Bisphosphonate

Last updated
The general chemical structure of bisphosphonate. The R-groups 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. Biphosphonate Structural Formulae.png
The general chemical structure of bisphosphonate. The R-groups 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 drugs used to treat osteoporosis. [1] They are called bisphosphonates because they have two phosphonate (PO(OH)
2) groups. They are thus also called diphosphonates ( bis- or di- + phosphonate ).

Contents

Evidence shows that they reduce the risk of fracture in post-menopausal women with osteoporosis. [2] [3] [4] [5] [6]

Bone tissue undergoes constant 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. [7]

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.

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. [8] 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. [9]

Post-menopausal osteoporosis

Bisphosphonates are recommended as a first line treatments for post-menopausal osteoporosis. [5] [10] [11] [12]

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. [2] 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%. [3] [4] Risedronate has also been shown to reduce the risk of hip fractures. [5] [6]

After five years of medications by mouth or three years of intravenous medication among those at low risk, bisphosphonate treatment can be stopped. [13] In those at higher risk ten years of medication by mouth or six years of intravenous treatment may be used. [13]

Cancer

Bisphosphonates reduce the risk of fracture and bone pain [14] in people with breast, [15] lung, [16] and other metastatic cancers as well as in people with multiple myeloma. [17] In breast cancer there is mixed evidence regarding whether bisphosphonates improve survival. [15] [18] [19] [20] 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. [15] Side effects associated with bisphosphonate treatment for people with breast cancer are mild and rare. [15]

Bisphosphonates can also reduce mortality in those with multiple myeloma and prostate cancer. [20]

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." [21]

Bisphosphonates have been used to reduce fracture rates in children with the disease osteogenesis imperfecta [22] and to treat otosclerosis [23] by minimizing bone loss.

Other bisphosphonates, including medronate (R1=H, R2=H) and oxidronate (R1=H, R2=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 inflammation and erosions of the esophagus, which is the main problem of oral N-containing[ further explanation needed ] 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 γδ T cells.

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. 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). [24]

A number of cases of severe bone, joint, or musculoskeletal pain have been reported, prompting labeling changes. [25]

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 US Food and Drug Administration did not recommend any alteration in prescribing of bisphosphonates based on AF concerns. [26] More recent meta-analyses have found strong correlations between bisphosphonate use and development of AF, especially when administered intravenously, [27] but that a significantly increased risk of AF that required hospitalization did not have an attendant increased risk of stroke or cardiovascular mortality. [28]

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 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. [29] [ obsolete source ] 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. [29] [30] [ non-primary source needed ] 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. [31]

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. [32] [33] [34]

Chemistry and classes

All bisphosphonate drugs share a common phosphorus-carbon-phosphorus "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 (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.

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. [35]

Mechanism of action

Bisphosphonates 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 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 R1) 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 osteoclasts, 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. [36]

There are two classes of bisphosphonate compounds: non-nitrogenous (no nitrogen in R2) and nitrogenous (R2 contains nitrogen). The two types of bisphosphonates work differently in inhibiting osteoclasts.

ClassNameR1R2Relative potency
(vs Etidronate=1)
Non-nitrogenous
 Etidronate (Didronel)OHCH31
Clodronate (Bonefos, Loron)ClCl10
Tiludronate (Skelid)Hp-Chlorophenylthio10
Nitrogenous
 Pamidronate (APD, Aredia)OH(CH2)2NH2100
Neridronate (Nerixia [lower-alpha 1] )OH(CH2)5NH2100
Olpadronate OH(CH2)2N(CH3)2500
Alendronate (Fosamax)OH(CH2)3NH2500
Ibandronate (Boniva - US, Bonviva - Asia)OH(CH2)2N(CH3)(CH2)4CH31000
Risedronate (Actonel)OH3-Pyridylmethyl2000
Zoledronate (Zometa, Aclasta)OH1H-imidazol-1-ylmethyl10000

Non-nitrogenous

The non-nitrogenous bisphosphonates (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 bisphosphonate has overall more negative effects than the nitrogen containing group, and is prescribed far less often. [37]

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). [38]

Bisphosphonates that contain isoprene chains at the R1 or R2 position can impart specificity for inhibition of GGPS1. [39]

HMG-CoA reductase pathway HMG-CoA reductase pathway.svg
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). [40]

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. [41]

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. In the 1990s their actual mechanism of action was demonstrated with the initial launch of alendronate by Merck & Co. [42]

Notes

Related Research Articles

<span class="mw-page-title-main">Osteoporosis</span> Skeletal disorder

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in fracture risk.

<span class="mw-page-title-main">Paget's disease of bone</span> Disease affecting bone remodeling

Paget's disease of bone is a condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the microscopic level, specifically excessive bone breakdown and subsequent disorganized new bone formation. These structural changes cause the bone to weaken, which may result in deformity, pain, fracture or arthritis of associated joints.

<span class="mw-page-title-main">Teriparatide</span> Pharmaceutical drug for treating osteoporosis

Teriparatide, sold under the brand name Forteo, is a form of parathyroid hormone (PTH) consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic agent used in the treatment of some forms of osteoporosis. Teriparatide is a recombinant human parathyroid hormone analog. It has an identical sequence to the 34 N-terminal amino acids of the 84-amino acid human parathyroid hormone.

<span class="mw-page-title-main">Alendronic acid</span> Chemical compound

Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementation, and lifestyle changes.

<span class="mw-page-title-main">Raloxifene</span> Chemical compound

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Zoledronic acid</span> Chemical compound

Zoledronic acid, also known as zoledronate and sold under the brand name Zometa among others, by Novartis among others, is a medication used to treat a number of bone diseases. These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Paget's disease of bone and Duchenne muscular dystrophy (DMD). It is given by injection into a vein.

<span class="mw-page-title-main">Osteopenia</span> Abnormally low bone mineral density

Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteoporosis. In 2010, 43 million older adults in the US had osteopenia. Unlike osteoporosis, osteopenia does not usually cause symptoms, and losing bone density in itself does not cause pain.

<span class="mw-page-title-main">Bazedoxifene</span> Chemical compound

Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly for cancer. It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for bazedoxifene as part of the combination drug Duavee in the prevention of postmenopausal osteoporosis. It is also being studied for possible treatment of breast cancer and pancreatic cancer.

<span class="mw-page-title-main">RANKL</span> Mammalian protein found in Homo sapiens

Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.

<span class="mw-page-title-main">Ibandronic acid</span> Chemical compound

Ibandronic acid is a bisphosphonate medication used in the prevention and treatment of osteoporosis and metastasis-associated skeletal fractures in people with cancer. It may also be used to treat hypercalcemia. It is typically formulated as its sodium salt ibandronate sodium.

<span class="mw-page-title-main">Osteonecrosis of the jaw</span> Medical condition

Osteonecrosis of the jaw (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws. Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature.

<span class="mw-page-title-main">Denosumab</span> Human monoclonal antibody

Denosumab, sold under the brand names Prolia and Xgeva among others, is a human monoclonal antibody used for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.

<span class="mw-page-title-main">Strontium ranelate</span> Chemical compound

Strontium ranelate, a strontium(II) salt of ranelic acid, is a medication for osteoporosis marketed as Protelos or Protos by Servier. Studies indicate it can also slow the course of osteoarthritis of the knee. The drug is unusual in that it both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts. It is therefore promoted as a "dual action bone agent" (DABA).

<span class="mw-page-title-main">Lasofoxifene</span> Chemical compound

Lasofoxifene, sold under the brand name Fablyn, is a nonsteroidal selective estrogen receptor modulator (SERM) which is marketed by Pfizer in Lithuania and Portugal for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). It also appears to have had a statistically significant effect of reducing breast cancer in women according to a study published in The Journal of the National Cancer Institute.

Senile osteoporosis has been recently recognized as a geriatric syndrome with a particular pathophysiology. There are different classification of osteoporosis: primary, in which bone loss is a result of aging and secondary, in which bone loss occurs from various clinical and lifestyle factors. Primary, or involuntary osteoporosis, can further be classified into Type I or Type II. Type I refers to postmenopausal osteoporosis and is caused by the deficiency of estrogen. While senile osteoporosis is categorized as an involuntary, Type II, and primary osteoporosis, which affects both men and women over the age of 70 years. It is accompanied by vitamin D deficiency, body's failure to absorb calcium, and increased parathyroid hormone.

Steroid-induced osteoporosis is osteoporosis arising from the use of glucocorticoids analogous to Cushing's syndrome but involving mainly the axial skeleton. The synthetic glucocorticoid prescription drug prednisone is a main candidate after prolonged intake. Bisphosphonates are beneficial in reducing the risk of vertebral fractures. Some professional guidelines recommend prophylactic calcium and vitamin D supplementation in patients who take the equivalent of more than 30 mg hydrocortisone, especially when this is in excess of three months. The use of thiazide diuretics, and gonadal hormone replacement has also been recommended, with the use of calcitonin, bisphosphonates, sodium fluoride or anabolic steroids also suggested in refractory cases. Alternate day use may not prevent this complication.

<span class="mw-page-title-main">Medication-related osteonecrosis of the jaw</span> Medical condition

Medication-related osteonecrosis of the jaw is progressive death of the jawbone in a person exposed to a medication known to increase the risk of disease, in the absence of a previous radiation treatment. It may lead to surgical complication in the form of impaired wound healing following oral and maxillofacial surgery, periodontal surgery, or endodontic therapy.

Romosozumab, sold under the brand name Evenity, is a medication used to treat osteoporosis. It has been found to decrease the risk of fractures of the spine.

Jane A. Cauley is a Distinguished Professor in the Department of Epidemiology and an Associate Dean for Research at the University of Pittsburgh.

<span class="mw-page-title-main">Discovery and development of bisphosphonates</span> Drugs used to treat bone disorders

Bisphosphonates are an important class of drugs originally commercialised in the mid to late 20th century. They are used for the treatment of osteoporosis and other bone disorders that cause bone fragility and diseases where bone resorption is excessive. Osteoporosis is common in post-menopausal women and patients in corticosteroid treatment where biphosphonates have been proven a valuable treatment and also used successfully against Paget's disease, myeloma, bone metastases and hypercalcemia. Bisphosphonates reduce breakdown of bones by inhibiting osteoclasts, they have a long history of use and today there are a few different types of bisphosphonate drugs on the market around the world.

References

  1. ↑ National Osteoporosis Society. "Drug Treatment". U.K. National Osteoporosis Society. Archived from the original on 6 November 2012. Retrieved 7 August 2012.
  2. 1 2 Eriksen EF, Díez-Pérez A, Boonen S (January 2014). "Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review". Bone. 58: 126–35. doi:10.1016/j.bone.2013.09.023. PMID   24120384.
  3. 1 2 Serrano AJ, Begoña L, Anitua E, Cobos R, Orive G (December 2013). "Systematic review and meta-analysis of the efficacy and safety of alendronate and zoledronate for the treatment of postmenopausal osteoporosis". Gynecol. Endocrinol. 29 (12): 1005–14. doi:10.3109/09513590.2013.813468. PMID   24063695. S2CID   20163452.
  4. 1 2 Gauthier, K; Bai, A; Perras, C; Cunningham, J; Ahuja, T; Richter, T; Kovacs, C (February 2012). "Denosumab, Raloxifene, and Zoledronic Acid for the Treatment of Postmenopausal Osteoporosis: Clinical Effectiveness and Harms". Rapid Response Report: Systematic Review. PMID   24278999.
  5. 1 2 3 Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, Kleerekoper M, Luckey MM, McClung MR, Pollack RP, Petak SM (2010). "American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis". Endocr Pract. 16 (Suppl 3): 1–37. doi:10.4158/ep.16.s3.1. PMC   4876714 . PMID   21224201.
  6. 1 2 Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY (January 2013). "European guidance for the diagnosis and management of osteoporosis in postmenopausal women". Osteoporos Int. 24 (1): 23–57. doi:10.1007/s00198-012-2074-y. PMC   3587294 . PMID   23079689.
  7. ↑ 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.
  8. ↑ "Strontium ranelate: cardiovascular risk—restricted indication and new monitoring requirements Article date: March 2014". MHRA.
  9. ↑ Allen, CS; Yeung, JH; Vandermeer, B; Homik, J (5 October 2016). "Bisphosphonates for steroid-induced osteoporosis". The Cochrane Database of Systematic Reviews. 2016 (10): CD001347. doi:10.1002/14651858.CD001347.pub2. PMC   6461188 . PMID   27706804.
  10. ↑ "Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society". Menopause. 17 (1): 25–54, quiz 55–6. 2010. doi:10.1097/gme.0b013e3181c617e6. PMID   20061894. S2CID   7980731.
  11. ↑ Hauk L (August 2013). "ACOG releases practice bulletin on osteoporosis". Am Fam Physician. 88 (4): 269–75. PMID   23944732.
  12. ↑ Compston J, Bowring C, Cooper A, et al. (August 2013). "Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013". Maturitas. 75 (4): 392–6. doi: 10.1016/j.maturitas.2013.05.013 . PMID   23810490.
  13. 1 2 Adler, Robert A; El-Hajj Fuleihan, Ghada; Bauer, Douglas C; Camacho, Pauline M; Clarke, Bart L; Clines, Gregory A; Compston, Juliet E; Drake, Matthew T; Edwards, Beatrice J; Favus, Murray J; Greenspan, Susan L; McKinney, Ross; Pignolo, Robert J; Sellmeyer, Deborah E (January 2016). "Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research". Journal of Bone and Mineral Research. 31 (1): 16–35. doi:10.1002/jbmr.2708. PMC   4906542 . PMID   26350171.
  14. ↑ Zhu M, Liang R, Pan LH, et al. (February 2013). "Zoledronate for metastatic bone disease and pain: a meta-analysis of randomized clinical trials". Pain Med. 14 (2): 257–64. doi: 10.1111/pme.12016 . PMID   23279447.
  15. 1 2 3 4 O'Carrigan, Brent; Wong, Matthew Hf; Willson, Melina L.; Stockler, Martin R.; Pavlakis, Nick; Goodwin, Annabel (2017). "Bisphosphonates and other bone agents for breast cancer". The Cochrane Database of Systematic Reviews. 10 (11): CD003474. doi:10.1002/14651858.CD003474.pub4. ISSN   1469-493X. PMC   6485886 . PMID   29082518.
  16. ↑ Lopez-Olivo MA, Shah NA, Pratt G, Risser JM, Symanski E, Suarez-Almazor ME (November 2012). "Bisphosphonates in the treatment of patients with lung cancer and metastatic bone disease: a systematic review and meta-analysis". Support Care Cancer. 20 (11): 2985–98. doi:10.1007/s00520-012-1563-z. PMC   3691019 . PMID   22956190.
  17. ↑ Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B (2017). "Bisphosphonates in multiple myeloma: a network meta-analysis". Cochrane Database Syst Rev. 2017 (12): CD003188. doi:10.1002/14651858.CD003188.pub4. PMC   6486151 . PMID   29253322.
  18. ↑ Ben-Aharon I, Vidal L, Rizel S, et al. (2013). "Bisphosphonates in the adjuvant setting of breast cancer therapy--effect on survival: a systematic review and meta-analysis". PLOS ONE. 8 (8): e70044. Bibcode:2013PLoSO...870044B. doi: 10.1371/journal.pone.0070044 . PMC   3753308 . PMID   23990894.
  19. ↑ Zhu J, Zheng Y, Zhou Z (June 2013). "Oral adjuvant clodronate therapy could improve overall survival in early breast cancer: results from an updated systematic review and meta-analysis". Eur. J. Cancer. 49 (9): 2086–92. doi:10.1016/j.ejca.2013.01.021. PMID   23452992.
  20. 1 2 Van Acker, HH; Anguille, S; Willemen, Y; Smits, EL; Van Tendeloo, VF (23 November 2015). "Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials". Pharmacology & Therapeutics. 158: 24–40. doi:10.1016/j.pharmthera.2015.11.008. PMID   26617219.
  21. ↑ Pontell D (July 2008). "A clinical approach to complex regional pain syndrome". Clinics in Podiatric Medicine and Surgery. 25 (3): 361–80, vi. doi:10.1016/j.cpm.2008.02.011. PMID   18486850.
  22. ↑ 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. S2CID   205834462.
  23. ↑ Brookler K (2008). "Medical treatment of otosclerosis: rationale for use of bisphosphonates". Int Tinnitus J. 14 (2): 92–6. PMID   19205157.
  24. ↑ 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. S2CID   53091343.
  25. ↑ 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.
  26. ↑ "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.
  27. ↑ Sharma A, Einstein AJ, Vallakati A, Arbab-Zadeh A, Walker MD, Mukherjee D, Homel P, Borer JS, Lichstein E (June 1, 2014). "Risk of Atrial Fibrillation With Use of Oral and Intravenous Bisphosphonates". American Journal of Cardiology. 113 (11): 1815–1821. doi:10.1016/j.amjcard.2014.03.008. PMID   24837258.
  28. ↑ Sharma A, Chatterjee S, Arbab-Zadeh A, Goyal S, Lichstein E, Ghosh J, Aikat S (October 2013). "Risk of serious atrial fibrillation and stroke with use of bisphosphonates: evidence from a meta-analysis". Chest. 144 (4): 1131–1322. doi:10.1378/chest.13-0675. PMID   23722644.
  29. 1 2 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.
  30. ↑ 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.
  31. ↑ 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/orr.s7521 .
  32. ↑ Andrici J, Tio M, Eslick GD (October 2012). "Meta-analysis: oral bisphosphonates and the risk of oesophageal cancer". Aliment. Pharmacol. Ther. 36 (8): 708–16. doi: 10.1111/apt.12041 . PMID   22966908. S2CID   5271005.
  33. ↑ Sun K, Liu JM, Sun HX, Lu N, Ning G (January 2013). "Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies". Osteoporos Int. 24 (1): 279–86. doi:10.1007/s00198-012-2158-8. PMID   23052941. S2CID   12625687.
  34. ↑ Oh YH, Yoon C, Park SM (October 2012). "Bisphosphonate use and gastrointestinal tract cancer risk: meta-analysis of observational studies". World J. Gastroenterol. 18 (40): 5779–88. doi: 10.3748/wjg.v18.i40.5779 . PMC   3484348 . PMID   23155320.
  35. ↑ "Bisphosphonates". courses.washington.edu. Retrieved 2018-09-19.
  36. ↑ Coxon FP, Thompson K, Roelofs AJ, Ebetino FH, Rogers MJ (May 2008). "Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells". Bone. 42 (5): 848–860. doi:10.1016/j.bone.2007.12.225. PMID   18325866.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ Wiemer, AJ; Wiemer, DF; Hohl, RJ (December 2011). "Geranylgeranyl diphosphate synthase: an emerging therapeutic target". Clinical Pharmacology and Therapeutics. 90 (6): 804–12. doi:10.1038/clpt.2011.215. PMID   22048229. S2CID   27913789.
  40. ↑ 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. S2CID   20316713.
  41. ↑ 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.
  42. ↑ Fleisch H (2002). "Development of bisphosphonates". Breast Cancer Res. 4 (1): 30–4. doi: 10.1186/bcr414 . PMC   138713 . PMID   11879557.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.