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Summary: Guidance is provided in an international setting on the assessment and specific treatment of postmenopausal women at low, high and very high risk of fragility fractures. Introduction: The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2019. This manuscript seeks to apply this in an international setting, taking additional account of further categorisation of increased risk of fracture, which may inform choice of therapeutic approach. Methods: Clinical perspective and updated literature search. Results: The following areas are reviewed: categorisation of fracture risk and general pharmacological management of osteoporosis. Conclusions: A platform is provided on which specific guidelines can be developed for national use to characterise fracture risk and direct interventions. [ABSTRACT FROM AUTHOR]

A guidance on the assessment and treatment of postmenopausal women at risk from fractures due to osteoporosis was recently published in Osteoporosis International as a joint effort of the International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (Kanis et al. in Osteoporos Int https://doi.org/10.1007/s00198-018-4704-5 , 2018). This manuscript updates the previous guidelines document, published in 2013 (Kanis et al. in Osteoporos Int 24:23-57, 2013) and is written in a European perspective. The present article reports and summarizes the main recommendations included in this 2018 guidance document. [ABSTRACT FROM AUTHOR]

Summary: This review, endorsed by the International Osteoporosis Foundation and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, summarizes several failings of the recent guidelines of the American College of Physicians (ACP) on the treatment of low bone density or osteoporosis to prevent fractures.Introduction: The ACP recently issued guidelines for the treatment of low bone density or osteoporosis to prevent fractures.Methods: Literature review and critical review of the ACP guidelines.Results: The guideline is lacking in scope due to the endorsement of treatment based on T-scores rather than fracture risk assessment and in failure to adequately consider anabolic therapies.Conclusions: The ACP guideline appears outdated. [ABSTRACT FROM AUTHOR]

The major application of FRAX in osteoporosis is to direct pharmacological interventions to those at high risk of fracture. Whereas the efficacy of osteoporosis treatment, with the possible exception of alendronate, is largely independent of baseline bone mineral density (BMD), it remains a widely held perception that osteoporosis therapies are only effective in the presence of low BMD. Thus, the use of FRAX in the absence of BMD to identify individuals requiring therapy remains the subject of some debate and is the focus of this review. The clinical risk factors used in FRAX have high evidence-based validity to identify a risk responsive to intervention. The selection of high-risk individuals with FRAX, without knowledge of BMD, preferentially selects for low BMD and thus identifies a risk that is responsive to pharmacological intervention. The prediction of fractures with the use of clinical risk factors alone in FRAX is comparable to the use of BMD alone to predict fractures and is suitable, therefore, in the many countries where facilities for BMD testing are sparse. In countries where access to BMD is greater, FRAX can be used without BMD in the majority of cases and BMD tests reserved for those close to a probability-based intervention threshold. Thus concerns surrounding the use of FRAX in clinical practice without information on BMD are largely misplaced. [ABSTRACT FROM PUBLISHER]

Summary: Daily teriparatide injections have been shown to reduce vertebral and non-vertebral fractures. Here, we demonstrate that the magnitude of fracture risk reduction is independent of baseline fracture probability assessed by FRAX. Introduction: Daily administration of 20 or 40 μg teriparatide has been shown to significantly decrease the risk of vertebral and non-vertebral fracture compared with placebo. The aim of the present study was to evaluate fracture risk assessed at baseline using the FRAX® tool and to determine the efficacy of teriparatide as a function of baseline fracture risk. Methods: One thousand six hundred thirty-seven postmenopausal women in the pivotal phase three trial, randomly assigned to receive placebo ( n = 544), teriparatide 20 μg per day ( n = 541) or teriparatide 40 μg per day ( n = 552), were studied. Baseline clinical risk factors were entered into country-specific FRAX models to compute the 10-year probability of major osteoporotic fractures with or without input of femoral neck BMD. Because there was no difference in effect of 20 and 40 μg teriparatide daily on fracture occurrence, the two active groups were merged. The interaction between probability of a major fracture and treatment efficacy was examined by Poisson regression. Results: The 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.2-67.2 %. Treatment with teriparatide was associated with a 37 % decrease in all non-vertebral fractures (95 % CI 10-56 %) and a 56 % decrease in low-energy non-vertebral fractures (95 % CI 24-75 %) compared with placebo. The risk of morphometric vertebral fractures decreased significantly by 66 % (95 % CI 50-77 %). Hazard ratios for the effect of teriparatide on the fracture outcome did not change significantly with increasing fracture probability ( p > 0.30). Similar findings were noted for the interaction when BMD was excluded from the FRAX model, or when probability of hip fracture was used as the marker of baseline risk. Conclusion: We conclude that teriparatide significantly decreases the risk of non-vertebral and morphometric vertebral fractures in women by a similar extent, irrespective of baseline fracture probability. [ABSTRACT FROM AUTHOR]

Summary: The aim of this study was to determine the efficacy of once-weekly teriparatide as a function of baseline fracture risk. Treatment with once-weekly teriparatide was associated with a statistically significant 79 % decrease in vertebral fractures, and in the cohort as a whole, efficacy was not related to baseline fracture risk. Introduction: Previous studies have suggested that the efficacy of some interventions may be greater in the segment of the population at highest fracture risk as assessed by the FRAX® algorithms. The aim of the present study was to determine whether the antifracture efficacy of weekly teriparatide was dependent on the magnitude of fracture risk. Methods: Baseline fracture probabilities (using FRAX) were computed from the primary data of a phase 3 study (TOWER) of the effects of weekly teriparatide in 542 men and postmenopausal women with osteoporosis. The outcome variable comprised morphometric vertebral fractures. Interactions between fracture probability and efficacy were explored by Poisson regression. Results: The 10-year probability of major osteoporotic fractures (without BMD) ranged from 7.2 to 42.2 %. FRAX-based hip fracture probabilities ranged from 0.9 to 29.3 %. Treatment with teriparatide was associated with a 79 % (95 % CI 52-91 %) decrease in vertebral fractures assessed by semiquantitative morphometry. Relative risk reductions for the effect of teriparatide on the fracture outcome did not change significantly across the range of fracture probabilities ( p = 0.28). In a subgroup analysis of 346 (64 %) participants who had FRAX probabilities calculated with the inclusion of BMD, there was a small but significant interaction ( p = 0.028) between efficacy and baseline fracture probability such that high fracture probabilities were associated with lower efficacy. Conclusion: Weekly teriparatide significantly decreased the risk of morphometric vertebral fractures in men and postmenopausal women with osteoporosis. Overall, the efficacy of teriparatide was not dependent on the level of fracture risk assessed by FRAX in the cohort as a whole. [ABSTRACT FROM AUTHOR]

Summary: Under current guidelines, based on prior fracture probability thresholds, inequalities in access to therapy arise especially at older ages (≥70 years) depending on the presence or absence of a prior fracture. An alternative threshold (a fixed threshold from the age of 70 years) reduces this disparity, increases treatment access and decreases the need for bone densitometry. Introduction: Several international guidelines set age-specific intervention thresholds at the 10-year probability of fracture equivalent to a woman of average BMI with a prior fracture. At older ages (≥70 years), women with prior fracture selected for treatment are at lower average absolute risk than those selected for treatment in the absence of prior fracture, prompting consideration of alternative thresholds in this age group. Methods: Using a simulated population of 50,633 women aged 50-90 years in the UK, with a distribution of risk factors similar to that in the European FRAX derivation cohorts and a UK-matched age distribution, the current NOGG intervention and assessment thresholds were compared to one where the thresholds remained constant from 70 years upwards. Results: Under current thresholds, 45.1 % of women aged ≥70 years would be eligible for therapy, comprising 37.5 % with prior fracture, 2.2 % with high risk but no prior fracture and 5.4 % selected for treatment after bone mineral density (BMD) measurement. Mean hip fracture probability was 11.3, 23.3 and 17.6 %, respectively, in these groups. Under the alternative thresholds, the overall proportion of women treated increased from 45.1 to 52.9 %, with 8.4 % at high risk but no prior fracture and 7.0 % selected for treatment after BMD measurement. In the latter group, the mean probability of hip fracture was identical to that observed in women with prior fracture (11.3 %). The alternative threshold also reduced the need for BMD measurement, particularly at older ages (>80 years). Conclusions: The alternative thresholds equilibrate fracture risk, particularly hip fracture risk, in those with or without prior fracture selected for treatment and reduce BMD usage at older ages. [ABSTRACT FROM AUTHOR]

Summary: Despite the proven predictive ability of bone mineral density, Fracture Risk Assessment Tool (FRAX®), bone turnover markers, and fracture for osteoporotic fracture, their use as targets for treatment of osteoporosis is limited. Introduction: Treat-to-target is a strategy applied in several fields of medicine and has recently become an area of interest in the management of osteoporosis. Its role in this setting remains controversial. This article was prepared following a European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group meeting convened under the auspices of the International Osteoporosis Foundation (IOF) to discuss the feasibility of applying such a strategy in osteoporosis in Europe. Methods: Potential targets range from the absence of an incident fracture to fixed levels of bone mineral density (BMD), a desired FRAX® score, a specified level of bone turnover markers or indeed changes in any one or a combination of these parameters. Results: Despite the proven predictive ability of all of these variables for fracture (particularly BMD and FRAX), their use as targets remains limited due to low sensitivity, the influence of confounders and current lack of evidence that targets can be consistently reached. Conclusion: ESCEO considers that it is not currently feasible to apply a treat-to-target strategy in osteoporosis, though it did identify a need to continue to improve the targeting of treatment to those at higher risk (target-to-treat strategy) and a number of issues for the research agenda. These include international consensus on intervention thresholds and definition of treatment failure, further exploration of the relationship between fracture and BMD, and FRAX and treatment efficacy and investigation of the potential of short-term targets to improve adherence. [ABSTRACT FROM AUTHOR]

There are occasional marked discordances in BMD T-scores at the lumbar spine (LS) and femoral neck (FN). We investigated whether such discordances could contribute independently to fracture prediction using FRAX. We studied 21,158 women, average age 63 years, from 10 prospective cohorts with baseline FRAX variables as well as FN and LS BMD. Incident fractures were collected by self-report and/or radiographic reports. Extended Poisson regression examined the relationship between differences in LS and FN T-scores (ΔLS-FN) and fracture risk, adjusted for age, time since baseline and other factors including FRAX 10-year probability for major osteoporotic fracture calculated using FN BMD. To examine the effect of an adjustment for ΔLS-FN on reclassification, women were separated into risk categories by their FRAX major fracture probability. High risk was classified using two approaches: being above the National Osteoporosis Guideline Group intervention threshold or, separately, being in the highest third of each cohort. The absolute ΔLS-FN was greater than 2 SD for 2.5 % of women and between 1 and 2 SD for 21 %. ΔLS-FN was associated with a significant risk of fracture adjusted for baseline FRAX (HR per SD change = 1.09; 95 % CI = 1.04-1.15). In reclassification analyses, only 2.3-3.2 % of the women moved to a higher or lower risk category when using FRAX with ΔLS-FN compared with FN-derived FRAX alone. Adjustment of estimated fracture risk for a large LS/FN discrepancy (>2SD) impacts to a large extent on only a relatively small number of individuals. More moderate (1-2SD) discordances in FN and LS T-scores have a small impact on FRAX probabilities. This might still improve clinical decision-making, particularly in women with probabilities close to an intervention threshold. [ABSTRACT FROM AUTHOR]

Summary: Guidance is provided in a European setting on the assessment and treatment of postmenopausal women at risk of fractures due to osteoporosis. Introduction: The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2008. This manuscript updates these in a European setting. Methods: Systematic literature reviews. Results: The following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk, general and pharmacological management of osteoporosis, monitoring of treatment, assessment of fracture risk, case finding strategies, investigation of patients and health economics of treatment. Conclusions: A platform is provided on which specific guidelines can be developed for national use. [ABSTRACT FROM AUTHOR]

Summary: The country-specific risk of hip fracture and the 10-year probability of a major osteoporotic fracture were determined on a worldwide basis from a systematic review of literature. There was a greater than 10-fold variation in hip fracture risk and fracture probability between countries. Introduction: The present study aimed to update the available information base available on the heterogeneity in the risk of hip fracture on a worldwide basis. An additional aim was to document variations in major fracture probability as determined from the available FRAX models. Methods: Studies on hip fracture risk were identified from 1950 to November 2011 by a Medline OVID search. Evaluable studies in each country were reviewed for quality and representativeness and a study (studies) chosen to represent that country. Age-specific incidence rates were age-standardised to the world population in 2010 in men, women and both sexes combined. The 10-year probability of a major osteoporotic fracture for a specific clinical scenario was computed in those countries for which a FRAX model was available. Results: Following quality evaluation, age-standardised rates of hip fracture were available for 63 countries and 45 FRAX models available in 40 countries to determine fracture probability. There was a greater than 10-fold variation in hip fracture risk and fracture probability between countries. Conclusions: Worldwide, there are marked variations in hip fracture rates and in the 10-year probability of major osteoporotic fractures. The variation is sufficiently large that these cannot be explained by the often multiple sources of error in the ascertainment of cases or the catchment population. Understanding the reasons for this heterogeneity may lead to global strategies for the prevention of fractures. [ABSTRACT FROM AUTHOR]

Summary: Treatment criteria published by the National Osteoporosis Guideline Group (NOGG) in the UK make more efficient use of bone mineral density (BMD) resources than the previous Royal College of Physicians (RCP) guideline. Introduction: We compared the effectiveness of the RCP case-finding strategy previously used in the UK and the updated guideline published by NOGG, which incorporates the FRAX® fracture probability tool. Methods: Comparisons were made by simulating population samples of 1000 women at ages between 50 and 85 years, using age-specific prevalence of risk factors and UK-derived fracture and mortality rates. Comparators comprised the number identified at high risk, the incidence of hip fracture and the femoral neck BMD in those identified, the number needed to scan to identify a hip fracture, the acquisition cost and the cost per hip fracture averted Results: Compared with the RCP strategy, NOGG identified slightly reduced numbers of women at high risk (average 34.6% vs. 35.7% across all ages), but with lower numbers of scans required at each age. For example, NOGG required only 3.5 scans at the age of 50 years to identify one case of hip fracture, whereas RCP required 13.9. At 75 years, the corresponding numbers were 0.9 and 1.5. Thus, the acquisition costs for identifying a hip fracture case and the total costs (acquisition and treatment) per hip fracture averted were lower. Conclusion: Compared to the RCP strategy, the FRAX-based NOGG strategy uses BMD resources more efficiently with lower acquisition costs and lower costs per hip fracture averted. [ABSTRACT FROM AUTHOR]

Summary: Recent studies have evaluated the performance of FRAX® in independent cohorts. The interpretation of most is problematic for reasons summarised in this perspective. Introduction: FRAX is an extensively validated assessment tool for the prediction of fracture in men and women. The aim of this study was to review the methods used since the launch of FRAX to further evaluate this instrument. Methods: This covers a critical review of studies investigating the calibration of FRAX or assessing its performance characteristics in external cohorts. Results: Most studies used inappropriate methodologies to compare the performance characteristics of FRAX with other models. These included discordant parameters of risk (comparing incidence with probabilities), comparison with internally derived predictors and inappropriate use and interpretation of receiver operating characteristic curves. These deficits markedly impair interpretation of these studies. Conclusion: Cohort studies that have evaluated the performance of FRAX need to be interpreted with caution and preferably re-evaluated. [ABSTRACT FROM AUTHOR]

Summary: The UK FRAX model was evaluated retrospectively in Polish women assessed 11 years previously for fracture risk. Results were compared with fracture risk observed during follow-up. The UK model can be used to stratify risk, but caution is required in interpretation of absolute fracture risk. Introduction: In the absence of a FRAX® model for Poland, the UK FRAX tool has been widely used. The aim of this study was to evaluate the validity of the surrogate model in a Polish setting. Methods: We studied a convenience sample of 501 women who had been referred for the assessment of bone mineral density and clinical risk factors 9-12 years previously. Incident fractures in the intervening period were self-reported by telephone interview. Fracture probabilities, calculated using the UK FRAX tool, were compared to the incidence of new fractures during follow-up. Results: Incident fractures were reported in 106 women. Incident fractures of the major osteoporotic fractures were reported in 89 women. The observed incidence of fractures rose progressively in women according to percentile of fracture probability. Between the 10th and 90th percentiles, hip fracture probability computed with bone mineral density (BMD) differed 49-fold. The range was fivefold in the case of a major osteoporotic fracture. The observed/expected ratio for fracture was significantly greater than unity when the expected number was calculated without BMD (1.79; 95% confidence interval = 1.44-2.21) and when BMD was included in the FRAX calculation (1.94; 95% confidence interval = 1.45-2.54). Conclusion: The UK FRAX tool categorised fracture risk well in this Polish cohort but significantly overestimated fracture risk. The UK model can be used to stratify risk in the population, but caution is required in interpretation of absolute risk. [ABSTRACT FROM AUTHOR]

Summary: The aim of the present study was to determine the efficacy of strontium ranelate as a function of baseline fracture risk. Treatment with strontium ranelate was associated with a significant 31% decrease in all clinical osteoporotic fractures (vertebral fractures included). Hazard ratios for the effect of strontium ranelate on the fracture outcome did not change significantly with increasing fracture probability. Introduction: Two previous studies have suggested that the efficacy of intervention may be greater in the segment of the population at highest fracture risk as assessed by the FRAX algorithms. The aim of the present study was to determine whether the anti-fracture efficacy of strontium ranelate was dependent of the level of fracture risk. Methods: The primary data of the two phase III studies (SOTI and TROPOS) of the effects of strontium ranelate in postmenopausal osteoporosis were combined. Country-specific probabilities were computed using the FRAX tool (version 2.0). The primary outcome variable comprised all clinical osteoporotic fractures (including clinical vertebral fractures). Interactions between fracture probability and efficacy were explored by Poisson regression. Results: The 10-year probability of major osteoporotic fractures (with BMD) ranged from 2.5% to 90.8%. FRAX-based hip fracture probabilities ranged from 0.1% to 90.3%. The incidence of clinical osteoporotic fractures (vertebral fractures excluded) and morphometric vertebral fractures increased with increasing baseline fracture probabilities. Treatment with strontium ranelate was associated with a 31% (95% CI = 20-39%) decrease in osteoporotic clinical fractures and a 40% decrease in vertebral fractures assessed by semiquantitative morphometry (95% CI = 31-48%) Hazard ratios for the effect of strontium ranelate on the fracture outcomes did not change significantly with increasing fracture probability. Conclusion: Strontium ranelate significantly decreased the risk of osteoporotic clinical fractures, non vertebral fractures and morphometric vertebral fractures in women. Overall, the efficacy of strontium ranelate was not dependent of the level of fracture risk assessed by FRAX [ABSTRACT FROM AUTHOR]

Purpose: To comment on the latest technology appraisal of the National Institute for Clinical Excellence (NICE) in osteoporosis.Methods: Review of NICE Technology Appraisal (TA464) on bisphosphonate use in osteoporosis.Results: The NICE appraisal on bisphosphonate use in osteoporosis indicates that treatment with oral bisphosphonates may be instituted at a FRAX 10-year probability of major osteoporotic fracture above 1%. Implementation would mean that all women aged 50 years or older are deemed eligible for treatment, a position that would increase the burden of rare long-term side effects across the population.Conclusion: Cost-effectiveness thresholds for low-cost interventions should not be used to set intervention thresholds but rather to validate the implementation of clinically driven intervention thresholds. [ABSTRACT FROM AUTHOR]

Summary: The number of individuals aged 50 years or more at high risk of osteoporotic fracture worldwide in 2010 was estimated at 158 million and is set to double by 2040. Introduction: The aim of this study was to quantify the number of individuals worldwide aged 50 years or more at high risk of osteoporotic fracture in 2010 and 2040. Methods: A threshold of high fracture probability was set at the age-specific 10-year probability of a major fracture (clinical vertebral, forearm, humeral or hip fracture) which was equivalent to that of a woman with a BMI of 24 kg/m and a prior fragility fracture but no other clinical risk factors. The prevalence of high risk was determined worldwide and by continent using all available country-specific FRAX models and applied the population demography for each country. Results: Twenty-one million men and 137 million women had a fracture probability at or above the threshold in the world for the year 2010. The greatest number of men and women at high risk were from Asia (55 %). Worldwide, the number of high-risk individuals is expected to double over the next 40 years. Conclusion: We conclude that individuals with high probability of osteoporotic fractures comprise a very significant disease burden to society, particularly in Asia, and that this burden is set to increase markedly in the future. These analyses provide a platform for the evaluation of risk assessment and intervention strategies. [ABSTRACT FROM AUTHOR]

The introduction of the FRAX algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. FRAX integrates the influence of several well-validated risk factors for fracture with or without the use of bone mineral density. Since age-specific rates of fracture and death differ across the world, FRAX models are calibrated with regard to the epidemiology of hip fracture (preferably from national sources) and mortality (usually United Nations sources). Models are currently available for 73 nations or territories covering more than 80% of the world population. FRAX has been incorporated into more than 80 guidelines worldwide, although the nature of this application has been heterogeneous. The limitations of FRAX have been extensively reviewed. Arithmetic procedures have been proposed in order to address some of these limitations, which can be applied to conventional FRAX estimates to accommodate knowledge of dose exposure to glucocorticoids, concurrent data on lumbar spine bone mineral density, information on trabecular bone score, hip axis length, falls history, type 2 diabetes, immigration status and recency of prior fracture. [ABSTRACT FROM AUTHOR]

Summary: The objective was to undertake a health economic analysis of denosumab for the treatment of osteoporosis in women from the UK, using the FRAX® tool. Denosumab was cost-effective in women with a risk of major osteoporotic fracture meeting or exceeding approximately 20 % who are unable to take, comply with or tolerate generic alendronate. Introduction: Denosumab is a novel biologic agent developed for the treatment of osteoporosis, which has been shown to reduce the risk of fractures in a phase-III trial. The objective of the present study was to undertake a health economic analysis of denosumab in women from the UK. Ten-year probabilities of a major osteoporotic fracture at which denosumab is a cost-effective alternative to no treatment, generic alendronate, risedronate and strontium ranelate were estimated. Methods: A previously published Markov model was adapted to incorporate fracture and mortality risk assessments based on absolute fracture probability, as estimated by FRAX®. The model included treatment persistence and residual effect after discontinuation. Results: At a willingness-to-pay (WTP) of £30,000 per quality-adjusted life year and a 10-year fracture probability equivalent to a woman with a prior fragility fracture, denosumab was cost-effective compared to no treatment from the age of 70 years. At the same WTP, denosumab was-irrespective of age-cost-effective compared to no treatment at a major osteoporotic fracture probability of approximately 20 %. Denosumab was estimated to cost-effectively replace strontium, risedronate and generic alendronate at 10-year probabilities exceeding 11, 19 and 32 %, respectively. Conclusion: FRAX® facilitates the estimation of cost-effectiveness-based intervention thresholds applicable to patients with different combinations of clinical risk factors, which more closely matches the situation in clinical practice. Denosumab is cost-effective in patients with major osteoporotic fracture probabilities meeting or exceeding approximately 20 % who are unable to take, comply with or tolerate generic alendronate. [ABSTRACT FROM AUTHOR]

Summary: The incidence of hip fracture, death and the estimated incidence of major osteoporotic fracture in France were used to determine the lifetime and 10-year probability of fracture and incorporated into a probability model (FRAX®) calibrated to the French population. Introduction: Fracture probabilities in the French population have not been determined. Our aim was to determine the incidence of hip fracture in France and the estimated 10-year probabilities of hip and major osteoporotic fractures. Methods: The study population included adults over 50 years living in France in 2004. Incident hip fracture cases were identified from the French PMSI database. Incidence of the other major osteoporotic fractures was imputed from the relationship between hip fracture incidence and other major fracture in Sweden. These data were used to calculate population-based fracture probabilities according to age and BMD using cutoff values for femoral neck T-scores from the NHANES III data in Caucasian women. The probability model (FRAX®) calibrated to the French population was used to compute individual fracture probabilities according to specific clinical risk factors. Results: We identified 15,434 men and 51,469 women with an incident hip fracture. The remaining lifetime probability of hip fracture at 50 years was approximately 10 and 30% respectively. With a femoral neck T-score of −2 SD, one in two women and one in five men would sustain a major osteoporotic fracture in their lifetime. The 10-year probability of other major osteoporotic fractures increased with declining T-score and increasing age. Low body mass index and other clinical risk factors had an independent effect on fracture probability whether or not BMD was included in the FRAX® model. Conclusion: This analysis provides detailed estimation on the risk of fracture in the French population and may help to define therapeutic guidelines. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Background. At present, FRAX is a well-known and widely-used risk assessment tool for major osteoporotic fractures. The Ukrainian version of the FRAX algorithm was presented in 2016; with the “intervention threshold” for additional DXA examination and antiosteoporotic treatment of the Ukrainian women published in 2019. However, the data on its possible uses in men are limited. The purpose of the study was to evaluate the possibilities of using the previously developed criteria of the Ukrainian FRAX algorithm in Ukrainian men. Materials and methods. We examined 653 outpatients aged 40–88 years (mean age (M ± SD) — 60.5 ± 11.8 years). We analyzed the results both in the general group and in the age subgroups; in particular, with an account of low-trauma fractures, included in the FRAX calculation, and compared them with the corresponding indices of the Ukrainian women. Results. The most frequent (26.6 %) risk factor for osteoporotic fractures in the group of Ukrainian men was a history of low-trauma fracture (the corresponding index in women was 51.3 %), its presence being the reason for antiosteoporotic treatment initiating. Following upon the risk of major osteoporotic fractures calculated by FRAX, only 6.7 % of men without previous fractures were found to require additional DXA examination in order to re-evaluate the osteoporotic fracture risk, and none had a high fracture risk. 73 % of men without fractures did not have any risk factor included in the FRAX algorithm. Conclusions. This study showed a greater need for both antiosteoporotic treatment without DXA assessment and additional densitometric examination for the osteoporotic fracture risk assessment for the Ukrainian women rather than men, along with a special attention to the presence of previous fractures in men, and consideration of other risk factors for osteoporosis, even those not included in this FRAX algorithm. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

Summary: A reduction in hip fracture incidence following population screening might reflect the effectiveness of anti-osteoporosis therapy, behaviour change to reduce falls, or both. This post hoc analysis demonstrates that identifying high hip fracture risk by FRAX was not associated with any alteration in falls risk. Introduction: To investigate whether effectiveness of an osteoporosis screening programme to reduce hip fractures was mediated by modification of falls risk in the screening arm. Methods: The SCOOP study recruited 12,483 women aged 70–85 years, individually randomised to a control (n = 6250) or screening (n = 6233) arm; in the latter, osteoporosis treatment was recommended to women at high risk of hip fracture, while the control arm received usual care. Falls were captured by self-reported questionnaire. We determined the influence of baseline risk factors on future falls, and then examined for differences in falls risk between the randomisation groups, particularly in those at high fracture risk. Results: Women sustaining one or more falls were slightly older at baseline than those remaining falls free during follow-up (mean difference 0.70 years, 95%CI 0.55–0.85, p < 0.001). A higher FRAX 10-year probability of hip fracture was associated with increased likelihood of falling, with fall risk increasing by 1–2% for every 1% increase in hip fracture probability. However, falls risk factors were well balanced between the study arms and, importantly, there was no evidence of a difference in falls occurrence. In particular, there was no evidence of interaction (p = 0.18) between baseline FRAX hip fracture probabilities and falls risk in the two arms, consistent with no impact of screening on falls in women informed to be at high risk of hip fracture. Conclusion: Effectiveness of screening for high FRAX hip fracture probability to reduce hip fracture risk was not mediated by a reduction in falls. [ABSTRACT FROM AUTHOR]

Among 62,275 women and 6455 men, FRAX stratified risk for incident major osteoporotic fracture (MOF) and incident hip fracture (HF) without sex interaction. Performance was good in those with osteoporosis regardless of how this was defined. Introduction Some studies have reported that FRAX performance differs according to sex and/or osteoporosis definitions. We evaluated whether the performance of FRAX to predict incidentMOF and HF in women and men was affected by the presence or absence of osteoporosis defined by World Health Organization (WHO) or National Osteoporosis Foundation (NOF) criteria. Methods We studied women and men age ≥ 40 years with baseline hip and spine DXA scans (1996–2013). Individuals were classified into four non-overlapping subgroups: osteoporosis by WHO criteria, osteoporosis exclusively by NOF criteria, high fracture risk by FRAX(MOF ≥ 20%or HF ≥ 3%, without osteoporosis), and low fracture risk (MOF < 20%and HF < 3% without osteoporosis). In each subgroup, we evaluated stratification (hazard ratios [HR]) and calibration (observed vs predicted 10-year fracture probability) for incident fracture. Results The population included 62,275 women (5345MOF and 1471 HF) and 6455 men (405MOF and 108 HF). FRAX scores were strongly predictive of MOF (HR per SD: women 2.12, 95% CI 2.06–2.18; men 1.89, 95% CI 1.73–2.08; sex interaction p value = 0.97) and HF (women 4.78, 95% CI 4.44–5.14; men 4.20, 95% CI 3.22–5.49; sex interaction p value = 0.71). FRAX scores gave similar HRs for MOF among the four subgroups (subgroup interaction p value 0.34 for women, 0.22 for men). Observed versus predicted 10-yearMOF and HF probability for the defined subgroups demonstrated a high level of concordance for women and men (all r2 ≥ 0.9). [ABSTRACT FROM AUTHOR]

Summary: Age-specific intervention and assessment thresholds were developed for seven Latin American countries. The intervention threshold ranged from 1.2% (Ecuador) to 27.5% (Argentina) at the age of 50 and 90 years, respectively. In the Latin American countries, FRAX offers a substantial advance for the detection of subjects at high fracture risk.Introduction: Intervention thresholds are proposed using the Fracture Risk Assessment (FRAX) tool. We recommended their use to calculate the ten-year probability of fragility fracture (FF) in both, men and women with or without the inclusion of bone mineral density (BMD). The purpose of this study is to compute FRAX-based intervention and BMD assessment thresholds for seven Latin American countries in men and women ≥ 40 years.Methods: The intervention threshold (IT) was set at a 10-year probability of a major osteoporotic fracture (MOF) equivalent to a woman with a prior FF and a body mass index (BMI) equal to 25.0 kg/m2 without BMD or other clinical risk factors. The lower assessment threshold was set at a 10-year probability of a MOF in women with BMI equal to 25.0 kg/m2, no previous fracture and no clinical risk factors. The upper assessment threshold was set at 1.2 times the IT.Results: For the seven LA countries, the age-specific IT varied from 1.5 to 27.5% in Argentina, 3.8 to 25.2% in Brazil, 1.6 up to 20.0% in Chile, 0.6 to 10.2% in Colombia, 0.9 up to 13.6% in Ecuador, 2.6 to 20.0% in Mexico, and 0.7 up to 22.0% in Venezuela at the age of 40 and 90 years, respectively.Conclusions: In the LA countries, FRAX-based IT offers a substantial advance for the detection of men and women at high fracture risk, particularly in the elderly. The heterogeneity of IT between the LA countries indicates that country-specific FRAX models are appropriate rather than a global LA model. [ABSTRACT FROM AUTHOR]

Summary: Many current guidelines for the assessment of osteoporosis, including those in Kuwait, initiate fracture risk assessment in men and women using BMD T-score thresholds. We compared the Kuwaiti guidelines with FRAX-based age-dependent intervention thresholds equivalent to that in women with a prior fragility fracture. FRAX-based intervention thresholds identified women at higher fracture probability than fixed T-score thresholds, particularly in the elderly. Purpose: A FRAX® model been recently calibrated for Kuwait, but guidance is needed on how to utilise fracture probabilities in the assessment and treatment of patients. Methods: We compared age-specific fracture probabilities, equivalent to women with no clinical risk factors and a prior fragility fracture (without BMD), with the age-specific fracture probabilities associated with femoral neck T-scores of −2.5 and −1.5 SD, in line with current guidelines in Kuwait. Upper and lower assessment thresholds for BMD testing were additionally explored using FRAX. Results: When a BMD T-score of −2.5 SD was used as an intervention threshold, FRAX probabilities of a major osteoporotic fracture in women aged 50 years were approximately twofold higher than those in women of the same age but with an average BMD. The increase in risk associated with the BMD threshold decreased progressively with age such that, at the age of 83 years or more, a T-score of −2.5 SD was associated with a lower probability of fracture than that of the age-matched general population with no clinical risk factors. The same phenomenon was observed from the age of 66 years at a T-score of −1.5 SD. A FRAX-based intervention threshold, defined as the 10-year probability of a major osteoporotic fracture in a woman of average BMI with a previous fracture, rose with age from 4.3% at the age of 50 years to 23%, at the age of 90 years, and identified women at increased risk at all ages. Qualitatively comparable findings were observed in the case of hip fracture probability and in men. Conclusion: Intervention thresholds based on BMD alone do not optimally target women at higher fracture risk than those on age-matched individuals without clinical risk factors, particularly in the elderly. In contrast, intervention thresholds based on fracture probabilities equivalent to a 'fracture threshold' consistently target women at higher fracture risk, irrespective of age. [ABSTRACT FROM AUTHOR]

Summary: In a large clinical registry for the province of Manitoba, Canada, FRAX predicted incident MOF and hip fracture from 1 to 15 years following baseline assessment. A simple linear rescaling of FRAX outputs seems useful for predicting both short- and long-term fracture risk in this population. Introduction: FRAX® estimates 10-year probability of major osteoporotic fracture (MOF) and hip fracture. We examined FRAX predictions over intervals shorter and longer than 10 years. Methods: Using a population-based clinical registry for Manitoba, Canada, we identified 62,275 women and 6455 men 40 years and older with baseline dual-energy X-ray absorptiometry scans and FRAX scores. Incident MOF and hip fracture were assessed up to 15 years from population-based data. We assessed agreement between estimated fracture probability from 1 to 15 years using linearly rescaled FRAX scores and observed cumulative fracture probability. The gradient of risk for FRAX probability and incident fracture was examined overall and for 5-year intervals. Results: FRAX predicted incident MOF and hip fracture for all time intervals. There was no attenuation in the gradient of risk for MOF even for years >10. Gradient of risk was slightly lower for hip fracture prediction in years >10 vs years <5, though HRs remained high. Linear agreement was seen in the relationships between observed vs predicted (rescaled) FRAX probabilities ( R 0.95-1.00). Among women, there was near-perfect linearity in MOF predictions. Deviations from linearity, with a slightly higher observed than predicted MOF probability, were most evident in the first years following a fracture event and after 10 years for hip fracture prediction in women using FRAX with BMD. Simulations showed that results were robust to large differences in fracture rates and moderate differences in mortality rates. Conclusions: FRAX predicts incident MOF and hip fracture up to 15 years and could be adapted to predict fracture over time periods shorter and longer term than 10 years in populations with fracture and mortality epidemiology similar to Canada. [ABSTRACT FROM AUTHOR]

Summary: In the UK, fracture risk guidance is provided by the National Osteoporosis Guideline Group (NOGG). NOGG usage showed widespread access through direct web-based linkage to FRAX. The facilitated interaction between fracture risk assessment and clinical guidelines could usefully be adopted in other countries. Introduction: In the UK, guidance on assessment of osteoporosis and fracture risk is provided by the National Osteoporosis Guideline Group (). We wished to determine access to this guidance by exploring website activity. Methods: We undertook an analysis of FRAX and NOGG website usage for the year between 1 July 2013 and 30 June 2014 using Google Analytics software. Results: During this period, there was a total of 1,774,812 sessions (a user interaction with the website) on the FRAX website with 348,964 of these from UK-based users; 253,530 sessions were recorded on the NOGG website. Of the latter, two-thirds were returning visitors, with the vast majority (208,766; 82 %) arising from sites within the UK. The remainder of sessions were from other countries demonstrating that some users of FRAX in other countries make use of the NOGG guidance. Of the UK-sourced sessions, the majority was from England, but the session rate (adjusted for population) was the highest for Scotland. Almost all (95.7 %) of the UK sessions arose from calculations being passed through from the FRAX tool () to the NOGG website, comprising FRAX calculations in patients without a bone mineral density (BMD) measurement (74.5 %) or FRAX calculations with a BMD result (21.2 %). National Health Service (NHS) sites were identified as the major source of visits to the NOGG website, comprising 79.9 % of the identifiable visiting locations, but this is an underestimate as many sites from within the NHS are not classified as such. Conclusion: The study shows that the facilitated interaction between web-based fracture risk assessment and clinical guidelines is widely used in the UK. The approach could usefully be adopted in other countries for which a FRAX model is available. [ABSTRACT FROM AUTHOR]

Summary: Falls and fractures share several common risk factors. Although past falls is not included as an input variable in the FRAX calculator, we demonstrate that FRAX probability predicts risk of incident falls in the MrOs Sweden cohort. Introduction: Although not included in the FRAX® algorithm, it is possible that increased falls risk is partly dependent on other risk factors that are incorporated into FRAX. The aim of the present study was to determine whether fracture probability generated by FRAX might also predict risk of incident falls and the extent that a falls history would add value to FRAX. Methods: We studied the relationship between FRAX probabilities and risk of falls in 1836 elderly men recruited to the MrOS study, a population-based prospective cohort of men from Sweden. Baseline data included falls history, clinical risk factors, bone mineral density (BMD) at femoral neck, and calculated FRAX probabilities. Incident falls were captured during an average of 1.8 years of follow-up. An extension of Poisson regression was used to investigate the relationship between FRAX, other risk variables, and the time-to-event hazard function of falls. All associations were adjusted for age and time since baseline. Results: At enrolment, 15.5 % of the men had fallen during the preceding 12 months (past falls) and 39 % experienced one or more falls during follow-up (incident falls). The risk of incident falls increased with increasing FRAX probabilities at baseline (hazard ratio (HR) per standard deviation (SD), 1.16; 95 % confidence interval (95%CI), 1.06 to 1.26). The association between incident falls and FRAX probability remained after adjustment for past falls (HR per SD, 1.12; 95%CI, 1.03 to 1.22). High compared with low baseline FRAX score (>15 vs <15 % probability of major osteoporotic fracture) was strongly predictive of increased falls risk (HR, 1.64; 95%CI, 1.36 to 1.97) and remained stable with time. Whereas past falls were a significant predictor of incident falls (HR, 2.75; 95%CI, 2.32 to 3.25), even after adjustment for FRAX, the hazard ratio decreased markedly with increasing follow-up time. Conclusions: Although falls are not included as an input variable, FRAX captures a component of risk for future falls and outperforms falls history with an extended follow-up time. [ABSTRACT FROM AUTHOR]

Summary: The incidence of hip fracture in Sweden is substantially lower in immigrants than in the population born in Sweden. Thus, the use of a FRAX® model in immigrants overestimates the risk of fracture, and the use of country of origin-specific models may be more appropriate. Introduction: Age-specific fracture and mortality rates vary between countries so that FRAX tools are country-specific. In the case of immigrants, it is not known whether the model for the original or the new country is most appropriate. The aim of this study was to compare the incidence of hip fractures in foreign-born and Swedish-born individuals residing in Sweden. Methods: We studied the incidence of hip fracture in all men and women aged 50 years or more in Sweden between 1987 and 2002. The population comprised 2.8 million Swedish-born and 270,000 foreign-born individuals. Results: Incident hip fractures occurred in 239,842 Swedish-born and 12,563 foreign-born individuals. The hip fracture incidence rose with age for both groups and was higher for women than men amongst both Swedish-born and foreign-born individuals. The hip fracture incidence for the Swedish-born cohort was approximately twice that of immigrants. For example, at the age of 70 years, the annual hip fracture incidence (per 100,000) was 450 (95 % CI 446-454) for a Swedish-born woman and 239 (95 % CI 223-257) for a foreign-born woman at the time of immigration. The hip fracture incidence rose slowly with time from immigration (0.6 % per annum, 95 % CI 0.5-0.8 %) but remained significantly lower than for Swedish-born individuals even after 40 years of residence. Conclusions: The incidence of hip fracture in Sweden is substantially lower in immigrants than in the population native to Sweden. Although there was a small rise in age- and sex-specific incidence after immigration, the incidence remained markedly lower than that observed in Swedish-born individuals. Thus, the use of a FRAX model for Sweden will overestimate the risk of fracture for foreign-born individuals living in Sweden. [ABSTRACT FROM AUTHOR]

Summary: Based on an extensive cohort study over 25 years, the present study supports the assumption that major osteoporotic fractures can be reasonably predicted from hip fracture rates. Introduction: The construct for FRAX models depends on algorithms to adjust for double counting of fracture outcomes in some models and in others, to estimate the incidence of a major fracture from hip fracture rates. The aim of the present study was to test the validity of these algorithms in a large prospective cohort. Methods: The incidence of hip, clinical spine, distal forearm, and humerus fracture was determined in the prospective and ongoing population-based Reykjavik Study with follow up of 257,001 person-years. The incidence of a first major fracture was compared with the correction factors used in FRAX to adjust the incidence of several fracture outcomes for double counting. In addition, the incidence of a major osteoporotic fracture estimated from the Icelandic hip fracture rates was compared with the Malmo ratios used in FRAX. Results: The adjustments necessary to account for multiple fracture outcomes were similar to those previously derived from Sweden. Additionally, incidence of a first major osteoporotic fracture was similar to that derived for FRAX models. Conclusion: The findings of the present study support the algorithms used in FRAX to estimate the incidence of a first major fracture and the predictive value of hip fracture for other major fractures. [ABSTRACT FROM AUTHOR]

Summary: Bazedoxifene and raloxifene were evaluated in the treatment of postmenopausal osteoporosis from health economic perspective in Europe. Based on a computer-based algorithm calculating efficacy of the treatments, bazedoxifene appears to be a cost-effective strategy compared to raloxifene, particularly in patients at high fracture risk. Introduction: The purpose of this study was to compare cost-effectiveness of bazedoxifene and raloxifene in eight European countries: Belgium, France, Germany, Ireland, Italy, Spain, Sweden, and the UK. Methods: The Fracture Risk Assessment Tool, which is a computer-based algorithm to calculate fracture probability using clinical risk factors alone or with bone mineral density, was incorporated in a Markov Tunnel model to evaluate cost-effectiveness of bazedoxifene 20 or 40 mg vs. raloxifene 60 mg in postmenopausal osteoporotic women. The efficacy of bazedoxifene and raloxifene for vertebral and non-vertebral fractures was measured as a function of the 10-year probability of a major osteoporotic fracture. The model estimated the incremental cost-effectiveness ratio and net monetary benefit (NMB) from a healthcare perspective, given the willingness to pay €30,000. Results: In postmenopausal osteoporotic women, bazedoxifene was a cost saving strategy compared to raloxifene in the countries studied. The median NMB of bazedoxifene compared to raloxifene increased monotonically with the 10-year fracture probability. In general, the median NMB became greater than 0 in women with 10-year probabilities of a major osteoporotic fracture between 5 and 10 % or above. The impact on results by varying the assumptions in the model was examined in sensitivity analysis. Conclusion: Bazedoxifene appears to be a cost-effective strategy compared to raloxifene for the treatment of postmenopausal osteoporotic women in Europe, particularly in patients at high fracture risk. [ABSTRACT FROM AUTHOR]

Summary: We investigated the fracture risk assessment tool (FRAX) Canada calibration and discrimination according to income quintile in 51,327 Canadian women, with and without a competing mortality framework. Our data show that, under a competing mortality framework, FRAX provides robust fracture prediction and calibration regardless of socioeconomic status (SES). Introduction: FRAX® predicts 10-year fracture risk. Social factors may independently affect fracture risk. We investigated FRAX calibration and discrimination according to SES. Methods: Women aged ≥50 years with baseline femoral neck bone mineral density (BMD) were identified from the Manitoba Bone Density Program, Canada ( n = 51,327), 1996-2011. Mean household income, extracted from 2006 census files, was categorized into quintiles. Ten-year fracture probabilities were calculated using FRAX Canada. Incident non-traumatic fractures were studied in relation to income quintile in adjusted Cox proportional hazards models. We compared observed versus predicted fractures with and without a competing mortality framework. Results: During mean 6.2 ± 3.7 years of follow up, there were 6,392 deaths, 3,723 women with ≥1 major osteoporotic fracture (MOF), and 1,027 with hip fractures. Lower income was associated with higher risk for death, MOF, and hip fracture in adjusted models (all p < 0.005). More women in income quintile 1 (lowest) versus quintile 5 experienced death (19 vs. 8 %), MOF (10 vs. 6 %), or hip fracture (3.0 vs. 1.3 %) (all p ≤ 0.001). Adjustment for competing mortality mitigated the effect of SES on FRAX calibration, and good calibration was observed. FRAX provided good fracture discrimination for MOF and hip fracture within each income quintile (all p < 0.001). Area under the curve was slightly lower for income quintiles 1 versus 5 for FRAX with BMD to predict MOF (0.68, 95 % CI 0.66-0.70 vs. 0.71, 95 % CI 0.69-0.74) and hip fracture (0.79, 95 % CI 0.76-0.81 vs. 0.87, 95 % CI 0.84-0.89). Conclusion: Increased fracture risk in individuals of lower income is offset by increased mortality. Under a competing mortality framework, FRAX provides robust fracture prediction and calibration regardless of SES. [ABSTRACT FROM AUTHOR]

A FRAX model for Colombia was released June 30, 2010. This article describes the data used to develop the Colombian FRAX model and illustrates its features compared to other countries. Hip fracture cases aged 50 years or more who were referred to all hospitals serving the city of Barranquilla were identified prospectively over a 3-year period (2004-2006). Age- and sex-stratified hip fracture incidence rates were computed using the 2005 census. Present and future numbers of hip fracture cases in Colombia were calculated from the age- and sex-specific incidence and the national population demography. Mortality rates for 1999 were extracted from nationwide databases and used to estimate hip fracture probabilities. For other major fractures (clinical vertebral, forearm, and humerus), incidence rates were imputed, using Swedish ratios for hip to other major osteoporotic fracture, and used to construct the FRAX model. Incidence of hip fracture increased with age, more markedly in women than in men. Over all ages, the female to male ratio was 1.7. By extrapolation, there were estimated to be 7,902 new hip fracture cases (2,673 men, 5,229 women) in Colombia in 2010, which was predicted to increase to 22,720 cases (7,568 men, 15,152 women) in 2035. The 10-year probability of hip or major fracture was increased in patients with a clinical risk factor, lower BMI, female gender, a higher age, and a decreased BMD T score. The remaining lifetime probability of hip fracture at the age of 50 years was 2.5 and 4.7 % in men and women, respectively, which were lower than rates in a Mexican population (3.8 and 8.5 %, respectively) and comparable with estimates for Venezuela (2.4 and 7.5 %, respectively). The FRAX tool is the first country-specific fracture-prediction model available in Colombia. It is based on the original FRAX methodology, which has been externally validated in several independent cohorts. Despite some limitations, the strengths make the Colombian FRAX tool a good candidate for implementation into clinical practice. [ABSTRACT FROM AUTHOR]

Summary: In order to update data underlying the Italian version of FRAX, we computed the national hip fracture incidence in Italy from hospitalization records for the year 2008. Mortality data and 10-year probabilities of major osteoporotic fractures were also updated. This revision will improve FRAX accuracy and reliability. Introduction: The original Italian version of FRAX® was based on five regional estimates of hip fracture risk undertaken up to 20 years previously. Our objective was to update hip fracture rates for the model with more recently derived data from the whole Italian population and more recent data on mortality. Methods: We analyzed the Italian national hospitalization database for the year 2008 in order to compute age- and sex-specific hip fracture incidence rates. Re-hospitalisations of the same patients within 1 year were excluded from the analysis. Hip fracture incidence rates were computed for the age range of 40-100 years, whereas the original FRAX model lacked data on the youngest and oldest age groups. In addition, we used the national mortality data for the same year 2008 to update the model. Ten-year fracture probabilities were re-calculated on the basis of the new fracture incidence rates. Results: The new hip fracture age- and sex-specific incidence rates were close to those used in the original FRAX tool, although some significant differences (not exceeding 25-30 %) were found for men aged 65-75 years and women under 55 years of age. In general, the revision resulted in decreased estimated 10-year probabilities in the younger age groups, whilst those in the older age groups were slightly increased. Conclusions: The Italian version of FRAX has been updated using the new fracture incidence rates. The impact of these revisions on FRAX is likely to increase the accuracy and reliability of FRAX in estimating 10-year fracture probabilities. [ABSTRACT FROM AUTHOR]

This review summarizes the available evidence-based data that form the basis for therapeutic intervention and covers the current status of glucocorticoid-induced osteoporosis (GIOP) management, regulatory requirements, and risk-assessment options. Glucocorticoids are known to cause bone loss and fractures, yet many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated. An European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis workshop was convened to discuss GIOP management and to provide a report by a panel of experts. An expert panel reviewed the available studies that discussed approved therapeutic agents, focusing on randomized and controlled clinical trials reporting on bone mineral density and/or fracture risk of at least 48 weeks' duration. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. The FRAX algorithm can be adjusted according to glucocorticoid dose. Available antiosteoporotic therapies such as bisphosphonates and teriparatide are efficacious in GIOP management. Several other agents approved for the treatment of postmenopausal osteoporosis may become available for GIOP. It is advised to stop antiosteoporotic treatment after glucocorticoid cessation, unless the patient remains at increased risk of fracture. Calcium and vitamin D supplementation as an osteoporosis-prevention measure is less effective than specific antiosteoporotic treatment. Fracture end-point studies and additional studies investigating specific subpopulations (pediatric, premenopausal, or elderly patients) would strengthen the evidence base and facilitate the development of intervention thresholds and treatment guidelines. [ABSTRACT FROM AUTHOR]

Summary: This paper provides a framework for the development of national guidelines for the management of glucocorticoid-induced osteoporosis in men and women aged 18 years and over in whom oral glucocorticoid therapy is considered for 3 months or longer. Introduction: The need for updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation and the European Calcified Tissue Society, which set up a joint Guideline Working Group at the end of 2010. Methods and results: The epidemiology of GIO is reviewed. Assessment of risk used a fracture probability-based approach, and intervention thresholds were based on 10-year probabilities using FRAX. The efficacy of intervention was assessed by a systematic review. Conclusions: Guidance for glucocorticoid-induced osteoporosis is updated in the light of new treatments and methods of assessment. National guidelines derived from this resource need to be tailored within the national healthcare framework of each country. [ABSTRACT FROM AUTHOR]

Summary: The incidence of hip fractures in Turkey increased markedly from that reported in 1988/1989 so that FRAX® models for Turkey should be revised. Introduction: The MEDOS study in 1988/1989 reported that men and women from Turkey had exceptionally low rates of hip fracture. The aim of the FRACTURK study was to estimate current and future hip fracture risks and the prevalence of osteoporosis in Turkey. Methods: Hip fracture cases in 2009 were identified from interviews of a population-based sample of 26,424 residents aged 50 years or more in 12 different regions of Turkey and in two hospital surveys. Bone mineral density was evaluated by DXA in an age-stratified sample of 1,965 men and women. Results: Hip fracture incidence in the community-based survey was similar to that in the hospital survey. The age-specific incidence in men and women was substantially higher than that reported for 1988/1989. At the age of 50 years, the remaining lifetime probability of a hip fracture was 3.5% in men and 14.6% in women. In 2009, there were approximately 24,000 hip fractures estimated in Turkey, 73% of which were found in women. Assuming no change in the age- and sex-specific incidence, the number of hip fractures was expected to increase to nearly 64,000 in 2035. The prevalence of osteoporosis at the femoral neck was 7.5% and 33.3% in men and women, respectively, aged 50 years or more. Conclusion: Although Turkey is still among the countries with low hip fracture rates in Europe, the incidence has increased markedly in the last 20 years. This finding can be used to recalibrate fracture risk assessment models for Turkey. [ABSTRACT FROM AUTHOR]

Summary: The FRAX tool has been calibrated to the entire Dutch population, using nationwide (hip) fracture incidence rates and mortality statistics from the Netherlands. Data used for the Dutch model are described in this paper. Introduction: Risk communication and decision making about whether or not to treat with anti-osteoporotic drugs with the use of T-scores are often unclear for patients. The recently developed FRAX models use easily obtainable clinical risk factors to estimate an individual's 10-year probability of a major osteoporotic fracture and hip fracture that is useful for risk communication and subsequent decision making in clinical practice. As of July 1, 2010, the tool has been calibrated to the total Dutch population. This paper describes the data used to develop the current Dutch FRAX model and illustrates its features compared to other countries. Methods: Age- and sex-stratified hip fracture incidence rates (LMR database) and mortality rates (Dutch national mortality statistics) for 2004 and 2005 were extracted from Dutch nationwide databases (patients aged 50+ years). For other major fractures, Dutch incidence rates were imputed, using Swedish ratios for hip to osteoporotic fracture (upper arm, wrist, hip, and clinically symptomatic vertebral) probabilities (age- and gender-stratified). The FRAX tool takes into account age, sex, body mass index (BMI), presence of clinical risk factors, and bone mineral density (BMD). Results: Fracture incidence rates increased with increasing age: for hip fracture, incidence rates were lowest among Dutch patients aged 50-54 years (per 10,000 inhabitants: 2.3 for men, 2.1 for women) and highest among the oldest subjects (95-99 years; 169 of 10,000 for men, 267 of 10,000 for women). Ten-year probability of hip or major osteoporotic fracture was increased in patients with a clinical risk factor, lower BMI, female gender, a higher age, and a decreased BMD T-score. Parental hip fracture accounted for the greatest increase in 10-year fracture probability. Conclusion: The Dutch FRAX tool is the first fracture prediction model that has been calibrated to the total Dutch population, using nationwide incidence rates for hip fracture and mortality rates. It is based on the original FRAX methodology, which has been externally validated in several independent cohorts. Despite some limitations, the strengths make the Dutch FRAX tool a good candidate for implementation into clinical practice. [ABSTRACT FROM AUTHOR]

Summary: Most patients designated as high risk of fracture using fracture risk assessment tool (FRAX) with femoral neck bone mineral density (BMD) (i.e., 10-year major osteoporotic fracture probability exceeding 20% or hip fracture exceeding 3%) have one or more T-scores in the osteoporotic range; conversely, almost no high risk patients have normal T-scores at all bone mineral density measurement sites. Introduction: We determined the agreement between a FRAX designation of high risk of fracture [defined as 10-year major osteoporotic fracture probability (≥20%) or hip fracture probability (≥3%)] and the WHO categorizations of bone mineral density according to T-score. Methods: Ten-year FRAX probabilities calculated with femoral neck BMD were derived using both Canadian and US white tools for a large clinical cohort of 36,730 women and 2,873 men age 50 years and older from Manitoba, Canada. Individuals were classified according to FRAX fracture probability and BMD T-scores alone. Results: Most individuals designated by FRAX as high risk of major osteoporotic fracture had a T-score in the osteoporotic range at one or more BMD measurement sites (85% with Canadian tool and 83% with US white tool). The majority of individuals deemed at high risk of hip fracture had one or more T-scores in the osteoporotic range (66% with Canadian tool and 64% with US white tool). Conversely, there were extremely few individuals (<1%) who were at high risk of major osteoporotic or hip fracture with normal T-scores at all BMD measurement sites. Conclusions: A FRAX designation of high risk of fracture is usually associated with a densitometric diagnosis of osteoporosis. [ABSTRACT FROM AUTHOR]

Summary: Fracture probability assessed without bone mineral density (BMD) could potentially be sufficient for clinical decision making in many individuals categorized as low or high fracture risk. For individuals falling in a moderate risk range, there is incremental value in using BMD in the probability calculation as this appropriately reclassifies risk in over one third of the individuals. Introduction: A new fracture risk assessment tool from the World Health Organization (FRAX®) estimates 10-year major osteoporotic and hip fracture probabilities from multiple clinical risk factors with or without hip BMD. The objective of this study is to determine whether fracture probability derived without BMD can be used to identify individuals who would be designated for treatment. Methods: A historical cohort of 36,730 women and 2,873 men aged 50 years and older drawn from the Manitoba Bone Density Program database, which contains clinical BMD results for the Province of Manitoba, Canada, was included in the study. Results: When 10-year probability for major osteoporotic fracture estimated without knowledge of BMD was high (≥20%), the vast majority (92.8%) qualified for intervention under the National Osteoporosis Foundation (NOF) guidelines, whereas among those at low risk (<10%), the vast majority (80.5%) did not satisfy any NOF intervention criteria. The benefit of including BMD in the risk assessment was greatest among those initially at moderate risk (10-19%) when fracture probability was derived without BMD, but this represented only 29.4% of the cohort (9.3% of those aged <65 years and 48.7% of those ≥65 years). Conclusions: Fracture probability derived without BMD is able to risk stratify women in terms of future fracture risk and could potentially be sufficient for clinical decision making in many of those designated at low or high fracture risk. [ABSTRACT FROM AUTHOR]

Summary: The FRAX® tool estimates a 10-year probability of fracture based upon multiple clinical risk factors and an optional bone mineral density (BMD) measurement obtained from the femoral neck. We describe a simple procedure for using lumbar spine BMD to enhance fracture risk assessment under the FRAX system. Introduction: Discordance between lumbar spine (LS) and femoral neck (FN) T-scores is common and a source of clinical confusion since the LS measurement is not an input variable for the FRAX algorithm. The purpose of this study is to develop a procedure for adjusting FRAX probability based upon the T-score difference between the LS and FN (termed offset). Methods: The Manitoba BMD database was used to identify baseline LS and FN dual-energy X-ray absorptiometry examinations (33,850 women and 2,518 men age 50 and older) with FRAX estimates for a major osteoporotic fracture categorized as low (<10%), moderate (10-20%), and high (>20%). Fracture outcomes were assessed from population-based administrative data. An approach was developed and internally validated using a split-cohort design. Results: The offset was found to significantly affect fracture risk [HR, 1.12 (95% CI, 1.06-1.18) per SD LS below FN] independent of the FRAX probability. The following rule was formulated: 'Increase/decrease FRAX estimate for a major fracture by one tenth for each rounded T-score difference between LS and FN.' In the validation subgroup, there was a significant improvement in the fracture prediction using FRAX with the proposed offset adjustment for major osteoporotic ( P = 0.007) and vertebral fracture prediction ( P < 0.001). For those at moderate risk under FRAX, 12.6% showed reclassification using the offset to a risk level that more accurately reflected their observed risk (25.2% reclassification for moderate risk discordant cases). Conclusion: A simple procedure that incorporates the offset between the LS and FN T-scores can enhance fracture risk prediction under the FRAX system. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The National Osteoporosis Foundation (NOF) recommends considering treatment in women with a 20% or higher 10-year probability of a major fracture. However, raloxifene reduces both the risk of vertebral fractures and invasive breast cancer so that raloxifene treatment may be clinically appropriate and cost-effective in women who do not meet a 20% threshold risk. The aim of this study was to identify cost-effective scenarios of raloxifene treatment compared to no treatment in younger postmenopausal women at increased risk of invasive breast cancer and fracture risks below 20%. Method: A micro-simulation model populated with data specific to American Caucasian women was used to quantify the costs and benefits of 5-year raloxifene treatment. The population evaluated was selected based on 10-year major fracture probability as estimated with FRAX® being below 20% and 5-year invasive breast cancer risk as estimated with the Gail risk model ranging from 1% to 5%. Results: The cost per QALY gained ranged from US $22,000 in women age 55 with 5% invasive breast cancer risk and 15–19.9% fracture probability, to $110,000 in women age 55 with 1% invasive breast cancer risk and 5–9.9% fracture probability. Raloxifene was progressively cost-effective with increasing fracture risk and invasive breast cancer risk for a given age cohort. At lower fracture risk in combination with lower invasive breast cancer risk or when no preventive raloxifene effect on invasive breast cancer was assumed, the cost-effectiveness of raloxifene worsened markedly and was not cost-effective given a willingness-to-pay of US $50,000. At fracture risk of 15–19.9% raloxifene was cost-effective also in women at lower invasive breast cancer risk. Conclusions: Raloxifene is potentially cost-effective in cohorts of young postmenopausal women, who do not meet the suggested NOF 10-year fracture risk threshold. The cost-effectiveness is contingent on their 5-year invasive breast cancer risk. The result highlights the importance of considering a woman''s full risk profile when considering anti-osteoporosis treatment. [Copyright &y& Elsevier]

The study estimated the cost-effectiveness of risedronate compared to no treatment in UK women using the FRAX algorithm for fracture risk assessment. A Markov cohort model was used to estimate the cost-effectiveness. Risedronate was found cost-effective from the age of 65 years, assuming a willingness to pay for a QALY of £30,000. The aim of this study was to assess the cost-effectiveness of risedronate for the prevention and treatment in a UK setting using the FRAX® algorithm for fracture risk assessment. A further aim was to establish intervention thresholds with risedronate treatment. The cost-effectiveness of risedronate was compared to no treatment in post-menopausal women with clinical risk factors for fracture using a Markov cohort model populated with data relevant for the UK. The model incorporated the features of FRAX® (the WHO risk assessment tool). The analysis had a health care perspective and quality adjusted life years was used as the main outcome measure. Treatment was cost-effective from the age of 65 years, assuming a willingness to pay for a QALY of £30,000. Treatment was also cost-effective at all ages in women who had previously sustained a fragility fracture or in women with a parental history of hip fracture with a bone mineral density set at the threshold of osteoporosis. At the £30,000 threshold value for a QALY, risedronate was on average found to cost-effective below the 10-year probability of a major osteoporotic fractures of 13.0%. Risedronate is a cost-effective agent for the treatment of established osteoporosis (osteoporosis and a prior fragility fracture) in women from the age of 50 years and older and above 65 years in women with osteoporosis alone. The results support the treatment recommendations in recent UK guidelines for osteoporosis. [ABSTRACT FROM AUTHOR]

The cost-effectiveness of strontium ranelate was compared to no treatment in UK women using the FRAX® algorithm for fracture risk assessment. At a willingness-to-pay of £30,000 per quality-adjusted life-year (QALY), strontium ranelate was generally cost-effective in women with prior fracture at the threshold of osteoporosis from an age of 65 years. The objectives of the study were to estimate the cost-effectiveness of strontium ranelate in the UK for the treatment of osteoporosis and to establish intervention thresholds for treatment using the FRAX® tool. The cost-effectiveness of strontium ranelate was compared to no treatment in postmenopausal women with clinical risk factors for fracture using a lifetime simulation model based on Markov cohort methodology that incorporated the features of FRAX®. At a threshold of £30,000 per QALY, strontium ranelate was generally cost-effective in women from an age of 65 years with prior fracture at the threshold of osteoporosis (i.e., a T-score of −2.5 SD) and in women with a prior fracture (and no information on bone mineral density) from the age of 65 years. At a threshold of £20,000, strontium ranelate became cost-effective at a 10-year fracture probability of 25.7% and at 16.9% with a threshold of £30,000 for a QALY. Strontium ranelate is a cost-effective agent for the treatment of established osteoporosis in women over the age of 65 years. Cost-effective scenarios were also found for the prevention and treatment of fractures associated with osteoporosis, in younger women with additional clinical risk factors. [ABSTRACT FROM AUTHOR]