<unk> s are structurally similar to pyrophosphate, but with a central carbon that can have up to two substituents (R1 and R2) instead of an oxygen atom. Because a<unk>  group mimics the structure of pyrophosphate, it can inhibit activation of enzymes that utilize pyrophosphate. The specificity of<unk> -based drugs comes from the two phosphonate groups (and possibly a hydroxyl at R1) that work together to coordinate calcium ions.<unk>  molecules preferentially bind to calcium ions. The largest store of calcium in the human body is in bones, so<unk> s accumulate to a high concentration only in bones.<unk> s, when attached to bone tissue, are released by osteoclasts, the bone cells that break down bone tissue.<unk>  molecules then attach to and enter osteoclasts where they disrupt intracellular enzymatic functions needed for bone resorption. There are two classes of<unk>  compounds: non-nitrogenous (no nitrogen in R2) and nitrogenous (R2 contains nitrogen). The two types of<unk> s work differently in killing osteoclasts. Class Name R1 R2 Relative potency(vs Etidronate=1) Etidronate (Didronel) OH CH3 1 Clodronate (Bonefos, Loron) Cl Cl 10 Tiludronate (Skelid) H p-Chlorophenylthio 10 Pamidronate (APD, Aredia) OH (CH2)2NH2 100 Neridronate (Nerixia) OH (CH2)5NH2 100 Olpadronate OH (CH2)2N(CH3)2 500 Alendronate (Fosamax) OH (CH2)3NH2 500 Ibandronate (Boniva - US, Bonviva - Asia) OH (CH2)2N(CH3)(CH2)4CH3 1000 Risedronate (Actonel) OH 3-Pyridylmethyl 2000 Zoledronate (Zometa, Aclasta) OH 1H-imidazol-1-ylmethyl 10000 Non-nitrogenous The non-nitrogenous<unk> s (diphosphonates) are metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a non-functional molecule that competes with adenosine triphosphate (ATP) in the cellular energy metabolism. The osteoclast initiates apoptosis and dies, leading to an overall decrease in the breakdown of bone. This type of<unk>  has overall more negative effects than the nitrogen containing group, and is prescribed far less often. Nitrogenous Nitrogenous<unk> s act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS) in the HMG-CoA reductase pathway (also known as the mevalonate pathway).<unk> s that contain isoprene chains at the R1 or R2 position can impart specificity for inhibition of GGPS1. HMG-CoA reductase pathway Disruption of the HMG CoA-reductase pathway at the level of FPPS prevents the formation of two metabolites (farnesol and geranylgeraniol) that are essential for connecting some small proteins to the cell membrane. This phenomenon is known as prenylation, and is important for proper sub-cellular protein trafficking (see "lipid-anchored protein" for the principles of this phenomenon). While inhibition of protein prenylation may affect many proteins found in an osteoclast, disruption to the lipid modification of Ras, Rho, Rac proteins has been speculated to underlie the effects of<unk> s. These proteins can affect both osteoclastogenesis, cell survival, and cytoskeletal dynamics. In particular, the cytoskeleton is vital for maintaining the "ruffled border" that is required for contact between a resorbing osteoclast and a bone surface. Statins are another class of drugs that inhibit the HMG-CoA reductase pathway. Unlike<unk> s, statins do not bind to bone surfaces with high affinity, and thus are not specific for bone. Nevertheless, some studies have reported a decreased rate of fracture (an indicator of osteoporosis) and/or an increased bone mineral density in statin users. The overall efficacy of statins in the treatment of osteoporosis remains controversial.
Bisphosphonate
Phosphate binder
Pamidronic acid
Etidronic acid
Sulfonylurea
Allopurinol
Risedronic acid
Alendronic acid