Drug-Induced Bone Loss: An Increasing Problem for Men with Prostate Cancer
Because testosterone promotes the proliferation of many types of prostate cancers, suppression of its androgenic effects has become a primary target for prostate cancer drug therapies. Androgen-suppressing drugs, such as the widely used luteinizing hormone-releasing hormone (LHRH) agonists reduce free testosterone, thus eliminating a major driver of cancer cell growth.
However, testosterone is also responsible for maintaining bone mineral density (BMD) in men, and rapid BMD loss is an unfortunate side effect of treatment with these drugs. The loss occurs within months of exposure, often rendering men osteoporotic with a markedly increased risk of fracture within one to two years of treatment. For patients who begin these therapies and already have low BMD, this situation may be particularly problematic. canada pharmacy mall
Over the last decade, a number of studies have shown that androgen-deprivation therapy (ADT) reduces BMD at a rate of 2% to 7% per year, reported Tracey Krupski, MD, MPH, of the Department of Urology at UCLA’s Geffen School of Medicine in Los Angeles. Dr. Krupski presented an analysis of Medicare data from more than 50,000 men, noting that the loss of BMD translates directly into a rise in fracture rates.
In this study, the rate of fractures over a five-year period was 19.3% for patients receiving ADT, compared with a rate of 12.6% for a group of similar men not receiving ADT. The hospitalization rate for fractures was 5.1% for men using ADT versus 2.3% for non-users. Greater drug exposure correlated directly with greater fracture rates.
“Many of these patients lose their independence, ending up in long-term care facilities,” said Dr. Krupski.
Matthew R. Smith, MD, and colleagues at Harvard Medical School presented data from more than 12,120 anonymous prostate cancer health insurance claims from Fortune 500 corporations. They found an alarming 13% increased risk of all types of fractures among men receiving gonadotropin-releasing hormone (GnRH) agonists such as leuprolide (Lupron®, TAP) and goserelin (Zoladex®, AstraZeneca). The risk of hip fractures was increased by 39%, and the vertebral fracture risk was increased by 22%. Mei Sheng Duh, ScD, also of Harvard Medical School, who presented the data for Dr. Smith, emphasized that these figures are conservative.
Christopher Ryan, MD, from the Oregon Health and Science University in Portland, presented data from prostate cancer patients treated with ADT for less than 12 months. The men underwent BMD assessments prior to randomization to either placebo or zoledronic acid (Zometa®, Novartis), 4 mg intravenously every three months for one year, in addition to ongoing ADT. Overall, 66.7% of the men were either osteopenic or frankly osteoporotic following ADT. Bone loss was higher at the femoral neck than at the lumbar spine or the total hip.
Median exposure to androgen-suppressing drugs in this cohort was only three months, suggesting that the loss of BMD occurred shortly after the onset of androgen suppression. The degree of bone loss correlated strongly with the duration of exposure.
The investigators studied many variables that might have affected BMD. They found that increased body mass index, calcium and vitamin D supplementation, exercise, and, surprisingly, alcohol consumption, were all associated with higher BMD and a lower risk of ADT-induced osteoporosis. Dr. Ryan had no explanation for the positive effect of alcohol (contrary to other evidence showing a direct relationship between alcoholism and osteoporosis), but he noted that a similar pattern has been observed in studies of osteoporosis in post-menopausal women.
Earlier trials have also shown zoledronic acid had the potential to counter the bone-depleting effects of ADT. The precise role of this drug in treatment strategies, Dr. Ryan added, should be much clearer when this 19-center trial is completed in the near future.
The synthetic hormone bicalutamide (Casodex drug, Astra-Zeneca) is a nonsteroidal antiandrogen that inhibits the action of testosterone without reducing testosterone levels. In light of data showing that bicalutamide does not induce BMD loss, it is likely to play an increasing role in the treatment of hormone-sensitive prostate cancers, according to Vivek Wadhwa, MD, from Arrowe Park Hospital in Wirral, United Kingdom. Bicalutamide is unique in that it works by blocking testosterone receptors on the surface of prostate cancer cells, thus preventing the cell proliferation signal without lowering actual testosterone levels.
Dr. Wadhwa and colleagues studied 430 men with locally advanced or metastatic prostate cancer. Those men who were already osteoporotic at the baseline assessment were treated with canadian bicalutamide plus calcium and vitamin D supplements. Those who had normal BMD or who were osteopenic received LHRH analogues. All patients were followed for five years.
The men with normal baseline BMD showed a marked loss of BMD beginning shortly after treatment with LHRH agonists. Mean T-scores, a measure of BMD, went from -0.25 at the baseline (within normal range) to -1.52 by the fourth year, indicating that the majority of patients had become osteopenic.
In the men who started out with osteopenia, LHRH agonist treatment had the effect of moving 60% of them into the osteo-porotic range within two years. Mean T-scores dropped from -1.72 at baseline to -3.78 by the fourth treatment year. In contrast, the patients receiving bicalutamide showed no significant change in BMD over the course of the study. The mean T-score at baseline was -3.54 in this cohort; by the fourth year, it was -3.78, a nonsignificant decrease.
Dr. Wadhwa and other researchers at the AUA meeting called for routine measurement of BMD prior to initiation of any antiandrogenic therapy for prostate cancer. In many cases, a drug like generic bicalutamide, or the addition of a bisphosphonate and vitamin D and calcium supplementation, can help prevent debilitating fractures, especially in men with a low BMD before the beginning of treatment.