Calcif Tissue Int (1991) [Suppl] 49:$46-$49 Calcified Tissue International 9 1991 Springer-Vertag New York Inc. Is There a Role for Vitamin D in Osteoporosis? Christel Lamberg-Allardt Endocrine Research Laboratory, University of Helsinki, Minerva Foundation Institute for Medical Research, Tukholmankatu 2, 00250 Helsinki, Finland Summary. Vitamin D has certain clearly defined effects on bone: vitamin D deficiency results in defective bone miner- alization, whereas 1,25-dihydroxy-vitamin D 3 (1,25-(OH)2D3) stimulates bone resorption. Studies of the use of 1,25- (OH)zD 3 to prevent or treat osteoporosis have given con- flicting results concerning bone remodeling. However, 1,25- (OH)2D 3 or other vitamin D metabolites seem to play a role in the correction of calcium malabsorption, which is a com- mon feature in osteoporosis. Key words: Osteoporosis - Vitamin D. Actions of Vitamin D Vitamin D is converted to 25-hydroxy-vitamin D (25-OH-D) in the liver and further to 1,25-dihydroxy-vitamin D (1,25- (OH)2D) in the kidney. 1,25-(OH)2D 3 is biologically the most active metabolite of Vitamin D 3. It exerts its effects primar- ily through a nuclear receptor in target tissues, where it stim- ulates or inhibits the synthesis of specific proteins. The main regulators of 1,25-(OH)2D 3 synthesis are parathyroid hor- mone (PTH), phosphate, and 1,25-(OH)2D 3 itself. The serum calcium concentration regulates 1,25-(OH)2D 3 synthesis in- directly via PTH. Vitamin D has many target tissues, as judged by the presence of nuclear receptors. It has been shown to play a role in many physiological processes besides its well-known role in calcium homeostasis. The main target tissues are, however, the intestine and bone. 1,25-(OH)2D3 increases the absorption of calcium and phosphorus from the intestine and mobilizes calcium and phosphorus from bone. There are two other target tissues related to calcium metab- olism: the parathyroid glands, where 1,25-(OH)2D 3 sup- presses the formation of PTH, and the kidney, where the main effect of 1,25-(OH)2D 3 is downregulation of its own synthesis. Vitamin D and Bone 1,25-(OH)2D 3 is a potent stimulator of bone resorption, caus- ing calcium and phosphorus to be released from the bone. Mineralization of the osteoid, however, is impaired in vita- min D deficiency--calcium and phosphorus are not laid down in the bone. The deficient mineralization is not a direct effect of the lack of vitamin D metabolites on bone cells but rather of a decreased supply of calcium and phosphorus in- duced by vitamin D deficiency. At least in the rat, vitamin D is not needed in the mineralization process [1] as long as there is a sufficient supply of calcium and phosphorus. As regards the effect of vitamin D on bone, most interest has lately focused on the effect of 1,25-(OH)2D 3, as the biologi- cally most active metabolite, although 24,25-dihydroxy- vitamin D (24,25-(OH)2D3), has also been studied to some extent, and seems to have other specific effects on bone tissue. Interestingly, 1,25-(OH)/-D-26,23-1actone, a natural metabolite of vitamin D, has been shown to inhibit bone resorption stimulated by 1,25-(OH)2D 3 and PTH, and to stim- ulate bone formation [2]. Actions of l,25-(OH)2D 3 on Bone Cells In Vitro Receptors for 1,25-(OH)2D 3 have been found in the osteo- blasts [3]. 1,25-(OH)2D 3 stimulates alkaline phosphatase ac- tivity in osteoblast-like cells [4]. In addition, it inhibits the synthesis of collagen type I [4], stimulates the synthesis of osteocalcin [5], and inhibits proteoglycan synthesis [6]. 1,25- (OH)2D 3 stimulates bone resorption in vitro in concentra- tions normally used in cell cultures (10- lo M to 10-8 M ) [7]. However, no nuclear receptors for 1,25-(OH)2D 3 have been detected in osteoclasts. Nevertheless, 1,25-(OH)2D 3 affects osteoclasts, though not directly. 1,25-(OH)2D 3 promotes the activity of osteoclasts in bone explants and enlarges the ruf- fled border area [8]. In vivo studies have revealed an in- crease in activity and number of osteoclasts [9]. 1,25- (OH)2D 3 enhances the differentiation and proliferation of osteoclastic progenitor or precursor cells [10]. The mech- anisms by which 1,25-(OH)2D 3 affects bone resorption and osteoclasts are not known. However, the effects seem to be mediated via the osteoblast, since stimulation of bone re- sorption by 1,25-(OH)2D 3 occurs when osteoblasts are present in osteoclast cultures [11]. One factor derived from osteoblasts that stimulates bone resorption has been shown to be stimulated by 1,25-(OH)2D 3 [12]. Actions of Vitamin D on Bone In Vivo The effect of vitamin D on bone resorption and bone forma- tion in vivo seems to differ between vitamin-D-replete and the vitamin D-depleted animals. In vitamin-D-depleted ani- mals, vitamin D promotes bone mineralization and healing of rickets [13]. In vitamin-D-replete animals, vitamin D stimu- lates bone resorption [14], with an increased osteoid [15]. Low doses of 1,25-(OH)2D 3 have no dramatic effects on bone calcium, but pharmacological doses increase trabecular dry weight, though mineralization is impaired [16-18], with ex- cess osteoid [17], hypertrophy of osteoblasts, and a decrease in the number of osteoclasts, at least when a high calcium diet is given [19]. Malluche et al. [20] studied the effect of 1,25-(OH)2D 3 in ovariohysterectomized dogs and found that it promoted osteoblast activity, normalizing it to control lev- els. After 8 months of therapy, however, fewer osteoblasts were seen than in the controls. It was concluded, therefore,