HMG-CoA reductase inhibitors, also known as statins, are a ubiquitous class of medication used for lowering cholesterol. In-vitro and animal studies have suggested that statins can activate osteoblast differentiation and have anabolic effects on bones; however, observational and experimental studies in humans have shown conflicting results.1-5 The exact mechanism of statins on bone growth is unknown; however, there are several hypotheses. The “Lipid Hypothesis” (Figure 1) suggests that lipid oxidation leads to activation of PPARγ, and production of isoprostanes including isoPGF2α and isoPGEα. PPARγ is associated with inhibition of osteoblast differentiation, while isoprostanes markers are associated with the induction of osteoclast differentiation and inhibition of osteoblast differentiation. This led to the the hypothesis that statins can decrease lipid oxidation, which can inhibit the action of PPARγ and isoprostane-mediated bone loss.6 The “statins hypothesis” (Figure 2) suggests that the anabolic bone activity of statins is due to the induction of osteoblast differentiation, suppression of osteoblast apoptosis and inhibiting osteoclastogenesis. Statins inhibits HMG-CoA reductase, which decrease the productions of isoprenoids farnesyl pyrophosphate (FPP) and Geranylgeranyl pyrophosphate (GGPP). The decrease in FPP and GGPP leads to upregulation of bone morphogenetic protein-2 (BMP-2) downstream, stimulating bone formation by increasing mesenchymal condensation. Statins inhibit osteoblast apoptosis by upregulating TGFβ/Smad3 kinases signaling. It also decreases osteoclastogenesis by upregulating osteoprotegerin (OPG), a decoy receptor that binds to RANKL to inhibit osteoclast differentiation.6
Lam, InLok; Traina, Andrea; and Lull, Melinda E., "An Examination of the Effects of Atorvastatin and Parathyroid Hormone on Osteoblast Activity" (2014). Doctoral External Publications. Paper 6.
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