Impact of Single or Combined Drug Therapy on Bone Regeneration in Healthy and Osteoporotic Rats

Abstract

Complications in bone regeneration in patients with systemic impaired bone metabolism (e.g., osteoporosis) represent a rapidly increasing clinical challenge. Alendronate and simvastatin are drugs commonly used to promote bone metabolism in osteoporotic conditions. The aim of this study was to evaluate initial bone regeneration within osseous defects grafted with beta-tricalcium phosphate (β-TCP) in adjunction with systemic coadministrations of alendronate and simvastatin (i.e., daily subcutaneous injection for 3 weeks) in healthy and osteoporotic rats. Eighty Wistar female rats were ovariectomized (OVX; n = 40) or sham operated (n = 40). Six weeks later, osseous defects (a 3-mm critical-sized defect) were created in the left femoral condyles and then grafted with β-TCP. From the day following graft installation, OVX and sham animals received for 3 weeks a daily subcutaneous injection of alendronate (50 μg/kg of body weight) and simvastatin (5 mg/kg of body weight), alone or in combination. A control group was included, which received subcutaneous saline administration. At the end of the 3 weeks, rats were euthanized and specimens (femoral condyles) were retrieved for histological evaluation and histomorphometric measurements, that is, bone area (BA%) and remaining bone graft (RBG%). In osteoporotic rats, 3 weeks of daily subcutaneous injection of combined therapy (alendronate plus simvastatin) led to a significant (p < 0.05) increase in BA% and a significant decrease in RBG% compared to healthy controls in osseous defects grafted with β-TCP (BA%: 28.6 ± 12.0 vs. 18.2 ± 7.6, RBG% 61.3 ± 11.1 vs. 70.7 ± 7.3). No significant differences in BA% and RBG% were found in the OVX rats for single treatments. Furthermore, healthy controls showed similar BA% and RBG% upon single or combined therapy compared to nontreated control rats. Daily coinjections (for 3 weeks) of alendronate plus simvastatin result in a significant enhancement of bone regeneration within osseous defects grafted with β-TCP in osteoporotic rats. Despite the expected effects on osteoporotic bone, our study did not confirm the hypothesized benefit of alendronate and simvastatin on bone regeneration in osseous defects in healthy conditions. The efficacy of the combination drug therapy on bone regeneration demands further investigation to elucidate molecular and cellular aspects underlying this therapy.

Impact statement

Recently, increasing concerns have existed about the effect of bone diseases, such as osteoporosis, on bone regeneration. This study was to assess if antiosteoporotic single or combined drug therapy can promote bone regeneration in adjunction with bone grafting using preclinical animal models. Interestingly, the results suggest that combined therapy of alendronate plus simvastatin results in significantly increased bone regeneration within osseous defects grafted with beta-tricalcium phosphate in osteoporotic rats during a three-week healing period.