McCloskey, Eugene, Paterson, Alexander H., Powles, Trevor and Kanis, John A.. (2021). Clodronate. Bone. 143, p. 115715. https://doi.org/10.1016/j.bone.2020.115715
|Authors||McCloskey, Eugene, Paterson, Alexander H., Powles, Trevor and Kanis, John A.|
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.
|Keywords||clodronate; ATP; macrophage-depletion; paget’s disease; multiple myeloma; breast cancer; osteoporosis|
|Journal citation||143, p. 115715|
|Digital Object Identifier (DOI)||https://doi.org/10.1016/j.bone.2020.115715|
|Research or scholarly||Research|
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|Online||27 Oct 2020|
|Publication process dates|
|Accepted||26 Oct 2020|
|Deposited||25 Aug 2021|
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