What is the optimal duration of bisphosphonate therapy?

Bisphosphonates suppress markers of bone turnover

These changes in bone remodeling with bisphosphonates are reflected by changes in markers of bone formation and resorption. The levels of markers of bone resorption—N-telopeptide cross-linked type I collagen (NTx) and C-telopeptide cross-linked type I collagen (CTx)—decrease rapidly and remain low. The markers of bone formation—propeptide of type I collagen, bone alkaline phosphatase, and osteocalcin—decrease gradually over 3 to 6 months and then remain low. As measured directly at the bone, bone formation appears to be more suppressed than as measured by biochemical markers in the serum.

In a risedronate trial,¹¹ the fracture rate decreased as the biochemical markers of bone turnover decreased, except when the markers were very low, in which case the fracture rate increased.

Without remodeling, cracks can accumulate

The bisphosphonates do not significantly increase bone volume, but they prevent microscopic architectural deterioration of the bone, as shown on microscopic computed tomographic imaging.¹² This prevents fractures for at least 5 years.

But bisphosphonates may have long-term negative effects. One purpose of bone remodeling is to refresh the bone and to repair the microscopic damage that accumulates within any structure. Without remodeling, cracks can accumulate. Because the development and repair of microcracks is complex, it is difficult to predict what will happen with long-term bisphosphonate use. Studies of biopsies from women taking bisphosphonates long-term are inconsistent: one study found accumulation of microcracks,¹³ but another did not.⁸

STUDIES OF LONG-TERM USE: FOCUS ON FRACTURES

For this review, I consider long-term bisphosphonate use to be greater than 5 years, and I will focus on fractures. Bone density is only a surrogate end point. Unfortunately, this fact is often not emphasized in the training of young physicians.

The best illustration of this point was in a randomized clinical trial of fluoride,¹⁴ in which the bone density of the treated group increased by 8% per year for 4 years, for a total increase of 32%. This is more than we ever see with current therapies. But the patients had more fractures with fluoride than with placebo. This is because the quality of bone produced after fluoride treatment is poor, and although the bone is denser, it is weaker.

Observational studies of fracture incidence in patients who continued taking bisphosphonates compared with those who stopped provide some weak evidence about long-term effectiveness.

Curtis et al¹⁵ found, in 9,063 women who were prescribed bisphosphonates, that those who stopped taking them during the first 2 years had higher rates of hip fracture than compliant patients. Those who took bisphosphonates for 3 years and then stopped had a rate of hip fracture during the next year similar to that of those who continued taking the drugs.

Meijer et al¹⁶ used a database in the Netherlands to examine the fracture rates in 14,750 women who started taking a bisphosphonate for osteoporosis between 1996 and 2004. More than half of the women stopped taking the drug during the first year, and they served as the control group. Those who took bisphosphonates for 3 to 4 years had significantly fewer fractures than those who stopped during the first year (odds ratio 0.54). However, those who took them for 5 to 6 years had slightly more fractures than those who took them for less than a year.

Mellström et al¹⁷ performed a 2-year uncontrolled extension of a 5-year trial of risedronate that had blinded controls.¹⁸ Initially, 407 women were in the risedronate group; 68 completed 7 years.

The vertebral fracture rate in the placebo group was 7.6% per year during years 0 through 3. In the risedronate group, the rate was 4.7% per year during years 0 through 3 and 3.8% per year during years 6 and 7. Nonvertebral fractures occurred in 10.9% of risedronate-treated patients during the first 3 years and in 6% during the last 2 years. Markers of bone turnover remained reduced throughout the 7 years. Bone mineral density of the spine and hip did not change from years 5 to 7. The study did not include those who took risedronate for 5 years and then discontinued it.

Bone et al¹⁹ performed a similar, 10-year uncontrolled extension of a 3-year controlled trial of alendronate.²⁰ There were 398 patients randomly assigned to alendronate, and 164 remained in the study for 8 to 10 years.

During years 8 through 10, bone mineral density of the spine increased by about 2%; no change was seen in the hip or total body. The nonvertebral fracture rate was similar in years 0 through 3 and years 6 through 10. Vertebral fractures occurred in approximately 3% of women in the first 3 years and in 9% in the last 5 years.

The FLEX trial: Continuing alendronate vs stopping

Only one study compared continuing a bisphosphonate vs stopping it. The Fracture Intervention Trial Long-Term Extension (FLEX)¹⁰ was an extension of the Fracture Intervention Trial (FIT)^21,22 of alendronate. I am reviewing this study in detail because it is the only one that randomized patients and was double-blinded.

In the original trial,^21,22 3,236 women were in the alendronate group. After a mean of 5 years on alendronate, 1,099 of them were randomized into the alendronate or placebo group.¹⁰ Those with T scores lower than −3.5 or who had lost bone density during the first 5 years were excluded.

The bone mineral density of the hip in the placebo group decreased by 3.4%, whereas in the alendronate group it decreased by 1.0%. At the spine, the placebo group gained less than the alendronate group.

Despite these differences in bone density, no significant difference was noted in the rates of all clinical fractures, nonvertebral fractures, vertebral fractures as measured on radiographs taken for the study (“morphometric” fractures, 11.3% vs 9.8%), or in the number of severe vertebral fractures (those with more than a two-grade change on radiography) between those who took alendronate for 10 years and those who took it for 5 years followed by placebo for 5 years.

However, fewer “clinical spine fractures” were observed in the group continuing alendronate (2.4% vs 5.3%). A clinical spine fracture was one diagnosed by the patient’s personal physician.

In FIT, these clinical fractures were painful in 90% of patients, and although the community radiographs were reviewed by a central radiologist, only 73% of the fractures were confirmed by subsequent measurements on the per protocol radiographs done at the study centers. About one-fourth of the morphometric fractures were also clinical fractures.²³ Therefore, I think morphometric fractures provide the best evidence about the effects of treatment—ie, that treatment beyond 5 years is not beneficial. Other physicians, however, disagree, emphasizing the 55% reduction in clinical fractures.²⁴

Markers of bone turnover gradually increased after discontinuation but remained lower than baseline even after 5 years without alendronate.¹⁰ There were no significant differences in fracture rates between the placebo and alendronate groups in those with baseline bone mineral density T scores less than −2.5.¹⁰ Also, after age adjustment, the fracture incidence was similar in the FIT and the FLEX studies.

Several years later, the authors published a post hoc subgroup analysis of these data.²⁵ The patients were divided into six subgroups based on bone density and the presence of vertebral fractures at baseline. This is weak evidence, but I include it because reviews in the literature have emphasized only the positive findings, or have misquoted the data: Schwartz et al stated that in those with T scores of −2.5 or below, the risk of nonvertebral fracture was reduced by 50%²⁵; and Shane²⁶ concluded in an editorial that the use of alendronate for 10 years, rather than for 5 years, was associated with significantly fewer new vertebral fractures and nonvertebral fractures in patients with a bone mineral density T score of −2.5 or below.²⁶

Data from Schwartz AV, et al; FLEX Research Group. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX Trial. J Bone Miner Res 2010; 25:976–982.