Effect of Statins on Bone Mineral Density and Bone Histomorphometry in Rodents

Abstract

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...

Fluvastatin Increases Bone Mineral Density in Postmenopausal Women

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Balance, falls, and bone health: Role of exercise in reducing fracture risk after stroke

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