Younger women who have been treated for breast cancer have a higher risk for osteopenia and osteoporosis than do their cancer-free peers, and that risk seems to rise when treatment involves chemotherapy plus hormone therapy or aromatase inhibitors alone. Researchers from Johns Hopkins Bloomberg School of Public Health, Baltimore, reported these findings in Breast Cancer Research.1 The study found that breast cancer survivors diagnosed up to age 50 had nearly twice the risk for osteopenia and osteoporosis as cancer-free women.
Kala Visvanathan, MD, MHS
Osteopenia and osteoporosis are known to be prevalent in older women treated for breast cancer, but “these findings show that even younger women have a relatively high risk of bone loss with standard breast cancer treatment,” noted the study’s senior author, Kala Visvanathan, MD, MHS. Dr. Visvanathan is Director of the Clinical Cancer Genetics and Prevention Service at the Johns Hopkins Sidney Kimmel Cancer Center and Professor of Oncology and Epidemiology at Johns Hopkins Bloomberg School of Public Health and School of Medicine.
Timing of Bone Loss
The risk of bone loss was higher among breast cancer survivors in the study after 2 years of follow-up. In an interview with The ASCO Post, Dr. Visvanathan said these results suggest that bone loss not only occurs among premenopausal women but earlier than we might think. “It is not 10 years later, when they are getting older,” she explained. “This bone loss is happening pretty soon after treatment, independent of menopause.”
The study authors concluded that their findings “provide support for a baseline evaluation of bone density and fracture risk assessment close to breast cancer diagnosis, particularly among young survivors being treated with combined chemotherapy and hormone therapy, so that prevention strategies and appropriate monitoring can be implemented early.” Dr. Visvanathan stressed that larger studies are needed to validate the findings and to quantify the degree of bone loss with different treatments.
All Study Patients Had Familial Cancer Risk
Participants were enrolled in the Breast and Ovarian Surveillance Service (BOSS) study, an ongoing prospective cohort study including women and men with familial risk for breast and/or ovarian cancer. The current analysis compared 211 breast cancer survivors, defined as women diagnosed with ductal carcinoma in situ (stage 0) or stages I to III breast cancer within the past 2.7 years, with 567 women with no history of breast cancer at baseline, except nonmelanoma skin cancer or cervical carcinoma in situ. The breast cancer survivors had a slightly higher mean age than did cancer-free women (48.1 years vs 44.7 years) and were more likely to be postmenopausal (51.6% vs 27.4%).
“Osteopenia and osteoporosis diagnoses were ascertained in baseline and follow-up questionnaires,” according to the study report. “In each questionnaire, participants were asked to indicate whether they had received a physician’s diagnosis of osteopenia or osteoporosis and the date of that diagnosis.” Self-report was validated in a subset.
The mean follow-up was 5.8 years. It is often difficult in studies among breast cancer survivors to identify the appropriate comparison group, Dr. Visvanathan commented. “However, it is important to have that comparison if you want to understand the impact of breast cancer on survivors compared with their cancer-free peers. We were in a unique situation because we are following women with and without cancer over time, so we can make these comparisons.”
Higher Risk for Osteopenia and Osteoporosis
All the breast cancer survivors had surgery prior to adjuvant therapy; 65% received hormone therapy and 50% received chemotherapy. This breakdown mirrors treatment in younger women, Dr. Visvanathan noted.
There seems to be an effect of cancer treatment on bone health that works independently of menopause—perhaps by directly inhibiting bone formation.— Kala Visvanathan, MD, MHS
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“Overall, breast cancer survivors had a 68% higher risk of osteopenia and osteoporosis than cancer-free women,” the researchers reported. The risk for women receiving chemotherapy plus hormone therapy was 2.7 times higher than for cancer-free women. The risk was greatest for women receiving chemotherapy plus aromatase inhibitors—3.83 times higher. The risk was 2.72 times higher for women who received aromatase inhibitors alone and 2.48 times higher for those who received chemotherapy plus tamoxifen, compared to cancer-free women. Tamoxifen alone did not increase the risk.
Although tamoxifen is thought to be generally protective against bone loss in postmenopausal women, whether it is beneficial or harmful to bones in premenopausal women is unclear, said Dr. Visvanathan, “we didn’t see harm from tamoxifen.”
Importantly, a higher breast cancer risk persisted even when women with premature menopause were excluded from the analysis. “There seems to be an effect of cancer treatment on bone health that works independently of menopause—perhaps by directly inhibiting bone stability and formation,” Dr. Visvanathan noted.
Estrogen Receptor Status
More than 75% of the cancer survivors had estrogen receptor–positive tumors. These women had more than two times the risk for osteoporosis and osteopenia, “likely due to hormone therapy rather than differences in tumor biology,” according to the study report. “This is supported by the fact that the highest risk of osteopenia and osteoporosis was found among breast cancer survivors treated with aromatase inhibitors alone and chemotherapy plus aromatase inhibitors.” By blocking the aromatase enzyme, aromatase inhibitors induce a “hypoestrogenic state associated with bone loss,” the researchers added.
Women with estrogen receptor–negative tumors did not receive aromatase inhibitors and had just a modest increase in osteoporosis and osteopenia compared with women who did not have cancer.
Increasing Awareness of Bone Loss
The publication of the study in Breast Cancer Research and articles in the medical press2,3 should serve to increase awareness among oncologists, primary care physicians, and patients about osteopenia and osteoporosis and the potential value of a bone density evaluation and the monitoring of bone health, including vitamin D levels in younger breast cancer survivors.
Following these women over time will be important to see whether the risk is transient or not, and perhaps it will be possible to predict those patients more likely to have bone loss.— Kala Visvanathan, MD, MHS
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The bone loss in premenopausal women in our study was not explained completely by premature menopause, Dr. Visvanathan said. More research is necessary to understand the underlying etiology, and these women need to be followed over time to understand the impact of any early bone loss. “We don’t have the long-term data yet to make broad recommendations on bone density evaluation and monitoring for younger women who have been treated for breast cancer,” Dr. Visvanathan said, but she added that clinicians should be aware of the risks.
The breast cancer survivors in the study were all treated with adjuvant therapy after surgery, suggesting that the increase in the risk for osteopenia and osteoporosis may be related to the therapy, Dr. Visvanathan said. “Following these women over time will be important to see whether the risk is transient or not, and perhaps it will be possible to predict those patients more likely to have bone loss,” she added. “We are going to try to obtain their DEXA [dual energy x-ray absorptiometry] scans to quantify the difference in bone loss.”
Future Studies
The next steps include a larger study over time and several studies to assess the frequency of monitoring breast cancer survivors by specific age and treatment groups, Dr. Visvanathan said. Other possible areas of study include lifestyle modifications to help reduce the risk factors for osteopenia and osteoporosis as well as improve overall health.
Dr. Visvanathan would like to acknowledge Cody Ramin, PhD, a doctoral student at Johns Hopkins at the time of the research. ■
DISCLOSURE: Dr. Visvanathan has institutional patents, royalties, or other intellectual property with Cepheid.
REFERENCES
1. Ramin C, May BJ, Roden RBS, Orellana MM, Hogan BC, McCullough MS, Petry D, Armstrong DK, Visvanathan K: Evaluation of osteopenia and osteoporosis in younger breast cancer survivors compared with cancer-free women: A prospective cohort study. Breast Cancer Res 20:134, 2018.
2. Preidt R: Younger breast cancer survivors suffer more bone loss from treatment. HealthDay, December 11, 2018. Available at https://consumer.healthday.com/cancer-information-5/breast-cancer-news-94/younger-breast-cancer-survivors-suffer-more-bone-loss-from-treatment-740117.html. Accessed January 16, 2019.
3. Schieszer J: Younger breast cancer patients at higher risk for osteoporosis. Cancer Therapy Advisor, December 12, 2018. Available at www.cancertherapyadvisor.com/breast-cancer/breast-cancer-younger-patients-higher-osteoporosis-risk-treatment/article/820550/. Accessed January 16, 2019.
