Bisphosphonate: Wikis

  

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In pharmacology, bisphosphonates (also called diphosphonates) are a class of drugs that prevent the loss of bone mass, used to treat osteoporosis and similar diseases.

Bone has constant turnover, and is kept in balance (homeostasis) by osteoblasts creating bone and osteoclasts digesting bone. Bisphosphonates inhibit the digestion of bone by osteoclasts.

Osteoclasts also have constant turnover and normally destroy themselves by apoptosis, a form of cell suicide. Bisphosphonates encourage osteoclasts to undergo apoptosis.[1]

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 and other conditions that feature bone fragility.

Contents

History

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.[2]

Chemistry and classes

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

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

The two PO3 (phosphonate) groups covalently linked to carbon determine both the name "bisphosphonate" and the function of the drugs.

The long side-chain (R2 in the diagram) determines the chemical properties, the mode of action and the strength of bisphosphonate drugs. The short side-chain (R1), often called the 'hook', mainly influences chemical properties and pharmacokinetics.

Pharmacokinetics

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

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

Bisphosphonate-based drugs' specificity comes from the two phosphonate groups (and possibly a hydroxyl at R1) that work together to coordinate calcium ions. Bisphophonate 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 breaks 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

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.[3]

Nitrogenous

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).[4]

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).[5]

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 are thus 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 osteoporosis remains controversial.

Uses

Bisphosphonates are used clinically for the treatment of osteoporosis, osteitis deformans (Paget's disease of the bone), bone metastasis (with or without hypercalcaemia), multiple myeloma, and other conditions that feature bone fragility.

In osteoporosis and Paget's, alendronate and risedronate are the most popular first-line drugs. If these are ineffective or the patient develops digestive tract problems, intravenous pamidronate may be used. As an alternative, strontium ranelate or teriparatide is used for refractory disease, and the SERM raloxifene is occasionally administered in postmenopausal women instead of bisphosphonates.

High-potency intravenous bisphosphonates have shown to modify progression of skeletal metastasis in several forms of cancer, especially breast cancer. In a randomized control trial, women with breast cancer that received zoledronic acid had a 36% reduction of risk for a recurrence of their breast cancer, a new cancer in the opposite breast, or metastasis to bone compared to women that did not receive that therapy.[6]

Other bisphosphonates, medronate (R1, R2 = H) and oxidronate (R1 = H, R2 = OH) are mixed with radioactive technetium and are injected for imaging bone and detecting bone disease.

Bisphosphonates are used on the International Space station by crew members on long-duration missions.

More recently, bisphosphonates have been used to reduce fracture rates in children with osteogenesis imperfecta[7] and in treatment of otosclerosis.[8]

Side-effects

  • 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.
  • There is a slightly increased risk for electrolyte disturbances, but not enough to warrant regular monitoring.
  • In chronic renal failure, the drugs are excreted much more slowly, and dose adjustment is required.
  • Bisphosphonates have been associated with osteonecrosis of the jaw; 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).[9]
  • A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes[10]
  • Recent studies have reported bisphosphonate use (specifically zoledronate and alendronate) as a risk factor for atrial fibrillation in women.[11][12][13 ] The inflammatory response to bisphosphonates or fluctuations in calcium blood levels have been suggested as possible mechanisms.[12] One study estimated that 3% of atrial fibrillation cases might have been due to alendronate use.[12] Until now however, the benefits of bisphosphonates generally outweigh this possible risk, although care needs to 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).[12] FDA has not yet confirmed a causal relationship between bisphosphonates and atrial fibrillation.[14][15]
  • Matrix metalloproteinase 2 may be a candidate gene for bisphosphonate-associated osteonecrosis of the jaws, since it is the only gene known to be associated with bone abnormalities and atrial fibrillation, both of which are side-effects of bisphosphonates. [16]
  • There are concerns that long-term bisphosphonate use can result in severe or over-suppression of bone turnover especially at the femur sub-trochanteric region. It is thought 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.[17]

Footnotes

  1. ^ Weinstein RS, Robertson PK, Manolagas SC, Giant osteoclast formation and long-term oral bisphosphonate therapy, N Engl J Med 2009;360:53-62
  2. ^ Fleisch H (2002). "Development of bisphosphonates". Breast Cancer Res 4 (1): 30–4. doi:10.1186/bcr414. PMID 11879557.  
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ Gnat, Michael, et al. (February 2009), "Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer," New England Journal of Medicine, 360:679-691
  7. ^ Shapiro JR, Sponsellor PD (December 2009). "Osteogenesis imperfecta: questions and answers". Curr. Opin. Pediatr. 21 (6): 709–16. doi:10.1097/MOP.0b013e328332c68f. PMID 19907330.  
  8. ^ Brookler K (2008). "Medical treatment of otosclerosis: rationale for use of bisphosphonates". Int Tinnitus J 14 (2): 92–6. PMID 19205157.  
  9. ^ Woo S, Hellstein J, Kalmar J (2006). "Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws". Ann Intern Med 144 (10): 753–61. PMID 16702591.  
  10. ^ 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.  
  11. ^ Black DM, Delmas PD, Eastell R, et al. (May 2007). "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis" ( – Scholar search). N. Engl. J. Med. 356 (18): 1809–22. doi:10.1056/NEJMoa067312. PMID 17476007. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17476007&promo=ONFLNS19.  
  12. ^ 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. http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=18443257.  
  13. ^ 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.  
  14. ^ "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. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070303.htm. Retrieved 2009-07-15.  
  15. ^ "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. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070303.htm. Retrieved 2009-07-15.  
  16. ^ Lehrer S, André Montazem, Lakshmi Ramanathan, Melissa Pessin-Minsley, John Pfail, Richard G. Stock, Rita Kogan. Bisphosphonate-Induced Osteonecrosis of the Jaws, Bone Markers, and a Hypothesized Candidate Gene. J Oral Maxillofacial Surgery 2009; 67(1):159-161 [1]
  17. ^ Lenart BA, Lorich DG, Lane JM. Atypical Fractures of the Femoral Diaphysis in Postmenopausal Women Taking Alendronate. N Engl J Med 358:1304, March 20, 2008 Correspondence.

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