Bisphosphonates actions

Oral bisphosphonates are poorly absorbed (less than 5%). Taking them in the presence of food or calcium supplementation further reduces absorption. After absorption, bisphosphonate uptake to the primary site of action is rapid and sustained. Once attached to bone tissue, bisphosphonates are released very slowly. These drugs are not metabolized and are excreted renally. They are not recommended for use in patients with renal insufficiency. 

Pamidronate and zoledronic acid are used most commonly and are potent inhibitors of osteoclast activity.29 The choice of bisphosphonate is a difficult one zoledronic acid is more efficacious in terms of response rate and longer duration of nor-mocalcemia but is approximately four times more expensive.30 Regardless of selection, the bisphosphonates should be administered at diagnosis owing to their delayed onset of action. 

Rodan GA. Mechanisms of action of bisphosphonates. Annu Rev Pharmacol Toxicol 1998 38 375-388. 

When diet and exercise have not been adequate to maintain good bone mineral density, the bisphosphonates are frequently prescribed. These molecules are actually incorporated into bone where they inhibit the action of osteoclasts. The biochemical consequence is an improvement in bone mineral density over time and the clinical consequence is a lessened frequency of bone fractures. 

Pharmacology Bisphosphonates act primarily on bone. Their major pharmacologic action is the inhibition of normal and abnormal bone resorption. There is no evidence that the bisphosphonates are metabolized. 

The bisphosphonates are all analogues of pyrophosphate. They inhibit osteoclast resorption of bone and they are able to inhibit the formation and dissolution of hydroxyapatite crystals, however their exact mechanism is not well understood. Other effects which have relevance for bone homeostasis include inhibition of the activities of PTH, prostaglandins and 1,25-dihydroxy vitamin D. Bisphosphonates bind to bone with high affinity. They have therefore a duration of action that continues long after their use has been stopped. 

Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley FP et al. Bisphosphonates an update on mechanisms of action and how these relate to clinical efficacy. Ann NY Acad Sci 2007 117 209-57. 

The bisphosphonates are synthetic organic compounds that are incorporated directly into the hydroxyapatite of bone and then inhibit osteoclastic bone resorption. This antiresorptive action makes them useful in the pharmacological treatment of hypercalcemia, osteoporosis, and Paget s disease. 

The bisphosphonates inhibit osteoclastic resorption of bone by binding to the hydroxyapatite crystals of bone. When osteoclasts first attach to bone in the active resorp-tive sites, the bisphosphonates are released from that bone. The release of these compounds locally prevents further osteoclastic attachment to those resorptive surfaces. The bisphosphonates also may inhibit resorption by inducing apoptosis of osteoclasts and by inhibiting release of interleukins and other compounds involved in bone resorption. The net result of actions of these compounds is inhibition of bone osteoclastic resorption. This action allows new bone formation to catch up in the remodeling process and can result in a net gain in bone density. 

Mechanism of Action A bisphosphonate that inhibits normal and abnormal bone resorption, without retarding mineralization. Therapeutic Effect Leads to significantly increased bone mineral density reverses the progression of osteoporosis. Pharmacokinetics Poorly absorbed after oral administration. Protein binding 78%. After oral administration, rapidly taken into bone, with uptake greatest at sites of active bone turnover. Excreted in urine. Terminal half-life Greater than lOyr (reflects release from skeleton as bone is resorbed). 

Mechanism of Action A bisphosphonate that inhibits the resorption of mineralized bone and cartilage inhibits increased osteoclastic activity and skeletal calcium release induced by stimulatory factors produced by tumors. Therapeutic Effect Increases urinary calcium and phosphorus excretion decreases serum calcium and phosphorus levels. 

The story of bisphosphonates (BPs) is typical for the development of drugs in the semi-rational era, when actions were based on seemingly logical assumptions. Although the actions luckily led to eventual success, the initial assumptions turned out to be greatly oversimplified, if not incorrect. 

Contrary to the original assumption which linked the inhibition of bone resorption solely to physico-chemical adsorption of the BP onto the bone surface, there is new evidence indicating cellular mechanisms of BP action, although a prerequisite of the biological activity is still the adsorption. The bisphosphonates deposited on the bone surface poison the bone-resorbing osteoclasts after being internalized by them. 

The benzothiophene derivative raloxifene (Evista /Lilly) is a selective estrogen receptor modulator (SERM). Raloxifene produces its biological actions via modulation (both activation and blockade) of estrogen receptors that ultimately results in decreased resorption of bone. The bisphosphonate derivative alendronate (Fosamax /Merck), an inhibitor of osteoclast-mediated bone resorption, is also useful in the treatment of osteoporosis. Both raloxifene and alendronate are useful in the treatment of osteoporosis in postmenopausal women. 

Roelofs, A.J., Thompson, K., Gordon, S., and Rogers, M.J. (2006). Molecular mechanisms of action of bisphosphonates current status. Clin Cancer Res 12 6222s-6230s. 

Cromartie, T.H., Fisher, K.J., and Grossman, J.N. (1999). The discovery of a novel site of action for herbicidal bisphosphonates. Pestic Biochem Physiol 63 114—126. 

Actions. These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces in vivo, where they can be released by bone-resorbing osteoclasts, resulting in inhibition of osteoclast function and osteoclast apoptosis. The bisphosphonates (alendronate, clodronate, etidronate, pamidronate, risedronate, tiludronate and zoledronate) inhibit the activation and function of osteoclasts and possibly directly stimulate formation of bone by the osteoblasts. They also bind strongly to hydroxyapatite crystals and, in high doses, can inhibit the mineralisation of bone. The doses at which effects on mineralisation occur are not related to antiresorptive efficacy. There is wide variation between these compoimds in terms of their capacity to inhibit... 

Pamidronate in the disodium form, a second-generation bisphosphonate, has an intermediate antiresorptive activity its continuous administration produces rapid suppression of bone resorption. Unlike etidronate, it does not impair bone mineralization at therapeutic dosages in patients with Paget s disease. Pamidronate inhibits osteoclast activity primarily by binding with hydroxyapatite crystals in the bone matrix, preventing the attachment of osteoclast precursor cells. Other mechanisms of action of matrix-bound pamidronate may include direct... 

Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des2003 9 2643-2658. Silverman SL, Maricic M. Recent developments in bisphosphonate therapy. Semin Arthritis Rheum 2007 37 1-12. 

L.l. Plotkin, T. Bellido, Bisphosphonate-induced, hemichannel-mediated, anti-apoptosis through the Src/ ERK pathway a gap junction-independent action of conncxin43, Cell Commun Adhes 8, 377-382 (2001). 

Russell RG, Watts NB, Ebetino FH et al (2008) Mechanisms of action of bisphosphonates similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19 733-759... 

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