Statins and osteoporosis: new role for old drugs

Abstract

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.

Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk

“…Expression of this gene is also modulated by the peroxisome proliferator-activated receptor (PPAR)-g2 transcription factor that has been shown to interfere with age-related bone loss via the activation of adipogenic and suppression of osteogenic programs of mesenchymal stem cells (31). Our results strengthen the putative connection between bone and lipid metabolism (32)(33)(34); however, further studies are needed to clarify the role of FABP3 and its genetic variations in the pathomechanism of bone loss.…”

Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway

“…Additional evidence that statins may have an antiresorptive effect has been shown by Woo et al (2000) using an in vitro assay for osteoclast formation (Takahashi et al 1988), suggesting that statins also exert inhibitory effects on the differentiation of osteoclasts by interfering with the fusion process by which osteoclast precursors develop into multinucleated osteoclast-like cells. Many clinical studies have suggested that statin use is associated with a reduced risk of bone fractures; however, only a modest increase in bone mass and inconsistent effects on bone turnover have been reported to date (Bauer 2003, Jadhav & Jain 2006. Given that !5% of an oral dose statin reaches the systemic circulation (Bellosta et al 2000), osteoblasts and osteoclasts are exposed to very low concentrations of statin with usual oral regimens.…”

Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species

“…Recently, it has been reported that simvastatin also has an effect on bone metabolism. Simvastatin has been found to increase bone formation (Mundy et al, 1999;Staal et al, 2003;Jadhav and Jain, 2006) by promoting osteoblast differentiation and mineralization (Maeda et al, 2001). Simvastatin may also inhibit the RANKL-induced NF-κB activation pathway that leads to suppression of osteoclastogenesis (Ahn et al, 2008) and inhibits induction of matrix metalloproteinase-9 which is related to bone resorption (Kim et al, 2009).…”