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Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Based on the current paradigm, a healthy bone is one with adequate mass without microarchitectural decay. However, these two features may not be sufficient to ensure that a bone is healthy. In addition, components must be correctly assembled and aligned. This ensures " the right amount of bone, at the right place " and thus, an optimal cohesion or interplay between constituents. Disorganization may be an independent contributor to bone abnormalities including fragility fractures. Indeed, many bone diseases may be characterized by the presence of disorganized bone, including osteogenesis imperfecta, hypophosphatasia, and atypical femur fractures (AFFs). Despite its likely importance, currently, there are no tools to quantify disorganization in vivo. We address this unmet need by describing a novel method for quantifying bone disorganization from X-ray images. Disorganization is quantified as variations in the orientation of bone components in relation to a target reference point. True disorganization created by disarranging (misplacing) pixels within the bone served as "gold standard." To further validate the method in clinical settings, we compared disorganization in three groups of femurs: (i) femurs of women with AFFs ( n  = 9); (ii) fracture-free femurs contralateral to AFFs ( n  = 9); and (iii) fracture-free femurs from controls ( n  = 25). There was excellent agreement between measured disorganization and "gold standard," with R 2 values ranging from 0.84 to 0.99. Precision error ranged from 1.72% to 4.69%. Disorganization produced by abnormalities associated with AFFs was accurately captured. Disorganization level was lowest in fracture-free control femurs, higher in fracture-free contralateral femurs to AFFs, and highest in femurs with AFFs (all p  < 0.0001). Quantification of disorganization, a novel biomarker, may provide novel insights into the pathogenesis of metabolic bone diseases beyond that provided by bone mineral density (BMD) or microarchitecture. We provide evidence that measurement of disorganization is likely to help identify patients at risk for fractures, especially in those poorly explained by BMD or microarchitecture such as AFFs. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Asian race, younger age, higher body mass index (BMI) and antiresorptive drugs have all been associated with atypical femur fractures (AFFs). This increased risk of AFF in Asians is important as by 2050, >50% of hip fractures globally will occur in Asia, with an increased demand for antiresorptive drugs being likely. It is also currently unclear whether AFF risk is increased in all Asian subgroups. We therefore aimed to identify the incidence of AFFs in an Australian tertiary hospital, the contribution of ethnic origin to AFF risk, and determine other clinical risk factors for AFF. From January 1, 2009 to December 31, 2017, 97 AFFs (82 complete and 15 incomplete) occurred in 71 individuals in the overall study population of 204,358. Patients with AFF were more likely to be female (88.7% vs 69.1%, p < 0.001) and younger [median (IQR): 74(52-92) years vs 83(75-88) years, p < 0.001] than the "typical" femur fracture group (n = 3330). The cumulative incidence rate of AFF was 4.2 per 100,000 person-years, far lower than for any ICD-10 AM coded "typical" femur fracture (202.9 per 100,000 person-years). Asians were 3.4 (95%CI, 2.1-5.6) times more likely to sustain an AFF than non-Asians, the highest incidence being in those from South East Asian countries (16.6 per 100,000 person years), suggesting differences in risk between Asian countries. In the nested case-control study, bisphosphonate use was an independent association with AFF development. We conclude Asian ethnicity is an important association with AFF in this large Australian cohort., Competing Interests: Declaration of competing interest PRE: has received research funding or honoraria from Amgen, Eli-Lilly and Theramex. AJV has received research funding or honoraria from Amgen. RZ has received research funding or honoraria from Amgen, MSD, Servier, GENZYME & AKP. He is a Director of StraxCorp Pty Ltd. All other authors state they do not have other conflicts of interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Advancing age is accompanied by a reduction in bone formation and remodeling imbalance, which produces microstructural deterioration. This may be partly caused by a diversion of mesenchymal cells towards adipocytes rather than osteoblast lineage cells. We hypothesized that microstructural deterioration would be associated with an increased marrow adiposity, and each of these traits would be independently associated with nonvertebral fractures and improve discrimination of women with fractures from controls over that achieved by femoral neck (FN) areal bone mineral density (aBMD) alone. The marrow adiposity and bone microstructure were quantified from HR-pQCT images of the distal tibia and distal radius in 77 women aged 40 to 70 years with a recent nonvertebral fracture and 226 controls in Melbourne, Australia. Marrow fat measurement from HR-pQCT images was validated using direct histologic measurement as the gold standard, at the distal radius of 15 sheep, with an agreement (R 2 = 0.86, p < 0.0001). Each SD higher distal tibia marrow adiposity was associated with 0.33 SD higher cortical porosity, and 0.60 SD fewer, 0.24 SD thinner, and 0.72 SD more-separated trabeculae (all p < 0.05). Adjusted for age and FN aBMD, odds ratios (ORs) (95% CI) for fracture per SD higher marrow adiposity and cortical porosity were OR, 3.39 (95% CI, 2.14 to 5.38) and OR, 1.79 (95% CI, 1.14 to 2.80), respectively. Discrimination of women with fracture from controls improved when cortical porosity was added to FN aBMD and age (area under the receiver-operating characteristic curve [AUC] 0.778 versus 0.751, p = 0.006) or marrow adiposity was added to FN aBMD and age (AUC 0.825 versus 0.751, p = 0.002). The model including FN aBMD, age, cortical porosity, trabecular thickness, and marrow adiposity had an AUC = 0.888. Results were similar for the distal radius. Whether marrow adiposity and cortical porosity indices improve the identification of women at risk for fractures requires validation in prospective studies. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Objectives: To determine sex-specific associations between insulin resistance and bone parameters measured by peripheral quantitative computed tomography in overweight and obese community-dwelling older adults., Study Design: Cross-sectional study of 79 community-dwelling overweight and obese adults (mean ± SD age 62.8 ± 7.9 years; body mass index 32.3 ± 6.1 kg/m 2 ; 58% women)., Main Outcome Measures: Peripheral quantitative computed tomography assessed distal radius and tibia trabecular volumetric bone mineral density (vBMD) and proximal radius and tibia cortical vBMD, periosteal circumference, endosteal circumference and stress-strain index. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score was calculated from fasting glucose and insulin values. Lean mass was assessed using dual-energy X-ray absorptiometry. Total minutes of moderate and vigorous physical activity (MVPA) were calculated using the Active Australia Survey., Results: Men and women in this cohort had no significant differences in fasting glucose and insulin concentrations, HOMA-IR values and diabetes prevalence (all P > 0.05). In women, HOMA-IR was positively correlated with proximal radius periosteal and endosteal circumference (r = 0.331; P = 0.034 and r = 0.325; P = 0.038, respectively). These associations became nonsignificant in multivariable regression analyses; however, HOMA-IR was negatively associated with proximal radius cortical vBMD (B = -4.79; 95% CI -8.66, -0.92) after adjusting for age, lean mass and MVPA. All associations between HOMA-IR and bone parameters became nonsignificant in a sensitivity analysis excluding individuals with diabetes, or self-reported use of glucose-lowering medications. There were no associations between HOMA-IR and bone parameters in men., Conclusions: Homeostatic Model Assessment of Insulin Resistance was negatively associated with radial cortical vBMD in overweight and obese older women, but not in men. Further studies are needed to clarify sex-specific associations between insulin resistance and bone health in overweight and obese older adults., (© 2019 John Wiley & Sons Ltd.)

Osteoporosis and osteopenia are increasingly prevalent conditions among older adults. Not only do the fractures associated with poor bone health have significant health consequences for the individual, but also their economic impact is placing increasing financial burden on governments and society. This study aimed to determine the direct economic cost of osteoporosis, osteopenia, and fractures among Australians aged 50 years and older in 2017. This study uses previous Australian data on the incidence and prevalence of osteoporosis and osteopenia together with recent Australian data on health service utilization after fracture to provide an estimate of the economic burden of osteoporosis. A bottom-up costing approach was used to determine the average direct health care and non-health care total costs of a fracture, as well as the average community health service costs of managing individuals with osteoporosis or osteopenia. The total direct cost of osteoporosis in Australia in 2017 was estimated to be $3.44 billion (AUD 2017, USD 2.77 billion). Treatment of fractures accounted for 68% of total direct costs, and non-fracture management of osteoporosis accounted for 32%. Hip fractures accounted for the highest proportion (43%) of the total direct cost of fractures, although fractures at "other" sites accounted for 38.5%. Fractures among individuals aged 70 years and older accounted for 74% of the direct costs (55% and 19% in women and men, respectively). Fracture costs in those with osteopenia accounted for 50% of direct fracture treatment costs. This up-to-date cost analysis estimated that costs in 2017 were three times higher than in 2007. These estimates will aid clinicians, policy makers, researchers, and health care organizations to acknowledge the economic importance of reducing osteoporosis-related fractures and associated costs. This provides a strong public health case to promote bone health that will assist in reducing future fracture-related costs. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Ageing, obesity and the metabolic syndrome (MetS) may all contribute to poor muscle health (sarcopenia). This study aimed to determine the cross-sectional associations between MetS (International Diabetes Federation classification) and sarcopenia (revised European Working Group on Sarcopenia in Older People definition) in 84 overweight and obese older adults. Components of sarcopenia included muscle strength (hand grip and leg extension), physical performance (stair climb test and short physical performance battery (SPPB), including gait speed and repeated chair stands time), muscle mass (appendicular lean mass (ALM), dual-energy X-ray absorptiometry), muscle size (peripheral quantitative computed tomography-determined calf and forearm cross-sectional area (CSA)) and muscle quality (muscle density and strength normalised to lean mass). Waist circumference was associated with greater muscle size, but poorer leg extension strength, chair stands and stair climb time, gait speed, SPPB scores and muscle quality measures (all p < 0.05). MetS was positively associated with ALM and forearm muscle CSA, and negatively associated with muscle quality measures and chair stands time (all p < 0.05). MetS is associated with larger muscle size, yet poorer muscle quality in overweight and obese older adults. Assessments of muscle function and quality should be considered for obese older adults and those with MetS.

Objectives: To determine whether associations of calf muscle density with physical function are independent of other determinants of functional decline in overweight and obese older adults., Methods: This was a secondary analysis of a cross-sectional study of 85 community-dwelling overweight and obese adults (mean±SD age 62.8±7.9 years; BMI 32.3±6.1 kg/m2; 58% women). Peripheral quantitative computed tomography assessed mid-calf muscle density (66% tibial length) and dual-energy X-ray absorptiometry determined visceral fat area. Fasting glucose, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein (CRP) were analysed. Physical function assessments included hand grip and knee extension strength, balance path length (computerised posturography), stair climb test, Short Physical Performance Battery (SPPB) and self-reported falls efficacy (Modified Falls Efficacy Scale; M-FES)., Results: Visceral fat area, not muscle density, was independently associated with CRP and fasting glucose (B=0.025; 95% CI 0.009-0.042 and B=0.009; 0.001-0.017, respectively). Nevertheless, higher muscle density was independently associated with lower path length and stair climb time, and higher SPPB and M-FES scores (all P⟨0.05). Visceral fat area, fasting glucose and CRP did not mediate these associations., Conclusions: Higher calf muscle density predicts better physical function in overweight and obese older adults independent of insulin resistance, visceral adiposity or inflammation.

Objectives: To determine characteristics of sarcopenic obesity that are independently associated with bone health and balance in older adults., Study Design: Cross-sectional study of 168 community-dwelling older adults (mean age 67.7 ± 8.4 years; 55% women)., Main Outcome Measures: Appendicular lean mass (ALM), whole-body areal BMD (aBMD) and body fat percentage were assessed by dual-energy X-ray absorptiometry. Peripheral quantitative computed tomography assessed muscle density and cortical volumetric BMD (vBMD), area, thickness, and strength-strain index (SSI) at 66% tibial length. Hand grip strength (dynamometry) and balance path length (computerised posturography) were assessed. Obesity was defined as high body fat percentage., Results: Greater lower-leg muscle density was associated with lower balance path length in men (r = -0.36; P < .01) and women (r = -0.40; P = < .01). Obese participants by body fat percentage did not differ to non-obese on bone indices, although a trend towards lower cortical vBMD was observed in obese compared with non-obese men (1041.4 ± 39.8 vs 1058.8 ± 36.1 mg/cm 3 ; P = .051). In multivariable models, ALM was positively associated with all bone parameters in obese women, and with whole-body aBMD, proximal tibial cortical area and SSI in non-obese women, and both non-obese and obese men (all P < .05). Lower-leg muscle density was also positively associated with cortical vBMD (B = 2.91; 95% CI 0.02, 5.80) and area (2.70; 0.06, 5.33) in obese women., Conclusions: Amongst components of sarcopenic obesity, higher ALM is a consistent independent predictor of better bone health. Low muscle density may also compromise bone health and balance. Interventions which improve muscle mass and composition may lower fracture risk in sarcopenic obesity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Prospective observational studies uniformly link vitamin D deficiency with the incidence of type 2 diabetes mellitus (T2DM), yet trials supplementing participants at risk of T2DM with vitamin D to reduce progression to T2DM have yielded inconsistent results. Inconsistencies between supplementation trials may be due to insufficient dosing or small sample sizes. Observational studies may also have reported spurious associations due to uncontrolled confounding by lifestyle or genetic factors. Alternatively, observational and intervention studies may not be entirely comparable. Observational studies show an association between higher vitamin D status, which is predominantly derived from sun exposure, and decreased incidence of T2DM. Trials intervene with vitamin D supplementation, and therefore may be missing alternate causes of the effect of sun exposure, as seen in observational studies. We propose that sun exposure may be the driving force behind the associations seen in observational studies; sun exposure may have additional benefits beyond increasing serum 25-hydroxyvitamin D (25OHD) levels. We performed an electronic literature search to identify articles that examined associations between sun exposure and T2DM and/or glucose metabolism. A best evidence synthesis was then conducted using outcomes from analyses deemed to have high methodological quality. Ten eligible full-text articles were identified, yielding 19 T2DM-related outcomes. The best evidence analysis considered 11 outcomes which were grouped into six outcome types: T2DM, fasting glucose, glucose tolerance, fasting insulin, insulin secretion and insulin sensitivity. There was moderate evidence to support a role of recreational sun exposure in reducing odds of T2DM incidence. High-level evidence was lacking; evidence presented for other outcomes was of low or insufficient level. This review highlights significant gaps in research pertaining to sun exposure and T2DM-related outcomes. Further research is encouraged as we aim to identify novel preventative strategies for T2DM., (© 2014 John Wiley & Sons Ltd.)

Objectives: To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity, insulin secretion, β-cell function, inflammation and metabolic markers., Design: 6-month randomized, placebo-controlled trial., Participants: Ninety-five adults with serum 25-hydroxyvitamin D [25(OH)D] ≤55 nmol/L at risk of type 2 diabetes (with prediabetes or an AUSDRISK score ≥15) were randomized. Analyses included participants who completed the baseline and final visits (treatment n = 35; placebo n = 45)., Intervention: Daily calcium carbonate (1,200 mg) and cholecalciferol [2,000-6,000 IU to target 25(OH)D >75 nmol/L] or matching placebos for 6 months., Measurements: Insulin sensitivity (HOMA2%S, Matsuda index), insulin secretion (insulinogenic index, area under the curve (AUC) for C-peptide) and β-cell function (Matsuda index x AUC for C-peptide) derived from a 75 g 2-h OGTT; anthropometry; blood pressure; lipid profile; hs-CRP; TNF-α; IL-6; adiponectin; total and undercarboxylated osteocalcin., Results: Participants were middle-aged adults (mean age 54 years; 69% Europid) at risk of type 2 diabetes (48% with prediabetes). Compliance was >80% for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group (91% achieved >75 nmol/L), but remained unchanged in controls. There were no significant changes in insulin sensitivity, insulin secretion and β-cell function, or in inflammatory and metabolic markers between or within the groups, before or after adjustment for potential confounders including waist circumference and season of recruitment. In a post hoc analysis restricted to participants with prediabetes, a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity (HOMA%S and Matsuda) was observed., Conclusions: Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity, insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes. However, in participants with prediabetes, supplementation with vitamin D and calcium may improve insulin sensitivity., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12609000043235.