Re: Statin-induced bone morphogenetic protein (BMP) 2 expression during bone regeneration: an immunohistochemical study

In their recent article, Alam et al.1 compared the osteoinductive activity of statin/atelocollagen sponge (ACS) implants and recombinant human bone morphogenetic protein 2 (rhBMP-2)/ACS implants in an immunohistochemical study. Because locally applied statins (specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the production of cholesterol) were discovered to be potent stimulators of bone formation by inducing BMP-2,2 these compounds were used as practical bone anabolic agents in different studies by several researchers, including us.3, 4

Alam et al.1 used pravastatin, which is a member of the statin family as an anabolic agent. They showed the osteoinductive activity of statin/ACS implants but couldn't observe new bone formation clearly. Statins differ in their lipophilicity/hydrophilicity, which reflects their potential to cross cellular membranes and their potency.5 Lipophilic statins, such as simvastatin, easily cross the cellular membrane to enter cells, but hydrophilic statins, such as pravastatin, rely on specific carrier mechanisms for entry into cells. In 2000, Sugiyama et al.6 reported that compactin and simvastatin, but not pravastatin, selectively induced human BMP-2 promoter activity, and they associated this result to pravastatin's structure. I think this statement also explains why Alam et al.1 could not see new bone formation clearly at the fourth week. Further investigations are needed to confirm the effect of pravastatin on regeneration of hard tissue defects in vivo.

Alam et al.1 determined no findings suggestive of inflammation at 10 mg local pravastatin application. I think this dose is very high for local statin application. It is known that local high-dose statin application causes considerable soft tissue inflammation.7 Stein et al.8 applied a single dose of 0.1, 0.5, 1.0, 1.5, or 2.2 mg simvastatin in methylcellulose gel on the lateral aspect of the mandible and determined that reducing simvastatin dose from 2.2 mg to 0.5 mg reduced inflammation to a more clinically acceptable level without sacrificing bone-growth potential. Lee et al.9 also confirmed that 0.5 mg statin produced the best bone growth/inflammation ratio. Pravastatin's related inflammatory reactions also need further investigations.

In the discussion section, Alam et al.1 wrote that Wong and Rabie10 reported newly formed bone observed after implantation of 10 mg simvastatin in rabbit bone defect. Wong and Rabie10 prepared a simvastatin solution at the concentration of 2.5 mg/mL by using a 10 mg simvastatin tablet and then used 0.2 mL from this solution to prepare the statin/collagen implant. I think the dose used in the Wong and Rabie's work was misunderstood.

In addition to their cholesterol-lowering activity, statins have pleiotropic effects, including antiinflammatory effect.11, 12 Although statins have antiinflammatory effects, local high-dose statin application causes considerable inflammation. This conflict needs clarification to prevent future clinical problems.