Association of serum phosphate, calcium and alkaline phosphatase with risk of incident fractures in healthy older adults.

BACKGROUND: Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodelling. We examined the associations between levels of phosphate, calcium, and alkaline phosphatase, 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 2,411 US participants aged ≥65 years. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and alkaline phosphatase measurement. Fracture data were collected post-randomization. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs). Phosphate, calcium, and alkaline phosphatase were analysed in deciles (D1-D10), with deciles 4-7 (31-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations. RESULTS: Of the 9915 participants, 907 (9·2%) persons had incident fractures recorded over 3·9 (SD 1·4) years. In the fully adjusted model, males in the top decile (D10) of phosphate had 78% higher risk of incident fracture (HR 1·78, 95% CI 1·25-2·54). No such association was observed for females (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.

Cardiometabolic Effects of Denosumab in Premenopausal Women with Breast Cancer Receiving Estradiol Suppression: RCT.

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 pre-clinical and observational studies, though 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 pre-specified 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, MAD, [95% confidence interval], 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 = 0.02, and -452 g [95%CI -783 to -122], P = 0.03, respectively). Total fat mass and waist circumference were lower in the denosumab group but not significantly so (-1792g [95% CI -3346 to -240], P = 0.08 and (- 3.77 cm [95% CI -6.76 to -0.79], P = 0.06, respectively). No significant treatment effects were detected in lean mass, BMI, hip circumference, fasting glucose, HOMA-IR, or lipid profile. CONCLUSIONS: 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.

Reducing hip and non-vertebral fractures in institutionalised older adults by restoring inadequate intakes of protein and calcium is cost-saving.

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.

A low serum alkaline phosphatase may signal hypophosphatasia in osteoporosis clinic patients.

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.

Bone Remodeling and Modeling: Cellular Targets for Antiresorptive and Anabolic Treatments, Including Approaches Through the Parathyroid Hormone (PTH)/PTH-Related Protein Pathway.

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.

Daily Low-Dose Aspirin and Risk of Serious Falls and Fractures in Healthy Older People: A Substudy of the ASPREE Randomized Clinical Trial.

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).

Bone Microarchitecture in Transgender Adults: A Cross-Sectional Study.

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).

The effect of denosumab and alendronate on trabecular plate and rod microstructure at the distal tibia and radius: A post-hoc HR-pQCT study.

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.

Bone microarchitecture and estimated failure load are deteriorated whether patients with chronic kidney disease have normal bone mineral density, osteopenia or osteoporosis.

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) mm2, p = 0.002, lower cortical volumetric BMD 543 (80.7) vs. 642 (81.7) mgHA/cm3 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/cm3 due to fewer and spatially disrupted trabeculae, lower FN-BMD 0.78 (0.12) vs. 0.94 (0.14) g/cm2 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.

Bilateral atypical femoral fractures during denosumab therapy in a patient with adult-onset hypophosphatasia.

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.

Recovery of quality of life is associated with lower mortality 5-year post-fracture: the Australian arm of the International Costs and Utilities Related to Osteoporotic Fractures Study (AusICUROS).

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.

High Cortico-Trabecular Transitional Zone Porosity and Reduced Trabecular Density in Men and Women with Stress Fractures.

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.

Physiological and Pharmacological Roles of PTH and PTHrP in Bone Using Their Shared Receptor, PTH1R.

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.

Heterogeneity in microstructural deterioration following spinal cord injury.

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.

Cost-effectiveness of treatment of women aged 70 years and older with both osteopenia and microstructural deterioration.

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.

Differing Effects of Zoledronic Acid on Bone Microarchitecture and Bone Mineral Density in Men Receiving Androgen Deprivation Therapy: A Randomized Controlled Trial.

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/cm3 [-2.0 to 15.4], p = 0.21) and tibia (1.9 mg HA/cm3 [-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/cm3 [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/cm2 [0.07 to 0.13]), p < 0.001), and total hip (0.04 g/cm2 [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.

Reduced Bone Modeling and Unbalanced Bone Remodeling: Targets for Antiresorptive and Anabolic Therapy.

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.

Aspirin and fracture risk: a systematic review and exploratory meta-analysis of observational studies.

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; I2=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; I2=0%; three studies; n=9686) and men (SMD 0.06, 95% CI -0.02 to 0.13, I2=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; I2=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.

Deterioration of Cortical and Trabecular Microstructure Identifies Women With Osteopenia or Normal Bone Mineral Density at Imminent and Long-Term Risk for Fragility Fracture: A Prospective Study.

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.