Bisphosphonates are the mainstay of osteoporosis therapy. Extensive clinical evaluation supports their utility in stemming progression of the disease and in reducing fracture risk. In the course of evaluating the optimal duration of bisphosphonate treatment the FDA found little benefit of treatment beyond 5 years.[1,2] Moreover, examination of studies where bisphosphonates had been administered for at least 3 years, and for which fracture data were compiled, revealed that bone mineral density at the femoral neck and lumbar spine was maintained but without a consistent reduction in fracture rate. In addition, the continued use of bisphosphonates after 5 years is associated with an increased risk of otherwise rare subtrochanteric femoral fractures, osteonecrosis of the jaw, and esophageal cancer. These findings led the FDA to issue revised recommendations for the use of these drugs after 3-5 years.
The new FDA recommendation, indicated in revised labeling, states that “the optimal duration of use has not been determined. The need for continued therapy should be re-evaluated on a periodic basis.” However, no specific limits on the duration of treatment were imposed. The FDA review noted that "there is no agreement on the extent to which cumulative use of bisphosphonates increases the risk" of atypical fractures.
Warnings and precautions for the use of bisphosphonates include:
Severe irritation of upper gastrointestinal (GI) mucosa can occur. Follow dosing instructions. Use caution in patients with active upper GI disease. Discontinue if new or worsening symptoms occur.
Hypocalcemia can worsen and must be corrected prior to use.
Severe bone, joint, muscle pain may occur. Discontinue use if severe symptoms develop.
Osteonecrosis of the jaw has been reported.
Atypical femur fractures have been reported. Evaluate new thigh or groin pain to rule out an incomplete femoral fracture.
Bisphosphonates included in the updated FDA recommendation are only those approved to treat osteoporosis, including FOSAMAX, FOSAMAX PLUS D, ACTONEL, ACTONEL with Calcium, BONIVA, ATELVIA, and RECLAST (and their generic equivalents). Not included in the new recommendations and labeling are bisphosphonate drugs that are used only to treat Paget's disease or malignancy-associated hypercalcemia (DIDRONEL, ZOMETA, SKELID, and their generic products).
Bisphosphonates were first approved in the US for the treatment and prevention of osteoporosis in 1995. These drugs exert their beneficial actions through a combination of physical and biochemical actions. Notably, bisphosphonates bind to hydroxyapatite in bone, where they are incorporated into the mineral matrix. Release of the drug from the bone mineral matrix requires bone resorption, and reduction in bone resorption is the primary mode of action of bisphosphonates. The terminal half-life of alendronate in humans is estimated to exceed 10 years, probably reflecting the slow release of alendronate from the skeleton. It is estimated that after 10 years of oral treatment with alendronate sodium (10 mg daily), the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the GI. Therefore, bone acts as a substantial reservoir for bisphosphonates, and must be considered when making recommendations about their long-term use.
In light of the FDA re-evaluation, we expect that many physicians will suggest that patients limit the use of bisphosphonates to no more than 5 years and possibly to 3 years. Whether a bisphosphonate-free period will permit a useful second application of the bisphosphonates remains to be established.
AccessMedicine from McGraw-Hill © 2012 The McGraw-Hill Companies