Bisphosphonates: Safety and Efficacy in the Treatment and Prevention of Osteoporosis



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Am Fam Physician. 2000 May 1;61(9):2731-2736.

Osteoporosis affects more than 28 million Americans. With the advent of accessible and affordable diagnostic studies, awareness and recognition of this disease by patients and clinicians are growing. Osteoporotic fractures of the spine and hip are costly and associated with significant morbidity and mortality. Over the past decade, a surge of new antiosteoporotic drugs have been labeled or are awaiting labeling by the U.S. Food and Drug Administration. One class of agents used to treat osteoporosis is the bisphosphonates, which inhibit bone resorption, cause an increase in bone mineral density and reduce the risk of future fractures caused by aging, estrogen deficiency and corticosteroid use. Overall, bisphosphonates have been shown to have a strong safety and tolerability profile.

The bisphosphonates are a class of chemicals that share a basic phosphate-carbon-phosphate core and bind strongly to calcium. Over the past two decades, these drugs have assumed a significant role in the treatment of osteoporosis because of their strong avidity for the skeleton and their relative ease of use. Although the precise mechanism of action is not completely understood, these agents strongly inhibit osteoclast-mediated bone resorption.1 As the bone remodeling cycle is slowed, formation and resorption are decreased, although resorption is inhibited more than formation. This process leads to a modest increase in bone mineral density (BMD).1  The osteogenic action of bisphosphonates and their relative lack of activity outside the skeleton have led to the increased use of these agents in treating osteoporosis. This article reviews the safety and efficacy of bisphosphonates in the prevention of bone loss and the treatment of established osteoporosis. Table 1 lists bisphosphonates that are presently available and those still under consideration.

TABLE 1

Bisphosphonates in the Treatment of Osteoporosis and Metabolic Disease

Drug Type Dosage FDA indication Comments

Etidronate (Didronel)

First generation

400 mg for 2 weeks every 3 months

Labeled in Canada and Europe but not in the United States

Few adverse events

Alendronate (Fosamax)

N-containing

10 mg per day

Treatment and prevention of PMO and GIO

Esophagitis/upper GI events

Second generation

5 mg per day

Tiludronate (Skelid)

S-containing

40 mg per day

Treatment of Paget's disease

No effect on fracture risk

Risedronate (Actonel)

N-containing

5 mg per day

Labeling is pending

GI side effects similar to placebo

Second generation

Pamidronate (Aredia)

N-containing

40 to 80 mg IV every 4 months

Hypercalcemia of malignancy

Some systemic effects with IV therapy; none with oral therapy

Second generation

Not labeled for treatment of osteoporosis

Ibandronate

Second generation

1 mg IV every 3 months

Not labeled by FDA; still in phase III trials

Well tolerated


FDA = U.S. Food and Drug Administration; PMO = postmenopausal osteoporosis; GIO = glucocorticoid-induced osteoporosis; GI = gastrointestinal; IV = intravenous.

TABLE 1   Bisphosphonates in the Treatment of Osteoporosis and Metabolic Disease

View Table

TABLE 1

Bisphosphonates in the Treatment of Osteoporosis and Metabolic Disease

Drug Type Dosage FDA indication Comments

Etidronate (Didronel)

First generation

400 mg for 2 weeks every 3 months

Labeled in Canada and Europe but not in the United States

Few adverse events

Alendronate (Fosamax)

N-containing

10 mg per day

Treatment and prevention of PMO and GIO

Esophagitis/upper GI events

Second generation

5 mg per day

Tiludronate (Skelid)

S-containing

40 mg per day

Treatment of Paget's disease

No effect on fracture risk

Risedronate (Actonel)

N-containing

5 mg per day

Labeling is pending

GI side effects similar to placebo

Second generation

Pamidronate (Aredia)

N-containing

40 to 80 mg IV every 4 months

Hypercalcemia of malignancy

Some systemic effects with IV therapy; none with oral therapy

Second generation

Not labeled for treatment of osteoporosis

Ibandronate

Second generation

1 mg IV every 3 months

Not labeled by FDA; still in phase III trials

Well tolerated


FDA = U.S. Food and Drug Administration; PMO = postmenopausal osteoporosis; GIO = glucocorticoid-induced osteoporosis; GI = gastrointestinal; IV = intravenous.

Prevention of Osteoporosis

PRIMARY PREVENTION OF BONE LOSS IN POSTMENOPAUSAL OSTEOPOROSIS

Changes in BMD determine the success of an osteoporosis prevention trial, while vertebral fractures are the primary end point in treatment studies. In prevention studies, women with normal or slightly low bone mass (osteopenia: T-scores of –1.0 or higher) are included. Several studies suggest that bisphosphonates preserve bone mass in healthy post-menopausal women.2-4 In two studies it was reported that oral cyclical etidronate maintained bone mass at the spine and hip compared with losses in bone mass at the spine and hip in women in the placebo group.2,3 In older postmenopausal women, the use of estrogen plus etidronate has been associated with a greater increase in spine BMD than the use of estrogen alone.5 Results of one study6 showed that, in women taking 5 mg per day of alendronate, an increase in BMD of 2 to 4 percent over baseline values was noted at the lumbar spine, femoral neck and greater trochanter of the hip, while women taking placebo had a decrease in BMD of 2 to 4 percent at those same sites. In another study,7 alendronate was compared with hormone replacement therapy (HRT) in 1,174 postmenopausal women less than 60 years of age. Women treated with 5 mg of alendronate daily showed a 3.5 percent increase over baseline in spine BMD and a 1.9 percent increase in BMD of the total hip. Women in the estrogen-progestin arm demonstrated a 4 percent increase over baseline values in spine BMD and a 1.8 to 3.2 percent increase in areas of the hip after two years of treatment.7 Preliminary trials of daily oral estrogen plus 10 mg of alendronate demonstrated a greater increase in spine BMD after two years compared with either drug taken alone.8

Risedronate, another bisphosphonate, was compared with placebo in young post-menopausal women. The women in the placebo group had a 4.3 percent decrease in spine BMD, compared with a 1.4 percent increase over baseline values in spine BMD in patients taking risedronate.9 In one study,10 it was reported that significant changes in spine and hip BMD occurred among older post-menopausal women taking 5 mg per day of ibandronate versus placebo.

Results of two studies using intravenous bisphosphonates (pamidronate and clodronate), given every three months, have shown that these forms increase bone mass in the hip and spine as effectively as oral administration.11,12 Overall, oral and intravenous bisphosphonates are effective in the prevention of bone loss in early- and late-postmenopausal women. The magnitude of increase in BMD is dosage-dependent and greater at the spine than at the hip or radius. This increase in BMD is also greater in older women.

PREVENTING BONE LOSS IN GIO

Therapeutic dosages of glucocorticoids are associated with rapid bone loss and a high risk of fracture. Although the pathophysiology of glucocorticoid-induced osteoporosis (GIO) is highly complex, excessive osteoclastic bone resorption occurs, particularly early in the administration of glucocorticoid therapy. Several bisphosphonates have proved effective in preventing GIO. Cyclical etidronate therapy prevents bone loss from the spine and hip in men and women who have recently begun glucocorticoid therapy and in patients receiving long-term therapy.13-17 Similarly, in patients using glucocorticoids, daily alendronate increased BMD and decreased the likelihood of sustaining a new fracture.18 Preliminary data from studies suggest that risedronate might also be effective in preventing bone loss and fractures in GIO.19 Adverse events, principally related to gastrointestinal (GI) irritation, have been reported in patients with GIO who use bisphosphonates. However, antiresorptive therapy with bisphosphonates is usually safe and effective in preventing the deleterious skeletal consequences of glucocorticoid excess.

PREVENTING BONE LOSS IN MEN

Osteoporosis is more common in women than in men, but osteoporotic fractures sometimes do occur in men. Unfortunately, there is little information concerning preventive or therapeutic approaches in men. Currently, no medicines are labeled by the U.S. Food and Drug Administration (FDA) for treatment or prevention of osteoporosis in men. Nevertheless, it is likely that bisphosphonates are as effective in men as they are in women. In small, uncontrolled trials, bisphosphonates have had positive effects on BMD in men with idiopathic osteoporosis and that related to some secondary causes, such as hypercalciuria.20,21 Preliminary data from a large, placebo-controlled trial22 of alendronate in men with osteoporosis also suggest a positive effect on BMD. In this trial, alendronate had similar effects in hypogonadal and normal men. Although the number of studies is limited, there is some support for the effectiveness of bisphosphonates in selected groups of men with low bone mass and fractures.

Treatment of Established Osteoporosis

Cyclical etidronate was the first regimen extensively evaluated for the treatment of established postmenopausal osteoporosis.23,24 During seven years of treatment, BMD in the spine increased by approximately 8 percent in women taking cyclical etidronate, and BMD of the hip increased 1 to 2 percent over baseline values. Sustained treatment with cyclical etidronate significantly decreased the vertebral fracture rate, but only in patients at highest risk for fracture. Because of this disparity, the FDA has not labeled etidronate (Didronel) for the treatment of osteoporosis.

The newer bisphosphonates have changed our approach to the management of osteoporosis because of increased effectiveness. Alendronate (Fosamax) is the first of these newer bisphosphonates to be labeled by the FDA for treatment and prevention of osteoporosis. In early trials, treatment with alendronate (10 mg daily) over a three-year period increased spine BMD by approximately 7 to 8 percent and BMD of the hip by 5 to 7 percent over baseline values.25-27 More recently, in the Fracture Intervention Trial (FIT),28,29 6,459 postmenopausal women with low femoral BMD were randomized to receive placebo or alendronate (5 mg per day). The daily alendronate dosage was increased to 10 mg per day during the third year of the study. The use of alendronate over three years increased spinal BMD to 8 percent over baseline, and there was a 50 percent decrease in the risk of new vertebral, hip and wrist fractures in women with at least one preexisting vertebral fracture at baseline. However, it must be noted that absolute change in BMD in these trials accounted for only one half of the risk reduction in new fractures.

In the second part of the FIT trial, in women without a preexisting vertebral fracture at baseline but low hip BMD (T-scores lower than −1.0), alendronate decreased the risk of clinical fractures by 36 percent in patients with the lowest baseline femoral BMD (classified as osteoporotic—T-scores lower than −2.5—by BMD). No antifracture efficacy was noted in the women taking alendronate who had BMD values in the osteopenic range.29

Risedronate (Actonel) will likely be the second bisphosphonate to be labeled by the FDA for the treatment of osteoporosis. Risedronate should be commercially available later this year. Results of two large studies30 support the efficacy of risedronate therapy in increasing BMD and in decreasing fracture risk in women with postmenopausal osteoporosis and previous fractures. In each study, patients were treated with supplemental calcium, vitamin D if needed, and risedronate or matching placebo for three years.

In the North American cohort of 2,458 subjects, treatment with 5 mg of risedronate daily increased spine BMD over baseline approximately 5 percent and decreased the risk of new vertebral fractures by 41 percent and the cumulative incidence of nonvertebral fractures by 39 percent.30 In the parallel multinational study of 1,226 women, treatment with 5 mg of risedronate daily for three years reduced the risk of new vertebral fractures by 49 percent and the risk of nonvertebral fractures by 33 percent.31

Based on the recently published guidelines of the National Osteoporosis Foundation, it is most cost effective to consider treating women with a bisphosphonate if they (1) are older than 65 years; (2) have multiple risk factors for osteoporosis (e.g., thinness, previous fractures and/or a family history of osteoporosis) and a T-score of lower than –1.5; and (3) are not currently using HRT.32 Although these guidelines may change, identification of high-risk patients is the first step in cost-effective treatment of osteoporosis with these newer agents.

Safety and Tolerability of Long-Term Bisphosphonate Therapy

Postmenopausal osteoporosis is a chronic medical condition that requires long-term treatment. Because of their relative safety, bisphosphonates have been labeled (for more than two decades) for the treatment of metabolic bone disorders such as Paget's disease. Cyclical etidronate has not been associated with systemic or bone toxicity.24 The newer bisphosphonates do not affect bone mineralization, induce osteomalacia, increase bone fragility or reduce bone quality.33-35 This is, in part, because the bisphosphonates reduce activation frequency (the birth of new bone remodeling units) but do not impair microfracture healing.1 The activation frequency of remodeling does not continue to decline with continued exposure, so bone formation continues, albeit at a reduced rate, while bone resorption is suppressed.36-38

The bisphosphonates have minimal non-skeletal toxicity because they bind to bone and are not taken up by other tissues. The reduction in renal function that occurs in animal models with administration of high-dosage parenteral bisphosphonate has not occurred in clinical practice. However, because bisphosphonates are excreted through glomerular filtration, intravenous administration of large dosages of pamidronate to patients with severe chronic renal failure or patients on dialysis may be accompanied by marked hypocalcemia and/or hypophosphatemia with associated tetany.39 Iritis, muscle aches and fever can also accompany intravenous bisphosphonate administration. This reaction, related to cytokine release, is reversible on discontinuation.

Bisphosphonates also have some GI side effects. In clinical trials, the magnitude and frequency of significant upper GI complications are similar to those with placebo28 but, in clinical practice, GI side effects are often noted. The reasons for this difference are not clear. Oral bisphosphonates seem to induce serious esophagitis in some patients, may result in gastritis and cause diarrhea.40 When used as recommended, serious esophageal complications are few. Patients with known esophageal disease (e.g., achalasia, stricture, Barrett's esophagus, severe reflux and scleroderma) should avoid taking oral bisphosphonates.

Patients who develop GI symptoms should immediately stop taking the medication. They may resume therapy with lower dosages or intermittent (weekly) dosing once the upper GI symptoms disappear.40 Cyclical etidronate (Didronel) has fewer upper GI side effects but more lower GI side effects than alendronate. Cyclical etidronate therapy may be considered for use in patients who cannot tolerate alendronate. Intravenous pamidronate (Aredia) may be used in patients with severe osteoporosis who have experienced fractures and cannot tolerate oral bisphosphonates. Whether the newer oral bisphosphonates will be better tolerated than existing ones is still unknown, but studies are now in progress to answer this important question.

The Authors

SUSAN L. GREENSPAN, M.D., is professor of medicine at the University of Pittsburgh (Pa.) School of Medicine. She is also director of the Osteoporosis Prevention and Treatment Center and associate program director at the General Clinical Research Center at the University of Pittsburgh Medical Center. She received her medical degree from Harvard Medical School, Boston, Mass. Dr. Greenspan completed an internship and residency in internal medicine at Beth Israel Deaconess Medical Center, Boston, and a fellowship in endocrinology at Massachusetts General Hospital, Boston.

STEVEN T. HARRIS, M.D., is a clinical professor at the University of California, San Francisco, School of Medicine. He is also chief of medicine at the Bone and Mineral Clinic at the University of California, San Francisco, where he received his medical degree.

HENRY BONE, M.D., is director of the Michigan Bone and Mineral Clinic, Detroit, Mich., and chairman of the Endocrine and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration. Dr. Bone received his medical degree from the University of Washington School of Medicine, Seattle, Wash.

PAUL D. MILLER, M.D., is a professor of medicine at the University of Colorado Health Sciences Center, Denver, Colo. He is also medical director at the Colorado Center for Bone Research, Lakewood. Dr. Miller received his medical degree from George Washington University School of Medicine, Washington, DC.

ERIC S. ORWOLL, M.D., is professor of medicine, assistant dean of research and an attending physician at Oregon Health Sciences University, Portland. He is also program director of the General Clinical Research Center. Dr. Orwoll received his medical degree from the University of Maryland School of Medicine, Baltimore. Dr. Orwoll also completed a fellowship in endocrinology and metabolism at the Oregon Health Sciences University.

NELSON B. WATTS, M.D., is a professor at Emory University School of Medicine, Atlanta. He also serves as director of the Osteoporosis and Bone Health Program and codirector of the Bone Densitometry Service at the Emory Clinic, Atlanta. Dr. Watts received his medical degree from the University of North Carolina at Chapel Hill School of Medicine.

CLIFFORD J. ROSEN, M.D., is director of the Maine Center for Osteoporosis Research and Education, an affiliate of St. Joseph Hospital, Bangor, Me. He is also a staff scientist at the Jackson Laboratory and a professor at the University of Maine in Orono. Dr. Rosen received his medical degree from the State University of New York Health Science Center at Syracuse.

Address correspondence to Clifford J. Rosen, M.D., Maine Center for Osteoporosis Research and Education, St. Joseph Hospital, 360 Broadway, Bangor, ME 04401. Reprints are not available from the authors.

Dr. Harris has received research support or sponsored presentations and received consulting fees from Boehringer Mannheim Therapeutics; Merck Research Laboratories; Proctor & Gamble Pharmaceuticals; Hoechst Marion Roussel. Dr. Watts has received research support, lecture honoraria or consulting fees from Eli Lilly & Company; Hoechst Marion Roussel; Merck & Company; Norland; Novartis; Proctor & Gamble Pharmaceuticals; Roche/Boehringer-Mannheim Pharmaceuticals; Solvay Pharmaceuticals; and Wyeth-Ayerst Pharmaceuticals.

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