Drug Criteria & Outcomes

"Breaking" update on bisphosphonate use in postmenopausal osteoporosis

By Ashley Morgan, PharmD Candidate, Auburn University

It is a well-known fact that as we get older, our bones lose mass and become increasingly weaker. For the 34 million Americans who have low bone mass, there is a much greater risk of developing osteoporosis, which is associated with a higher incidence of broken bones.

Along with broken bones comes the effect on morbidity, mortality, and health care costs, which are three primary concerns for any disease state and its treatment. All fractures may result in chronic pain, disability, deformity, and/or depression. A hip fracture associated with osteoporosis can increase mortality by 10-20%. Direct medical costs associated with treatment of fractures related to osteoporosis approached $18 billion in 2002. To prevent osteoporotic fractures, action must be taken to decrease the development of osteoporosis.


The most common method of preventing osteoporosis begins years before the majority of patients begin to see any symptoms associated with decreased bone mass. Including adequate amounts of calcium and vitamin D in the diet is important regardless of age; however, getting enough during childhood and adolescence when bone is actively growing is vital to future bone health. A daily calcium intake of 1,300 mg is recommended for all children and adolescents ages 9-18 years. Adults ages 19-50 years should consume 1,000 mg of calcium daily, and 1,200 mg is recommended for adults age 51 years and older.

To ensure maximum calcium absorption, adequate vitamin D consumption (200 IU for those ≤ age 50, 400 IU for those ages 51-70, and 600 IU for everyone age 71 and older) is necessary. To prevent osteoporosis development, it is also important to get adequate weight-bearing aerobic and strengthening exercise. Decreasing alcohol and caffeine intake and implementing smoking cessation are also important to bone health.

Bisphosphonate Treatment

An ever-increasing number of women experience bone loss despite following diet and exercise recommendations. This population requires pharmacologic therapy to prevent or treat osteoporosis. Available classes of antiresorptive medications include bisphosphonates, selective estrogen receptor modulators (SERMs), estrogens, parathyroid hormone, and calcitonin. All of the medications in these respective classes demonstrate similar reduction in vertebral fracture rates in postmenopausal women. This article will focus on the use of bisphosphonates for the treatment of osteoporosis.

Bisphosphonates provide the greatest increases in bone mineral density among the antiresorptive therapies by binding to bone apatite, or active sites of bone remodeling. Osteoclast binding to bone is inhibited because these destructive cells cannot adhere to bone surfaces which contain bisphosphonates. Although these agents have been proven efficacious at increasing bone mineral density, there are several disadvantages to the use of these medications.

Oral bisphosphonates (alendronate, risedronate, and ibandronate) are associated with adverse effects such as heartburn, esophageal irritation, esophagitis, abdominal pain, diarrhea, and other GI effects. Alendronate and risedronate therapy has been linked to severe bone, joint, and muscle pain, as well as ocular inflammation. Loss of teeth and osteonecrosis of the jaw have been reported with IV bisphosphonates given at high doses and rarely with oral alendronate.

To avoid esophageal injury and to ensure adequate absorption, there are important administration recommendations for patients taking oral bisphosphonates. They must be taken following an overnight fast with eight ounces of plain water while the patient is in an upright position. The patient must avoid taking anything by mouth, with the exception of plain water, for at least 30 minutes (60 minutes for ibandronate).

Bisphosphonate therapy is also associated with hypocalcemia and renal toxicity, so serum calcium and creatinine should be monitored before beginning and throughout treatment with these agents.

Alendronate (Fosamax®) and risedronate (Actonel®) were the first two agents in this class to be approved by the FDA for prevention and treatment of postmenopausal osteoporosis. Both of these medications also have indications for treatment of men with osteoporosis and are administered orally. For prevention of osteoporosis, alendronate 5 mg ($79 for a 30-day supply) is administered daily or 35 mg ($73 for four doses) is given weekly. In regimens for the treatment of osteoporosis, doses given for prevention are doubled; a daily dose of 10 mg costs approximately $75 for a 30-day supply, and four doses of 70 mg weekly costs $73. Fosamax plus D is currently available, and it contains 2,800 IU of vitamin D3 in addition to the 70 mg weekly dose of alendronate. This formulation has a comparable price with the regular weekly dose of alendronate without vitamin D supplementation.

Similar to alendronate, risedronate is equally effective given orally once daily, once weekly, or monthly (two doses given on consecutive days). Doses recommended for treatment and prevention of osteoporosis include 5 mg daily, 35 mg weekly, or 150 mg monthly (two doses of 75 mg). A 30-day supply of 5 mg tablets costs approximately $75, and four 35 mg tablets cost $72. Actonel® with Calcium is a product that co-packages the 35 mg tablet of risedronate given weekly with calcium carbonate tablets each containing 500 mg of elemental calcium to be taken on the remaining six days of the week.

Ibandronate (Boniva®) was the third bisphosphonate to receive FDA approval for prevention and treatment of osteoporosis. Ibandronate is available in an oral and intravenous formulation. Orally, a patient can either take 2.5 mg daily or 150 mg monthly to increase bone mineral density. Alternatively, an intravenous dose of 3 mg of ibandronate can be given once every three months. A one-year trial comparing two doses of the IV formulation to 2.5 mg daily oral ibandronate revealed a statistically significant (P < 0.001) increase in bone mineral density in both of the IV doses. The IV formulation is also associated with decreased adverse effects which contribute to increased patient compliance.

The most recent bisphosphonate to receive FDA approval for treatment of postmenopausal osteoporosis is zoledronic acid (Reclast®). This medication was approved for treatment of Paget's disease before receiving approval for osteoporosis in August 2007. Zoledronic acid is unique among the bisphosphonates because it is only given once a year as a 5 mg intravenous infusion. A randomized, double-blinded, clinical trial was published in the New England Journal of Medicine comparing the zoledronic acid once-yearly 15-minute infusion to placebo. This study had a duration of three years and included 7,765 postmenopausal women ages 65-89 years. The zoledronic acid treatment group demonstrated significant reductions in the following types of fractures: morphometric vertebral, hip, nonvertebral, and any clinical fracture.

The five most common adverse events experienced by patients in the study within three days of infusion of zoledronic acid were pyrexia, myalgia, influenza-like symptoms, headache, and arthralgia. The use of this medication can cause hypocalcemia, so calcium and vitamin D supplementation is recommended. Zoledronic acid was also associated with an increase in serum creatinine of > 0.5 mg/dL; however, theses changes were transient and no significant difference was observed in this group compared to placebo at the end of the three-year study period. Although an increase in the incidence of serious atrial fibrillation was observed in the zoledronic acid treatment group, no statistical difference in the prevalence of atrial fibrillation was found a subgroup of 559 patients who underwent electrocardiography monitoring. The authors of the study recommend further trials with zoledronic acid to accurately assess the association observed between zoledronic acid use and atrial fibrillation.

There was no difference between the treatment and placebo group in incidence of stroke. Throughout the study period, there were no spontaneous reports of osteonecrosis of the jaw. Zoledronic acid was generally well-tolerated in study participants, but patients receiving this medication should be regularly monitored for all of the adverse events mentioned above.

Cost and reimbursement

At first glance, the price of zoledronic acid may seem like a significant disadvantage. The medication costs $1,042 for a single 5 mg dose. Zoledronic acid is covered by Medicare, and most reimbursement is expected to come from either Medicare Part A or Part B. Medicare is expected to pay 80% of the cost while the patient or secondary insurer pays 20% of cost. Thus, the patient is responsible for paying $208 when receiving the injection; this would correspond to a monthly cost of around $17 for the medication, which is comparable to the cost of oral bisphosphonate therapies. Zoledronic acid is also expected to be covered under private insurance and managed care organizations, but may require prior authorization.


Postmenopausal osteoporosis is a very prevalent disorder and is commonly treated with bisphosphonate therapy. The oral agents in this class are very efficacious at increasing bone mineral density but are associated with some negative adverse effects and restrictive administration recommendations. The once-yearly zoledronic acid infusion offers an effective alternative to the oral options with a well-tolerated adverse effect profile. All bisphosphonate users should be reminded that calcium and vitamin D supplementation is still vital to bone health despite pharmacological treatment for osteoporosis.


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National Osteoporosis Foundation web site. Available at: www.NOF.org. Accessed Sept. 24, 2007.

O'Connell MB, Seaton TL. Osteoporosis and osteomalacia. In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysological Approach. 6th ed. New York, NY: McGraw-Hill; 2005:1645-1669.

Reclast [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2007.