how bisphosphonates are taken and why they work for osteoporosis
The oral nitrogenous bisphosphonates are analogs of pyrophosphate, so they avidly bind to bone. They have very poor intestinal absorption (<1%) that is further inhibited by the presence of food or medications in the gastrointestinal (GI) tract. Their major side effect is esophageal and GI pain. In order to maximize intestinal absorption and minimize GI toxicity, they should be taken first thing each morning on an empty stomach with a full glass of water. The patient should then remain upright and take nothing by mouth for at least 30 to 60 minutes after medication ingestion. The absorbed bisphosphonate goes through the bloodstream and binds to bone with a terminal half-life in bone of up to 10 years. Approximately 50% to 60% of a dose does not bind to bone and is excreted unchanged in the urine. There are no drug interactions. Some of the bisphosphonate adsorbed to bone is ingested by the osteoclast during bone remodeling. The bisphosphonate acts on the osteoclast by binding and blocking the intracellular enzyme, farnesyl diphosphate synthase (FPPS), in the HMG CoA-reductase pathway (also known as the mevalonate pathway). Disruption of this pathway at the level of FPPS prevents the formation of two metabolites that are essential for connecting some small proteins (Ras, Rho, Rac) to the cell membrane, a process known as prenylation, which is important for proper subcellular protein trafficking. This interferes with lipid modification of the osteoclast cell membrane/cytoskeleton that is needed for maintaining the “ruffled border.” This leads to osteoclast apoptosis, causing significantly reduced bone resorption without directly affecting bone formation. Consequently, bone formation temporarily exceeds resorption and bone mass increases. After about 24 months, bone formation declines to the level of resorption and bone mass stabilizes. Over this time, bone mass increases 4% to 8% in the spine and 3% to 6% in the hip. This is accompanied by a 33% to 68% relative risk reduction for incident vertebral fractures and a 40% to 50% reduction in hip fractures (not with ibandronate) depending upon the bisphosphonate that is studied. Zoledronic acid may be the most effective due to its antiresorptive potency, IV administration, and compliance.