Question

How long should postmenopausal women continue to take bisphosphonate therapy for osteoporosis?

Commentary from Paul D. Miller, MD

Bisphosphonates are biological analogues of naturally occurring pyrophosphates, by-products of adenosine metabolism, and were developed after the discovery that these nonmetabolized compounds have a high affinity for the calcium-phosphorus surface and can prevent both bone resorption or mineralization, depending on the type and dose of bisphosphonate.^[1] The second-generation aminobisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) have a ratio of inhibiting bone resorption to bone formation of greater than 1,000:1 and therefore do not inhibit mineralization or induce osteomalacia.

Bisphosphonates have a long retention time in bone and, while their affinity and detachment to the denuded resorptive cavity differ among bisphosphonates in vitro and in vivo in animal models, it is unknown if there are differences in the so-called bone half-life in human beings.^[2] Nevertheless, the bisphosponates do get buried in bone and can remain there for years.

There have been several clinical and biochemical developments that have led clinicians to rethink how to use bisphosphonates in their postmenopausal population. These include:

The advancements made in understanding bisphosphonate biology in the past decade have been enormous.^[3-4] The knowledge that bisphosphonates are recycled back into the circulation by two separate mechanisms (transcytosis, emanating through the osteoclast cell membrane; and detachment from bone during remodeling, retaining their molecular structure and biological activity) has given bisphosphonates as a class pharmacokinetic properties that are nonexistent for any other drugs used in any disease management.^[5] After a bone "loading" period, it appears that the amount of bisphosphonate released back into the circulation can maintain BMD and BTM for a period of time, possibly years.^[6-7] There may be differences among bisphosphonates in the duration of this effect, and a finite period of administration may be needed (possibly 5 y) before this sustained benefit after discontinuation can be observed.^[8] Nevertheless, based on these data, there is a wider discussion evolving in medical practice concerning a "drug holiday" in postmenopausal women after 5 to 7 years of bisphosphonate administration, monitoring BMD and BTM on an annual basis to assess if the biological activity of sustaining the lower bone turnover is maintained. There are numerous opinions on which populations should be offered a drug holiday, and there is no standard of care for these approaches.^[9-10]

The use of bisphosphonates in younger postmenopausal women increased following the publication of the Women's Health Initiative (WHI), after which many women discontinued estrogen yet were concerned about their skeletal health. Women who were osteopenic were often prescribed bisphosphonates, at which time the metabolic bone community began to ask the question: "Is this use for life?" This question was not often asked when bisphosphonates were initiated in older patients. As data defined the sustained biological effect and persistence of effect of bisphosphonates after long term use, and the absolute fracture risk data from the World Health Organization (WHO) 10-year fracture risk assessment model (FRAX) clarified that these younger, untreated postmenopausal women were actually at fairly low 10-year fracture risk,^[11] clinicians began to ask questions about duration of therapy. Whatever low risk these patients had before treatment was now even lower with treatment, and discussions surrounding drug holiday became more common. While there is no consensus on these approaches and management must be individualized, higher-risk patients (who had a previous low-trauma fracture, or were more elderly [≥65 y] with BMD criteria for osteoporosis) are often not offered a drug holiday since their baseline risk is high.

Even though the Fracture Intervention Trial Long-term Extension (FLEX) data did not show an increase in hip, nonvertebral, or morphometric vertebral fractures in those subsets of patients randomized from the original Fracture Intervention Trials (FIT) taking alendronate for 5 years following 5 years without treatment, there was a statistically significant increase in clinical vertebral fractures in those patients off of alendronate for 5 years.^[6] Hence, despite the limitations of the FLEX data (selection bias and cofounders due to selection of some but not all of the original FIT population), it still remains unclear if bone strength is maintained at all skeletal sites during a drug holiday. There are observational data that a lower hip fracture risk off of alendronate may not be certain if the initial duration of use of alendronate is under 2 years.^[8] Hence, if a drug holiday is considered in lower-risk, younger women, a minimum duration of 5 years of alendronate use seems reasonable. As mentioned, there may be differences among the bisphosphonates in duration of effect, though there are not head-to-head data defining these durations or offset period. There are preliminary data that the reduction in bone turnover after a single injection of zoledronic acid (4-5 mg) may be sustained beyond a year^[12] even though the standard of care is to follow the registered labeling from the Food and Drug Administration (FDA) for zoledronic acid (5 mg/y × 3 y) following the reduction in all fractures in the pivotal zoledronic acid clinical trial.^[13] Monitoring BMD and BTM is, at the present time, the only means to judge sustained biological efficacy.^[14-15]

Another less scientifically sound reason for considering a drug holiday is the anecdotal observational data on the risk of either ONJ or diaphyseal (femur) fractures in very small numbers of patients on bisphosphonates. In contrast to the greater risk (1%-10%) for ONJ seen in the oncology population who have received high doses of intravenous pamidronate or zoledronic acid in combination with chemotherapy for metastatic (to bone) carcinomas or multiple myeloma, there have been fewer than 100 adjudicated cases of ONJ validated in the osteoporosis population who receive the far lower doses of bisphosphonates.^[16] Yet, the perception in the general dental and lay public is that ONJ is common, which has often led to unnecessary discontinuation of bisphosphonates. Such a decision in high-risk patients could possibly render them at far greater risk for fracture than the calculated attributable risk of ONJ in the postmenopausal population (<0.7>

Finally, there have been several anecdotal reports of the development of spontaneous, often bilateral diaphyseal femoral shaft fractures with long-term (≥5 y) use of alendronate.^[17] The mechanism associated with these fractures is unknown. It is also unknown if these types of fractures are seen in people not exposed to bisphosphonates because the reporting of such cases has not been systematic. Once large Medicare databases are carefully studied, we may know if these unusual fractures are confined to the bisphosphonate-exposed population. To date, all of these cases have been associated with long-term alendronate use. It is unknown if this is a class effect or not, since alendronate was the first FDA-approved bisphosphonate for osteoporosis management and has the largest exposed population. Therefore, only time and careful reporting will tell if these fractures are specific to alendronate, or if they might also be seen with other bisphosphonates or in nonbisphosphonate-treated populations. Nevertheless, due to the intense media exposure and the unique litigation climate that pervades US medicine, patients and our colleagues are starting to question drug holidays for this potential fracture risk concern as well. There is no science to guide us here, and patient management must be individualized. Like the broader issue of a drug holiday in any patient, the potential risks and benefits of discontinuation need to be discussed.

Bisphosphonates will continue to be used to benefit patients with a variety of diseases including postmenopausal osteoporosis. The vast majority of treated patients have reduced fracture burden and costs, along with an exceptional safety record. It is the responsibility of practitioners to examine the issue of drug holidays, given the strong science that has evolved in bisphosphonate pharmacokinetics, and be open-minded about potential safety issues that demand good science to clarify. In the meantime, consideration of bisphosphonate drug holidays continues to be based on opinion, without a standard of care, and individualized for each patient.

From the NAMS Menopause e-Consult-newsletter released October 2008

For more, please visit http://www.menopause.org/Members/eConsulteNewsletter.aspx