Statins and bone remodeling

Effects of statins on bone remodeling were suggested by the finding that nitrogen-containing bisphosphonates exert their cytotoxic effects on osteoclasts by interfering with the mevalonate pathway, a step further downstream from the site of action of statins (62) (Fig. 2Go). Murine osteoclast formation in cultures was inhibited by both lovastatin and alendronate (a nitrogen-containing bisphosphonate). Furthermore, rabbit osteoclast formation and activity are also inhibited by lovastatin and by alendronate and reversed by mevalonate and geranylgeraniol, respectively (63). These findings suggest that statins, via their effects on osteoclasts, possibly inhibit bone resorption.

Statins were also shown to stimulate bone formation in several studies. In vitro, statins increase the number of osteoblasts and the amount of new bone formation in mouse skull bones (63). Similar effects were also seen in vivo when simvastatin or lovastatin was injected sc over the skull bone of mice. Furthermore, oral administration of simvastatin to rats increased trabecular bone volume and the rate of new bone formation (64). These findings were confirmed by further studies; for example, transdermal lovastatin (65) and cerivastatin were shown to increase bone mass in rodents at doses similar to the dose used in humans in the treatment of hypercholesterolemia (66). All of these findings illustrate positive effects of statins on bone remodeling in the form of inhibition of bone resorption and stimulation of bone formation. The question remains whether statins would emerge as a treatment for osteoporosis that could increase bone formation and reduce fractures. Several published studies, mostly observational, have evaluated the association of statin use and fracture risk (67, 68, 69, 70, 71); one reanalyzed data from a randomized controlled study (the LIPID trial) (72). These studies showed inconsistent results; for example, upon analysis of the General Practice Research Database, Meier et al. (6) reported a risk of hip fracture to be reduced almost by half among statin users (relative risk, 0.55; 95% confidence interval, 0.44–0.66). However, reanalysis of the General Practice Research Database using age- and gender-matched controls for each of the 218,062 patients with fractures showed no relationship between statin use and nonspine fractures (67). The adjusted relative risk for hip fracture among older women in this group was 0.80. This uncertainty regarding the effects of statins on fracture risk needs to be addressed in randomized controlled trials in the future. However, the exciting possibility of a newer generation of statin with a stronger affinity to bone, which could lower both CVD and fracture risks, remains to be seen.

Conclusion

In summary, accumulating evidence from basic research and clinical trials indicates that statins have pleiotropic effects that may largely account for the clinical benefits observed. These agents have been shown to stabilize unstable plaques, improve vascular relaxation, and promote new vessel formation. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. These actions are mediated, in part, by the effects on small G-proteins, modulation of signaling cascades, transcription, and gene expression. The clinical relevance of these effects is beginning to be recognized, and ongoing studies will be able to answer these many questions in the near future.