Insulin resistance, bone health, and fracture risk.

Insulin resistance, defined as an impaired biological response to insulin stimulation in target tissues, arises most frequently in the presence of central obesity. Although obesity is generally associated with increased bone mass, recent data challenge this view and, if complicated by T2DM, obese patients are at high risk for fragility fractures. IR may play a key role in this increased fracture risk through effects on bone quality rather than bone quantity. Further understanding of the mechanisms and approaches to prevent osteoporotic fractures in IR-related diseases is needed. CLINICAL RELEVANCE: The dramatic increase in obesity and metabolic syndrome (MetS) over the last half-century has led to a worldwide epidemic of type 2 diabetes mellitus (T2DM) as well as in the incidence of insulin resistance (IR). IR is defined as an impaired biological response to insulin stimulation in target tissues and is primarily related to the liver, muscle, and adipose tissue. The most frequent underlying cause is central obesity, and it is known that excess abdominal adipose tissue secretes increased amounts of free fatty acids, which directly affects insulin signalling, reduces glucose uptake in muscle, and triggers excessive triglyceride synthesis and gluconeogenesis in the liver. When pancreatic ß cells are unable to secrete the higher levels of insulin needed, T2DM, the main complication of IR, occurs. OBSERVATIONS: Although obesity is generally associated with increased bone mass, recent data challenge this view and highlight the multifaceted nature of the obesity-bone relationship. Patients with T2DM are at significant risk for well-known complications of diabetes, including retinopathy, nephropathy, macrovascular disease, and neuropathy, but it is clear that they are also at high risk for fragility fractures. Moreover, recent data provide strong evidence that IR may key role in the increased fracture risk observed in both obesity and T2DM. CONCLUSIONS: In this concise review article, the role of IR in increased risk of osteoporotic fractures in MetS, obesity, and T2DM is discussed and summarised, including consideration of the need for fracture risk assessment as a 'preventive measure', especially in patients with T2DM and chronic MetS with abdominal obesity. Personalised and targeted diagnostic and therapeutic approaches to prevent osteoporotic fractures in IR-related diseases are needed and could make significant contributions to health outcomes.

Extra-osseous Roles of the RANK-RANKL-OPG Axis with a Focus on Skeletal Muscle.

PURPOSE OF REVIEW: This review aims to consolidate recent observations regarding extra-osseous roles of the RANK-RANKL-OPG axis, primarily within skeletal muscle. RECENT FINDINGS: Preclinical efforts to decipher a common signalling pathway that links the synchronous decline in bone and muscle health in ageing and disease disclosed a potential role of the RANK-RANKL-OPG axis in skeletal muscle. Evidence suggests RANKL inhibition benefits skeletal muscle function, mass, fibre-type switching, calcium homeostasis and reduces fall incidence. However, there still exists ambiguity regarding the exact mechanistic actions and subsequent functional improvements. Other potential RANK-RANKL-OPG extra-osseous roles include regulation of neural-inflammation and glucose metabolism. Growing evidence suggests the RANK-RANKL-OPG axis may play a regulatory role in extra-osseous tissues, especially in skeletal muscle. Targeting RANKL may be a novel therapy in ameliorating loss of muscle mass and function. More research is warranted to determine the causality of the RANK-RANKL-OPG axis in extra-osseous tissues, especially those affected by aging.

Clinical utility of the fracture risk assessment tool (FRAX) in biopsy-confirmed coeliac disease.

BACKGROUND: People with coeliac disease (CD) are at increased risk of osteoporosis and fractures. Currently, baseline dual-energy X-ray absorptiometry (DXA) is recommended for all patients with newly diagnosed CD. We aimed to determine the prevalence of osteoporosis and the clinical utility of the Fracture Risk Assessment Tool (FRAX) in predicting major osteoporotic fractures (MOF) in patients with biopsy-proven CD. METHODS: We retrospectively collected data for consecutive adult patients with biopsy-proven CD between 2001 and 2015 who underwent DXA scanning within 1 year of diagnosis and were followed up for a minimum of 7 years. Fracture risk was assessed using FRAX scores, and the incidence of major osteoporotic fractures during the follow-up period was analysed. RESULTS: A total of 593 patients (median age 45.0 years, 68.5% female) were included. The prevalence of osteopenia and osteoporosis were 32.3% and 14.5%, respectively. Increasing age (OR 1.06, p < .0001), decreasing BMI (OR 0.90, p = .003), and higher baseline immunoglobulin A-tissue tissue transglutaminase titre (OR 1.04, p = .03) were significantly associated with increased risk of osteoporosis. The sensitivity, specificity, positive and negative predictive values of the FRAX tool to predict MOF were 21.2%, 91.3%, 16.3%, 93.5%, respectively. A higher risk of fractures was associated with ongoing gluten exposure (OR 1.86, p = .02), previous fractures (OR 2.69, p = .005), and older age (OR 1.03, p < .0001). CONCLUSION: Osteoporosis is a common finding in patients with CD. The FRAX tool showed high specificity in predicting osteoporotic fractures and could be used to aid with patient selection for DXA scanning in some cases.

Sarcopenia definitions and their association with injurious falls in older Swedish women from the Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone fractures (SUPERB) study.

Associations between different sarcopenia definitions and the risk of injurious falls were investigated in 75-80-year-old women in the Swedish SUPERB cohort. Only sarcopenia according to the Sarcopenia Definitions and Outcomes Consortium (SDOC) definition was associated with incident injurious falls with and without fractures in older women. PURPOSE: To investigate the association between three commonly used sarcopenia definitions and the risk of injurious falls in a population of older Swedish women. METHODS: A total of 2,883 75-80-year-old women with complete data on relevant sarcopenia definitions from the Swedish SUPERB cohort were studied. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC: low handgrip strength and gait speed), revised European Working Group on Sarcopenia in Older People (EWGSOP2: low appendicular lean mass index (ALMI, dual-energy X-ray absorptiometry (DXA)-derived), appendicular lean mass (kg)/height (m2), hand grip strength (kg), or low chair stand time (s)), and Asian Working Group for Sarcopenia (AWGS: low ALMI and hand grip strength (kg) or low gait speed (m/s)). Questionnaires captured the occurrence of falls in the past 12 months. Incident injurious falls were identified using national registers. Cox regression (hazard ratios (HR) and 95% confidence intervals (CI)) analyses were performed without adjustment and after adjustment for age, body mass index, previous falls, and the Charlson comorbidity index. RESULTS: During a median (IQR) follow-up time of 7.06 (6.2-7.9) years, there were 491 injurious falls without fracture and 962 injurious falls when also including falls resulting in a fracture. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased risk of injurious falls. Individuals with sarcopenia defined by SDOC had a higher risk of injurious falls with and without fracture (HR 2.11; 95% CI, 1.63-2.73 and HR, 2.16; 95% CI, 1.55-3.02, respectively). CONCLUSION: Sarcopenia definitions confined to muscle function and strength such as SDOC, rather than including DXA-determined ALMI (EWGSOP2 and AWGS), are associated with incident injurious falls with and without fractures in older women.

Race-specific FRAX models are evidence-based and support equitable care: a response to the ASBMR Task Force report on Clinical Algorithms for Fracture Risk.

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

IOF position on scientists and societies operating in conflict zones.

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

Predictive value of sarcopenia components for all-cause mortality: findings from population-based cohorts.

BACKGROUND: Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited. AIM: We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors. METHODS: Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index). RESULTS: Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed. CONCLUSIONS: Grip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

Update on fracture risk assessment in osteoporosis.

PURPOSE OF REVIEW: The assessment of fracture risk is playing an ever-increasing role in osteoporosis clinical management and informing international guidelines for osteoporosis. FRAX, a fracture risk calculator that provides individualized 10-year probabilities of hip and major osteoporotic fracture, has been widely used since 2008. In this review, we recap the development and limitations of intervention thresholds and the role of absolute fracture risk. RECENT FINDINGS: There is an increasing awareness of disparities and inequities in the setting of intervention thresholds in osteoporosis. The limitations of the simple use of prior fracture or the DXA-derived BMD T -score threshold are increasingly being discussed; one solution is to use fracture risk or probabilities in the setting of such thresholds. This approach also permits more objective assessment of high and very high fracture risk to enable physicians to make choices not just about the need to treat but what agents to use in individual patients. SUMMARY: Like all clinical tools, FRAX has limitations that need to be considered, but the use of fracture risk in deciding who to treat, when to treat and what agent to use is a mechanism to target treatment equitably to those at an increased risk of fracture.

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.

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.

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.

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.

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.

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.

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.

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 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.

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.