February 2009
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Zoledronic Acid Prevents Bone Loss in Women Receiving Chemotherapy for Early-Stage Breast Cancer
Chemotherapy agents can accelerate bone loss and are associated with increased risk of fracture.
Research by Dawn L. Hershman, MD, MS, and colleagues
Survival rates among women in the United States with breast cancer are rising, with currently more than 3 million women breast cancer survivors,1-3 according to analyses. There are, however, costs associated with this improved survival, according to a recent report. Young women with early-stage breast cancer who undergo chemotherapy often have temporary or permanent menstrual cycle cessation,4 putting them at greater risk of adverse consequences associated with premature estrogen deficiency.5-7 Dawn L. Hershman, MD, MS, and colleagues wrote that bone loss in this population has been shown to range between 3% to 8% in the lumbar spine and 2% to 4% in the total hip.8,9 The Women's Health Initiative Observational Study data show that postmenopausal breast cancer survivors have a 15% increased risk of fracture compared with their counterparts who do not have a history of breast cancer.10
Dr. Hershman, the Florence Irving Assistant Professor of Medicine and Epidemiology and Co-Director of the Breast Program of the Herbert Irving Comprehensive Cancer Center, Columbia University, and colleagues discuss zoledronic acid treatment among women receiving chemotherapy for early-stage breast cancer in a recent report (Journal of Clinical Oncology. 2008;26:4739–4745); the following is a summary of their findings.
The biphosphonates oral clodronate and intravenous (IV) pamidronate have been shown by Fuleihan and others to reduce chemotherapy-associated bone loss.8,11,12 Patients receiving the relatively weak bisphosphonate clodronate, however, had persistent significant lumbar spine bone loss (2.2%) at 2 years. The more potent oral bisphosphonate, alendronate, is widely used for treating postmenopausal osteoporosis. Unfortunately that agent is associated with adverse gastrointestinal effects13—an issue of particular concern among women undergoing chemotherapy, Dr. Hershman said. IV zoledronic acid is effective for preventing bone loss in premenopausal women receiving combined endocrine-blockade therapy.14
Dr. Hershman's group undertook an investigation to evaluate the efficacy of every-3-month zoledronic acid treatment in reducing bone loss in premenopausal women with breast cancer receiving chemotherapy. The team also sought to examine zoledronic acid's effect on markers of bone turnover, characterize the natural history of bone loss, and confirm the tolerability of zoledronic acid in combination with chemotherapy.
PATIENTS AND METHODS
Included women were newly diagnosed as premenopausal with histologically proven, nonmetastatic breast cancer, the investigators wrote. Enrollment took place after surgery but before chemotherapy, and investigators did not determine the chemotherapeutic regimens. Excluded patients had a T-score less than –2.0 at any site, fragility fracture, prior therapy with a bisphosphonate or calcitonin, lumbar spine anatomy precluding accurate bone mineral density (BMD) measurement of three lumbar vertebrae, serum creatinine 2 mg/dL, or pregnancy, according to the journal report.
Patients were randomized to IV zoledronic acid 4 mg over 15 minutes every 3 months for 12 months or placebo. Dr. Hershman said that stratified treatment assignment was based on tumor hormone-receptor status, and the investigators noted baseline information including tumor stage, history of fractures, reproductive and menstrual history, tobacco exposure, alcohol intake, and medications. A chemistry panel, intact parathyroid hormone, 25-hydroxyvitamin-D, bone-specific alkaline phosphatase (BSAP; a marker of bone formation), and serum C-telopeptide of type I collagen (CTX; a marker of bone resorption) were taken. All patients were also given oral calcium and vitamin D supplements, the investigators wrote.
Study visits were scheduled at 6, 9, 12, 18, 24, 36, and 52 weeks after randomization, and patients were questioned about bone pain and toxicities at each visit. Dr. Hershman's team measured BMD of the lumbar spine (L1 to L4), total hip, and femoral neck using dual-energy x-ray absorptiometry at randomization and at 24, and 52 weeks using Hologic QDR 4500 bone densitometers (Hologic, Inc, Bedford, MA). Patients were assessed using the same machine at each follow-up visit, and all results were reviewed by a third party. If there was excessive bone loss—defined as > 8% decrease over 6 months)—the investigators was notified, according to the report. Fasting serum for CTX and BSAP was obtained before initiation of chemotherapy and at follow-up visits at 6, 12, 24, 36, and 52 weeks.
Dr. Hershman and colleagues said that the primary efficacy endpoints gathered included percent change in lumbar spine BMD at 24 and 52 weeks after chemotherapy initiation. Secondary endpoints included percent change in total hip and femoral neck BMD and changes in CTX and BSAP at 24 and 52 weeks.
BASELINE CHARACTERISTICS
A total of 114 women were randomized, 103 completed the baseline evaluation, and five withdrew before the 24-week assessment. Between the 24-week and 52-week assessments 11 patients withdrew, and two patients were not included in the analyses because baseline and follow-up BMDs were measured on different densitometers, according to the journal article. At baseline, mean age (42 ±6 years) and mean body mass index (26 ±5 kg/m²) were similar between groups, and the groups were also comparable with regard to stage, treatment duration, hormone receptor status, and race. Dr. Hershman noted that this was a racially/ethnically diverse group of women, with 51% non-Hispanic white patients, 35% Hispanic patients, 12% African American patients, and 2% Asian patients. The groups were well balanced with respect to menstrual history and risk factors for osteoporosis, although patients in the placebo group reported higher use of calcium supplementation, the investigators noted. Tamoxifen and aromatase inhibitor use were similar between the groups.
Baseline lumbar spine, femoral neck, and total hip BMDs were normal and comparable in both groups. In addition, baseline BSAP and CTX were similar between groups, they wrote. The percentage of patients with lumbar spine z scores between –1.0 and –2.0 at baseline was 9% in the placebo group and 11% in the zoledronic acid group.
RESULTS
Lumbar spine, femoral neck, and total hip BMD remained stable in the zoledronic acid group at 24 and 52 weeks, accoriding to Dr. Hershman's findings. Women randomized to placebo, however, had a significant decrease in lumbar spine BMD at 24 (–3.2%) and 52 weeks (–4.4%). At 52 weeks, total hip and femoral neck BMD had also decreased significantly from baseline by –2.1% and –1.5%, respectively, according to the report. The percentage of patients with z-scores less than –1.0 at 52 weeks increased from 9% to 14% in the zoledronic acid group and from 11% to 24% in the placebo group. By 52 weeks, 29% of the patients had a 5% loss of BMD at one of the three sites tested. Of these patients, 17 (61%) were in the placebo group, and 11 (39%) were in the zoledronic acid group. In the placebo group, change in BMD was not correlated with type of chemotherapy, baseline BMD, or permanence of menstrual cessation, the investigators wrote.
BSAP and CTX were significantly different between the groups at 24 and 52 weeks. Serum BSAP increased 24% above baseline at 6, 12, and 24 weeks, with a further increase to 47% above baseline at 52 weeks in placebo-assigned women. Serum CTX also increased 30% above baseline at 12 weeks, doubled by 24 weeks, and remained markedly elevated. In the zoledronic acid group, serum BSAP increased by 16% at 6 weeks, and then continued to decline gradually. After an initial 26% decline in serum CTX from baseline to 6 weeks, this marker returned to baseline level by 12 weeks, and rose to 56% above baseline by 52 weeks. In the zoledronic acid group, suppression levels of BSAP and CTX decreased between 24 and 52 weeks, according to the article.
Treatment was well tolerated, Dr. Hershman noted. There were no serious adverse events reported, and no cases of a change in renal function or osteonecrosis of the jaw. Eye discomfort was significantly more common among zoledronic acid-treated women versus placebo (47% vs 25%, respectively; P<.01). No patient had cancer recurrence during the 52-week study period.
DISCUSSION
Premenopausal women with breast cancer experience significant bone loss during the first year after initiating chemotherapy, this study revealed. Bone loss rate was highest at the lumbar spine. Although less severe, significant losses were also seen at the femoral neck and total hip, Dr. Hershman and colleagues wrote. Bone loss was accompanied by highly significant increases in bone turnover markers, indicating an increase in bone remodeling activity. IV zoledronic acid every 3 months completely prevented the bone loss, either suppressed or attenuated the increase in bone turnover markers, and was well tolerated.
"Our results are consistent with previous data,"8,12,15-17 the investigators wrote. "Delmas et al15 evaluated cyclic risedronate use in women who entered menopause following chemotherapy, and Greenspan et al16 studied weekly oral risedronate in patients who had completed chemotherapy. Patients in these studies were older and had lower baseline BMD than our study patients, and the rate of loss in the placebo group was less than we observed. In both studies, however, BMD remained stable or increased in women treated with risedronate. Two other studies of bisphosphonate were conducted among premenopausal women randomized prior to chemotherapy initiation. The amount of bone loss in the placebo arm of both of these investigations was comparable to our results."
AROMATASE INHIBITOR USE
The use of aromatase inhibitors to prevent breast cancer recurrence in postmenopausal women is becoming increasingly common, according to the journal report. These drugs, however, accelerate bone loss and are associated with increased risk of fracture.18,19 Dr. Hershman and colleagues wrote that in premenopausal women receiving combined endocrine therapy with gonadotropin-releasing hormone agonists and aromatase inhibitors, longer duration of treatment is associated with dramatically increased bone loss.
"A study that evaluated the combination of goserelin and anastrozole found that the mean percent decrease in BMD was 6% over the first year and 17.4% over 3 years," the investigators noted. "When the hormonal therapy was discontinued and menses resumed, however, much of the loss was reversed.14,20 Patients undergoing chemotherapy rarely regain normal menstruation with current treatment strategies."
Bisphosphonates inhibit osteoclast-mediated bone resorption and are associated with suppression of bone resorption markers and bone formation, Dr. Hershman's group said.
"We observed that bone turnover markers increased in the placebo group and were significantly lower in the zoledronic acid group at most points," the investigators wrote. "Our results differ from that of Fuleihan,8 possibly because zoledronic acid is more potent and has a longer duration of action than pamidronate. One zoledronic acid infusion can suppress bone resorption markers for 1 year in postmenopausal women with osteoporosis.21,22 Despite the difference we observed between the treatment groups, zoledronic acid given at this relatively high dose, did not completely prevent an increase in serum CTX. At 1 year, this level was 50% above baseline."
TO TREAT OR NOT TO TREAT?
The researchers wrote that their results are consistent with previous studies demonstrating that significant bone loss occurs in premenopausal women undergoing chemotherapy for breast cancer, and bisphosphonates can prevent this bone loss. Whether clinicians should be concerned about preventing this bone loss, however, remains less clear, they said.
"Low BMD and biochemical evidence of increased bone resorption (CTX) are independent risk factors for fracture in elderly women,23 however, the relationship between BMD fracture risk is different in younger women compared with older women,24 the investigators wrote. "Younger women, generally, are at much lower short-term risk of fracture than elderly women, even in the setting of relatively low BMD. Women in our study were young and had BMD z-scores greater than –2.0, therefore their BMD was within the expected range.25 When the women in our study were compared with the WHO criteria for diagnosis of osteoporosis in postmenopausal white women,26 17% at baseline had low bone mass or osteopenia with T-scores between –1.0 and –2.5. No patient fractured or developed osteoporosis."
Initiating preventive antiresorptive therapy in older postmenopausal women with breast cancer at high short-term risk of fracture appears obvious, Dr. Hershman and colleagues said. Administering bisphosphonates to young women at low short-term risk of fractures to prevent acute bone loss that could potentially result in future fractures, however, may not be necessary, beneficial, or cost effective.
"The statistically significant bone loss seen particularly at the lumbar spine in untreated women, and the number of women who had >5% loss at one BMD site, raise concerns regarding future bone health," wrote the investigators. "We know that bone loss continues over time27 and may be worsened by therapies used to prevent a recurrence of cancer.18 Also, chemotherapy-induced ovarian dysfunction causes an average of a 10-year earlier onset of menopause,6 and these women are therefore estrogen deficient longer than women who have natural menopause.28 This extrapolates to a >20% bone loss over the 5- to 10-year breast cancer treatment period. It remains unclear when to intervene."29
IMPLICATIONS AND FUTURE DIRECTIONS
These results, showing that zoledronic acid prevented bone loss, reduced serum markers of bone turnover, and was well tolerated in premenopausal women with breast cancer undergoing chemotherapy, have important implications, Dr. Hershman and colleagues concluded. The number of young breast cancer survivors is increasing, and these women will enter menopause early as well as experience a prolonged period of estrogen deficiency and an increased long-term risk of osteoporotic fracture.
Questions remain, however, regarding the optimal time to initiate bisphosphonates, the appropriate dose and duration of therapy, and the potential for preemptive intervention to reduce future fractures, they added. It is not known whether these questions can be answered. "But 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 continuing at regular intervals."
Conni Bergmann Koury, Editor-in-Chief, prepared this summary.
Dawn L. Hershman, MD, the Florence Irving Assistant Professor of Medicine and Epidemiology, and Codirector of the Breast Program of the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY. She can be reached at dlh23@columbia.edu.
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