The mechanism of action of the bisphosphonates (BPs) has evolved as new generations of drugs have been developed. The function of the first generation bisphosphonates differs from the more recent nitrogen containing BPs but both are apparently internalised by endocytosis of a membrane-bound vesicle where the drug is most likely in a complex with Ca ions. This does not concern other cells in the bone as this takes place 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.