“For many women, stopping alendronate after 5 years for up to 5 more years does not significantly increase fracture risk, but women at high risk of vertebral fractures—such as those who already have a vertebral fracture or those [who might have] very low bone density—may benefit by continuing beyond 5 years.”
Fewer data are available for risedronate. Over 5 years, women on risedronate had continued modest increases in spine bone density, and relative stabilization of femoral-neck bone density, judging from findings from the Vertebral Efficacy With Risedronate Therapy-Multinational (VERT-MN) trial (Bone 2003;32:120–6). Women on placebo had a reduction in femoral-neck bone density and a relative stabilization of spine bone density during the 2-year extension of the trial that originally was designed to run 3 years. During the 2 years of the extension, women on risedronate had more than a 50% reduction in vertebral fractures, compared with women who stopped therapy.
Even fewer data are available for ibandronate. In a 3-year study of almost 3,000 women, the incidence of new vertebral fractures in women on oral daily ibandronate (2.5 mg) was 11%, compared with 6% for women in the placebo group (Bone 2005;37:651–4).
“There are potential concerns with long-term bisphosphonate therapy,” said Dr. Khosla. One important question is whether the continued and potent inhibition of bone turnover could be harmful because of the increased mineralization of bone that has been observed in animal models.
There is also concern about the accumulation of microdamage. “Here, the thought is that because bone constantly needs to repair microcracks and microfractures, if you [inhibit] resorption for long periods of time, these microcracks will accumulate, and you can start to see a paradoxical increase in fractures in various sites because you haven't repaired the skeleton normally,” said Dr. Khosla.
Animal and human studies do show that bisphosphonate-induced inhibition of bone resorption is associated with increased bone mineralization. Increased bone mineralization does increase bone strength, but only up to a point because bone also becomes too stiff.
However, despite the results of animal studies with high doses of bisphosphonates, there is no evidence in humans for increased accumulation of microdamage. “This is a theoretical concern,” said Dr. Khosla.