Bisphosphonates Pharmacology and Use in the Treatment of Osteoporosis

Bisphosphonates are analogs of naturally occurring compounds, pyrophosphates (P–O–P). P–O–P are byproducts of adenosine triphosphate (ATP) metabolism but have little or no biological activity in healthy individuals because they undergo rapid enzymatic degradation by ubiquitous pyrophosphatases (e.g., acid phosphatase and alkaline phosphatase) (the exception is hypophosphatasia, a condition leading to buildup of pyrophosphates due to lack of alkaline phosphatase). The substitution of a carbon atom in place of oxygen makes the molecule a bisphosphonate (P–C–P) . Bisphosphonates have a high affinity for bone and are not metabolized. Bisphosphonate that does not bind to bone is rapidly excreted in the urine unchanged. Renal excretion is accomplished by glomerular filtration as well as proximal tubular secretion, so that the clearance of bisphosphonates exceeds the clearance of inulin [an accurate measure of glomerular filtration rate (GFR)]. Because bisphosphonates are not metabolized, they also have no effect on the pharmacokinetics (PK) of other drugs. Thus modification of dosing of other medications (e.g., warfarin) is not required when a bisphosphonate is added….