Role of vitamin D, its metabolites, and analogs in the management of osteoporosis.

Vitamin D and its metabolites are well-established regulators of bone mineral homeostasis. Their clearest role is in the prevention and treatment of rickets and osteomalacia, bone diseases characterized by inadequate bone formation, and mineralization. Much of the effectiveness of vitamin D and its active metabolite 1,25(OH)2D in treating such disorders rests with their ability to increase serum levels of calcium and phosphate principally by stimulating intestinal calcium and phosphate absorption. Osteoporosis is not a disease resulting from obvious deficiencies in vitamin D, calcium, and phosphate. More subtle deficiencies, however, may be found, especially among the elderly with decreased intake of dairy products, reduced sunlight exposure, and less efficient intestinal absorption of bone minerals. Such subtle deficiencies may account for the ability of vitamin D and calcium supplementation to have a beneficial effect on bone mineral density in this population. Estrogen administration to postmenopausal females raises 1,25(OH)2D levels, presumably through increased renal production, and this increase is associated with increased intestinal calcium transport. Serum measurements of the vitamin D metabolites in general, however, and 1,25(OH)2D in particular do not consistently show evidence of a decrease at the time of menopause. Although most studies show a fall in intestinal calcium transport with age, which can be reversed with 1,25(OH)2D or estrogen, even these observations have not been found consistently. Thus, some investigators have addressed the issue of tissue resistance to 1,25(OH)2D and have noted decreased VDR in the intestine and reduced 1,25(OH)2D accumulation by bone with age. Despite no obvious deficiency of vitamin D in most patients with osteoporosis, clinical trials with vitamin D or 1,25(OH)2D show promise. Vitamin D treatment will probably prove most efficacious in populations with marginal vitamin D intake and/or limited sunlight exposure; high doses would not be required, and the treatment would be safe. This would be a physiologic and not a pharmacologic use of vitamin D. The use of 1,25(OH)2D for treatment of osteoporosis in individuals with adequate nutrition and sunlight exposure may require somewhat higher than physiologic doses to be effective. Perhaps such doses are necessary to stimulate osteoblast activity and/or differentiation; by raising the serum calcium level, such doses of 1,25(OH)2D might block its otherwise stimulatory effect on osteoclast number and activity. Such doses run the risk of hypercalcemia and hypercalciuria, leading to nephrolithiasis and/or nephrocalcinosis. These undesirable side effects appear to be less common with the use of 1 alpha OHD compared with 1,25(OH)2D, but this may be because of the lower levels of calcium consumption in Japan where 1 alpha OHD is widely prescribed.(ABSTRACT TRUNCATED AT 400 WORDS)