## 4 Discussion  
This study aimed to evaluate whether the systemic administration of alendronate, simvastatin, or their combination is capable to promote peri-implant bone responses in healthy and osteoporoori animal models. Results showed no effects of pharmacological treatment on biomechanical push-out testing, irrespective of bone condition. Further, similar histomorphometric bone area (BA%) results were observed for saline controls in osteopororotic and healthy bone conditions. In contrast, three weeks of daily subcutaneous administration of alendronate, simvastatin, or their combination led to a  
Figure 8: Bar-chart with mean and standard deviation, based on histomorphometric assessment, showing (**A**) bone area (BA%) and (**B**) bone-to-implant contact (BIC%) for the pooled data of the various drug treatment groups between osteopororotic and healthy conditions. (* indicates \(p<0.01\)). Figure 7: Bar-chart with mean and standard deviation, based on histomorphometric assessment, showing (**A**) bone area (BA%) and (**B**) bone-to-implant contact (BIC%) for all study groups. (* indicates \(p<0.05\)). significant increase (\(p<0.05\)) in BA% around titanium implants in osteopororotic as well as healthy bone conditions, compared to saline controls. In osteopororotic bone conditions, alendronate treatment was shown to significantly enhance BA% around implants compared to simvastatin or the combination of alendronate and simvastatin. Overall, the BA% after treatment with pharmacological agents was significantly higher in healthy compared to osteopororotic bone conditions. However, systemic treatment with alendronate, simvastatin, or their combination did not alter BIC% levels compared to saline controls in either osteopororotic and healthy bone conditions. In clinical practice, several anti-osteoporotic drugs are used for the treatment of osteoporosis [21]. Recommendations and guidelines for the use of anti-osteoporotic drugs are based on clinical evidence and trials [31]. Additionally, improving the treatment protocols, using powerful drugs, and selecting the optimal route of administration are necessary to control impaired bone metabolism in patients who suffer from osteoporosis. For example, various treatment options have been suggested, mostly comprising treatment with anti-osteoporotic drugs, such as BPs [32]. Pre-clinical studies have already been performed to study the effect of such treatments on peri-implant bone regeneration in both healthy and osteopororotic animal models [9; 18; 19; 33; 34; 35]. Despite existing evidence that single treatment with BPs or simvastatin can enhance bone formation around dental implants in healthy and osteopororotic animal models, only limited work has been dedicated toward the effect of combined administration of anti-resorptive and anabolic agents [22; 23; 24; 25; 36; 37]. In addition, there is a wide variation in the route of administration of such pharmacological agents, the timing in relation to osteoporosis induction and subsequent implant placement, as well as implantation time. Consequently, the current study was conducted as part of a consecutive series of studies focused on the effect of anti-resorptive agents on bone healing around dental implants in healthy and osteopororotic bone conditions [20]. The data of our study corroborate those from other studies, although minor differences are apparent. For the evaluation of the osseointegration of titanium implants, histomorphometric BA% and BIC% are the most traditional analytic methods to determine the amount of contact osteogenesis (0-500 \(\upmu\)m) and distance osteogenesis (500-1000 \(\upmu\)m), as previously defined and described [14]. Distance osteogenesis originates from the existing bone or from the blood of the bone marrow and periosteum. In relation to this, we hypothesized that systemic administration of anti-osteoporotic drugs (alendronate, simvastatin or their combination) treats the existing osteopororotic bone tissue surrounding titanium implants and triggers peri-implant bone formation.