## 1 Introduction
For the preparation of these compounds, metal ions, such as Ca\({}^{2+}\), Mg\({}^{2+}\), Zn\({}^{2+}\), Fe\({}^{2+/3+}\), etc., in specific doses were utilized. Three isotypical coordination complexes with the general chemical formula {[M\({}_{2}\)(H\({}_{4}\)ALE)\({}_{4}\)(H\({}_{2}\)O)\({}_{2}\)]:1.5H\({}_{2}\)O] were fabricated by the combination of the drug ALE with various amounts of Mg\({}^{2+}\), Ca\({}^{2+}\), or Sr\({}^{2+}\) cations. The  
Figure 1: Schematic structures of inorganic pyrophosphate (PPi, **left**) and geminal bisphosphonate (BP, **right**), in their fully deprotonated forms. therapeutic action of these compounds was found to be dependent on the long release period and also on the contribution of the released metal ions in order to improve the osteoblast metabolic activity [10]. Mg\({}^{2+}\)- and Ca\({}^{2+}\)-containing complexes and coordination polymers of various structural motifs were synthesized with four BP drugs (etidronate, pamidronate, alendronate and meridonate) [11]. They were studied as CDSs based on the premise that the metal-O(phosphonate) coordination bond can undergo hydrolysis due to the low pH, which will induce the controlled release of the active BP drug. These were coined \"self-sacrificial MOFs\". The coordination of the BP drug by the metal ions resulted in substantially reduced initial release rates and lower final % release compared to the respective control system (with \"free\" drug and no metals). These compounds do not exhibit higher cytotoxicity than the \"free\" drug in the NIH3T3 mouse embryonic cell line [11]. RIS (commercial name Actonel) is a 3 rd generation BP drug, which exhibits an affinity constant \(K_{\text{app}}=21.9\pm 1.7\times 10^{5}\) M\({}^{-1}\) for hydroxyapatite. This value is higher than those of the 2 nd generation BPs, but lower than those of the other 3 rd generation BPs [12]. The binding affinity influences drug absorption and retention by the bone skeleton, the release of the absorbed drug and also the half-life of its attachment on the bone surface. These features affect its osteoclast inhibition potency. RIS was approved in 1998 for the treatment of several bone-related disorders (e.g., postmenopausal, corticosteroid-induced osteoporosis). Recently, we initiated a systematic multi-approach study of metal-containing coordination polymers in which the linker is a BP drug. The scope of this study includes the reliable and reproducible synthesis of such metal-BP systems, their full structural elucidation, and, most importantly, their ability to act as \"self-sacrificial\" sources of the BP drug. In this work, the 3 rd generation anti-osteoporotic drug RIS was used for the synthesis of two new coordination polymers, namely [Ca(RIS)(H\({}_{2}\)O)]\({}_{\text{n}}\) (Ca-RIS) and [Sr(RIS)(H\({}_{2}\)O)]\({}_{\text{n}}\) (Sr-RIS). These two novel compounds were physicochemically and structurally characterized and were also evaluated for their RIS release features under acidic conditions (pH = 1.3) that mimic the human stomach. Importantly, it was observed that RIS shows low solubility under acidic conditions. Hence, in order to fully and reliably study the drug release profiles of \"free\" RIS, Ca-RIS and Sr-RIS, it was necessary to utilize two cationic drug solubility enhancers, namely, a linear polyethyleneimine polymer (LPEI) and an amine-terminated polyaminoamide dendrimer (PAMAM-2). To the best of our knowledge, this is the first systematic controlled release study of the RIS drug.