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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.
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.
FDA Approved Routes/Administration Schedule for Osteoporosis
Some Bisphosphonate Comparative Efficacy Trials
Jansen JP, et al. Semin Arthritis Rheum. 2011; 40:275-284.
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
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
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
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.
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
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
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.
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)
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
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 (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.
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 (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.
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.
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.
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.
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).
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.
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.
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).
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.
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.
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.
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