Osteoporosis is a state of reduced skeletal mass characterized by various rates of bone remodeling. Multiple locally elaborated factors have been identified that appear to influence the cellular events in bone remodeling. The possible role(s) of these factors in the pathogenesis of osteoporosis is unknown. One such factor, interleukin 1 (IL-1), is of particular interest, as this protein is known to stimulate bone resorption and perhaps formation. Consequently, we have measured the spontaneous secretion of IL-1 activity by cultured peripheral blood monocytes obtained from 22 osteoporotic patients and 14 age-matched control subjects. Monocytes from osteoporotic patients produced more IL-1 than did monocytes from control subjects. When patients were grouped according to monocyte-produced IL-1 activity, dynamic parameters of bone formation, as judged by quantitative histomorphometric analysis of iliac crest bone biopsies and by circulating levels of bone 4-carboxyglutamic acid protein (BGP)-a marker of bone formation-were higher in subjects with elevated IL-1 activity; whereas, indices of bone resorption and static indices of bone formation were similar in subjects with either high or normal IL-1 activity. IL-1 activity released by peripheral blood monocytes appears to reflect bone formation rate in osteoporotic patients and may be of pathogenetic significance in a subset of individuals with osteoporosis.Primary osteoporosis is an extremely common condition in which inadequate accumulation of bone tissue during maturation or excessive loss thereafter (or both) culminates in a clearly subnormal level of bone mass (1). Among its clinical forms are senile osteoporosis attributable to the undefined impact ofaging on bone remodeling, postmenopausal osteoporosis reflecting excessive bone loss due to estrogen (and perhaps progestin) withdrawal, and idiopathic osteoporosis, a poorly understood acceleration of bone loss occurring in young men and premenopausal women (2). In each case, the insufficiency of bone mass is visualized as stemming from a remodeling disturbance in which bone resorption exceeds formation.The various clinical forms of primary osteoporosis also exhibit histological heterogeneity, as disclosed by quantitative histomorphometric studies with bone biopsies (3). Subsets of these osteoporotic populations exhibit "high-turnover" disease, characterized by accelerated rates of remodeling. At the other end of the spectrum are patients with "low-turnover" osteoporosis characterized by low rates of remodeling (4). High-turnover osteoporosis is of special interest because it could stem from an abnormality of one or more of the factors known to activate bone remodeling. However, studies have failed to incriminate significant differences in systemically elaborated remodeling stimulators, including parathyroid hormone, calcitonin, calcitriol (1a,25-dihydroxyvitamin D3), and insulin-like growth factor 1 (5-7).Evidence has accumulated that suggests that cells of the monocyte-macrophage series may serve as local ...

Mineral homestasis and skeletal morphology were studied in freely fed control, streptozotocin-induced diabetic, and insulin-treated diabetic rats 7 weeks after the induction of diabetes. The untreated diabetic animals were characterized by modest hypercalcemia, hyperphosphatemia, and striking hypercalciuria and phosphaturia. Insulin treatment corrected the hypercalcemia and markedly reduced the calciuria (P < 0.001), but had no significant effect on the urinary phosphate levels. Circulating immunoreactive parathyroid hormone (iPTH) was detectable in only 6% of untreated diabetic animals compared to 30% of controls. Furthermore, in untreated diabetic animals, the circulating levels of iPTH, when detectable, approximated the lower limits of the assay. The urinary cAMP levels of untreated diabetic animals were markedly decreased. Both iPTH and urinary cAMP approximated control levels in insulin-treated rats. Conversely, plasma immunoreactive calcitonin was increased in the diabetic rats compared to control animals (P < 0.001) and was partially corrected by insulin treatment (P < 0.05). Plasma corticosterone was elevated 10-fold in the untreated diabetic rats and was not significantly influenced by insulin therapy.The bone histology of the diabetic animals reflected the biochemical changes. Parameters of skeletal turnover, notably the quantity of nonmineralized bone matrix, reflecting boneforming sites (P < 0.01), and the numbers of osteoclasts (P < 0.025), were significantly diminished in the diabetic animal. Furthermore, diabetic vertebrae failed to assume a tetracycline label. Biochemical parameters of bone turnover, namely skeletal alkaline phosphatase activity and urinary hydroxyproline excretion, were likewise decreased. Untreated diabetes resulted in growth arrest, as evidenced by a significant reduction (P < 0.005) in the width of the epiphyseal growth plate. Insulin therapy in these chronically diabetic rats resulted in the normalization of all histometric parameters of skeletal turnover and growth.We conclude that prolonged streptozotocin-induced diabetes mellitus in the rat results in reduced bone turnover and growth arrest, which are completely corrected by insulin therapy. Whether this response to therapy reflects a direct insulin effect on skeletal tissue or results from the associated correction of mineral derangements and decreased PTH secretion which characterize the chronic experimental diabetic state remains to be resolved. (Endocrinology 108: 2228, 1981) T HE COEXISTENCE of diabetes meUitus and altered bone and mineral metabolism has been established by a number of investigators both in diabetic patients and in animals with experimentally induced insulin deficiency syndromes (1-5). However, the pathogenesis of these alterations, their natural evolution, and their response to therapy remain ill defined. Earlier clinical studies implicated poor metabolic control, ketoacidosis, and nutritional deprivation (1), but recent reports indicate that skeletal derangements in diabetes are not

Vitamin A toxicity has been associated with alterations in mineral metabolism and may result in osteopenia, fractures, deformities, and growth arrest. The pathogenesis of the bone lesions that occur in vitamin A toxicity is, however, ill defined and was examined in the present study. The administration of pharmacological doses of vitamin A to growing male rats resulted in weakness and spontaneous fractures. Undecalcified bone histology of vitamin A toxic animals was characterized by increased bone resorption, osteoclastosis, a paucity of trabecular surfaces covered with osteoid, and lesions which appear to be pathognomonic of hypervitaminosis A. The serum calcium and magnesium levels of vitamin A-toxic animals were unremarkable, but serum phosphate levels were significantly higher than control values. Urinary hydroxyproline excretion reflected bone histology and was significantly increased in experimental rats. Circulating levels of the potent bone resorbers, PTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D, were, however, comparable in vitamin A-toxic and control animals, suggesting a possible direct effect of vitamin A on bone. Subsequently, the effects of vitamin A (retinol) on in vitro collagen synthesis (incorporation of [3H]proline into collagen) and bone resorption (45Ca release from bone) were examined using a fetal rat calvarial culture. Retinol added to the culture medium for 20-24 h in concentrations ranging from 0.5-10 micrograms/ml selectively inhibited collagen synthesis in a dose-dependent fashion. Higher concentrations of retinol were toxic and resulted in a general inhibition of protein synthesis. Bone resorption was stimulated by 0.5 and 2.5 micrograms/ml retinol. We conclude that vitamin A toxicity in rats causes bone lesions, the genesis of which can be explained, at least in part, by a direct effect of the vitamin on skeletal tissue.