General and Supportive CareCancer treatment-induced bone loss in premenopausal women: A need for therapeutic intervention?
Introduction
Worldwide, 1.38 million new breast cancer cases were reported in 2008.1 In the United States in 2009, breast cancer occurred in an estimated 25,100 women under 45 years of age and in 229,550 women over 45 years of age.2 It has been reported that approximately 25% of breast cancers occur in women less than 50 years of age (i.e., premenopausal) in Europe and the United States.3 Overall, the majority (∼75%) of breast cancers are estrogen receptor-positive, although estrogen receptor-negative disease is more frequent in premenopausal (37%) than postmenopausal women (21%).4
Current treatment guidelines recommend that premenopausal women with hormone receptor-negative disease receive adjuvant chemotherapy, and that those with hormone receptor-positive disease receive adjuvant endocrine therapy (tamoxifen ± ovarian function suppression) with or without adjuvant chemotherapy based on the biology and extent of the primary tumor within the breast and regional lymph nodes.[5], [6], [7] Adjuvant therapy regimens typically also include trastuzumab in patients with HER2-positive tumors.[5], [7] A recent Cochrane Database systematic analysis of data from 14 clinical trials (N > 13,000) in premenopausal women with endocrine-sensitive breast cancer suggested that adjuvant ovarian function suppression (OFS) with a luteinizing hormone-releasing hormone (LHRH) agonist alone, OFS plus tamoxifen, or OFS plus chemotherapy provided greater clinical benefit (i.e., improved progression-free and overall survival) compared with chemotherapy alone.8 Further, the reduced side effects with OFS compared with chemotherapy may make it a more attractive option in low to intermediate-risk patients. In premenopausal women with hormone-receptor positive breast cancer, the use of aromatase inhibitors in combination with OFS has only been examined in the clinical trial setting and their use is not currently approved unless the patient becomes postmenopausal.
Among the adjuvant therapy options for premenopausal patients with breast cancer, both endocrine therapy (ovarian suppression and tamoxifen) and chemotherapy can result in substantial bone loss from suppression of estrogen levels and premature menopause. Direct negative effects of chemotherapy on bone have also been reported, although the relevance of these effects in the context of the type and dose of agents used in treating breast cancer is uncertain.[9], [10], [11] In addition, anecdotal evidence from individual premenopausal patients suggests that clinical risk factors, such as family history of osteoporosis, may contribute to bone loss and fracture risk; however, systematic evaluation of these factors is urgently needed. Therefore, regular exercise and adequate calcium and vitamin D supplementation combined with bone-conserving therapies such as bisphosphonates may potentially reduce the long-term risk of fractures in premenopausal women with breast cancer regardless of type of adjuvant therapy. However, retrospective analyses and/or case-controlled studies are needed to quantify the presumed reduction in fracture risk.
Section snippets
Assessing fracture risk
Evaluation of baseline bone mineral density (BMD) is typically not performed in premenopausal women with breast cancer. Existing osteoporosis treatment guidelines and algorithms, such as the World Health Organization Fracture Risk Assessment Tool (FRAX®), are designed for assessing fracture risk in older healthy patients (age range 40–90 years).12 As a result, the FRAX tool fails to incorporate risk factors, such as cancer treatments and premature menopause (and the resulting rapid bone loss),
Amenorrhea in premenopausal women receiving cancer treatment
Several studies suggest that premature menopause and secondary amenorrhea may be relatively frequent in premenopausal women receiving anticancer therapies (Table 1[11], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35] and Table 2[36], [37], [38], [39], [40], [41], [42], [43], [44]). For example, a case-controlled study of 88 premenopausal women with breast cancer found that the majority (71%) experienced amenorrhea after six cycles of chemotherapy and
Effects of chemotherapy
In addition to the negative effect that adjuvant cancer therapy can have on ovarian function in premenopausal women with breast cancer, much of the evidence strongly suggests that there is also a negative effect on bone. Cancer treatment-induced bone loss (CTIBL) has been measured in a significant proportion of patients who become temporarily or permanently amenorrheic following chemotherapy. Trials examining the influence of adjuvant therapy on BMD in premenopausal women with breast cancer
Antiresorptive therapy for preventing CTIBL in premenopausal women
Several clinical trials have provided insight into whether antiresorptive therapies can effectively prevent CTIBL in premenopausal women with breast cancer. Bisphosphonates inhibit osteoclast-mediated bone resorption and have long been used to prevent and treat postmenopausal osteoporosis. To date, evidence for the efficacy of bisphosphonates in the prevention of CTIBL is derived from multiple clinical trials (Table 2).[36], [37], [38], [39], [40], [41], [42], [43], [44]
Conflict of interest
Dr. Hadji has received honoraria and unrestricted educational grants from Amgen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Aventis, and Wyeth. Dr. Aapro has conducted studies and is a consultant on bisphosphonates for Amgen, Bayer-Schering, Novartis, and Roche. Dr. Body has received consultancy and speaker fees from Novartis and Amgen. Dr. Bundred has received lecture fees from Novartis, Pfizer, and Roche, and research funding from Novartis, Pfizer, and Merck. Dr.
Acknowledgments
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Jerome F. Sah, PhD, and Michael Hobert, PhD, ProEd Communications, Inc., for medical editorial assistance with this manuscript.
References (58)
- et al.
Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2010) - et al.
Practical guidance for the management of aromatase inhibitor-associated bone loss
Ann Oncol
(2008) Prevention and treatment of side-effects of systemic treatment: bone loss
Ann Oncol
(2010)- et al.
Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment
Ann Oncol
(2011) - et al.
Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group
Cancer Treat Rev
(2008) - et al.
The annual incidence and seasonal variation of fractures of the distal radius in men and women over 25 years in Dorset, UK
Injury
(2004) - et al.
Official positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference
J Clin Densitom
(2008) - et al.
The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients. The International Breast Cancer Study Group
Ann Oncol
(1990) - et al.
The influence of chemotherapy on bone mineral density, quantitative ultrasonometry and bone turnover in pre-menopausal women with breast cancer
Eur J Cancer
(2009) - et al.
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy
Lancet Oncol
(2008)
Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809
Eur J Cancer
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial
Lancet Oncol
Global cancer statistics
CA Cancer J Clin
Recent trends in breast cancer among younger women in the United States
J Natl Cancer Inst
Estrogen receptor breast cancer phenotypes in the surveillance, epidemiology, and end results database
Breast Cancer Res Treat
American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer
J Clin Oncol
Bone mineral density loss during adjuvant chemotherapy in pre-menopausal women with early breast cancer: is it dependent on oestrogen deficiency?
Breast Cancer Res Treat
The fracture risk assessment tool (FRAX((R))): applications in clinical practice
J Womens Health (Larchmt)
The utility and limitations of FRAX: a US perspective
Curr Osteoporos Rep
Fractures before menopause: a red flag for physicians
Osteoporos Int
Fractures between the ages of 20 and 50 years increase women’s risk of subsequent fractures
Arch Intern Med
Official positions of the International Society for Clinical Densitometry
J Clin Endocrinol Metab
Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer
Br J Cancer
Chemotherapy induced amenorrhoea in a randomised trial of adjuvant chemotherapy duration in breast cancer
Eur J Cancer
Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group
J Clin Oncol
The risk of premature menopause induced by chemotherapy for early breast cancer
J Womens Health Gend Based Med
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