Estrogen receptor modulator reduces ADT fractures

Chicago-Androgen deprivation therapy leads to an increased risk of bone fractures and other side effects of estrogen deficiency in men with prostate cancer, but those effects can be successfully treated with the use of an oral selective estrogen receptor modulator, suggest the results of a large, prospective, randomized trial presented at the AUA annual meeting in Chicago.

The 1,389 men in the trial were randomized to receive either toremifene (Acapodene), 80 mg daily, or placebo for up to 24 months. Nearly one in four patients in the placebo group suffered new or worsening morphometric vertebral fractures, clinical fragility fractures, or bone loss >7%.

In the toremifene cohort, however, there was a greater than 50% reduction in vertebral fractures (p<.05). (The drug is not currently approved for prevention of bone fractures in men with prostate cancer undergoing androgen deprivation therapy, but its manufacturer, GTx, Inc., has submitted a new drug application.)

A phase II study had shown that a 60-mg daily dose of toremifene yielded a statistically significant, yet minimal improvement in bone mineral density (BMD) in the lumbar spine at 6 months as measured by dual energy x-ray absortiometry (J Urol 2008; 179:152-5). Investigators chose the 80-mg dose for the present trial based on its expected safety profile and projected additional benefit in BMD.

The drug's maker, GTx, Inc., has submitted a new drug application with the FDA for toremifene, 80 mg, an oral selective estrogen receptor modulator for the prevention of bone fractures in men with prostate cancer undergoing androgen deprivation therapy.

Patient monitoring key

All patients entering the study had undergone androgen deprivation therapy for at least 6 months, had serum PSA levels ≤4.0 ng/mL, and were at least 70 years of age or were at or below World Health Organization standards for spine or hip BMD.

New morphometric vertebral fractures were the primary clinical endpoint, while secondary endpoints included BMD, worsening vertebral fractures, lipid changes, breast pain, hot flashes, and clinical fragility fractures.

Patients with >7% bone loss were considered to be at high risk for fracture and were removed from the study.

Among patients treated with placebo, the rate of new morphometric vertebral fractures was 4.93%, while the rate of such fractures combined with worsening vertebral fractures was 9.9%. Including patients who had >7% bone loss with all fractures pushed the rate to 23.9%.

"This trial provides solid evidence for the importance of monitoring, treatment, and prevention of fractures in men on androgen deprivation therapy," Dr. Lin said. "Men are living longer on ADT and they want to maintain their independence. We know these men are at high risk for fracture and that fractures reduce survival. It is our responsibility to monitor and treat as appropriate our patients to reduce this risk of fracture."

In the past, Dr. Lin said, urologists were not especially cognizant of fracture risk in prostate cancer patients, nor did men themselves often report fractures to their urologists.

"Today, there is a better understanding of ADT, its impact on bone health, and, in particular, its impact on estrogen, a key hormone responsible for bone health," he said.

Several previous studies have validated the elevated risk of fracture in patients with prostate cancer undergoing ADT, Dr. Lin noted (N Engl J Med 2005; 352:154-64).

Co-authors Domingo Rodriguez, MD, and Ronald A. Morton Jr., MD, are employees of GTx, which funded the study.