Ten years of data on Fosamax in postmenopausal osteoporosis

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Rheumawire

Mar 18, 2004

Ten years of data on alendronate in postmenopausal osteoporosis

Boston, MA - Ten-year data on alendronate (Fosamax®, Merck & Co) in the

treatment of osteoporosis in postmenopausal women show that the drug has

sustained therapeutic effects on bone-mineral density (BMD) and

remodeling and give no indication that the antifracture efficacy

diminishes over time [1]. The drug was also well tolerated, say the

researchers, led by Dr Henry Bone (Michigan Bone and Mineral Clinic,

Detroit).

The data come from the Alendronate Phase 3 Osteoporosis Treatment Study,

in which 2 trials, originally involving 994 women followed for 3 years,

had several extensions, so that many of the women were followed for a

total of 10 years. The work was supported by the manufacturer, Merck &

Co, and the results are reported in the March 18, 2004 issue of the New

England Journal of Medicine.

" Long-term data on the safety and efficacy of bisphosphonates are

particularly important because these agents reside in bone for long

periods, " comments Dr Gordon Strewler (Beth Israel Deaconess Center and

Harvard Medical School, Boston, MA) in an accompanying editorial [2]. He

says the data reported by Bone et al provide " convincing evidence that

the biochemical effects of alendronate on bone turnover remain stable

over the course of 10 years of therapy, without any progression of its

antiresorptive action or noticeable increase in the incidence of

fractures. "

Nevertheless, Strewler says, more information is needed. In particular,

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.

Alendronate is the only drug to have US FDA approval for the treatment

of osteoporosis to increase BMD and to reduce the incidence of both

spine and hip fractures in postmenopausal women, the company points out

in a press release highlighting the results. For this indication, the

standard dose is 10 mg daily (although recently a once-weekly 70-mg

formulation has become available).

In the study reported by Bone et al, 1 group of women took 10 mg daily

continuously for 10 years (n=78). Another group took alendronate 5 mg

daily continuously for 10 years (n=86).

There were 2 other groups in the study. The discontinuation group

initially took alendronate 20 mg daily for 2 years, followed by

alendronate 5 mg for 3 years, and then continued on placebo for 5 years

(n=83).

The last group initially took placebo for 3 years, then had 2 years of

alendronate 10 mg daily, and was then dropped from the study (this was

the only group to be followed for only 5 years).

The primary end point of the study was BMD at the lumbar spine, measured

yearly by dual-energy x-ray absorptiometry (DEXA), and secondary end

points were BMD at several other points as well as biochemical markers

of bone formation and resorption.

Treatment with alendronate 10 mg daily for 10 years produced mean BMD

increases of 13.7% at the lumbar spine, 10.3% at the trochanter, 5.4% at

the femoral neck, and 6.7% at the total proximal femur, compared with

baseline values. Smaller gains occurred in the 5-mg alendronate group,

Bone et al comment.

In the discontinuation group (who took alendronate for 5 years and were

followed on placebo for the next 5 years), the BMD at the lumbar spine

did not change significantly after year 5, and the BMD at the lumbar

spine, trochanter, total hip, and total body remained significantly

above baseline values at year 10.

Markers of bone remodeling fell on treatment with alendronate and then

stabilized at a level within the normal premenopausal range, and this

effect was sustained through 10 years of treatment. In the

discontinuation group, the levels of bone remodeling markers increased

within a year of stopping, but the mean values remained below baseline

values, Bone et al report. In the editorial, Strewler notes that in this

discontinuation group, bone resorption was still inhibited by more than

50% even 5 years after stopping the drug.

" The partial maintenance of the drug's effect after the discontinuation

of therapy could be useful, particularly if adherence with therapy is

inconsistent, " comment Bone et al. They contrast the gradual loss of

effect seen with alendronate with the relatively rapid decline in BMD

and increase in bone turnover seen after discontinuation of therapy with

estrogen and also with raloxifene (Evista®, Lilly), adding that with

estrogen a rapid diminution in antifracture efficacy has also been

reported after discontinuation.

The 10-year study does not offer much information about the antifracture

efficacy of alendronate. Data on fractures and height loss were

collected, but for use as a safety rather than efficacy measure, because

of the small numbers involved.

In the initial 3-year phase 3 trial, the rate of new vertebral fractures

in the placebo group was significantly higher than that seen in the

pooled alendronate groups (6.2% vs 3.2%, p=0.03), but there was no

difference among the 3 alendronate-dose groups. In the extension studies

(years 6 through 10), the proportions of women with new vertebral

fractures did not differ significantly between the 3 groups that were

left (ie, the group that had been taking the drug for 5 years and then

stopped and the 2 groups that were continuing with therapy), the authors

comment.

Bone et al calculated the increase in the incidence of fractures that

would have been expected if the original placebo group had continued

untreated, and " our observations do not suggest any association between

prolonged use of alendronate and an excess risk of fracture. "

" Although the differences were not statistically significant, the fewest

morphometric vertebral fractures, least height loss, and lowest rate of

nonvertebral fractures occurred in the group given 10-mg alendronate,

which also had the greatest cumulative exposure to alendronate. Thus,

there were no indicators of any adverse cumulative effect, " they say.

" Other indicators of safety and tolerability were similar among the

groups during years 8 through 10, " they add.

Zosia Chustecka

Sources

1. Bone HG, Hosking D, Devogelaer JP et al. Ten years' experience with

alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;

(350):1189-1199.

2. Strewler GJ. Decimal point--osteoporosis therapy at the 10-year mark.

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

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org