Calcium deficiency causes osteoporosis in experimental animals because the skeleton is sacrificed for the preservation of the plasma (ionic) calcium and to meet obligatory calcium losses in the feces and urine. (Vitamin D deficiency, on the other hand, causes rickets and osteomalacia largely because of the loss of the calcemic action of vitamin D, which leads to hypocalcemia, secondary hyperparathyroidism, and hypophosphatemia.) The concept that human osteoporosis, particularly in postmenopausal women, results from negative calcium balance represents a working hypothesis that fits many, but not all of the available data. In normal women, the crucial event is a rise in obligatory urinary calcium loss, which may result from an increase in the complexed fraction of the plasma calcium, due in turn to an increase in plasma bicarbonate. Prospective trials with calcium supplements have, however, yielded conflicting results. In osteoporotic women, a further increase in urinary calcium combined with calcium malabsorption produces a further increase in bone resorption, but some impairment of bone formation due to declining androgens may constitute an additional risk factor with advancing age. The suppressibility of urinary hydroxyproline by calcium supplementation in those patients who can absorb calcium, and by calcitriol in those who cannot, supports the calcium deficiency model, but more trials are needed to establish its validity.