## 2 Materials and Methods
### Synthetic Protocols  
**Synthesis of sodium hydrogen (1-hydroxy-1-phosphono-2-(pyridin-3-yl)ethyl) phosphonate (sodium risedronate pentahemih hydrate, Na-RIS-2.5H\({}_{2}\)O). ** The sodium salt of RIS was prepared by following a previously reported methodology, but with some modifications [18]. A mixture of 3-pyridineacetic acid hydrochloride (30 g, 0.17 mol), phosphorous acid (14.2 g, 0.17 mol), and methanesulfonic acid (60 mL) was heated to 65-70 \({}^{\circ}\)C followed by the addition of PCI\({}_{3}\) (30.2 mL, 47.5 g, 0.35 mol, 2.0 eq) for over 0.5-1 h under nitrogen atmosphere. After the PCI\({}_{3}\) addition, the mixture was stirred overnight at 65-70 \({}^{\circ}\)C, and cold distilled water (200 mL) was added to a cooled solution with vigorous stirring. After refluxing overnight, the reaction mixture was allowed to cool to room temperature and pH adjusted to 4-4.5 by 50% NaOH. Then, 200 mL of EtOH was added by stirring and the mixture was left overnight at ambient temperature. The formed solid was collected by filtration, washed with 50% EtOH and finally with acetone, and dried under reduced pressure. The final product (Na-RIS-2.5H\({}_{2}\)O) was obtained as a white powder (45.5 g, 86% yield). \({}^{1}\)H NMR (D\({}_{2}\)O): 8.75-8.72 (m, 1H), 8.59-8.55 (m, 2H), 7.94-7.90 (m, 1H), 3.45 (t, 2H, \({}^{3}\)\({}_{\rm{HP}}\) = 12.1). \({}^{13}\)C NMR (D\({}_{2}\)O, CD\({}_{3}\)OD as ref.) \(\&\) 150.1, 143.3, 139.4, 139.1 (t, \({}^{3}\)\({}_{\rm{CP}}\) = 9.0), 126.9, 74.5 (t \({}^{1}\)\({}_{\rm{CP}}\) = 134.2, P-C)- 37.0 \({}^{31}\)P NMR (D\({}_{2}\)O) \(\&\) 17.0. **Hydrothermal synthesis of Ca-RIS. ** Na-RIS-2.5H\({}_{2}\)O (9 mg, 0.025 mmol) and CaCl\({}_{2}\cdot\)2H\({}_{2}\)O (2 mg, 0.0125 mmol) were dissolved in 3.25 mL H\({}_{2}\)O. The solution pH was adjusted to 2.5 (using stock solutions of NaOH and HCl, as needed). The final mixture was placed in a Teflon-lined reactor and was heated at 120 \({}^{\circ}\)C for 3 days. After cooling at room temperature, colorless crystals formed and were isolated by filtration. Bulk product purity was confirmed by powder X-ray diffraction (comparison of the calculated and experimental powder patterns) and elemental analyses. Yield: 2 mg (47%). The synthesis of Ca-RIS was also repeated at a Ca:RIS molar ratio of 1:1. The same product was obtained, albeit at lower yields (26%). Elemental analysis: Calcd. for {Ca[(C\({}_{5}\)H\({}_{4}\)NH)CH\({}_{2}\)C(OH)(PO\({}_{3}\)H)(PO\({}_{3}\))](H\({}_{2}\)O)\({}_{\rm{In}}\), M.W. 339.19: C 24.79; H 3.27; N 4.13. Found: C 24.94; H 3.40; N 4.10. **Hydrothermal synthesis of Sr-RIS. ** Na-RIS-2.5H\({}_{2}\)O (35 mg, 0.10 mmol) and SrCl\({}_{2}\cdot\)6H\({}_{2}\)O (13 mg, 0.05 mmol) were dissolved in 3.25 mL H\({}_{2}\)O. The solution pH was adjusted to 2.5 (using stock solutions of NaOH and HCl, as needed). The final solution was placed in a Teflon-lined reactor and was heated at 120 \({}^{\circ}\)C for 3 days. After cooling at room temperature, colorless crystals formed and were isolated by filtration. Bulk product purity was confirmed by powder X-ray diffraction (comparison of the calculated and experimental patterns) and elemental analyses. Yield: 4 mg (21%). The synthesis of Sr-RIS was also repeated at a Sr:RIS molar ratio of 1:1. The same product was obtained, albeit at lower yields (5%). Elemental analysis: Calcd. for [Sr[(C\({}_{5}\)H\({}_{4}\)NH)CH\({}_{2}\)C(OH)(PO\({}_{3}\)H)(PO\({}_{3}\))](H\({}_{2}\)O)]\({}_{\rm In}\), M.W. 386.73: C 21.74; H 2.87; N 3.62. Found: C 21.73; H 2.96; N 3.54. **Scaled-up synthesis of Ca-RIS. ** Na-RIS:2.5H\({}_{2}\)O (175 mg, 0.50 mmol) was dissolved in 65 mL H\({}_{2}\)O, and the pH of the solution was adjusted to 2.5 (using stock solution of HCL, as needed). Subsequently, CaCl\({}_{2}\):2H\({}_{2}\)O (73 mg, 0.50 mmol) was added to that solution under stirring. The final mixture was placed in a flask and heated at 80 \({}^{\circ}\)C under stirring for 3 days. A white microcrystalline powder precipitated, which was isolated by filtration and washed with deionized water.