Clodronate

• Published in: Bone (New York, N.Y.) N.Y.), 2021-02, Vol.143, p.115715, Article 115715
• Main Authors: McCloskey, Eugene, Paterson, Alexander H., Powles, Trevor, Kanis, John A.
• Format: Article
• Language: English
• Subjects: ATP; Breast cancer; Clodronate; Macrophage-depletion; Multiple myeloma; Osteoporosis; Paget's disease
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2020.115715

Two early observations about the first generation bisphosphonate, clodronate, suggested that it would likely have clinical utility; specifically, it was a more potent anti-resorptive but a less potent inhibitor of mineralisation than its predecessor etidronate. The known mechanism of action differs from that of the later nitrogen-containing bisphosphonates, as clodronate is metabolised intracellularly to a toxic analog of adenosine triphosphate, AppCCl2p, which causes mitochondrial dysfunction, impaired cellular energy metabolism and osteoclast apoptosis. For pre-clinical studies in a variety of disease models, liposomal clodronate has become the agent of choice for macrophage depletion, for example in a recent study to enhance haematopoietic chimerism and donor-specific skin allograft tolerance in a mouse model. For clinical use, clodronate was developed in oral and injectable formulations; while poorly absorbed from the gastro-intestinal tract, its absorption at 1–3% of the administered dose is approximately three-fold higher than for nitrogen-containing bisphosphonates. Following an early setback due to an erroneous association with toxic adverse events, a number of successful clinical studies have established clodronate, predominantly in its oral formulations, as a highly successful treatment in Paget's disease, hypercalcaemia (benign and malignant), multiple myeloma, and early or metastatic breast cancer. Novel uses in other disease areas, including veterinary use, continue to be explored. •Clodronate, the most widely used non-nitrogen bisphosphonate, continues in clinical use 50 years after its development•The mechanism of action differs from nitrogen-containing bisphosphonates•It is tolerated at high oral doses with a good safety profile•It is effective in reducing skeletal complications of early and late cancer, and in the reduction of osteoporotic fractures•Its use in other areas, including veterinary medicine, continues to be explored and developed.