Statins and bones

Mundy and colleagues7 were the first to report that incubation of cultured mouse or human bone cells with statins enhanced the expression of bone morphogenetic protein-2 (BMP-2) mRNA. Incubation with 2.5 pmol simvastatin increased the production of the protein by 2.7 times in human bone cells. BMP-2 is an important mediator in osteoblast differentiation and bone formation. In subsequent experiments, Mundy and coworkers added various statins to neonatal mouse calvarial bones in organ culture. Each statin that was tested increased new bone formation by approximately 2-3 times. They confirmed these results in vivo in mice: a course of 3 subcutaneous injections per day over 5 days over the calvaria produced an increase of about 50% in new bone formation. Similarly, 35-day oral administration of simvastatin (5-50 mg/kg per day by gastric gavage) to both intact and ovariectomized rats resulted in increases of 39%-94% in trabecular bone volume.7A parallel increase in bone formation rates was noted, indicating significant anabolic effects of the statin treatment. These anabolic effects were associated with a decrease in osteoclast numbers.7 These provocative experimental findings paved the way for observational studies of the association between statin use and quality of bone in both men and women.-2 At least 20% of women older than 50 years suffer from osteoporosis; bone fractures due to osteoporosis occur in approximately 1.5 million individuals in the United States annually.13 Several pharmacological interventions are currently used to modulate the rate of bone remodelling in osteoporosis.14-18 The concept of bone remodelling and current interventions are summarized in Fig. 1. Among therapeutic agents, both nitrogen-containing bisphosphonates (N-BPs) and statins interfere with the mevalonate cholesterol biosynthesis pathway, albeit at 2 different points. In addition, N-BPs can directly induce apoptosis of osteoclasts through a number of intracellular mechanisms,19 whereas statins, as previously discussed, induce an increase in expression of BMP-2 mRNA and protein.7,20 Thus, as well as inhibiting the mevalonate pathway, statins and NBPs may produce dual benefits in the prevention of bone fracture by stimulation of bone formation and inhibition of bone resorption.7,19-22 In conclusion, several observational studies indicate that statins reduce the risk of bone fracture. This significant unanticipated effect appears to be independent of cholesterol lowering, becau