## 4 Discussion
Comparisons between treatments of individual administration of alendronate or simvastatin and their combination showed that alendronate had a major increasing effect on peri-implant bone area (BA%) in the osteopororotic bone conditions. In healthy bone conditions, this effect was not observed; here, all treatments enhanced peri-implant BA% compared to saline controls. These findings in healthy bone conditions corroborate those reported by others, which demonstrated improvement of the peri-implant bone formation upon daily systemic treatment with BPs [30; 38]. On the other hand, no additive effect of the combined treatment was observed. In addition, in our study the effect of simvastatin in osteopororotic bone conditions was less. [PERSON] et al. [39] performed a systematic review of the efficacy of statin treatment for osteoporosis and its efficacy toward fracture rates and bone mineral density (BMD) in osteopororotic patients in clinical studies. Their meta-analysis indicated that statins decrease fracture risk and increase BMD, but this effect was more significant in male over female patients. We used female rats in our work, which can explain the lesser efficacy of simvastatin treatment. Further, it has to be emphasized that no difference in BA% was observed for saline controls in osteopororotic and healthy bone conditions. We assume that this is due to the rather short implantation time and the implant shape used. All rats were euthanized three weeks after implant installation. Bone healing after creation of the implant bed starts with blood clot formation and an inflammatory response. Subsequently, callus tissue is deposited, which remodels into lamellar bone. Bone remodeling is associated with a decrease in bone amount, as bone trabeculae become thinner and intertrabecular voids increase in size. The start of bone formation and remodeling in rats is usually completed within three weeks [40]. In the current study, skeletally mature female rats with an age of three months were used to mimic elderly females, which inherently have slower bone formation rates compared to young rats. Apparently, bone remodeling was not completed yet three weeks after implant installation and resulted in similar BA% for the osteopororotic and healthy rats without pharmacological treatment. This effect could have even been enhanced by the implant design used. The implants in the current study had a cylindrical shape without screw threads and were placed press-fit in the implant bed, which had the same diameter as the implant. In clinical practice, threaded dental implants are used, which are installed in the bone using an undersized surgical technique. It has been shown that the implant installation technique has a significant effect on bone formation around implants [41; 42]. Our data showed that treatment with anti-osteoporotic drugs (alendronate, simvastatin or their combination) did not affect bone-to-implant contact (BIC) levels, which were comparable for osteopororotic and healthy bone conditions. It has to be noted that published data are inconsistent regarding the BIC% outcomes. Some studies have shown a significant increase in BIC% level related to BP therapy, whereas others have not. For instant, [PERSON] et al. [38] showed that daily subcutaneous treatment with 25 ug/kg body weight ibandronate for 28 days improved bone-to-implant contact of uncoated titanium implants. In contrast, [PERSON] et al. [30] found that the systemic administration of alendronate resulted in BIC% levels comparable to the non-treated controls. Further, [PERSON] et al. [43], assessed BIC% in ovariectomized (OVX) and sham-operated rats assigned to daily subcutaneous injections of either saline or ibandronate (1 or 25 ug/kg body weight) and found no difference between experimental groups. These inconsistent observations can be partly explained by differences in the experimental design, type of drugs, administration route, dose, and evaluation periods. [PERSON] et al.