Dear Editors,

I read with great interest the article by Wang and colleagues [1].

This work shows that simvastatin markedly promotes fracture healing compared with a placebo. I would like to complete the discussion of Wang and coworkers [1] by introducing a major route through which simvastatin could promote healing.

Diminished bone formation during fracture healing is related to the premature resorption of callus associated with increased osteoclast activity. The osteoclastic cells, which cause impaired healing, are thought to be recruited from normal monocytic pre-osteoclasts by stromal cell expression of the ligand for receptor activator of nuclear factor kappaB (RANKL). RANKL is an osteoclastogenesis factor released by osteoblasts, stromal cells, and activated T cells. RANK is a receptor that is present on the cell membrane of osteoclasts, monocytes, and osteoblasts [2, 3]. Studies have shown the role of RANKL in delay union as evidenced by the inhibitory effect of osteoprotegerin (a decoy receptor of RANKL) on RANKL-mediated osteoclastogenesis [4, 5].

Fusion of the cell membrane of mononuclear pre-osteoclasts is a critical initial step in osteoclast maturation. Cholesterol in the membranes of monocytes is involved in the osteoclast-like cell formation via cellular membrane fusion events. The addition of native LDL cholesterol increases osteoclast viability by suppressing spontaneous apoptosis, while cholesterol removal strongly induces apoptosis in osteoclast. Moreover, cholesterol removal by HDL, apolipoprotein A1 (ApoA1) or methyl-β-cyclodextrin (MBCD) triggers induction of apoptosis and OCL death. Cholesterol in the cell membrane is derived from de novo synthesis via HMG-CoA reductase [6, 7].

Simvastatin (HMG-CoA reductase inhibitor) is a hypolipidemic drug belonging to the class of pharmaceuticals called statins. Also, data obtained in recent studies have demonstrated that simvastatin stimulate the OPG production by osteoblasts which can lead to a significant reduction in RANKL [8]. Therefore, these important mechanisms should be borne in mind as the major mechanisms for simvastatin-induced healing.