“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.
Another major concern has been the association between bisphosphonate use and jaw osteonecrosis.
“This is a very feared complication of long-term biphosphonate therapy,” said Dr. Khosla. “This is something that is just coming to [our] attention, and we haven't quite figured out how to deal with it.”
The exposed bone that is the hallmark of jaw osteonecrosis occurs in other conditions, sometimes confounding diagnosis. The American Society for Bone and Mineral Research created a task force to examine the relationship between bisphosphonates and jaw osteonecrosis. One goal is to develop a case definition for bisphosphonate-associated jaw osteonecrosis.
Although data on jaw osteonecrosis associated with oral bisphosphonate use are limited, it's estimated that the risk is somewhere between 1 in 10,000 and less than 1 in 100,000 patient-treatment years. “This may be an underestimate because of underreporting,” said Dr. Khosla. The estimate may also be low because the risk is associated with cumulative exposure, and perhaps this complication will become more common with more patients on oral bisphosphonates for longer periods.
“It's clear that the risk of jaw osteonecrosis in patients with cancer, treated with high doses of intravenous bisphosphonates, is higher,” said Dr. Khosla. In these patients, the risk is estimated to be 1-10 per 100 patients.
“I think that all we can do as physicians is provide information and factor in the patient's values. I don't think as a physician you can completely leave the decision to the patient. They get bewildered.”