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Editorial |
Academic Unit of Bone Metabolism, University of Sheffield, Sheffield S5 7AU, United Kingdom
Address all correspondence and requests for reprints to: Professor Richard Eastell, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom. E-mail: r.eastell{at}sheffield.ac.uk.
The publication of the ReBBeCa Study in this issue (1) is an advance in the clinical management of the woman with breast cancer. This study set out to evaluate the effect of a bisphosphonate, risedronate, given at the United States Food and Drug Administration (FDA)-approved dose (35 mg once a week), on the bone mineral density of women treated with chemotherapy for breast cancer. In the placebo group, there was bone loss over the period of 1 yr; this was even present in 70% of the women taking tamoxifen. In the risedronate group, there was prevention of this bone loss, and the difference between risedronate and placebo was significant for both the lumbar spine and total hip.
The study supports a 2-yr study of a similar group of women with breast cancer who received chemotherapy and had accelerated bone loss despite tamoxifen therapy, and a cyclical regimen (at a nonlicensed dose) of risedronate prevented bone loss (2). Bisphosphonates that are not licensed for the treatment of osteoporosis have also been shown to prevent chemotherapy-induced bone loss, such as clodronate given orally (3, 4, 5) or iv (6), and pamidronate given iv (7).
There is evidence for an increase in the rate of bone loss after chemotherapy for breast cancer in observational studies (8) and in the placebo groups of the studies cited above. This is most likely a consequence of the high risk of inducing menopause, especially in women of age 40 yr in whom more than 80% may enter the menopause after chemotherapy (8). Indeed, the increase in bone turnover markers occurs within 6 months of giving chemotherapy. Thus, acute estrogen deficiency is likely to explain the accelerated bone loss and is likely to result in an increased risk of fracture.
In large-scale studies of women treated for breast cancer, there is an increased risk of fracture. For example, in the observational component of the Women’s Health Initiative, the risk of fracture is increased, even after adjusting for confounding factors (9), when the increase in risk is about 15%. It is likely that the use of chemotherapy contributes to this increase. Radiotherapy to the breast has been associated with an increase in the risk of rib fracture in a dose-dependent manner (10). The restricted use of hormone therapy may also add to the risk factors for bone loss (11). The use of aromatase inhibitors has been associated with an increase in bone turnover and accelerated bone loss; there may also be an increase in fracture risk, although in the large trials it is hard to separate out the effects of the aromatase inhibitors and the effect of tamoxifen (12).
The risk factors for breast cancer in the population are the opposite of those for osteoporosis. Thus, it is a paradox that women treated for breast cancer should be at increased risk of fracture. For example, an early menarche (less than age 12 yr) is such an important risk factor for breast cancer that it is a component of the Gail score, the most commonly used way of predicting breast cancer risk in an individual (13). Late menarche (after age 14 yr) is one of the most consistent predictors of fracture (spine, wrist, and hip) from epidemiological studies (14). Thus, the lifetime exposure to estrogen may relate directly to the risk of breast cancer and indirectly to the risk of osteoporosis. In some studies (15), but not all (16), high bone mineral density is a risk factor for breast cancer, whereas low bone mineral density is invariably a risk factor for fracture (17).
It is likely that the paradox is explained by estrogen deficiency that develops in women treated for breast cancer. Thus, women who develop breast cancer may well have bone mineral density that is normal or above average at the time of diagnosis, but, after the estrogen deficiency induced by chemotherapy or aromatase inhibitors, they have an increase in bone turnover, accelerated bone loss, and increased risk of fracture.
There are still some practical clinical questions: 1) How can we best identify breast cancer survivors who are high risk for fracture? 2) Do commonly used treatments for osteoporosis, such as bisphosphonates, reduce bone loss in such women?
The current approach recommended for the identification of such women is to use the American Society for Clinical Oncology (ASCO) guidelines (18) and to measure bone mineral density. There is an initiative by a working group of the World Health Organization to develop an algorithm to estimate absolute fracture risk that can be used for treatment decisions. It is likely that such an algorithm could incorporate risk factors such as cancer-treatment-induced bone loss.
The ReBBeCa study (1) provides evidence that bisphosphonate therapy is likely to be useful in preventing chemotherapy-induced bone loss. There are currently ongoing clinical trials with aromatase inhibitors and bisphosphonates, such as the ZFAST trial (19) (letrozole and zoledronate) or SABRE trial (anastrozole and risedronate). These should inform us whether bisphosphonates can be used to prevent bone loss due to aromatase inhibitors.
What is the endocrinologist to do while we await further studies? We could base our approach on the ASCO guidelines (18). In survivors of breast cancer who have taken chemotherapy or who are planning to start aromatase inhibitors, we should evaluate fracture risk by measuring bone mineral density of the lumbar spine and total hip and identifying key risk factors. These would include a past history of fracture (since age 40 yr), slender body habitus (weight <57 kg), current smoking habit, or family history of fracture (first-degree relative with hip fracture before age 80 yr). If the T-score is above –1 at both sites, then give reassurance that the risk of fracture is low and encourage habits that promote bone health. This would include a regular exercise program, avoidance of cigarette smoking and excess alcohol consumption, a diet rich in calcium, and adequate exposure to sunshine. If the T-score is less than –2.5 at either site, then we should use an FDA-approved treatment for the prevention of bone loss, such as risedronate (35 mg once a week), alendronate (70 mg once a week), or ibandronate (150 mg once a month). I would not recommend treatments that might attenuate the benefits of an aromatase inhibitor (such as hormone replacement therapy or raloxifene) or treatments for which we have no experience in this clinical setting. We can monitor therapy every 1–2 yr to ensure bone mineral density increase (or 3–6 months to show that bone turnover markers decrease). In those patients with a T-score between –1 and –2.5, other risk factors might influence the decision to treat with a bisphosphonate, as listed above. In the absence of such factors, a period of observation (2 yr) would be appropriate and treatment should be started if bone loss is accelerated (>5% loss over 2 yr would be more than average on an aromatase inhibitor; Ref. 20). An oral bisphosphonate treatment would be appropriate if such accelerated bone loss was identified or if several risk factors for fracture were present.
Received November 6, 2006.
Accepted November 10, 2006.
References
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