February 2009
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Protecting Bone Health in Men With Prostate Cancer Undergoing ADT
Evidence supports initiating biphosphonate therapy early in the course of ADT.
Research by Susan L. Greenspan, MD, and colleagues
The use of androgen-deprivation therapy (ADT) in nonmetastatic and advanced prostate cancer is common, and has increased during recent years.1-3 It has been well-documented that ADT is associated with significant bone loss,4-10 and that loss is most pronounced during the first 12 months following treatment initiation.11 Shahinian and others have reported that long-term ADT use is associated with a double to quadruple fracture risk increase.12-16
BACKGROUND
Susan L. Greenspan, MD, and others have reported that oral17 and intravenous18-20 alendronate therapy can prevent bone loss and maintain bone mass in men receiving ADT. What is less clear, according to a report in the Journal of Clinical Oncology (2008;26:4426–4434), is the extent of changes in bone mass or turnover after discontinuation of biphosphonate therapy and whether continuation of treatment would provide additional benefit. Therefore, Dr. Greenspan, Associate Program Director, General Clinical Research Center Director, Osteoporosis Prevention and Treatment Center in the University of Pittsburgh Division of Endocrinology and Metabolism, and colleagues, conducted a trial to determine whether men should continue biphosphonate therapy to prevent bone loss, as well as the effects of ADT duration on different related variables. The following is a summary of the full report, mentioned above.
Dr. Greenspan and colleagues' randomized, double-blind, placebo-controlled, partial-crossover trial included a total of 112 men aged ≤85 years who were receiving ADT for nonmetastatic prostate cancer.17 Her team previously reported on the first-year results;17 and the current report focuses on the second year of oral therapy. The investigators wrote that men were randomized to alendronate 70 mg once weekly or placebo with a second randomization at year 2 for those who were initially assigned to active treatment. The outcomes evaluated included bone mineral density (BMD) and bone turnover markers.
RESULTS
According to the report, there were no significant differences in baseline characteristics between the groups, and at baseline the average age was 71.4 years (±8.6). Mean duration of ADT was 25.5 months (±14.0), prostate-specific antigen (PSA) level was a mean of 1.1 ng/mL (±4.3; median 0.10). Although there were small differences in BMD across the three groups, Dr. Greenspan noted that they observed no differences in bone turnover markers. As per World Health Organization (WHO) classification,21-22 41% of the men had osteoporosis, 49% had low bone mass, and 11% were normal, they wrote.
Changes in year 2. At year 2, the men randomized to alendronate a second time (alendronate-alendronate group) did not differ from those assigned placebo in BMD at the lateral spine, femoral neck, one-third distal radius, total radius, or bone markers. There were, however, small differences in spine and hip BMD, the investigators said.
During the second year, men in the alendronate-alendronate group experienced a mean increase in BMD of 2.3% at the spine (P=.005) and 1.3% at the total hip (P=.10) relative to the 1-year measurements. BMD was stable for the femoral neck and one-third distal radius. This is compared with the men assigned alendronate-placebo, who experienced a BMD mean decrease of 1.9% at the one-third distal radius (P=.006) and 2.1% at the total radius (P<.001). Spine and hip BMD remained stable, they reported.
Serum C-telopeptide cross-linked collagen type 1 (CTX) decreased a mean of 18.6% (P=.008) among alendronate-assigned men but other bone markers were stable. Among men in the placebo group, urinary N-telopeptide cross-linked collagen type 1 (NTX) increased a mean of 70.5% (P=.010). Significant increases in serum intact N-terminal propeptide of type 1 collagen (P1NP) and bone-specific alkaline phosphatase were also observed the investigators.
Within group changes at 2 years. At the end of 2 years, men in the alendronate-alendronate group had the largest BMD increase versus baseline: 6.7% (±5.6%) at the spine (P<.001), 1.6% (±2.7%) at the total hip (P=.011), and 3.2% (±7.1%) at the femoral neck (P=.041; all P<.05), the investigators wrote. Men in the alendronate-placebo group and the placebo-alendronate groups also had statistically significant increases at the spine; changes for total and femoral neck, however, were not significant for both groups. Bone density at the one-third distal radius decreased in all groups except among men who received 2-year treatment with alendronate. Biochemical markers of bone turnover were significantly below baseline in all three groups at 2 years, Dr. Greenspan and colleagues found.
Between-group differences at 2 years. Compared with men assigned alendronate-placebo, the alendronate-alendronate group had greater increases in BMD at the PA spine, lateral spine, femoral neck, ultradistal and total distal radius after 2 years. There were no differences in WHO classification of osteoporosis after 2 years between the alendronate-alendronate group and both placebo groups.
EFFECTS OF TREATMENT
Sustained treatment. "We compared 12 to 24 month gains in BMD to see if there was additional benefit with sustaining treatment for 24 months versus 12 months," Dr. Greenspan wrote. "Using a mixed-model analysis adjusted for baseline, we compared alendronate-alendronate and alendronate-placebo groups. The men assigned to alendronate for the additional 12 months had a significantly greater percentage point increase in BMD compared with men assigned alendronate-placebo at the spine, lateral spine, total hip, trochanter, one-third distal, ultradistal, and total radial sites."
Delayed treatment. Differences in BMD were compared between men who initiated treatment at baseline (alendronate-alendronate and alendronate-placebo) and those who delayed treatment (placebo-alendronate), the researchers wrote. Men who did not have delayed treatment, on average, had a gain in BMD that was greater at the spine, femoral neck, ultradistal radius, and total radius, versus men who delayed treatment at 12 months, they found.
"In short, we found that men initially assigned to alendronate and reassigned to continue treatment at year 2 had additional gains in bone density at the spine and hip (P<.01 for both)," Dr. Greenspan and colleagues wrote. "The men were randomized to placebo in year 2 maintained density at the spine and hip, but lost BMD at the forearm. Those men who began treatment with alendronate at year 2 had improvements in bone mass at the spine and hip, but saw less of an improvement compared with those who were assigned to alendronate treatment at baseline." Additionally, the alendronate-alendronate-assigned men experienced a mean increase at the spine and hip (P<.05) for both and bone turnover remained suppressed, they noted.
"We believe our results provide preliminary evidence supporting the initiation of biphosphonate therapy early in the course of ADT," the investigators concluded. "Because bone loss occurs when ADT begins,11 early screening of BMD and preventive measures, such as calcium, vitamin D and exercise, should be encouraged."9,10,23
Improvements in BMD among men with prostate cancer are the most marked in those who continue therapy with alendronate, Dr. Greenspan's group added. "Delay in this therapy is detrimental to bone health. Therefore we assert that men with low bone mass or osteoporosis should be considered early for once-weekly oral therapy with alendronate, and treatment should continue for at least 2 years in men with prostate cancer undergoing ADT."
Conni Bergmann Koury, Editor-in Chief, prepared this summary.
Susan L. Greenspan, MD, is Associate Program Director, General Clinical Research Center Director, Osteoporosis Prevention and Treatment Center in the University of Pittsburgh Division of Endocrinology and Metabolism. She may be reached at greenspans@dom.pitt.edu.
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