Elsevier

Cancer Treatment Reviews

Volume 38, Issue 6, October 2012, Pages 798-806
Cancer Treatment Reviews

General and Supportive Care
Cancer treatment-induced bone loss in premenopausal women: A need for therapeutic intervention?

https://doi.org/10.1016/j.ctrv.2012.02.008Get rights and content

Abstract

Current clinical treatment guidelines recommend cytotoxic chemotherapy, endocrine therapy, or both (with targeted therapy if indicated) for premenopausal women with early-stage breast cancer, depending on the biologic characteristics of the primary tumor. Some of these therapies can induce premature menopause or are specifically designed to suppress ovarian function and reduce circulating estrogen levels. In addition to bone loss associated with low estrogen levels, cytotoxic chemotherapy may have a direct negative effect on bone metabolism. As a result, cancer treatment-induced bone loss poses a significant threat to bone health in premenopausal women with breast cancer. Clinical trials of antiresorptive therapies, such as bisphosphonates, have demonstrated the ability to slow or prevent bone loss in this setting. Current fracture risk assessment tools are based on data from healthy postmenopausal women and do not adequately address the risks associated with breast cancer therapy, especially in younger premenopausal women. We therefore recommend that all premenopausal women with breast cancer be informed about the potential risk of bone loss prior to beginning anticancer therapy. Women who experience amenorrhea should have bone mineral density assessed by dual-energy X-ray absorptiometry and receive regular follow-up to monitor bone health. Regular exercise and daily calcium and vitamin D supplementation are recommended. Women with a Z-score <−2.0 or Z-score ⩽−1.0 and/or a 5–10% annual decrease in bone mineral density should be considered for bisphosphonate therapy in addition to calcium and vitamin D supplements.

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.

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