gms | German Medical Science

Objectives: Delayed and failed bone healing remains a major burden in orthopedic and trauma surgery. Segmental bone defects caused by high-energy trauma, infections and tumor are particularly associated with a high rate of non-union formation. Non-unions are considered to be the result of an avascular and biologically inert environment. Hence, new treatment approaches need to stimulate angiogenesis to improve the process of bone regeneration.

Cilostazol, a phosphodiesterase 3-inhibitor, has demonstrated pro-angiogenic as well as pro-ostoegenic effects in vitro and in vivo. Therefore, we investigated wether Cilostazol stimulates bone formation and improves bone repair in a critical size defect model in mice.

Methods: In 12–14 weeks old CD-1 mice a 1.8 mm femoral segmental defect was created and stabilized with a custom-made pin-clip device. The animals were treated with a daily dose of mg/kg body weight p.o., controls received equal amounts of saline. Two, 5 and 10 weeks after surgery, the process of bone regeneration was analyzed by X-ray, biomechanics, photoacoustic imaging,µ-CT, histology, immunhistochemistry and Western blot analysis.

Results and conclusion: Cilostazol-treated animals showed a significantly increased bending stiffness at 10 weeks after surgery. This was associated with an enhanced oxygen saturation within the callus tissue as well as increased amount of high mineralized bone tissue when compared to controls. Moreover, the histological analysis revealed a higher number of TRAP positive osteoclasts at 5 and 10 weeks after surgery. Further immunohistochemical analysis demonstrated a higher number of CD-31 positive microvessels within the callus tissue of Cilostazol-treated animals at 10 weeks after surgery.

Further biochemical analysis by Western blotting showed a significantly increased expression of VEGF in Cilostazol-treated mice when compared to controls.

These findings indicate that Cilostazol stimulates angiogenesis and bone regeneration by enhancing the expression of the pro-angiogenic marker VEGF, inducing micro vessel formation, increasing the oxygen saturation within the callus tissue, and thus, stimulating bone formation in critical size bone defects. Therefore, Cilostazol may be a promising compound in the treatment of non-union formation in clinical practice.