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Bisphosphonates
Mechanism
of Action
Available Bisphosphonates and Indications
Alendronate
Risedronate
Comparative Trial
Side-Effects/Administration Guidelines
Mechanism of Action
The bisphosphonates are synthetic compounds characterized by a phosphate-carbon-phosphate structure, and are potent pharmacologic agents that are useful in the management of osteoporosis. Bisphosphonates are adsorbed to the surface of hydroxyapatite crystals in the bone. The mechanism of action of the bisphosphonates in osteoporosis has not been definitively elucidated.14 Lower bone resorption seen with these agents may be due to a direct action on osteoclasts (bone- resorbing cells), an indirect effect on osteoclast recruitment, or both. At sufficient doses, bisphosphonates also retard the mineralization of bone, by inhibiting formation of new crystals, blocking the transformation of amorphous calcium phosphate to hydroxyapatite, and delaying the aggregation of apatite crystals into larger crystals.15 However, these agents do not inhibit the bone matrix synthesizing ability of osteoblasts (bone-forming cells). Bisphosphonate bound to the bone surface becomes covered with new bone during the formation part of the remodeling cycle. It appears that drug bound within the bone matrix is not active, and remains in the bone for years. Because intraskeletal bisphosphonates no longer have activity against osteoclasts, they must be administered continually in order to reap the benefits of their pharmacological activity.16
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Available Bisphosphonates and Indications
Listed here are five bisphosphonates that are currently available in the United States and their FDA-approved indications. Subsequent discussions pertain only to alendronate and risedronate, therapies approved by US-FDA for the management of osteoporosis.
Alendronate: Fosamax®
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Etidronate: Didronel®
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Pamidronate:
Aredia®
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Risedronate:Actonel®
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Tiludronate:Skelid®
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Alendronate
Evidence-Based Effects on BMD and Fracture Reduction
The effect of alendronate on fractures is documented in the Fracture Intervention Trial (FIT). The FIT is a large study evaluating a total of 6459 subjects and has two distinct arms. 17,18 In one arm of the study,17 2027 postmenopausal women with a history of vertebral fractures received 5 to 10 mg of alendronate or placebo for three years. Treatment with alendronate led to a significant decline in new vertebral fractures, with the risk reduced by 47 percent. The risk of hip and wrist fractures was also significantly reduced by alendronate treatment, by 51 and 48 percent, respectively. Patients receiving alendronate also were at a 20 percent lower risk for all clinical fractures.17
ALENDRONATE: EFFECT ON NEW VERTEBRAL AND NONVERTEBRAL FRACTURES
(Patients With at Least One Baseline Vertebral Fracture)
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| *P<.001 vs placebo. P=.047 vs placebo.P=.013 vs placebo. |
Subgroup analysis of the FIT study 17 results revealed that the reduction in risk of fracture was consistent regardless of age, baseline bone mineral density, or the number of vertebral fractures at baseline.19 This analysis provides direct evidence that antiresorptive therapy with the bisphosphonate alendronate increases bone mass and reduces fracture risk in very elderly women at highest risk. The implications of these results are that even in this group of high-risk women (> 75 years of age with advanced osteoporosis), it is never too late to institute treatment with alendronate in order to prevent fractures. Since the risk reductions observed with alendronate treatment were consistent within fracture risk categories, more fractures were prevented by treating women at highest risk.
The analysis from FIT II 18, a trial conducted to test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in 4432 women who have low BMD but no vertebral fractures, 4 years of alendronate treatment produced a significant reduction in radiographic vertebral fractures by 44% overall. The drug significantly reduced the risk of clinical fractures among women with osteoporosis, but not among women with higher BMD.
A published meta-analysis of prevention of nonvertebral fractures by alendronate confirmed that treatment with this drug reduces the risk of nonvertebral fractures over at least 3 years.20 The estimated cumulative incidence of nonvertebral fractures after 3 years was 12.6% in the placebo group and 9.0% in alendronate group. A reduction in risk was consistent across each of the studies and at each major site of osteoporotic fracture, including the hip and wrist.
Osteoporosis is a common complication of long-term glucocorticoid therapy and bisphosphonates in general are effective at preventing and treating corticosteroid-induced bone loss at the lumbar spine and femoral neck. 21 Alendronate, specifically increased bone density in patients receiving glucocorticoid therapy in two 48-week, randomized, placebo-controlled studies of two doses of alendronate in 477 men and women, 17 to 83 years of age, who were receiving glucocorticoid therapy.22 It is now approved by the FDA in the US for treatment of steroid-induced osteoporosis.
Recently, the FOSIT study 23 demonstrated that in postmenopausal women with low bone mass (lumbar spine BMD, T-score <2), alendronate is well tolerated and produces significant, progressive increases in BMD at the lumbar spine and hip in addition to significant reduction in the risk of nonvertebral fracture (47% reduction at one year, p=.021).
Effects of Alendronate in Men and Other Ethnic Groups
Osteoporosis in men has significant morbidity; approximately 25-30% of all hip fractures occur in men, with a significant increase in mortality post-hip fracture. Recently, a two-year double-blind trial studied the effect of 10 mg of alendronate or placebo, given daily, on bone mineral density in 241 men (age, 31 to 87 years; mean, 63) with osteoporosis, and concluded that in men with osteoporosis, alendronate significantly increases spine, hip, and total-body bone mineral density and helps prevent vertebral fractures and decreases in height.24
Osteoporosis
is a growing health problem in Asian women and it is expected that half of the
world's hip fractures will occur in Asia in 50 years' time. As the use of HRT
is extremely low in postmenopausal Asian women, nonhormonal agents will be more
acceptable for the treatment and prevention of osteoporosis. The efficacy, tolerability,
and acceptability of alendronate for Asian women was evaluated in 70 osteoporotic
southern Chinese women in a prospective, randomized, double-blind study which
concluded that alendronate treatment for 1 year resulted in significant improvement
in BMD at all sites measured when compared with placebo.25
Once-Weekly Dosing
Once weekly dosing regimen (70 mg once weekly) of alendronate has been approved by the FDA in the US, providing patients with a more convenient, therapeutically equivalent alternative to daily dosing, potentially enhancing compliance and long-term adherence to therapy. The pharmacokinetic rationale and data for once weekly dosing is well described.26 A recent published trial and a review elucidate the efficacy, tolerability, and safety of alendronate as a once weekly drug.27, 28
A recent study found that alendronate 10 mg daily used following HRT withdrawal ìincreased or maintained both spine and hip BMD and prevented the increase in bone resorption seen with withdrawal of HRTî. During the 12 month study, alendronate treatment produced a 2.3% mean increase (95% confidence interval [CI], 1.7%-3.0%) in spine BMD compared with a mean loss of 3.2% (95% CI, - 4.6% to - 1.7%) in patients receiving placebo.28a
Risedronate
Evidence-Based Effects on BMD and Fracture Reduction
The efficacy of risedronate
on fracture reduction in postmenopausal women was recently confirmed in a randomized,
double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women
younger than 85 years with at least 1 vertebral fracture at baseline. Treatment
with 5 mg per day of risedronate, compared with placebo, decreased the cumulative
incidence of new vertebral fractures by 41 % (95% confidence interval [CI],
18%-58%) over 3 years (11.3 % vs 16.3%; P= .003). A fracture reduction of 65%
(95% CI, 38%-81 %) was observed after the first year (2.4% vs 6.4%; P<.001).
The cumulative incidence of nonvertebral fractures over 3 years was reduced
by 39% (95% CI, 6%-61 %) (5.2 % vs 8.4%; P = .02). Bone mineral density increased
significantly compared with placebo at all points measured. The overall safety
profile of risedronate, including gastrointestinal safety, was similar to that
of placebo.29
A recent trial shed light on the efficacy of risedronate on the incidence of hip fractures in several thousand elderly women: overall, the incidence of hip fracture among all the women assigned to risedronate was 2.8 percent, as compared with 3.9 percent among those assigned to placebo (relative risk, 0.7; 95 percent confidence interval, 0.6 to 0.9; P=0.02). In the group of women with osteoporosis (those 70 to 79 years old), the incidence of hip fracture among those assigned to risedronate was 1.9 percent, as compared with 3.2 percent among those assigned to placebo (relative risk, 0.6; 95 percent confidence interval, 0.4 to 0.9; P=0.009). In the group of women selected primarily on the basis of nonskeletal risk factors (those at least 80 years of age), the incidence of hip fracture was 4.2 percent among those assigned to risedronate and 5.1 percent among those assigned to placebo (P=0.35). The authors concluded that risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density.30
Although it appears that these agents (alendronate and reisedronate) may be interchangeable, further comparative study is needed to clarify any perceived advantages or disadvantages. So far, alendronate studies predominate in the literature.
Risendronate 35 mg Once-a-Week is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In clinical trials, it was found to be as effective as risendronate 5 mg daily.30a
Comparative TrialTrials comparing antiresorptive therapies for the treatment of osteoporosis are lacking, however, this study 31 compared the effects of oral alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. Women at least 5 years postmenopause (n = 299) were randomized to either 10 mg alendronate, matching alendronate placebo, or open-label intranasal calcitonin 200 IU daily for 12 months. Hip and spine bone mineral density (BMD) and markers of bone turnover were measured, and safety and tolerability were assessed. Alendronate significantly produced greater increases in BMD than calcitonin at 12 months at the lumbar spine, trochanter, and femoral neck. Changes in BMD with calcitonin were greater than with placebo at the femoral neck, but were not different from placebo at either the trochanter or lumbar spine. The authors concluded that, in postmenopausal women with osteoporosis, 12 months of therapy with alendronate produced significantly greater increases in BMD of the hip and spine and greater decreases in bone turnover than intranasal calcitonin.
Side-Effects/Administration Guidelines
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In general, bisphosphonates are well tolerated. Adverse effects are usually mild and include abdominal and musculoskeletal pain. Less frequently reported adverse events include nausea, dyspepsia, constipation, diarrhea, and flatulence.6
Bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture, have been reported in patients In some cases these have been severe and required hospitalization. Clinicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking bisphosphonates and/or who fail to swallow it with a full glass (6-8 oz) of water, and/or who continue to take the drug after developing symptoms suggestive of esophageal irritation.
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