Asia-Pacific consensus on long-term and sequential therapy for osteoporosis.

Objectives: This study aimed to present the Asia-Pacific consensus on long-term and sequential therapy for osteoporosis, offering evidence-based recommendations for the effective management of this chronic condition. The primary focus is on achieving optimal fracture prevention through a comprehensive, individualized approach. Methods: A panel of experts convened to develop consensus statements by synthesizing the current literature and leveraging clinical expertise. The review encompassed long-term anti-osteoporosis medication goals, first-line treatments for individuals at very high fracture risk, and the strategic integration of anabolic and antiresorptive agents in sequential therapy approaches. Results: The panelists reached a consensus on 12 statements. Key recommendations included advocating for anabolic agents as the first-line treatment for individuals at very high fracture risk and transitioning to antiresorptive agents following the completion of anabolic therapy. Anabolic therapy remains an option for individuals experiencing new fractures or persistent high fracture risk despite antiresorptive treatment. In cases of inadequate response, the consensus recommended considering a switch to more potent medications. The consensus also addressed the management of medication-related complications, proposing alternatives instead of discontinuation of treatment. Conclusions: This consensus provides a comprehensive, cost-effective strategy for fracture prevention with an emphasis on shared decision-making and the incorporation of country-specific case management systems, such as fracture liaison services. It serves as a valuable guide for healthcare professionals in the Asia-Pacific region, contributing to the ongoing evolution of osteoporosis management.

Prolonged bone health benefits for breast cancer patients following adjuvant bisphosphonate therapy: the BoHFAB study.

Adjuvant bisphosphonates are often recommended in postmenopausal women with early breast cancer at intermediate-to-high risk of disease recurrence, but the magnitude and duration of their effects on bone mineral density (BMD) and bone turnover markers (BTMs) are not well described. We evaluated the impact of adjuvant zoledronate on areal BMD and BTMs in a sub-group of patients who had completed the large 5-yr randomized Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial. About 224 women (recurrence free) who had completed the AZURE trial within the previous 3 mo were recruited from 20 UK AZURE trial sites. One hundred twenty had previously been randomized to zoledronate (19 doses of 4 mg over 5 yr) and 104 to the control arm. BMD and BTMs were assessed at sub-study entry, 6 (BTMs only), 12, 24, and 60 mo following the completion of AZURE. As expected, mean BMD, T-scores, and Z-scores at sub-study entry were higher in the zoledronate vs the control arm. At the lumbar spine, the mean (SD) standardized BMD (sBMD) was 1123 (201) and 985 (182) mg/cm2 in the zoledronate and control arms, respectively (P < .0001). The baseline differences in sBMD persisted at all assessed skeletal sites and throughout the 5-yr follow-up period. In patients completing zoledronate treatment, BTMs were significantly lower than those in the control arm (α- and ß-urinary C-telopeptide of type-I collagen, both P < .00001; serum intact pro-collagen I N-propeptide, P < .00001 and serum tartrate-resistant acid phosphatase 5b, P = .0001). Some offset of bone turnover inhibition occurred in the 12 mo following the completion of zoledronate treatment. Thereafter, during the 60 mo of follow-up, all BTMs remained suppressed in the zoledronate arm relative to the control arm. In conclusion, in addition to the known anti-cancer benefits of adjuvant zoledronate, there are likely to be positive, lasting benefits in BMD and bone turnover.

FRAX predicts cardiovascular risk in women undergoing osteoporosis screening: the Manitoba bone mineral density registry.

Osteoporosis and cardiovascular disease (CVD) are highly prevalent in older women, with increasing evidence for shared risk factors and pathogenesis. Although FRAX was developed for the assessment of fracture risk, we hypothesized that it might also provide information on CVD risk. To test the ability of the FRAX tool and FRAX-defined risk factors to predict incident CVD in women undergoing osteoporosis screening with DXA, we performed a retrospective prognostic cohort study which included women aged 50 yr or older with a baseline DXA scan in the Manitoba Bone Mineral Density Registry between March 31, 1999 and March 31, 2018. FRAX scores for major osteoporotic fracture (MOF) were calculated on all participants. Incident MOF and major adverse CV events (MACE; hospitalized acute myocardial infarction [AMI], hospitalized non-hemorrhagic cerebrovascular disease [CVA], or all-cause death) were ascertained from linkage to population-based healthcare data. The study population comprised 59 696 women (mean age 65.7 ± 9.4 yr). Over mean 8.7 yr of observation, 6021 (10.1%) had MOF, 12 277 women (20.6%) had MACE, 2274 (3.8%) had AMI, 2061 (3.5%) had CVA, and 10 253 (17.2%) died. MACE rates per 1000 person-years by FRAX risk categories low (10-yr predicted MOF <10%), moderate (10%-19.9%) and high (≥20%) were 13.5, 34.0, and 64.6, respectively. Although weaker than the association with incident MOF, increasing FRAX quintile was associated with increasing risk for MACE (all P-trend <.001), even after excluding prior CVD and adjusting for age. HR for MACE per SD increase in FRAX was 1.99 (95%CI, 1.96-2.02). All FRAX-defined risk factors (except parental hip fracture and lower BMI) were independently associated with higher non-death CV events. Although FRAX is intended for fracture risk prediction, it has predictive value for cardiovascular risk.

Evidence-Based Guideline for the management of osteoporosis in men.

Historically, osteoporosis has been viewed as a disease of women, with research, trials of interventions and guidelines predominantly focused as such. It is apparent, however, that this condition causes a substantial health burden in men also, and that its assessment and management must ultimately be addressed across both sexes. In this article, an international multidisciplinary working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases presents GRADE-assessed recommendations for the diagnosis, monitoring and treatment of osteoporosis in men. The recommendations are based on a comprehensive review of the latest research related to diagnostic and screening approaches for osteoporosis and its associated high fracture risk in men, covering disease burden, appropriate interpretation of bone densitometry (including the use of a female reference database for densitometric diagnosis in men) and absolute fracture risk, thresholds for treatment, and interventions that can be used therapeutically and their health economic evaluation. Future work should specifically address the efficacy of anti-osteoporosis medications, including denosumab and bone-forming therapies.

Sarcopenia definitions and their association with fracture risk in older Swedish women.

The purpose of this study was to investigate the prevalence of three sarcopenia definitions and their associations with fracture risk in older Swedish women when adjusted for fracture risk assessment (FRAX)-based risk factors; 2,883 women with a mean age of 77.8 years were included. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC; low handgrip strength [kg] and gait speed (m/s)), revised European Working Group on Sarcopenia in Older People (EWGSOP2; low appendicular lean mass index, appendicular lean mass [ALM]/height; kg/m2], and hand grip strength [kg]), and Asian Working Group for Sarcopenia (AWGS; low ALM (kg), and hand grip strength [kg]) definitions. Femoral neck T-score was obtained from dual-energy X-ray absorptiometry. All fractures, confirmed by X-ray or medical record review, were subsequently categorized as major osteoporotic fractures (MOFs) and hip fractures. Deaths were verified through regional registers. The total follow-up time was 6.4 ± 1.3 (mean ± SD) yr. Cox regression (hazard ratios [HR] and 95% CIs) analyses were performed with adjustment for age, FRAX variables, and femoral neck T-score. Sarcopenia prevalence was 4.5% (n = 129) according to SDOC, 12.5% (n = 360) for EWGSOP2, and 10.3% (n = 296) defined by AWGS. Individuals with sarcopenia defined by SDOC had a higher mortality risk than individuals without sarcopenia (HR: 3.41; 95% CI: 2.51, 4.62) after adjusting for age and FRAX variables. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased fracture risk after adjusting for age and FRAX variables. Individuals with sarcopenia defined by SDOC had a higher risk for any fractures (HR: 1.48; 95% CI: 1.10, 1.99) and MOF (HR: 1.42; 95% CI: 1.03, 1.98) compared with individuals without sarcopenia after adjusting for clinical risk factors used in FRAX. In conclusion, sarcopenia defined by SDOC, incorporating muscle function/strength, was the only sarcopenia definition associated with fracture risk in older women.

This study aimed to investigate the risk of sarcopenia on fracture risk in older Swedish women. Data were utilized from 2,883 women aged 75­80 yr in the Swedish Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures cohort. Sarcopenia was defined using three different definitions, including the Sarcopenia Definitions and Outcomes Consortium (SDOC), which includes grip strength and gait speed, while the revised European Working Group on Sarcopenia in Older People (EWGSOP2) and the Asian Working Group for Sarcopenia (AWGS) definitions include appendicular lean mass measured by dual-energy X-ray absorptiometry and grip strength. The results demonstrated that SDOC-defined sarcopenia was associated with a higher mortality risk, with increased risk of any fractures, and major osteoporotic fractures, whereas the EWGSOP2 and AWGS definitions were not associated with fracture risk. In summary, the study demonstrates that sarcopenia defined by SDOC, considering muscle function and strength, rather than lean mass, was the only investigated sarcopenia definition associated with fracture risk.

Risk of Fractures and Falls in Men with Advanced or Metastatic Prostate Cancer Receiving Androgen Deprivation Therapy and Treated with Novel Androgen Receptor Signalling Inhibitors: A Systematic Review and Meta-analysis of Randomised Controlled Trials.

CONTEXT: The addition of androgen receptor signalling inhibitors (ARSIs) to standard androgen deprivation therapy (ADT) has improved survival outcomes in patients with advanced prostate cancer (PCa). Advanced PCa patients have a higher incidence of osteoporosis, compounded by rapid bone density loss upon commencement of ADT resulting in an increased fracture risk. The effect of treatment intensification with ARSIs on fall and fracture risk is unclear. OBJECTIVE: To assess the risk of falls and fractures in men with PCa treated with ARSIs. EVIDENCE ACQUISITION: A systematic review of EMBASE, MEDLINE, The Cochrane Library, and The Health Technology Assessment Database for randomised control trials between 1990 and June 2023 was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analyses guidance. Risk ratios were estimated for the incidence of fracture and fall events. Subgroup analyses by grade of event and disease state were conducted. EVIDENCE SYNTHESIS: Twenty-three studies were eligible for inclusion. Fracture outcomes were reported in 17 studies (N = 18 811) and fall outcomes in 16 studies (N = 16 537). A pooled analysis demonstrated that ARSIs increased the risk of fractures (relative risk [RR] 2.32, 95% confidence interval [CI] 2.00-2.71; p < 0.01) and falls (RR 2.22, 95% CI 1.81-2.72; p < 0.01) compared with control. A subgroup analysis demonstrated an increased risk of both fractures (RR 2.13, 95% CI 1.70-2.67; p < 0.01) and falls (RR 2.19, 95% CI 1.53-3.12; p < 0.0001) in metastatic hormone-sensitive PCa patients, and an increased risk of fractures in the nonmetastatic (RR 2.27, 95% CI 1.60-3.20; p < 0.00001) and metastatic castrate-resistant (RR 2.85, 95% CI 2.16-3.76; p < 0.00001) settings. The key limitations include an inability to distinguish fragility from pathological fractures and potential for a competing risk bias. CONCLUSIONS: Addition of an ARSI to standard ADT significantly increases the risk of fractures and falls in men with prostate cancer. PATIENT SUMMARY: We found a significantly increased risk of both fractures and falls with a combination of novel androgen signalling inhibitors and traditional forms of hormone therapy.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

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.

Clinical Use of Trabecular Bone Score: The 2023 ISCD Official Positions.

Osteoporosis can currently be diagnosed by applying the WHO classification to bone mineral density (BMD) assessed by dual-energy x-ray absorptiometry (DXA). However, skeletal factors other than BMD contribute to bone strength and fracture risk. Lumbar spine TBS, a grey-level texture measure which is derived from DXA images has been extensively studied, enhances fracture prediction independent of BMD and can be used to adjust fracture probability from FRAX® to improve risk stratification. The purpose of this International Society for Clinical Densitometry task force was to review the existing evidence and develop recommendations to assist clinicians regarding when and how to perform, report and utilize TBS. Our review concluded that TBS is most likely to alter clinical management in patients aged ≥ 40 years who are close to the pharmacologic intervention threshold by FRAX. The TBS value from L1-L4 vertebral levels, without vertebral exclusions, should be used to calculate adjusted FRAX probabilities. L1-L4 vertebral levels can be used in the presence of degenerative changes and lumbar compression fractures. It is recommended not to report TBS if extreme structural or pathological artifacts are present. Monitoring and reporting TBS change is unlikely to be helpful with the current version of the TBS algorithm. The next version of TBS software will include an adjustment based upon directly measured tissue thickness. This is expected to improve performance and address some of the technical factors that affect the current algorithm which may require modifications to these Official Positions as experience is acquired with this new algorithm.

Fracture prediction in rheumatoid arthritis: validation of FRAX with bone mineral density for incident major osteoporotic fractures.

OBJECTIVES: FRAX® uses clinical risk factors, with or without bone mineral density (BMD), to calculate 10-year fracture risk. Rheumatoid arthritis (RA) is a risk factor for osteoporotic fracture and a FRAX input variable. FRAX predates the current era of RA treatment. We examined how well FRAX predicts fracture in contemporary RA patients. METHODS: Administrative data from patients receiving BMD testing were linked to the Manitoba Population Health Research Data Repository. Observed cumulative 10-year Major Osteoporotic Fracture (MOF) probability was compared with FRAX-predicted 10-year MOF probability with BMD for assessing calibration. MOF risk stratification was assessed using Cox regression. RESULTS: RA patients (N = 2,099, 208 with incident MOF) and non-RA patients (N = 2,099, with 165 incident MOF) were identified. For RA patients, FRAX predicted 10-year risk was 13.2% and observed 10-year MOF risk was 13.2% (95% CI 11.6% to 15.1%). The slope of the calibration plot was 0.67 (95% CI 0.53-0. 81) in those with RA vs 0.98 (95% CI 0.61-1.34) in non-RA patients. Risk was overestimated in RA patients with high FRAX scores (>20%), but FRAX was well-calibrated in other groups. FRAX stratified risk in those with and without RA (hazard ratios 1.52, 95% 1.25-1.72 vs 2.00, 95% 1.73-2.31), with slightly better performance in the latter (p-interaction = 0.004). CONCLUSIONS: FRAX predicts fracture risk in contemporary RA patients but may slightly overestimate risk in those already at high predicted risk. Thus, the current FRAX tool continues to be appropriate for fracture risk assessment in RA patients.

FRAX® Adjustment Using Renormalized Trabecular Bone Score (TBS) from L1 Alone may be Optimal for Fracture Prediction: The Manitoba BMD Registry.

Lumbar spine trabecular bone score (TBS) used in conjunction with FRAX® improves 10-year fracture prediction. The derived FRAX risk adjustment is based upon TBS measured from L1-L4, designated TBSL1-L4-FRAX. In prior studies, TBS measurements that include L1 and exclude L4 give better fracture stratification than L1-L4. We compared risk stratification from TBS-adjusted FRAX using TBS derived from different combinations of upper lumbar vertebral levels renormalized for level-specific differences in individuals from the Manitoba Bone Density Program aged >40 years with baseline assessment of TBS and FRAX. TBS measurements for L1-L3, L1-L2 and L1 alone were calculated after renormalization for level-specific differences. Corresponding TBS-adjusted FRAX scores designated TBSL1-L3-FRAX, TBSL1-L2-FRAX and TBSL1-FRAX were compared with TBSL1-L4-FRAX for fracture risk stratification. Incident major osteoporotic fractures (MOF) and hip fractures were assessed. The primary outcome was incremental change in area under the curve (ΔAUC). The study population included 71,209 individuals (mean age 64 years, 89.8% female). Before renormalization, mean TBS for L1-3, L1-L2 and L1 was significantly lower and TBS-adjusted FRAX significantly higher than from using TBSL1-L4. These differences were largely eliminated when TBS was renormalized for level-specific differences. During mean follow-up of 8.7 years 6745 individuals sustained incident MOF and 2039 sustained incident hip fractures. Compared with TBSL1-L4-FRAX, use of FRAX without TBS was associated with lower stratification (ΔAUC = -0.009, p < 0.001). There was progressive improvement in MOF stratification using TBSL1-L3-FRAX (ΔAUC = +0.001, p < 0.001), TBSL1-L2-FRAX (ΔAUC = +0.004, p < 0.001) and TBSL1-FRAX (ΔAUC = +0.005, p < 0.001). TBSL1-FRAX was significantly better than all other combinations for MOF prediction (p < 0.001). Incremental improvement in AUC for hip fracture prediction showed a similar but smaller trend. In conclusion, this single large cohort study found that TBS-adjusted FRAX performance for fracture prediction was improved when limited to the upper lumbar vertebral levels and was best using L1 alone.

Adjusting Trabecular Bone Score (TBS) for Level-Specific Differences Reduces FRAX®-Based Treatment Reclassification in Patients with Vertebral Exclusions: The Manitoba BMD Registry.

Trabecular bone score (TBS) is a FRAX®-independent risk factor for fracture prediction. TBS values increase from cranial to caudal, with the following mean differences between TBSL1-L4 and individual lumbar vertebrae: L1 -0.093, L2 -0.008, L3 +0.055 and L4 +0.046. Excluding vertebral levels can affect FRAX-based treatment recommendations close to the intervention threshold. We examined the effect of adjusting for level-specific TBS differences in individuals with vertebral exclusions due to structural artifact on TBS-adjusted FRAX-based treatment recommendations. We identified 71,209 individuals aged ≥40 years with TBS and FRAX calculations through the Manitoba Bone Density Program. In the 24,428 individuals with vertebral exclusions, adjusting TBS using these level-specific factors agreed with TBSL1-L4 (mean difference -0.001). We compared FRAX-based treatment recommendations for TBSL1-L4 and for non-excluded vertebral levels before and after adjusting for level-specific TBS differences. Among those with baseline major osteoporotic fracture risk ≥15 %, TBS with vertebral exclusions reclassified FRAX-based treatment in 10.6 % of individuals compared with TBSL1-L4, and was reduced to 7.2 % after adjusting for level-specific differences. In 11,131 patients where L1-L2 was used for BMD reporting (the most common exclusion pattern with the largest TBS effect), treatment reclassification was reduced from 13.9 % to 2.4 %, respectively. Among individuals with baseline hip fracture risk ≥2 %, TBS vertebral exclusions reclassified 7.1 % compared with TBSL1-L4, but only 4.5 % after adjusting for level-specific differences. When L1-L2 was used for BMD reporting, treatment reclassification from hip fracture risk was reduced from 9.2 % to 5.2 %. In conclusion, TBS and TBS-adjusted FRAX-based treatment recommendations are affected by vertebral level exclusions for structural artifact. Adjusting for level-specific differences in TBS reduces reclassification in FRAX-based treatment recommendations.

Effect of BMI-Discordant Abdominal Tissue Thickness on Fracture Probability: A Registry-Based Study.

FRAX, which is used to assess fracture probability, considers body mass index (BMI), but BMI may not reflect individual variation in body composition and distribution. We examined the effect of BMI-discordant abdominal thickness on FRAX-derived fracture probability for major osteoporotic fracture (MOF) and hip fracture. We studied 73,105 individuals, mean age 64.2 years. During mean 8.7 years, 7048 (9.6%) individuals sustained incident MOF, including 2155 (3.0%) hip fractures. We defined abdominal thickness index (ATI) as the difference between abdominal thickness measured by dual-energy X-ray absorptiometry (DXA) and thickness predicted by BMI using sex-stratified regression. ATI was categorized from lower (<-2 cm, -2 to -1 cm) to higher (1-2 cm, >+2 cm) with referent around zero (-1 to +1 cm). Adjusted for FRAX probability, increasing ATI was associated with incident MOF and hip fracture (p < 0.001). For the highest ATI category, MOF risk was increased (hazard ratio [HR] = 1.23, 95% confidence interval [CI] 1.12-1.35) independent of FRAX probability. Similar findings were noted for hip fracture probability (HR = 1.28, 95% CI 1.09-1.51). There was significant age-interaction with much larger effects before age 65 years (HR = 1.44, 95% CI 1.23-1.69 for MOF; 2.29, 95% CI 1.65-3.18 for hip fracture). In contrast, for the subset of individuals with diabetes, there was also increased risk for those in the lowest ATI category (HR = 1.73, 95% CI 1.12-2.65 for MOF; 2.81, 95% CI 1.59-4.97 for hip fracture). Calibration plots across ATI categories demonstrated deviation from the line of identity in women (calibration slope 2.26 for MOF, 2.83 for hip fracture). An effect of ATI was not found in men, but this was inconclusive as the sex-interaction terms did not show significant effect modification. In conclusion, these data support the need to investigate increased abdominal thickness beyond that predicted by BMI and sex as a FRAX-independent risk factor for fracture. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Adjusting FRAX Estimates of Fracture Probability Based on a Positive Vertebral Fracture Assessment.

Importance: FRAX is the most widely used and validated fracture risk prediction tool worldwide. Vertebral fractures, which are an indicator of subsequent osteoporotic fractures, can be identified using dual-energy x-ray absorptiometry (DXA) vertebral fracture assessment (VFA). Objective: To assess the calibration of FRAX and develop a simple method for improving FRAX-predicted fracture probability in the presence of VFA-identified fracture. Design, Setting, and Participants: This prognostic study analyzed the DXA and VFA results of all individuals who underwent a VFA between March 31, 2010, and March 31, 2018, who were included in the Manitoba Bone Mineral Density Registry. These individuals were randomly assigned to either the development cohort or validation cohort. A modified algorithm-based qualitative approach was used by expert readers to code VFAs as positive (≥1 vertebral fractures detected) or negative (0 vertebral fracture detected). Statistical analysis was conducted from August 7, 2022, to May 22, 2023. Exposures: FRAX scores for major osteoporotic fracture (MOF) and hip fracture were calculated with or without VFA results. Main Outcomes and Measures: Incident fractures and death were ascertained using linked population-based health care provincial data. Cumulative incidence curves for MOF and hip fracture were constructed, including competing mortality, to predict the 10-year observed risk of fracture. The observed probability was compared with FRAX-predicted fracture probability with and without VFA results and recalibrated FRAX from derived multipliers. Results: The full cohort of 11 766 individuals was randomly allocated to the development cohort (n = 7854; 7349 females [93.6%]; mean [SD] age, 75.7 [6.8] years) or the validation cohort (n = 3912; 3713 females [94.9%]; mean [SD] age, 75.5 [6.9] years). Over a mean (SD) observation time of 3.8 (2.3) years, with the longest observation at 7.5 years, FRAX was well calibrated in subgroups with negative VFA results. For individuals without a prior clinical fracture but with a positive VFA result, the 10-year FRAX-predicted MOF probability was 16.3% (95% CI, 15.7%-16.8%) without VFA information and 23.4% (95% CI, 22.7%-24.1%) with VFA information. The observed 10-year probabilities were 26.9% (95% CI, 26.0%-27.8%) and 11.2% (95% CI, 10.3%-12.1%), respectively, resulting in recalibration multipliers of 1.15 (95% CI, 0.87-1.43) for MOF and 1.31 (95% CI, 0.75-1.87) for hip fracture. For individuals with a prior clinical fracture and a positive VFA result, the 10-year FRAX-predicted probabilities were 25.0% (95% CI, 24.2%-25.7%) for MOF and 9.3% (95% CI, 8.7%-10.0%) for hip fracture. The observed 10-year probabilities were 38.1% (95% CI, 37.0%-39.1%) for MOF and 16.4% (95% CI, 15.4%-17.4%) for hip fracture, resulting in a recalibration multiplier of 1.53 (95% CI, 1.10-1.96) for MOF and 1.76 (95% CI, 1.17-2.35) for hip fracture. Good calibration (>0.90) was confirmed using the derived multipliers in the validation cohort. Conclusions and Relevance: Results of this prognostic study suggest that FRAX underestimated fracture risk in patients with VFA-identified fractures. Simple multipliers could recover FRAX calibration in individuals with VFA-identified fractures.

Update on the clinical use of trabecular bone score (TBS) in the management of osteoporosis: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International Osteoporosis Foundation (IOF) under the auspices of WHO Collaborating Center for Epidemiology of Musculoskeletal Health and Aging.

PURPOSE: Trabecular bone score (TBS) is a grey-level textural measurement acquired from dual-energy X-ray absorptiometry lumbar spine images and is a validated index of bone microarchitecture. In 2015, a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) published a review of the TBS literature, concluding that TBS predicts hip and major osteoporotic fracture, at least partly independent of bone mineral density (BMD) and clinical risk factors. It was also concluded that TBS is potentially amenable to change as a result of pharmacological therapy. Further evidence on the utility of TBS has since accumulated in both primary and secondary osteoporosis, and the introduction of FRAX and BMD T-score adjustment for TBS has accelerated adoption. This position paper therefore presents a review of the updated scientific literature and provides expert consensus statements and corresponding operational guidelines for the use of TBS. METHODS: An Expert Working Group was convened by the ESCEO and a systematic review of the evidence undertaken, with defined search strategies for four key topics with respect to the potential use of TBS: (1) fracture prediction in men and women; (2) initiating and monitoring treatment in postmenopausal osteoporosis; (3) fracture prediction in secondary osteoporosis; and (4) treatment monitoring in secondary osteoporosis. Statements to guide the clinical use of TBS were derived from the review and graded by consensus using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: A total of 96 articles were reviewed and included data on the use of TBS for fracture prediction in men and women, from over 20 countries. The updated evidence shows that TBS enhances fracture risk prediction in both primary and secondary osteoporosis, and can, when taken with BMD and clinical risk factors, inform treatment initiation and the choice of antiosteoporosis treatment. Evidence also indicates that TBS provides useful adjunctive information in monitoring treatment with long-term denosumab and anabolic agents. All expert consensus statements were voted as strongly recommended. CONCLUSION: The addition of TBS assessment to FRAX and/or BMD enhances fracture risk prediction in primary and secondary osteoporosis, adding useful information for treatment decision-making and monitoring. The expert consensus statements provided in this paper can be used to guide the integration of TBS in clinical practice for the assessment and management of osteoporosis. An example of an operational approach is provided in the appendix. This position paper presents an up-to-date review of the evidence base, synthesised through expert consensus statements, which informs the implementation of Trabecular Bone Score in clinical practice.

Hemoglobin Levels Improve Fracture Risk Prediction in Addition to FRAX Clinical Risk Factors and Bone Mineral Density.

CONTEXT: Anemia and decreasing levels of hemoglobin (Hb) have previously been linked to increased fracture risk, but the added value to FRAX, the most utilized fracture prediction tool worldwide, is unknown. OBJECTIVE: To investigate the association between anemia, Hb levels, bone microstructure, and risk of incident fracture and to evaluate whether Hb levels improve fracture risk prediction in addition to FRAX clinical risk factors (CRFs). METHODS: A total of 2778 community-dwelling women, aged 75-80 years, and part of a prospective population-based cohort study in Sweden were included. At baseline, information on anthropometrics, CRFs, and falls was gathered, blood samples were collected, and skeletal characteristics were investigated using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. At the end of follow-up, incident fractures were retrieved from a regional x-ray archive. RESULTS: The median follow-up time was 6.4 years. Low Hb was associated with worse total hip and femoral neck bone mineral density (BMD), and lower tibia cortical and total volumetric BMD, and anemia was associated with increased risk of major osteoporotic fracture (MOF; hazard ratio 2.04; 95% CI 1.58-2.64). Similar results were obtained for hip fracture and any fracture, also when adjusting for CRFs. The ratio between 10-year fracture probabilities of MOF assessed in models with Hb levels included and not included ranged from 1.2 to 0.7 at the 10th and 90th percentile of Hb, respectively. CONCLUSION: Anemia and decreasing levels of Hb are associated with lower cortical BMD and incident fracture in older women. Considering Hb levels may improve the clinical evaluation of patients with osteoporosis and the assessment of fracture risk.

Real-world evidence: new opportunities for osteoporosis research. Recommendations from a Working Group from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

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.

Estimating the future clinical and economic benefits of improving osteoporosis diagnosis and treatment among postmenopausal women across eight European countries.

A population-level, cross-sectional model was developed to estimate the clinical and economic burden of osteoporosis among women (≥ 70 years) across eight European countries. Results demonstrated that interventions aimed at improving fracture risk assessment and adherence would save 15.2% of annual costs in 2040. PURPOSE: Osteoporosis is associated with significant clinical and economic burden, expected to further increase with an ageing population. This modelling analysis assessed clinical and economic outcomes under different hypothetical disease management interventions to reduce this burden. METHODS: A population-level, cross-sectional cohort model was developed to estimate numbers of incident fractures and direct costs of care among women (≥ 70 years) in eight European countries under different hypothetical interventions: (1) an improvement in the risk assessment rate, (2) an improvement in the treatment adherence rate and (3) a combination of interventions 1 and 2. A 50% improvement from the status quo, based on existing disease management patterns, was evaluated in the main analysis; scenario analyses evaluated improvement of either 10 or 100%. RESULTS: Based on existing disease management patterns, a 44% increase in the annual number of fractures and costs was predicted from 2020 to 2040: from 1.2 million fractures and €12.8 billion in 2020 to 1.8 million fractures and €18.4 billion in 2040. Intervention 3 provided the greatest fracture reduction and cost savings (a decrease of 17.9% and 15.2% in fractures and cost, respectively) in 2040 compared with intervention 1 (decreases of 8.7% and 7.0% in fractures and cost, respectively) and intervention 2 (10.0% and 8.8% reductions in fracture and cost, respectively). Scenario analyses showed similar patterns. CONCLUSION: These analyses suggest that interventions which improve fracture risk assessment and adherence to treatments would relieve the burden of osteoporosis, and that a combination strategy would achieve greatest benefits.

FRAX Adjustment by Trabecular Bone Score with or Without Bone Mineral Density: The Manitoba BMD Registry.

Trabecular bone score (TBS), a texture measure derived from spine dual-energy x-ray absorptiometry (DXA) images, is a FRAX®-independent risk factor for fracture. The TBS adjustment to FRAX assumes the presence of femoral neck BMD in the calculation. However, there are many individuals in whom hip DXA cannot be acquired. Whether the TBS-adjustment would apply to FRAX probabilities calculated without BMD has not been studied. The current analysis was performed to evaluate major osteoporotic fracture (MOF) and hip fracture risk adjusted for FRAX with and without femoral neck BMD. The study cohort consisted of 71,209 individuals (89.8% female, mean age 64.0 years). During mean follow-up 8.7 years, 6743 (9.5%) individuals sustained one or more incident MOF, of which 2037 (2.9%) sustained a hip fracture. Lower TBS was significantly associated with increased fracture risk when adjusted for FRAX probabilities, with a slightly larger effect when BMD was not included. Inclusion of TBS in the risk calculation gave a small but significant increase in stratification for fracture probabilities estimated with and without BMD. Calibration plots showed very minor deviations from the line of identity, indicating overall good calibration. In conclusion, the existing equations for incorporating TBS in FRAX estimates of fracture probability work similarly when femoral neck BMD is not used in the calculation. This potentially extends the range of situations where TBS can be used clinically to those individuals in whom lumbar spine TBS is available but femoral neck BMD is not available.

Trabecular Bone Score Vertebral Exclusions Affect Risk Classification and Treatment Recommendations: The Manitoba Bmd Registry.

Lumbar spine trabecular bone score (TBS), a texture measure derived from spine dual-energy x-ray absorptiometry (DXA) images, is a bone mineral density (BMD)-independent risk factor for fracture. Lumbar vertebral levels that show structural artifact are excluded from BMD measurement. TBS is relatively unaffected by degenerative artifact, and it is uncertain whether the same exclusions should be applied to TBS reporting. To gain insight into the clinical impact of vertebral exclusion on TBS, we examined the effect of lumbar vertebral exclusions in routine clinical practice on tertile-based TBS categorization and TBS adjusted FRAX-based treatment recommendations. The study population consisted of 71,209 individuals aged 40 years and older with narrow fan-beam spine DXA examinations and retrospectively-derived TBS. During BMD reporting, 34.3% of the scans had one or more vertebral exclusions for structural artifact. When TBS was derived from the same vertebral levels used for BMD reporting, using fixed L1-L4 tertile cutoffs (1.23 and 1.31 from the McCloskey meta-analysis) reclassified 17.9% to a lower and 6.5% to a higher TBS category, with 75.6% unchanged. Reclassification was reduced from 24.4% overall to 17.2% when level-specific tertile cutoffs from the software manufacturer were used. Treatment reclassification based upon FRAX major osteoporotic fracture probability occurred in 2.9% overall, but in 9.6% of those with baseline risk ≥15%. For treatment based upon FRAX hip fracture probability, reclassification occurred in 3.4% overall, but in 10.4% in those with baseline risk ≥2%. In summary, lumbar spine TBS measurements based upon vertebral levels other than L1-L4 can alter the tertile category and treatment recommendations based upon TBS-adjusted FRAX calculation, especially for those close to or exceeding the treatment cut-off. Manufacturer level-specific tertile cut-offs should be used if vertebral exclusions are applied.

Vertebral Level Variations in Trabecular Bone Score and Effect on Fracture Prediction: The Manitoba BMD Registry.

Trabecular bone score (TBS), a texture measure derived from spine dual-energy x-ray absorptiometry (DXA) images, is a bone mineral density (BMD)-independent risk factor for fracture. TBS is reportedly insensitive to degenerative changes, and it is uncertain whether the same rules for excluding lumbar vertebral levels from BMD measurement should be applied to TBS. The current analysis was performed to explore inter-vertebral variation in TBS measurements from L1 to L4, how this relates to clinically identified structural artifact resulting in vertebral level exclusion from BMD reporting, and area under the curve (AUC) for incident fracture. The study population comprised 70,762 individuals aged 40 years and older at the time of baseline spine DXA assessment (mean age 64.1 years, 89.7% female), among whom 24,289 (34.3%) had one or more vertebral exclusions. Both TBS and BMD showed a similar cranial/caudal inter-vertebral gradient. Compared with L1-4, TBS from L1 alone was lower (mean difference -0.096; -7.6%) while TBS from L4 alone was 0.046 (3.6%) greater, similar in those without and with visual structural artifact. During mean follow-up of 8.7 years, 6744 (9.5%) individuals sustained incident major osteoporotic fractures. TBS from L1 alone gave significantly higher AUC for incident fracture than L1-4, which was in turn significantly higher than L2, L3 and L4 alone, seen in those without and with visual structural artifact. In contrast, AUCs for BMD showed minimal variation from L1 to L4, and was higher for L1-4 than for any individual lumbar vertebral level. In summary, we found inter-vertebral TBS variations within the lumbar spine are overall similar to BMD but are relatively unaffected by visual structural artifact. Fracture outcomes showed the strongest association with TBS measured from L1 alone. Further investigation is need to understand the cause and clinical application of these differences.