This study demonstrated that a single infusion of zoledronic acid suppressed bone turnover for at least 12 months and increased BMD of the hip and spine in men receiving a GnRH agonist for nonmetastatic prostate cancer. Compared with placebo, zoledronic acid increased BMD of the lumbar spine and hip by 7.1% and 2.6%, respectively. In a placebo-controlled study of 106 men with nonmetastatic prostate cancer, zoledronic acid administered every 3 months increased BMD of the lumbar spine and hip by 7.8% and 3.9%, respectively.8
Although the current study did not directly compare the two schedules of zoledronic acid treatment, the similarity of BMD results and persistent suppression of serum N-telopeptide throughout the 12-month study suggest that annual zoledronic acid is sufficient to prevent bone loss in hypogonadal men.
The observed efficacy of annual zoledronic acid in these hypogonadal men with prostate cancer is consistent with the results of zoledronic acid in postmenopausal women with osteoporosis. In a multicenter, randomized trial, 351 postmenopausal women were assigned to receive placebo or zoledronic acid every 3, 6, or 12 months, and effects on BMD and biochemical markers of bone turnover were studied.9
In women treated with once-yearly zoledronic acid, changes in spine and femoral neck BMD were significantly higher than in women treated with placebo at 12 months after treatment, and bone resorption markers remained suppressed after 12 months. The changes seen with annual zoledronic acid were comparable to changes seen with more frequent administration. The study concluded that annual infusion of zoledronic acid is effective therapy for postmenopausal osteoporosis.
Treatment with bisphosphonates can have adverse consequences. An emerging literature has linked bisphosphonates, particularly high doses of zoledronic acid, with osteonecrosis of the jaw.10–13
Zoledronic acid is also associated with a risk of renal failure when administered in doses much higher than in the current study.14
The relative risk of osteonecrosis, and likely of other potential complications, may increase with the cumulative dose of zoledronic acid. Thus, if comparable efficacy can be achieved with less frequent administration, fewer adverse consequences may be observed.
Other bisphosphonates also increase BMD in GnRH agonist-treated men. A randomized, placebo-controlled trial of 47 men with prostate cancer demonstrated that pamidronate (60 mg intravenously every 3 months) prevents loss of BMD in the hip and spine in men initiating treatment with GnRH agonists.1
BMD of the spine, trochanter, and hip significantly declined (3.3% ± 0.7%, 2.1% ± 0.6%, and 1.8% ± 0.4%, respectively) in men treated with GnRH agonists and placebo but did not significantly change at any skeletal site in men treated with GnRH agonists and pamidronate. Similar results were reported in a second randomized controlled trial, in which men treated with pamidronate manifested increased BMD of the spine and femoral neck compared with men treated with placebo.15
In both studies, pamidronate significantly reduced levels of bone turnover markers compared with placebo.
GnRH agonist–induced bone loss can also be prevented with selective estrogen receptor modulators such as raloxifene and toremifene in men with prostate cancer.16,17
Other agents, including denosumab (AMG-162; Amgen, Thousand Oaks, CA), a novel antibody targeted against receptor activator of nuclear factor-kb ligand, are currently being investigated as potential therapies for osteoporosis in men with nonmetastatic prostate cancer.
In men with androgen-independent prostate cancer and bone metastases, frequent treatment with zoledronic acid (4 mg every 3 weeks) decreases the risk of disease-related skeletal complications, including fractures.18
In a double-blind randomized trial of 643 men with androgen-independent prostate cancer, zoledronic acid (4 or 8 mg every 3 weeks) reduced the relative risk of developing skeletal-related events (defined as pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone, or a change of antineoplastic therapy to treat bone pain) by 25% and increased the median time to first skeletal-related event by more than 160 days. Given the results of this study, zoledronic acid (4 mg every 3 to 4 weeks) was approved to treat men with hormone-refractory prostate cancer metastatic to bone, and this remains the only known effective schedule to prevent disease-related skeletal complications in men with metastatic prostate cancer. Our observation that annual zoledronic acid increases BMD in men with nonmetastatic prostate cancer does not justify less frequent administration to prevent disease-related skeletal complications in men with metastatic prostate cancer.
There are some potential limitations to this study. The study was powered to detect a significant change in BMD and was not powered to assess the impact on fracture risk. Larger randomized trials would be required to assess the effect of different schedules of zoledronic acid on fracture risk. Also, only a single schedule of zoledronic acid administration was analyzed; additional studies are needed to determine whether even less frequent administration might provide similar benefits. The baseline characteristics of both groups were similar, although the mean duration of prior GnRH agonist treatment was longer in men assigned to zoledronic acid than in men assigned to placebo. Because BMD decreases at a steady rate regardless of the duration of past GnRH agonist exposure,19
this difference would not seem to explain the observed significant differences in changes in BMD and biochemical markers between the groups. Finally, the patient population in this study was restricted to nonmetastatic prostate cancer, and extrapolation to men with bone metastases would not be appropriate.
In summary, zoledronic acid (4 mg once in 12 months) significantly increased BMD of the hip and spine in men receiving a GnRH agonist for prostate cancer. Annual zoledronic acid may represent a convenient and effective strategy to prevent osteoporosis in hypogonadal men.