Treating Osteoporosis: Bisphosphonates

Bisphosphonates Prevent Vertebral Fractures
Alendronate and risedronate reduce the incidence of new vertebral fractures by 40% to 50% after 3 years of treatment in postmenopausal women with osteoporosis, including those with radiographically verified vertebral fractures at baseline.(26-29)

Short-term benefit. The benefit becomes apparent early on, which is especially important to patients who already have vertebral fractures, in view of their high risk for subsequent fractures. A post hoc analysis found a lower relative risk of clinical vertebral fractures after 1 year of alendronate therapy (59%, P <.001) in patients with at least one vertebral fracture or a T score of less than -2.5.(30)

In two prospective studies in postmenopausal women with osteoporosis who had at least one vertebral fracture at baseline, risedronate reduced the risk of morphometric vertebral fractures at 1 year by 65% (27) and 61%. (28) Pooled data from risedronate trials demonstrated a reduction (P <.01) in clinical vertebral fracture risk as early as 6 months after start of treatment. (31) Among women with two or more radiographically determined vertebral fractures at baseline, a 68% (P < .001) risk reduction in new vertebral fractures was observed after 1 year of treatment with risedronate. (32)

Long-term benefit. Patients had 63% fewer symptomatic vertebral fractures on alendronate vs placebo during a 4-year period in the Fracture Intervention Trial (FIT) (P <.001). (33) Skeletal benefits have been reported for up to 10 years, with bone density increased slightly in the spine and maintained in the hip during treatment years 4 to 10 (fracture risk reduction was not calculated because the extension of the trial was not placebo-controlled). (34,35)

A placebo-controlled 2-year extension of the Vertebral Efficacy With Risedronate Therapy-Multinational (VERT-MN) study of 265 patients showed that morphometric vertebral fracture risk was reduced by 59% (P = .01) during years 4 and 5 with daily risedronate vs placebo. (36) An open-label 2- year extension showed a sustained effect with a nearly constant incidence of vertebral fractures throughout treatment (4.7% for years 0-3, 5.2% for years 4-5, and 3.8% for years 6-7). (37)

Once-a-week pills Risedronate and alendronate are available as once-weekly formulations, which have demonstrated similar benefits in lumbar spine and hip bone density and in bone turnover markers compared with their once-a-day counterparts. (38-40) The incidence of clinical vertebral fractures was also similar for both formulations of alendronate after 1 and 2 years of therapy. (38,40) A post hoc analysis found that the 1-year risk of morphometric vertebral fractures was reduced by 77% (P = .018) for patients on once-weekly risedronate vs a historical placebo control group. (41)

Less effect on nonvertebral fracture risk
There is conflicting evidence about whether alendronate reduces the risk of nonvertebral fractures. The FIT authors found no significant risk reduction.(26,42) However, the Fosamax International Trial (FOSIT) found that it reduced the risk over 1 year by 47% (P = .021) in postmenopausal women with low bone mass (T score -2 or below). (43) Another post hoc analysis also showed that nonvertebral fracture risk declined after 2 years (26%, P = .011).(30)

Risedronate reduced nonvertebral fracture risk by up to 39% in long-term prospective clinical trials. (27,28,44) Pooled results from four major trials indicate that risk is reduced by 74% (P = .001) at 1 year and that risk reduction is evident as early as 6 months.(45)

Hip fracture risk. FIT found that in 2,027 women with at least one existing vertebral fracture, alendronate reduced hip fracture risk by 51% (P = .047). (26) However, risk was not reduced in subjects with low bone density in the femoral neck or in subjects who had no vertebral fractures at baseline. (42)

In a prospective, double-blind, placebocontrolled trial,(44) risedronate reduced the incidence of hip fracture by 40% (P = .009) in 5,445 women with confirmed osteoporosis (mean T scores about -2.7 to -2.9) and by 60% (P = .003) in 1,703 women who had vertebral fractures at baseline. However, it did not significantly reduce hip fractures in a group of women over age 80 without confirmed osteoporosis.

These data underscore that hip fractures and falls pose a serious risk to older women, who should be screened with DXA to establish the diagnosis of osteoporosis. The data also underscore the need to prevent falls in this population.

Upper GI Side Effects of Bisphosphonates
To reduce the risk of esophageal irritation, patients should be advised not to lie down for 30 minutes after they have taken their dose.(46,47)

After alendronate was introduced in 1995, there were numerous reports of upper gastrointestinal (GI) problems, including ulcerative or erosive esophagitis and esophageal stricture. These occurred more often and more severely than was predicted from clinical trials,(48) in which the reported rates of upper GI adverse events for patients taking either alendronate or risedronate were similar to those of placebo. (26-29,42,44)

However, a newer review indicates that reports of esophagitis have declined, possibly because physicians have become more aware of the problem and are advising their patients about how to take these medications.(49)

Is risedronate better tolerated than alendronate?
It is possible that subjects in the clinical trials of risedronate were more likely than those in the alendronate trials to have had a history of GI problems at baseline. Risedronate trials did not exclude patients with acute GI disorders or those taking acid-suppressive therapy or nonsteroidal anti-inflammatory drugs (including aspirin), (27,28,44) while some of the alendronate trials did exclude women with active peptic ulcer disease (26,29,42) or dyspepsia. (26,42)

A retrospective analysis of a claims database of nearly 4,000 men and women older than 65 years found that once-daily risedronate was associated with significantly fewer GI adverse events and medical costs related to these events than once-daily and once-weekly alendronate. (50,51) Moreover, risedronate recipients in these analyses were more likely to have had GI problems before treatment than were the alendronate recipients.

However, pooled data from 10,068 patients (> 98% postmenopausal women) treated with risedronate or placebo for up to 3 years showed no significant difference in the incidence of upper GI adverse events overall or after stratification for upper GI disease or use of nonsteroidal anti-inflammatory drugs, H2-blockers, or proton pump inhibitors. (52) It is difficult to be certain whether risedronate is more tolerable than alendronate without head-to-head clinical studies. Regardless, now that once-weekly formulations of both medications are available, patients may find it easier to comply with instructions and minimize potential GI problems.

Cleveland Clinic Journal of Medicine
Volume 71, Number 10, October 2004

The author has indicated that he has received grant or research support from the Wyeth, Pfizer, Proctor and Gamble, Sanofi, NPS, and Alexis corporations and is on the speakers' bureaus of the Abbott, Merck, and Proctor and Gamble corporations. This paper discusses treatments that are experimental or are not approved by the US Food and Drug Administration for the use under discussion.