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Dec.21.2021

Bisphosphonates

Summary

  • Bisphosphonates are used for the treatment and prevention of bone fractures in patients with or at risk of osteoporosis, the prevention of skeletal events in patients with bone metastases and multiple myeloma, Paget's disease, and for the treatment of hypercalcemia of malignancy.
  • Bisphosphonates work by inhibiting osteoclast-mediated bone resorption without directly inhibiting bone formation; second- and third-generation nitrogen-containing bisphosphonates (e.g., alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid) are more potent osteoclast inhibitors than first generation bisphosphonates (e.g., etidronate).
  • Most second- and third-generation bisphosphonates are considered first-line therapy for the treatment of osteoporosis in postmenopausal women; many agents are also useful for osteoporosis treatment in men and osteoporosis due to chronic corticosteroid treatment. Ibandronate is not considered the first-line bisphosphonate choice since sufficient evidence is limited to reductions in vertebral fractures.
  • For osteoporosis prevention, the second- and third-generation bisphosphonates appear to offer similar benefits across the class to increase bone mineral density; the balance of costs, benefits, and harms of treating osteopenic patients with bisphosphonates is most favorable when the estimated risk for fracture is high.
  • For osteoporosis, zoledronic acid is given once yearly as a short IV infusion but may cause acute phase reactions. Ibandronate may be given intravenously as an injection every 3 months. Orally available bisphosphonates (alendronate, risedronate, ibandronate) are taken daily, weekly, or monthly and require patients to remain standing or sitting up for at least 30 minutes after administration, and medication adherence may be an issue for some patients.
  • Guidelines for Paget's disease prefer the use of zoledronic acid due to the superiority of this drug in providing control of the disease and longer durability of response following single-dose administration.
  • IV pamidronate and zoledronic acid are considered equally effective in reducing skeletal-related adverse events in patients with bone metastases; however, data from one pooled analysis demonstrated superior complete response rates with zoledronic acid compared with pamidronate in patients with hypercalcemia of malignancy.
  • Risks of bisphosphonate treatment include osteonecrosis of the jaw. When given orally, there is a risk for esophageal, stomach or intestinal ulcers, esophagitis, and esophageal erosions. Patients with osteoporosis at low-risk for fracture should be considered for bisphosphonate discontinuation after 3 to 5 years of use and reassessed periodically for fracture risk.

Pharmacology/Mechanism of Action

Bisphosphonates bind to hydroxyapatite in the bone and prevent bone resorption by inhibiting osteoclastic activity and inducing osteoclast apoptosis; bone formation is not directly affected. Oral bisphosphonates are poorly absorbed (less than 1%) from the gastrointestinal tract, and only about 50% of absorbed drug is taken up in bone with the rest being excreted unchanged in the urine. The addition of a nitrogen or amino group to the bisphosphonate agent increases the potency for osteoclast inhibition. Non-nitrogen containing agents, etidronate and tiludronate, are considered first generation bisphosphonates. Zoledronic acid has the highest potency for mineral matrix binding.[50514]

 

 

Relative Potency

Etidronate

1

Tiludronate

(off market)

10

Pamidronate

100

Alendronate

500

Ibandronate

1000

Risedronate

2000

Zoledronic Acid

10,000

Therapeutic Use

Selection of one bisphosphonate over another is often based on patient specific factors (e.g., renal function, pre-existing esophageal disease), patient or provider dosage form preference (for osteoporosis), or cost.

Osteoporosis

  • Alendronate, risedronate and zoledronic acid are considered equally effective and most of the newer bisphosphonates are considered first-line therapy options for the treatment of osteoporosis in postmenopausal women and reduce both vertebral and nonvertebral fracture risk. Many agents are also effective for osteoporosis treatment due to chronic corticosteroid treatment.[62806][61918][50521][62806][66837][67122][67125]
  • Ibandronate is not considered a first-line bisphosphonate choice for osteoporosis treatment since evidence is insufficient to determine the effect of ibandronate on nonvertebral fractures (e.g., hip fractures); experts state ibandronate may be considered initially for patients requiring spine-specific osteoporosis therapy.[62806][66837][67122][67125]
  • Bisphosphonates are effective in men with osteoporosis to increase bone density and reduce the risk for vertebral fracture; however, study data are less robust in men regarding reductions in nonvertebral fracture. There is a lack of evidence regarding the most effective therapies in men.[62806][62806][66837][67122][67125]
  • The optimal treatment duration has not been determined; reevaluate treatment on a periodic basis. Continue an oral bisphosphonate for up to 10 years in postmenopausal women who are initially at very high risk of fracture and remain at high risk. Consider discontinuation after 5 years of stability in high-risk postmenopausal women.[66837] For those patients at low or moderate risk for fracture, consider stopping alendronate after 3 to 5 years.[28644] After discontinuation of therapy, continue to periodically reassess fracture risk.[62806][66837][67122][67125]
  • For osteoporosis prevention, the second- and third-generation bisphosphonates appear to offer similar benefits across the class to increase bone mineral density; the balance of costs, benefits, and harms of treating osteopenic patients with bisphosphonates is most favorable when the estimated risk for fracture is high.[62806][50515]

 

FDA Approved Routes/Administration Schedule for Osteoporosis

   

Postmenopausal Women

MaleGlucocorticoid-Induced

Treatment

Prevention

Alendronatedaily

X

X

X

X

weekly

X

X

X

 
IbandronateDaily

X

X

  
Weekly

X

X

  
q3 months (IV)

X

   
Risedronatedaily

X

X

 

X

weekly

X

X

X

 
monthly

X

X

  
Zoledronic acidYearly (IV)

X

 

X

X

q2 yrs (IV) 

X

  

Paget's disease

  • Guidelines for Paget's disease prefer the use of zoledronic acid due to the superiority of this drug in providing control of disease and a longer-term duration of response following single-dose administration; although, oral alendronate and risedronate regimens are also effective for this indication.
  • All of the mentioned bisphosphonates stabilize osteolytic lesions in these patients, reduce pain, and improve quality of life; however, the effect of alendronate or risedronate may not be as durable as with zoledronic acid and retreatment with these oral drugs may be required between 1 and 6 years.[63474][28644][52249]

Hypercalcemia of malignancy

  • Generally, zoledronic acid and pamidronate are considered to be equally effective in treating hypercalcemia of malignancy; however, a pooled analysis of 2 trials comparing zoledronic acid to pamidronate found that zoledronic was more effective than pamidronate in reducing serum calcium.[50522]

Bone metastases

  • Clinical practice guidelines support the use of bisphosphonates for the treatment of bone metastases in patients with multiple myeloma[50518][50519] and breast cancer.[50520]
  • IV pamidronate and zoledronic acid are generally considered equally effective in reducing skeletal-related adverse events in patients with bone metastases.[50523]
  • Ibandronate has been used orally and parenterally for this purpose in selected patients.[63524][63527]

Comparative Efficacy

Some Bisphosphonate Comparative Efficacy Trials

Citation

Design

Results

Osteoporosis

Jansen JP, et al. Semin Arthritis Rheum. 2011; 40:275-284.[50521]

Meta-analysis of 8 randomized controlled trials evaluating the efficacy of bisphosphonates for prevention of vertebral, hip and nonvertebral-nonhip fractures in over 20,000 postmenopausal women with osteoporosis followed for 3 years

Vertebral fractures

Zoledronic acid vs Placebo: RR = 0.3; 95% CrI, 0.23-0.37

Zoledronic acid vs Alendronate: RR = 0.55; 95% CrI, 0.41-0.76

Zoledronic acid vs Risedronate; RR = 0.5; 95% CrI, 0.36-0.7

Zoledronic acid vs Ibandronate: RR = 0.58; 95% CrI, 0.37-0.92

 

Hip fractures

Zoledronic acid vs Placebo: RR = 0.58; 95% CrI, 0.41-0.82

Zoledronic acid vs Etidronate: RR = 0.05; 95% CrI, 0.00-0.7

Alendronate vs Placebo: RR = 0.61; 95% CrI, 0.39-0.95

Alendronate vs Etidronate: RR = 0.05; 95% CrI, 0.00-0.75

 

Nonvertebral-nonhip fractures

Zoledronic acid vs Placebo: RR = 0.8; 95% CrI, 0.68-0.94

Risedronate vs Placebo: RR = 0.62; 95% CrI, 0.43-0.88

Risedronate vs Ibandronate: RR = 0.56; 95% CrI, 0.35-0.9

Hypercalcemia / Bone Metastases

Machado M, et al. Clin Ther. 2009;31:962-979.[50523]

Meta-analysis of 18 randomized controlled trials that evaluated the efficacy of clodronate, pamidronate, and zoledronic acid in reducing skeletal-related events and overall mortality compared with placebo in cancer patients with metastatic bone disease

Skeletal-related event

Zoledronic acid vs Placebo: RR = 0.70; 95% CI, 0.61-0.81

Pamidronate vs Placebo: RR = 0.81; 95% CI, 0.73-0.91

 

Pathologic fractures

Zoledronic acid vs Placebo: RR = 0.6; 95% CI, 0.47-0.76

Pamidronate vs Placebo: RR = 0.9; 95% CI, 0.75-1.07

 

Reduction in hypercalcemia

Zoledronic acid vs Placebo: RR = 0.27; 95% CI, 0.1-0.72

Pamidronate vs Placebo: RR = 0.6; 95% CI, 0.41-0.86

Major P, et al. J Clin Oncol 2001;19:558-67.[50522]

Pooled analysis of 2 randomized, double-blind, double dummy clinical trials (n=287) that evaluated the efficacy and safety of zoledronic acid (4 or 8 mg IV) and pamidronate (90 mg IV) for treating hypercalcemia of malignancy

Rate of complete response by day 10 (normalization of calcium to < 10.8 mg/dl)

Zoledronic acid 4 mg: 88.4% (p=0.002 vs. pamidronate)

Zoledronic acid 8 mg: 86.7% (p=0.015 vs. pamidronate)

Pamidronate 69.7%

 

Time to relapse

Zoledronic acid 4 mg: 30 days (p=0.001 vs. pamidronate)

Zoledronic acid 8 mg: 40 days (p=0.007 vs. pamidronate)

Pamidronate 17 days

Abbreviations: CrI, credible interval; RR, relative risk

Adverse Reactions/Toxicities

Acute phase reactions

Acute phase reactions have been reported with bisphosphonate use, with fever being the most common symptom. Other flu-like syndrome symptoms include chills, flushing, bone pain, arthralgias, and myalgia. These reactions are more commonly reported with intravenous bisphosphonate therapy. Most symptoms start within 3 days of IV bisphosphonate therapy and resolve within 7 to 14 days or less. Many cases require no specific treatment. Premedication and subsequent treatment with acetaminophen may help with acute phase reaction symptoms.

Gastrointestinal adverse reactions

Gastrointestinal (GI) adverse effects are a concern with oral bisphosphonate therapy and include esophagitis, esophageal ulcers and erosions (some cases with bleeding and rarely followed by stricture or perforation), GI irritation, and gastric and duodenal ulcers. Oral bisphosphonates are better tolerated if patients remain upright for at least 30 minutes following the dose. Patients need to strictly adhere to instructions for administration, remaining upright, and taking the product exactly as directed to help limit upper GI events. Rare cases of gastric and duodenal ulcers have been reported. Rarely, esophageal cancer has also been reported with oral bisphosphonates which is thought to be associated with pre-existing esophageal pathology.

Musculoskeletal adverse reactions

Severe and sometimes incapacitating bone, joint, and/or muscular pain may occur after initiation of bisphosphonate therapy. The time to onset of symptoms typically varies from 1 day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported with bisphosphonate use. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, bone surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. Patients with suspected ONJ should be referred to an oral surgeon; however, oral surgery may exacerbate the condition. Consider discontinuing therapy in patients who develop ONJ after a risk/benefit analysis.

Bone Fractures

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These atypical breaks can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral, and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. Some reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Assess patients presenting with an atypical fracture for symptoms and signs of fracture in the contralateral limb. Consider interruption of bisphosphonate therapy after performing an individual risk/benefit assessment.

Atrial fibrillation

While bisphosphonates were thought at one time to be associated with atrial fibrillation, most evidence suggests that there is no increased risk, and any increased risk noted in any trial has been deemed by the FDA to be a chance finding. A 2015 meta-analysis concluded that there is no significant association between oral or intravenous bisphosphonate use and total cardiovascular events, stroke, myocardial infarction, or cardiovascular death. However, zolendronic acid was associated with a modest increase in risk of atrial fibrillation.[50525][63833]

Drug Interactions

The following represent the typical drug interactions noted with the bisphosphonates. Clinicians are advised to review patient medication profiles for potential interacting medications or supplements.

Mulitvalent cation-containing antacids, supplements, or vitamins

Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of oral bisphosphonates. Therefore, instruct patients to separate the administration of these agents. Depending on the specific bisphosphonate, the oral bisphosphonate should be administered 30 to 60 minutes before any oral medications, including medications containing multivalent cations (such as antacids, supplements or vitamins).

Aspirin and Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, including aspirin, are associated with gastrointestinal (GI) irritation, a risk for esophageal adverse events, and a risk of nephrotoxicity; bisphosphonates are also associated with these potential side effects. Some studies show a potential increase in upper GI events in patients taking aspirin-containing products. However, NSAIDs may be administered to patients taking bisphosphonates with caution; in some studies where a majority of patients received concomitant NSAIDs with or without bisphosphonates, the incidence of upper GI adverse events was similar in patients taking a bisphosphonate compared to those taking placebo.

Drugs that are nephrotoxic

Coadministration of certain bisphosphonates with other potentially nephrotoxic drugs (e.g., cyclosporine, aminoglycosides) may increase the risk of nephrotoxicity. This risk may be particularly relevant with intravenous use of pamidronate disodium or zoledronic acid infusions. Monitor for renal toxicity if concomitant use is required.

Safety Issues

Dental disease / Osteonecrosis of the jaw

Dental examination and preventive dentistry should be considered before starting bisphosphonate therapy, as dental extractions may be a risk factor for developing osteonecrosis of the jaw (ONJ). Additionally, patients should avoid oral surgery during bisphosphonate therapy if possible. Other risk factors for ONJ include poor oral hygiene, cancer diagnosis, concomitant therapies (e.g., chemotherapy, corticosteroids), and comorbidities (e.g., anemia, coagulopathy, infection).[28644][29352][29558]

Esophageal disease

Oral bisphosphonates may cause upper gastrointestinal mucosal irritation and may aggravate existing esophageal conditions such as Barrett's esophagus, dysphasia, gastritis, duodenitis, and ulcers. Oral bisphosphonates are better tolerated if patients remain upright for at least 30 minutes following the dose; specific product instructions should be strictly followed. All the oral bisphosphonates are contraindicated in patients with esophageal abnormalities such as stricture or achalasia.[28644][29352][29558]

Hypocalcemia

Hypocalcemia may occur with bisphosphonate use. Alendronate, ibandronate, zoledronic acid (Reclast), and risedronate are contraindicated in patients with hypocalcemia. Hypocalcemia must be corrected before initiating therapy. Ensuring adequate dietary intake of calcium and vitamin D during treatment is especially important in patients who are taking bisphosphonates for Paget's disease or for the treatment or prevention of osteoporosis.[28644][29352][29558]

Renal impairment

Bisphosphonates are excreted via the kidney and drug accumulation due to renal impairment can cause further renal dysfunction. Due to an increased risk of renal failure, zoledronic acid (Reclast only) is contraindicated in patients with a creatinine clearance less than 35 mL/minute or evidence of acute renal impairment. All bisphosphonates should be used with caution in patients with renal impairment; renal function monitoring is recommended. Alendronate, ibandronate, risedronate, pamidronate, and zoledronic acid are not recommended in patients with severe renal impairment.[28644][29352][29558][31027][43421][58724]

[28644]Fosamax (alendronate) tablets and oral solution package insert. Whitehouse Station, NJ: Merck and Co., Inc.; 2019 Aug.

[29352]Actonel (risedronate) tablets package insert. Madison, NJ: Allergan, USA, Inc.; 2019 Nov.

[29558]Boniva (ibandronate) tablets package insert. South San Francisco, CA: Genentech USA, Inc.; 2016 Dec.

[31027]Pamidronate disodium injection package insert. Lake Forest, IL: Hospira, Inc.; 2021 Apr.

[43421]Reclast (zoledronic acid) injection package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020 Apr.

[50514]Drake MT, Clarke BL, and Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008;83(9):1032-1045.

[50515]Agency for Healthcare Research and Quality (AHRQ) comparative effectiveness review no. 53. Treatment to prevent fractures in men and women with low bone density or osteoporosis: update of a 2007 report. Rockville, MD: U.S. Department of Health and Human Services, March 2012; AHRQ publication no. 12-EHC023-EF.

[50518]Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007;25(17):2464-2472.

[50519]Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 2009;20(8):1303-1317.

[50520]Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011;29(9):1221-1227.

[50521]Jansen JP, Bergman GJ, Huels J, et al. The efficacy of bisphosphonates in the prevention of vertebral, hip, andnonvertebral-nonhip fractures in osteoporosis: a network meta-analysis. Semin Arthritis Rheum 2011;40(4):275-284.

[50522]Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19(2):558-567.

[50523]Machado M, Cruz LS, Tannus G, et al. Efficacy of clodronate, pamidronate, and zoledronate in reducing morbidity and mortality in cancer patients with bone metastasis: a meta-analysis of randomized clinical trials. Clin Ther 2009;31(5):962-979

[50525]Kim SY, Kim MJ, Cadarette SM, et al. Bisphosphonates and risk of atrial fibrillation: a meta-analysis. Arthritis Res Ther 2010;12(1):R30.

[52249]Binosto (alendronate sodium) effervescent tablets for oral solution package insert. Morristown, NJ: Ascend Therapeutics; 2020 Oct.

[58724]Zoledronic acid injection package insert. Columbus, OH: BluePoint Laboratories; 2020 Jun.

[61918]Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for Diagnosis and Treatment of Osteoporosis. Endocr Pract 2016;22(Suppl 4):1-41.

[62806]Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Intern Med. 2017;166:818-839. Epub 2017 May 9. Erratum in: Ann Intern Med. 2017;167:448.

[63474]Singer FR, Bone HG 3rd, Hosking DJ, et al; Endocrine Society. Paget's disease of bone: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:4408-4422.

[63524]Body JJ, Diel IJ, Lichinitzer M, et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer. 2004;90:1133-1137.

[63527]Bondronat 6 mg (ibandronate) injection for dilution for infusion, European product label. Essex, UK; Atnahs Pharma UK Limited: 2018 April. Available at: https://www.medicines.org.uk/emc/product/9375/smpc

[63833]Kim DH, Rogers JR, Fulchino LA, Kim CA, Solomon DH, Kim SC. Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS One. 2015;10:e0122646. eCollection 2015.

[66837]Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocr Pract 2020;26(Suppl 1):1-46.

[67122]Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society. Menopause. 2021;28:973-997.

[67125]Eastell R, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2019;104:1595-1622.

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