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Context: Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodeling., Objective: We examined the associations between levels of phosphate, calcium (Ca), and alkaline phosphatase (ALP), and fracture risk in initially healthy older individuals., Methods: A post hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial recruited 16 703 Australian participants aged 70 years and older and 2411 US participants aged 65 years and older. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and ALP measurement. Fracture data were collected post randomization. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. Phosphate, Ca, and ALP were analyzed in deciles (D1-D10), with deciles 4 to 7 (31%-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations., Results: Of the 9915 participants, 907 (9.2%) individuals had incident fractures recorded over 3.9 (SD 1.4) years. In the fully adjusted model, men in the top decile (D10) of phosphate had a 78% higher risk of incident fracture (HR 1.78; 95% CI, 1.25-2.54). No such association was observed for women (HR 1.09; 95% CI, 0.83-1.44). The population attributable fraction in men within the D10 phosphate category is 6.9%., Conclusion: This result confirms that high-normal serum phosphate levels are associated with increased fracture risk in older men., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: As thyroid disorders are common amongst the elderly, this study aims to evaluate the reference interval (RI) for thyroid stimulating hormone (TSH) in healthy adults aged 70 years and over., Methods: A proposed RI was determined from the Australian participants of the ASPirin in Reducing Events in the Elderly (ASPREE) randomised trial. Participants had no history of cardiovascular disease, thyroid cancer, dementia, or life-threatening illnesses. Participants prescribed with any thyroid-related medication at baseline were excluded. TSH levels were measured using a commercial chemiluminescence microparticle immunoassay. The RI was determined using the middle 95th percentile of the logarithmic transformed data of baseline TSH. Cox proportional hazard regression models were used to validate the RI by assessing disease incidence over time., Results: A total of 10,995 participants had baseline TSH measures. Median (IQR) age was 73.9 (71.8-77.3) years. We propose a RI of 0.34-3.75 mU/L. TSH levels did not differ by age or sex. At baseline, there was no association between symptoms associated with thyroid disease and levels of TSH. Over the follow-up period of up to 11 years, no association was seen between baseline TSH levels and relevant disease outcomes for participants within the RI., Conclusions: From a group of initially healthy, community-dwelling adults aged >=70 years, we propose a RI of TSH to best represent euthyroidism. This concentration was not associated with an increased risk of thyroid related symptoms or outcomes, confirming its appropriateness for clinical use., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background and Aims: Correction of calcium and protein undernutrition using milk, yoghurt, and cheese in older adults in aged care homes is associated with reduced fractures and falls. However, these foods contain potentially atherogenic fats. We aimed to determine whether this intervention that increased dairy consumption to recommended levels adversely affects serum lipid profiles., Method and Results: This was a sub-group analysis of a 2-year cluster-randomised trial involving 60 aged care homes in Australia. Thirty intervention homes provided additional milk, yoghurt, and cheese on menus while 30 control homes continued with their usual menus. A sample of 159 intervention and 86 controls residents (69% female, median age 87.8 years) had dietary intakes recorded using plate waste analysis and fasting serum lipids measured at baseline and 12 months. Diagnosis of cardiovascular disease and use of relevant medications were determined from medical records. Outcome measures were serum total, HDL and LDL cholesterol and ApoA-1 & B. Intervention increased daily dairy servings from 1.9 ± 1.0 to 3.5 ± 1.4 (p < 0.001) while controls continued daily intakes of ≤2 servings daily (1.7 ± 1.0 to 2.0 ± 1.0 (p = 0.028). No group differences were observed for serum total cholesterol/high-density lipoprotein-C (TC/HDL-C) ratio, Apoprotein B/Apoprotein A-1 (ApoB/ApoA-1) ratio, low-density lipoprotein-C (LDL-C), non-HDL-C, or triglycerides (TGs) at 12 months., Conclusion: Among older adults in aged care homes, correcting insufficiency in intakes of calcium and protein using milk, yoghurt and cheese does not alter serum lipid levels, suggesting that this is a suitable intervention for reducing the risk of falls and fractures., Clinical Trial Registry: Australian New Zealand Clinical Trials Registry (ACTRN12613000228785) 2012; https://www.anzctr.org.au., Competing Interests: Declaration of competing interest SI has received lecture fees from Abbott, Nestle Health Science, UK Dairy Baord, and European Milk Forum. CF, SP, JR, SV, DLH and ES have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Context: Menopause is associated with changes in musculoskeletal, body composition, and metabolic parameters that may be amplified in premenopausal women receiving estradiol suppression for breast cancer. Denosumab offsets deleterious skeletal effects of estradiol suppression and has been reported to have effects on body composition and metabolic parameters in preclinical and observational studies, but evidence from double-blind randomized controlled trials is limited., Objective: To assess the effect of denosumab on body composition and metabolic parameters., Methods: In a prespecified secondary analysis of a 12-month randomized, double-blind, placebo-controlled trial, 68 premenopausal women with breast cancer initiating ovarian function suppression and aromatase inhibition were randomized to denosumab 60-mg or placebo administered at baseline and 6 months. Outcome measures were total and regional fat and lean mass (DXA), body mass index (BMI), waist and hip circumference, fasting glucose, HOMA-IR, and lipid profile. Using a mixed model, between-group mean adjusted differences over time are reported., Results: Over 12 months, relative to placebo, android and gynoid fat mass decreased in the denosumab group (-266 g [95% CI -453 to -79], P = .02, and -452 g [-783 to -122], P = .03, respectively). Total fat mass and waist circumference were lower in the denosumab group but not significantly (-1792 g [-3346 to -240], P = .08 and (- 3.77 cm [-6.76 to -0.79], P = .06, respectively). No significant treatment effects were detected in lean mass, BMI, hip circumference, fasting glucose, HOMA-IR, or lipid profile., Conclusion: In premenopausal women receiving estradiol suppression, denosumab decreases some measures of fat mass with no detectable effects on other measures of body composition or metabolic parameters., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women., Methods: In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437)., Results: Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm 3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm 3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm 3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm 2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm 2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm 2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted., Conclusion: Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

Bone is continuously in a state of building and renewal, though the process of remodeling that takes place at many sites asynchronously throughout the skeleton, with bone formation and resorption equal at these sites (bone multicellular units). Remodeling takes place on bone surfaces, both on trabeculae and in the cortex, and serves the purposes of replacing old bone or that damaged by microfractures throughout the skeleton. The bone loss and consequent osteoporotic fractures that result from excess resorption over formation have mainly been prevented or treated by antiresorptive drugs that inhibit osteoclast formation and/or activity. Virtually all of the evidence leading to acceptance of antiresorptive drugs as treatment has depended upon their prevention of vertebral fractures. In recent decades, new prospects came of anabolic treatments that partly restore bone volume and microstructure restore bone that has been lost. The first of these was parathyroid hormone (PTH), shown by daily injection to increase markers of bone formation and prevent fractures. This field of interest enlarged with the discovery of PTH-related protein (PTHrP), so closely related in structure and action to PTH. The structural relationship between PTH and PTHrP is important in assessing their physiological and pharmacological roles, with the N-terminal domains of the 2 having virtually equal actions on target cells. Abaloparatide, a peptide analogue based on the structures of PTHrP and PTH, has been approved in some countries as a therapy for osteoporosis. Treatment through the PTH receptor activation pathway, and probably with any anabolic therapy, needs to be followed by antiresorptive treatment in order to maintain bone that has been restored. No matter how effective anabolic therapies for the skeleton become, it seems highly likely that there will be a continuing need for antiresorptive drugs.

Background: older adults in aged care account for 30% of the population burden of hip fractures. Nutritional interventions to correct under nutrition reduce these debilitating fractures, perhaps partly by reducing falls and slowing deterioration in bone morphology., Objective: to determine whether a nutritional approach to fracture risk reduction in aged care homes is cost-effective., Design: cost-effectiveness was estimated based on results from a prospective 2-year cluster-randomised controlled trial and secondary data. Intervention residents consumed a total of 3.5 daily servings of milk, yoghurt and/or cheese, resulting in 1,142 mg of calcium and 69 g of protein compared with the daily intakes of 700 mg of calcium and 58 g of protein consumed by the control group., Setting: fifty-six aged care homes., Participants: residents for 27 intervention (n = 3,313) and 29 control (n = 3,911) homes., Methods: ambulance, hospital, rehabilitation and residential care costs incurred by fracture were estimated. The incremental cost-effectiveness ratios per fracture averted within a 2-year time horizon were estimated from the Australian healthcare perspective applying a 5% discount rate on costs after the first year., Results: intervention providing high-protein and high-calcium foods reduced fractures at a daily cost of AU$0.66 per resident. The base-case results showed that the intervention was cost-saving per fracture averted, with robust results in a variety of sensitivity and scenario analyses. Scaling the benefits of intervention equates to a saving of AU$66,780,000 annually in Australia and remained cost-saving up to a daily food expenditure of AU$1.07 per resident., Conclusions: averting hip and other non-vertebral fractures in aged care residents by restoring nutritional inadequacy of protein and calcium is cost-saving., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Low serum alkaline phosphatase (ALP) was found in 9% of patients attending an osteoporosis clinic, 0.6% of hospital patients, and 2/22 with an atypical femoral fracture. Hypophosphatasia was diagnosed in 3% of osteoporosis clinic patients with low ALP. Low ALP is a screening tool for hypophosphatasia, a condition potentially aggravated by antiresorptive therapy., Introduction: Hypophosphatasia (HPP) is an inherited disorder associated with impaired primary mineralisation of osteoid (osteomalacia). HPP may be misdiagnosed as osteoporosis, a reduction in the volume of normally mineralized bone. Both illnesses may result in fragility fractures, although stress and atypical fractures are more common in HPP. Antiresorptive therapy, first-line treatment for osteoporosis, is relatively contraindicated in HPP. Misdiagnosis and mistreatment can be avoided by recognising a low serum alkaline phosphatase (ALP). Our aim was to determine the prevalence of a low ALP (< 30 IU/L) in patients attending an osteoporosis clinic, in a hospital-wide setting, and in a group of patients with atypical femoral fractures (AFF)., Methods: This was a retrospective study of patients attending an osteoporosis clinic at a tertiary hospital during 8 years (2012-2020). Patients were categorised into those with a transiently low ALP, those with low ALP on ≥ 2 occasions but not the majority of measurements, and those with a persistently low ALP. ALP levels were also assessed in hospital-wide records and a group of patients with AFF., Results: Of 1839 patients attending an osteoporosis clinic, 168 (9%) had ≥ 1 low ALP, 50 (2.7%) had low ALP for ≥ 2 months, and seven (0.4%) had persistently low ALP levels. HPP was diagnosed in five patients, four of whom had persistently low ALP levels. The prevalence of HPP was 0.3% in the osteoporosis clinic and 3% in patients with ≥ 1 low ALP. Low ALP occurred in 0.6% of all hospital patients and 2/22 with AFF., Conclusion: Persistently low ALP in osteoporosis clinic attendees is easy to identify and signals the possibility of hypophosphatasia, a condition that may be mistaken for osteoporosis and incorrectly treated with antiresorptive therapy., (© 2022. Crown.)

Objectives: Malnutrition, particularly protein insufficiency, is common in institutionalised older adults and increases morbidity, mortality, and costs. We aimed to determine whether 12 months supplementation using high-protein foods (milk, cheese, yoghurt) prevents malnutrition in older adults., Design: Cluster randomised control study., Setting: Sixty Australian aged care facilities., Participants: Older adults living in aged care homes (n=654, mean age 86.7±7.2 years, 72% females). Intervention Facilities randomly allocated to a high-protein (n=30 intervention) or regular (n=30 controls) menu., Measurements: Nutritional status assessed using the Mini Nutrition Assessment (MNA) tool and fasting morning blood samples (n=302) assayed for haemoglobin (Hb) and albumin. Food intake was monitored 3-monthly using visual plate waste assessment. Measurements at baseline and month 12 were analysed using random effects model accounting for clustering (facility), repeated measure and confounders., Results: Addition of 11g of protein as 1.5 servings of high-protein foods daily preserved nutritional status that deteriorated in controls [MNA screen (-0.68, 95%CI: -1.03, -0.32, p<0.001) and total (-0.90, 95%CI: -1.45, -0.35, p=0.001) scores], resulting in group differences in MNA screen (0.62, 95%CI: 0.17, 1.06, p=0.007) and total (0.81, 95%CI: 0.11, 1.51, p=0.023) scores and group difference in Hb (3.60g/L, 95%CI: 0.18, 7.03, p=0.039), the net result of preservation with intervention (0.19g/L, 95%CI: -2.04, 2.42, p=0.896) and a decline in controls (-3.41g/L, 95%CI: -6.01, -0.82, p=0.010). No group differences were observed for serum albumin., Conclusion: Consumption of high-protein foods is a pragmatic approach to maintaining nutritional status in older adults in aged-care., Competing Interests: SI has received lecture fees from Abbott, Nestle Health Science, UK Dairy Board, Israel Milk Board and European Milk Forum. ES has received research support from Amgen and MSD, and has received lecture fees from Amgen, Eli Lilly, and Allergan. ES is a scientific consultant for StraxCorp and shareholder. SP, JR, XW and MB have no conflicts of interest to declare.

Importance: Falls and fractures are frequent and deleterious to the health of older people. Aspirin has been reported to reduce bone fragility and slow bone loss., Objective: To determine if daily low-dose aspirin (100 mg) reduces the risk of fractures or serious falls (fall-related hospital presentations) in healthy older men and women., Design, Setting, and Participants: This substudy of a double-blind, randomized, placebo-controlled trial studied older adult men and women in 16 major sites across southeastern Australia. The ASPREE-FRACTURE substudy was conducted as part of the Australian component of the ASPREE trial. Between 2010 and 2014 healthy (free of cardiovascular disease, dementia or physical disability), community-dwelling volunteers aged 70 years or older were recruited to participate in the ASPREE trial. Potentially eligible participants were identified by medical practitioners and trial personnel and were then sent a letter of invitation to participate. Interested participants were screened for suitability. Eligible participants with medical practitioner authorization and adherent to a 4-week run-in medication trial were randomized. Data were analyzed from October 17, 2019, to August 31, 2022., Interventions: Participants in the intervention group received a daily dose of oral 100 mg enteric-coated (low-dose) aspirin. The control group received a daily identical enteric-coated placebo tablet., Main Outcomes and Measures: The primary outcome of ASPREE-FRACTURE was the occurrence of any fracture. The secondary outcome was serious fall resulting in hospital presentation., Results: In total, 16 703 people with a median (IQR) age of 74 (72-78) years were recruited, and 9179 (55.0%) were women. There were 8322 intervention participants and 8381 control participants included in the primary and secondary outcome analysis of 2865 fractures and 1688 serious falls over the median follow-up of 4.6 years. While there was no difference in the risk of first fracture between the intervention and control participants (hazard ratio, 0.97; 95% CI, 0.87-1.06; P = .50), aspirin was associated with a higher risk of serious falls (total falls 884 vs 804; incidence rate ratio, 1.17; 95% CI, 1.03-1.33; P = .01). Results remained unchanged in analyses that adjusted for covariates known to influence fracture and fall risk., Conclusions and Relevance: In this substudy of a randomized clinical trial, the failure of low-dose aspirin to reduce the risk of fractures while increasing the risk of serious falls adds to evidence that this agent provides little favorable benefit in a healthy, White older adult population., Trial Registration: This substudy is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000347561).

Gender-affirming hormone therapy aligns physical characteristics with an individual's gender identity, but sex hormones regulate bone remodeling and influence bone morphology. We hypothesized that trans men receiving testosterone have compromised bone morphology because of suppression of ovarian estradiol production, whereas trans women receiving estradiol, with or without anti-androgen therapy, have preserved bone microarchitecture. We compared distal radial and tibial microarchitecture using high-resolution peripheral quantitative computed tomography images in a cross-sectional study of 41 trans men with 71 cis female controls, and 40 trans women with 51 cis male controls. Between-group differences were expressed as standardized deviations (SD) from the mean in age-matched cisgender controls with 98% confidence intervals adjusted for cross-sectional area (CSA) and multiple comparisons. Relative to cis women, trans men had 0.63 SD higher total volumetric bone mineral density (vBMD; both p = 0.01). Cortical vBMD and cortical porosity did not differ, but cortices were 1.11 SD thicker (p < 0.01). Trabeculae were 0.38 SD thicker (p = 0.05) but otherwise no different. Compared with cis men, trans women had 0.68 SD lower total vBMD (p = 0.01). Cortical vBMD was 0.70 SD lower (p < 0.01), cortical thickness was 0.51 SD lower (p = 0.04), and cortical porosity was 0.70 SD higher (p < 0.01). Trabecular bone volume (BV/TV) was 0.77 SD lower (p < 0.01), with 0.57 SD fewer (p < 0.01) and 0.30 SD thicker trabeculae (p = 0.02). There was 0.56 SD greater trabecular separation (p = 0.01). Findings at the distal radius were similar. Contrary to each hypothesis, bone microarchitecture was not compromised in trans men, perhaps because aromatization of administered testosterone prevented bone loss. Trans women had deteriorated bone microarchitecture either because of deficits in microstructure before treatment or because the estradiol dosage was insufficient to offset reduced aromatizable testosterone. Prospective studies are needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

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

Background: Age-related trabecular microstructural deterioration and conversion from plate-like trabeculae to rod-like trabeculae occur because of unbalanced rapid remodeling. As denosumab achieves greater remodeling suppression and lower cortical porosity than alendronate, we hypothesized that denosumab might also preserve trabecular plate microstructure, bone stiffness and strength more effectively than alendronate., Methods: In this post hoc analysis of a phase 2 study, postmenopausal women randomized to placebo (P, n = 74), denosumab (D, n = 72), or alendronate (A, n = 68). HR-pQCT scans of the distal radius and tibia were performed at baseline and Month-12 (M12). Trabecular compartment was subjected to Individual Trabecula Segmentation while finite element analysis was performed to estimate stiffness and strength. Percent change from baseline at M12 of each parameter was compared between patient groups., Results: At the distal tibia, in the placebo group, plate surface area (pTb.S, -1.3%) decreased while rod bone volume fraction (rBV/TV, +4.5%) and number (rTb.N, +2.1%) increased. These changes were prevented by denosumab but persisted despite alendronate therapy (pTb.S: -1.7%; rBV/TV: +6.9%; rTb.N: +3.0%). Both treatments improved whole bone stiffness (D: +3.1%; A: +1.8%) and failure load (D: +3.0%; A: +2.2%); improvements using denosumab was significant compared to placebo (stiffness: p = 0.004; failure load: p = 0.003). At the distal radius, denosumab increased total trabecular bone volume fraction (BV/TV, +3.4%) and whole bone failure load (+4.0%), significantly different from placebo (BV/TV: p = 0.044; failure load: p = 0.046). Significantly different effects of either drug on plate and rod microstructure were not detected., Conclusions: Denosumab preserved trabecular plate microstructure. Alendronate did not. However, estimated strength did not differ between denosumab and alendronate treated groups., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Measurement of bone mineral density (BMD) is recommended in patients with chronic kidney disease (CKD). However, most persons in the community and most patients with CKD have osteopenia, suggesting fracture risk is low. Bone loss compromises bone microarchitecture which increases fragility disproportionate to modest deficits in BMD. We therefore hypothesized that patients with CKD have reduced estimated failure load due to deterioration in microarchitecture irrespective of whether they have normal femoral neck (FN) BMD, osteopenia or osteoporosis., Methods: We measured distal tibial and distal radial microarchitecture in 128 patients with CKD and 275 age- and sex-matched controls using high resolution peripheral quantitative computed tomography, FN-BMD using bone densitometry and estimated failure load at the distal appendicular sites using finite element analysis., Results: Patients versus controls respectively had: lower tibial cortical area 219 (40.7) vs. 237 (35.3) mm 2 , p = 0.002, lower cortical volumetric BMD 543 (80.7) vs. 642 (81.7) mgHA/cm 3 due to higher porosity 69.6 (6.19) vs. 61.9 (6.48)% and lower matrix mineral density 64.2 (0.62) vs. 65.1 (1.28)%, lower trabecular vBMD 92.2 (41.1) vs. 149 (43.0) mgHA/cm 3 due to fewer and spatially disrupted trabeculae, lower FN-BMD 0.78 (0.12) vs. 0.94 (0.14) g/cm 2 and reduced estimated failure load 3825 (1152) vs. 5778 (1467) N, all p < 0.001. Deterioration in microarchitecture and estimated failure load was most severe in patients and controls with osteoporosis. Patients with CKD with osteopenia and normal FN-BMD had more deteriorated tibial microarchitecture and estimated failure load than controls with BMD in the same category. In univariate analyses, microarchitecture and FN-BMD were both associated with estimated failure load. In multivariable analyses, only microarchitecture was independently associated with estimated failure load and accounted for 87% of the variance., Conclusions: Bone fragility is likely to be present in patients with CKD despite them having osteopenia or normal BMD. Measuring microarchitecture may assist in targeting therapy to those at risk of fracture., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To assess the antifracture efficacy and safety of a nutritional intervention in institutionalised older adults replete in vitamin D but with mean intakes of 600 mg/day calcium and <1 g/kg body weight protein/day., Design: Two year cluster randomised controlled trial., Setting: 60 accredited residential aged care facilities in Australia housing predominantly ambulant residents., Participants: 7195 permanent residents (4920 (68%) female; mean age 86.0 (SD 8.2) years)., Intervention: Facilities were stratified by location and organisation, with 30 facilities randomised to provide residents with additional milk, yoghurt, and cheese that contained 562 (166) mg/day calcium and 12 (6) g/day protein achieving a total intake of 1142 (353) mg calcium/day and 69 (15) g/day protein (1.1 g/kg body weight). The 30 control facilities maintained their usual menus, with residents consuming 700 (247) mg/day calcium and 58 (14) g/day protein (0.9 g/kg body weight)., Main Outcome Measures: Group differences in incidence of fractures, falls, and all cause mortality., Results: Data from 27 intervention facilities and 29 control facilities were analysed. A total of 324 fractures (135 hip fractures), 4302 falls, and 1974 deaths were observed. The intervention was associated with risk reductions of 33% for all fractures (121 v 203; hazard ratio 0.67, 95% confidence interval 0.48 to 0.93; P=0.02), 46% for hip fractures (42 v 93; 0.54, 0.35 to 0.83; P=0.005), and 11% for falls (1879 v 2423; 0.89, 0.78 to 0.98; P=0.04). The risk reduction for hip fractures and falls achieved significance at five months (P=0.02) and three months (P=0.004), respectively. Mortality was unchanged (900 v 1074; hazard ratio 1.01, 0.43 to 3.08)., Conclusions: Improving calcium and protein intakes by using dairy foods is a readily accessible intervention that reduces the risk of falls and fractures commonly occurring in aged care residents., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12613000228785., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: funding support from the organisations listed above; SI has received lecture fees from Abbott; TVN has received research support and lecture fees from Amgen, MSD, and Novartis; ES has received research support from Amgen and MSD and lecture fees from Amgen, Eli Lilly, and Allergan; ES is a scientific consultant for StraxCorp and shareholder; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Summary: Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or 'osteoporosis' to identify a low ALP level is recommended., Learning Points: Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is contraindicated in HPP. Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis. Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory. Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly. Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.

Parathyroid hormone (PTH) and the paracrine factor, PTH-related protein (PTHrP), have preserved in evolution sufficient identities in their amino-terminal domains to share equivalent actions upon a common G protein-coupled receptor, PTH1R, that predominantly uses the cyclic adenosine monophosphate-protein kinase A signaling pathway. Such a relationship between a hormone and local factor poses questions about how their common receptor mediates pharmacological and physiological actions of the two. Mouse genetic studies show that PTHrP is essential for endochondral bone lengthening in the fetus and is essential for bone remodeling. In contrast, the main postnatal function of PTH is hormonal control of calcium homeostasis, with no evidence that PTHrP contributes. Pharmacologically, amino-terminal PTH and PTHrP peptides (teriparatide and abaloparatide) promote bone formation when administered by intermittent (daily) injection. This anabolic effect is remodeling-based with a lesser contribution from modeling. The apparent lesser potency of PTHrP than PTH peptides as skeletal anabolic agents could be explained by lesser bioavailability to PTH1R. By contrast, prolongation of PTH1R stimulation by excessive dosing or infusion, converts the response to a predominantly resorptive one by stimulating osteoclast formation. Physiologically, locally generated PTHrP is better equipped than the circulating hormone to regulate bone remodeling, which occurs asynchronously at widely distributed sites throughout the skeleton where it is needed to replace old or damaged bone. While it remains possible that PTH, circulating within a narrow concentration range, could contribute in some way to remodeling and modeling, its main physiological role is in regulating calcium homeostasis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Little is known about factors that lead to excess mortality post-fracture. This study demonstrated that 5-year mortality is lower in older adults who recovered to their pre-fracture health-related quality of life (HRQoL) at 12-months compared to those who did not recover. Our results highlight the importance of post-fracture interventions known to improve HRQoL., Introduction: Fragility fractures lead to increased mortality and decreased health-related quality of life (HRQoL) in older adults, although whether an association exists between these outcomes remains uncertain. The aim of this study was to determine whether recovery of HRQoL 12-month post-fracture is associated with lower 5-year mortality., Methods: This data linkage study included 524 adults (mean age: 70.2 years; 79.2% women) with fragility fracture (150 hip, 261 distal forearm, 61 vertebral, 52 humerus) from the Australian arm of the International Costs and Utilities Related to Osteoporotic fractures Study (AusICUROS). HRQoL was measured using the EQ-5D-3L and all-cause mortality post-fracture was ascertained from the Australian National Death Index (NDI). Cox proportional hazards models were used to assess the association between HRQoL recovery (vs. non-recovery) and all-cause mortality within 5 years., Results: Overall, 279 participants (53.2%) recovered to their pre-fracture HRQoL at 12-month follow-up. There were 70 deaths (13.4%) during the 5-year post-fracture. Mortality rate was the highest in hip fracture participants (24.7%), followed by vertebral (16.4%), humeral (13.5%), and distal forearm fracture participants (6.1%). After adjustment for age, pre-fracture HRQoL, and fracture site, mortality risk was lower in participants who recovered to their pre-fracture HRQoL at 12-months compared to those who did not recover (HR = 0.56, 95% CI: 0.33-0.96, p = 0.034)., Conclusion: This study provides evidence that HRQoL recovery post-fracture is associated with improved 5-year survival in older adults. The extent to whether current interventions known to improve HRQoL post-fracture could prevent some of these deaths is unknown., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

To determine whether stress fractures are associated with bone microstructural deterioration we quantified distal radial and the unfractured distal tibia using high resolution peripheral quantitative computed tomography in 26 cases with lower limb stress fractures (15 males, 11 females; mean age 37.1 ± 3.1 years) and 62 age-matched healthy controls (24 males, 38 females; mean age 35.0 ± 1.6 years). Relative to controls, in men, at the distal radius, cases had smaller cortical cross sectional area (CSA) ( p = 0.012), higher porosity of the outer transitional zone (OTZ) ( p = 0.006), inner transitional zone (ITZ) ( p = 0.043) and the compact-appearing cortex (CC) ( p = 0.023) while trabecular vBMD was lower ( p = 0.002). At the distal tibia, cases also had a smaller cortical CSA ( p = 0.008). Cortical porosity was not higher, but trabecular vBMD was lower ( p = 0.001). Relative to controls, in women, cases had higher distal radial porosity of the OTZ ( p = 0.028), ITZ ( p = 0.030) not CC ( p = 0.054). Trabecular vBMD was lower ( p = 0.041). Distal tibial porosity was higher in the OTZ ( p = 0.035), ITZ ( p = 0.009), not CC. Stress fractures are associated with compromised cortical and trabecular microstructure.

Objective: Treatment is usually withheld from women with osteopenia even though they are the source of over 70% of all women having fragility fractures. As microstructural deterioration increases fracture risk and zoledronate reduces it, we aimed to determine whether identifying and treating women with osteopenia and severe microstructural deterioration is cost-effective. We also compared the health economic outcomes of 'global' versus 'targeted' treatment using SFS of women aged ≥70 years with osteopenia., Design: We assessed the cost-effectiveness from using a Markov model that simulated 10-year follow up of women with osteopenia. Decision analysis compared measurement of distal radial microstructure using high resolution peripheral computed tomography (at a cost of USD $210) to target women with severe microstructural deterioration for zoledronate treatment, compared to standard care defined as measurement of bone mineral density (BMD) with treatment recommended when femoral neck BMD T score is ≤-2.5 SD with or without a prevalent fracture. In the 'global' treatment approach, high resolution peripheral quantitative tomography (HRpQCT) was not undertaken., Setting: US healthcare system., Participants: A hypothetical cohort of 1000 women aged ≥70 years with osteopenia and no previous fractures was studied., Measures: Fractures, deaths, years of life lived, quality-adjusted life years (QALYs) lived and costs. Data inputs were obtained from published sources. A 3% annual discount rate was applied to future health benefits and costs., Results: Women in the standard care group incurred 327 fractures during 7341.0 years and 4914.2 QALYs lived. Women in the intervention group incurred 300 fractures (number needed to treat 37) during 7359.2 years and 4928.8 QALYs lived. Net costs were USD $4,862,669 and $4,952,004, respectively, equating to 18.1 years of life saved and 14.6 QALYs saved, and incremental cost-effectiveness ratios of $4992 per year of life saved and $6135 per QALY saved. These ratios are well within the threshold considered to be cost-effective. Sensitivity analyses indicated the results were robust. Relative to standard of care, 'global' and 'targeted' treatment respectively resulted in 0.0364 vs. 0.0181 years of life (YoLS) saved per person, and 0.0292 and 0.0146 QALYs saved per person. The net costs per person for the respective approaches were $US 359 and $US 89. The incremental cost-effectiveness ratios were $9864 per YoLS and $12,290 per QALY saved for the 'global' approach and $4992 per YoLS and $6135 per QALY saved for the 'targeted' approach., Conclusion: Identifying and treating women ≥70 years of age with osteopenia and microstructural deterioration with zoledronate cost-effectively reduces the morbidity and mortality imposed by fragility fractures. This 'targeted' approach is more cost-effective than a 'global' approach and incurs only 25% of total costs., Implication: Women with osteopenia with bone fragility due to microstructural deterioration should be identified and targeted for treatment., Summary: Women with osteopenia have 70% of fractures. Treating those with microstructural deterioration conferred an incremental cost-effectiveness ratio of $4992/year of life saved and $6135 per QALY saved., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Modelling and remodelling adapt bone morphology to accommodate strains commonly encountered during loading. If strains exceed a threshold threatening fracture, modelling-based bone formation increases bone volume reducing these strains. If unloading reduces strains below a threshold that inhibits resorption, increased remodelling-based bone resorption reduces bone volume restoring strains, but at the price of compromised bone volume and microstructure. As weight-bearing regions are adapted to greater strains, we hypothesized that microstructural deterioration will be more severe than at regions commonly adapted to low strains following spinal cord injury., Methods: We quantified distal tibial, fibula and radius volumetric bone mineral density (vBMD) using high-resolution peripheral quantitative computed tomography in 31 men, mean age 43.5 years (range 23.5-75.0), 12 with tetraplegia and 19 with paraplegia of 0.7 to 18.6 years duration, and 102 healthy age- and sex-matched controls. Differences in morphology relative to controls were expressed as standardized deviation (SD) scores (mean ± SD). Standardized between-region differences in vBMD were expressed as SDs (95% confidence intervals, CI)., Results: Relative to controls, men with tetraplegia had deficits in total vBMD of -1.72 ± 1.38 SD at the distal tibia (p < 0.001) and - 0.68 ± 0.69 SD at distal fibula (p = 0.041), but not at the distal radius, despite paralysis. Deficits in men with paraplegia were -2.14 ± 1.50 SD (p < 0.001) at the distal tibia and -0.83 ± 0.98 SD (p = 0.005) at the distal fibula while distal radial total vBMD was 0.23 ± 1.02 (p = 0.371), not significantly increased, despite upper limb mobility. Comparing regions, in men with tetraplegia, distal tibial total vBMD was 1.04 SD (95%CI 0.07, 2.01) lower than at the distal fibula (p = 0.037) and 1.51 SD (95%CI 0.45, 2.57) lower than at the distal radius (p = 0.007); the latter two sites did not differ from each other. Results were similar in men with paraplegia, but total vBMD at the distal fibula was 1.06 SD (95%CI 0.35, 1.77) lower than at the distal radius (p = 0.004)., Conclusion: Microarchitectural deterioration following spinal cord injury is heterogeneous, perhaps partly because strain thresholds regulating the cellular activity of mechano-transduction are region specific., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Androgen deprivation therapy (ADT) given to men with prostate cancer causes rapid and severe sex steroid deficiency, leading to increased bone remodeling and accelerated bone loss. To examine the effects of a single dose of zoledronic acid on bone microarchitecture, we conducted a 2-year randomized placebo controlled trial in 76 men, mean age (interquartile range [IQR]) 67.8 years (63.8 to 73.9) with non-metastatic prostate cancer commencing adjuvant ADT; 39 were randomized to zoledronic acid and 37 to matching placebo. Bone microarchitecture was measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). Using a mixed model, mean adjusted differences (MAD; 95% confidence interval [95% CI]) between the groups are reported as the treatment effect at several time points. Over 24 months, zoledronic acid showed no appreciable treatment effect on the primary outcomes for total volumetric bone mineral density (vBMD); radius (6.7 mg HA/cm 3 [-2.0 to 15.4], p = 0.21) and tibia (1.9 mg HA/cm 3 [-3.3 to 7.0], p = 0.87). Similarly, there were no between-group differences in other measures of microarchitecture, with the exception of a modest effect of zoledronic acid over placebo in total cortical vBMD at the radius over 12 months (17.3 mgHA/cm 3 [5.1 to 29.5]). In contrast, zoledronic acid showed a treatment effect over 24 months on areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) at all sites, including lumbar spine (0.10 g/cm 2 [0.07 to 0.13]), p < 0.001), and total hip (0.04 g/cm 2 [0.03 to 0.05], p < 0.001). Bone remodeling markers were initially suppressed in the treatment group then increased but remained lower relative to placebo (MADs at 24 months CTX -176 ng/L [-275 to -76], p < 0.001; P1NP -18 mg/L [-32 to -5], p < 0.001). These findings suggest that a single dose of zoledronic acid over 2 years is ineffective in preventing the unbalanced bone remodeling and severe microstructural deterioration associated with ADT therapy. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

More than 70% of women sustaining fractures have osteopenia or "normal" bone mineral density (BMD). These women remain undetected using the BMD threshold of -2.5 SD for osteoporosis. As microstructural deterioration increases bone fragility disproportionate to the bone loss producing osteopenia/normal BMD, we hypothesized that the structural fragility score (SFS) of ≥70 units, a measure capturing severe cortical and trabecular deterioration, will identify these women. Distal radial images were acquired using high-resolution peripheral quantitative tomography in postmenopausal French women, mean age 67 years (range 42-96 years); 1539 women were followed for 4 years (QUALYOR) and 561 women followed for 8 years (OFELY). Women with osteopenia or normal BMD accounted for ~80% of fractures. Women ≥70 years, 29.2% of the cohort, accounted for 39.2% to 61.5% of fractures depending on follow-up duration. Women having fractures had a higher SFS, lower BMD, and a higher fracture risk assessment score (FRAX) than women remaining fracture-free. In each BMD category (osteoporosis, osteopenia, normal BMD), fracture incidence was two to three times higher in women with SFS ≥70 than <70. In multivariable analyses, associations with fractures remained for BMD and SFS, not FRAX. BMD was no longer, or weakly, associated with fractures after accounting for SFS, whereas SFS remained associated with fracture after accounting for BMD. SFS detected two-to threefold more women having fractures than BMD or FRAX. SFS in women with osteopenia/normal BMD conferred an odds ratio for fracture of 2.69 to 5.19 for women of any age and 4.98 to 12.2 for women ≥70 years. Receiver-operator curve (ROC) analyses showed a significant area under the curve (AUC) for SFS, but not BMD or FRAX for the women ≥70 years of age. Targeting women aged ≥70 years with osteopenia indicated that treating 25% using SFS to allocate treatment conferred a cost-effectiveness ratio < USD $21,000/QALY saved. Quantifying microstructural deterioration complements BMD by identifying women without osteoporosis at imminent and longer-term fracture risk. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Objectives: This review provides insights into the potential for aspirin to preserve bone mineral density (BMD) and reduce fracture risk, building knowledge of the risk-benefit profile of aspirin., Methods: We conducted a systematic review and exploratory meta-analysis of observational studies. Electronic searches of MEDLINE and Embase, and a manual search of bibliographies was undertaken for studies published to 28 March 2018. Studies were included if: participants were men or women aged ≥18 years; the exposure of interest was aspirin; and relative risks, ORs and 95% CIs for the risk of fracture or difference (percentage or absolute) in BMD (measured by dual energy X-ray absorptiometry) between aspirin users and non-users were presented. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklists for observational studies. Pooled ORs for any fracture and standardised mean differences (SMDs) for BMD outcomes were calculated using random-effects models., Results: Twelve studies met the inclusion criteria and were included in the meta-analysis. Aspirin use was associated with a 17% lower odds for any fracture (OR 0.83, 95% CI 0.70 to 0.99; I 2 =71%; six studies; n=511 390). Aspirin was associated with a higher total hip BMD for women (SMD 0.03, 95% CI -0.02 to 0.07; I 2 =0%; three studies; n=9686) and men (SMD 0.06, 95% CI -0.02 to 0.13, I 2 =0%; two studies; n=4137) although these associations were not significant. Similar results were observed for lumbar spine BMD in women (SMD 0.03, 95% CI -0.03 to 0.09; I 2 =34%; four studies; n=11 330) and men (SMD 0.08; 95% CI -0.01 to 0.18; one study; n=432)., Conclusions: While the benefits of reduced fracture risk and higher BMD from aspirin use may be modest for individuals, if confirmed in prospective controlled trials, they may confer a large population benefit given the common use of aspirin in older people., Competing Interests: Competing interests: ALB, KS, JP, SK, PE, SAW, RGC, ES and JJM are the members of the investigator group for the ASPREE-Fracture substudy., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Osteocalcin (OC), an osteoblast-specific secreted protein expressed by mature osteoblasts, is used in clinical practice and in research as a marker of bone turnover. The carboxylated (cOC) and undercarboxylated (ucOC) forms may have a different biological function but age-specific reference ranges for these components are not established. Given the different physiological roles, development of reference ranges may help to identify people at risk for bone disease., Methods: Blood was collected in the morning after an overnight fast from 236 adult men (18 to 92 years old) free of diabetes, antiresorptive, warfarin or glucocorticoid use. Serum was analyzed for total osteocalcin (tOC) and the ucOC fraction using the hydroxyapatite binding method. cOC, ucOC/tOC and cOC/tOC ratios were calculated. Reference intervals were established by polynomial quantile regression analysis., Results: The normal ranges for young men (≤30 years) were: tOC 17.9-56.8 ng/mL, ucOC 7.1-22.0 ng/mL, cOC 8.51-40.3 ng/mL (2.5th to 97.5th quantiles). Aging was associated with a "U" shaped pattern for tOC, cOC and ucOC levels. ucOC/tOC ratio was higher, while cOC/tOC ratio was lower in men of advanced age. Age explained ∼31%, while body mass index explained ∼4%, of the variance in the ratios., Conclusions: We have defined normal reference ranges for the OC forms in Australian men and demonstrated that the OC ratios may be better measures, than the absolute values, to identify the age-related changes on OC in men. These ratios may be incorporated into future research and clinical trials, and their associations with prediction of events, such as fracture or diabetes risk, should be determined., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bone loss during advancing age is the net result of reduced modeling-based bone formation upon the outer (periosteal) envelope and unbalanced remodeling by basic multicellular units (BMUs) upon the three (intracortical, endocortical, and trabecular) components of the inner (endosteal) bone envelope. Each BMU deposits less bone than resorbed, reducing total bone volume and deteriorating the microstructure of the diminished residual bone volume.Antiresorptive agents like bisphosphonates reduce, but do not abolish, the rate of bone remodeling - fewer BMUs remodel, "turn over," the volume of bone. Residual unbalanced remodeling continues to slowly reduce total bone volume and deteriorate bone microstructure. By contrast, denosumab virtually abolishes remodeling so the decrease in bone volume and the deterioration in microstructure cease. The less remodeled matrix remains, leaving more time to complete the slow process of secondary mineralization which reduces the heterogeneity of matrix mineralization and allows it to become glycosylated, changes that may make the smaller and microstructurally deteriorated bone volume more brittle. Neither class of antiresorptive restores bone volume or its microstructure, despite increases in bone mineral density misleadingly suggesting otherwise. Nevertheless, these agents reduce vertebral and hip fractures by 50-60% but only reduce nonvertebral fractures by 20-30%.Restoring bone volume, microstructure, and material composition, "curing" bone fragility, may be partly achieved using anabolic therapy. Teriparatide, and probably abaloparatide, produce mainly remodeling-based bone formation by acting on BMUs existing in their resorption, reversal, or formation phase at the time of treatment and by promoting bone formation in newly initiated BMUs. Romosozumab produces modeling-based bone formation almost exclusively and decreases the surface extent of bone resorption. All three anabolic agents reduce vertebral fracture risk relative to untreated controls; parathyroid hormone 1-34 and romosozumab reduce vertebral fracture risk more greatly than risedronate or alendronate, respectively. Evidence for nonvertebral or hip fracture risk reduction relative to untreated or antiresorptive-treated controls is lacking or inconsistent. Only one study suggests sequential romosozumab followed by alendronate reduces vertebral, nonvertebral, and hip fracture risk compared to continuous alendronate alone. Whether combined antiresorptive and anabolic therapy result in superior fracture risk reduction than monotherapy is untested.

Introduction: Appendicular fractures are less common in Chinese than Caucasian women. Bone mineral density (BMD) is lower, not higher than in Caucasians because Chinese have smaller appendicular dimensions than Caucasians. However, smaller bones may offset the liability to fracture by being assembled with a more robust microstructure. We hypothesized that Chinese assemble an appendicular skeleton with a thicker, less porous and more mineralized cortex that is less deteriorated in advanced age than in Caucasians., Methods: We compared anthropometry in 477 Chinese and 278 Caucasian women and compared bone microstructure using high-resolution peripheral quantitative computed tomography in another cohort of 186 Chinese and 381 Caucasian women aged 18 to 86 years, all living in Melbourne, Australia. Trabecular plate (p) and rod (r) bone volume/total volume (BV/TV) were quantified using individual trabecula segmentation (ITS). Bone strength was estimated using micro-finite element analysis (μFEA)., Results: Premenopausal Chinese were shorter than Caucasian women, mainly due to shorter leg length. Distal radial total cross sectional area (CSA) was 14.8% smaller (p < 0.001). After adjusting for age and total CSA, Chinese had similar cortical and medullary areas but 0.30 SD lower cortical porosity and 0.27 SD higher matrix mineral density (both p < 0.05). Trabecular plate-to-rod ratio was 0.55 SD higher due to a 0.41 SD higher pBV/TV and 0.36 SD lower rBV/TV (p ranging 0.001 to 0.023). Chinese also had 0.36 SD greater whole bone stiffness and 0.36 SD greater failure load than Caucasians (both p < 0.05). After adjusting for age and total CSA, postmenopausal Chinese had 3.3% smaller cortical area, medullary area was 2.1% larger, cortical porosity was no lower, matrix mineral density and pBV/TV were no higher compared with Caucasians at the distal radius. Whole bone stiffness was 0.39 SD lower and failure load was 0.40 SD lower in Chinese (both p < 0.05)., Conclusion: Chinese build a more robust skeleton than Caucasians during growth, an advantage not observed in advanced age due to greater bone loss or race-specific secular trends in bone morphology., (Copyright © 2019 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.)

Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.

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.)

CVD is common in older adults. Consumption of 'meat' (beef, pork, lamb, game, poultry, seafood, eggs) and dairy foods (milk, cheese, yoghurt) is encouraged in older adults as these foods provide protein and nutrients such as essential fatty acids, Ca, Fe, Zn and vitamins A, D and B 12 required for healthy ageing. However, these foods also contain saturated fats considered detrimental to cardiovascular health. To determine the effect of their consumption on CVD risk we assessed associations between fat intake from 'meat' and dairy foods and serum cholesterol levels in 226 aged-care residents (mean age 85·5 years, 70 % female). Dietary intake was determined over 2 d using visual estimation of plate waste. Fat content of foods was determined using nutrition analysis software (Xyris, Australia). Fasting serum total cholesterol (TC), LDL-cholesterol and HDL-cholesterol were measured, and the TC:HDL-cholesterol ratio calculated. Associations were determined using random-effect models adjusted for CVD risk factors using STATA/IC 13.0. Total fat and saturated fat from 'meat' and dairy foods were associated with higher serum HDL-cholesterol levels, and dairy fat intake and number of servings were associated with a lower TC:HDL-cholesterol ratio. Every 10 g higher intake of fat and saturated fat from dairy products, and each additional serving was associated with a -0·375 (95 % CI -0·574, -0·175; P = 0·0002), a -0·525 (95 % CI -0·834, -0·213; P = 0·001) and a -0·245 (95 % CI -0·458, -0·033; P = 0·024) lower TC:HDL-cholesterol ratio, respectively. Provision of dairy foods and 'meat' in recommended amounts to institutionalised older adults potentially improves intakes of key nutrients with limited detriment to cardiovascular health.

In mice, glucocorticoid-induced insulin resistance occurs largely through impaired osteoblast function and decreased circulating undercarboxylated osteocalcin (ucOC). Whether these mechanisms contribute to glucocorticoid-induced insulin resistance in humans has yet to be established. In addition, the effects of glucocorticoids on the exercise-induced increase in circulating ucOC and insulin sensitivity are also unknown. We hypothesized that acute glucocorticoid treatment would lead to basal and postexercise insulin resistance in part through decreased circulating ucOC and ucOC-mediated skeletal muscle protein signaling. Nine healthy men completed two separate cycling sessions 12 hours after ingesting either glucocorticoid (20 mg prednisolone) or placebo (20 mg Avicel). The homeostatic model assessment was used to assess basal insulin sensitivity and a 2-hour euglycemic-hyperinsulinemic clamp was commenced 3 hours after exercise to assess postexercise insulin sensitivity. Serum ucOC and skeletal muscle protein signaling were measured. Single-dose glucocorticoid ingestion increased fasting glucose (27%, p < 0.01) and insulin (83%, p < 0.01), and decreased basal insulin sensitivity (-47%, p < 0.01). Glucocorticoids reduced insulin sensitivity after cycling exercise (-34%, p < 0.01), reduced muscle GPRC6A protein content (16%, p < 0.05), and attenuated protein phosphorylation of mTOR Ser2481 , Akt Ser374 , and AS160 Thr642 (59%, 61%, and 50%, respectively; all ps < 0.05). Serum ucOC decreased (-24%, p < 0.01) which correlated with lower basal insulin sensitivity (r = 0.54, p = 0.02), lower insulin sensitivity after exercise (r = 0.72, p < 0.05), and attenuated muscle protein signaling (r = 0.48-0.71, p < 0.05). Glucocorticoid-induced basal and postexercise insulin resistance in humans is associated with the suppression of circulating ucOC and ucOC-linked protein signaling in skeletal muscle. Whether ucOC treatment can offset glucocorticoid-induced insulin resistance in human subjects requires further investigation. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Distal forearm fractures during growth are more common in males than females. Because metaphyseal cortical bone is formed by coalescence of trabeculae emerging from the periphery of the growth plate, we hypothesized that the later onset of puberty in males produces a longer delay in trabecular bone formation and coalescence, which leaves a transient phase of high cortical porosity, low matrix mineral density, and high trabecular density relative to females. We quantified the nondominant distal radial microstructure using high-resolution peripheral quantitative computed tomography in 214 healthy Chinese boys and 219 Chinese girls aged between 7 and 17 years living in Hong Kong. Measurements of 110 slices (9.02 mm) were acquired 5 mm proximal to the growth plate of the nondominant distal radius. Porosity was measured using StrAx1.0 (Straxcorp, Melbourne, VIC, Australia) and trabecular plate and rod structure were measured using individual trabecula segmentation (ITS). Mechanical properties were estimated using finite element analysis (FEA). Results were adjusted for age, total bone cross-sectional area (CSA), dietary calcium intake, and physical activity. In boys, total bone CSA was 17.2% to 22.9% larger throughout puberty, cortical/total bone CSA was 5.1% smaller in Tanner stage 2 only, cortical porosity was 9.4% to 17.5% higher, and matrix mineral density was 1.0% to 2.5% lower in Tanner stage 2 to 5, than girls. Boys had higher trabecular rod BV/TV in Tanner stage 3 and 4, but higher trabecular plate BV/TV and plate to rod ratio in Tanner stage 5, than girls. Boys had 17.0% lower apparent modulus than girls in Tanner stage 2. A transient phase of higher porosity due to dissociation between bone mineral accrual and linear growth may contribute to higher distal radial bone fragility in Chinese boys compared to girls. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Advancing age and reduced loading are associated with a reduction in bone formation. Conversely, loading increases periosteal apposition and may reduce remodeling imbalance and slow age-related bone loss, an important outcome for the proximal femur, which is a common site of fracture. The ability to take advantage of bone's adaptive response to increase bone strength has been hampered by a lack of knowledge of which exercises and specific leg muscles load the superior femoral neck: a common region of microcrack initiation and progression following a sideways fall. We used an in vivo method of quantifying focal strains within the femoral neck in postmenopausal women during walking, stair ambulation, and jumping. Relative to walking, stair ambulation and jumping induced significantly higher strains in the anterior and superior aspects of the femoral neck, common regions of microcrack initiation and progression following a fall. The gluteus maximus, a hip extensor muscle, induced strains in the femoral neck during stair ambulation and jumping, in contrast to walking which induced strains via the iliopsoas, a hip flexor. The ground reaction force was closely associated with the level of strain during each task, providing a surrogate indicator of the potential for a given exercise to load the femoral neck. The gluteal muscles combined with an increased ground reaction force relative to walking induce high focal strains within the anterosuperior region of the femoral neck and therefore provide a target for exercise regimens designed to slow bone loss and maintain or improve microstructural strength. Model files used for calculating femoral neck strains are available at uitbl.mechse.illinois.edu/downloads © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Absolute values of cortical porosity and trabecular density are used to estimate fracture risk, but these values are the net result of their growth-related assembly and age-related deterioration. Because bone loss affects both cortical and trabecular bone, we hypothesized that a surrogate measure of bone fragility should capture the age-related deterioration of both traits, and should do so independently of their peak values. Accordingly, we developed a structural fragility score (SFS), which quantifies the increment in distal radial cortical porosity and decrement in trabecular density relative to their premenopausal mean values in 99 postmenopausal women with forearm fractures and 105 controls using HR-pQCT. We expressed the results as odds ratios (ORs; 95% CI). Cortical porosity was associated with fractures in the presence of deteriorated trabecular density (OR 2.30; 95% CI, 1.30 to 4.05; p  = 0.004), but not if trabecular deterioration was absent (OR 0.96; 95% CI, 0.50 to 1.86; p  = 0.91). Likewise, trabecular density was associated with fractures in the presence of high cortical porosity (OR 3.35; 95% CI, 1.85 to 6.07; p  < 0.0001), but not in its absence (OR 1.60; 95% CI, 0.78 to 3.28; p  = 0.20). The SFS, which captures coexisting cortical and trabecular deterioration, was associated with fractures (OR 4.52; 95% CI, 2.17 to 9.45; p  < 0.0001). BMD was associated with fracture before accounting for the SFS (OR 5.79; 95% CI, 1.24 to 27.1; p  = 0.026), not after (OR 4.38; 95% CI, 0.48 to 39.9; p  = 0.19). The SFS was associated with fracture before (OR 4.67; 95% CI, 2.21 to 9.88) and after (OR 3.94; 95% CI, 1.80 to 8.6) accounting for BMD (both p s < 0.0001). The disease of bone fragility is captured by cortical and trabecular deterioration: A measurement of coexisting cortical and trabecular deterioration is likely to identify women at risk for fracture more robustly than absolute values of cortical porosity, trabecular density, or BMD. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Purpose of Review: Bone densitometry provides a two-dimensional projected areal apparent bone mineral density that fails to capture the heterogeneity of bone's material composition and macro-, micro-, and nano-structures critical to its material and structural strength. Assessment of the structural basis of bone fragility has focused largely on trabecular bone based on the common occurrence of fragility fractures at sites with substantial amounts of trabecular bone. This review focuses on the contribution of cortical bone to bone fragility throughout life., Recent Findings: Accurately differentiating cortical and trabecular bone loss has important implications in quantifying bone fragility as these compartments have differing effects on bone strength. Recent advances in imaging methodology have improved distinction of these two compartments by (i) recognition of a cortico-trabecular transitional zone and (ii) quantifying bone microstructure in a region of interest that is a percentage of bone length rather than a fixed point. Additionally, non-invasive three-dimensional imaging methods allow more accurate quantification of changes in the cortical, trabecular, and cortico-trabecular compartments during growth, aging, disease, and treatment. Over 75% of the skeleton is assembled as cortical bone. Of all fragility fractures, ~ 80% are appendicular and involve regions rich in cortical bone and ~ 70% of all age-related appendicular bone loss is cortical and is mainly due to unbalanced intracortical remodeling which increases cortical porosity. The failure to achieve the optimal peak bone microstructure during growth due to disease and the deterioration in cortical and trabecular bone produced by bone loss compromise bone strength. The loss of strength produced by microstructural deterioration is disproportionate to the bone loss producing this deterioration. The reason for this is that the loss of strength increases as a 7th power function of the rise in cortical porosity and a 3rd power function of the fall in trabecular density (Schaffler and Burr in J Biomech. 21(1):13-6, 1988), hence the need to quantify bone microstructure.

The prevalence of fragility fractures increases as longevity increases the proportion of the elderly in the community. Until recently, the majority of studies have targeted women with osteoporosis defined as a bone mineral density (BMD) T score of < -2.5 SD, despite evidence that the population burden of fractures arises from women with osteopenia. Antiresorptive agents reduce vertebral and hip fracture risk by ~50 percent during 3 years but efficacy against non-vertebral fractures, 80% of all fractures in the community, is reported in few studies, and of those, the risk reduction is only 20-30%. Recent advances in the use of antiresorptives and anabolic agents has addressed some of these unmet needs. Zoledronic acid is now reported to reduce vertebral and non-vertebral fractures rates in women with osteopenia. Studies using teriparatide demonstrate better vertebral and clinical (symptomatic vertebral and non-vertebral) antifracture efficacy than risedronate. Abaloparatide, a peptide sharing amino acid sequences with teriparatide, reduces vertebral and non-vertebral fractures. Romosozumab, a monoclonal antibody suppressing sclerostin, reduces vertebral and non-vertebral fractures within a year of starting treatment, and does so more greatly than alendronate. Some recent studies signal undesirable effects of therapy but provide essential cautionary insights into long term management. Cessation of denosumab is associated with a rapid increase in bone remodeling and the uncommon but clinically important observation of increased multiple vertebral fractures suggesting the need to start alternative anti-resorptive therapy around the time of stopping denosumab. Antiresorptives like bisphosphonates and denosumab suppress remodeling but not completely. Antifracture efficacy may be limited, in part, as a consequence of continued unsuppressed remodeling, particularly in cortical bone. Bisphosphonates may not distribute in deeper cortical bone, so unbalanced intracortical remodeling continues to cause microstructural deterioration. In addition, suppressed remodeling may compromise the material composition by increasing matrix mineral density and glycosylation of collagen. As antiresorptive agents do not restore microstructural deterioration existing at the time of starting treatment, under some circumstances, anabolic therapy may be more appropriate first line treatment. Combining antiresorptive and anabolic therapy is an alternative but whether anti-fracture efficacy is greater than that achieved by either treatment alone is not known.

The diagnostic threshold for osteoporosis, a bone mineral density (BMD) T-score ≤ -2.5, signals an increased risk for fracture. However, most fragility fractures arise among the majority of women with 'osteopenia' or 'normal' BMD. We hypothesized that a BMD T-score of -2.5, even if not intended as a treatment threshold, paradoxically may create disincentive to initiating treatment of women with osteopenia or normal BMD at high risk for fracture. From a population-based BMD registry covering the Province of Manitoba, Canada, we identified 3735 untreated women aged ≥ 50 years undergoing BMD screening in 2006-2015 found to qualify for Osteoporosis Canada guidelines-based treatment. The main outcome was prescription of an approved osteoporosis medications in the year after BMD testing ascertained from a population-based pharmacy database. We estimated adjusted odds ratios (OR, 95% confidence interval [CI]) for treatment initiation based on BMD, major fracture history (non-traumatic vertebral, hip or multiple fractures), age, and calendar year (to examine the impact of treatment guidelines published in 2010). Among these women, 50% (1853) initiated treatment: 71% with osteoporosis, 21% with osteopenia, and 5% with normal BMD with similar values in those with a prior major fracture (71%, 19%, 5%, respectively). Compared to women with osteoporosis, adjusted ORs for treatment of high risk women with osteopenia or normal BMD alone were 0.10 (95% CI 0.09-0.12) and 0.02 (95% CI 0.01-0.04), respectively, and no higher in women with a prior major fracture (OR 1.00, 95% CI 0.84-1.19) or following introduction of treatment guidelines (p = 0.294). In summary, we found evidence that the diagnostic threshold for osteoporosis may serve as a disincentive to initiation of treatment in many women at high risk for incident fracture., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland) and compared with VivaCT 40 (µCT) at 19-micron voxel size. Associations between MMD and porosity were studied in 94 healthy vitamin D-replete premenopausal women, 77 postmenopausal women, and in a 27-year-old woman with vitamin D-dependent rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR-pQCT and µCT correlated (R = 0.87; p < 0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r 2  = 0.5 and -0.4, respectively) and correlated inversely in pre- and postmenopausal women (both r 2  = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post- than in premenopausal women (porosity 40.3% ± 7.0 versus 34.7% ± 3.5, respectively; MMD 65.4% ± 1.8 versus 66.6% ± 1.4, respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower and porosity was 5.6 SD higher than the respective trait means in premenopausal women. BMD was reduced (Z-scores femoral neck -4.3 SD, lumbar spine -3.8 SD). Low-radiation HR-pQCT may facilitate noninvasive quantification of bone's MMD and microstructure in health, disease, and during treatment. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Two women presenting with fragility fractures during lactation had bone mineral density (BMD) reduced more greatly than usually associated with lactation. The first woman was 29 years old with a BMD T-score of - 3.2 SD at the spine and- 2.0 SD at the femoral neck. The second woman was 35 years old with a BMD T-score of - 4.5 SD at the spine and - 2.8 SD at the femoral neck. Both women had increased cortical porosity and reduced trabecular density. Investigation identified an elevated serum tryptase, and marrow biopsy confirmed the diagnosis of mastocytosis. Lactation causes bone loss, but the occurrence of fractures in the setting of severe deficits in BMD and microstructural deterioration signals the need to consider additional causes of bone loss.

After menopause, remodeling becomes unbalanced and rapid. Each of the many remodeling transactions deposits less bone than it resorbed, producing microstructural deterioration. Trabecular bone is said to be lost more rapidly than cortical bone. However, because 80% of the skeleton is cortical, we hypothesized that most menopause-related bone loss and changes in bone microstructure are cortical, not trabecular in origin, and are the result of intracortical remodeling. Distal tibial and distal radial microstructure were quantified during 3.1 years (range, 1.5 to 4.5 years) of follow-up using high-resolution peripheral quantitative computed tomography and StrAx software in 199 monozygotic and 125 dizygotic twin pairs aged 25 to 75 years in Melbourne, Australia. The annual increases in tibial cortical porosity accelerated, being 0.44%, 0.80%, and 1.40% in women remaining premenopausal, transitioning to perimenopause, and from perimenopausal to postmenopause, respectively. Porosity increased in the compact-appearing, outer, and inner transitional zones of the cortex (all p < 0.001). The annual decrease in trabecular bone volume/tissue volume (BV/TV) also accelerated, being 0.17%, 0.26%, and 0.31%, respectively. Little bone loss was observed before menopause. The reduction in BV/TV was due to a decrease in trabecular number (p < 0.001). The greatest bone loss, 7.7 mg hydroxyapatite (HA) annually, occurred in women transitioning from perimenopausal to postmenopause and of this, 6.1 mg HA (80%) was cortical. Results were similar for the distal radius. Despite microarchitectural changes, no significant bone loss was observed before menopause. Over 90% of appendicular bone loss occurs during and after menopause, over 80% is cortical, and this may explain why 80% of fractures are appendicular. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Objective: Although it has been established that sufficient protein is required to maintain good nutritional status and support healthy aging, it is not clear if the pattern of protein consumption may also influence nutritional status, especially in institutionalized elderly who are at risk of malnutrition. Therefore, we aim to determine the association between protein intake distribution and nutritional status in institutionalized elderly people., Design: Cross-sectional study among 481 institutionalized older adults., Methods: Dietary data from 481 ambulant elderly people (68.8% female, mean age 87.5 ± 6.3 years) residing in 52 aged-care facilities in Victoria, Australia, were assessed over 2 days using plate waste analysis. Nutritional status was determined using the Mini-Nutritional Assessment tool and serum (n = 208) analyzed for albumin, hemoglobin, and IGF-1. Protein intake distribution was classified as: spread (even distribution across 3 meals, n = 65), pulse (most protein consumed in one meal, n = 72) or intermediate (n = 344). Regression analysis was used to investigate associations., Results: Mean protein intakes were higher in the spread (60.5 ± 2.0 g/d) than intermediate group (56.0 ± 0.8 g/d, P = .037), and tended to be higher than those in the pulse group (55.9 ± 1.9 g/d, P = .097). Residents with an even distribution of protein intake achieved a higher level of the recommended daily intake for protein (96.2 ± 30.0%) than the intermediate (86.3 ± 26.2%, P = .008) and pulse (87.4 ± 30.5%, P = .06) groups, and also achieved a greater level of their estimated energy requirements (intermediate; P = .039, pulse; P = .001). Nutritional status (Mini-Nutritional Assessment score) did not differ between groups (pulse; 20.5 ± 4.5, intermediate; 21.0 ± 2.5, spread; 20.5 ± 3.5), nor did any other indices of nutritional status., Conclusions: Meeting protein requirements is required before protein distribution may influence nutritional status in institutionalized elderly. Achieving adequate protein and energy intakes is more likely when protein is distributed evenly throughout the day. Provision of high protein foods especially at breakfast, and in the evening, may support protein adequacy and healthy aging, especially for institutionalized elderly., (Copyright © 2017 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: In premenopausal women with early estrogen-receptor-positive breast cancer, combined ovarian suppression and aromatase inhibition reduce estradiol production precipitously. The resulting unbalanced and rapid bone remodelling replaces older bone with less bone that is less fully mineralized. We hypothesized that these changes result in severe microstructural deterioration and reduced matrix mineralization density., Methods: Images of the distal radius and distal tibia were acquired using high-resolution peripheral quantitative computed tomography in a cross-sectional study of 27 premenopausal women, mean age 43.3years (range 30.4 to 53.7) with early breast cancer made estradiol deficient for 17months (range 6-120) using ovarian suppression and aromatase inhibition, 42 healthy age-matched premenopausal and 35 postmenopausal controls, mean age 62.6years (range 60.2 to 65.5). Cortical and trabecular microstructure were quantified using Strax software., Results: Compared with premenopausal controls, the women with breast cancer had 0.75 SD (95% CI 0.21 to 1.29) lower distal radial trabecular bone volume due to 1.29 SD (0.71 to 1.87) fewer trabeculae. Cortical porosity was 1.25 SD (0.59 to 1.91) higher but cortical thickness was not reduced. Compared with postmenopausal controls 20years older, cases had comparable or lower trabecular bone volume and comparable cortical porosity and thickness. Matrix mineral density was 1.56 SD (0.90 to 2.22) lower than in premenopausal controls and 2.17 SD (1.50 to 2.84) lower than in postmenopausal controls. Results at the tibia were similar., Conclusion: The severe cortical porosity and trabecular deterioration associated with estradiol depletion and the longevity of premenopausal women with early breast cancer treated with endocrine therapy provide a compelling rationale to investigate the efficacy of antiresorptive therapy initiated at the time of breast cancer treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Individuals differ in forearm length. As microstructure differs along the radius, we hypothesized that errors may occur when sexual and racial dimorphisms are quantified at a fixed distance from the radio-carpal joint., Methods: Microstructure was quantified ex vivo in 18 cadaveric radii using high resolution peripheral quantitative computed tomography and in vivo in 158 Asian and Caucasian women and men at a fixed region of interest (ROI), a corrected ROI positioned at 4.5-6% of forearm length and using the fixed ROI adjusted for cross sectional area (CSA), forearm length or height. Secular effects of age were assessed by comparing 38 younger and 33 older women., Results: Ex vivo, similar amounts of bone mass fashioned adjacent cross sections. Larger distal cross sections had thinner porous cortices of lower matrix mineral density (MMD), a larger medullary CSA and higher trabecular density. Smaller proximal cross-sections had thicker less porous cortices of higher MMD, a small medullary canal with little trabecular bone. Taller persons had more distally positioned fixed ROIs which moved proximally when corrected. Shorter persons had more proximally positioned fixed ROIs which moved distally when corrected, so dimorphisms lessened. In the corrected ROIs, in Caucasians, women had 0.6 SD higher porosity and 0.6 SD lower trabecular density than men (p<0.01). In Asians, women had 0.25 SD higher porosity (NS) and 0.5 SD lower trabecular density than men (p<0.05). In women, Asians had 0.8 SD lower porosity and 0.3 SD higher trabecular density than Caucasians (p<0.01). In men, Asians and Caucasians had similar porosity and trabecular density. Results were similar using an adjusted fixed ROI. Adjusting for secular effects of age on forearm length resulted in the age-related increment in porosity increasing from 2.08 SD to 2.48 SD (p<0.05)., Conclusion: Assessment of sex, race and age related differences in microstructure requires measurement of anatomically equivalent regions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: Vitamin D "insufficiency" and "deficiency" are defined as serum 25-hydroxyvitamin D [25(OH)D] levels <75 and <30 nmol/L, respectively. We aimed to determine whether these values signal hypocalcemia and hypophosphatemia, secondary hyperparathyroidism, high bone remodeling, low areal bone mineral density (aBMD), microstructural deterioration, or reduced matrix mineralization density (MMD) and so suggest whether bone fragility is present., Methods: Concentrations of 25(OH)D, calcium, phosphate, creatinine, and parathyroid hormone (PTH) were measured in 11,855 participants. Serum C-terminal telopeptide of type 1 collagen, procollagen type 1 N-terminal propeptide (P1NP), aBMD, and distal radius microstructure and MMD were measured in a second subset of 150 participants., Results: A breakpoint for calcium, PTH, and alkaline phosphatase was identified at a threshold 25(OH)D level <30 nmol/L. There was no plateau beyond 75 nmol/L. In the subgroup with measurements of bone morphology, no associations were detectable between serum 25(OH)D concentration, aBMD, trabecular density, cortical porosity, or MMD. Among 1439 participants with serum 25(OH)D <30 nmol/L, 6.1% had low serum calcium, 3.4% had low serum phosphate, 6.1% had high alkaline phosphatase, and 34.2% had elevated PTH. Most participants did not have any abnormalities., Conclusion: At a 25(OH)D threshold of ≤30 nmol/L, abnormalities in biochemical features support the notion of a "deficiency" state predisposing to bone disease. However, no deleterious effects were found in participants within an insufficiency threshold of a 25(OH)D level of 30 to 75 nmol/L, which challenges the rationale justifying vitamin D supplementation in these individuals., (Copyright © 2017 Endocrine Society)

Introduction: The pharmacokinetic profile of parathyroid hormone (PTH) determines its effects on bone resorption and formation. When administered intermittently, anabolic effects are favored in comparison with the continuous treatment. Among the intermittent treatment regimens, lower frequency of administration may have a lower effect on bone remodeling. We therefore hypothesized that weekly administration of teriparatide will produce less increase in intracortical remodeling and porosity than reported using daily treatment., Methods: We treated 17 female New Zealand white rabbits aged 6months for 1month with teriparatide [human PTH(1-34)] as follows. (i) Vehicle-treated Control (n=4); (ii) 20μg/kg daily (n=3); (iii) 40μg/kg daily (n=3); (iv) 140μg/kg weekly (n=3); (v) 280μg/kg weekly (n=4). Proximal femurs were imaged ex vivo using micro-CT (Scanco Viva CT-40) at 15μmvoxel size. Areas, pore size, and porosity were analyzed on the total, compact cortex (CC), and transitional zones in a 10mm length region of interest (ROI) starting at the midshaft using StrAx1.0., Results: Compared to controls, the 20μg/kg daily was associated with 3.0% higher porosity in the transitional zone (p=0.09) while the 40μg/kg daily was associated with a higher porosity in the cortex (8.7%; p=0.04) and in the transitional zone (5.7%; p=0.007). The daily regimens were also associated with a greater proportion of porosity due to pores >15μm 2 ; particularly in the transitional zone where 20 and 40μg/kg daily increased porosity 2 fold (p=0.06) and 5 fold (p=0.04) relative controls respectively. The 140 and 280μg/kg weekly were not associated with an increase in porosity. There was no difference in total, compact or transitional zone cross sectional areas between the groups., Conclusion: Effects of intermittent teriparatide depend on the dose and frequency of administration. Daily dosing, particularly the higher dose, but not weekly dosing, increased cortical porosity. Work is needed to investigate the effects of the regimens on bone formation., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Estrogen deficiency associated with menopause is accompanied by an increase in the rate of bone remodeling and the appearance of a remodeling imbalance; each of the greater number of remodeling transactions deposits less bone than was resorbed, resulting in microstructural deterioration. The newly deposited bone is also less completely mineralized than the older bone resorbed. We examined whether breastfeeding, an estrogen-deficient state, compromises bone microstructure and matrix mineral density. Distal tibial and distal radial microarchitecture were quantified using high-resolution peripheral quantitative computed tomography in 58 women before, during, and after breastfeeding and in 48 controls during follow-up of 1 to 5 years. Five months of exclusive breastfeeding increased cortical porosity by 0.6% (95% confidence interval [CI] 0.3-0.9), reduced matrix mineralization density by 0.26% (95% CI 0.12-0.41) (both p < 0.01), reduced trabecular number by 0.22 per mm (95% CI 0.15-0.28), and increased trabecular separation by 0.07 mm (95% CI 0.05-0.08) (all p < 0.001). Relative to prebreastfeeding, at a median of 2.6 years (range 1 to 4.8) after cessation of breastfeeding, cortical porosity remained 0.58 SD (95% CI 0.48-0.68) higher, matrix mineralization density remained 1.28 SD (95% CI 1.07-1.49) lower, and trabeculae were 1.33 SD (95% CI 1.15-1.50) fewer and 1.06 SD (95% CI 0.91-1.22) more greatly separated (all p < 0.001). All deficits were greater than in controls. The results were similar at distal radius. Bone microstructure may be irreversibly deteriorated after cessation of breastfeeding at appendicular sites. Studies are needed to establish whether this deterioration compromises bone strength and increases fracture risk later in life. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)