View source for Bisphosphonate

{{Short description|Pharmaceutical drugs for preventing bone loss}}
{{Distinguish|Biphosphate (disambiguation){{!}}Biphosphate}}
{{Redirect-distinguish|Diphosphonate|Diphosphate}}
[[File:Biphosphonate Structural Formulae.png|thumb|200x200px|The general chemical structure of bisphosphonate. The [[Substituent|R-group]]s determine the chemical properties of the drug, and distinguishes individual types of bisphosphonates. This chemical structure affords a high affinity for calcium hydroxyapatite, allowing for rapid and specific skeletal targeting.]]

'''Bisphosphonates''' are a class of drugs that prevent the loss of [[bone density]], used to treat [[osteoporosis]] and similar diseases. They are the most commonly prescribed to treat osteoporosis.<ref name="Nat Osteo Soc">{{cite web|last=National Osteoporosis Society|title=Drug Treatment|url=http://www.nos.org.uk/page.aspx?pid=264&srcid=234|publisher=U.K. National Osteoporosis Society|access-date=7 August 2012|archive-url=https://web.archive.org/web/20121106105018/http://www.nos.org.uk/page.aspx?pid=264&srcid=234|archive-date=6 November 2012|url-status=dead}}</ref>

Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis.<ref name="Eriksen EF, Díez-Pérez A, Boonen S 126–35">{{cite journal |vauthors=Eriksen EF, Díez-Pérez A, Boonen S |title=Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review |journal=Bone |volume=58 |pages=126–35 | date=January 2014|pmid=24120384 |doi=10.1016/j.bone.2013.09.023}}</ref><ref name="Serrano AJ, Begoña L, Anitua E, Cobos R, Orive G 1005–14">{{cite journal |vauthors=Serrano AJ, Begoña L, Anitua E, Cobos R, Orive G |title=Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis |journal=Gynecol. Endocrinol. |volume=29 |issue=12 |pages=1005–14 | date=December 2013|pmid=24063695 |doi=10.3109/09513590.2013.813468 |s2cid=20163452 }}</ref><ref name="gauthier">{{cite journal|last1=Gauthier|first1=K|last2=Bai|first2=A|last3=Perras|first3=C|last4=Cunningham|first4=J|last5=Ahuja|first5=T|last6=Richter|first6=T|last7=Kovacs|first7=C|title=Denosumab, Raloxifene, and Zoledronic Acid for the Treatment of Postmenopausal Osteoporosis: Clinical Effectiveness and Harms|journal=Rapid Response Report: Systematic Review|date=February 2012|pmid=24278999}}</ref><ref name=AACE2010/><ref name="Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY 23–57">{{cite journal |vauthors=Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY |title=European guidance for the diagnosis and management of osteoporosis in postmenopausal women |journal=Osteoporos Int |volume=24 |issue=1 |pages=23–57 | date=January 2013|pmid=23079689 |pmc=3587294 |doi=10.1007/s00198-012-2074-y }}</ref>

[[Bone tissue]] undergoes constant [[bone remodeling|remodeling]] 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.<ref>{{cite journal |vauthors=Weinstein RS, [[Paula Roberson|Roberson PK]], Manolagas SC |title=Giant osteoclast formation and long-term oral bisphosphonate therapy |journal=N. Engl. J. Med. |volume=360 |issue=1 |pages=53–62 |date=January 2009 |pmid=19118304 |pmc=2866022 |doi=10.1056/NEJMoa0802633}}</ref>

The uses of bisphosphonates include the prevention and treatment of osteoporosis, [[Paget's disease of bone]], [[bone metastasis]] (with or without [[hypercalcemia]]), [[multiple myeloma]], [[primary hyperparathyroidism]], [[osteogenesis imperfecta]], [[fibrous dysplasia]], and other conditions that exhibit bone fragility.

==Chemical structure and mechanistic aspects==
The term bisphosphonate refers to the presence two [[phosphonate]] ({{chem2|PO2(OH)-}}) groups. They are also called '''diphosphonates''' (''[[wikt:bis-#Prefix|bis-]]'' or ''[[wikt:di-#Prefix|di-]]'' + ''[[phosphonate]]'').  The {{chem2|PO2(OH)-}} groups readily lose an additional proton giving ({{chem2|PO3(2-)}} groups, which have a particular high affinity for metal ions.


They are structurally close analogues of [[pyrophosphate]] (abbreviated PP<sub>i</sub>).<ref>{{cite journal |doi=10.1016/j.bone.2011.04.022 |title=Bisphosphonates: The first 40years |date=2011 |last1=Russell |first1=R. Graham G. |journal=Bone |volume=49 |issue=1 |pages=2–19 |pmid=21555003 }}</ref>. Like pyrophosphate, bisphosphonates inhibit the growth and dissolution of bone.  Unlike pyrophosphate, bis(phosphonates) are very stable in aqueous solution.  They resist break down by hydrolysis because the P-C-P or P-N-P linkages are more robust than P-O-P linkages. Bis(phosponate)s are proposed to interfere with osteoclasts, which cause bone resorption.

==Medical uses==
Bisphosphonates are used to treat osteoporosis, [[osteitis deformans]] (Paget's disease of the bone), bone [[metastasis]] (with or without hypercalcemia), multiple myeloma, and other conditions involving fragile, breakable bone.

In osteoporosis and Paget's, the most popular first-line bisphosphonate drugs are [[alendronate]] and [[risedronate]]. If these are ineffective or if the person develops digestive tract problems, intravenous [[pamidronate]] may be used. [[Strontium ranelate]] or [[teriparatide]] are used for refractory disease. The use of strontium ranelate is restricted  because of increased risk of [[venous thromboembolism]], [[pulmonary embolism]] and serious cardiovascular disorders, including [[myocardial infarction]].<ref>{{cite web|title=Strontium ranelate: cardiovascular risk—restricted indication and new monitoring requirements Article date: March 2014|url=http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON392870|publisher=MHRA}}</ref> In postmenopausal women, the [[selective estrogen receptor modulator]] [[raloxifene]] is occasionally administered instead of bisphosphonates. Bisphosphonates are beneficial in reducing the risk of [[vertebral fracture]] in [[steroid induced osteoporosis]].<ref>{{cite journal|last1=Allen|first1=CS|last2=Yeung|first2=JH|last3=Vandermeer|first3=B|last4=Homik|first4=J|title=Bisphosphonates for steroid-induced osteoporosis.|journal=The Cochrane Database of Systematic Reviews|date=5 October 2016|volume=2016|issue=10|pages=CD001347|pmid=27706804|doi=10.1002/14651858.CD001347.pub2|pmc=6461188}}</ref>

===Post-menopausal osteoporosis===
Bisphosphonates are recommended as a first line treatments for post-menopausal osteoporosis.<ref name=AACE2010>{{cite journal | pmid = 21224201 | pmc=4876714 | volume=16 | title=American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis | year=2010 | journal=Endocr Pract | pages=1–37 |vauthors=Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, Kleerekoper M, Luckey MM, McClung MR, Pollack RP, Petak SM | issue=Suppl 3 | doi=10.4158/ep.16.s3.1}}</ref><ref>{{cite journal |title=Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society |journal=Menopause |volume=17 |issue=1 |pages=25–54; quiz 55–6 |year=2010 |pmid=20061894 |doi=10.1097/gme.0b013e3181c617e6 |s2cid=7980731}}</ref><ref>{{cite journal |author=Hauk L |title=ACOG releases practice bulletin on osteoporosis |journal=Am Fam Physician |volume=88 |issue=4 |pages=269–75 | date=August 2013|pmid=23944732 }}</ref><ref>{{cite journal |vauthors=Compston J, Bowring C, Cooper A |title=Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013 |journal=Maturitas |volume=75 |issue=4 |pages=392–6 | date=August 2013|pmid=23810490 |doi=10.1016/j.maturitas.2013.05.013 |display-authors=etal|doi-access=free }}</ref>

Long-term treatment with bisphosphonates produces anti-fracture and bone mineral density effects that persist for 3–5 years after an initial 3–5 years of treatment.<ref name="Eriksen EF, Díez-Pérez A, Boonen S 126–35"/> The bisphosphonate alendronate  reduces the risk of hip, vertebral, and wrist fractures by 35-39%; zoledronate reduces the risk of hip fractures by 38% and of vertebral fractures by 62%.<ref name="Serrano AJ, Begoña L, Anitua E, Cobos R, Orive G 1005–14"/><ref name="gauthier"/> Risedronate has also been shown to reduce the risk of hip fractures.<ref name=AACE2010/><ref name="Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY 23–57"/>

After five years of medications by mouth or three years of intravenous medication among those at low risk, bisphosphonate treatment can be stopped.<ref name=Ad2016/> In those at higher risk ten years of medication by mouth or six years of intravenous treatment may be used.<ref name=Ad2016>{{cite journal|last1=Adler|first1=Robert A|last2=El-Hajj Fuleihan|first2=Ghada|last3=Bauer|first3=Douglas C|last4=Camacho|first4=Pauline M|last5=Clarke|first5=Bart L|last6=Clines|first6=Gregory A|last7=Compston|first7=Juliet E|last8=Drake|first8=Matthew T|last9=Edwards|first9=Beatrice J|last10=Favus|first10=Murray J|last11=Greenspan|first11=Susan L|last12=McKinney|first12=Ross|last13=Pignolo|first13=Robert J|last14=Sellmeyer|first14=Deborah E|title=Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research|journal=Journal of Bone and Mineral Research|date=January 2016|volume=31|issue=1|pages=16–35|doi=10.1002/jbmr.2708|pmid=26350171|pmc=4906542}}</ref>

===Cancer===
Bisphosphonates reduce the risk of fracture and bone pain<ref>{{cite journal |vauthors=Zhu M, Liang R, Pan LH |title=Zoledronate for metastatic bone disease and pain: a meta-analysis of randomized clinical trials |journal=Pain Med |volume=14 |issue=2 |pages=257–64 | date=February 2013|pmid=23279447 |doi=10.1111/pme.12016 |display-authors=etal|doi-access=free }}</ref> in people with breast,<ref name=OCarrigan2017>{{Cite journal|last1=O'Carrigan|first1=Brent|last2=Wong|first2=Matthew Hf|last3=Willson|first3=Melina L.|last4=Stockler|first4=Martin R.|last5=Pavlakis|first5=Nick|last6=Goodwin|first6=Annabel|date=2017|title=Bisphosphonates and other bone agents for breast cancer|journal=The Cochrane Database of Systematic Reviews|volume=10|issue=11|pages=CD003474|doi=10.1002/14651858.CD003474.pub4|issn=1469-493X|pmid=29082518|pmc=6485886}}</ref> lung,<ref>{{cite journal |vauthors=Lopez-Olivo MA, Shah NA, Pratt G, Risser JM, Symanski E, Suarez-Almazor ME |title=Bisphosphonates in the treatment of patients with lung cancer and metastatic bone disease: a systematic review and meta-analysis |journal=Support Care Cancer |volume=20 |issue=11 |pages=2985–98 | date=November 2012|pmid=22956190 |pmc=3691019 |doi=10.1007/s00520-012-1563-z }}</ref> and other metastatic cancers as well as in people with multiple myeloma.<ref>{{cite journal |vauthors=Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B |title=Bisphosphonates in multiple myeloma: a network meta-analysis |journal=Cochrane Database Syst Rev |volume= 2017|pages=CD003188 |year=2017 |issue=12 |pmid=29253322|doi=10.1002/14651858.CD003188.pub4 |pmc=6486151 }}</ref> In breast cancer there is mixed evidence regarding whether bisphosphonates improve survival.<ref name=OCarrigan2017 /><ref>{{cite journal |vauthors=Ben-Aharon I, Vidal L, Rizel S |title=Bisphosphonates in the adjuvant setting of breast cancer therapy--effect on survival: a systematic review and meta-analysis |journal=PLOS ONE |volume=8 |issue=8 |pages=e70044 |year=2013 |pmid=23990894 |pmc=3753308 |doi=10.1371/journal.pone.0070044 |bibcode=2013PLoSO...870044B |display-authors=etal|doi-access=free }}</ref><ref>{{cite journal |vauthors=Zhu J, Zheng Y, Zhou Z |title=Oral adjuvant clodronate therapy could improve overall survival in early breast cancer: results from an updated systematic review and meta-analysis |journal=Eur. J. Cancer |volume=49 |issue=9 |pages=2086–92 | date=June 2013|pmid=23452992 |doi=10.1016/j.ejca.2013.01.021 }}</ref><ref name=VanAcker2015 /> A 2017 Cochrane review found that for people with early breast cancer, bisphosphonate treatment may reduce the risk of the cancer spreading to the person's bone, however, for people who had advanced breast cancer bisphosphonate treatment did not appear to reduce the risk of the cancer spreading to the bone.<ref name=OCarrigan2017 /> Side effects associated with bisphosphonate treatment for people with breast cancer are mild and rare.<ref name=OCarrigan2017 />

Bisphosphonates can also reduce mortality in those with multiple myeloma and prostate cancer.<ref name=VanAcker2015>{{cite journal|last1=Van Acker|first1=HH|last2=Anguille|first2=S|last3=Willemen|first3=Y|last4=Smits|first4=EL|last5=Van Tendeloo|first5=VF|title=Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials.|journal=Pharmacology & Therapeutics|date=23 November 2015|pmid=26617219|doi=10.1016/j.pharmthera.2015.11.008|volume=158|pages=24–40}}</ref>

===Other===
Evidence suggests that the use of bisphosphonates would be useful in the treatment of [[complex regional pain syndrome]], a neuro-immune problem with high MPQ scores, low treatment efficacy and symptoms which can include regional osteoporosis. In 2009  bisphosphonates were "among the only class of medications that has survived placebo-controlled studies showing statistically significant improvement (in CRPS) with therapy."<ref>{{cite journal |author=Pontell D |title=A clinical approach to complex regional pain syndrome |journal=Clinics in Podiatric Medicine and Surgery |volume=25 |issue=3 |pages=361–80; vi |date=July 2008  |pmid=18486850 |doi=10.1016/j.cpm.2008.02.011}}</ref>

There is observational evidence and molecular explanation for some bisphosphonates offering a level of protection against [[COVID-19]].<ref>{{cite journal |author=Thompson J |title=Association between Bisphosphonate use and COVID-19 related outcomes |journal=eLife |volume=12 |pages=e79548 |date=2023 |doi=10.7554/eLife.79548|doi-access=free |pmid=37534876 |pmc=10691801 }}</ref><ref>{{cite journal |author=Muzaffar-Ur-Rehman M |title=In silico evaluation of bisphosphonates identifies leading candidates for SARS-CoV-2 RdRp inhibition |journal=Journal of Molecular Graphics and Modelling |volume=136 |pages=108939 |date=May 2025|doi=10.1016/j.jmgm.2024.108939|pmid=39799876 |doi-access=free }}</ref>

Bisphosphonates have been used to reduce fracture rates in children with the disease [[osteogenesis imperfecta]]<ref>{{cite journal |vauthors=Shapiro JR, Sponsellor PD |title=Osteogenesis imperfecta: questions and answers |journal=Current Opinion in Pediatrics |volume=21 |issue=6 |pages=709–16 |date=December 2009 |pmid=19907330 |doi=10.1097/MOP.0b013e328332c68f |s2cid=205834462 }}</ref> and to treat [[otosclerosis]]<ref>{{cite journal |author=Brookler K |title=Medical treatment of otosclerosis: rationale for use of bisphosphonates |journal=Int Tinnitus J |volume=14 |issue=2 |pages=92–6 |year=2008 |pmid=19205157 }}</ref> by minimizing bone loss.

Other bisphosphonates, including [[medronate]] (R<sup>1</sup>=H, R<sup>2</sup>=H) and [[oxidronate]] (R<sup>1</sup>=H, R<sup>2</sup>=OH), are mixed with radioactive [[technetium]] and injected, as a way to image bone and detect bone disease.

==Adverse effects==

===Common===
Oral bisphosphonates can cause upset [[stomach]] and [[esophagitis|inflammation]] and erosions of the [[esophagus]], which is the main problem of oral ''N''-containing{{explain|date=October 2020}} preparations, that is ones containing "normal" unbranched chains. 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 [[gamma/delta T cells|γδ T cells]].

Bisphosphonates, when administered intravenously for the treatment of cancer, have been associated with [[bisphosphonate-induced osteonecrosis of the jaw|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. [[Phossy jaw]] has been described since Victorian times. Some 60% of cases are preceded by a dental surgical procedure (that involves 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).<ref>{{cite journal |vauthors=Woo S, Hellstein J, Kalmar J | title = Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws | journal = Ann Intern Med | volume = 144 | issue = 10 | pages = 753–61 | year = 2006 | pmid = 16702591 | doi=10.7326/0003-4819-144-10-200605160-00009| s2cid = 53091343 }}</ref>

A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes.<ref>{{cite journal |vauthors=Wysowski D, Chang J | title = Alendronate and risedronate: reports of severe bone, joint, and muscle pain | journal = Arch Intern Med | volume = 165 | issue = 3 | pages = 346–7 | year = 2005 | pmid = 15710802 | doi = 10.1001/archinte.165.3.346-b}}</ref>

Some studies have identified bisphosphonate use as a risk factor for [[atrial fibrillation]] (AF), though meta-analysis of them finds conflicting reports. {{As of|2008}}, the [[Food and Drug Administration|US Food and Drug Administration]] did not recommend any alteration in prescribing of bisphosphonates based on AF concerns.<ref>{{cite web|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070303.htm |archive-url=https://web.archive.org/web/20090710001533/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070303.htm |url-status=dead |archive-date=July 10, 2009 |title=Update of Safety Review Follow-up to the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates |access-date=2009-07-15 |date = October 2008|work=Postmarket Drug Safety Information for Patients and Providers |publisher=[[Food and Drug Administration (United States)]] }}</ref> More recent meta-analyses have found strong correlations between bisphosphonate use and development of AF, especially when administered intravenously,<ref>{{cite journal| date= June 1, 2014 |volume= 113 |issue= 11 |pages= 1815–1821 |journal= American Journal of Cardiology |title= Risk of Atrial Fibrillation With Use of Oral and Intravenous Bisphosphonates |vauthors= Sharma A, Einstein AJ, Vallakati A, Arbab-Zadeh A, Walker MD, Mukherjee D, Homel P, Borer JS, Lichstein E |doi= 10.1016/j.amjcard.2014.03.008 |pmid= 24837258 }}</ref> but that a significantly increased risk of AF that required hospitalization did not have an attendant increased risk of stroke or cardiovascular mortality.<ref>{{cite journal |journal=   Chest|date= October 2013 |volume= 144 |issue= 4 |pages= 1131–1322 |title= Risk of serious atrial fibrillation and stroke with use of bisphosphonates: evidence from a meta-analysis |vauthors= Sharma A, Chatterjee S, Arbab-Zadeh A, Goyal S, Lichstein E, Ghosh J, Aikat S |pmid= 23722644 |doi= 10.1378/chest.13-0675 }}</ref>

===Long-term risks===
In large studies, women taking bisphosphonates for osteoporosis have had unusual fractures ("bisphosphonate fractures") in the [[femur]] (thigh bone) in the shaft ([[diaphysis]] or [[Human trochanter|sub-trochanteric]] region) of the bone, rather than at the femoral neck, which is the most common site of fracture. However, these fractures are 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 is more than the increase in unusual shaft fractures.<ref name="Shane">{{cite journal |author=Shane E |title=Evolving data about subtrochanteric fractures and bisphosphonates |journal=N. Engl. J. Med. |volume=362 |issue=19 |pages=1825–7 |date=May 2010 |pmid=20335574 |doi=10.1056/NEJMe1003064 }}</ref>{{Obsolete source|reason=Needs a more recent secondary source summarizing recent studies.|date=April 2019}} 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.<ref name="Shane"/><ref>{{cite journal |vauthors=Lenart BA, Lorich DG, Lane JM |title=Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate |journal=N. Engl. J. Med. |volume=358 |issue=12 |pages=1304–6 |date=March 2008 |pmid=18354114 |doi=10.1056/NEJMc0707493 |doi-access=free }}</ref>{{npsn|date=April 2019}} In cases where there is concern of such fractures occurring, [[teriparatide]] is potentially a good alternative because it does not cause as much damage as a bisphosphonate does by suppressing bone turnover.<ref name=Arkan>{{cite journal|author2=Bakir K Kadum|author3=Göran O Sjödén|title=Bisphosphonate-induced femoral fragility fractures: What do we know?|journal=Orthopedic Research and Reviews|date=31 March 2010|volume=2|issue=1|pages=27–34|doi=10.2147/orr.s7521|author=Arkan S Sayed-Noor|doi-access=free}}</ref>

Three meta analyses have evaluated whether bisphosphonate use is associated with an increased risk of esophageal cancer.  Two studies concluded that there was no evidence of increased risk.<ref>{{cite journal |vauthors=Andrici J, Tio M, Eslick GD |title=Meta-analysis: oral bisphosphonates and the risk of oesophageal cancer |journal=Aliment. Pharmacol. Ther. |volume=36 |issue=8 |pages=708–16 | date=October 2012|pmid=22966908 |doi=10.1111/apt.12041 |s2cid=5271005 |doi-access=free }}</ref><ref>{{cite journal |vauthors=Sun K, Liu JM, Sun HX, Lu N, Ning G |title=Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies |journal=Osteoporos Int |volume=24 |issue=1 |pages=279–86 | date=January 2013|pmid=23052941 |doi=10.1007/s00198-012-2158-8 |s2cid=12625687 }}</ref><ref>{{cite journal |vauthors=Oh YH, Yoon C, Park SM |title=Bisphosphonate use and gastrointestinal tract cancer risk: meta-analysis of observational studies |journal=World J. Gastroenterol. |volume=18 |issue=40 |pages=5779–88 | date=October 2012|pmid=23155320 |pmc=3484348 |doi=10.3748/wjg.v18.i40.5779 |doi-access=free }}</ref>

== Chemistry and classes ==
All bisphosphonate drugs share a common phosphorus-carbon-phosphorus "backbone":

The two {{chem|PO|3}} ([[phosphonate]]) groups [[covalent]]ly linked to [[carbon]] determine both the name "bis''phospho''nate" and the function of the drugs. ''Bis'' refers to the fact that there are two such groups in the molecule.

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

See nitrogenous and non-nitrogenous sections in ''Mechanism of action'' below.

== 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. Once bisphosphonates are in bone, they have a very long elimination [[half-life]] that can exceed ten years.<ref>{{Cite web|url=https://courses.washington.edu/bonephys/opbis.html|title=Bisphosphonates|website=courses.washington.edu|access-date=2018-09-19}}</ref>

== Mechanism of action ==
Bisphosphonates are structurally similar to [[pyrophosphate]], but with a central carbon that can have up to two [[substituent]]s (R<sup>1</sup> and R<sup>2</sup>) instead of an oxygen atom. Because a bisphosphonate group mimics the structure of pyrophosphate, it can inhibit activation of enzymes that utilize pyrophosphate.

The specificity of bisphosphonate-based drugs comes from the two phosphonate groups (and possibly a hydroxyl at R<sup>1</sup>) that work together to coordinate calcium ions. Bisphosphonate molecules preferentially bind to [[calcium]] ions. 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 released by [[osteoclast]]s, the bone cells that break down bone tissue. Bisphosphonate molecules then attach to and enter osteoclasts where they disrupt intracellular enzymatic functions needed for [[bone resorption]].<ref>{{cite journal |vauthors= Coxon FP, Thompson K, Roelofs AJ, Ebetino FH, Rogers MJ |title= Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells |journal= Bone |date= May 2008 |volume= 42 |issue= 5 |pages= 848–860 |doi= 10.1016/j.bone.2007.12.225 |pmid= 18325866 }}</ref>

There are two classes of bisphosphonate compounds: non-nitrogenous (no [[nitrogen]] in R<sup>2</sup>) and nitrogenous (R<sup>2</sup> contains nitrogen). The two types of bisphosphonates work differently in inhibiting osteoclasts.

{|class=wikitable
! Class
! Name
! R<sup>1</sup>
! R<sup>2</sup>
! Relative potency<br>(vs Etidronate=1)
|-
! rowspan=3 {{vert header|cellstyle=vertical-align:middle|Non-nitrogenous}}
! [[Etidronic acid|Etidronate]] (Didronel)
| OH
| CH<sub>3</sub>
| 1
|-
! [[Clodronate]] (Bonefos, Loron)
| Cl
| Cl
| 10
|-
! [[Tiludronate]] (Skelid)
| H
| ''p''-Chlorophenylthio
| 10
|-
! rowspan=7 {{vert header|cellstyle=vertical-align:middle|Nitrogenous}}
! [[Pamidronate]] (APD, Aredia)
| OH
| [CH<sub>2</sub>]<sub>2</sub>NH<sub>2</sub>
| 100
|-
! [[Neridronate]] (Nerixia{{efn|[https://www.drugs.com/international/nerixia.html Not sold in the United States]}})
| OH
| [CH<sub>2</sub>]<sub>5</sub>NH<sub>2</sub>
| 100
|-
! [[Olpadronate]]
| OH
| [CH<sub>2</sub>]<sub>2</sub>N(CH<sub>3</sub>)<sub>2</sub>
| 500
|-
! [[Alendronate]] (Fosamax)
| OH
| [CH<sub>2</sub>]<sub>3</sub>NH<sub>2</sub>
| 500
|-
! [[Ibandronate]] (Boniva - US, Bonviva - Asia)
| OH
| [CH<sub>2</sub>]<sub>2</sub>N(CH<sub>3</sub>)[CH<sub>2</sub>]<sub>4</sub>CH<sub>3</sub>
| 1000
|-
! [[Risedronate]] (Actonel)
| OH
| 3-Pyridylmethyl
| 2000
|-
! [[Zoledronate]] (Zometa, Aclasta)
| OH
| 1''H''-imidazol-1-ylmethyl
| 10000
|}

=== Non-nitrogenous ===
The non-nitrogenous bisphosphonates (diphosphonates) are [[metabolism|metabolised]] in the [[cell (biology)|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 bisphosphonate has overall more negative effects than the nitrogen containing group, and is prescribed far less often.<ref>{{cite journal |vauthors=Frith J, Mönkkönen J, Blackburn G, Russell R, Rogers M | title = Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro | journal = J Bone Miner Res | volume = 12 | issue = 9 | pages = 1358–67 | year = 1997 | pmid = 9286751 | doi = 10.1359/jbmr.1997.12.9.1358| doi-access = free }}</ref>

=== Nitrogenous ===
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).<ref>{{cite journal |vauthors=van Beek E, Cohen L, Leroy I, Ebetino F, Löwik C, Papapoulos S | title = Differentiating the mechanisms of antiresorptive action of nitrogen containing bisphosphonates | journal = Bone | volume = 33 | issue = 5 | pages = 805–11 |date=November 2003 | pmid = 14623056 | doi = 10.1016/j.bone.2003.07.007}}</ref>

Bisphosphonates that contain [[isoprene]] chains at the R<sup>1</sup> or R<sup>2</sup> position can impart specificity for inhibition of [[GGPS1]].<ref>{{cite journal|last1=Wiemer|first1=AJ|last2=Wiemer|first2=DF|last3=Hohl|first3=RJ|title=Geranylgeranyl diphosphate synthase: an emerging therapeutic target.|journal=Clinical Pharmacology and Therapeutics|date=December 2011|volume=90|issue=6|pages=804–12|pmid=22048229|doi=10.1038/clpt.2011.215|s2cid=27913789}}</ref>
[[File:HMG-CoA reductase pathway.svg|thumb|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).<ref>{{cite journal |vauthors=Van Beek E, Löwik C, van der Pluijm G, Papapoulos S | title = 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 | journal = J Bone Miner Res | volume = 14 | issue = 5 | pages = 722–9 | year = 1999 | pmid = 10320520 | doi = 10.1359/jbmr.1999.14.5.722| s2cid = 20316713 }}</ref>

While inhibition of protein prenylation may affect many proteins found in an [[osteoclast]], disruption to the lipid modification of [[Ras (protein)|Ras]], [[Rho family of GTPases|Rho]], [[Rac (GTPase)|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.

[[Statin]]s 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 (bone)|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.<ref name=Uzzan2007>{{cite journal| last=Uzzan| first=B| title=Effects of statins on bone mineral density: a meta-analysis of clinical studies| journal=Bone| year=2007| volume=40| issue=6| pages=1581–7| doi=10.1016/j.bone.2007.02.019| pmid=17409043|display-authors=etal}}</ref>

==History==
{{main|Discovery and development of bisphosphonates}}
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. In the 1990s their actual mechanism of action was demonstrated with the initial launch of [[alendronate]] by [[Merck & Co.]]<ref>{{cite journal | author = Fleisch H | title = Development of bisphosphonates | journal = Breast Cancer Res | volume = 4 | issue = 1 | pages = 30–4 | year = 2002 | pmid = 11879557 | doi = 10.1186/bcr414 | pmc = 138713 | doi-access = free }}</ref>
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==Notes==
{{notelist}}

==References==
{{reflist|30em}}

==External links==
*[https://web.archive.org/web/20160304194229/http://myeloma.org/ArticlePage.action?tabId=1&menuId=151&articleId=1165&aTab=-3&tBack=%5EIndexPage.action%3FtabId%3D1%3AmenuId%3D151%3AindexPageId%3D47%3AparentMenuItemId%3D151%3AcategoryId%3D70%5E&tDisplayBack=true International Myeloma Foundation article on bisphosphonates]

{{Major drug groups}}
{{Bisphosphonates}}

[[Category:Bisphosphonates| ]]
[[Category:Farnesyl pyrophosphate synthase inhibitors]]