J Bone Miner Res doi: 10.1002/jbmr.4152.
Three years of high-dose vitamin D supplementation (400, 4000, 10,000 IU) in healthy vitamin D-sufficient individuals aged 55-70 years (serum 25(OH)D 30-125 nmol/L at baseline), resulted in a negative dose-response relationship for bone density and strength. This study examined whether response differed between males and females. 311 participants (53% male) were randomized to 400 (M=61, F=48), 4000 (M=51, F=49), or 10,000 (M=53, F=49) IU daily vitamin D3 . Participants were scanned on high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure total volumetric BMD (TtBMD) at baseline, 6, 12, 24 and 36 months. Finite element analysis estimated bone strength. Balance, physical function, and clinical biochemistry parameters were also assessed. Constrained linear mixed effects models determined time-by-treatment group-by-sex interactions. Baseline, three-month, and three-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L (400); 81.3, 115.3, and 132.2 (4000); and 78.4, 188.0, and 144.4 (10,000). There were significant time-by-treatment group-by-sex interactions for TtBMD at the radius (p=0.002) and tibia (p=0.005). Treatment with 4000 or 10,000 compared to 400 IU resulted in TtBMD losses in females, but this was not observed with males. After three years, females lost 1.8% (400), 3.8% (4000) and 5.5% (10,000), whereas males lost 0.9% (400), 1.3% (4000) and 1.9% (10,000) at the radius. At the tibia, losses in TtBMD were smaller, but followed a similar trend. There were no significant bone strength interactions. Vitamin D supplementation with 4000 or 10,000 IU, compared with 400 IU daily, resulted in greater losses of TtBMD over three years in healthy vitamin D-sufficient females, but not males. These results are clinically relevant, as vitamin D supplementation is widely administered to postmenopausal females for osteoporosis prevention. Our findings do not support a benefit of high-dose vitamin D supplementation for bone health, and raise the possibility of harm for females.