Bisphosphonates

• 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][50638][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

• 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]

• 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]

• 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]

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.[50525][63833]

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).[28644][29352][29558]

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 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]

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]