Bisphosphonates

• Alendronate, risedronate and zoledronic acid are considered equally effective and are considered first-line therapy options for the treatment of osteoporosis in postmenopausal women and reduce vertebral, hip and nonvertebral fracture risk.[72399][72401] A meta-analysis of 10 randomized trials involving 23,384 postmenopausal females with osteoporosis, concluded 12.4 months were needed to avoid one nonvertebral fracture per 100 subjects taking bisphosphonates. [72400] Many agents are also effective for osteoporosis treatment due to chronic corticosteroid treatment.[50638][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 individuals requiring spine-specific osteoporosis therapy.[66837][67122][67125][72399][72401]
• 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.[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 individuals 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. [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 individuals with bisphosphonates is most favorable when the estimated risk for fracture is high.[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 or risedronate regimen is also effective for this indication.[43421][63474] [72403]
• Alendronate or risedronate may stabilize osteolytic lesions in these individuals, reduce pain, and improve quality of life; however, the effect of an oral bisphosphonate may not be as durable as with zoledronic acid and retreatment with these oral drugs may be required between 1 and 6 years.[29352][28644][52249][63474]
• Pamidronate is also indicated for Paget's disease but requires a 4-hour infusion for 3 consecutive days to achieve a total dose of 90 mg. [31027]

• Generally, zoledronic acid and pamidronate are considered to be equally effective in treating hypercalcemia of malignancy; however, evidence shows that the response rate is higher with zoledronic acid than with pamidronate and zoledronic acid is easier to administer.[58724][72407]
• While either denosumab or an IV bisphosphonate are reasonable treatment options, some clinical guidelines recommend the use of denosumab over IV bisphosphonates for hypercalcemia of malignancy with the addition of calcitonin when severe hypercalcemia is present.[72407]

• Clinical practice guidelines support the use of bisphosphonates for the treatment of bone metastases in individuals with multiple myeloma or breast cancer.[72408][72409]
• Bone-modifying agents are recommended for individuals with metastatic breast cancer with evidence of bone destruction. One bone-modifying agent is not recommended over another. IV pamidronate and zoledronic acid are generally considered equally effective in reducing skeletal-related adverse events in individuals with bone metastases.[72409]
• Ibandronate has been used orally and parenterally for this purpose in selected individuals, but doesn't have a labeled indication for the treatment of bone metastases. A meta-analysis showed similar efficacy to zoledronic acid in reducing skeletal-related events, but ibandronate recipients were likely to experience more abdominal pain and less adverse renal effects compared to zoledronic acid.[72410]

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.[31826][43421]

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 individuals remain upright for at least 30 minutes following the dose and take the medication with at least 4 to 8 ounces of water, depending on the product. Individuals prescribed bisphosphonates need to strictly adhere to instructions for administration, remaining upright, and taking the product exactly as directed to help limit upper GI events. If a possible esophageal reaction, such as irritation, worsening heartburn or pain upon swallowing develops, the individual should discontinue the medication and inform the care team. Rare cases of gastric and duodenal ulcers have been reported.[28644][29558][42080][52249]

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 individuals had relief of symptoms after stopping. A subset of individuals had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.[28644][29558][42080]

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. Individuals with suspected ONJ should be referred to an oral surgeon; however, oral surgery may exacerbate the condition. Consider discontinuing therapy in individuals who develop ONJ after a risk/benefit analysis.[28644] [29558][42080][43421]

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated individuals. 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 individuals 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 individuals 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 individuals 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 individuals 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.[28644][29558][42080][52249]

Zoledronic acid may be associated with a modest increase in the risk of atrial fibrillation, but studies have not consistently demonstrated the clinical significance of this finding based on prescribing information. A meta-analysis concluded that there is no significant association between oral or intravenous bisphosphonate use and total major adverse cardiovascular events (MACE) such as stroke, myocardial infarction, or cardiovascular death. One retrospective cohort study of 82,704 new users of bisphosphonates identified a 25% reduction in cardiovascular events responsible for hospitalizations among those with 80% or better adherence rate when compared to controls. However, another retrospective cohort study utilizing a large record database, revealed 16% increased risk of MACE among bisphosphonate users compared to controls, which was also statistically significant.[43421][72395][72397]

Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of oral bisphosphonates. Therefore, instructions should be provided 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).[28644][29558][42080]

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 individuals taking aspirin-containing products. However, NSAIDs may be administered to individuals taking bisphosphonates with caution; in some studies where a majority of subjects received concomitant NSAIDs with or without bisphosphonates, the incidence of upper GI adverse events was similar in people taking a bisphosphonate compared to those taking placebo.[28644][29558][42080]

Coadministration of certain bisphosphonates with other potentially nephrotoxic drugs (e.g., cyclosporine, aminoglycosides, loop diuretics) 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.[31027][43421]

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 individuals remain upright for at least 30 minutes following the dose; specific product instructions should be strictly followed. All the oral bisphosphonates are contraindicated in individuals 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 individuals with hypocalcemia. Hypocalcemia must be corrected before initiating therapy. Ensuring adequate dietary intake of calcium and vitamin D during treatment is especially important in individuals who are taking bisphosphonates for Paget 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 individuals with a creatinine clearance less than 35 mL/minute or evidence of acute renal impairment. All bisphosphonates should be used with caution in individuals with renal impairment; renal function monitoring is recommended. Alendronate, ibandronate, risedronate, pamidronate, and zoledronic acid are not recommended in individuals with severe renal impairment.[28644][29352][29558][31027][43421][58724]