## 1 Introduction  
Loss of teeth (i.e., edentulism) is regarded as a major health problem in dentistry [1; 2]. Consequently, titanium implants have become the treatment of choice for replacing missing teeth [3]. Contemporary titanium implant therapy in healthy patients has resulted in significant long-term success following treatment [4]. However, complications related to the healing process of titanium implants may occur in patients with systemic impaired bone metabolism and turnover, e.g., osteoporosis [5]. This is a major systemic condition affecting bone physiology and might lead to increased risk of implant failure [6; 7; 8]. In the past, several approaches have been used to enhance titanium implant success in patients with impaired bone condition [9]. For instance, different surgical techniques, such as the undersized drilling technique and osteotome, have been used to improve the primary stability of titanium implants in low-quality bone. Further, titanium implant design has been changed to enhance initial implant stability and surface modifications have been applied to stimulate osseointegration [10; 11]. These implant surface treatments aim to stimulate bone formation at the implant surface (i.e., contact osteogenesis) [11; 12], including implant surface roughness at the nano-level or the deposition of calcium-phosphate coatings. However, such surface modifications do not offer a beneficial effect on bone formation at a distance up to 1 mm (i.e., distance osteogenesis) from the implant surface [13; 14]. In principle, both contact and distance osteogenesis are needed to promote the osseointegration of titanium implants. In view of this, one suggested method is to provide the implant surface with bioactive molecules, like growth factors, but the reported data are not consistent [11; 15]. In addition, safety issues hamper the application of growth factors [16]. Therefore, the use of bone-targeting agents and drugs, which do not trigger a toxic or adverse side effect and have a confirmed beneficial effect on bone formation, has been proposed [17]. As a consequence, therapeutic pharmacological agents are used that are already widely applied for the treatment of bone disorders like osteoporosis. The additional advantage of such pharmacological agents (e.g., bisophosphonates and statins) is that they are not limited to applications for improving peri-implant bone formation in impaired bone conditions, but can also be used in healthy patients with bone of poor quality, i.e., very trabecular, spongy bone [10; 18; 19; 20]. The principle of treatment with bisophosphonates and statins is based on their systemic or local administration [10]. Bisphosphonate drugs (BPs) exhibit a potent anti-resorptive effect on bone through inhibition of osteoclasts and have been postulated to enhance bone healing through reduction of undesirable bone remodeling around titanium implants [21]. However, BPs might be less able to control bone metabolism compared to anabolic agents (e.g., statins, parathyroid hormone), which are capable of osteoblastic stimulation [10]. Therefore, anabolic and anti-resorptive therapies have been used individually or in combination to treat patients with osteoporotic bone conditions [21; 22]. It is alluring to hypothesize that the administration of a combination of anti-resorptive BPs and anabolic statins has a synergistic effect on peri-implant healing [23; 24; 25; 26]. In view of this, it has to be noticed that anabolic and anti-resorptive pharmacological agents have been evaluated in several studies [13; 18; 19; 23; 24; 27; 28] for their effects on bone implant osseointegration. However, there is a lack of evidence as to whether combined administration of anabolic and anti-resorptive pharmacological agents at the time of implant placement has a synergistic effect on the peri-implant bone responses and implant osseointegration.