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Bisphosphonate

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Last Update: January 7, 2019.

Indications

Bisphosphonates define a class of drugs which are widely indicated since the 1990s to treat osteoporosis both in men and women. Their effectiveness to treat osteoporosis and other conditions is related to their ability to inhibit bone resorption.[1][2][3]

  • FDA-approved indications for bisphosphonates include treatment of osteoporosis in postmenopausal women, osteoporosis in men, glucocorticoid-induced osteoporosis, hypercalcemia of malignancy, Paget disease of the bone, and malignancies with metastasis to the bone.
  • Non-FDA-approved indications include treatment of osteogenesis imperfecta in children as well as adults and prevention of glucocorticoid-induced osteoporosis.

Mechanism of Action

Bisphosphonates have a structure similar to native pyrophosphate and are divided into two groups: nitrogen-containing and non-nitrogen containing bisphosphonates. Nitrogen-containing bisphosphonates include alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid. Non-nitrogen containing bisphosphonates include etidronate, clodronate, and tiludronate. All bisphosphonates inhibit bone resorption by attaching to hydroxyapatite binding sites on the bone, particularly in areas with active resorption. As bone is resorbed by osteoclasts, the bisphosphonate that is embedded in the bone in released and impairs the osteoclast’s ability to continue bone resorption.[2][4][5]

Nitrogen-containing bisphosphonates work by inhibiting farnesyl pyrophosphate synthase, which is important in promoting attachment of the osteoclast to the bone. As a result, the osteoclast detaches from the bone surface, thus inhibiting bone resorption.

Non-nitrogen containing bisphosphonates, on the other hand, are metabolized within the cell to substrates that replace the terminal pyrophosphate moiety of adenosine triphosphate, forming a nonfunctional molecule which competes with adenosine triphosphate in the energy metabolism of the cell. This initiates osteoclast apoptosis which in turn leads to an overall decrease in the bone breakdown.

Nitrogen-containing bisphosphonates are much more potent antiresorptive agents than the non-nitrogen-containing bisphosphonates. In addition, non-nitrogen containing bisphosphonates are found to have high potential to inhibit bone mineralization and can cause osteomalacia. For this reason, they are no longer used widely.

Administration

Alendronate, risedronate, and ibandronate are given orally, most commonly at weekly (alendronate, risedronate) or monthly (risedronate and ibandronate) intervals. Zoledronic acid and pamidronate are administered intravenously, and there is also an intravenous preparation of ibandronate that may be used. Intravenous preparations are beneficial in patients who cannot tolerate oral bisphosphonates or in whom oral bisphosphonates are contraindicated such as the presence or history of esophageal stricture.[6][7]

Alendronate is given as 35 mg once weekly for the prophylaxis of osteoporosis in postmenopausal females and as 70 mg once weekly for the treatment of osteoporosis in men and women. For Paget disease of bone in males and females, alendronate is given orally as 40 mg once daily for 6 months, and risedronate is given 30 mg orally daily for 2 months. Risedronate is given as 35 mg once weekly and 150 mg once a month. Ibandronate sodium is given as 150 mg orally once a month or 3 mg intravenously every month. Zoledronic acid is given as 4 mg to 5 mg intravenously over at least 15 to 30 minutes every 12 months for the treatment of osteoporosis. Pamidronate is given as 30 mg to 60 mg by slow intravenous infusion every 3 to 6 months for the treatment of hypercalcemia of malignancy, Paget disease, and bone metastasis.

Patients should receive supplemental calcium 1000 to 1200 mg/day and vitamin D 800 to 1000 international units/day if dietary intake is inadequate. Bisphosphonates should be taken as first medication in the morning and more than 30 minutes before the first food intake, beverage (except water), or any other medication. Patients should be instructed to stay erect, not to lay down for at least thirty minutes or until the first food intake of the day to reduce esophageal irritation/ulceration. Milk and milk products, coffee, orange juice, and food may reduce the absorption of alendronate.

Adverse Effects

Side effects of bisphosphonates includes: acute phase reaction (10% to 30%) with transient pyrexia with myalgias, arthralgias, headaches, and influenza-like symptoms, transient hypocalcemia (18%), hypophosphatemia (10%), musculoskeletal paib (less than or equal to 6%), flatulence (less than or equal to 4%), headache and gastroesophageal reflux disease (3%), constipation or diarrhea (less than or equal to 3%), abdominal pain (2% to 7%), esophageal ulcer (2%), acid regurgitation (1% to 5%), abdominal distension, gastric ulcer, gastritis and muscle cramps (less than or equal to 1%).

Other Adverse Effects

One of the most severe adverse effects is bisphosphonate-related osteonecrosis of the jaw (BRONJ). BRONJ is diagnosed if all the following criteria are met:

  • History of treatment with a bisphosphonate;
  • Those who had more than 8 weeks of exposed bone in the maxillofacial region
  • No radiation therapy to the jaw

The American Association of Oral and Maxillofacial Surgeons has further defined the stages of Bisphosphonate-related osteonecrosis of the jaw (BRONJ) as follows:

  • Stage 0: Indicated by no visible bone but nonspecific symptoms. Common treatment includes Symptomatic treatment and conservative management of underlying dental issues; antibiotics are recommended if the infection is present.
  • Stage 1: Indicated by exposed, inflamed necrotic bone without symptoms. Common treatment includes antimicrobial rinses (if the infection is not present).
  • Stage 2: Indicated by exposed, necrotic bone with local signs or symptoms of infection. Common treatment includes symptomatic treatment, antimicrobial rinses, and systemic antibiotics.
  • Stage 3: Indicated by exposed, necrotic bone with pain and infection, pathologic fracture, extraoral fistula and extensive osteolysis. Common treatment includes symptomatic treatment, systemic antibiotics and superficial surgical debridement of the necrotic bone.

Dose modification or preferably stopping oral bisphosphonate therapy should be done in patients exhibiting systemic symptoms since bisphosphonates are known to affect the jaw completely and may lead to progression of BRONJ.

Another serious adverse effect of bisphosphonates is atypical femoral fracture typically involving diaphysis or sub-trochanteric region of the femur.  It is caused by pathophysiological alterations of the bone quality and fracture repair process resulting in over-suppression of bone turnover.  

Due to potential serious nature of BRONJ and atypical femur fracture, a two year drug holiday is recommended after 5 to 10 years for the oral bisphosphonates and 3 to 5 years for zoledronic acid.

Contraindications

Widely documented contraindications include hypersensitivity to the bisphosphonate, hypocalcemia, abnormalities of the esophagus such as achalasia, esophageal stricture, esophageal varices, Barrett's esophagus, inability to stand or sit upright for at least 30 minutes, history of bariatric surgery (Roux-en-Y gastric bypass) and in chronic kidney disease with glomerular filtration rate less than 30 to 35 mL/min.

Monitoring

Bone mineral density should be evaluated 1 to 2 years after initiating therapy and every two years or more frequently in patients deemed high risk. Annual measurements of height, weight, serum calcium, 25- hydroxyvitamin D and assessment of back pain for the development of compression fractures should be done.

In some circumstances, monitoring of biochemical markers of bone resorption such as N-telopeptide of type-1 collagen, C-terminal telopeptide of type 1-collagen and pyridinoline cross-links, and markers of bone formation such as bone-specific alkaline phosphatase, osteocalcin, and N-terminal propeptide of type 1 procollagen before and after 3 months after bisphosphonate initiation can be helpful in monitoring the effectiveness of the medication in inhibiting bone resorption and measuring compliance. However, these assays are fraught with significant variability within individual patients and poor standardization, so they are not routinely used.

Alkaline phosphatase should be monitored at 6 to 12 weeks after the treatment initiation in patients with a history of Paget disease and should be repeated at 6-month to 12-month intervals.[8][9]

Enhancing Healthcare Team Outcomes

There is no question that the bisphosphonates can reduce the risk of osteoporosis but the drugs are also expensive and have some serious adverse effects. Pharmacists should assist in monitoring the patient for adverse events and appropriate dosing. The key to treatment of osteoporosis is prevention, and it is here that the role of nurses is vital. The nurses should encourage the public to modify their lifestyle to reduce the risk of osteoporosis. This means discontinuing tobacco, becoming physically active and limiting the intake of caffeine, alcohol and animal protein and at the same time increasing the intake of dairy products. Individuals at risk for osteoporosis should be encouraged to undergo periodic bone densitometry studies to diagnose the condition early and take steps to prevent fractures. The patient with confirmed osteoporosis should have a dietary and physical therapy consult before discharge. Finally, low impact exercises such as walking and bicycling are recommended.[10][11] (Level V)

Outcomes

The prognosis for patients who have early detection and treatment of osteoporosis is good. Patients can increase their bone mass and lower the fracture risk with bisphosphonates. But at the same time, they must make a positive change in their lifestyle. For those who have developed fractures, pain control and use of orthotic devices may be helpful. [12][13][14](Level V). Unfortunately, compliance with bisphosphonate therapy is not high due to the cost of the drugs and side effects. Hence, patient education is necessary.

Questions

To access free multiple choice questions on this topic, click here.

References

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Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiødt M. Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat. Rev. 2018 Sep;69:177-187. [PubMed: 30055439]
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Farrell KB, Karpeisky A, Thamm DH, Zinnen S. Bisphosphonate conjugation for bone specific drug targeting. Bone Rep. 2018 Dec;9:47-60. [PMC free article: PMC6037665] [PubMed: 29992180]
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Miller K, Steger GG, Niepel D, Lüftner D. Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer. Prostate Cancer Prostatic Dis. 2018 Nov;21(4):461-472. [PMC free article: PMC6283859] [PubMed: 29988100]
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Bernardi S, Di Girolamo M, Necozione S, Continenza MA, Cutilli T. Antiresorptive drug-related osteonecrosis of the jaws, literature review and 5 years of experience. Musculoskelet Surg. 2018 Jun 14; [PubMed: 29948937]
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US Preventive Services Task Force. Curry SJ, Krist AH, Owens DK, Barry MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW, Kemper AR, Kubik M, Landefeld CS, Mangione CM, Phipps MG, Pignone M, Silverstein M, Simon MA, Tseng CW, Wong JB. Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. JAMA. 2018 Jun 26;319(24):2521-2531. [PubMed: 29946735]
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Viswanathan M, Reddy S, Berkman N, Cullen K, Middleton JC, Nicholson WK, Kahwati LC. Screening to Prevent Osteoporotic Fractures: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2018 Jun 26;319(24):2532-2551. [PubMed: 29946734]
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Aparecida Cariolatto F, Carelli J, de Campos Moreira T, Pietrobon R, Rodrigues C, Bonilauri Ferreira AP. Recommendations for the Prevention of Bisphosphonate-Related Osteonecrosis of the Jaw: A Systematic Review. J Evid Based Dent Pract. 2018 Jun;18(2):142-152. [PubMed: 29747794]
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Simm PJ, Biggin A, Zacharin MR, Rodda CP, Tham E, Siafarikas A, Jefferies C, Hofman PL, Jensen DE, Woodhead H, Brown J, Wheeler BJ, Brookes D, Lafferty A, Munns CF., APEG Bone Mineral Working Group. Consensus guidelines on the use of bisphosphonate therapy in children and adolescents. J Paediatr Child Health. 2018 Mar;54(3):223-233. [PubMed: 29504223]
10.
Albergaria BH, Chalem M, Clark P, Messina OD, Pereira RMR, Vidal LF. Consensus statement: osteoporosis prevention and treatment in Latin America-current structure and future directions. Arch Osteoporos. 2018 Aug 24;13(1):90. [PMC free article: PMC6132387] [PubMed: 30143914]
11.
Nuti R, Brandi ML, Checchia G, Di Munno O, Dominguez L, Falaschi P, Fiore CE, Iolascon G, Maggi S, Michieli R, Migliaccio S, Minisola S, Rossini M, Sessa G, Tarantino U, Toselli A, Isaia GC. Guidelines for the management of osteoporosis and fragility fractures. Intern Emerg Med. 2019 Jan;14(1):85-102. [PMC free article: PMC6329834] [PubMed: 29948835]
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Kim J, Jang SB, Kim SW, Oh JK, Kim TH. Clinical effect of early bisphosphonate treatment for pyogenic vertebral osteomyelitis with osteoporosis: An analysis by the Cox proportional hazard model. Spine J. 2019 Mar;19(3):418-429. [PubMed: 30172897]
13.
Rouach V, Goldshtein I, Wolf I, Catane R, Chodick G, Iton A, Stern N, Cohen D. Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer. J Bone Oncol. 2018 Sep;12:91-95. [PMC free article: PMC6107893] [PubMed: 30148062]
14.
Lou S, Wang L, Wang Y, Jiang Y, Liu J, Wang Y. Combination therapy of anabolic and nonbisphosphonates antiresorptive agents for the treatment of osteoporosis: A meta-analysis. Medicine (Baltimore). 2017 Dec;96(52):e9534. [PMC free article: PMC6392516] [PubMed: 29384970]
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Bookshelf ID: NBK470248PMID: 29262103

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