The Role of Bisphosphonates in the Adjuvant Setting for Breast Cancer

The Role of Bisphosphonates in the Adjuvant Setting for Breast Cancer

ABSTRACT: Bone health is a critical issue in the management of women with breast cancer. Many women who develop breast cancer are postmenopausal, which already predisposes them to osteoporosis. Systemic treatments for breast cancer, including chemotherapy and endocrine therapy, decrease circulating levels of estrogen in both pre- and postmenopausal women, further accelerating the natural process of bone loss. The primary concern in breast cancer patients is that this accelerated bone loss, known as cancer treatment–induced bone loss (CTIBL), will lead to an increase in fractures, chronic pain, and loss of mobility. Bisphosphonates are highly effective at slowing the rate of bone loss in postmenopausal women with osteoporosis and at preventing skeletal-related events in women with metastatic breast cancer. Many studies are now focusing on the role of bisphosphonates in preventing CTIBL in the adjuvant setting. Both oral and intravenous bisphosphonates have shown promising activity in preventing CTIBL in patients receiving chemotherapy or hormonal therapy. In addition, emerging data indicate that the use of bisphosphonates in the adjuvant setting may prevent disease recurrence and prolong survival. Data from a number of ongoing trials will further elucidate the role of bisphosphonates in the adjuvant setting over the next few years.

Most women with early-stage breast cancer are treated with systemic therapy following surgery in order to prevent disease recurrence. Depending on the individual characteristics of her tumor, a patient may receive chemotherapy, endocrine therapy, or a combination of both.[1] Endocrine therapies, which include gonadotropin-releasing hormone (GnRH), luteinizing hormone-releasing hormone (LHRH) agonists, antiandrogens (eg, bicalutamide, flutamide), and aromatase inhibitors (AIs), decrease circulating levels of estrogen. Lower levels of estrogen lead to an increase in bone resorption and a slowing of bone formation, resulting in overall loss of bone mass.[2] Chemotherapy also lowers estrogen levels by inducing premature ovarian dysfunction in the majority of premenopausal women.[3,4] A second mechanism of chemotherapy-induced bone loss involves a direct nonhormonal toxic effect on bone cells.[2] The combination of both chemotherapy and endocrine therapy places women at a high risk of cancer treatment–induced bone loss (CTIBL).

CTIBL exposes breast cancer patients to increased skeletal morbidity which can lead to chronic pain, decreased mobility, and ultimately, a shorter survival time.[5] Early identification of patients who are at risk for CTIBL is critical to improving their outcome with preventive therapy. Bisphosphonates are the standard of care for reducing the risk of skeletal-related events (SREs) in patients with metastatic bone disease, but no guidelines have yet been established for the use of bisphosphonates in the adjuvant setting. In this review, we will discuss the evolving role of bisphosphonates in the adjuvant setting, including a focus on data indicating that bisphosphonates not only promote bone health, but also may prevent disease recurrence and prolong survival.

Pathogenesis of Bone Loss

Bone remodeling is the normal process by which bone health is maintained. Bone remodeling involves the balanced turnover of bone elements, which includes resorption of existing bone by osteoclasts and formation of new bone by osteoblasts. The activity of osteoclasts and osteoblasts is regulated by both local factors and systemic hormones, including estrogen. The active form of estrogen, estradiol, appears to have a stimulatory effect on osteoblasts, which is believed to contribute to the maintenance of bone mass in healthy adult females.[6]

Bone mineral density (BMD) loss occurs when an imbalance develops in the normal process of bone remodeling. The imbalance may be the result of increased activity of osteoclasts or decreased activity of osteoblasts, which causes disruption of the microarchitecture of the bone. The structural integrity of the bone is thus compromised, leading to fragility and an increased risk of fracture.[7] Adjuvant breast cancer treatments that alter estrogen levels may lead to a decrease in the bone-building activity of osteoblasts, and thus can have an impact on bone health in breast cancer patients.

Cancer Treatment-Induced Bone Loss (CTIBL)

Chemotherapy-Induced Bone Loss

More than 60% of breast cancer patients undergoing adjuvant chemotherapy will experience ovarian failure within 1 year of beginning their treatment.[2] The rate of ovarian dysfunction in premenopausal women aged > 50 years is > 90%, and remains substantially higher for women aged > 40 years compared with those < 40 years of age.[4] Chemotherapy-
induced menopause, either temporary or permanent, has been associated with significant bone loss; on average, women experience a > 7% decrease in BMD within the first year.[3] In addition to inducing menopause, cytotoxic chemotherapy is also believed to cause CTIBL by a direct toxic effect of the chemotherapy on bone cells. This toxic effect can decrease BMD by another 1% in the first year following treatment.[2,3]

Aromatase Inhibitor–Associated Bone Loss

All of the endocrine therapies can significantly affect bone health, but aromatase inhibitors (AIs) are perhaps of the greatest concern because of their ability to almost completely eliminate circulating estrogen. The Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial has demonstrated the superiority of AIs over tamoxifen in postmenopausal women with early-stage breast cancer,[8,9] leading to a significant increase in women taking AIs. Although anastrozole (Arimidex) had a better overall safety profile than tamoxifen, anastrozole was associated with a greater fracture incidence (11% vs 7.7%, respectively).[8,9] Aromatase inhibitors are now also being studied in premenopausal women in combination with ovarian ablation or suppression, which is likely to contribute to the growing concern about AI-associated bone loss (AIBL).

Another important clinical concern with AIBL is the duration of exposure to endocrine therapy. AIBL is more rapid than bone loss associated with menopause (with total hip BMD loss of 1.7% and lumbar spine BMD loss of 2.6% during the first year, ATAC investigators reported),[8] and the severity increases with treatment duration. AI therapy was initially approved for 5 years, but several studies are now evaluating treatment duration of more than 5 years. In the MA 17 trial, patients were treated in the adjuvant setting with 5 years of letrozole (Femara) after completing 5 years of tamoxifen. Two years into treatment with the AI, women experienced a decrease of 3.6% in total hip BMD, compared with 0.71% for placebo (P = .044), and a BMD decrease of 5.3% at the lumbar spine, compared with 0.70% for placebo (P = .008).[10] As the duration of AI therapy lengthens, the importance of minimizing the risks of AIBL becomes even more critical.

The Role of Bisphosphonates in Preventing CTIBL

Bisphosphonates are antiresorptive agents that prevent bone loss by interfering with normal osteoclast activation and function and by inducing osteoclast apoptosis. They have been shown to prevent bone loss in the postmenopausal setting, and are now used extensively in women with a diagnosis of osteoporosis or osteopenia. Both oral and intravenous forms of bisphosphonates have been studied in patients with breast cancer. In patients who already have bone metastases, intravenous bisphosphonates have been shown to decrease pathologic fractures, bone pain, hypercalcemia, spinal cord compression, and the need for palliative radiation to bone.[11] These observations have led researchers to investigate the role of bisphosphonates in prevention of bone loss in the adjuvant setting.

Oral Bisphosphonates

The oral bisphosphonates, clodronate and risedronate (Actonel), have both been shown to decrease bone loss associated with chemotherapy-induced ovarian failure.[12,13] One study randomized women who had received six cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) to either 3 years of oral clodronate at 1,600 mg daily or placebo. At 2 years of follow-up, patients who took clodronate and were amenorrheic experienced 38% less of a decrease in mean lumbar spine bone loss compared with the control group.[12] The benefit persisted at 5 years of follow-up, when patients who received clodronate were found to have a 5.8% decrease in BMD from baseline at the lumbar spine, compared with a 9.7% decrease in the placebo arm (P = .008). Clodronate was generally well-tolerated, with no significant difference in the adverse events reported between treatment groups. A recent 10-year update of this trial reported that patients who received clodronate continued to have less BMD loss, indicating the importance of initiating bisphosphonate treatment at the time of chemotherapy.[14]

In the similar study of oral risedronate in premenopausal women, mean BMD of the lumbar spine and femoral neck was significantly reduced by 2.5% (P = .041) and 2.6% (P = .029), respectively, compared with women who received placebo.[13] After 3 years, differences in BMD remained significant at the lumbar spine (P = .024), femoral neck (P = .011), and trochanter (P = .008). Risedronate was also well-tolerated; adverse events were reported to be mild and similar between the treatment groups, with no evidence of laboratory abnormalities.

Risedronate has also been evaluated in postmenopausal women with breast cancer. In one study, 87 postmenopausal women received chemotherapy followed by either risedronate at a dosage of 35-mg weekly for 2 years or placebo. Nearly 70% of patients had estrogen receptor (ER)-positive disease, and thus also required concomitant endocrine therapy. These ER-positive patients who took risedronate had a 2.4% decrease in BMD at the lumbar spine, compared with a 4.8% decrease in patients taking placebo.[15] All of these studies demonstrate that oral bisphosphonates appear to reduce CTIBL, although bone integrity is still somewhat compromised.


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