a National Training Scheme for Bone Densitometry. This online course provides a founda-tion in osteoporosis and DXA. All ROS course infor-mation is available here https://theros.org.uk/healt hcare-professionals/courses-and-cpd/.

Recommendations for commissioners of healthcare

In 2017, the National Falls Prevention Coordination Group with Public Health England (PHE). Produced a falls and fracture consensus statement and resource pack with the aim of reducing falls and fracture risk and improving management of fractures, including second-ary prevention.

(https://www.gov.uk/government/publications/falls-and-fractures-consensus-statement). The guidance is aimed at local commissioning and strategic leads in Eng-land with a remit for falls, bone health and healthy ageing.Following this, NHS RightCare, working with PHE and the Royal Osteoporosis Society(ROS), developed a Falls and Fragility Fractures Pathway https://www.england.nhs.uk/rightcare/products/pathways/falls-and-fragility-fract ures-pathway/) which defines three priorities that commis-sioners responsible for falls and fragility fractures should optimise as a priority:(i) falls prevention,(ii) detecting and managing osteoporosis and(iii) optimal support after a fragility fracture. The ROS has developed an online Fracture Liaison Service Implementation Toolkit(https://

theros.org.uk/healthcare-professionals/fracture-liaison-services/implementation-toolkit/) designed to enable FLS Commissioning. In England, the move to Integrated Care Systems(ICS) provides an opportunity to embed enhanced pathways of care for patients at risk of fragility fracture,including imminent fracture risk[326], as part of rou-tine service delivery, for example enabling direct referrals between different secondary care services to streamline patient care pathways.

Where healthcare funding is not delivered through a com-missioning structure, the recommendations below apply to bodies providing healthcare funding and to local health boards. Thus, in Wales, these recommendations apply to the Welsh Government and to local health boards (that are funded directly from the Welsh Government) when setting their Integrated Medium-Term Plans (IMTPs). In Northern Ireland, health and social care are integrated and are the responsibility of the Department of Health. Health services are commissioned by the Health and Social Care Board (HSCB) through local commissioning groups from the five Health and Social Care Trusts. Thus, in Northern Ireland,these recommendations apply to the HSCB and to the five local commissioning groups.

Recommendations

Based upon the evidence presented in this guideline, the NOGG makes the following recommendations to service leaders and/or commissioners of healthcare who:

1.Should recognise that fractures due to osteoporosis are a significant and growing public health issue with consequent high health and social care costs and ensure that fragility fractures are addressed explicitly in their local healthcare programmes (Strong recom-mendation).

2.Should ensure that local healthcare programmes address approaches to reduce the prevalence of avoidable risk factors for osteoporosis and fractures related to falls and poor bone health and, in so doing, make explicit the roles of both the NHS and other agencies(Strong recom-mendation).

3.Should ensure electronic patient health record sys-tems have FRAX, and the link to the NOGG website,integrated to aid identification and treatment of those at risk of fragility fracture, and that electronic patient health record systems enable clear, and where pos-sible automated, electronic communication between FLS and primary care teams (Strong recommenda-tion).

4.Should put arrangements in place so that those at risk of osteoporotic fractures have the opportunity to receive appropriate investigation (e.g., fracture risk assessment,

119

Page 34 of 50

Archives of Osteoporosis(2025) 20:119

falls risk assessment, bone density measurement), life-style advice(e.g., about diet, exercise, and smoking) and bone protective drug therapy[NICE Quality Standards 149, 2017]. The latter includes the availability of par-enteral drug therapies in primary care and community healthcare settings(Strong recommendation).

5.Should ensure that accurate, up-to-date consistent information about pharmacological drug interventions is widely available to postmenopausal women and men aged $\geq 50$ years, their healthcare advocates and profes-sional advisers, so that patients can make informed deci-sions about treatment and treatment adherence (Strong recommendation).

6.Integrated Care Systems(ICS) should specifically address the burden of fragility fractures on the local economy and ensure that Fracture Liaison Services are available for all patients who sustain a fragility fracture(Strong recommendation).

7. ICS should bring together local specialists, generalists,and other stakeholders, including patient representatives,to agree local treatment practices and referral pathways for the management of osteoporosis and prevention of fragility fractures. It is often helpful to identify a lead clinician in both primary and secondary care. The rec-ommendations of this group should take account of local resources and relevant cost-effectiveness data.Local guidelines should be consistent with the evidence presented in this document. Once local guidelines have been agreed, they should be widely disseminated to relevant professionals and potential patients, and the necessary service changes made to allow the guidelines to be implemented. Implementation should be audited,and appropriate changes in practice should be instituted where standards are not met, with appropriate monitor-ing of compliance to guidelines thereafter(Strong rec-ommendation).

Review criteria for audit and quality improvement

Quality standards for osteoporosis

Osteoporosis Society in 2017(https://theros.org.uk/media/0dillsrh/ross-op-standards-november-2017.pdf)

3.The Royal Osteoporosis Society has produced five clini-cal quality toolkits: DXA quality,Hip fracture, Vertebral fracture, Fracture Liaisoni Service (FLS) implementa-tion, and virtual and telephone appointments(https://theros.org.uk/healthcare-professionals/clinical-quality-hub/clinical-quality-toolkits/).

Primary care

4.Documentation of the proportion of postmenopausal women and men age≥50 years registered with a general practice:

a) With a fracture code, who have been assessed to determine whether their fracture was a fragility(low-trauma) fracture.

b)With one or more risk factors for fragility fracture,who receive formal fracture risk assessment.

c)With a prior fragility fracture, who have had a DXA scan with the result recorded.

d)Calculated to be high or very high risk by FRAX assessment, who have been offered drug treatment.

e)With an incident hip fracture, those who receive pharmacological drug therapy for osteoporosis

f)Who are prescribed pharmacological drug therapy for osteoporosis and who have had confirmed adherence to osteoporosis therapy within the last 12 months.

g)Who are prescribed pharmacological drug therapy for osteoporosis and have had a 5-year and 10-year review.

h) Who are prescribed denosumab, who have received timely(within 4 weeks of due date) follow-up injec-tion.

i)Who are on oral glucocorticoids for≥3 months and have had a fracture risk assessment.

j) With documented discussion of fracture risk assess-ment and a treatment decision.

Fracture liaison services

5. The Royal Osteoporosis Society(ROS) published in 2019 six key standards for FLS with a corresponding timeline for the achievement of these six steps, with examples of audit and evidence[313]. This was fol-lowed by issuing the FLS Implementation Toolkit(https://theros.org.uk/healthcare-professionals/clini

Archives of Osteoporosis

(2025) 20:119

Page 35 of 50 119

119

cal-quality-hub/fracture-liaison-services/implementa-tion-toolkit/).

6.The Royal College of Physicians FLS Database National Audit (https://www.rcplondon.ac.uk/proje cts/fracture-liaison-service-database-fls-db) is com-missioned by the Healthcare Quality Improvement Partnership (HQIP) as part of the Falls and Fragility Fracture Audit Programme. The FLS-DB is included in the HQIP listing for national audits that must be reported in each English hospital trust's Quality Account and is required by the Welsh Government for all Health Boards in Wales. These form part of the National Clinical Audit Patient Outcomes Programme.All FLS sites that treat fractures are eligible to par-ticipate. The FLS-DB sets out 11 Key Performance Indicators (KPIs) which are designed to measure per-formance against technology assessments, guidance on osteoporosis and clinical standards for FLSs from the NICE, the ROS and NOGG.

<BeginOfPara>7.The International Osteoporosis Foundation (IOF) Cap-ture the Fracture Best Practice Framework outlines 13 standards for FLS delivery with criteria and targets spec-ified for bronze, silver, or gold levels of achievement(https://www.capturethetracture.org/best-practice-frame work).

DXA reporting

8.The ROS published in 2019 six quality standards for DXA reporting with a corresponding audit template[51].

Summary of main recommendations

This guideline summary addresses the assessment, diag-nosis, and current treatments for osteoporosis, including recommendations to prevent fragility fractures. It applies to postmenopausal women and to men aged 50 years or older.

Concerning assessment of fracture risk in postmenopausal women, and men age $\geq$ 50 years:

1.Conduct a FRAX assessment in people with a clinical risk factor for fragility fracture.

2.Measure BMD in people with intermediate fracture risk by FRAX(amber) to refine the estimate of 10-year risk.

3.Measure BMD in people with high and very high frac-ture risk by FRAX (red) to guide drug choice and pro-vide a baseline for BMD monitoring.

4.Consider imaging to look for a vertebral fracture in people with acute onset back pain who have risk factors for osteoporosis, and/or in people with a his-tory of≥4cm height loss, kyphosis, recent or cur-rent long-term oral glucocorticoid therapy, or a BMD T-score $\leq$ -2.5.

5.Assess falls risk in patients with osteoporosis and/or fra-gility fractures and offer those at risk an exercise pro-gramme to improve balance and muscle strength.

Regarding drug treatment to prevent fractures in postmenopausal women, and men age $\geq 50$ years:

6. Offer drug treatment to people at high and very high risk of fracture.

7.If BMD measurement is not practical (e.g. due to frailty), use the online NOGG intervention thresholds based on FRAX, to guide treatment decisions.

8.Consider, particularly in older people, drug treatment in those with a prior and/or recent fragility fracture.

When selecting drug treatments to prevent fractures in postmenopausal women, and men age $\geq 50$ years:

9. Consider the level of fracture risk, any additional clini-cal risk factors, patient choice, and the cost-effective-ness of treatment when deciding on a particular drug treatment.

10. Start treatment promptly following a fragility fracture,because the risk of re-fracture is highest immediately after a fracture and the risk remains elevated.

11.Consider referral of very high-risk patients to an oste-oporosis specialist in secondary care for assessment and consideration of parenteral treatment(some may need first-line anabolic drug treatment, especially if multiple vertebral fractures). Indications of very high risk include the presence of important risk factors,including a recent vertebral fracture(within the last 2 years), $\geq 2$ vertebral fractures (whenever they have occurred), BMD T-score $\leq-3.5$ , treatment with high-dose glucocorticoids ( $\geq 7.5 mg$ /day of prednisolone or equivalent over 3 months); the presence of multiple clinical risk factors, particularly with a recent fragility fracture indicating high imminent risk of re-fracture;or other indicators of very high fracture risk, including as defined by FRAX.

12.In other patients for whom treatment is indicated, offer antiresorptive therapy with oral bisphosphonates(alen-dronate or risedronate) or intravenous zoledronate, or in postmenopausal women age $\leq$ 60 years, hormone replacement therapy.

119

Page 36 of 50

Archives of Osteoporosis (2025) 20:119

(2025) 20:119

13.Consider alternative treatment options if first-line bisphosphonates are unsuitable or not tolerated; deno-sumab, ibandronate, raloxifene, strontium ranelate,teriparatide, abaloparatide, or romozozumab.

14.Following treatment with an anabolic agent (teri-paratide, abaloparatide or romozosumab), start alen-dronate, zoledronate, or denosumab without delay.

When postmenopausal women, and men age≥50 years, have started drug treatment:

<BeginOfPara>15. Regularly review patients‘tolerance of, and adherence to, oral drug treatments.

16. Remember long-term treatment is often required because osteoporosis is a long-term condition for which there is currently no cure.

17. Plans to prescribe oral bisphosphonates for at least 5 years, or intravenous bisphosphonates for at least 3 years and then re-assess fracture risk. Longer durations of treatment will be needed in those who are older (age ≥ 70 years), have had a hip or verte-brl fracture, are on high-dose oral glucocorticoids(≥ 7.5 mg/day of prednisolone or equivalent over 3 months), or have a further fragility fracture dur-ing osteoporosis treatment. In lower risk patients, a temporary treatment pause of 18 to 36 months can be considered after 5 years' oral bisphosphonate or 3 years' intravenous bisphosphonate (see clinical flowcharts on p.50 and p.51).

18.Before starting denosumab, ensure the long-term treat-ment plan considers the potential need to stop deno-sumab and how this would be managed.

19.Do not stop denosumab treatment without a plan for subsequent anti-resorptive therapy, where renal func-tion permits.

20.Repeat fracture risk assessment after any new fracture,regardless of when this occurs.

21.Reassess fracture risk 18 months to 3 years after paus-ing drug treatment.

When postmenopausal women, and men age≥50 years, are treated with oral glucocorticoids:

<BeginOfPara>22. If starting $\geq$ 7.5 mg/day prednisolone or equivalent for the next 3 months, start bone protective treatment at the same time(without waiting for a DXA scan, which can follow later).

<EndOfPara>23. Offer antiresorptive therapy with oral bisphospho-nates (alendronate or risedronate) or intravenous zoledronate, and in those at very high risk of ver-tebral fracture, refer for consideration of anabolic therapy.

24.Consider denosumab as an alternative treatment option.

When advising on lifestyle and dietary measures:

25. Recommend a healthy, balanced diet, moderation of alcohol consumption and avoidance of smoking.

26. Ensure a sufficient dietary calcium and vitamin D intake and supplement these as necessary.

27. Encourage a combination of regular weight-bearing and muscle strengthening exercise.

Regarding fracture prevention services:

28. Patients who sustain a fragility fracture should have access to a multidisciplinary, coordinator-based Frac-ture Liaison Service(FLS) which enables timely frac-ture and falls risk assessment, investigation,treatment,and monitoring.

29.Ensure that diagnostic imaging services routinely evaluate the spine in all imaging of postmenopausal women and men aged $\geq$ 50 years in which the spine is visualised and report vertebral fractures using stand-ardised methods.

When a postmenopausal woman, or a man age≥50 years has a symptomatic osteoporotic vertebral fracture:

30. Consider referral to an exercise programme which provides progressive muscle strengthening activity,including back extensor muscle strengthening and/or endurance exercise.

31.Investigate for underlying causes of fragility fracture.

32.Start treatment promptly to reduce the risk of further fractures.

The evidence presented in this guideline underpins a further series of recommendations made for leaders and commissioners of healthcare services, as well as criteria for audit and quality improvement in primary and secondary care settings.

Archives of Osteoporosis

(2025) 20:119

Page 37 of 50 119

119

Appendix 1

List of stakeholders from 2021

Association for Clinical Biochemistry and Laboratory Medicine.

Bone Research Society.

British Geriatrics Society.

British Orthopaedic Association.

British Orthopaedic Research Society.

British Menopause Society.

British Society for Rheumatology.

European Calcified Tissues Society.

European Society for Clinical and Economic Aspects of

Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.

International Osteoporosis Foundation.

Osteoporosis 2000.

Osteoporosis Dorset.

Primary Care Rheumatology and Musculoskeletal Medi-cine Society.

Royal College of Physicians.

Royal Osteoporosis Society.

Royal Pharmaceutical Society.

Society for Endocrinology.

The Nutrition Society.

Appendix 2 Grading of evidence

Levels of evidence for studies of intervention

la From systematic review and meta-analysis of ran-domised controlled trials (RCTs).

<BeginOfPara>Ib Individual RCT(s)(with narrow confidence intervals).

Ⅱa Systematic review of at least one non-randomised controlled trial or well-designed cohort study.

IIb Individual cohort study or low quality RCTs.

Ⅲa Systematic review of at least one case-controlled study.

ⅢIb Individual case-control study.

Ⅳ Expert committee reports or opinions and/or clini-cal experience of authorities, case series(and poor-quality cohort and case-control studies).

Levels of evidence for validity of candidate risk factors

Ia Systematic reviews or meta-analysis of level I studies with a high degree of homogeneity.

<BeginOfPara>Ib Systematic reviews or meta-analysis with moderate or poor homogeneity.

<BeginOfPara>Ic Level I studies(with appropriate populations and inter-nal controls.

Ⅱa Systematic reviews or meta-analysis of level II studies.

Ⅱb Level II studies (in appropriate population or lacking an internal control).

Ⅲa Systematic reviews or meta-analysis of level III studies.

Ⅲb Case-control studies.

IV Evidence from expert committees without explicit critical scientific analysis or that based on physiology, basic research or first principles.

Of note,FRAX risk factors are all grade A or B according to evidence for reversibility of risk[75]

Grading of recommendations

Recommendations follow the Grading of Recommenda-tions Assessment, Development, and Evaluation GRADE binary classification of recommendations as either strong or conditional (also known as discretionary or qualified recom-mendations) [327]. Recommendations have been made after assessment of [328]:

1.The balance between desirable and undesirable effects-The larger the difference between the desirable and undesirable effects, the more likely a strong recommen-dation is warranted.

2.The quality of evidence - the higher the quality of evi-dence, the more likely a strong recommendation is war-ranted.

3.Values and preferences - the more variability/uncertainty in values and preferences, the more likely a conditional recommendation is warranted.

4. Costs(resource allocation) - the higher the costs of an intervention (i.e., the more resources consumed), the more likely a conditional recommendation is war-ranted.

For example, a strong recommendation applies where the clinician considers that most people ought to receive the intervention, or where adherence to the recommenda-tion could be used as a performance or quality indicator and that deviation from this recommendation would prompt documentation of a clinician's rationale. NICE suggests using‘offer’(or similar action wording such as ‘measure’‘advise’，‘commission’ or ‘refer’) when describing a strong recommendation [329].

A conditional recommendation applies where the clini-cian examines the evidence and prepares to discuss this with a patient together with the patient's values and pref-erences, or where documentation of the discussion of the pros and cons of an intervention is the indicator of quality,rather than the course of action itself. NICE suggests using wording such as‘consider’ when describing conditional rec-ommendations. Where insufficient evidence is available or the evidence available is lacking or equivocal, recommendations are not made.

119 Page 38 of 50

Archives of Osteoporosis(2025) 20:119

Appendix 3

Table 8 The quality of systematic reviews and meta-analyses used in the formulation of 2021 recommendations was assessed using AMSTAR 2(https://amstar.ca/Amstar-2.php).

|Topic|Reference|Type of study|AMSTAR2 grading|Reference| |---|---|---|---|---| |Fracture risk assessment and case finding|Bai et al 2020|MA|Low|[71]| |Fracture risk assessment and case finding|Gausden et al 2017|SR|Medium|[106]| |Fracture risk assessment and case finding|Johannesdottir et al 2018|SR|Low|[54]| |Fracture risk assessment and case finding|Kanis et al 2016|SR|Medium|[90]| |Fracture risk assessment and case finding|Marshall et al 1996|MA|Critically Low|[40]| |Fracture risk assessment and case finding|Merlijn et al 2019|SR& MA|Critically Low|[113]| |Fracture risk assessment and case finding|Mortensen et al 2020|SR& MA|Medium|[77]| |Fracture risk assessment and case finding|Singh-Ospina et al 2017|SR& MA|Low|[84]| |Fracture risk assessment and case finding|Vilaca et al 2020|SR& MA|Low|[70]| |Fracture risk assessment and case finding|Zhang et al 2020|SR& MA|Low|[115]| |Fracture risk assessment and case finding|Kanis et al 2016|SR|Medium|[90]| |Fracture risk assessment and case finding|Non-pharmacological management of osteoporosis|Babatunde et al 2020|SR& MA|Medium| |Fracture risk assessment and case finding|Pharmacological treatment options|El-Khoury et al 2013|SR& MA|Medium| |Fracture risk assessment and case finding|Pharmacological treatment options|Darling et al 2019|SR& MA|Medium| |Fracture risk assessment and case finding|Pharmacological treatment options|Fabiani et al 2019|SR& MA|Medium| |Fracture risk assessment and case finding|Pharmacological treatment options|Gillespie et al 2012|SR& MA|High| |Fracture risk assessment and case finding|Pharmacological treatment options|Groenendijk et al 2019|SR& MA|Medium| |Fracture risk assessment and case finding|Pharmacological treatment options|Iguacel et al 2018|SR& MA|High| |Fracture risk assessment and case finding|Pharmacological treatment options|Howe et al 2011|SR& MA|High| |Fracture risk assessment and case finding|Pharmacological treatment options|Jepsen et al 2017|SR& MA|Medium| |Fracture risk assessment and case finding|Pharmacological treatment options|Kahwati et al 2018|SR& MA|Medium| |Kelley et al 2000|Pharmacological treatment options|SR& MA|Medium|[170]| |Kemmler et al 2020|Pharmacological treatment options|SR& MA|Low|[168]| |Kuntors et al 2018|Pharmacological treatment options|SR& MA|Medium|[172]| |Min et al 2017|Pharmacological treatment options|SR& MA|Low|[183]| |Shen et al 2015|Pharmacological treatment options|SR& MA|Medium|[182]| |Sherrington et al 2017|Pharmacological treatment options|SR& MA|Low|[178]| |Sherrington et al 2019|Pharmacological treatment options|SR& MA|High|[176]| |Yao et al 2019|Pharmacological treatment options|SR& MA|Medium|[160]| |Zhao et al 2019|Pharmacological treatment options|SR& MA|Low|[177]| |Beaudart et al 2025|Pharmacological treatment options|SR& MA|Critically Low|[188,241]| |Diez-Perez et al 2019|SR& MA|Medium|[241]|| |Gartlehner et al 2017|SR& MA|Medium|[330]|| |Nayak et al 2017|SR& MA|Low|[331]|| |Poon et al 2018|SR& MA|Low|[290]|| |Simpson et al 2020|SR& MA|Medium|[242]|| |Zeng et al 2019|SR& MA|Medium|[332]|| |Deng et al 2020|SR& MA|Low|[283]|| |Dennison et al 2019|SR|Medium|[215]|| |Gedmintas et al 2013|SR& MA|Medium|[276]|| |Khan et al 2015|SR|Medium|[269]|| |Miyashita et al 2020|SR& MA|Low|[295]|| |Nayak et al 2019|SR& MA|High|[258]|| |Tsourdi et al 2020|SR|Medium|[213]|| |Wang et al 2018|SR& MA|Critically Low|[333]|| |Yanbeiy et al 2019|SR& MA|Low|[334]||

Archives of Osteoporosis(2025) 20:119

Page 39 of 50119

Table 8(continued)

|Topic|Reference|Type of study|AMSTAR2 grading|Reference| |---|---|---|---|---| |Management of symptomatic osteoporotic vertebral fractures|Al-Sari et al 2016|SR& MA|Low|[14]| |Models of care for fracture prevention|British Geriatric Society 2013|SR|Medium|[298]| |Models of care for fracture prevention|Buchbinder et al 2018|SR& MA|High|[306]| |Models of care for fracture prevention|Ebeling et al 2019|SR& MA|Critically Low|[303]| |Models of care for fracture prevention|Gibbs et al 2019|SR|Medium|[302]| |Models of care for fracture prevention|Hofler et al 2020|SR|Low|[305]| |Models of care for fracture prevention|Knopp-Sihota et al 2012|SR& MA|Medium|[299]| |Models of care for fracture prevention|Svensson et al 2017|SR|Low|[304]| |Ganda et al 2013|SR& MA|Critically Low|[314]|| |Ganda et al 2019|SR& MA|Low|[315]|| |Martin et al 2020|SR& MA|Medium|[323]|| |Paskins et al 2020|SR|Medium|[335]|| |Wu et al 2018|SR|Critically Low|[309]|| |Wu et al 2018|SR& MA|Low|[316]||

SR, Systematic Review. MA, Meta-analysis

Acknowledgements The NOGG is grateful to the stakeholders and the Committee of Scientific Advisors of the International Osteoporino-sis Foundation and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases(ESCEO) for their endorsement of this manuscript.

Declarations

Conflict of interest The National Osteoporosis Guideline Group(NOGG) Guideline Writing Group is divided into two groups, a Guideline Development Group(GDG) and an Expert Advisory Group(EAG). The GDG consists of eight voting members(CLG,JC, JE, JK, RL, SL, ZP, ZP, JT), and three lay members(JB, JP, NV).One member has a financial disclosure, unrelated to drug develop-ment(CJ received honoraria for speaking at a CME approved bone academy meeting and for consultancy relating to the characterisa-tion of people at very high fracture risk), and the remaining ten have no financial disclosures. ZP is funded by the National Institute for Health Research(NHR)(Clinician Scientist Award(CS-2018-18-ST2-010)/NIHR Academy). ZP has undertaken consultancy for non-promotional activities for UCB. One member(JK) is also a member of the FRAX group; hence, all FRAX-based recommendations had to be agreed by consensus of all the GDG. The Chair(CLG) has no dis-closures; she is funded by the National Institute for Health and Care Research(NHR302394). The EAG is composed of nine members;all of whom have relevant conflicts of interest. DA has received advi-sory/speaking fees from UCB and Internis Pharma. CC has received advisory/speaking fees from Amgen, Danone, Eli Lilly, GKyowa Kirin, Medtronic, Merck, Nestle, Novartis, Pfizer, Roche, Servier,Shire, Takeda and UCB. NG is on the advisory board of UCB, Novo Nordisk, and Shire/Takeda and has received fees from UCB and Takeda. NCH has received advisory board/consultancy fees/hono-raria from Alliance for Better Bone Health, A mgen, MSD, EliLilly,UCB, Radius, Servier, Shire, Consilient Healthcare and Internis Pharma. EMC has received advisory/honoraria from A mgen, Con-silient Healthcare, Kyowa Kirin, Elially, Fresenius Kabi, Internis,Obseva, Radius Inc and Redx Pharma and received research fund-ing from A mgen, Internis, and Radius Inc. KM has received con-

ference sponsorship from Abbvie, Alexion, UCB, Novartis, Kyowa Kirin, Lilly, Pfizer and Internis and advisory/honoraria from Alexion and UCB.KP received advisory/speaker fees from UCB, which were then donated to charities. DR has received advisory fees from UCB, Theramex and Osteolabs. MS has received advisory/speaker fees from UCB, and speaker fees from A mgen and Gedeon Richter. All members of the GDG and EAG have read NICE's‘Policy on declar-ing and managing interests for NICE advisory boards’(version 1.1, July 2019). Disclosures of all members of both groups are available on the NOGG website. Both the GDG and the EAG attend online meetings and take part in email discussions. However, voting on the recommendations is restricted to the GDG. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

References

1. Compston J, Cooper A, Cooper C, Francis R, Kanis JA, Marsh D, McCloskey EV, Reid DM, Selby P, Wilkins M(2009) Guide-lines for the diagnosis and management of osteoporosis in post-menopausal women and men from the age of 50 years in the UK.Maturitas 62:105-108

119 Page 40 of 50

Archives of Osteoporosis(2025) 20:119

2. Compston J, Bowring C, Cooper A et al(2013) Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National osteoporosis guideline group(NOGG) update 2013. Maturitas 75:392-396

3. Compston J, Cooper A, Cooper C et al(2017) UK clinical guide-line for the prevention and treatment of osteoporosis. Arch Osopeos 12:43

4.Gregson CL, Armstrong DJ, Bowden J et al(2022) UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 17:58

5. Harvey NC, McCloskey E, Kanis JA, Compston J, Cooper C(2018) Cost-effective but clinically inappropriate: new NICE intervention thresholds in osteoporosis(technology appraisal 464). Osteoporos Int 29:1511-1513

6. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khal-tae V N(1994) The diagnosis of osteoporosis. J Bone Miner Res 9:1137-1141

7. van Staa TP, Dennison EM, Leufkens HG, Cooper C(2001) Epi-demiology of fractures in England and Wales. Bone 29:517-522

8. Borgstrom F, Karlsson L, Ortsater G et al(2020) Fragility frac-tures in Europe: burden, management and opportunities. Arch Osteoporos 15:59

9. Wainwright SA, Marshall LM, Ensrud KE, Cauley JA, Black DM, Hillier TA, Hochberg MC, Vott Orw, Wolf ES, for the Study of Osteoporotic Fractures Research G(2005) Hip frac-ture in women without osteoporosis. J Clin Endocrinol Metabol 90:2787-2793

10.Schuit SCE, van der Klift M, Weel AEAM, de Laet CEDH,Burger He, Seman E, Hofman A, Uitterlinden AG, van Leeuwen JPTM, Pols HAP(2004) Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study. Bone 34:195-202

11. Kanis JA, Odén A, Johnell O, Johansson H, De Laet C, Brown J,Burckhardt P, Cooper C, Christiansen C., Cummings S, Eisman JA, Fujiwara S, Gliuer C, Goltzman D, Hans D, Krieg MA, La Croix A, McCloskey E, Mellstrom D, Melton 3rd LJ, Pols H, Reeve J,Sanders K, Schott AM, Silman A, Torgerson D, Staa T van, Watts NB, Yoshimura N(2007) The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 18:1033-1046

12. Royal College of Physicians (2019) National hip fracture data-base annual report. https://www.nhf.dco.uk/files/2019Report Files/NHFD_2019_Annual_Report_v101.pdf

13. NHS National Services Scotland(2019) Scottish hip fracture audit. Hip fracture care pathway report 2019. https://www.shfa.scot.nhs.uk/Reports/_docs/2019-08-20-SHFA-Report.pdf

14. Al-Sari UA, Tobias J, Clark E(2016) Health-related quality of life in older people with osteoporotic vertebral fractures: a sys-tematic review and meta-analysis. Osteoporos Int.27:2891-2900

15.Griffin XL, Parsons N, Achten J, Fernandez M, Costa ML(2015)Recovery of health-related quality of life in a United Kingdom hip fracture population. The warwick hip trauma evaluation-a prospective cohort study. Bone Joint 197 b:372-382

16.Leal J, Gray AM, Prieto-Alhambra, Dren NK, Cooper C,Javidak MK, Judge A(2016) Impact of hip fracture on hospital care costs: a population-based study. Osteoporos Int 27:549-558

17.Kanis JA,Norton N, Harvey NC,Jacobson T, Johansson H, Lor-enton M,Cmloskey EV,Willers C,F B(2021)SCOPE2021:a new scorecard for osteoporosis in Europe. Arch Osteoporos doi.org/https://doi.org/10.1007/s11657-020-00871-9:

18. Royal College of Physicians(2018) National hip fracture data-base annual report.https://www.nhf.dco.uk/files/2018Report Files/NHFD-2018-Annual-Report-v101.pdf

19. Royal College of Physicians(2021) The challenge of the next decade: are hip fracture services ready? A review of data from

the national hip fracture database(January-December 2019).RCP,London

20. Hawley S, Javaid MK, Prieto-Alhambra D, Lippett J, Sheard S,Arden NK, Cooper C, Judge A(2016) Clinical effectiveness of orthogeriatric and fracture liaison service models of care for hip fracture patients: population-based longitudinal study. Age Ageing 45:236-242

21. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA,Center JR(2009) Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women.JAMA 301:513-521

22. Johnell O,Kanis JA, Odén A, Sernbo I, Redlund-Johnell I, Pet-terson C, De Laet C, Jonsson B(2004) Mortality after osteo-porotic fractures. Osteoporos Int 15:38-42

23. Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B, Oglesby AK(2003) The components of excess mortality after hip frac-ture. Bone 32:468-473

24. Bhimjianyani A, Neuberr J, Jones T, Ben-Shlomo Y, Gregson CL(2018) The effect of social deprivation on hip fracture inci-dence in England has not changed over 14 years: an analysis of the English hospital episodes statistics(2001-2015). Osteo-poros Int 29:115-124

25. Bhimijaniy A, Neuburger J, Jones T, Ben-Shlomo Y, Gregson CL(2018) Inequalities in hip fracture incidence are greatest in the north of England: regional analysis of the effects of social deprivation on hip fracture incidence across England. Public Health 162:25-31

26. Curtis EM, van der Velde R, Moon RJ, van den Bergh JP,Geusens P, de Vries F, van Staa TP, Cooper C, Harvey NC(2016) Epidemiology of fractures in the United Kingdom 1988-2012: variation with age, sex, geography, ethnicity and socioeconomic status. Bone 87:19-26

27. van der Velde RY, Wyers CE, Curtis EM, Geusens PPMM, van den Bergh JPw, de Vries F, Cooper C, van Staa TP, Harvey NC(2016) Secular trends in fracture incidence in the UK between 1990 and 2012. Osteoporos Int 27:3197-3206

28. Kanis JA, Johansson H, Oden A, McCloskey EV(2011) Guid-ance for the adjustment of FRAX according to the dose of glucocorticoids. Osteoporos Int 22:809-816

29. Leslie WD, Morin S, Lix LM, Johansson H, Oden A, McCloskey E,Kanis JA(2012) Fracture risk assessment without bone density measurement in routine clinical practice. Osteoporos Int 23:75-85

30. Johansson H, Kanis JA, Oden A et al(2014) Impact of femoral neck and lumbar spine BMD discordances on FRAX probabili-ties in women: a meta-analysis of international cohorts. Calcified Tiss Inter 95:428-435

31. McCloskey EV,Oden A, Harvey NC et al(2016) A meta-analysis of trabecular bone score in fracture risk prediction and its rela-tionship to FRAX.J Bone Mineral Res 31:940-948

32.Leslie WD,Lix LM,Morin SN,Johansson H,Oden A,Cclo-Hskey EV,Kanis JA(2016) Adjusting hip fracture probability in men and women using hip axis length: the Manitoba bone density database.J Clin Dentons 19:326-331

33. Masud T, Binkley N, Boonen S, Hannan MT(2011) Official positions for FRAX® clinical regarding falls and frailty: can falls and frailty be used in FRAX? From joint official positions development conference of the International Society for Clini-cal Densitometry and International Osteoporosis Foundation on FRAX®. J Clin Densitom 14:194-204

34. Vandenput L, Johansson H, McCloskey EV et al(2024) A meta-analysis of previous falls and subsequent fracture risk in cohort studies. Osteoporos Int 35:469-494

35. Johansson H, Odén A, Lorentzon M, McCloskey E, Kanis JA,Harvey NC, Karlsson MK, Mellstrom D(2015) Is the Swedish FRAX model appropriate for Swedish immigrants? Osteoporos Int.26:2617-2622

Archives of Osteoporosis(2025) 20:119

Page 41 of 50 119

119

36. Wandell P, Li X, Carlsson AC, Sundquist J, Sundquist K(2021)Osteoporotic fractures among foreign-born individuals: a national Swedish study. Osteoporos Int 32:343-352

37.Leslie WD, Johansson H, McCloskey EV, Harvey NC, Kanis JA,Hans D(2018) Comparison of methods for improving fracture risk assessment in diabetes: the Manitoba BMD registry. J Bone Miner Res 33:1923-1930

38. Schini M, Bhatia P, Shreef H, Johansson H, Harvey NC, Lorent-zon M, Kanis JA, Bandmann O, McCloskey EV(2023) Increased fracture risk in Parkinson's disease- an exploration of mecha-nisms and consequences for fracture prediction with FRAX.Bone 168:116651

39.Kanis JA, Johansson H, Harvey NC, Gudnason V, Sigurdsson G,Siggeirscotir, K Lorentzom M, Liu E, Vandenupl L, McCloskey EV(2020) Adjusting conventional FRAX estimates of fracture probability according to the recence of retinetic of neutrals. Osteo poros Int 31:1817-1828

40.Adams AL,Fischer H,Kopperdahl DL et al(2018) Osteoporosis and hip fracture risk from routine computed tomography scans:the fracture, osteoporosis, and CT utilization study(FOCUS). J Bone Miner Res 33:1291-1301

41. Johannesdottir F, Allaire B, Bouxsein ML(2018) Fracture prediction by computed tomography and finite element anal-ysis: current and future perspectives. Curr Osteoporos Rep 16:411-422

42.Pickhardt PJ, Bodené G, Brett A, Brown JK, Binkley N(2015)Comparison of femoral neck BMD evaluation obtained using Lunar DXA and QCT with asynchronous calibration from CT colonography. J Clin Densitom 18:5-12

43. Cann CE, Adams JE, Brown JK, Brett AD(2014) CTXA hip-an extension of classical DXA measurements using quantitative CT.

44.Ziemlewicz TJ, Maciejewski A, Binkley N, Brett AD, Brown JK,Pickardt P(2016) Opportunistic quantitative CT bone min-eral density measurement at the proximal femur using routine contrast-enhanced scans: direct comparison with DXA in 355 adults.J Bone Miner Res 31:1835-1840

45. Lenchik L, Weaver AA, Ward RJ, Boone JM, Boutin RD(2018)Opportunistic screening for osteoporosis using computed tomog-raphy: state of the art and argument for paradigm shift. Curr Rheumatol Rep 20:74

46.Kanis JA, on behalf of the WHO Scientific Group(2007) Assess-ment of osteoporosis at the primary health-care level. Technical report. WHO Collaborating Centre, University of Sheffield, UK,Sheffield 2008

47.Laet C,Kanis J,Oden A et al(2005) Body mass index as a predictor of fracture risk: a meta-analysis. Osteoposor Int 16:1330-1338

48.Leslie WD, Schousboe JT, Morin SN, Martinez Pau L, Lmp,Johansson H, McCloskey EV, Harvey NC, Kanis JA(2020)Fracture risk following high-trauma versus low-trauma fracture: a registry-based cohort study. Osteoporos Int 31:1059-1067

49. Kanis JA, Johnell O, De Laet C et al(2004) A meta-analysis of previous fracture and subsequent fracture risk. Bone 35:375-382

50. Johansson H, Oden A, McCloskey EV, Kanis JA(2014) Mild morphometric vertebral fractures predict vertebral fractures but not non-vertebral fractures. Osteoporos Int 25:235-241

51. Kanis JA, Johansson H, Odén A et al(2018) Characteristics of recurrent fractures. Osteoporos Int 29:1747-1757

52. Excellence. NiHfac 2019 (NICE guideline [NG132]: hyperpar-athyroidism (primary): diagnosis, assessment and initial manage-ment. https://www.nice.org.uk/guidance/ng132/chapter/Recom mendations#diagnostic-testing-in-primary-care

53.Kanis JA, Johansson H, Oden A et al(2004) A family history of fracture and fracture risk: a meta-analysis. Bone 35:1029-1037

54.Kanis JA, Johnell O, Oden A et al(2005) Smoking and fracture risk: a meta-analysis. Osteoporos Int 16(2):155-162

55. van Staaa TP, Leufens HG, Abenhaim L, Zhang B, Cooper C(2000) Oral corticosteroids and fracture risk: relationship to daily and cumulative dose. Rheumatology(Oxford) 39:1383-1389

56.Kanis JA, Johansson H, Oden A et al(2004) A meta-analysis of prior corticosteroid use and fracture risk. J Bone Mineral Research 19:893-899

57. Kanis JA, Johansson H, Johnell O, Oden A, De Laet C, Eisman JA, Pols H, Tenenhouse A(2005) Alcohol intake as a risk factor for fracture. Osteoporos Int 16:737-742

58.Vilaca T, Schini M, Harman S, Sutton A, Poku E, Allen IE, Cum-tings SR, Eastell R(2020) The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: a systematic review and meta-analysis update. Bone 137:115457

59. Bai J, Gao Q, Wang C, Dai J(2020) Diabetes mellitus and risk of low-energy fracture: a meta-analysis. Aging Clin Exp Res 32:2173-2186

60.Leslie WD, Rubin MR, Schwartz AV, Kanis JA(2012) Type 2 diabetes and bone. J Bone Miner Res 27(11):2231-7.https://doi.org/10.1002/jbm.1759

61.Giangregorio L.M.Leslie WD, Lix LM, Johansson H, Oden A,McCloskey E, Kanis JA(2012) FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res 27:301-308

62. Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E(2009)BMD, clinical risk factors and their combination for hip fracture prevention. Osteoporos Int 20:1675-1682

63. Kanis JA, McCloskey E, Johansson H, Oden A, Leslie WD(2012) FRAX(8) with and without bone mineral density. Calcif Tissue Int 90:1-13

64.McClung MR, Geousens P, Miller PD, Hip intervention program study group at 1(2001) Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344:333-340

65.Mortensen SJ,Mohamadi A,Wright CL,Chan JJ,Weaver MJ,von Keudell A,Nazarian A(2020) Medications as a risk factor for fragility hip fractures: a systematic review and meta-analysis.Calcif Tissue Int 107:1-9

66. Vestergaard P, Rejunmark L, Mosekilde L (2007) Fracture risk associated with parkinsonism and anti-Parkinson drugs. Calcif Tissue Int 81:153-161

67. Arbouw ME, Movig KL, van Staa TP, Egberts AC, Souverein PC, de Vries F(2011) Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study. Osteo-poros into 22:2197-2204

68. Lee YK, Lee EG, Kim HY, Lee Y, Lee SM, Suh DC, Yoo JI,Lee S(2020) Osteoporotic fractures of the spine, hip, and other locations after adjuvant endocrine therapy with aromatase inhibi-tors in breast cancer patients: a meta-analysis. J Korean Med Sci 35:e403

69.Myint ZW,Momo HD,Otto DE,Yan D,Wang P,Kolesar JM(2020) Evaluation of fall and fracture risk among men with prostate cancer treated with androgen receptor inhibitors:a systematic review and meta-analysis. JAMA Netw Open 3:e2025826

70.Cosman F,Cauley J,Aestell R,Boonen S,Palermo L,Reid IR,Cummings SR, Black DM(2014) Reassessment of fracture risk in women after 3 years of treatment with zoledronic acid: when is it reasonable to continue treatment? J Clin Endocrinol Metab 99:4546-4554

71.Palermo A,D'Onofrio L,Eastell R,Schwartz AV,Pozilli P,Napoli N(2015) Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int 26:2073-2089

72.Singh-Ospina N, Maraka S, Rodriguez-Gutierrez R, Davidge-Pitts C, Nippold B, Prokop LJ, Murad MH(2017) Effect of sex steroids on the bone health of transgender individuals: a

119 Page 42 of 50

Archives of Osteoporosis(2025) 20:119

systematic review and meta-analysis. J Clin Endocrinol Metab 102:3904-3913

73. Diez-Perez A, Adachi JD, Agnusdei D et al(2012) Treatment failure in osteoporosis. Osteoporosis Int 23:2769-2774

74. Lorentzon M, Branco J, Brandi ML et al(2019) Algorithm for the use of biochemical markers of bone turnover in the diagno-sis, assessment and follow-up of treatment for osteoporosis. Adv Ther 36:2811-2824

75. Johansson H, Oden A, Kanis JA, McCloskey EV, Morris HA,Cooper C, Vasikaran S(2014) A meta-analysis of reference markers of bone turnover for prediction of fracture. Calcif Tis-sue Int 94:560-567

76. Kanis JA, Johansson H, Harvey NC et al(2021) The use of 2-,5-, and 10-year probabilities to characterize fracture risk after a recent sentinel fracture. Osteoporos Int 32:47-54

77. McCloskey EV, Borgstrm F, Cooper C, Harvey NC, Javaid MK,Lorentzon M, Kanis JA(2021) Short time horizons for fracture prediction tools: time for a rethink. Osteoporosis Int 32(6):1019-1025.https://doi.org/10.1007/s00198-021-05962-y

78. Kanis JA, Harvey NC, Cooper C, Johansson H, Odén A, McClo-skey EV(2016) A systematic review of intervention thresholds based on FRAX: a report prepared for the National Osteoporosis Guideline Group and the International Osteoporosis Foundation.Arch Osteoporos 11:25

79. Hippisley-Cox J, Coupland C(2009) Predicting risk of osteo-porotic fracture in men and women in England and Wales: pro-spective derivation and validation of QFractureScores. BMJ.https://doi.org/10.1136/bmj.b4229

80. National Institute for Health and Care Excellence(2012) Osteo-porosis: assessing the risk of fragility fracture. NICE clinical guideline[CG14]. Manchester. NICE.http://www.nice.org.uk/guidance/cg146

81. National Institute for Health and Care Excellence(NICE)(2017) Osteoporosis: quality standard[QS149]. Manchester,NICE.https://www.nice.org.uk/guidance/qs149

82.De Laet CE, Van Hout BA, Burger B, Weel AE, Hofman A,Pols HA(1998) Hip fracture prediction in elderly men and women: validation in the Rotterdam study. J Bone Miner Res 13:1587-1593

83. Binkley N, Adler R, Bilezikian JP(2014) Osteoporosis diagnosis in men: the T-score controversy revisited. Curr Osteoporos Rep 12:403-409

84.Wandell P,Li X,Carlsson AC, Sundquist J, Sundquist K(2021)Osteoporotic fractures in second-generation immigrants and Swedish natives. Osteoporos Int 32:1343-1350

85. Kanis JA, Johnell O, Oden A et al(2006) The use of multiple sites for the diagnosis of osteoporosis. Osteoporos Int 17:527-534

86. Leslie WD, Tsang JF, Caetano PA, Lix LM(2007) Number of osteoporotic sites and fracture risk assessment: a cohort study from the Manitoba bone density program. J Bone Miner Res 22:476-483

87.Leslie WD, Martineau P, Bryanton M, Lix LM(2019) Which is the preferred site for bone mineral density monitoring as an indicator of treatment-related anti-fracture effect in routine clinical practice? A registry-based cohort study. Osteoporos Int 30:1445-1453

88. Royal Osteoporosis Society(2019) Reporting dual energy X-ray absorptiometry scans in adult fracture risk assessment:standards for quality. https://theros.org.uk/media/xhhyy52/ros-reporting-dxa-scans-in-adult-fracture-risk-assessment-august-2019.pdf

99. Marshall D, Johnell O, Wedel H(1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254-1259

90. Johnell O, Kanis JA, Oden A et al(2005) Predictive value of BMD for hip and other fractures. J Bone Miner Res 20:1185-1194

91. Kanis JA(2002) Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359:1929-1936

92. Kanis JA, Gluer CC(2000) An update on the diagnosis and assessment of osteoporosis of osteoporosis with densitometry. Committee of Scientific Advisors. Int Osteoporo Found Osteoporos Int 11:192-202

93.Schini M, Vilaca T, Poku E, Harnan S, Sutton A, Allen IE, Cum-rings SR, Eastell R(2020) The risk of hip and non-vertebral fractures in patients with Parkinson's disease and parkinsonism:a systematic review and meta-analysis. Bone 132:115173

94. Brennan SL, Leslie WD, Lix LM, Johansson H, Oden A, McClo-sky E, Kanis JA(2014) FRAX provides robust fracture predic-tion regardless of socioeconomic status. Osteoporos Int 25:61-69

95. Leslie WD, Orwoll ES, Nielson CM, Morin SN, Majumdar SR,Johansson H, Odén A, McCloskey EV, Kanis JA(2014) Esti-mated lean mass and fat mass differentially affect femoral bone density and strength index but are not FRAX independent risk factors for fracture. J Bone Miner Res 29:2511-2519

96.Ye C,Leslie WD,Al-Azazi S et al(2024) Fracture risk prediction using the fracture risk assessment tool in individuals with cancer.JAMA Oncol.https://doi.org/10.1001/jamaoncol.2024.4318

97.Whitlock RH, Leslie WD, Shaw J, Rigatto C, Thorlacius L,Komenda P, Collider D, Kanis JA, Tangri N(2019) The fracture risk assessment tool(FRAX®) predicts fracture risk in patients with chronic kidney disease. Kidney Int 95:447-454

98. Fischhoff B, Brewer Noel Noel T, Downs JS(2018) Communicating risks and benefits: an evidence-based user's guide. US Depart-ment of Health and Human Services Food and Drug Administra-tion, US

99.Fink HA, Milavetz DL, Palermo L, Nevitt MC, Cauley JA,Genant HK, Black DM, Ensrud KE(2005) What proportion of incident radiographic vertebral deformities is clinically diag-nosed and vice versa? J Bone Miner Res 20:1216-1222

100. Melton LJ 3rd,Atkinson EJ, Cooper C,O'Fallon WM, Riggs BL(1999) Vertebral fractures predict subsequent fractures. Osteo-poros in 10:214-221

101. Lindsay R, Silverman SL, Cooper C et al(2001) Risk of new vertebral fracture in the year following a fracture. JAMA 285:320-323

102. Jang HD, Kim EH, Lee JC, Choi SW, Kim K, Shin BJ(2020)Current concepts in the management of osteoporotic vertebral fractures: a narrative review. Asian Spine J 14:898-909

103. Leweicki EM(2010) Bone densitometry and vertebral fracture assessment. Curr Osteoporos Rep 8:123-130

104.Gausden EB, Nwachukwu BU, Schreiber JJ, Lorich DG, Lane JM(2017) Opportunistic use of CT imaging for osteoporosis screening and bone density assessment: a qualitative systematic review.J Bone Joint Surg Am 99:1580-1590

105. Bromley PA, Clark EM, Poole KE(2020) Computer-aided diagnostic systems for osteoporotic vertebral fracture detection:opportunities and challenges. J Bone Miner Res 35:2305-2306

106. Kolanu N, Silverne EJ, Ho BH, Pham H, Hansen A, Pauley E,Quirk AR, Sweeney SC, Center JR, Pocock NA(2020) Clinical utility of computer-aided diagnosis of vertebral fractures from computed tomography images. J Bone Miner Res 35:2307-2312

107. Howlett DC,Drink KJ,Mahmood N, Illes J, Griffin J, Javaid K(2020) Radiology reporting of osteoporotic vertebral fragil-ity fractures on computed tomography studies: results of a UK national audit. Eur Radiol 30:4713-4723

108.Kim YM, Demissie S, Genant HK, Cheng X, Yu W, Samelson EJ, Kiel DP, Bouxsein ML(2012) Identification of prevalent vertebral fractures using CT lateral scout views: a comparison of semi-automated quantitative vertebral morphometry and radiolo-giat semi-quantitative value of Steoporos Int 23:1007-1016

109. Rubin KH, Rothman MJ, Holmberg T et al(2018) Effectiveness of a two-step population-based osteoporosis screening program

Archives of Osteoporosis(2025) 20:119

Page 43 of 50 119

119

using FRAX: the randomized risk-stratified osteoporosis strategy evaluation(ROSE) study. Osteoporosis Int 29:567-578

110. Merlijn T, Swart KM, van Schoor NM et al(2019) The effect of a screening and treatment program for the prevention of fractures in older women: a randomized pragmatic trial. J Bone Miner Res 34:1993-2000

111. Merlijn T, Swart KMA, van der Horst HE, Netenboles JC, Elders PJM(2020) Fracture prevention by screening for high fracture risk: a systematic review and meta-analysis. Osteoporosis Int 31:251-257

112.Ismail AA, Cooper C, Felsenberg D, Varlow J, Kanis JA, Silman AJ, O'Neill TW (1999) Number and type of vertebral deformi-ties: epidemiological characteristics and relation to back pain and height loss. European Vertebral osteoporosis study group.Osteoporos Int 9:206-213

113. Zhang Q, Dong J, Zhou D, Liu F(2020) Comparative risk of frac-ture for baratic procedures in patients with obesity: a systematic review and Bayesian network meta-analysis. Int J Surg(London,England) 75:13-23.

114.Kanis JA, McCloskey EV, Johansson H, Strom O, Borgstrom F,Oden A(2008) Case finding for the management of osteoporosis with FRAX-assessment and intervention thresholds for the UK.Osteoporos Int 19:1395-1408

115. National Institute for Health and Care Excellence(2019) Bis-phosphonates for treating osteoporosis. Technology appraisal guidance[TA464].https://www.nice.org.uk/guidance/ta464

116. McCloskey E, Kanis JA, Johansson H et al(2015) FRAX-based assessment and intervention thresholds-an exploration of thresh-olds in women aged 50 years and older in the UK. Osteoporosis Int 26:2091-2099

117. Shepstone L, Lenaghan E, Cooper et al(2018) Screening in the community to reduce fractures in older women(SCOOP): a randomised controlled trial. Lancet 391:741-747

118. Cosman F,Crittenden DB, Adachi JD et al(2016) Romozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 375:1532-1543

119.Saag KG,Petersen J,Brandi ML,Karaplis AC,Lorentzon M,Thomas T, Maddox J, Fan M, Meisner PD, Grauer A(2017)Romosuzomab or aldenorate for fracture prevention in women with osteoporosis. N Engl J Med 377:1417-1427

120. Kendler DL, Marin F, Zerbini CAF et al(2018) Effects of teri-parate and risedronate on new fractures in post-menopausal women with severe osteoporosis(VERO): a multicentre, dou-ble-blind, double-dummy, randomised controlled trial. Lancet 391:230-240

121.Miller PD,Hattersley G, Riis BJ et al(2016) Effect of abalopara-tide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: a randomized clinical trial. JAMA 316:722-733

122.Kanis JA, Harvey NC, McCloskey E et al(2020) Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures. Osteoporos Int 31:1-12

123.Delmas PD, Genant HK, Crans GG, Stock JL, Wong M, Siris E, Adachi JD(2003) Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonverbral fractures:results from the MORE Trial. Bone 33:522-532

124.Kanis JA, Cooper C, Rizzoli R, Reginstar JY(2019) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 30:3-44

125.Johnell O,Oden A,Caulin F,Kanis JA(2001) Acute and long-term increase in fracture risk after hospitalization for vertebral fracture. Osteoporos Int 12:207-214

126. Giangregorio LM, Leslie MD(2010) Time since prior fracture is a risk modifier for 10-year osteoporotic fractures. J Bone Miner Res 25:1400-1405

127. Dretakis KE, Dretakis EK, Papakitsou EF, Psarakis S, Sterio-poulos K(1998) Possible predisposing factors for the second hip fracture. Calcif Tissue Int 62:366-369

128.Nymark T., Lauritsen JM, Ovesen O, Rock ND, Jeune B(2006)Short time-frame from first to second hip fracture in the Funen County hip fracture study. Osteoporos Int 17:1353-1357

129. Ryg J, Rejnmark L, Overgaard S, Brixen K, Vestergaard P(2009)Hip fracture patients at risk of second hip fracture: a nationwide population-based cohort study of 169,145 cases during 1977-2001.J Bone Miner Res 24:1299-1307

130. van Geel TA, van Helden S, Geusens PP, Winkens B, Dinant GJ(2009) Clinical subsequent fractures cluster in time after first fractures.Ann Rheum Dis 68:99-102

131. Johansson H, Sigeirdsdottir K, Harvey NC, Odén A, Gudnason V, McCloskey E, Sigurdsson G, Kanis JA(2017) Imminent risk of fracture after fracture. Osteoporos Int 28:775-780

132.Kanis JA, Johansson H, Harvey NC, Gudnason V, Sigurdsson G,Sigdeirgsdirotir K, Lorentzon M, Liu E, Vandenput L, McCloskey EV(2021) The effect on subsequent fracture risk of age, sex, and prior fracture site by recency of prior fracture. Osteoporos Int.https://doi.org/10.1007/s00198-020-05803-4

133. Body JJ, Marin F,Kendler DL et al(2020) Efficacy of teriparatide compared with risedronate on FRAX(@-)-defined major osteoporo-tic fractures: results of the VERO clinical trial. Osteoporosis inter-national: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteopo-rosis Foundation of the USA 31:1935-1942

134. Lyles KW, Colon-Emeric CS, Magaziner JS et al(2007) Zole-dronic acid and clinical fractures and mortality after hip fracture.N Engl J Med 357:1799-1809

135.Kanis JA, Johansson H, Harvey NC, Lorentzon M, Liu E,Vandenput L, EV.M(2021) An assessment of interven-tion thresholds for very high fracture risk applied to the NOGG guidelines. Osteoporos Int https://doi.org/10.1007/s00198-00021-05942-00192

136.Kanis JA,Rizzoli R,Cooper C,Register JY(2014) Challenges for the development of bone-forming agents in Europe. Calcif Tissue Int 94:469-473

137. Johansson H, Kanis JA, Oden A, Compston J, McCloskey E(2012) A comparison of case-finding strategies in the UK for the management of hip fractures. Osteoporos Int 23:907-915

138. Cummings SR, Black DM, Thompson DE et al(1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture interven-tion trial. JAMA 280:2077-2082

139.Eastell R, Black DM, Boonen S et al(2009) Effect of once-yearly zonedonic acid five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol Metab 94:3215-3225

140.Harvey NC,Kanis JA,Odén A,Nakamura T,Shiraki M,Sugi-moto T,Kuroda T, Johansson H, McCloskey EV(2015) Efficacy of weekly teriparate does not vary by baseline fracture prob-ability calculated using FRAX. Osteoporos Int 26:2347-2353

141.McCloskey E(2016) A BMD threshold for treatment efficacy in osteoporosis? A need to consider the whole evidence base.Osteoporos Int 27:417-419

142.Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Wong S,Wiessing KR,Bolland MJ,Bastin S,Gamble GD(2018) Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med 379:2407-2416

143.Comman F, Hattersley G, Hu MY, Williams GC, Fitzpatrick LA,Black DM(2017) Effects of abaloparatide-SC on fractures and bone mineral density in subgroups of postmenopausal women with osteoporosis and varying baseline risk factors. J Bone Miner Res 32:17-23

119 Page 44 of 50

Archives of Osteoporosis(2025) 20:119

144. McCloskey EV, Johansson H, Oden A, Harvey NC, Jiang H,Modin S, Fitzpatrick L, Kanis JA(2017) The effect of abalo-parate-sc on fracture risk is independent of baseline FRAX fracture probability: a post hoc analysis of the ACTIVE study. J Bone Miner Res 32:1625-1631

145. Johansson H, Oden A, Johnell O, Jonsson B, de Laet C, Oglesby A, McCloskey EV, Kayan K, Jalava T, Kanis JA(2004) Optimi-zation of BMD measurements to identify high risk groups for treatment-a test analysis. J Bone Mineral Res 19-906-913

16. Leslie WD, Majumdar SR, Lix LM, Johansson H, Oaden A, Mccloskey E, Kanis JA(2012) High fracture probability with FRAX usually indicates densitometric osteoporosis: implications for clinical practice. Osteoporos Int 23:391-397

147. Leslie MD, Lix LM, Johansson H, Oden A, McCloskey E, Kanis JA(2012) Does osteoporosis therapy invalidate FRAX for frac-ture prediction? J Bone Miner Res 27:1243-1251

148.Fabiani R, Naldini G, Chiavarini M(2019) Dietary patterns in relation to low bone mineral density and fracture risk: a system-atic review and meta-analysis. Advances in nutrition(Bethesda,Md) 10:219-236

15. Lin P-H,Ginty F,Appel LJ, Aickin M, Bohannon A, Garnero P,Barclay D, Svetbley LP(2003) The DASH diet and sodium reduc-tion improve markers of bone turnover and calcium metabolism in adults.J Nutr 133:313-3136

150. Groenendijk I, den Boeft L, van Loon LJC, de Groot L(2019)High versus low dietary protein intake and bone health in older adults: a systematic review and meta-analysis. Comput Struct Biotechnol J 17:1101-1112

151. Darling, ALM, Sanders RF, Sahni S, Zhu K, Hewitt CE, Prince RL, Millward DJ, Lanham-New SA(2019) Dietary protein and bone health across the life-course: an updated systematic review and meta-analysis over 40 years. Osteoporos Int 30:741-761

152.Myint MW, Wu J, Wong E, Chan SP, To TS, Chau MW, Ting KH,Fung PM,Au KS(2013) Clinical benefits of oral nutritional supplementation for elderly hip fracture patients: a single blind randomised controlled trial. Age Ageing 42:39-45

153. Iguacel I,Miguel-Berges ML,Gómez-Bruton A,Moreno LA,Julian C(2019) Veganism, vegetarianism, bone mineral density,and fracture risk: a systematic review and meta-analysis. Nutr Rev 77:1-18

154. Tong TYN, Appleby PN, Armstrong MEG, Fensom GK, Knup-pel A, Papier K, Perez-Cornago A, Travis RC, Key TJ(2020)Vegetarian and vegan diets and risks of total and site-specific fractures: results from the prospective EPIC-Oxford study. BMC Med 18:353

155. Department of Health(1991) Dietary reference values for food energy and nutrients for the United Kingdom. HMSO, London

156. Scientific Advisory Committee on Nutrition(SACN)(2016)Vitamin D and Health. https://www.gov.uk/government/groups/scientific-advisory-committee-on-nutrition

157.Royal Osteoporosis Society(2018) Vitamin D and bone health: a practical clinical guideline for patient administration. https://strwe brpdromedia.blob.core.windows.net/media/ef2ideu2/ros-vitam in-d-and-bone-health-in-adults-february-2020.pdf

158.Yao P, Bennett D, Mafham M, Lin X, Chen Z, Armitage J,Clarke R(2019) Vitamin D and calcium for the prevention of fracture: a systematic review and meta-analysis. JAMA Netw Open 2:e1917789

159. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A(2007) Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 370:657-666

160. Group.DVDIPaORT(2010) Patient level pooled analysis of 6850 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340:b5463

161. Harvey NC, Biver E, Kaufman JM et al(2017) The role of cal-cium supplementation in healthy musculoskeletal ageing. Osteo-poros in 28:447-462

162. Kahlawi LC, Weber RP, Pan H, Gourlay M, LeBlanc E, Coker-Schimmer M, Viswanathan M(2018) Vitamin D, calcium, or combined supplementation for the primary prevention of frac-tures in community-dwelling adults: evidence report and sys-tematic review for the US preventive services task force. JAMA 319:1600-1612

163. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotow-icz MA, Young D, Nicholson GC(2010) Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303:1815-1822

164. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R, Dick W, Willett WC, Egli A(2016)Monthly-hood of vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med 176:175-183

165. Howe TE, Shea B, Dawson LJ, Downie F, Murray A, Ross C,Harbour RT,Caldwell LM,Creed G(2011) Exercise for pre-venting and treating osteoporosis in postmenopausal women.Cochrane Database SyStv Rev 6(7):Cd000333.https://doi.org/10.1002/14651858.CD000333.pub2

166.Kemmler W, Shojaa M, Kohl M, von Stengel S(2020) Effects of different types of exercise on bone mineral density in postmeno-pausal women: a systematic review and meta-analysis. Calcif Tissue Int 107:409-439

167. Babatunde OO, Burton AL, Hind K, Paskins Z, Forsyth JJ(2020) Exercise interventions for preventing and treating low bone mass in the forearm: a systematic review and meta-analysis.Arch Phys Med Rehabil 101:487-511

168. Kelley GA, Kelley KS, Kohrt WM(2013) Exercise and bone mineral density in men: a meta-analysis of randomized controlled trials. Bone 53:103-111

169. Royal Osteoporosis Society(2018) Strong, steady and straight; an expert consensus statement on physical activity and exercise for osteoporosis.https://theros.org.uk/media/o05h1153/ros-strong-steady-straight-quick-guide-february-2019.pdf

170.Kunutsor SK, Leyland S, Skelton DA, James L, Cox M, Gib-bons N, Whitney J, Clark EM(2018) Adverse events and safety issues associated with physical activity and exercise for adults with osteoporosis and osteopenia: a systematic review of observational studies and an updated review of interventional studies. J Frailty Sarcopenia Falls 3:155-178

171. Bhasin S,Gill TM, Reuben DB et al(2020) A randomized trial of a multifactorial strategy to prevent serious fall injuries. N Engl J Med 383:129-140

172. Lamb SE, Bruce J, Hossain A et al(2020) Screening and inter-vention to prevent falls and fractures in older people. N Engl J Med 383:1848-1859

173. El-Khoury F, Cassou B, Charles M-A, Dargent-Molina P(2013) The effect of fall prevention exercise programmes on fall induced injuries in community dwelling older adults:systematic review and meta-analysis of randomised con-trolled trials. BMJ 347:f6234. https://doi.org/10.1136/bmj.f6234.

174. Sherrington C, Fairhall NJ, Wallbank GK, Tiedemann A,Michaleff ZA, Howard K, Clemson L, Hopewell S, Lamb SE(2019) Exercise for preventing falls in older people living in the community. Cchrane Database Syst Rev 1:Cd012424

175. Zhao R, Bu, Chen X(2019) The efficacy and safety of exer-cise for prevention of fall-related injuries in older people with different health conditions, and differing intervention proto-cols: a meta-analysis of randomized controlled trials. BMC Geriatr 19:341

Archives of Osteoporosis(2025) 20:119

Page 45 of 50119

176. Sherrington C, Michaleff ZA, Fairhall N, Paul SS, Tiede-mann A, Whitney J, Cumming RG, Herbert RD, Close JCT,Lord SR(2017) Exercise to prevent falls in older adults: an updated systematic review and meta-analysis. Br J Sports Med 51:1750-1758

177. Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C,Gates S, Clemson LM, Lamb SE(2012) Interventions for pre-venting falls in older people living in the community. Cochrane Database Syst Rev 2012(9):CDQ001746. https://doi.org/10.1002/14651858.CD007146.pub3

178.Jepsen DB,Thomsen K,Hansen S,Jorgensen NR,Masud T, Ryg J(2017) Effect of whole-body vibration exercise in preventing falls and fractures: a systematic review and meta-analysis. BMJ Open 7:e018342

179. Thorin MH, Wihlborg A, Akesson K, Gerdhem P(2016) Smok-ing, smoking cessation, and fracture risk in elderly women followed for 10 years. Osteoporos Int 27:249-255

180.Shen GS,Li Y,Zhao G,Zhou HB,Xie ZG,Xu W,Chen HN,Dong QR, Xu YJ(2015) Cigarette smoking and risk of hip fracture in women: a meta-analysis of prospective cohort stud-ies. Injury 46:1333-1340

181.Min W, An R, Li S, Feng J, Yang J, Huang Z(2017) The effects of preoperative smoking cessation on the healing of fractures and postoperative complications: a systematic review and meta-analysis. Biomed Res 28:1883-1889

182. Agoons DD,Acons Boemn,Emmanuel KE, Matawalle FA,Cun-ningham JM(2021) Association between electronic cigarette use and fragility fractures among US adults. Am J Med Open 1-6:100002

183.Song TH, Shim JC, Jung DU, Moon JJ, Jeon DW, Kim SJ, Oh MK(2018) Increased bone mineral density after abstinence in male patients with alcohol dependence. Clin Psychopharmacol Neurosci 16:282-289

184. Department of Health(2016) UK chief medical officers' alco-hol guidelines review summary of the proposed new guide-lines. Williams Lea. https://assets.publishing.service.gov.uk/media/5a7f51b4e5274a2e87db5206/summary.pdf

185.Crandall CJ,Newberry SJ,Diamant A,Lim YW,Gellad WF,Booth MJ, Motala A, Shekelle PG(2014) Comparative effec-tiveness of pharmacologic treatments to prevent fractures: an updated systematic review. Ann Intern Med 161:711-723

186. Beaudart C, Veronese N, Douxils Fils et J al(2025) Ph1 receptor agonists for fracture risk: a systematic review and network meta-analysis. Osteoporosis Int 36:951-967

187. Black DM, Cummings SR, Karpf DB et al(1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Interv Trial Res Group Lan-cet 348:1535-1541

188. Orwell E,Etinger M, Weiss et al(2000) Alendronate for the treatment of osteoporosis in men. N Engl J Med 343:604-610

189.Saag KG,Enkey R,Schnetrier T,Glucocorticoid-induced osteo-porosis intervention study group et al(1998) Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis.N Engl J Med 339:292-299

190.Harris ST, Watts NB, Genant HK et al(1999) Effects of rise-dronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized con-trolled trial. Vertebral efficacy with risedronate therapy(VERT)study Group. JAMA 282:1344-1352

191. Reginner J,Minne HW,Sorensen OH et al(2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral efficacy with risedronate therapy(VERT) Study Group. Osteoporos Int 11:83-91

192. Boonen S, Orwoll ES, Wenderoth D, Stoner KJ, Eusebio R,Delmas PD(2009) Once-weekly rushedron in men with

osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J Bone Miner Res 24:719-725

19. Wallach S, Cohen S, Reid DM et al(2000) Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 67:277-285

19. Reid DM, Hughes RA, Laan RF, Sacco-Gibson NA, Wenderoth DH, Adami S, Eusebio RA, Devogelaer JP(2000) Efficacy and safety of daily rivondrate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial.European corticosteroid-induced osteoporosis treatment study.J Bone Miner Res 15:1006-1013

195. Delmas PD, Recker RR, Chesnut CH 3rd, Skag A, Stakkestad JA,Emkey R, Gilbride J, Schimmer RC, Christiansen C(2004) Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporosis Int 15:792-798

196.Chesutn CH 3rd,Skag A,Christiansen C et al(2004) Effects of oral ibronandate administered daily or intermittently on frac-ture risk in postmenopausal osteoporosis. J Bone Miner Res 19:1241-1249

197. Reginster JY, Adami S, Lakatos P et al(2006) Efficacy and tol-erability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis 65:654-661

198.Eisman JA,Civitelli R, Adami S et al(2008) Efficacy and toler-ability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study.J Rheumatol 35:488-497

199. Black DM, Delmas PD, Eastell R et al(2007) Once-yearly zole-dronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809-1822

20.Boonen S, Reginter JY, Kaufman JM et al(2012) Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med 367:1714-1723

201. Reid DM, Devogela Jr, Saag K et al(2009) Zoledronic acid and risedronate in the prevention and treatment of glucocorti-coid-induced osteoporosis(HORIZON): a multicentre, dou-ble-blind, double-dummy, randomised controlled trial. Lancet 373:1253-1263

202.Reid IR,Horne AM,Lihov B,Stewart A,Garratt E,Bastin S,Gamble GD(2020) Effects of zoledronate on cancer, cardiac events, and mortality in osteopenic older women. J Bone Miner Res 35:20-27

203.Reid IR, Gamble GD, Mesenbrink P, Lakatos P, Black DM(2010) Characterization of and risk factors for the acute-phase response after zoledronic acid. J Clin Endocrinol Metab 95:4380-4387

204.Saag KG,Wagman RB,Geusens P,Adachi JD,Messina OD,Emkey R, Chapurlat R, Wang A, Pannacciulli N, Lems WF(2018) Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study. Lancet Diabe-tes Endocrinol 6:445-454

205.Cummings SR,San Martin J, McClung MR et al(2009) Deno-sumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756-765

206. Bone HG, Wagmann RB, Brandi ML et al(2017) 10 years of denosumab treatment in postmenopausal women with osteo-porosis; results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 5:513-523

207. Langdahl Bl, Tegljberg CS, Ho PR et al(2015) A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial. J Clin Endocrinol Metab 100:1335-1342

119 Page 46 of 50

Archives of Osteoporosis(2025) 20:119

208.(2014) https://www.gov.uk/drug-safety-update/denosumab-monit oring-recommended Accessed January 7th 2021

209. Bone HG, Bolognese MA, Yuen CK, Kender DL, Miller PD,Yang YC,Grazette L,San Martin J,Gallagher JC(2011) Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass.J Clin Endocrinol Metab 96:972-980

210.Miller PD,Wagman RB,Peacock M, Lewieck EM, Bolognese MA, Weinstein RL, Ding B, San Martin J, McClung MR(2011)Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J Clin Endocrinol Metab 96:394-402

211. Tsourdi E, Zillikens MC, Meier C et al(2020) Fracture risk and management of discontinuation of denosumab therapy: a system-atic review and position statement by ECTS. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgaa756

12.Cummings SR, Ferrari S, Eastell R et al(2018) Vertebral frac-tures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 33:190-198

213. Dennison EM, Cooper C, Kanis JA, Bruyere O, Silverman S, McCloskey E, Abrahamsen B, Prieto-Alhambra D, Ferrari S(2019) Fracture risk following intermission of osteoporosis therapy. Osteoporosis Int 30:1733-1743

214. Reid IR, Horne AM, Mihov B, Gamble GD(2017) Bone loss after denosumab: only partial protection with zoledronate. Calc Tissue Int 101:371-374

215. Horne AM, Mihov B, Reid IR(2019) Effect of zoledronate on bone loss after rosmozumoladen/dosumahos: 2-year follow-up. Cal-cif Tissue Int 105:107-108

216. Anastasilakis AD, Papapoulos, Polyzos SA, Appelman-Dijkstra NM, Makras P(2019) Zoledronate for the preven-tion of bone loss in women discontinuing denosumabat treat-ment. A prospective 2-year clinical trial. J Bone Mineral Res 34:2220-2228

217. Everts-Graber J, Reichenbach S, Ziswiler HR, Studer U,Lehmann T(2020) A single infusion of zoledronate in postmen-opausal women following denosumab discontinuation results in partial conservation of bone mass gains. J Bone Miner Res 35:1207-1215

218. Solling AS, Harsloff T, Langdahl B(2020) Treatment with zole-dronate subsequent to denosumab in osteoporosis: a randomized trial.J Bone Miner Res 35:1858-1870

19. Makras P, Appelman-Dijkstra NM, Papapouls SE, van Wissen S, Winter EM, Polyzos SA, Yavropoulou MP, Anastasilakis AD(2021) The duration of denosumab treatment and the efficacy of zoledronate to preserve bone mineral density after its discontinu-ation.J Clin Endocrinol Metab 106:e4155-e4162

220. Tsourdi E, Langdahl B, Cohen-Solman, A Mubry-Rozier B, Eriksen EF, Guafabens N, Obermayer-Pietsch R, Bralston SH, Eastell R,Zillikens MC(2017) Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 105:11-17

221. Kendler D,Chines A,Clark P,Ebeling PR, McClung M,Rhee E,Huang S, Stad RK(2020) Bone mineral density after transition-ing from denosumab to alendronate. J Clin Endocrinolim Netab 105:e255-264

222.Marjoribanks J,Farquhar C,Roberts H,Lethaby A(2012) Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 1(1):CD004143. https://doi.org/10.1002/14651858.CD004143.pub5

223. Rossou JE, Anderson GL, Prentice RL et al(2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288:321-333

224. National Institute for Health and Care Excellence(NICE)(2019) Menopause: diagnosis and management. NICE guideline[NG23].https://www.nice.org.uk/guidance/ng23

225. El Khoudary SR, Aggarwal B, Beckie TM et al(2020) Meno-pause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation 142:e506-e532

226. Medicines and Healthcare products Regulatory Agency(2019) Hor-none replacement therapy(HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping. https://www.gov.uk/drug-safetyupdate/hormone-repla cement-therapy-hrt-further-information-on-the-known-increased-risk-of-breast-cancer-with-hrt-and-itspersistence-after-stopping

227. Society BM(2024) Consensus statement: the benefits and risks of HRT before and after a breast cancer diagnosis. https://thebms.org.uk/wp-content/uploads/2024/04/08-BMS-ConsensusStatem ent-Benefits-risks-of-HRT-before-after-a-breast-cancer-diagn osis-MARCH2024-A.pdf

228.Gallagher J, Goldgar D(1990) Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A rand-onized controlled study. Ann Intern Med 113:649-655

229. Ettinger B, Black DM, Mitlak BH et al(1999) Reduction of ver-tebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clini-cal trial. Multiple outcomes of raloxifene evaluation(MORE)Investigators. JAMA 282:637-645

230. Barrett-Connor E, Cox DA, Song J, Mitlak B, Mosca L, Grady D(2009) Ruloxafine and risk for stroke based on the framingham stroke risk score. Am J Med 122:754-761

231.Barrett-Connor E, Mosca L, Collins P, Geiger MJ, Grady D Kornitzer M, McNabb MA, Wenger NK, Raloxifene Use for The Heart Trial I(2006) Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355:125-137

232.Meunier PJ, Roux C, Seeman E et al(2004) The effects of stron-tium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459-468

233. Reginer JY, Seeman E, De Vernejoul MC et al(2005) Stron-tium ranateel reduces the risk of nonvertebral fractures in post-menopausal women with osteoporosis: treatment of periph-eral osteoporosis(TROPOS) study. J Clin Endocrinol Metab 90:2816-2822

234. Kaufman JM, Arnan M, Bianchi G et al(2013) Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men.J Clin Endocrinol Metab 98:592-601

235. Osborne V, Layton D, Perrio M, Wilton L, Shakir SA(2010)Incidence of venous thromboembolism in users of strontium ranelate: an analysis of data from a prescription-event monitor-ing study in England. Drug Saf 33:579-591

236.European Medicines Agency(2013) Recommendation to restrict the use of Protelos/ Osseor(strontium ranelate). Euro-pean Medicines Agency(EMA).https://www.ema.europa.eu/en/news/recommendation-restrict-use-protelos-osseor-stron tiumanelate

237. Blake GM, Compston JE, Fogelman I(2009) Could strontium ranelate have a synergistic role in the treatment of osteoporosis?J Bone Miner Res 24:1354-1357

238. Neer RM, Arnaud CD, Zanchetta JR et al(2001) Effect of para-thyroid hormone(1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434-1441

239.Diez-Perez A, Marin F, Eriksen EF, Kendler DL, Krege JH,Delgado-Rodriguez M (2019) Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: a systematic review and meta-analysis. Bone 120:1-8

Archives of Osteoporosis(2025) 20:119

Page 47 of 50 119

119

240.Simpson EL,Martyn-St James M, Hamilton J,Wong R,Gittoes N,Selby P, Davis S(2020) Clinical effectiveness of denosumab,raloxifene,romosozumab, and teriparatide for the prevention of osteoporotic fragility fractures: a systematic review and network meta-analysis. Bone 130:115081

241. Orwell ES, Scheele WH, Paul S, Adami S, Syversen U, Diez-Perez A, Kaufman JM, Clancy AD, Gaich GA(2003) The effect of teriparatide/human parathyroid hormone(1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 18:9-17

242.Saag KG,Zanchetta JR, Devogelaer JP, Adler RA,Eastell R,See K, Krege JH, Krohn K, Warner MR(2009) Effects of teriparatide versus aldentone for treating glucocorticoid-induced osteopo-rosis: thirty-six-month results of a randomized, double-blind,controlled trial. Arthritis Rheum 63:3346-3355

243.Barrionuevo P, Kapoor E,asi N et al(2019) Efficacy of pharma-cological therapies for the prevention of fractures in postmeno-pausal women: a network meta-analysis.J Clin Endocrinol Metab 104:1623-1630

244. Register JY, Bianic F, Campbell R, Martin M, Williams SA,Fitzpatrick LA(2019) Abaloparate for risk reduction of non-vertebral and vertebral fractures in postmenopausal women with osteoporosis: a network meta-analysis. Osteoporosis Int 30:1465-1473

245. Lewiecki EM, Blicharski T, Goemaere S, Lippuner K, Meisner PD, Miller PD, Miyauchi A, Maddox J, Chen L, Horlait S(2018)A phase III randomized placebo-controlled trial to evaluate effi-cacy and safety of romosozumab in men with osteoporosis. J Clin Endocrinol Metab 103:3183-3193

246. Kendler DL, Bone HG, Massari F et al(2019) Bone mineral density gains with a second 12-month course of romozosumab therapy following placebo or denosumab. Osteoporos Int 30:2437-2448

247. Rittammer RS, Bologne E, Mittinger MP, Hanley DA, Hodsman AB, Kendler DL, Rosen CJ(2000) Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 85:2129-2134

248.Leder BZ, Tsai JN, Uihlein AV, Wallace PM, Lee H, Neer RM, Burnett-Bowie SA(2015) Denosumab and teriparatide transitions in postmenopausal osteoporosis(the DATA-switch study): extension of a randomised controlled trial. Lancet 386:1147-1155

249. Cosman F, Crittenden DB, Ferrari S, Khan A, Lane NE, Lip-puner K, Matsumoto T, Milmont CE, Libanati C, Grauer A(2018) FRAME study: the foundation effect of building bone with 1 year of romosozumab leads to continued lower frac-ture risk after transition to denosumab. J Bone Miner Res 33:1219-1226

250.McClung MR, Brown JP, Diez-Perez A et al(2018) Effects of 24 months of treatment with romozosumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: a randomized, double-blind, phase 2, par-allel group study.J Bone Miner Res 33:1397-1406.https://doi.org/10.1002/jbmr.3452

251. Lewiecki EM, Dinavahi RV, Lazaretti-Castro M, Ebeling PR,Adachi JD, Miyauchi A, Gielen E, Milmonte CE, Libanati C,Grauer A(2019) One year of romosozumab followed by two years of denosumab maintains fracture risk reductions: results of the FRAME extension study. J Bone Miner Research 34:419-428

252. Bone HG, Cosman F, Miller PD et al(2018) ACTIVEExtend: 24 months of alendronate after 18 months of abaloparotide or pla-cebo for postmenopausal osteoporosis. J Clin Endocrinol Metab 103:2949-2957

253. Langdahl BL, Libanati C, Critenden DB et al(2017) Romo-sozumab(sclerostin monoclonal antibody) versus teriparate

in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet 390:1585-1594

254. Keaveny TM,Crittenden DB,Bolognese MA et al(2017) Greater gains in spine and hip strength for romozosumab compared with teriparate in postmenopausal women with low bone mass.J Bone Miner Research 32:1956-1962

255.Ebina K, Hirao M, Tsuboi H et al(2020) Effects of prior osteo-porosis treatment on early treatment response of romozumab in patients with postmenopausal osteoporosis. Bone 140:115574

256.Nayak S, Greenspan SL(2019) A systematic review and meta-analysis of the effect of bisphosphonate drug holidays on bone mineral density and osteoporotic fracture risk. Osteoporos Int 30:705-720

257. National Institute for Health and Care Excellence(2016) Multi-morbidity: clinical assessment and management. NICE guideline[NG56].https://www.nice.org.uk/guidance/ng56

258.Adler RA,El-Hajj Fuleihan G, Bauer DC et al(2016) Managing osteoporosis in patients on long-term bisphosphonate treatment:report of a task force of the American Society for Bone and Mineral Research J, Bone Miner Research 31:16-35

259.Fink HA, MacDonald R, Forte ML et al(2019) Long-term drug therapy and drug discontinuations and holidays for osteoporlo-sis fracture prevention: a systematic review. Ann Intern Med 171:37-50

260.Ensrud KE, Barrett-Connor EL, Schwartz A et al(2004) Ran-domized trial of effect of alendronate continuation versus dis-continuation in women with low BMD: results from the Frac-ture intervention trial long-term extension. J Bone Min Res 19:1259-1269

216.Black DM, Schwartz AV, Ensrud KE et al(2006) Effects of con-tinuing or stopping alendronate after 5 years of treatment: the fracture intervention trial long-term extension(FLEX): a rand-omized trial. JAMA 296:2927-2938

262.Ravn P, Christensen JO, Baumann M, Clemmesen B(1998)Changes in biochemical markers and bone mass after withdrawal of ibandronate treatment: prediction of bone mass changes during treatment. Bone 22:559-564

263.Watts NB,Chines A,Olszynski WP,McKeever CD,McClung MR,Zhou X,Grauer A(2008) Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int 19:365-372

264. Black DM, Reid IR, Boonen S et al(2012) The effect of 3 ver-sus 6 years of zoledronic acid treatment of osteoporosis: a rand-omized extension to the HORIZON-Pivotal Fracture Trial(PFT).J Bone Mineral Research 27:243-254

26.Kim TY,Bauer DC, McNabb BL,Schafer AL,Cosman F, Black DM,Eastell R(2019) Comparison of BMD changes and bone formation marker levels 3 years after bisphosphonate discon-tinuation: FLEX and HORIZON-PFT extension I trials. J Bone Miner Res 34:810-816

266. Bauer DC, Schwartz A, Palermo L, Cauley J, Hochberg M, San-tora A, Cummings R, Black DM(2014) Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy: the FLEX study. JAMA Intern Med 174:1126-1134

267.Khan AA, Morrison A, Hanley DA et al(2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus.J Bone Miner Res 30:3-23

268. Khosla S, Burr D, Cauley J et al(2007) Bisphosphonate-associ-ated osteonecrosis of the jaw: report of a task force of the Ameri-can Society for Bone and Mineral Research. J Bone Miner Res 22:1479-1491

26.Scottish Dental Clinical Effectiveness Programme(2017) Oral health management of patients at risk of medication-related oste-onecrosis of the jaw: dental clinical guidance. https://www.sdcep.p

119 Page 48 of 50

Archives of Osteoporosis(2025) 20:119

(2025) 20:119

org.uk/wp-content/uploads/2017/04/SDCEP-Oral-Health-Manag ement-of-Patients-at-Risk-of-MRONJ-Guidance-full.pdf

270.Salzman R, Hoza J, Perina V, Stárek I(2013) Osteonecrosis of the external auditory canal associated with oral bisphospho-nate therapy: case report and literature review. Otol Neurotol 34:209-213

271. Black DM, Abrahamsen B, Bouxsein ML, Einhorn T, Napoli N(2019) Atypical femur fractures: review of epidemiology, rela-tionship to bisphosphonates, prevention, and clinical manage-ment. Endocr Rev 40:333-368

272.Shane E, Burr D, Ebeling PR et al(2010) Atypical subtrocanic and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Minr 25:2267-2294

273. Shane E, Burr D, Abrahamsen B et al(2014) Atypical sub-trochanacteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research J. Bone Hinager Res 29:1-23

274.Gedminates L, Solomon DH, Kim SC(2013) Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 28:1729-1737

275. Abrahams B, Eiken P, Prieto-Alhambra D, Eastell R(2016)Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of adenlorate: nationwide cohort and nested case-control study. BM35:335365

276. van de Laarschot DM, McKenna MJ, Abrahamsen B, Langdahl B, Cohen-Solal M, Guababens N, Eastell R, Ralston SH, Zillik-ens MC(2020) Medical management of patients after atypical femur fractures: a systematic review and recommendations from the European Calcified Tissue Society. J Clin Endocrinol Metab 105:1682-1699

277. Carter M(2019) Prevention of glucocorticoid-induced osteopo-rosis: clinical audit to evaluate the implementation of National Osteoporosis Guideline Group 2017 guidelines in a primary care setting.J Clin Densitom 22:25-30

278. van Staa TP, Leufkens HG, Cooper C(2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteo-poros Int 13:777-787

279.Adachi JD, Saag KG, Delmas PD et al(2001) Two-year effects of alonderrate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind,placebo-controlled extension trial. Arthritis Rheum 44:202-211

280. Cohen S, Levy RM, Keller M et al(1999) Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, mul-ticenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 42:2309-2318

281.Deng J, Silver Z, Huang E, Zheng E, Kavanagh K, Wen A,Cheng W, Dobransky J, Sanger S, Grammatopoulos G(2020)Pharmacological prevention of fractures in patients undergoing glucocorticoid therapies: a systematic review and network meta-analysis. Rheumatology(Oxford).https://doi.org/10.1093/rheumatology/keaa228

282. Brown JE, Handforth C, Compston JE et al(2020) Guidance for the assessment and management of prostate cancer treatment-induced bone loss A consensus position statement from an expert group. J Bone Oncol 25:100311

283.Watts NB,Adler RA,Bilezianik JP,Drake MT,Eastell R,Orwoll ES,Finkelstein JS, Endocrine S(2012) Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97:1802-1822

284.Adler Robert A(2024) Osteoporosis in men. Endotext. https://www.ncbi.nlm.nih.gov/books/NBK558007/

285.Mittan D, Lee S, Miller E, Perez RC, Basler JW, Bruder JM(2002) Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 87:3656-3661

286. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS(2005) Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154-164

287. Joseph JS, Lam V, Patel MI(2019) Preventing osteoporosis in men taking androgen deprivation therapy for prostate can-cer: a systematic review and meta-analysis. Eur Urol Oncol 2:551-561

288.Poon Y, Pechlivanoglou N, Albaih SMH, Naimark D, Hoch JS,Papadimitropoulos E, Hogan ME, Krahn M(2018) Systematic review and network meta-analysis on the relative efficacy of osteoporotic medications: men with prostate cancer on continu-ous androgen-deprivation therapy to reduce risk of fragility frac-tures. BJU Int 121:17-28

289.Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McClos-key EV, Powles T, Selby P, Coleman RE(2008) Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK expert group. Cancer Treat Rev 34(Suppl 1):S3-18

290.Hadji P, Aapro MS, Body JJ et al(2017) Management of aro-matase inhibitor-associated bone loss(AIBL) in postmenopau-sal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol 7:1-12

291. National Institute for Health and Care Excellence(NICE)(2017)Early breast cancer(preventing recurrence and improving sur-vival): adjuvant bisphosphonates[ES15]. https://www.nice.org.uk/advice/es15

29. Waas K, Lima Ferreira J, Tsourdi E, Body JJ, Hadji P, Zil-likens MC(2021) Updated guidance on the management of cancer treatment-induced bone loss(CTIBL) in pre- and post-menopausal women with early-stage breast cancer. J Bone Oncol 28:100355

293.Miyashita H, Saitoi S, Kuno T, Cruz C, Malamud S, Kim SM(2020) Bone modifying agents for bone loss in patients with aromatase inhibitor as adjuvant treatment for breast cancer;insights from a network meta-analysis. Breast Cancer Res Treat 181:279-289

294. World Health Organization(1987) Traitement de la douleur can-céreuse. Organisation monondiale de la Santé, Genève

295.Schofield P(2018) The assessment of pain in older people: UK national guidelines. Age Ageing 47:1i-122

296. British Geriatric Society(2013) Guidance on the management of pain in older people. Age Ageing 42:i1-i57

297.Knopp-Sihota JA, Newburn-Cook CV, Homik J, Cummings GG,Voaklander D (2012) Calcitonin for treating acute and chronic pain of recent and remote osteoporotic vertebral compression fractures: a systematic review and meta-analysis. Osteoporos Int 23:17-38

298.European Medicines Agency (2012) European Medicines Agency recommends limiting long-term use of calcitonin medicines.https://www.ema.europa.eu/en/news/european-medicines-agency-recommends-limiting-long-term-use-calcitonin-medic ines

299. Armingeat T, Brondino R, Pham T, Legré V, Lafforgue P(2006)Intravenous pamidronate for pain relief in recent osteoporotic

Archives of Osteoporosis(2025) 20:119

Page 49 of 50119

119

vertebral compression fracture: a randomized double-blind con-trolled study. Osteoporosis Int: 17:1659-1665

300. Gibbs JC, MacIntyre NJ, Ponzano M, Templeton JA, Thabane L,Papaioannou A, Giangreggio LM(2019) Exercise for improving outcomes after osteoporotic vertebral fracture. Cochrane Data-base Syst Rev 7(7):CD008618.https://doi.org/10.1002/14651858.CD008618.pub3

301. Ebeling PR, Akesson K, Bauer DC et al(2019) The efficacy and safety of vertebral augmentation: a second ASBMR task force report.J Bone Miner Res 34:3-21.https://doi.org/10.1002/jbmr.

302. Svensson HK, Olson LE, Hansson T, Karlsson J, Hansson-Olof-sson E(2017) The effects of person-centered or other supportive interventions in older women with osteoporotic vertebral com-pression fractures-a systematic review of the literature. Osteo-poros Int 28:2521-2540

303. Hofler RC, Jones GA(2020) Bracing for acute and subacute osteoporotic compression fractures: a systematic review of the literature. World Neurosurg 141:e453-e460

304. Buchbinder R, Johnston RV, Rischin KJ, Homik J, Jones CA,Golmohammadi K, Kallmes DF(2018) Percutaneous vertebro-plasty for osteoporotic vertebral compression fracture. Cochrane Database Syst Rev 11:Cd006349

305.Zambito A, Bianchini D, Gatti D, Rossini M, Adami S, Viapi-ana O(2007) Interferential and horizontal therapies in chronic low back pain due to multiple vertebral fractures: a randomized,double blind, clinical study. Osteoporosis Int 18:1541-1545

306. Axelsson KF, Johansson H, Lundh D, Möller M, Lorentzon M(2020) Association between recurrent fracture risk and imple-mentation of fracture liaison services in four Swedish hospitals:of a cohort study.J Bone Miner Res:35:1216-1223

307. Wu CH,Tu ST,Chang YF,Chan DC,Chen JT,Lin CH,Sing S, Dasari M, Chen JF,Tsai KS(2018) Fracture liaison services improve outcomes of patients with osteoporosis-related frac-tures: a systematic literature review and meta-analysis. Bone 111:92-100

308. Department of Health(2009) Fracture prevention services- an economic evaluation. https://data.parliam.uk/DepositedPapers/Files/DEP2011-0324/DEP2011-0324.pdf

309. NHS_RightCare(2017) Falls and fragility fractures pathway.https://www.england.nhs.uk/rightcare/products/pathways/falls-and-fragility-fractures-pathway/

310.Javaid MK, Kyer C, Mitchell PJ et al(2015) Effective secondary fracture prevention: implementation of a global benchmarking of clinical quality using the IOF capture the fracture(R) best prac-tice framework tool. Osteoporosis Int 26:2573-2578

311. Royal Osteoporosis Society(2019) Effective secondary preven-tion of fragility fractures: clinical standards for fracture liaison services https://theros.org.uk/media/leubz33w/ros-clinical-stand ards-for-fracture-liaison-services-august-2019.pdf

312. Ganda K, Puech M, Chen JS, Speerin R, Blease J, Center JR,Eisman JA, March L, Seibel MJ(2013) Models of care for the secondary prevention of osteoporous fractures: a systematic review and meta-analysis. Osteoporosis Int 24:393-406

313. Ganda K, Mitchell PJ, Seibel MJ(2019) Chapter 3, models of secondary fracture prevention: systematic review and meta analysis of outcomes. In: Seibel MJ, Mitchell PJ(ed) Secondary Fracture Prevention an International Perspective, Elsevier Inc,pp 33-62

314. Wu CH, Chen CH, Chen PH, Yang JJ, Chang PC, Huang TC,Bagga S, Sharma Y, Lin RM, Chan DC(2018) Identifying char-acteristics of an effective fracture liaison service: systematic literature review. Osteoporos Int 29:1023-1047

315. Public Health England(2017) Falls and fracture consensus statement: supporting commissioning for prevention Public Health England with the National Falls Prevention Coordina-tion Group.http://www.gov.uk/phe

316. Royal Osteoporision, Society(2017) Clinical guidance for the effective identification of vertebral fractures https://theros.org.uk/healthcare-professionals/tools-and-resources/clinical-guida nce/

317. Bullock L, Crawford-Manning F, Cottrell E al(2021) Develop-ing a model fracture liaison service consultation with patients,carers and clinicians: a Delphi survey to inform content of the iFrapP complex consultation intervention. Arch Osteoporos 16:58

318. Paskins Z, Torres Redan VD, Hawarden AW et al(2020) Qual-ity and effectiveness of osteoporosis treatment decision aids:a systematic review and environmental scan. Osteoporos Int 31:1837-1851

319. National Institute for Health and Care Excellence(2009) Medi-cines adherence: involving patients in decisions about prescribed medicines and supporting adherence. Clinical guideline[CG76].https://www.nice.org.uk/guidance/cg76

320.Cornelissen D, de Kunder S,Si L, Reginster JY,Evers S, Boonen A, Hilgismann M(2020) Interventions to improve adherence to anti-osteoporosis medications: an updated systematic review.Osteoporos Int 31:1645-1669

321. Martin J, Viprey M, Castagne B, Merle B, Giroudon C, Chapur-lat R, Schott AM(2020) Interventions to improve osteoporlo-sis care: a systematic review and meta-analysis. Osteoporos Int 31:429-446

322.Clynes MA,Westbury LD,Dennison EM,Kanis JA,Javaid MK,Harvey NC,Fujita M,Cooper C,Leslie WD,Shuhart CR(2020)Bone densitometry worldwide: a global survey by the ISCD and IOF. Osteoporosis Int 31:1779-1786

323. The Health Foundation(2021) Quality improvement made simple: what everyone should know about health care quality improvement, 3rd edn. The Health Foundation, 8 Salisbury Square, London

324. Javaid MK, Harvey NC, McCloskey E, Kanis JA, C C(2021)Assessment and management of imminent fracture risk in the setting of the fracture liaison service. Osteo Internat in press:https://doi.org/10.1007/s00198-021-06284-9

325.Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ 3rd,Khaltaev N(2008) A reference standard for the description of osteoporosis. Bone A42:467-475

326. International Society for Clinical Densitometry(ISCD)(2019)Adult official positions of the ISCD. https://iscd.org/learn/offic ial-positions/adult-positions/

327.Andrews J,Guyat G, Oxman AD et al(2013) Grade guide-lines:14. Going from evidence to recommendations: the signifi-cance and presentation of recommendations. J Clin Epidemiol 66:719-725

328. Jaeschke R, Guyatt GH, Dellinger P, Schünemann H, Levy MM,Kunz R, Norris S, Bion J(2008) Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elu-sive.BMI 337:a7444

329. National Institute for Health and Care Excellence(NICE)(2012)The guidelines manual. NICE process and methods[PMG6].Section 9 Developing and wording guideline recommendations.https://www.nice.org.uk/process/pmg6/chapter/developing-and-wording-guideline-recommendations

330. Gartlehner G, Patel SV, Feltner C, Weber RP, Long R, Mul-ican K, Boland E, Lux L, Viswanathan M(2017) Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: evidence report and systematic

119 Page 50 of 50

Archives of Osteoporosis(2025) 20:119

(2025) 20:119

review for the US Preventive Services Task Force. JAMA 318:2234-2249

331.Nayak S, Greenspan SL(2017) Osteoporosis treatment efficacy for men: a systematic review and meta-analysis. J Am Geriatr Soc 65:490-495

32. Zeng LF, Pan BQ, Liang GH et al(2019) Does routine anti-oste-oporosis medication lower the risk of fractures in male subjects?An updated systematic review with meta-analysis of clinical tri-als. Front Pharmacol 10:882

333. Wang YK,Zhang YM,Qin SQ,Wang X,Ma T,Guo JB,Zhu C, Luo ZJ(2018) Effects of alendronate for treatment of gluco-corticoid-induced osteoporosis: a meta-analysis of randomized controlled trials. Medicine(Baltimore) 97:e12691

334. Yanbeiya Z, Hansen KE(2019) Denosumab in the treatment of glucocorticoid-induced osteoporosis: a systematic review and meta-analysis. Drug Des Devel Ther 13:2843-2852

335. Paskins Z,Torres Roldan VD,Hawarden AW et al(2020) Quality and effectiveness of osteoporosis treatment decision aids: a sys-tematic review and environmental scan. Osteoporos Int. https://doi.org/10.1007/s00198-020-05479-w

Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

All members gave up their time voluntarily, without any remuneration for their work.

Authors and Affiliations

Celia L. Gregon ${}^{1,2}$ . David J. Armstrong ${}^{3}$ . Christina Avinerou ${}^{4,5}$ . Jean Bowden ${}^{25}$ . Cyrus Cooper ${}^{6,7,8}$ .

Lucy Douglas, ${ }^{9,10}$ . John Edwards ${ }^{11,12}$ . Neil J. L. Gittoes ${ }^{13}$ . Nicholas C. Harvey ${ }^{6,7}$ . John A. Kanis ${ }^{14}$ . Sarah Leyland ${ }^{15}$ .

Rebecca Low ${}^{16,17}$ . Eugene McCloskey ${}^{18}$ . Katie Moss ${}^{19}$ . Jane Parker ${}^{26}$ . Zoe Paskins ${}^{20}$ . Kenneth Poole ${}^{21}$ .

David M. Reid 22. Mike Stone 23. Julia Tomson 15. Nic Vine 27. Juliet Compston 24. National Osteoporosis Guideline

Group(NOGG)

Celia.L.Gregson celia.gregson@bristol.ac.uk

1 Musculoskeletal Research Unit, Bristol Medical School,Learning and Research Building, University of Bristol,Southmead Hospital, Bristol BS10 5NB, UK

2 Royal United Hospital NHS Foundation Trust, Bath, UK

3 Western Health and Social Care Trust(NI), Nutrition Innovation Centre for Food and Health, Ulster University,Belfast, UK

4 Sterndale Surgery, London, UK

5 Department of Primary Care and Population Health,University College London, London, UK

<BeginOfPara>6 MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK

7 NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

8 NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

9 Lindley Group Practice Huddersfield, Huddersfield, UK

${}^{10}$ Musculoskeletal Medicine and Rheumatology, East Lancashire Hospitals NHS Trust, Blackburn, UK

${}^{11}$ Primary Care Centre Versus Arthritis, School of Medicine,Keele University, Keele, Staffordshire, UK

${}^{12}$ Wolstanton Medical Centre, Newcastle-Under-Lyme, UK

${}^{13}$ Centre for Endocrinology, Diabetes and Metabolism, Queen Elizabeth Hospital, University Hospitals Birmingham&University of Birmingham, Birmingham, UK

${}^{14}$ Centre for Metabolic Bone Diseases, University of Sheffield,Sheffield, UK

15 Royal Osteoporosis Society, Bath, UK

16 Marcham Road Health Centre, Abingdon, UK

17 Metabolic Bone Disease, Nuffield Orthopaedic Centre,Uxford, UK

18 Department of Oncology & Metabolism, MRC Versus Arthritis Centre for Integrated Research in Musculoskeletal Ageing(CIMA), Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK

19 St.George's University Hospital, London, UK

20 School of Medicine, Keele University, Haywood Academic Rheumatology Centre, Haywood Hospital, Midlands Partnership NHS Foundation Trust, Keele, Stoke-On-Trent,UK

21 Department of Medicine, University of Cambridge,Cambridge, UK

${}^{22}$ University of Aberdeen, Aberdeen, Scotland

23 University Hospital Llandough, Cardiff and Vale University Health Board, Llandough, UK

${}^{24}$ School of Clinical Medicine, University of Cambridge,Cambridge, UK

25 West Midlands, Birmingham, UK

26 Preston, Lancashire, UK

27 Plymouth, Devon, UK