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...

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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.

The high prevalence of diabetes supports early postpartum oral glucose tolerance testing. Several women had undiagnosed diabetes. The risk factors identified could be useful for prenatal risk stratification.