NEW ORLEANS—Prostate cancer patients who are treated with Gonadotropin-Releasing Hormone (GnRH) analogs are at greatly increased risk of osteoporosis and bone fractures, reported Tracey Krupski, MD, and Matthew Smith, MD, PhD, at the 40th annual meeting of the American Society of Clinical Oncology.
Though commonly thought of as a condition of older, post-menopausal women, there is growing evidence that men also experience significant bone loss as they age. GnRH analogs, which suppress androgens and are widely used to treat prostate cancer, increase the risk considerably.
Data from a multicenter comparison of fracture rates in nearly 4,000 prostate cancer patients on GnRH agonists versus nearly 8,000 patients who did not take androgen suppressing agents, show a 25% increase in fracture risk among the men on the androgen suppressing drugs. This is the largest study yet undertaken on the impact of androgen suppression on bone; Drs. Smith and Krupski are both members of the multicenter research team.
The data indicate that fracture risk correlates strongly with age, as well as dose and duration of exposure to androgen suppressing drugs.
The findings have major public health implications, given that more than 500,000 men are put on GnRH agonists every year, said Dr. Smith, of the Massachusetts General Hospital, Boston. Most are elderly, and already at increased risk for both bone loss and for the falls that typically result in fractures. The problem only increases with time; the survival benefit obtained by suppressing androgens means that men so treated will be exposed to many more months of treatment, further increasing the fracture risk.
Dr. Krupski, of the University of California, Los Angeles, believes clinicians treating men on these drugs need to monitor bone mineral density (BMD) regularly, especially if a patient has been on treatment for a few years already.
This is not the first study to point to a connection between androgen suppression and osteoporosis: several earlier studies suggested the possibility, but these were small and methodologically flawed.
Dr. Smith and his colleagues used 1991–2001 claims data from a 5% national random sample of Medicare beneficiaries, and identified 3,887 men with non-metastatic prostate cancer diagnoses who took GnRH agonists or other androgen suppressants. They also selected 7,774 well-matched men with similar diagnoses but who did not take the drugs. The mean longitudinal follow up time was 7 years.
Roughly 33% of the men on GnRH agonists had one or more fractures during the study period. Adjusting for survival, fracture incidence during the final year of analysis was 83% for those on androgen suppression versus 56% in the controls. For men on long-term androgen-suppression (greater than 1.9 years) the overall fracture rate was 46% versus 41% for those on short-term therapy (less than 1.9 years). Androgen deprivation carried a relative risk of 1.25 for all types of fractures. For hip fractures, it was 1.46, and vertebral fractures, it was 1.63.
The investigators also found an interesting ethnic difference: African-American men on GnRH agonists appeared to be at relatively lower risk for fractures than White European-Americans on the same drugs. The researchers have not yet analyzed the data for Hispanic or Asian men, and they have not yet ventured a hypothesis to explain the finding.
Dr. Smith believes the increased fracture risk is a class effect. There was nothing in the data to suggest there is any meaningful difference between the various GnRH agonists.
The bottom-line clinical message is that men treated with GnRH analogs are subject to more rapid declines in BMD, on the order of 8% per year. This is similar to the rate of bone loss seen in women during the first years after menopause.
However, these findings should not be taken to mean that all prostate cancer patients on androgen-suppression should be put on bisphosphonates or other anti-osteoporosis drugs. In some cases, they can be managed by nutritional means, including increased intake of calcium and vitamin D.
Dr. Smith advised against wreckless use of osteoporosis medications. “The strategy I favor is assessment of risk by getting baseline pre-treatment BMD measurements, monitoring BMD periodically during therapy, and only intervening when the fracture risk is excessive based on bone loss. It is a more onerous approach, but it will reduce excessive use of expensive drugs.”
