Bisphosphonate

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Basic structure of a bisphosphonate on top. To compare the structure of pyrophosphate below. Note the similarity in structure.

Bisphosphonates (also called diphosphonates) are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis.[1] They are called bisphosphonates because they have two phosphonate (PO
3
) groups and are similar in structure to pyrophosphate.

Evidence shows that they reduce the risk of osteoporotic fracture in those who have had previous fractures.[2][3]

Bone undergoes constant turnover and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts destroying bone. Bisphosphonates inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis, or cell death, thereby slowing bone loss.[4]

The uses of bisphosphonates include the prevention and treatment of osteoporosis, osteitis deformans ("Paget's disease of bone"), bone metastasis (with or without hypercalcaemia), multiple myeloma, primary hyperparathyroidism, osteogenesis imperfecta, fibrous dysplasia, and other conditions that feature bone fragility.

Medical uses[edit]

Most physicians use bisphosphonates to treat osteoporosis, osteitis deformans (Paget's disease of the bone), bone metastasis (with or without hypercalcaemia), multiple myeloma, and other conditions involving fragile, breakable bone. In osteoporosis and Paget's, the most popular first-line bisphosphonate drugs are alendronate (Merck) and risedronate. If these are ineffective or if the patient develops digestive tract problems, intravenous pamidronate (Novartis) may be used. Strontium ranelate (protelos, Servier) or teriparatide (Eli Lilly) are used for refractory disease. The use of strontiumranelate is restricted because of increased risk of venous thromboembolism, pulmonary embolism and serious cardiovascular disorders, including myocardial infarction.[5] In postmenopausal women, the selective estrogen receptor modulator raloxifene is occasionally administered instead of bisphosphonates.

Other bisphosphonates, including medronate (R
1
=H, R
2
=H) and oxidronate (R
1
=H, R
2
=OH), are mixed with radioactive technetium and injected, as a way to image bone and detect bone disease. Bisphosphonates have been used to reduce fracture rates in children with the disease osteogenesis imperfecta,[6] to treat otosclerosis.,[7] and by crew members on long-duration missions on the International Space Station[citation needed] to minimize bone loss.

Efficacy[edit]

For prevention of fractures three Cochrane reviews came to the conclusion that there was no important decrease in hip fracture for those without previous osteoporotic fractures and a small reduction in hip fracture for those with previous osteoporotic fractures.[8][9][10] Another review did not find benefit in those who have not had a previous vertebral fracture.[11]

Adverse effects[edit]

Common[edit]

Oral bisphosphonates can cause upset stomach and inflammation and erosions of the esophagus, which is the main problem of oral N-containing preparations. This can be prevented by remaining seated upright for 30 to 60 minutes after taking the medication. Intravenous bisphosphonates can give fever and flu-like symptoms after the first infusion, which is thought to occur because of their potential to activate human γδ T cells. These symptoms do not recur with subsequent infusions.[citation needed]

Bisphosphonates, when administered intravenously for the treatment of cancer, have been associated with osteonecrosis of the jaw (ONJ), with the mandible twice as frequently affected as the maxilla and most cases occurring following high-dose intravenous administration used for some cancer patients. Some 60% of cases are preceded by a dental surgical procedure (that involve the bone), and it has been suggested that bisphosphonate treatment should be postponed until after any dental work to eliminate potential sites of infection (the use of antibiotics may otherwise be indicated prior to any surgery).[12]

A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes[13] Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaw, since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side-effects of bisphosphonates.[14]

Recent studies have reported bisphosphonate use (specifically zoledronate and alendronate) as a risk factor for atrial fibrillation in women.[15][16][17] The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms.[16] One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use.[16] Until now, however, the benefits of bisphosphonates, in general, outweigh this risk, although care must be taken in certain populations at high risk of serious adverse effects from atrial fibrillation (such as patients with heart failure, coronary artery disease, or diabetes).[16] FDA has not yet confirmed a causal relationship between bisphosphonates and atrial fibrillation.[18][19]

Long-term risks[edit]

In large studies, women taking bisphosphonates for osteoporosis have had unusual fractures ("bisphosphonate fractures") in the femur (thigh bone) in the shaft (diaphysis or sub-trochanteric region) of the bone, rather than at the head of the bone, which is the most common site of fracture. However, these unusual fractures are extremely rare (12 in 14,195 women) compared to the common hip fractures (272 in 14,195 women), and the overall reduction in hip fractures caused by bisphosphonate far outweighed the unusual shaft fractures.[20] There are concerns that long-term bisphosphonate use can result in over-suppression of bone turnover. It is hypothesized that micro-cracks in the bone are unable to heal and eventually unite and propagate, resulting in atypical fractures. Such fractures tend to heal poorly and often require some form of bone stimulation, for example bone grafting as a secondary procedure. This complication is not common, and the benefit of overall fracture reduction still holds.[20][21] In cases where there is concern of such fractures occurring, teriparatide is potentially a good alternative due to it reducing damage caused by suppression of bone turnover.[22]

A 2010 study suggests that the risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over about a five-year period. In Europe and North America, the incidence of oesophageal cancer at age 60–79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years' use of oral bisphosphonates.[23] There have been conflicting findings from studies evaluating the risk of esophageal cancer. Esophagitis and other esophageal events have been reported, particularly in patients who do not follow the specific directions for use of oral bisphosphonates.[24]

Chemistry and classes[edit]

All bisphosphonate drugs share a common P-C-P "backbone":

The two PO
3
(phosphonate) groups covalently linked to carbon determine both the name "bisphosphonate" and the function of the drugs. Bis refers to the fact that there are two such groups in the molecule.

The long side-chain (R
2
in the diagram) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side-chain (R
1
), often called the 'hook', mainly influences chemical properties and pharmacokinetics.

Pharmacokinetics[edit]

Of the bisphosphonate that is resorbed (from oral preparation) or infused (for intravenous drugs), about 50% is excreted unchanged by the kidney. The remainder has a very high affinity for bone tissue, and is rapidly adsorbed onto the bone surface.

Mechanism of action[edit]

Bisphosphonates' mechanisms of action all stem from their structures' similarity to pyrophosphate (see figure above). A bisphosphonate group mimics pyrophosphate's structure, thereby inhibiting activation of enzymes that utilize pyrophosphate.

Bisphosphonate-based drugs' specificity comes from the two phosphonate groups (and possibly a hydroxyl at R
1
) that work together to coordinate calcium ions. Bisphosphonate molecules preferentially "stick" to calcium and bind to it. The largest store of calcium in the human body is in bones, so bisphosphonates accumulate to a high concentration only in bones.

Bisphosphonates, when attached to bone tissue, are "ingested" by osteoclasts, the bone cells that break down bone tissue.

There are two classes of bisphosphonate: the N-containing and non-N-containing bisphosphonates. The two types of bisphosphonates work differently in killing osteoclast cells.

side chains of bisphosphonate molecules

Non-nitrogenous[edit]

Non-N-containing bisphosphonates:

The non-nitrogenous bisphosphonates(disphosphonates) are metabolised in the cell to compounds that replace the terminal pyrophosphate moiety of ATP, forming a nonfunctional 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.[25]

Nitrogenous[edit]

N-containing bisphosphonates:

Nitrogenous bisphosphonates 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).[27]

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).[28]

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 bisphosphonates. 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 bisphosphonates, 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.[29]

History[edit]

Bisphosphonates were developed in the 19th century but were first investigated in the 1960s for use in disorders of bone metabolism. Their non-medical use was to soften water in irrigation systems used in orange groves. The initial rationale for their use in humans was their potential in preventing the dissolution of hydroxylapatite, the principal bone mineral, thus arresting bone loss. Only in the 1990s was their actual mechanism of action demonstrated with the initial launch of Fosamax (alendronate) by Merck & Co..[30]

Footnotes[edit]

  1. ^ National Osteoporosis Society. "Drug Treatment". U.K. National Osteoporosis Society. Retrieved 7 August 2012. 
  2. ^ Wells G, Cranney A, Peterson J, et al. (2008). "Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD004523. doi:10.1002/14651858.CD004523.pub3. PMID 18254053. 
  3. ^ Wells GA, Cranney A, Peterson J, et al. (2008). "Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women". Cochrane Database of Systematic Reviews (1): CD001155. doi:10.1002/14651858.CD001155.pub2. PMID 18253985. 
  4. ^ Weinstein RS, Roberson PK, Manolagas SC (January 2009). "Giant osteoclast formation and long-term oral bisphosphonate therapy". N. Engl. J. Med. 360 (1): 53–62. doi:10.1056/NEJMoa0802633. PMC 2866022. PMID 19118304. 
  5. ^ "Strontium ranelate: cardiovascular risk—restricted indication and new monitoring requirements Article date: March 2014". MHRA. 
  6. ^ Shapiro JR, Sponsellor PD (December 2009). "Osteogenesis imperfecta: questions and answers". Current Opinion in Pediatrics 21 (6): 709–16. doi:10.1097/MOP.0b013e328332c68f. PMID 19907330. 
  7. ^ Brookler K (2008). "Medical treatment of otosclerosis: rationale for use of bisphosphonates". Int Tinnitus J 14 (2): 92–6. PMID 19205157. 
  8. ^ Wells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD001155. doi:10.1002/14651858.CD001155.pub2. PMID 18253985. 
  9. ^ Wells, GA; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD003376. doi:10.1002/14651858.CD003376.pub3. PMID 18254018. 
  10. ^ Wells, G; Cranney, A; Peterson, J; Boucher, M; Shea, B; Robinson, V; Coyle, D; Tugwell, P (Jan 23, 2008). "Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.". The Cochrane database of systematic reviews (1): CD004523. doi:10.1002/14651858.CD004523.pub3. PMID 18254053. 
  11. ^ "A Systematic Review of the Efficacy of Bisphosphonates Sep - Oct 2011". Therapeutics Letter. 
  12. ^ Woo S, Hellstein J, Kalmar J (2006). "Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws". Ann Intern Med 144 (10): 753–61. doi:10.7326/0003-4819-144-10-200605160-00009. PMID 16702591. 
  13. ^ Wysowski D, Chang J (2005). "Alendronate and risedronate: reports of severe bone, joint, and muscle pain". Arch Intern Med 165 (3): 346–7. doi:10.1001/archinte.165.3.346-b. PMID 15710802. 
  14. ^ Lehrer S, Montazem A, Ramanathan L, et al. (January 2009). "Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene". J. Oral Maxillofac. Surg. 67 (1): 159–61. doi:10.1016/j.joms.2008.09.015. PMID 19070762. 
  15. ^ Black DM, Delmas PD, Eastell R, et al. (May 2007). "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis". N. Engl. J. Med. 356 (18): 1809–22. doi:10.1056/NEJMoa067312. PMID 17476007. 
  16. ^ a b c d Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM (April 2008). "Use of alendronate and risk of incident atrial fibrillation in women". Arch. Intern. Med. 168 (8): 826–31. doi:10.1001/archinte.168.8.826. PMID 18443257. 
  17. ^ Cummings SR, Schwartz AV, Black DM (May 2007). "Alendronate and atrial fibrillation". N. Engl. J. Med. 356 (18): 1895–6. doi:10.1056/NEJMc076132. PMID 17476024. 
  18. ^ "Early Communication of an Ongoing Safety Review on Bisphosphonates: Alendronate (Fosamax, Fosamax Plus D), Etidronate (Didronel), Ibandronate (Boniva), Pamidronate (Aredia), Risedronate (Actonel, Actonel W/Calcium), Tiludronate (Skelid), and Zoledronic acid (Reclast, Zometa)". Postmarket Drug Safety Information for Patients and Providers. Food and Drug Administration (United States). 2007-10-01. Retrieved 2009-07-15. 
  19. ^ "Update of Safety Review Follow-up to the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates". Postmarket Drug Safety Information for Patients and Providers. Food and Drug Administration (United States). October 2008. Retrieved 2009-07-15. 
  20. ^ a b Shane E (May 2010). "Evolving data about subtrochanteric fractures and bisphosphonates". N. Engl. J. Med. 362 (19): 1825–7. doi:10.1056/NEJMe1003064. PMID 20335574. 
  21. ^ Lenart BA, Lorich DG, Lane JM (March 2008). "Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate". N. Engl. J. Med. 358 (12): 1304–6. doi:10.1056/NEJMc0707493. PMID 18354114. 
  22. ^ Arkan S Sayed-Noor; Bakir K Kadum; Göran O Sjödén (31 March 2010). "Bisphosphonate-induced femoral fragility fractures: What do we know?". Orthopedic Research and Reviews 2 (1): 27–34. doi:10.2147/ORRS7521. Retrieved 26 April 2012. 
  23. ^ Green, J.; Czanner, G.; Reeves, G.; Watson, J.; Wise, L.; Beral, V. (2010). "Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort". BMJ 341: c4444. doi:10.1136/bmj.c4444. PMC 2933354. PMID 20813820.  edit
  24. ^ http://www.drugs.com/fda/oral-osteoporosis-bisphosphonates-safety-communication-potential-increased-risk-esophageal-cancer-13003.html
  25. ^ Frith J, Mönkkönen J, Blackburn G, Russell R, Rogers M (1997). "Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro". J Bone Miner Res 12 (9): 1358–67. doi:10.1359/jbmr.1997.12.9.1358. PMID 9286751. 
  26. ^ (not sold in the United States)
  27. ^ van Beek E, Cohen L, Leroy I, Ebetino F, Löwik C, Papapoulos S (November 2003). "Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates". Bone 33 (5): 805–11. doi:10.1016/j.bone.2003.07.007. PMID 14623056. 
  28. ^ Van Beek E, Löwik C, van der Pluijm G, Papapoulos S (1999). "The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates". J Bone Miner Res 14 (5): 722–9. doi:10.1359/jbmr.1999.14.5.722. PMID 10320520. 
  29. ^ Uzzan, B; et al. (2007). "Effects of statins on bone mineral density: a meta-analysis of clinical studies". Bone 40 (6): 1581–7. doi:10.1016/j.bone.2007.02.019. PMID 17409043. Retrieved 2012-07-13. 
  30. ^ Fleisch H (2002). "Development of bisphosphonates". Breast Cancer Res 4 (1): 30–4. doi:10.1186/bcr414. PMC 138713. PMID 11879557. 

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