IMPORTANCE Few studies have assessed the effects of daily vitamin D doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report vitamin D intakes of at least 4000 IU per day.OBJECTIVE To assess the dose-dependent effect of vitamin D supplementation on volumetric bone mineral density (BMD) and strength.DESIGN, SETTING, AND PARTICIPANTS Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L. INTERVENTIONS Daily doses of vitamin D 3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day. MAIN OUTCOMES AND MEASURESCo-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis. RESULTSOf 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10 000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (−3.9 mg HA/cm 3 [95% CI, −6.5 to −1.3]) and 10 000 IU group (−7.5 mg HA/cm 3 [95% CI, −10.1 to −5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of −1.2% (400 IU group), −2.4% (4000 IU group), and −3.5% (10 000 IU group). Tibial volumetric BMD differences from the 400 IU group were −1.8 mg HA/cm 3 (95% CI, −3.7 to 0.1) in the 4000 IU group and −4.1 mg HA/cm 3 in the 10 000 IU group (95% CI, −6.0 to −2.2), with mean percent change values of −0.4% (400 IU), −1.0% (4000 IU), and −1.7% (10 000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12).CONCLUSIONS AND RELEVANCE Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful.

Background: Although dual-energy x-ray absorptiometry (DXA) assessed areal bone density (aBMD) is the clinical standard for determining fracture risk, the majority of older adults who sustain a fracture do not have osteoporosis (T-score < −2.5). Importantly, bone fragility results not only from low BMD, but also from deterioration in bone structure. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) data from eight cohorts to evaluate whether HR-pQCT indices were associated with fracture risk independently of femoral neck (FN) aBMD and FRAX (Fracture Risk Assessment Tool) score. Methods: Participants included 7,254 individuals (66% women) from cohorts in the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazards models to estimate hazards ratios (HRs) for the association between bone parameters (per standard deviation, SD, deficit) and incident fracture, adjusting for age, sex, height, weight and cohort. Findings: Mean baseline age was 69 (±9) years (range, 40 to 96). Cumulative incidence of fracture was 11% (n=765) over a mean follow-up time of 4.6 (± 2.4) years. The majority of participants (92%) had a femoral neck T-score >−2.5, and thus did not meet diagnostic criteria for osteoporosis. Failure load was the bone measure most strongly associated with risk of fracture: tibia HR=2.40 (1.98-2.91), radius HR=2.13 (1.77-2.56), per SD decrease in failure load. HRs for other bone indices ranged from HR=1.12 (1.03-1.23) per SD increase in tibia cortical porosity to HR=1.58 (1.45-1.72) per SD decrease in radius trabecular volumetric bone density (vBMD). After further adjustment for FN aBMD or FRAX, HRs were attenuated, but most bone parameters remained significantly associated with fracture. Cortical density, trabecular number, and trabecular thickness at the distal radius were the best set of predictors of fracture; while the same indices plus cortical area were identified for the tibia. These HR-pQCT indices and failure load improved prediction of fracture, beyond FN aBMD alone or FRAX. Interpretation: Results from this large international cohort of women and men confirm prior studies showing that deficits in trabecular and cortical bone density and structure contribute to fracture risk independently of aBMD and FRAX. Measurements of cortical and trabecular bone density and morphology at the peripheral skeleton may improve identification of those at highest risk for fracture. Funding: National Institutes of Health, National Institute of Arthritis Musculoskeletal and Skin Diseases, R01AR061445

The purpose of this study was to develop age-, site-, and sex-specific centile curves for common high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite-element (FE) parameters for males and females older than 16 years. Participants (n = 866) from the Calgary cohort of the Canadian Multicentre Osteoporosis Study (CaMos) between the ages of 16 and 98 years were included in this study. Participants' nondominant radius and left tibia were scanned using HR-pQCT. Standard and automated segmentation methods were performed and FE analysis estimated apparent bone strength. Centile curves were generated for males and females at the tibia and radius using the generalized additive models for location, scale, and shape (GAMLSS) package in R. After GAMLSS analysis, age-, sex-, and site-specific centiles (10th, 25th, 50th, 75th, 90th) for total bone mineral density and trabecular number as well as failure load have been calculated. Clinicians and researchers can use these reference curves as a tool to assess bone health and changes in bone quality. © 2016 American Society for Bone and Mineral Research.