FOSAMAX

FOSAMAX is used for the treatment or prevention of osteoporosis in women after menopause. It reduces the chance of having a hip or spinal fracture. FOSAMAX is also for the treatment of osteoporosis in both men and women receiving corticosteroid medications (for example, prednisone).

It works by reducing the activity of the cells that cause bone loss. Decreasing the faster rate of bone loss that occurs after menopause or with use of corticosteroid medications, increasing the amount of bone in most patients. These effects are seen as soon as three months after therapy with FOSAMAX has begun. These effects continue as long as you keep taking FOSAMAX. The density of bone is maintained or increased and the bone is less likely to fracture.

FOSAMAX is the only osteoporosis therapy with proven efficacy through 10 years²

Side Effects:
Like all prescription drugs, FOSAMAX may cause side effects. Side effects usually have been mild. They generally have not caused patients to stop taking FOSAMAX. Some patients treated with FOSAMAX experienced abdominal (stomach) pain. This is the most commonly reported side effect. Less frequently reported side effects are:

Nausea, heartburn, irritation or pain of the esophagus (the tube that connects your mouth with your stomach), vomiting, difficulty swallowing, a full or bloated feeling in the stomach, constipation, diarrhea, black and/or bloody stools, stomach or other peptic ulcers (some severe), and gas.

Bone, muscle or joint pain, headache, or an altered sense of taste were also experienced by some patients. Rarely, a rash (occasionally made worse by sunlight) or eye pain have occurred. Allergic reactions such as hives or, rarely, swelling of the face, lips, tongue and/or throat which may cause difficulty in breathing or swallowing have also been reported. Mouth ulcers have occurred when the tablet was chewed or dissolved in the mouth.

Instructions for taking FOSAMAX
These are the important things you must do to help make sure you will benefit from FOSAMAX:

If you have difficulty or pain upon swallowing, chest pain, or new or worsening heartburn, stop taking FOSAMAX and call your doctor.

It is important that you continue taking FOSAMAX for as long as your doctor prescribes it. FOSAMAX can treat your osteoporosis or help you from getting osteoporosis only if you continue to take it.

If you miss a dose do not take it later in the day. Continue your usual schedule of 1 tablet once a day the next morning.

MINNEAPOLIS, Sept. 22, 2003 - In one-year head-to-head trials comparing FOSAMAX® (alendronate sodium) once-weekly, the most prescribed medicineⁱ for osteoporosis treatment, to Evista, FOSAMAX 70 mg provided significantly greater increases in bone mineral density (BMD) at one-year at the lumbar spine and total hip compared to Evista (raloxifene) 60 mg once-daily. Findings from these two studies, one conducted in the U.S. and one internationally, were presented this week at the 25^th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR).

"These studies are important because they are the first to compare weekly alendronate to raloxifene once daily," said Risa Kagan, M.D., co-medical director, FORE-Foundation for Osteoporosis Research and Education, Oakland, Calif. and a researcher on the study. "Because these medicines work by different mechanisms, clinical studies like these provide doctors with helpful information on efficacy and tolerability, which helps in making treatment decisions for patients."

Significantly more women responded to treatment with FOSAMAX than with Evista
In both of these studies, after one year of treatment, postmenopausal women taking FOSAMAX experienced a two-fold increase in BMD at the lumbar spine, the primary endpoint, compared to patients receiving Evista (U.S. study: 4.4 percent increase from baseline for FOSAMAX versus 1.9 percent increase for Evista, p<0.001; international study: increases of 4.8 percent and 2.2 percent, respectively). At the total hip , FOSAMAX increased BMD by 2.0 percent after one year of treatment in the U.S. study compared to a 1.0 percent increase for Evista, (p< 0.001); international study: increases of, 2.3 percent and 0.8 percent, respectively.

Differences in efficacy at both the spine and hip were seen as early as six months in both studies. On a secondary study endpoint, bone mineral density at the hip trochanter, a specific region of the hip, FOSAMAX increased BMD 3.2 percent from baseline at 12 months compared to Evista, which provided a 1.8 percent increase in BMD at 12 months (p<0.001) in the U.S. study; international study: increases of 2.9 percent and 1.0 percent, respectively.

FOSAMAX was more effective than Evista on other endpoints measured in the studies. The percentage of patients either maintaining or increasing bone mineral density at the lumbar spine (= 0 percent increase in BMD at 12 months) was 94 percent for FOSAMAX compared to 75 percent for Evista at 12 months in the U.S. study; international study: 87 percent and 73 percent, respectively (p<0.001).

Both studies showed similar overall rate of upper GI events in the two treatment groups
In both studies, there were no significant differences between the two treatments in overall adverse events and no differences in upper gastrointestinal events; more than 97 percent of patients in each treatment group experienced no upper GI events that led to discontinuation (FOSAMAX, 97.7 percent, Evista, 98.3 percent).

The EFFECT (Efficacy of FOSAMAX vs Evista Comparison Trial) trials were double-blind, randomized, one-year studies conducted in 17 countries, including the U.S. In the U.S., 451 postmenopausal women with osteoporosis received either FOSAMAX 70 mg once-weekly (N=221) or Evista 60 mg once-daily (N=230) and, in addition, calcium 500 mg and vitamin D 400 mg daily. Internationally, 487 women participated, with 246 receiving FOSAMAX and 241 receiving Evista.

All patients in the studies had osteoporosis as defined by a BMD T-score of 2.0 standard deviations or greater below young normal mean bone mass at either the lumbar spine or total hip. BMD was measured in both groups at baseline and again at six and 12 months of treatment. All BMD measures were validated by a quality assurance center and laboratory tests were performed by a central testing facility.

All patients were at least 40 years of age or older and at least six months past menopause. Patients with a history of breast or uterine cancer, or who used medicines that included a bisphosphonate, a parathyroid hormone (PTH), estrogen, estrogen analogues, or selective estrogen receptor modulators (SERMS) within one year of the study were excluded from enrollment.

Laurie Barclay, MD

March 17, 2004 — Long-term use of alendronate continues to be protective against osteoporosis without causing harm, according to the results of a 10-year follow-up study published in the March 18 issue of the New England Journal of Medicine.

"The reduction in the risk of fracture during antiresorptive treatment has been related to the magnitude of changes in bone mineral density and remodeling activity," write Henry G. Bone, MD, from Michigan Bone and Mineral Clinic in Detroit, and colleagues from the Alendronate Phase III Osteoporosis Treatment Study Group. "Alendronate, a potent inhibitor of bone resorption, has produced sustained reductions in biochemical markers of bone remodeling into the premenopausal range and consistent dose-related increases in bone mineral density in a variety of populations, including elderly women."

In this multinational, double-blind study, postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. The initial three-year phase of the study compared three daily doses of alendronate with placebo. In years 4 and 5, women originally randomized to the placebo group received alendronate and then were discharged, while women in the original active-treatment groups continued to receive alendronate.

During years 6 and 7, and 8 through 10, women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Throughout the 10 years, blinding was continued, and women maintained their randomized group assignments.

Of 247 women who completed all four phases of the study, treatment with 10 mg of alendronate daily for 10 years was associated with mean increases from baseline in bone mineral density of 13.7% at the lumbar spine (95% confidence interval [CI], 12.0% - 15.5%), 10.3% at the trochanter (95% CI, 8.1% - 12.4%), 5.4% at the femoral neck (95% CI, 3.5% - 7.4%), and 6.7% at the total proximal femur (95% CI, 4.4% - 9.1%). Increases in bone minimal density were not as pronounced in the group that received 5 mg alendronate daily.

Serial measurement of bone density and biochemical markers of bone remodeling revealed that discontinuation of alendronate resulted in a gradual loss of effect. Based on safety data, including incidence of fractures and measurements of stature, prolonged treatment did not appear to result in any loss of benefit.

"Continuous treatment with 10 mg of alendronate daily for 10 years was associated with sustained therapeutic effects on bone density and remodeling, with no indication that the antifracture efficacy of the drug was diminished," the authors write. "Because each therapeutic agent used for the treatment of osteoporosis may have unique characteristics, our observations should not be assumed to apply to other treatments for osteoporosis."

Merck Research Laboratories supported this study and has financial arrangements with several of its authors, who also report various financial arrangements with other pharmaceutical companies.

In an accompanying editorial, Gordon J. Strewler, MD, from Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts, discusses the pros and cons of increased mineralization.

"Although 10 years of alendronate treatment appears to be safe, the optimal duration of treatment has not been established," he writes. "Better data regarding the relative risk of fracture associated with continued treatment as compared with the discontinuation of treatment will be required for good clinical decision making."

N Engl J Med. 2004;350:1172-1174, 1189-1199

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Young People Get Osteoporosis Too