## 1 Introduction  
Bisphosphonates (BPs) have been used as drugs for anomalies of calcium metabolism and bone disorders for over 40 years [1]. Etidronate was the first bisphosphonate drug that was synthesized, and it has been administered in humans since the late 1970s. Bisphosphonates are chemically and enzymatically stable analogues of the inorganic pyrophosphate (PPi) and they present high affinity for hydroxyapatite (HAP), the principal natural mineral component of bone and teeth. The structural stability of BPs can be realized by replacing the bridging oxygen atom in PPi with a carbon atom (Figure 1). The hydrolysis-resistant P-C-P backbone and the high affinity for bone render BPs more efficient inhibitors of bone resorption than PPi [2]. Over 300 bisphosphonates were synthesized by modifying the R\({}_{1}\) and R\({}_{2}\) substituents of the geminal (P-C-P) bisphosphonate structure. Each bisphosphonate exhibits a different binding affinity for the mineral surface and biological activity. BPs can be distinguished based on their chemical structures and their biological activities. The non-nitrogen BPs constitute the 1 st generation, and they react with the aminoacyl-tRNA synthases, which integrates them with adenosine in order to form methylene-containing ATP analogues(AppCH\({}_{2}\)p). The cells accumulate the AppCH\({}_{2}\)p and it later causes their apoptosis. Nevertheless, they exhibit lower efficacy as inhibitors of osteoclasts. The 2 nd and 3 rd generations include nitrogen-containing BPs, which present higher anti-resorptive action because they are capable to inhibit the farnesyl pyrophosphate synthase (FPPS), an important enzyme of the mevalonate pathway. As a result, they produce a toxic metabolite, which could cause osteoclast apoptosis. The 3 rd generation drugs display different types of nitrogen-containing heterocyclic rings in their structures, and studies showed that they exhibit the most potent antiresorptive activity [3,4]. The BP drugs are administered orally, intravenously and, in some cases, via injection. Their bioavailability is very low, with only \(<\)6% (depending on the individual BP) of the dose being absorbed by the intestine, distributed via blood in the body and finally uptaken by the bones. For that reason, the therapeutic dosages should be increased in order to achieve effective patient treatment. These high doses induce several side effects, such as hypocalcemia, osteomyelitisitis, osteonecrosis of the lower jaw, \"flu\"-like symptoms, bone pain, and gastro-intestinal, ocular and renal side effects. [5]. In order to reduce these side effects, it is necessary to devise and construct new drug delivery systems (DDSs) that could be able, ideally, to release the drug in a predictable and controlled manner. Many different types of DDS containing BP drugs have been reported. Some examples follow. Titanium implants coated with calcium zeolite were used as controlled delivery systems (CDSs) for the drug risedronate (RIS). It was found that one year is needed for the release of 30% of the total drug quantity [6]. Biphasic calcium phosphate (BCP) scaffolds were loaded with the drug alendronate (ALE). The drug release notwithstanding, the osteogenic activity in MG-63 cells and mineralization in vivo based on a rat tibial defect model were evaluated. The drug release was dose dependent, and the ALE/BCP scaffolds operated as enhancers for bone formation [7]. Furthermore, BPs can act as organic ligands for, or linkers between, metal ions due to the presence of the anionic phosphonate groups. These display strong affinity for metal ions in aqueous solutions [8]. Metal-containing hybrid materials were constructed after the combination of BPs with biologically acceptable metal ions. Various biological applications of coordination compounds and metal organic frameworks (MOFs) have already been published [9]. Some have been evaluated for their controlled drug release features under different conditions that mimic the conditions in human body (e.g., the gastrointestinal tract).