Continuing Education Activity

Bisphosphonates define a class of drugs widely indicated since the 1990s to treat osteoporosis both in men and women. Their effectiveness in treating osteoporosis and other conditions is related to their ability to inhibit bone resorption. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment of patients using bisphosphonate drugs.

Objectives:

• Summarize the mechanism of action of bisphosphonates.
• Identify the approved indications for bisphosphonate therapy.
• Review the potential adverse events for bisphosphonate drugs.
• Outline the importance of improving care coordination among the interprofessional team to improve outcomes for patients using bisphosphonate therapy for indicated conditions.

Indications

Bisphosphonates define a class of drugs widely indicated since the 1990s to treat osteoporosis both in men and women. Their effectiveness in treating 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 the treatment of osteogenesis imperfecta in children as well as adults and the prevention of glucocorticoid-induced osteoporosis.

Mechanism of Action

Bisphosphonates have a structure similar to native pyrophosphate and divide 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 osteoclasts resorb bone, the bisphosphonate embedded in the bone is 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 that competes with adenosine triphosphate in the energy metabolism of the cell. This situation initiates osteoclast apoptosis, which in turn leads to an overall decrease in bone breakdown.

Nitrogen-containing bisphosphonates are much more potent antiresorptive agents than non-nitrogen-containing bisphosphonates. Also, non-nitrogen-containing bisphosphonates are found to have a high potential to inhibit bone mineralization and can cause osteomalacia. For this reason, they are no longer in broad-based use.

Efficacy Of Bisphosphonates

All bisphosphonates improve bone mineral density in postmenopausal women with osteoporosis. Alendronate, risedronate, and zoledronic acid decrease the risk of spine, hips, and other nonvertebral fractures. Ibandronate has not consistently been shown to reduce the risk of hip fractures.

• Alendronate: Reduces vertebral fracture risk by about 50%, hip fractures, and other nonvertebral fractures by about 30%.[6][7]
• Risedronate: Reduces vertebral and nonvertebral fractures by about 40%.[8]
• Zoledronic acid: Reduces vertebral fracture risk by about 70%, hip fractures, and other nonvertebral fractures by about 35%.[9][10]
• Ibandronate: Reduces vertebral fractures by about 50%. No reduction in risk of nonvertebral fractures.[11]

Administration

Alendronate, risedronate, and ibandronate are given orally, most commonly at weekly (alendronate, risedronate) or monthly (risedronate and ibandronate) intervals. The administration of zoledronic acid and pamidronate is intravenous, and there is also an intravenous preparation of ibandronate. Intravenous preparations are beneficial in patients who cannot tolerate oral bisphosphonates or where oral bisphosphonates are contraindicated, such as the presence or history of esophageal stricture.[12][13]

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 six months, and risedronate is given 30 mg orally daily for two 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 to treat 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. Patients should take oral bisphosphonates as the first medication in the morning and more than 30 minutes before the first food intake, beverage (except water), or any other medication. Patients should receive instruction to stay upright, 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 decrease the absorption of oral bisphosphonates.

Adverse Effects

Bisphosphonates are generally well tolerated, with most adverse effects being non-severe. Reports exist of some serious adverse effects with bisphosphonate use, but these are extremely rare.

1. Gastrointestinal Adverse Effects

All oral bisphosphonates have correlations with upper gastrointestinal adverse effects, including gastrointestinal reflux, esophagitis, esophageal/gastric ulcers, and gastritis. Gastrointestinal side effects are the most common reason for the discontinuation of oral bisphosphonates. The risk increases in patients who take concomitant NSAIDs.[14] Proper administration of oral bisphosphonates may help to reduce the risk of these gastrointestinal adverse effects. Clinicians should avoid oral bisphosphonates in patients who are at a higher risk of these gastrointestinal adverse effects, including those who are not able to sit upright for at least 30 minutes after taking the bisphosphonate, and patients with esophageal disorders such as achalasia, esophageal stricture, Barrett's esophagus, and esophageal varices and patients who have undergone Roux-en-Y gastric bypass. The risk of upper gastrointestinal adverse effects may be slightly lower with risedronate compared to alendronate.  Other gastrointestinal adverse effects include abdominal pain, diarrhea, and constipation, which can occur in up to 5% of patients.

2. Infusion Reaction

Intravenous bisphosphonates have associations with an infusion/acute phase reaction characterized by flu-like symptoms, fevers, myalgias, arthralgias, and headaches within 1 to 3 days of the infusion.  The symptoms usually respond to acetaminophen or NSAIDs and resolve within a few days.  The risk of the acute phase reaction is highest with the 1st infusion of the intravenous bisphosphonate (up to 30%), and the risk declines significantly with further dosing (less than 7%). This infusion/acute phase reaction is usually mild and self-limiting and does not necessitate discontinuation of the intravenous bisphosphonate therapy.

3. Hypocalcemia

Transient hypocalcemia is a common issue secondary to bisphosphonate use, and the incidence may be as high as 18%. Severe hypocalcemia, however, is rare. Hypocalcemia is more common, secondary to intravenous bisphosphonates, and in patients with an underlying untreated vitamin-D deficiency, hypocalcemia, poor calcium intake, and hypoparathyroidism.[15][16] Calcium and vitamin-D deficiency require correction before initiating bisphosphonates, especially intravenous bisphosphonates.

4. Arthralgia and Myalgia

Bone, joint, and muscle pain can occur secondary to bisphosphonates.  The symptoms are rare, with an incidence of less than 5%. Symptoms are usually mild, although there have been reports of severe pain.[17] The onset of musculoskeletal pain can occur within days two years after starting bisphosphonates and may not always resolve entirely after discontinuation of bisphosphonates.

5. Ocular Adverse Effects

Rare ocular adverse effects, including uveitis, conjunctivitis, and scleritis, have been reported with all bisphosphonates.[18] The incidence is infrequent (less than 1%).[19]

6. Atypical Femur Fractures

Another rare but serious adverse effect of bisphosphonates is an atypical femoral fracture, typically involving diaphysis or sub-trochanteric region of the femur. Over suppression of bone turnover, pathophysiological alteration in the bone quality, and impairment of fracture repair process, or thought to be responsible for these atypical femur fractures, which are considered stress fractures. The incidence is 3.2 to 50 cases per 100,000 person-years, and the risk increases with the duration of exposure to bisphosphonates.  Atypical femur fractures are usually not seen within the first five years of bisphosphonate treatment, with most cases reported with more than seven years of bisphosphonate treatment. Initial symptoms are dull aching pain in the groin. Plain X-rays may reveal cortical thickening. Findings of radiographs, especially if early/mild, shall be confirmed by further imaging with magnetic resonance imaging (MRI) or bone scintigraphy. Bisphosphonates shall be discontinued in patients who suffer an atypical femur fracture in one leg; if the drug is not stopped, these patients are at higher risk of developing atypical femur fracture in the other leg. Discontinuation of bisphosphonate is associated with a decline in this risk. A drug holiday shall be considered after prolonged exposure to bisphosphonates when clinically appropriate.

7. Osteonecrosis of the Jaw

One of the most severe adverse effects is bisphosphonate-related osteonecrosis of the jaw (BRONJ). Most cases of BRONJ have occurred in patients with multiple myeloma and breast cancer treated with high doses of intravenous bisphosphonates. It has also been reported in patients taking bisphosphonates for osteoporosis with an incidence of approximately 1 in 10,000 to 1 in 100,000.[20] The risk factors for BRONJ include the use of intravenous bisphosphonates, higher dose and prolonged duration of exposure, pre-existing dental disease, dental implants, dental extraction, and poorly fitting dentures. The use of glucocorticoids and anticancer therapy, history of diabetes, smoking, and cancer may be other risk factors.[20] A diagnosis of BRONJ must meet all the following criteria:

• History of treatment with a bisphosphonate;
• Those who had more than eight 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. Standard 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. Standard treatment includes symptomatic treatment, systemic antibiotics, and superficial surgical debridement of the necrotic bone.

If planning an invasive dental procedure, the recommendation is to delay the initiation of bisphosphonate therapy for a few months to allow for healing of the jaw. In patients who have been on bisphosphonates for more than four years and are planning for an invasive dental procedure, recommendations are to stop the bisphosphonate two months before the dental procedure and resume them after jaw healing has been complete. When clinically appropriate, consider a drug holiday after 3 to 5 years of intravenous bisphosphonates and 5 to 10 years of oral bisphosphonates.

Contraindications

Contraindications to bisphosphonates include:

1. History of hypersensitivity to the bisphosphonate
2. Hypocalcemia
3. Chronic kidney disease with a glomerular filtration rate of less than 30 to 35 mL/min
4. Avoid oral bisphosphonates in patients with esophageal disorders 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).
5. History of atypical femur fracture secondary to bisphosphonates
6. History of osteonecrosis of the jaw secondary to bisphosphonates

Monitoring

Serum calcium, vitamin D, and renal function require baseline monitoring before initiating bisphosphonates. In patients with calcium and/or vitamin D deficiency, the recommendation is to correct the deficiency before starting bisphosphonates. The clinician should take a detailed dental history before initiating bisphosphonates, and therapy initiation should delay if planning an invasive dental procedure in the near future. Bone mineral density shall 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 an assessment of back pain to check for the development of compression fractures are also necessary.

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 three months after bisphosphonate initiation can help monitor 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.[21][22]

Enhancing Healthcare Team Outcomes

Bisphosphonates are very efficacious in the prevention of fractures in patients with osteoporosis. They are relatively safe, although they do have correlations with some rare and serious adverse effects. Patient education is crucial to ensure compliance and effective treatment of osteoporosis. Patients shall receive education to eliminate other risk factors associated with osteoporotic fractures, including smoking cessation, weight-bearing exercises, avoiding excessive alcohol intake, and increasing dairy product intake.[23][24] The nursing team can assist with patient education and ensuring compliance with medications. Primary care clinicians play the most important role in identifying individuals with a high risk for osteoporosis and fractures and ensure primary prevention. Pain control and orthotic devices can assist patients who have already developed fractures.[25][26][27] Referral to specialists such as endocrinologists or rheumatologists shall be considered, especially in complicated cases. These are all examples of the kind of interprofessional teamwork necessary to manage treatment with bisphosphonates successfully. Early detection, patient education, and an interprofessional team approach can ensure better outcomes and prevent fractures in high-risk patients. [Level 5]