Nashville, Tenn. – Despite concerns about long-term bisphosphonate therapy resulting in the continued suppression of bone turnover and inhibition of normal repair and replacement of damaged bone, recent clinical trials suggest that treatment for up to 10 years is not harmful, according to a California researcher speaking here at the 27th Annual Meeting of the American Society for Bone and Mineral Research.

In his presentation, titled "What Is the Optimal Duration of Bisphosphonate Therapy?", Steven R. Cummings, MD, professor of medicine and epidemiology at the University of California, San Francisco, noted that large placebo-controlled clinical trials assessing the effects of bisphosphonates on fracture risk have typically lasted 3 to 5 years, although one recent study included postmenopausal women who were treated for up to 10 years.¹ Ten-year fracture rates were estimated on the basis of the 3-year experience of the placebo group. Although no formal statistical comparisons were made, projected fracture rates in the placebo group appeared to be higher than the rate of patients who received alendronate for 10 years.

Overall, the continuous treatment with 10 mg/day of alendronate for 10 years was associated with sustained therapeutic effects on bone density, and discontinuation resulted in a gradual loss of effect over time.

In this 2004 study of the long-term use of alendronate, patients were randomly assigned  to placebo or to 5 mg, 10 mg, or 20 mg of alendronate. Placebo treatment continued for 3 years, at which time patients in the placebo group received alendronate for 2 years and then were discharged from the study. Patients who received 5 mg or 10 mg of alendronate remained on the therapy for 10 years. The 20-mg alendronate group remained on that dose for 2 years, then switched to 5 mg for 3 years, and then received placebo for 5 years.¹ 

Effects of long-term bisphosphonate therapy

One concern about long-term bisphosphonate therapy is that continued suppression of bone turnover might inhibit the normal process of repair and replacement of damaged bone, according to Dr. Cummings. Preclinical evidence suggests that long-term treatment with a bisphosphonate leads to accumulation of uniform, homogeneous mineralization, which might be less resistant to shear stress. 

"At that point, you might wonder whether the patient would ask, ‘Can we take a [drug] holiday? Can we stop?'" Dr. Cummings said. He described a scenario of a 71-year-old woman who met the diagnostic criteria for osteoporosis. She had a T-score of -2.3 at the femoral neck and -2.9 at the spine and also had a vertebral fracture at T12. Appropriately, the patient began treatment with a bisphosphonate, did well with the therapy, and had an improved T-score when she returned 6 years later for a routine visit.

The results of the multinational randomized double-blind 10-year study "gives some assurance that continuing alendronate for 10 years was not harmful and might have reduced fracture risk to some degree," said Dr. Cummings.

Additional research

The FIT Long-Term Extension (FLEX) trial has also provided evidence that long-term bisphosphonate therapy is not harmful and might provide sustained benefits,² according to Dr. Cummings. The FLEX trial involved patients who received alendronate for 5 years during the Fracture Intervention Trial.³ During the FLEX extension phase, patients were randomized to placebo or to continuing alendronate for another 5 years.
 
Patients randomized to placebo during the extension had a rebound of the bone resorption marker CTX to near-baseline levels, and bone density decreased by 2% compared with patients who remained on alendronate for 10 years. The incidence of nonvertebral fractures did not differ between treatment groups. Vertebral fracture rates also did not differ when assessed morphometrically, but the clinical vertebral fracture rate was reduced by 50% in patients who received alendronate for 10 years.

Future of bisphosphonates

Currently, there are no definitive answers, and physicians have little information to guide them and their patients regarding the long-term use of bisphosphonates, Dr. Cummings says. Yet the available data provide a measure of reassurance that continuation of bisphosphonate therapy beyond 5 years is not harmful and might afford continued protection against bone loss and fracture.

References

1. Bone HG, Hosking D, Devogelaer J-P. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350;1189-1199.

2. Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: Results from the fracture intervention trial long-term extension. J Bone Miner Res. 2004;19:1259-1269.

3. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA. 1998;280:2077-2082.