page_title: Discovery and development of bisphosphonates
section_title: Mechanism of action
hierarchical_section_title: Discovery and development of bisphosphonates / Mechanism of action
caption_attribution_description: English: The mevalonate pathway and the inhibition of the key branch-point enzyme FPPS.
context_page_description: Bisphosphonates are an important class of drugs originally introduced about half a century ago. They are used for the treatment of osteoporosis and other bone disorders that cause bone fragility and diseases where bone resorption is excessive. Osteoporosis is common in post-menopausal women and patients in corticosteroid treatment where biphosphonates have been proven a valuable treatment and also used successfully against Paget's disease, myeloma, bone metastases and hypercalcemia. Bisphosphonates reduce breakdown of bones by inhibiting osteoclasts, they have a long history of use and today there are a few different types of bisphosphonate drugs on the market around the world.
context_section_description: The mechanism of action of the bisphosphonates (BP's) has evolved as new generations of drugs have been developed. The function of the first generation bisphosphonates differs from the more recent nitrogen containing BP's but both are apparently internalised by endocytosis of a membrane-bound vesicle where the drug is most likely in a complex with Ca²⁺ ions. This does not concern other cells in the bone as this takes places by a selective uptake of osteoclasts.
  The common function which applies to all bisphosphonate drugs is a physicochemical interaction with the bone mineral to prevent the physical resorption of the bone by the osteoclasts. This is especially relevant at sites where bone remodelling is most active. The bisphosphonates have an intrinsic affinity for the calcium ions (hydroxyapatite) of the bone mineral just as the endogenous pyrophosphates. The difference lies in the non-hydrolysable carbon-phosphorus bond of the bisphosphonates which prevents their metabolism and at the same time ensure an effective absorption from the gastrointestinal tract.
  The primary inhibiting action of the first generation of bisphosphonates on osteoclasts is by inducing apoptosis. The mechanism of action is apparently by the formation of an ATP analogue or metabolite of the bisphosphonates like etidronic acid and clodronic acid. The ATP analogue accumulates in the cytosol of the osteoclast with a cytotoxic effect.
  The primary mechanism of action of the more developed nitrogen containing bisphosphonates is however by cellular effects on osteoclasts through inhibition of the mevalonate pathway and in particular the subsequent formation of isoprenoid lipids. The inhibition takes place at a key branch point in the pathway catalyzed by farnesyl pyrophosphate synthase (FPPS). Isoprenoid lipids are necessary for post-translational modifications of small GTP-binding regulatory proteins like Rac, Rho and Ras of the Ras superfamily. The function of osteoclasts depends on them for a variety of cellular processes like apoptosis.
caption: Bisphosphonates inhibit the enzyme FPPS of the mevalonate pathway and prevent the biosynthesis of isoprenoid lipids and eventually the post-translational modifications of osteoclasts.