Vitamin D insufficiency is characterized biochemically by the presence of secondary hyperparathyroidism, which can contribute to bone loss in osteopenic patients. Over a 2-yr period of evaluation of 118 consecutive, free living patients with osteopenia or osteoporosis, we identified 18 subjects with depressed serum 25-hydroxyvitamin D (250HD; < or = 14 ng/mL). Twelve of these subjects harbored a low 25OHD level and consented to undergo replacement with 50,000 IU vitamin D2 twice weekly for 5 weeks. Five hundred thousand units of oral vitamin D2 resulted in significant increases in 25OHD (+24.3+/-16.9 ng/mL; P < 0.001) and the fasting urinary calcium/creatinine excretion ratio (+0.06+/-0.004; P = 0.01) and significant decreases in the serum concentration of PTH (-32.9+/-36.9 pg/mL; P < 0.001) and osteocalcin (-4.9+/-2.4 ng/mL; P < 0.001). Vitamin D repletion was associated with a significant 4-5% annualized increase in bone mineral density at both the lumbar spine (P < 0.001) and the femoral neck (P = 0.03), indicating that resolution of vitamin D insufficiency in a population of patients with low bone mass results in a rapid rebound increase in bone mineral density.