Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use

• Published in: Bone (New York, N.Y.) N.Y.), 2022-03, Vol.156, p.116289-116289, Article 116289
• Main Authors: Ebetino, Frank H., Sun, Shuting, Cherian, Philip, Roshandel, Sahar, Neighbors, Jeffrey D., Hu, Eric, Dunford, James E., Sedghizadeh, Parish P., McKenna, Charles E., Srinivasan, Venkat, Boeckman, Robert K., Russell, R. Graham G.
• Format: Article
• Language: English
• Subjects: Bisphosphonates; Bone Neoplasms - drug therapy; Bone resorption; Bone targeting; Diphosphonates - pharmacology; Diphosphonates - therapeutic use; Farnesyl diphosphate synthase (FDPS/FPPS); Humans; Hydroxyapatite; Mevalonic Acid - metabolism; Nitrogen; Osteoclasts; Structure-Activity Relationship
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2021.116289

The bisphosphonates ((HO)2P(O)CR1R2P(O)(OH)2, BPs) were first shown to inhibit bone resorption in the 1960s, but it was not until 30 years later that a detailed molecular understanding of the relationship between their varied chemical structures and biological activity was elucidated. In the 1990s and 2000s, several potent bisphosphonates containing nitrogen in their R2 side chains (N-BPs) were approved for clinical use including alendronate, risedronate, ibandronate, and zoledronate. These are now mostly generic drugs and remain the leading therapies for several major bone-related diseases, including osteoporosis and skeletal-related events associated with bone metastases. The early development of chemistry in this area was largely empirical and only a few common structural features related to strong binding to calcium phosphate were clear. Attempts to further develop structure-activity relationships to explain more dramatic pharmacological differences in vivo at first appeared inconclusive, and evidence for mechanisms underlying cellular effects on osteoclasts and macrophages only emerged after many years of research. The breakthrough came when the intracellular actions on the osteoclast were first shown for the simpler bisphosphonates, via the in vivo formation of P-C-P derivatives of ATP. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates in the 1980s and 1990s led to the key discovery that the antiresorptive effects of these more complex analogs on osteoclasts result mostly from their potency as inhibitors of the enzyme farnesyl diphosphate synthase (FDPS/FPPS). This key branch-point enzyme in the mevalonate pathway of cholesterol biosynthesis is important for the generation of isoprenoid lipids that are utilized for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Since then, it has become even more clear that the overall pharmacological effects of individual bisphosphonates on bone depend upon two key properties: the affinity for bone mineral and inhibitory effects on biochemical targets within bone cells, in particular FDPS. Detailed enzyme–ligand crystal structure analysis began in the early 2000s and advances in our understanding of the structure-activity relationships, based on interactions with this target within the mevalonate pathway and related enzymes in osteoclasts and other cells have continued to be the focus of research efforts to this day.