In athletes with similar training habits, those with stress fractures are more likely to have lower bone density, lower dietary calcium intake, current menstrual irregularity, and lower oral contraceptive use.

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

Abstract-Statins have been postulated to affect bone metabolism. We investigated the effects of different doses of simvastatin (1,5,10, and 20 mg · kg Ϫ1 · d Ϫ1 ), atorvastatin (2.5 mg · kg Ϫ1 · d Ϫ1 ), and pravastatin (10 mg · kg Ϫ1 · d Ϫ1 ) administered orally for 12 weeks to intact female Sprague-Dawley rats and the effect of 20 mg · kg Ϫ1 · d Ϫ1 simvastatin in sham-operated and ovariectomized rats on femoral bone mineral density (BMD) and quantitative bone histomorphometry (QBH) and compared them with controls. BMD was decreased by 1 mg · kg Ϫ1 · d Ϫ1 simvastatin (Pϭ0.042), atorvastatin (Pϭ0.0002), and pravastatin (Pϭ0.002). The effect on QBH parameters differed with different doses of simvastatin (ANOVA, Pϭ0.00012). QBH parameters of both bone formation and resorption were equivalently and markedly increased by 20 mg · kg Ϫ1 · d Ϫ1 simvastatin in 2 separate groups of intact rats and were reflected by a relatively unchanged BMD. At lower doses, 1 mg · kg Ϫ1 · d Ϫ1 simvastatin decreased bone formation while increasing bone resorption, as reflected by a marked decrease in BMD. Ovariectomized animals receiving 20 mg · kg Ϫ1 · d Ϫ1 simvastatin showed no change in BMD relative to the untreated, ovariectomized controls; their increase in bone formation was smaller than in sham-operated rats receiving simvastatin, and there was no change in bone resorption. Dose-response curves of simvastatin for bone formation and resorption differed. These studies indicate that (1) statins decrease BMD in rodents, (2) high-dose simvastatin increases bone formation and resorption, (3) low-dose simvastatin decreases bone formation and increases bone resorption, (4) the effects of simvastatin on QBH differ at different dosages, (5) the effects of simvastatin seen in intact rats are not observed in ovariectomized rats, and (6) Key Words: atorvastatin Ⅲ bone histomorphometry Ⅲ bone mineral density Ⅲ pravastatin Ⅲ simvastatin T he hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are widely used in the treatment of dyslipidemia in an age group that has an increased prevalence of osteoporosis. The statins, apart from reducing the intracellular cholesterol pool, also reduce other products of the mevalonate pathway, including the isoprenoids farnesyl diphosphate and geranylgeranyl diphosphate. Farnesyl diphosphate and geranylgeranyl diphosphate are attached to the carboxy terminal of numerous monomeric, small GTP-binding proteins to form cytosolic prenylated proteins. Prenylation is furthermore essential for the membrane localization and function of these prenylated proteins, including Rac and Rho. 1 Rac and Rho are pivotal in mediating the cytoskeletal changes initiated by growth factors and integrins, leading to membrane ruffling, the formation of lamellipodia and stress fibers, and resulting in the activation of polarized and motile cells, including macrophages and osteoclasts. 2,3 Alendronate, a nitrogen-containing bisphosphonate used in the treatment of osteoporosis, inhibits prenylation and thereby inhibits the osteoc...

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.

To assess the relationship between the decreased bone mass observed in young insulin-requiring diabetic patients and vitamin D metabolism, we measured serum 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D concentration in 45 white, insulin-dependent diabetic subjects, 7-18 yr of age. Metacarpal cortical thickness in 87% of these diabetics was below the mean for their respective ages, while 16% had a cortical thickness value greater than 2 sDs below the mean. Serum calcium and phosphate concentrations were normal, immunoreactive parathyroid hormone was in the low normal range, and total serum alkaline phosphatase was elevated compared to age- and sex-matched controls. Circulating 24,25-dihydroxyvitamin D concentrations were significantly elevated, and 1,25-dihydroxyvitamin D was significantly decreased. The increase in 24,25-dihydroxyvitamin D was greater in the diabetics with the most severe bone loss and was maximally increased during the first 5 yr of clinical diabetes. No apparent correlation was seen between metabolic control, as measured by hemoglobin A1C and urine and plasma glucose, and the circulating levels of the vitamin D metabolites. Despite appropriate insulin replacement, alterations in vitamin D metabolism occur in the young insulin-dependent diabetic and could relate to the decrease in cortical bone mass observed in these patients.

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BackgroundDespite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown.MethodsIn this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants.ResultsAmong 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%–45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008).ConclusionsThe prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.

Calcium homeostasis was studied in freely fed control, streptozotocin diabetic, long-term and short-term insulin-treated diabetic rats 7 wk after the induction of diabetes. In contrast to the short-term (5-12 day) diabetic rat model, intestinal absorption of calcium was markedly enhanced in chronically insulin-deficient animals. Moreover, conventional balance studies showed that these animals were in positive calcium balance despite severe hypercalciuria. Intestinal hyperabsorption of calcium in long-standing diabetic rats occurred despite low levels of circulating 1,25-dihydroxyvitamin D and hypercorticosteronism and was attended by hypercalcemia and suppression of both plasma parathyroid hormone (PTH) and urinary cyclic 3',5'-AMP (cAMP). Long-term insulin replacement completely normalized the intestinal hyperabsorption of calcium, corrected the plasma calcium, and significantly increased circulating PTH and urinary cAMP excretion. Insulin therapy also corrected the decreased plasma 1,25-dihydroxyvitamin D observed in untreated diabetic animals. Intestinal hyperabsorption of calcium appeared to be only partially corrected by short-term insulin therapy. The accumulated results reveal decided differences in calcium homeostasis and hormonal response between the rats with long-standing diabetes and those with diabetes of short duration.