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Sequential romosozumab-to-alendronate or sequential teriparatide-to-alendronate can be a cost-effective treatment option for postmenopausal women at very high risk of fracture., Purpose: To estimate the 10-year probability of a major osteoporotic fracture (MOF) at which sequential treatment with romosozumab or teriparatide followed by alendronate, compared with alendronate alone, becomes cost-effective in a UK setting., Methods: A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), in women receiving sequential treatment with either romosozumab or teriparatide followed by alendronate, compared with alendronate alone. Patients aged 50 to 90 years with a recent MOF, hip or spine fracture were followed from the start of a 5-year treatment until the age of 100 years or death. The analysis had a healthcare perspective. Efficacy of romosozumab, teriparatide and alendronate was derived from phase III randomised controlled trials. Resource use and unit costs were derived from the literature. Cost-effectiveness intervention threshold (CEIT), defined as the 10-year probability of a major osteoporotic fracture at which treatment becomes cost-effective, was compared with clinically appropriate intervention thresholds for bone-forming treatment in women with very high fracture risk as recommended by the UK National Osteoporosis Guideline Group (NOGG)., Results: The base case analysis showed that sequential romosozumab-to-alendronate treatment was cost-effective from a 10-year MOF probability of 18-35% and above depending on age and site of sentinel fracture at a willingness to pay (WTP) of £30,000. For teriparatide-to-alendronate, treatment was cost-effective at a 10-year MOF probability of 27-57%. The results were sensitive to pricing of the drugs but relatively insensitive to treatment duration, romosozumab persistence assumptions, and site of sentinel fracture. The CEITs for romosozumab-to-alendronate treatment were lower than the clinical thresholds from the age of 70 years meaning that treatment could be considered both cost-effective and aligned with the NOGG treatment guidelines. By contrast, for teriparatide-to-alendronate the CEITs were higher than the clinical thresholds irrespective of age. However, cost-effective scenarios were found in the presence of strong clinical risk factors in addition to a recent sentinel fracture., Conclusion: The results of this study indicate that sequential romosozumab-to-alendronate or teriparatide-to-alendronate treatment can be a cost-effective treatment option for postmenopausal women at very high risk of fracture., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Task Force on 'Clinical Algorithms for Fracture Risk' commissioned by the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee has recommended that FRAX® models in the US do not include adjustment for race and ethnicity. This position paper finds that an agnostic model would unfairly discriminate against the Black, Asian and Hispanic communities and recommends the retention of ethnic and race-specific FRAX models for the US, preferably with updated data on fracture and death hazards. In contrast, the use of intervention thresholds based on a fixed bone mineral density unfairly discriminates against the Black, Asian and Hispanic communities in the US. This position of the Working Group on Epidemiology and Quality of Life of the International Osteoporosis Foundation (IOF) is endorsed both by the IOF and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO)., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Associations between different sarcopenia definitions and the risk of injurious falls were investigated in 75-80-year-old women in the Swedish SUPERB cohort. Only sarcopenia according to the Sarcopenia Definitions and Outcomes Consortium (SDOC) definition was associated with incident injurious falls with and without fractures in older women., Purpose: To investigate the association between three commonly used sarcopenia definitions and the risk of injurious falls in a population of older Swedish women., Methods: A total of 2,883 75-80-year-old women with complete data on relevant sarcopenia definitions from the Swedish SUPERB cohort were studied. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC: low handgrip strength and gait speed), revised European Working Group on Sarcopenia in Older People (EWGSOP2: low appendicular lean mass index (ALMI, dual-energy X-ray absorptiometry (DXA)-derived), appendicular lean mass (kg)/height (m 2 ), hand grip strength (kg), or low chair stand time (s)), and Asian Working Group for Sarcopenia (AWGS: low ALMI and hand grip strength (kg) or low gait speed (m/s)). Questionnaires captured the occurrence of falls in the past 12 months. Incident injurious falls were identified using national registers. Cox regression (hazard ratios (HR) and 95% confidence intervals (CI)) analyses were performed without adjustment and after adjustment for age, body mass index, previous falls, and the Charlson comorbidity index., Results: During a median (IQR) follow-up time of 7.06 (6.2-7.9) years, there were 491 injurious falls without fracture and 962 injurious falls when also including falls resulting in a fracture. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased risk of injurious falls. Individuals with sarcopenia defined by SDOC had a higher risk of injurious falls with and without fracture (HR 2.11; 95% CI, 1.63-2.73 and HR, 2.16; 95% CI, 1.55-3.02, respectively)., Conclusion: Sarcopenia definitions confined to muscle function and strength such as SDOC, rather than including DXA-determined ALMI (EWGSOP2 and AWGS), are associated with incident injurious falls with and without fractures in older women., (© 2024. The Author(s).)

This position paper of the International Osteoporosis Foundation reports the findings of an IOF Commission to consider to recommend rules of partnership with scientists belonging to a country which is currently responsible for an armed conflict, anywhere in the world. The findings and recommendations have been adopted unanimously by the Board of IOF., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

This study evaluated the cost-effectiveness of sequential treatment with romosozumab-to-alendronate compared to alendronate monotherapy and teriparatide-to-alendronate, in postmenopausal osteoporotic women from a Belgian healthcare perspective. Romosozumab-to-alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide-to-alendronate for osteoporotic women at high risk of fracture in Belgium., Purpose: This study aimed to evaluate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate compared to alendronate monotherapy and teriparatide followed by alendronate, in postmenopausal osteoporotic women at high risk of fracture, from a Belgian healthcare perspective. Romosozumab is reimbursed in Belgium since December 2021., Methods: A Markov microsimulation model was used to evaluate the cost-effectiveness of romosozumab-to-alendronate compared to alendronate monotherapy and to teriparatide-to-alendronate over a lifetime horizon. Patients transition between five different health states every 6 months based on fracture risks or death. The model was populated with Belgium-specific epidemiological and cost data, where available. The fracture risk reduction of romosozumab treatment was collated from the ARCH study, and from a published network meta-analysis. Costs were included from a healthcare perspective (NIHDI). Cost-effectiveness was reported in terms of costs per quality-adjusted life year (QALY), reported in Euro (€) 2022. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed., Results: Romosozumab-to-alendronate was associated with 0.12 additional QALYs at an additional cost of €2314 compared to alendronate monotherapy, resulting in an ICER of €19,978. Compared to teriparatide-to-alendronate, romosozumab-to-alendronate was found to be dominant, with higher QALYs and lower costs. The base-case results were robust to uncertainty in the input parameters when conducting the sensitivity analysis., Conclusion: Sequential treatment with romosozumab followed by alendronate was found to be cost-effective compared to alendronate monotherapy and dominant compared to teriparatide followed by alendronate for postmenopausal women with osteoporosis at high risk of fracture in Belgium., (© 2024. The Author(s).)

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm., Introduction: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD)., Methods: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients., Results: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men., Conclusions: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction., (© 2024. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The RICO study indicated that most patients would like to receive information regarding their fracture risk but that only a small majority have actually received it. Patients globally preferred a visual presentation of fracture risk and were interested in an online tool showing the risk., Purpose: The aim of the Risk Communication in Osteoporosis (RICO) study was to assess patients' preferences regarding fracture risk communication., Methods: To assess patients' preferences for fracture risk communication, structured interviews with women with osteoporosis or who were at risk for fracture were conducted in 11 sites around the world, namely in Argentina, Belgium, Canada at Hamilton and with participants from the Osteoporosis Canada Canadian Osteoporosis Patient Network (COPN), Japan, Mexico, Spain, the Netherlands, the UK, and the USA in California and Washington state. The interviews used to collect data were designed on the basis of a systematic review and a qualitative pilot study involving 26 participants at risk of fracture., Results: A total of 332 women (mean age 67.5 ± 8.0 years, 48% with a history of fracture) were included in the study. Although the participants considered it important to receive information about their fracture risk (mean importance of 6.2 ± 1.4 on a 7-point Likert scale), only 56% (i.e. 185/332) had already received such information. Globally, participants preferred a visual presentation with a traffic-light type of coloured graph of their FRAX® fracture risk probability, compared to a verbal or written presentation. Almost all participants considered it important to discuss their fracture risk and the consequences of fractures with their healthcare professionals in addition to receiving information in a printed format or access to an online website showing their fracture risk., Conclusions: There is a significant communication gap between healthcare professionals and patients when discussing osteoporosis fracture risk. The RICO study provides insight into preferred approaches to rectify this communication gap., (© 2023. The Author(s).)

A large international meta-analysis using primary data from 64 cohorts has quantified the increased risk of fracture associated with a previous history of fracture for future use in FRAX., Introduction: The aim of this study was to quantify the fracture risk associated with a prior fracture on an international basis and to explore the relationship of this risk with age, sex, time since baseline and bone mineral density (BMD)., Methods: We studied 665,971 men and 1,438,535 women from 64 cohorts in 32 countries followed for a total of 19.5 million person-years. The effect of a prior history of fracture on the risk of any clinical fracture, any osteoporotic fracture, major osteoporotic fracture, and hip fracture alone was examined using an extended Poisson model in each cohort. Covariates examined were age, sex, BMD, and duration of follow-up. The results of the different studies were merged by using the weighted β-coefficients., Results: A previous fracture history, compared with individuals without a prior fracture, was associated with a significantly increased risk of any clinical fracture (hazard ratio, HR = 1.88; 95% CI = 1.72-2.07). The risk ratio was similar for the outcome of osteoporotic fracture (HR = 1.87; 95% CI = 1.69-2.07), major osteoporotic fracture (HR = 1.83; 95% CI = 1.63-2.06), or for hip fracture (HR = 1.82; 95% CI = 1.62-2.06). There was no significant difference in risk ratio between men and women. Subsequent fracture risk was marginally downward adjusted when account was taken of BMD. Low BMD explained a minority of the risk for any clinical fracture (14%), osteoporotic fracture (17%), and for hip fracture (33%). The risk ratio for all fracture outcomes related to prior fracture decreased significantly with adjustment for age and time since baseline examination., Conclusion: A previous history of fracture confers an increased risk of fracture of substantial importance beyond that explained by BMD. The effect is similar in men and women. Its quantitation on an international basis permits the more accurate use of this risk factor in case finding strategies., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

This narrative review summarises the recommendations of a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) for the conduct and reporting of real-world evidence studies with a focus on osteoporosis research., Purpose: Vast amounts of data are routinely generated at every healthcare contact and activity, and there is increasing recognition that these real-world data can be analysed to generate scientific evidence. Real-world evidence (RWE) is increasingly used to delineate the natural history of disease, assess real-life drug effectiveness, understand adverse events and in health economic analysis. The aim of this work was to understand the benefits and limitations of this type of data and outline approaches to ensure that transparent and high-quality evidence is generated., Methods: A ESCEO Working Group was convened in December 2022 to discuss the applicability of RWE to osteoporosis research and approaches to best practice., Results: This narrative review summarises the agreed recommendations for the conduct and reporting of RWE studies with a focus on osteoporosis research., Conclusions: It is imperative that research using real-world data is conducted to the highest standards with close attention to limitations and biases of these data, and with transparency at all stages of study design, data acquisition and curation, analysis and reporting to increase the trustworthiness of RWE study findings., (© 2023. The Author(s).)

Key statements of the Russian clinical guidelines on the diagnosis and treatment of osteoporosis are summarized. They were developed by a task force representing the key Russian professional associations involved in the management of osteoporosis and approved by the Russian Ministry of Health., Purpose: To summarize key statements of the Russian clinical practice guidelines for the diagnosis and treatment of osteoporosis., Methods: The Russian clinical guidelines on the diagnosis and treatment of osteoporosis were developed by a task force representing the key Russian professional associations involved in the management of osteoporosis: These comprised the Russian Association of Endocrinologists, the Russian Association for Osteoporosis, the Association of Rheumatologists of Russia, the Association of Orthopedic surgeons and Traumatologists of Russia, the Russian Association of Gynecologists-Endocrinologists, and the Russian Association of Gerontologists and Geriatrics. The guidelines are based on a systematic literature review and principles of evidence-based medicine and were compiled in accordance with the requirements for clinical recommendations developed by the Ministry of Health of the Russian Federation., Results: Key statements included in the Russian guidelines of osteoporosis approved by the Russian Ministry of Health in 2021 are summarized. The statements are graded based on levels of evidence and supported by short comments. The guidelines are focused on the current approach to screening, diagnosis, differential diagnosis, and treatment of osteoporosis., Conclusion: These guidelines are a practical tool for general practitioners, as well as medical specialists, primarily endocrinologists, rheumatologists, orthopedic surgeons, and other physicians who are involved in the management of patients with osteoporosis., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The incidence of hip and major osteoporotic fracture was increased in patients with primary hyperparathyroidism even in patients not referred for parathyroidectomy. The risk of death was also increased which attenuated an effect on fracture probabilities. The findings argue for widening the indications for parathyroidectomy in mild primary hyperparathyroidism., Introduction: Primary hyperparathyroidism (PHPT) is associated with an increase in the risk of fracture. In FRAX, the increase in risk is assumed to be mediated by low bone mineral density (BMD). However, the risk of death is also increased and its effect on fracture probability is not known., Objective: The aim of this study was to determine whether PHPT affects hip fracture and major osteoporotic fracture risk independently of bone mineral density (BMD) and whether this and any increase in mortality affects the assessment of fracture probability., Methods: A register-based survey of patients with PHPT and matched controls in Denmark were identified from hospital registers. The incidence of death, hip fracture, and major osteoporotic fracture were determined for computing fracture probabilities excluding time after parathyroidectomy. The gradient of risk for fracture for differences in BMD was determined in a subset of patients and in BMD controls. The severity of disease was based on serum calcium and parathyroid hormone levels., Results: We identified 6884 patients with biochemically confirmed PHPT and 68,665 matched population controls. On follow-up, excluding time after parathyroidectomy in those undergoing surgery, patients with PHPT had a higher risk of death (+52%), hip fracture (+48%), and major osteoporotic fracture (+36%) than population controls. At any given age, average 10-year probabilities of fracture were higher in patients with PHPT than population controls. The gradient of fracture risk with differences in BMD was similar in cases and controls. Results were similar when confined to patients not undergoing parathyroidectomy. Fracture probability decreased with the severity of disease due to an increase in mortality rather than fracture risk., Conclusion: The risk of hip and other major osteoporotic fracture is increased in PHPT irrespective of the disease severity. Fracture probability was attenuated due to the competing effect of mortality. The increased fracture risk in patients treated conservatively argues for widening the indications for parathyroidectomy in mild PHPT., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

A greater propensity to falling is associated with higher fracture risk. This study provides adjustments to FRAX-based fracture probabilities accounting for the number of prior falls., Introduction: Prior falls increase subsequent fracture risk but are not currently directly included in the FRAX tool. The aim of this study was to quantify the effect of the number of prior falls on the 10-year probability of fracture determined with FRAX®., Methods: We studied 21,116 women and men age 40 years or older (mean age 65.7 ± 10.1 years) with fracture probability assessment (FRAX®), self-reported falls for the previous year, and subsequent fracture outcomes in a registry-based cohort. The risks of death, hip fracture, and non-hip major osteoporotic fracture (MOF-NH) were determined by Cox proportional hazards regression for fall number category versus the whole population (i.e., an average number of falls). Ten-year probabilities of hip fracture and major osteoporotic fracture (MOF) were determined according to the number of falls from the hazards of death and fracture incorporated into the FRAX model for the UK. The probability ratios (number of falls vs. average number of falls) provided adjustments to conventional FRAX estimates of fracture probability according to the number of falls., Results: Compared with the average number of falls, the hazard ratios for hip fracture, MOF-NH and death were lower than unity in the absence of a fall history. Hazard ratios increased progressively with an increasing number of reported falls. The probability ratio rose progressively as the number of reported falls increased. Probability ratios decreased with age, an effect that was more marked the greater the number of prior falls., Conclusion: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability according to the number of prior falls., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

This position paper of the International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) addresses the rationale for separate diagnostic and intervention thresholds in osteoporosis. We conclude that the current BMD-based diagnostic criteria for osteoporosis be retained whilst clarity is brought to bear on the distinction between diagnostic and intervention thresholds., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

The risk of a recurrent fragility fracture is high following a first fracture and higher still with more than one prior fracture. This study provides adjustments to FRAX-based fracture probabilities accounting for the number of prior fractures., Introduction: Prior fractures increase subsequent fracture risk. The aim of this study was to quantify the effect of the number of prior fractures on the 10-year probability of fracture determined with FRAX®., Methods: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Ten-year probabilities of hip fracture and major osteoporotic fracture (MOF) were determined according to the number of prior osteoporotic fractures over a 20-year interval from the hazards of death and fracture. Fracture probabilities were also computed for a prior osteoporotic fracture irrespective of the number of previous fractures. The probability ratios provided adjustments to conventional FRAX estimates of fracture probability according to the number of prior fractures., Results: Probability ratios to adjust 10-year FRAX probabilities of a hip fracture and MOF increased with the number of prior fractures but decreased with age in both men and women. Probability ratios were similar in men and women and for hip fracture and MOF. Mean probability ratios according to the number of prior fractures for all scenarios were 0.95, 1.08, 1.21 and 1.35, for 1,2, 3 and 4 or more prior fractures, respectively. Thus, a simple rule of thumb is to downward adjust FRAX-based fracture probabilities by 5% in the presence of a single prior fracture and to uplift probabilities by 10, 20 and 30% with a history of 2, 3 and 4 or more prior fractures, respectively., Conclusion: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability according to the number of prior fractures., (© 2022. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

In a combined analysis of 25,389 postmenopausal women aged 50-79 years, enrolled in the two Women's Health Initiative hormone therapy trials, menopausal hormone therapy vs. placebo reduced the risk of fracture regardless of baseline FRAX fracture probability and falls history., Introduction: The aim of this study was to determine if the anti-fracture efficacy of menopausal hormone therapy (MHT) differed by baseline falls history or fracture risk probability as estimated by FRAX, in a combined analysis of the two Women's Health Initiative (WHI) hormone therapy trials., Methods: A total of 25,389 postmenopausal women aged 50-79 years were randomized to receive MHT (n = 12,739) or matching placebo (n = 12,650). At baseline, questionnaires were used to collect information on falls history, within the last 12 months, and clinical risk factors. FRAX 10-year probability of major osteoporotic fracture (MOF) was calculated without BMD. Incident clinical fractures were verified using medical records. An extension of Poisson regression was used to investigate the relationship between treatment and fractures in (1) the whole cohort; (2) those with prior falls; and (3) those without prior falls. The effect of baseline FRAX probability on efficacy was investigated in the whole cohort., Results: Over 4.3 ± 2.1 years (mean ± SD), MHT (vs. placebo) significantly reduced the risk of any clinical fracture (hazard ratio [HR] 0.72 [95% CI, 0.65-0.78]), MOF (HR 0.60 [95% CI, 0.53-0.69]), and hip fracture (0.66 [95% CI, 0.45-0.96]). Treatment was effective in reducing the risk of any clinical fracture, MOF, and hip fracture in women regardless of baseline FRAX MOF probability, with no evidence of an interaction between MHT and FRAX (p > 0.30). Similarly, there was no interaction (p > 0.30) between MHT and prior falls., Conclusion: In the combined WHI trials, compared to placebo, MHT reduces fracture risk regardless of FRAX probability and falls history in postmenopausal women., (© 2022. The Author(s).)

We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures., Introduction: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors., Methods: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible., Results: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed., Conclusions: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266))., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

This study identified the costs and health-related quality of life impacts of several post-fracture multidisciplinary care pathways specific to individual skeletal site (hip, distal forearm, vertebrae, humerus). These care pathways may assist healthcare providers in allocating resources for osteoporotic fractures in more effective and cost-efficient ways., Introduction: This micro-costing study was undertaken to provide the estimated healthcare costs of several fracture site-specific health service use pathways associated with different trajectories of health-related quality of life (HRQoL) 12-months post-fracture., Methods: The study included 4126 adults aged ≥ 50 years with a fragility fracture (1657 hip, 681 vertebrae, 1354 distal forearm, 434 humerus) from the International Costs & Utilities Related to Osteoporotic fractures Study (ICUROS). ICUROS participants were asked to recall the frequency and duration (where applicable) of their health and community care service use at 4- and 12-month follow-up visits. Patient-level costs were identified and aggregated to determine the average cost of healthcare use related to the fracture in each care pathway (presented in Australian 2021 dollars). Mean cost differences were calculated and analysed using a one-way analysis of variance (ANOVA) and post hoc Bonferroni correction to determine any statistically significant differences., Results: The total direct cost of fractures was estimated at $89564, $38926, $18333, and $38461AUD per patient for hip, vertebral, wrist, and humeral participants, respectively. A Kruskal-Wallis test yielded a statistically significant difference in cost values between most care pathways (p < 0.001). Of the 20 care pathways, those associated with recovery of HRQoL had lower mean costs per patient across each fracture site., Conclusions: This study identified the costs and HRQoL impacts of several multidisciplinary care pathways for individual fracture sites based on the health service utilization of an international cohort of older adults. These care pathways may assist healthcare providers in allocating resources for fragility fractures in more effective and cost-efficient ways., (© 2022. The Author(s).)

Vertebral fracture (VF) is a strong predictor of subsequent fracture. In this study of older women, VF, identified by dual-energy X-ray absorptiometry (DXA) vertebral fracture assessment (VFA), were associated with an increased risk of incident fractures and had a substantial impact on fracture probability, supporting the utility of VFA in clinical practice., Purpose: Clinical and occult VF can be identified using VFA with dual-energy X-ray absorptiometry (DXA). The aim of this study was to investigate to what extent VFA-identified VF improve fracture risk prediction, independently of bone mineral density (BMD) and clinical risk factors used in FRAX., Methods: A total of 2852 women, 75-80 years old, from the prospective population-based study SUPERB cohort, were included in this study. At baseline, BMD was measured by DXA, VF diagnosed by VFA, and questionnaires used to collect data on risk factors for fractures. Incident fractures were captured by X-ray records or by diagnosis codes. An extension of Poisson regression was used to estimate the association between VFA-identified VF and the risk of fracture and the 5- and 10-year probability of major osteoporotic fracture (MOF) was calculated from the hazard functions for fracture and death., Results: During a median follow-up of 5.15 years (IQR 4.3-5.9 years), the number of women who died or suffered a MOF, clinical VF, or hip fracture was 229, 422, 160, and 124, respectively. A VFA-identified VF was associated with an increased risk of incident MOF (hazard ratio [HR] = 1.78; 95% confidence interval [CI] 1.46-2.18), clinical VF (HR = 2.88; 95% [CI] 2.11-3.93), and hip fracture (HR = 1.67; 95% [CI] 1.15-2.42), adjusted for age, height, and weight. For women at age 75 years, a VFA-identified VF was associated with 1.2-1.4-fold greater 10-year MOF probability compared with not taking VFA into account, depending on BMD., Conclusion: Identifying an occult VF using VFA has a substantial impact on fracture probability, indicating that VFA is an efficient method to improve fracture prediction in older women., (© 2022. The Author(s).)

The Danish Fracture Risk Evaluation Model (FREM) was found to predict fracture risk independent of 10-year fracture probability derived with the FRAX® tool including bone mineral density from DXA., Introduction: FREM was developed from Danish public health registers without DXA information to identify high imminent risk of major osteoporotic fracture (MOF) and hip fracture (HF), while FRAX® estimates 10-year fracture probability from clinical risk factors and femoral neck bone mineral density (BMD) from DXA. The FREM algorithm showed significant 1- and 2-year fracture risk stratification when applied to a clinical population from Manitoba, Canada. We examined whether FREM predicts 10-year fracture risk independent of 10-year FRAX probability computed with BMD., Methods: Using the Manitoba BMD Program registry, we identified women and men aged ≥ 45 years undergoing baseline BMD assessment. We calculated FREM and FRAX scores, and identified incident fractures over 10 years. Hazard ratios (HRs) for incident fracture were estimated according to FREM quintile, adjusted for FRAX probability. We compared predicted with observed 10-year cumulative fracture probability estimated with competing mortality., Results: The study population comprised 74,446 women, mean age 65.2 years; 7945 men, mean age 67.5 years. There were 7957 and 646 incident MOF and 2554 and 294 incident HF in women and men, respectively. Higher FREM scores were associated with increased risk for MOF (highest vs middle quintile HRs 1.49 women, 2.06 men) and HF (highest vs middle quintile HRs 2.15 women, 2.20 men) even when adjusted for FRAX. Greater mortality with higher FREM scores attenuated its effect on 10-year fracture probability. In the highest FREM quintile, observed slightly exceeded predicted 10-year probability for MOF (ratios 1.05 in women, 1.49 in men) and HF (ratios 1.29 in women, 1.34 in men)., Conclusions: Higher FREM scores identified women and men at increased fracture risk even when adjusted for FRAX probability that included BMD; hence, FREM provides additional predictive information to FRAX. FRAX slightly underestimated 10-year fracture probability in those falling within the highest FREM quintile., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

This observational study prospectively assessed direct and indirect costs related to patient management over 18 months following hip, clinical vertebral, humeral, or distal forearm fracture events in France. It appears that their levels were much higher than the previous estimates, raising the burden of osteoporosis-related fractures on public health expenditures., Introduction: This prospective observational study assessed the costs related to patient management over the 18-month period following the event of a hip, clinical vertebral, humeral, or distal forearm fracture in France., Methods: Individuals aged ≥ 50 years old with the diagnosis of a fragility fracture in six French University Hospitals were enrolled in the International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS). All resources used over the defined period and related to fracture and the underlying osteoporosis management were collected by questionnaires at baseline, 4 months, 12 months, and 18 months. Information was collected by direct or phone contact completed by patients' records and interviews of partner, family, and general practitioners. Costs were estimated from a societal perspective, including direct and indirect costs. We implemented recursive partitioning analysis (RPA), a statistical learning algorithm to identify predictors of costs., Results: Four hundred thirty-one patients (mean age 72.5 years; 84.6% women) were evaluated. Among them, 17.6% had a prior fracture in the last 5 years. Approximately half of the whole group lived alone in the community, and 56.8% were from a low- or middle-income category. Over the 18-month period of evaluation, total costs (including initial fracture-related and follow-up ones) were 23 926 €, 14 561 €, and 6 905 € for the hip, clinical vertebral, and distal forearm fracture, respectively. Over a year, costs related to a humeral fracture were 10 319 €. The RPA identified mobility impairment prior to fracture as a predictor of increase in costs related to fracture., Conclusions: Our study for the first time prospectively assessed total costs related to the four main osteoporotic fractures in France. It appears that their levels were much higher than previous estimates, raising the burden of osteoporosis-related fractures on public health expenditures., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

The Fracture Risk Evaluation Model (FREM) identifies individuals at high imminent risk of major osteoporotic fractures. We validated FREM on 74,828 individuals from Manitoba, Canada, and found significant fracture risk stratification for all FREM scores. FREM performed better than age alone but not as well as FRAX® with BMD., Introduction: The FREM is a tool developed from Danish public health registers (hospital diagnoses) to identify individuals over age 45 years at high imminent risk of major osteoporotic fractures (MOF) and hip fracture (HF). In this study, our aim was to examine the ability of FREM to identify individuals at high imminent fracture risk in women and men from Manitoba, Canada., Methods: We used the population-based Manitoba Bone Mineral Density (BMD) Program registry, and identified women and men aged 45 years or older undergoing baseline BMD assessment with 2 years of follow-up data. From linked population-based data sources, we constructed FREM scores using up to 10 years of prior healthcare information., Results: The study population comprised 74,828 subjects, and during the 2 years of observation, 1612 incident MOF and 299 incident HF occurred. We found significant fracture risk stratification for all FREM scores, with AUC estimates of 0.63-0.66 for MOF for both sexes and 0.84 for women and 0.65-0.67 for men for HF. FREM performed better than age alone but not as well as FRAX® with BMD. The inclusion of physician claims data gave slightly better performance than hospitalization data alone. Overall calibration for 1-year MOF prediction was reasonable, but HF prediction was overestimated., Conclusion: In conclusion, the FREM algorithm shows significant fracture risk stratification when applied to an independent clinical population from Manitoba, Canada. Overall calibration for MOF prediction was good, but hip fracture risk was systematically overestimated indicating the need for recalibration., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

In this study of 695 Australian older adults (aged ≥50 years), we found that men and women had a similar trajectory of health-related quality of life (HRQoL) recovery following fragility fracture at any skeletal site. These results provide us with critical knowledge that improves our understanding of health outcomes post-fracture., Introduction: Mortality is higher in men than that in women following a fragility fracture, but it is unclear whether recovery of patient-reported outcomes such as health-related quality of life (HRQoL) differs between sexes. This study aimed to identify sex differences in HRQoL recovery 12 months post-fracture., Methods: Data were from the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study (AusICUROS). Participants recruited to AusICUROS were adults aged ≥50 years who sustained a fragility fracture. HRQoL was measured using the EQ-5D-3L at three time-points post-fracture: within 2 weeks (including pre-fracture recall) and at 4 and 12 months. Multivariate logistic regression analyses were undertaken, adjusting for confounders including age, education, income, and healthcare utilization post-fracture., Results: Overall, 695 AusICUROS participants (536 women, 77.1%) were eligible for analysis with fractures at the hip (n = 150), distal forearm (n = 261), vertebrae (n = 61), humerus (n = 52), and other skeletal sites (n = 171). At the time of fracture, men were younger, reported a higher income, and were more likely to be employed, compared with women. For all fracture sites combined, there were no differences between men and women in recovery to pre-fracture HRQoL at 12-month follow-up (adjusted OR = 1.09; 95% CI: 0.75-1.61). When stratified by fracture site, no significant sex differences were seen for hip (OR = 1.02; 95% CI: 0.42-2.52), distal forearm (OR = 1.60; 95% CI: 0.68-3.78), vertebral (OR = 2.28; 95% CI: 0.61-8.48), humeral (OR = 1.62; 95% CI: 0.16-9.99), and other fractures (OR = 1.00; 95% CI: 0.44-2.26)., Conclusion: Community-dwelling men and women who survived the 12 months following fragility fracture had a similar trajectory of HRQoL recovery at any skeletal site., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

We compared, for women in Pakistan, the utility of intervention thresholds either at a T-score ≤  - 2.5 or based on a FRAX probability equivalent to women of average body mass index (BMI) with a prior fragility fracture. Whereas the FRAX-based intervention threshold identified women at high fracture probability, the T-score threshold was less sensitive, and the associated fracture risk decreased markedly with age., Purpose: The fracture risk assessment algorithm FRAX® has been recently calibrated for Pakistan, but guidance is needed on how to apply fracture probabilities to clinical practice., Methods: The age-specific 10-year probabilities of a major osteoporotic fracture were calculated in women with average BMI to determine fracture probabilities at two potential intervention thresholds. The first comprised the age-specific fracture probabilities associated with a femoral neck T-score of - 2.5. The second approach determined age-specific fracture probabilities that were equivalent to a woman with a prior fragility fracture, without bone mineral density (BMD). The parsimonious use of BMD was additionally explored by the computation of upper and lower assessment thresholds for BMD testing., Results: When a BMD T-score ≤  - 2.5 was used as an intervention threshold, FRAX probabilities in women aged 50 years were approximately two-fold higher than in women of the same age but with no risk factors and average BMD. The relative increase in risk associated with the BMD threshold decreased progressively with age such that, at the age of 80 years or more, a T-score of - 2.5 was actually protective. The 10-year probability of a major osteoporotic fracture by age, equivalent to women with a previous fracture, rose with age from 2.1% at the age of 40 years to 17%, at the age of 90 years, and identified women at increased risk at all ages., Conclusion: Intervention thresholds based on BMD alone do not effectively target women at high fracture risk, particularly in the elderly. In contrast, intervention thresholds based on fracture probabilities equivalent to a 'fracture threshold' target women at high fracture risk., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

In women of ages 75-80 years, a low one leg standing time (OLST) was associated with an increased risk of incident fractures, independently of bone mineral density and clinical risk factors. OLST contributed substantially to fracture probability, indicating that the test should be considered when evaluating fracture risk in older women., Introduction: Physical function and risk of falls are important risk factors for fracture. A few previous studies have suggested that a one leg standing time (OLST) less than 10 s predicts fracture risk, but the impact of OLST, in addition to known clinical risk factors, for fracture probability is unknown. The aim of this study was to determine the independent contribution of OLST to fracture probability in older women., Methods: The Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures (SUPERB) is a prospective population-based study of 3028 women 75-80 years old, recruited from the greater Gothenburg area in Sweden. At baseline, information on risk factors was collected using questionnaires, bone mineral density was measured with dual-energy X-ray absorptiometry (DXA), and OLST was performed., Results: During a median follow-up of 3.6 years (IQR 1.5 years), X-ray-verified incident fractures were identified using health records. OLST was available in 2405 women. OLST less than 10 s was associated with an increased risk for incident hip fracture (Hazard Ratio (HR) 3.02, 95% Confidence Interval (CI) [1.49-6.10]), major osteoporotic fracture (HR 95% CI 1.76 [1.34-1.46]), and nonvertebral fracture (HR 95% CI 1.61 [1.26-2.05]) in Cox regression analyses adjusted for age, height, and weight. Depending on BMD, the 4-year fracture probability increased by a factor of 1.3 to 1.5 in a 75-year-old woman with a low OLST (<10 s)., Conclusion: A low OLST has a substantial impact on fracture probability and should be considered when evaluating fracture risk in older women., (© 2021. The Author(s).)

The National Osteoporosis Guideline Group (NOGG) has developed intervention thresholds based on FRAX® to characterise patients at high and very high risk of fracture., Introduction: Guidelines for the assessment of fracture risk have begun to categorise patients eligible for treatment into high and very high risk of fracture to inform choice of therapeutic approach. The aim of the present study was to develop intervention thresholds based on the hybrid assessment model of NOGG., Methods: We examined the impact of intervention thresholds in a simulated cross-sectional cohort of women age 50 years or more from the UK with the distribution of baseline characteristics based on that in the FRAX cohorts. The prevalence of very high risk using the hybrid model was compared with age-dependent thresholds used by the International Osteoporosis Foundation and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (IOF/ESCEO). The appropriateness of thresholds was tested based on the populations treated with anabolic agents., Results: With an upper intervention threshold using the IOF/ESCEO criteria, 56% of women age 50 years or more would be characterised at very high risk. This compares with 36% using the IOF/ESCEO criteria and an age-specific intervention threshold over all ages. With an upper intervention threshold of 1.6 times the pre-existing intervention threshold, 10% of women age 50 years or more would be characterised at very high risk. The data from phase 3 studies indicate that most trial participants exposed to romosozumab or teriparatide would fall into the very high-risk category., Conclusions: Proposals for FRAX-based criteria for very high risk for the NOGG hybrid model categorise a small proportion of women age 50 years or more (10%) in this highest risk stratum. The level of risk identified was comparable to that of women enrolled in trials of anabolic agents., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

In a simulated population of older women, we demonstrate that an upward shift in the population distribution of BMD by approximately 0.3SD may decrease the risk of incident fractures to the same extent as an intervention targeted to those with T-score less than -2.5., Introduction: To investigate the impact of population level or targeted alterations to BMD on the incidence of fractures., Methods: We used a simulated cohort of 49,242 women with age and body mass index distribution from the UK, and prevalence of other clinical risk factors based on European FRAX® cohorts. Using FRAX probabilities of major osteoporotic fracture (MOF: hip, clinical vertebral, distal forearm, proximal humerus) and hip fracture, calculated with femoral neck BMD, we determined the expected number of fractures over 10 years, stratified by 10-year age band from 50 years. We then investigated the effect of (i) uplifting all individuals with T-score below -2.5 to be exactly -2.5 (high-risk strategy) and (ii) shifting the entire BMD distribution upwards (population strategy)., Results: Overall, the high-risk strategy prevented 573 MOF including 465 hip fractures. Moving the BMD T-score distribution upward by 0.27SD gave an equivalent reduction in numbers of MOF; for hip fractures prevented, this was 0.35SD. A global upward 0.25SD BMD shift prevented 524 MOF including 354 hip fractures, with corresponding figures for an increase of 0.5SD being 973 MOF prevented and 640 hip fractures prevented. The ratio of hip fracture to MOF prevented differed by the two approaches, such that for the high-risk strategy, the ratio was 0.81, and for the population strategy was 0.68 (0.25SD BMD uplift) and 0.66 (0.5SD BMD uplift). The numbers of fractures prevented by the high-risk strategy increased with age. In contrast, the age-related increase in numbers of fractures prevented with the population strategy rose with age, but peaked in the 70-79-year age band and declined thereafter., Conclusions: Both strategies reduced the numbers of expected incident fractures, with contrasting relative impacts by age and fracture site. Whilst the current analysis used UK/European anthropometric/risk factor distributions, further analyses calibrated to the distributions in other settings globally may be readily undertaken. Overall, these findings support the investigation of both population level interventions and those targeted at high fracture risk groups., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

The risk of a recurrent fragility fracture varies by age and sex, as by site and recency of sentinel fracture., Introduction: The recency of prior fractures affects subsequent fracture risk. Variable recency may obscure other factors that affect subsequent fracture risk. The aim of this study was to quantify the effect of a sentinel fracture by site, age, and sex where the recency was held constant., Methods: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture incidence was compared to that of the general population determined at fixed times after a sentinel fracture (humeral, clinical vertebral, forearm, hip, and minor fractures). Outcome fractures comprised a major osteoporotic fracture and hip fracture., Results: Sentinel osteoporotic fractures were identified in 9504 men and women. Of these, 3616 individuals sustained a major osteoporotic fracture as the first subsequent fracture, of whom 1799 sustained a hip fracture. Hazard ratios for prior fracture were consistently higher in men than in women and decreased progressively with age. Hazard ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus, forearm, or minor osteoporotic fracture., Conclusion: The risk of a recurrent fragility fracture varies by age, sex, and site of sentinel fracture when recency is held constant., (© 2020. International Osteoporosis Foundation and National Osteoporosis Foundation.)

This study aimed to determine the interaction between baseline FRAX ® fracture probability and romosozumab efficacy. Using an ITT approach, it was determined that the efficacy of romosozumab on clinical fracture, osteoporotic fracture, and major osteoporotic fracture is significantly greater in patients at high baseline fracture risk, when compared with placebo., Introduction: Post hoc analyses of placebo-controlled osteoporosis treatment studies have shown significantly greater reductions of fracture incidence for higher fracture risk patients. This study determined the interaction between baseline FRAX ® fracture probability and romosozumab efficacy in the placebo-controlled first year of the phase 3 FRAME study (NCT01575834)., Methods: Using an ITT approach, an extension of Poisson regression analysis studied the relationship between treatment, FRAX ® 10-year probability of major osteoporotic fracture (MOF, calculated without BMD) and risk of first incident fracture (adjusting for age and follow-up time). Treatment interactions considered outcomes of all clinical fractures, osteoporotic fractures, MOF, clinical vertebral fractures, and morphometric vertebral fractures. Two-sided p value of < 0.1 for the interaction between treatment and FRAX ® was considered significant., Results: Compared with placebo, romosozumab reduced the incidence of all fracture outcomes in the first year (range: 32% reduction in MOF [p = 0.07] to 80% reduction in clinical vertebral fractures [p = 0.038]). Significant interactions were observed between efficacy and baseline FRAX ® probability for composite outcomes of clinical fractures, osteoporotic fractures, and MOF (p = 0.064-0.084), but not vertebral fractures (p > 0.3). For example, romosozumab decreased all clinical fractures by 22% at the 25th centile of FRAX ® probability but the reduction was 41% at the 75th centile. Exclusion of vertebral fractures from each composite fracture outcome (i.e. only nonvertebral fractures included) showed even stronger interactions with baseline FRAX ® probability (p = 0.036-0.046)., Conclusions: Efficacy of romosozumab on clinical fracture, osteoporotic fracture, and MOF is significantly greater in patients at high baseline fracture risk compared with placebo., (© 2021. The Author(s).)

A novel cost-effectiveness model framework was developed to incorporate the elevated fracture risk associated with a recent fracture and to allow sequential osteoporosis therapies to be evaluated. Treating patients with severe osteoporosis after a recent fracture with a bone-forming agent followed by antiresorptive therapy can be cost-effective compared with antiresorptive therapy alone. Incorporating these novel technical attributes in economic evaluations can support appropriate policy and reimbursement decision-making., Purpose: To develop a cost-effectiveness model accommodating increased fracture risk after a recent fracture and treatment sequencing., Methods: A micro-simulation cost-utility model was developed to accommodate both treatment sequencing and increased risk with recent fracture. The risk of fracture was estimated and simulated using the FRAX® algorithms combined with Swedish registry data on imminent fracture relative risk. In the base-case cost-effectiveness analysis, a sequential treatment starting with a bone-forming agent for 12 months followed by an antiresorptive agent for 48 months initiated immediately after a major osteoporotic fracture (MOF) in a 70-year-old woman with a T-score of 2.5 or less was compared to an antiresorptive treatment alone for 60 months. The model was populated with data relevant for a UK population reflecting a personal social service perspective., Results: The cost per additional quality-adjusted life year (QALY) gained in the base-case setting was estimated at £34,584. Sensitivity analyses revealed the sequential treatment to be cost-saving compared with administering a bone-forming treatment alone. Without simulating an elevated fracture risk immediately after a recent fracture, the cost per QALY changed from £34,584 to £62,184., Conclusion: Incorporating imminent fracture risk in economic evaluations has a significant impact on the cost-effectiveness when evaluating fracture prevention treatments in patients with osteoporosis who sustained a recent fracture. Bone-forming treatment followed by antiresorptive therapy can be cost-effective compared to antiresorptive therapy alone depending on treatment acquisition costs.

Romosozumab is a novel bone-building drug that reduces fracture risk. This health economic analysis indicates that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture., Purpose: To estimate the cost-effectiveness of sequential treatment with romosozumab followed by alendronate ("romosozumab-to-alendronate") compared with alendronate alone in patients with severe osteoporosis at high risk of fracture in Sweden., Methods: A microsimulation model with a Markov structure was used to simulate fractures, costs, and quality-adjusted life years (QALYs), for women treated with romosozumab-to-alendronate or alendronate alone. Patients aged 74 years with a recent major osteoporotic fracture (MOF) were followed from the start of treatment until the age of 100 years or death. Treatment with romosozumab for 12 months was followed by alendronate for up to 48 months or alendronate alone with a maximum treatment duration of 60 months. The analysis had a societal perspective. Efficacy of romosozumab and alendronate were derived from phase III randomized controlled trials. Resource use and unit costs were collected from the literature. Cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) with QALYs as effectiveness measures., Results: The base case analysis showed that sequential romosozumab-to-alendronate treatment was associated with 0.089 additional QALYs at an additional cost of €3002 compared to alendronate alone, resulting in an ICER of €33,732. At a Swedish reference willingness-to-pay per QALY of €60,000, romosozumab-to-alendronate had a 97.9% probability of being cost-effective against alendronate alone. The results were most sensitive to time horizon, persistence assumptions, patient age, and treatment efficacy., Conclusion: The results of this study indicate that sequential romosozumab-to-alendronate can be a cost-effective treatment option for postmenopausal women with severe osteoporosis at high risk of fracture.

We identified large between-ethnicity calibration differences in the Canadian FRAX® tool which substantially overestimated the major osteoporotic fracture (MOF) risk in Asian women and Black women, and overestimated hip fracture risk in Asian women., Purpose: FRAX® is calibrated using population-specific fracture and mortality data. The need for FRAX to accommodate ethnic diversity within a country is uncertain. We addressed this question using the population-based Manitoba Bone Mineral Density (BMD) Program registry and self-reported ethnicity., Methods: The study population was women aged 40 years or older with baseline FRAX assessments (Canadian and other ethnic calculators), fracture outcomes, and self-reported ethnicity (White N = 68,907 [referent], Asian N = 1910, Black N = 356). Adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time to MOF and hip fracture were estimated. We examined candidate variables from DXA that might contribute to ethnic differences including skeletal size, hip axis length (HAL), trabecular bone score (TBS), and estimated body composition., Results: Adjusted for baseline risk using the Canadian FRAX tool with BMD, Asian women compared with White women were at much lower risk for MOF (HR 0.46, 95% CI 0.35-0.59) and hip fracture (0.16, 95% CI 0.08-0.34). Black women were also at lower MOF risk (HR 0.58, 95% CI 0.32-1.00); there were no hip fractures. The US ethnic-specific FRAX calculators accounted for most of the between-ethnicity differences in MOF risk (86% for Asian, 92% for Black) but only partially accounted for lower hip fracture risk in Asian women (40%). The candidate variables explained only a minority of the effect of ethnicity. Gradient of risk in analyses was similar (p-interactions ethnicity*FRAX non-significant)., Conclusions: We identified significant ethnic differences in performance of the Canadian FRAX tool with fracture probability overestimated among Asian and Black women. The US ethnic calculators helped to address this discrepancy for MOF risk assessment, but not for hip fracture risk among Asian women.

The increase in fracture risk associated with a recent fragility fracture is more appropriately captured using a 10-year fracture probability than 2- or 5-year probabilities., Introduction: The recency of prior fractures affects subsequent fracture risk. The aim of this study was to quantify the effect of a recent sentinel fracture, by site, on the 2-, 5-, and 10-year probability of fracture., Methods: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) occurring within the previous 2 years and probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios were used to adjust fracture probabilities over a 2-, 5-, and 10-year time horizon., Results: As expected, probabilities decreased with decreasing time horizon. Probability ratios varied according to age and the site of sentinel fracture. Probability ratios to adjust for a prior fracture within the previous 2 years were higher the shorter the time horizon, but the absolute increases in fracture probabilities were much reduced. Thus, fracture probabilities were substantially lower with time horizons less than 10 years., Conclusion: The 10-year probability of fractures is the appropriate metric to capture the impact of the recency of sentinel fractures. The probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures, adjustments which can readily inform clinical decision-making.

The COVID-19 pandemic, and its management, is markedly impacting the management of osteoporosis as judged by access to online FRAX fracture risk assessments. Globally, access was 58% lower in April than in February 2020. Strategies to improve osteoporosis care, with greater use of fracture risk assessments, offer a partial solution., Introduction: The COVID-19 pandemic is having a significant detrimental impact on the management of chronic diseases including osteoporosis. We have quantified the global impact by examining changes in the usage of online FRAX fracture risk assessments before and after the declaration of the pandemic (11 March 2020)., Methods: The study comprised a retrospective analysis using GoogleAnalytics data on daily sessions on the FRAX® website ( www.sheffield.ac.uk/FRAX ) from November 2019 to April 2020 (main analysis period February-April 2020), and the geographical source of that activity., Results: Over February-April 2020, the FRAX website recorded 460,495 sessions from 184 countries, with 210,656 sessions in February alone. In March and April, the number of sessions fell by 23.1% and 58.3% respectively, a pattern not observed over the same period in 2019. There were smaller reductions in Asia than elsewhere, partly related to earlier and less-marked nadirs in some countries (China, Taiwan, Hong Kong, South Korea and Vietnam). In Europe, the majority of countries (24/31, 77.4%) reduced usage by at least 50% in April. Seven countries showed smaller reductions (range - 2.85 to - 44.1%) including Poland, Slovakia, Czech Republic, Germany, Norway, Sweden and Finland. There was no significant relationship between the reduction in FRAX usage and measures of disease burden such as COVID-attributed deaths per million of the population., Conclusion: This study documents a marked global impact of the COVID-19 pandemic on the management of osteoporosis as reflected by FRAX online fracture risk assessments. The analysis suggests that impact may relate to the societal and healthcare measures taken to ameliorate the pandemic.

This paper explores use of metrics that combine fracture outcomes that add power to phase 3 studies and provide a surrogate outcome for regulatory agencies., Introduction: The aim of this study was to develop an analytic framework that would combine information from all fracture outcomes (including radiographic vertebral fractures) in phase 3 studies to provide a metric for the assessment of treatment efficacy., Methods: Data from the phase 3 study of denosumab were used as an exemplar comparing the effects of active intervention with placebo on the risk of all fractures associated with osteoporosis. Fracture outcomes were assigned utility weights drawn from the published literature and applied to age-specific health state values of the general population. For each fracture outcome in each arm of the study, cumulative disutility was computed to serve as the principal end point. The hypothesis tested was that treatment with denosumab results in a significant reduction in mean fracture-related disutility., Results: Treatment with denosumab was associated with significantly lower utility loss compared with placebo. For patients treated with denosumab, mean utility loss was 42% less than with placebo (4.5 vs. 7.5 QALYs/1000 patient years, respectively, p < 0.001)., Conclusions: Denosumab significantly decreased utility loss. The use of metrics that combine fracture outcomes may provide added power to phase 3 studies and provide a surrogate outcome for regulatory agencies.

The timed up and go (TUG) test measures physical performance and predicts falls in the elderly. In older women, TUG time predicts the risk of major osteoporotic fracture and hip fracture independently of clinical risk factors and bone mineral density, and has a substantial impact on fracture probabilities., Introduction: The timed up and go (TUG) test measures physical performance and predicts falls in the elderly. A slow TUG has been associated with an increased fracture risk, but it is unclear whether the association is independent of clinical risk factors and bone mineral density (BMD). The aim of this study was to investigate if TUG time was associated with fracture risk independently of clinical risk factors and BMD and to determine its impact on fracture probabilities in older women., Methods: A standardized questionnaire was used to assess information regarding clinical risk factors in the large population-based SUPERB study of 3028 older women (75-80 years). At baseline, the TUG test was performed and BMD measured with DXA. The association between TUG time and the risk of hip fracture and major osteoporotic fracture (MOF) was examined using an extension of Poisson regression., Results: Fracture incidence increased steeply with increasing TUG time up to 12 s and subsequently started to level off. A slow TUG time was therefore defined as TUG > 12 s, a cutoff level then used in Cox models to study the association between slow TUG and fracture risk. A slow TUG time was associated with an increased risk of fracture (MOF 2.39 [1.80-3.18] and hip fracture 2.96 [1.62-5.40]). These associations were slightly attenuated but remained significant after adjustment for clinical risk factors and femoral neck BMD. Depending on BMD, the 4-year fracture probability of MOF increased by a factor of 1.5-1.9 in a 75-year-old woman with slow TUG (> 12 s)., Conclusion: The TUG time predicts the risk of MOF and hip fracture independently of clinical risk factors and BMD and has a substantial impact on fracture probabilities, indicating that inclusion of the TUG test in patient evaluation should be considered in order to improve fracture prediction in older women.

Celiac disease is associated with an increased fracture risk but is not a direct input to the FRAX® calculation. When celiac disease is considered as a secondary osteoporosis risk factor or BMD is included in the FRAX assessment, FRAX accurately predicts fracture risk., Introduction: The fracture risk assessment tool (FRAX®) uses clinical factors and bone mineral density (BMD) measurement to predict 10-year major osteoporotic (MOF) fracture probability. The study aim was to determine whether celiac disease affects MOF risk independent of FRAX score., Methods: The Manitoba BMD Registry includes clinical data, BMD measurements, 10-year probability of MOF calculated for each individual using the Canadian FRAX tool and diagnosed celiac disease. Using linkage to population-based healthcare databases, we identified incident MOF diagnoses over the next 10 years for celiac disease and general population cohorts., Results: Celiac disease (N = 693) was associated with increased fracture risk adjusted for FRAX score computed without secondary osteoporosis or BMD (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.11-1.86). Celiac disease was no longer a significant risk factor for fracture when secondary osteoporosis or BMD were included in the FRAX calculation (p > 0.1). In subjects with celiac disease, each SD increase in FRAX score (calculated with and without secondary osteoporosis or BMD) was associated with higher risk of incident MOF (adjusted HR 1.66 to 1.80), similar to the general population (p-interaction > 0.2). Including celiac disease as secondary osteoporosis or including BMD in FRAX 10-year MOF probability calculations (10.1% and 8.6% respectively) approximated the observed cumulative 10-year MOF probability (10.8%, 95% CI 7.8-13.9%)., Conclusions: Celiac disease is associated with an increased risk of major osteoporotic fractures. When celiac disease is considered as a secondary osteoporosis risk factor or BMD is included in FRAX assessment, FRAX accurately predicts fracture risk.

We provide an evidence base and guidance for the use of menopausal hormone therapy (MHT) for the maintenance of skeletal health and prevention of future fractures in recently menopausal women. Despite controversy over associated side effects, which has limited its use in recent decades, the potential role for MHT soon after menopause in the management of postmenopausal osteoporosis is increasingly recognized. We present a narrative review of the benefits versus risks of using MHT in the management of postmenopausal osteoporosis. Current literature suggests robust anti-fracture efficacy of MHT in patients unselected for low BMD, regardless of concomitant use with progestogens, but with limited evidence of persisting skeletal benefits following cessation of therapy. Side effects include cardiovascular events, thromboembolic disease, stroke and breast cancer, but the benefit-risk profile differs according to the use of opposed versus unopposed oestrogens, type of oestrogen/progestogen, dose and route of delivery and, for cardiovascular events, timing of MHT use. Overall, the benefit-risk profile supports MHT treatment in women who have recently (< 10 years) become menopausal, who have menopausal symptoms and who are less than 60 years old, with a low baseline risk for adverse events. MHT should be considered as an option for the maintenance of skeletal health in women, specifically as an additional benefit in the context of treatment of menopausal symptoms, when commenced at the menopause, or shortly thereafter, in the context of a personalized benefit-risk evaluation.

The risk of a recurrent fragility fracture is particularly high immediately following the fracture. This study provides adjustments to FRAX-based fracture probabilities accounting for the site of a recent fracture., Introduction: The recency of prior fractures affects subsequent fracture risk. The aim of this study was to quantify the effect of a recent sentinel fracture, by site, on the 10-year probability of fracture determined with FRAX., Methods: The study used data from the Reykjavik Study fracture register that documented prospectively all fractures at all skeletal sites in a large sample of the population of Iceland. Fracture probabilities were determined after a sentinel fracture (humeral, clinical vertebral, forearm and hip fracture) from the hazards of death and fracture. Fracture probabilities were computed on the one hand for sentinel fractures occurring within the previous 2 years and on the other hand, probabilities for a prior osteoporotic fracture irrespective of recency. The probability ratios provided adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures., Results: Probability ratios to adjust 10-year FRAX probabilities of a major osteoporotic fracture for recent sentinel fractures were age dependent, decreasing with age in both men and women. Probability ratios varied according to the site of sentinel fracture with higher ratios for hip and vertebral fracture than for humerus or forearm fracture. Probability ratios to adjust 10-year FRAX probabilities of a hip fracture for recent sentinel fractures were also age dependent, decreasing with age in both men and women with the exception of forearm fractures., Conclusion: The probability ratios provide adjustments to conventional FRAX estimates of fracture probability for recent sentinel fractures.

In a global survey of fracture liaison services, most reported that DXA access met needs. However, adherence to basic DXA quality and reporting procedures was confirmed by only around 50% of institutions and many required education for operators/interpreters. Overall, there is significant variability in the access to, and quality of, DXA services worldwide., Introduction: While the use of dual-energy X-ray absorptiometry (DXA) has been widely adopted worldwide for the assessment of bone mineral density, the quality of DXA facilities is unknown. To address this, a global survey of fracture liaison services (FLS) was conducted by the International Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) to assess the quality of their DXA facilities., Methods: A questionnaire for the accessibility and quality of DXA services was co-created by representatives of the ISCD and the IOF and made available to institutions who participated in the Capture the Fracture Best Practice Framework. From a list of 331 contacted invitees, 124 FLS centres responded; analyses were based on 121 centres with suitable data., Results: Over 70% of institutions reported that, for over 90% of the time, DXA access met service needs, and the scanning/reporting quality was perceived as excellent. However, 25% of DXA facilities reported not being accredited by a professional/governmental organization, and adherence to some basic DXA quality assurance and reporting procedures was confirmed by < 50% of services. Importantly, in excess of 50% of institutions stated that they desired ongoing education in osteoporosis and DXA for operators and interpreters., Conclusion: 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 densitometry, many centres are falling short of the standards of the IOF-ISCD Osteoporosis Essentials criteria.

Community-based screening and treatment of women aged 70-85 years at high fracture risk reduced fractures; moreover, the screening programme was cost-saving. The results support a case for a screening programme of fracture risk in older women in the UK., Introduction: The SCOOP (screening for prevention of fractures in older women) randomized controlled trial investigated whether community-based screening could reduce fractures in women aged 70-85 years. The objective of this study was to estimate the long-term cost-effectiveness of screening for fracture risk in a UK primary care setting compared with usual management, based on the SCOOP study., Methods: A health economic Markov model was used to predict the life-time consequences in terms of costs and quality of life of the screening programme compared with the control arm. The model was populated with costs related to drugs, administration and screening intervention derived from the SCOOP study. Fracture risk reduction in the screening arm compared with the usual management arm was derived from SCOOP. Modelled fracture risk corresponded to the risk observed in SCOOP., Results: Screening of 1000 patients saved 9 hip fractures and 20 non-hip fractures over the remaining lifetime (mean 14 years) compared with usual management. In total, the screening arm saved costs (£286) and gained 0.015 QALYs/patient in comparison with usual management arm., Conclusions: This analysis suggests that a screening programme of fracture risk in older women in the UK would gain quality of life and life years, and reduce fracture costs to more than offset the cost of running the programme.

Prior high-trauma fractures identified through health services data are associated with low bone mineral density (BMD) and future fracture risk to the same extent as fractures without high-trauma., Introduction: Some have questioned the usefulness of distinguishing high-trauma fractures from low-trauma fractures. The aim of this study is to compare BMD measurements and risk of subsequent low-trauma fracture in patients with prior high- or low-trauma fractures., Methods: Using a clinical BMD registry for the province of Manitoba, Canada, we identified women and men age 40 years or older with fracture records from linked population-based healthcare data. Age- and sex-adjusted BMD Z-scores and covariate-adjusted hazard ratios (HR) with 95% confidence intervals (CI) for incident fracture were studied in relation to prior fracture status, categorized as high-trauma if associated with external injury codes and low-trauma otherwise., Results: The study population consisted of 64,428 women and men with no prior fracture (mean age 63.7 years), 858 with prior high-trauma fractures (mean age 65.1 years), and 14,758 with prior low-trauma fractures (mean age 67.2 years). Mean Z-scores for those with any prior high-trauma fracture were significantly lower than in those without prior fracture (P < 0.001) and similar to those with prior low-trauma fracture. Median observation time for incident fractures was 8.8 years (total 729,069 person-years). Any prior high-trauma fracture was significantly associated with increased risk for incident major osteoporotic fracture (MOF) (adjusted HR 1.31, 95% CI 1.08-1.59) as was prior low-trauma fracture (adjusted HR 1.55, 95% CI 1.47-1.63), and there was no significant difference between the two groups (prior trauma versus low-trauma fracture P = 0.093). A similar pattern was seen when incident MOF was studied in relation to prior hip fracture or prior MOF, or when the outcome was incident hip fracture or any incident fracture., Conclusions: High-trauma and low-trauma fractures showed similar relationships with low BMD and future fracture risk. This supports the inclusion of high-trauma fractures in clinical assessment for underlying osteoporosis and in the evaluation for intervention to reduce future fracture risk.

During median follow-up 6.0 years in 11,495 individuals, prior absolute and annualized measured height loss was significantly greater in those with subsequent incident fracture compared with those without incident fracture., Purpose: FRAX® accepts baseline height and weight as input variables, but does not consider change in these parameters over time., Aim: To evaluate the association between measured height or weight loss on subsequent fracture risk adjusted for FRAX scores, risk factors, and competing mortality., Methods: Using a dual-energy x-ray absorptiometry (DXA) registry for the Province of Manitoba, Canada, we identified women and men age 40 years or older with height and weight measured at the time of two DXA scans. Cox regression analyses were performed to test for a covariate-adjusted association between prior height and weight loss with incident fractures occurring after the second scan using linked population-based healthcare data., Results: The study population consisted of 11,495 individuals (average age 68.0 ± 9.9 years, 94.6% women). During median follow-up 6.0 years, records demonstrated incident major osteoporotic fracture (MOF) in 869 individuals, hip fractures in 265, clinical vertebral fractures in 207, and any fracture in 1203. Prior height loss was significantly greater in individuals with fracture compared with those without fracture, regardless of fracture site. Mortality was greater in those with prior height loss (HR per SD 1.11, 95% CI 1.06-1.17) or weight loss (HR per SD 1.26, 95% CI 1.19-1.32). Each SD in height loss was associated with increased fracture risk (MOF 12-17%, hip 8-19%, clinical vertebral 28-37%, any fracture 14-19%). Prior weight loss was associated with 21-30% increased risk for hip fracture, but did not increase risk for other fractures. Height loss of 3.0 cm or greater more than doubled the risk for subsequent fracture., Conclusions: Prior height loss is associated with a small but significant increase in risk of incident fracture at all skeletal sites independent of other clinical risk factors and competing mortality as considered by FRAX. Prior weight loss only increases risk for subsequent hip fracture.

We studied the risk for hip fracture before and after total knee replacement (TKR) in the entire population in Sweden. Women and men had a low risk for hip fracture before TKR but an increased risk the first year after TKR., Purpose: It is known that osteoarthritis is associated with high bone mass. We therefore studied the risk of hip fracture before and after total knee replacement (TKR), risk of different hip fracture types, and risk subdivided in genders and age groups., Methods: We followed the total Swedish population born between 1902 and 1952 (n = 4,258,934) during the period 1987-2002 and identified all patients with TKR due to primary OA (n = 39,291), and all patients with hip fracture (n = 195,860) in the Swedish National Inpatient Register. The risk time analyses were based on Poisson regression models., Results: The hazard ratio (HR) for hip fracture the last year before TKR was 0.86 (95% CI 0.74 to 1.00) and the first year after 1.26 (95% CI 1.11 to 1.42) compared to individuals without TKR. The HR for femoral neck fracture 0-10 years after TKR was 0.95 (95% CI 0.89 to 1.01) and for trochanteric fracture was 1.13 (95% CI 1.06 to 1.21). The HR for hip fracture in the age group 50-74 was 1.28 (95% CI 1.14 to 1.43) and in the age group 75-90 years was 0.99 (95% CI 0.94 to 1.04) 0-10 years after TKR, compared to individuals without TKR., Conclusion: Individuals had a low risk for hip fracture before TKR but an increased risk the first year after TKR. The risk in individuals below age 75 years and for trochanteric fractures was increased after TKR. Possible explanations include changed knee kinematics after a TKR, physical activity level, fall risk, and other unknown factors.