"Our study confirms that women experience significant bone loss due to cancer treatments and that zoledronic acid can prevent this loss."—Dawn L. Hershman, MD
"Our study confirms that women experience significant bone loss due to cancer treatments and that zoledronic acid can prevent this loss," said lead author Dawn L. Hershman, MD, assistant professor of medicine at Columbia University's College of Physicians and Surgeons in New York City.Zometa stabilized BMD, reduced bone turnover in premenopausal breast cancer survivors
The study was a randomized, double-blind, multicenter, phase III trial comparing treatment with zoledronic acid or placebo every 3 months for 12 months. The investigators enrolled 101 patients, 85 of whom completed the 12-month evaluation. All were premenopausal, with mean age of 42 years. All were followed for 12 months while undergoing chemotherapy following surgery for early-stage breast cancer; all were given oral vitamin D and calcium supplements.
The primary endpoint was change in bone mineral density (BMD), measured via scans of the lower spine and hip. Scans were performed prior to chemotherapy and at 6 and 12 months. Secondary endpoints were percentage changes in markers of bone turnover at 12 months.
Patients who received zoledronic acid had stable BMD at both 6 and 12 months. Patients who received placebo showed a significant decline in lumbar spine BMD: 2.4% at 6 months and 4.1% at 12 months (P <.0001 vs zoledronic acid). In the hip, BMD declines were 0.8% at 6 months and 2.6% at 12 months.
“The intravenous administration of 4 mg zoledronic acid every 3 months completely prevented the bone loss, either suppressed or attenuated the increase in bone turnover markers, and was well tolerated,” Dr. Hershman said. The secondary outcome variables were markers of bone formation (bone-specific alkaline phosphatase, BSAP), and bone resorption (C-telopeptide of type I collagen, CTX). In the placebo group, BSAP rose to 24% above baseline at 6, 12, and 24 weeks and to 47% above baseline at 52 weeks. Also in the placebo group, CTX increased 30% above baseline at 12 weeks, doubled by 24 weeks, and stayed elevated at 52 weeks.
Zoledronic acid held BSAP increase to 16% at 6 weeks, and then it decreased. CTX in the zoledronic acid group declined 26% at 6 weeks, returned to baseline at 12 weeks, and rose to 56% above baseline at 52 weeks. Side effects did not differ significantly between the two groups.
“Premenopausal women receiving chemotherapy for breast cancer sustained significant bone loss at the lumbar spine and hip, whereas BMD remained stable in women who received zoledronic acid. Administration of zoledronic acid during the first year of chemotherapy is an effective and well-tolerated strategy for preventing bone loss,” the researchers wrote.
Translating research into practice
Dr. Hershman notes that >3 million women in the US are breast cancer survivors and that bone loss ranges from 3% to 8% in the lumbar spine and 2% to 8% in the total hip. About 55,000 women under age 55 are diagnosed with breast cancer each year, and many are treated with chemotherapies that can temporarily or permanently induce estrogen deficiency and early menopause. Because estrogen is critical for building and maintaining bone mass, the longer a woman is estrogen deficient, the higher her risk for long-term bone loss. In addition, bone loss can be further exacerbated by some subsequent hormonal therapies, such as ovarian suppression.
Extrapolated over the standard 5 to 10 year treatment period for breast cancer, the researchers say women with breast cancer undergoing early menopause could sustain a bone loss of >20%, which may put them at increased risk for bone fractures. Prior studies with oral clodronate and alendronate have shown that these bisphosphonates can reduce the amount of bone loss associated with cancer chemotherapy, but alendronate is associated with gastrointestinal side effects that might be particularly problematic in women receiving chemotherapy, according to Dr. Hershman.
“[Although] our findings are promising, it's too early for us to recommend this drug for all premenopausal women undergoing chemotherapy for breast cancer because we don't yet have all the information we need on dosing, cost effectiveness, and whether this drug actually prevents bone fractures. However, this research does show we need to be more vigilant about monitoring patients' bone densities before and during treatment, so we can protect bone health and offset bone fracture or osteoporosis risk.”
Lori Pierce, MD, commented, “These early results demonstrating prevention in bone loss at 12 months are particularly encouraging in light of data from other studies suggesting a reduction in breast cancer recurrence following treatment with zoledronic acid.” Dr. Pierce is a breast cancer and radiation oncology expert at the University of Michigan and a spokesperson for the American Society of Clinical Oncology.
The researchers note that the major unanswered questions are when to start bisphosphonates, the appropriate dose, how long to continue treatment, and whether preemptive intervention will reduce fractures.
“It is unclear whether these questions can ever be answered because such studies would necessarily be of long duration. However, given the number of women who experience significant and substantial bone loss, the standard of care for premenopausal women should at least include BMD measurements starting before initiation of chemotherapy and [should continue] at regular intervals thereafter,” Dr. Hershman said.
Reference
1. Hershman DL, McMahon DJ, Crew KD, et al. Zoledronic acid prevents bone loss in premenopausal women undergoing adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol. 2008; [published online ahead of print August 18, 2008]. doi: 10.1200/JCO.2008.16.4707.
PubMed: Related Articles