Bone Physiology and the Impact of Cancer
Healthy bone is in a constant state of remodeling, with bone-derived osteoblasts and osteoclasts working together to preserve structural integrity and minimize the risk of fragility fractures. In people of normal health, the relationship between osteoblastic bone formation and osteoclastic bone resorption is finely balanced through the coupled influence of cytokines and other humoral factors. Malignancy disturbs this balance and results in a loss of the normal structural integrity of the skeleton.
Treatment-induced bone loss
The causes of bone loss in cancer patients and the subsequent functional consequences are multifactorial. They include both the side effects of specific anticancer therapies and preexisting clinical risk factors for fracture, such as advanced age, use of glucocorticoids, a history of smoking, low body mass index, a family or personal history of fragility fracture, and low bone mineral density (BMD). The rate of bone loss in patients undergoing treatment for cancer also depends on the menopausal status of the patient, and on average is two to three times more rapid than the natural rate of age-related bone loss.
Premenopausal women are protected from bone loss because their bodies still produce estradiol and inhibins, which act directly on bone to maintain bone mass. However, accelerated bone loss in premenopausal women will occur if ovarian failure is induced by anticancer treatment, or if the protective effects of estrogen on bone are inhibited by estrogen receptor modulators such as tamoxifen. Suppression of ovarian function will cause rapid bone loss that persists for the duration of amenorrhea. However, in patients who receive chemotherapy and remain permanently amenorrheic, the indirect effects of chemotherapy on bone loss will persist. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-12 trial of ovarian suppression with endocrine therapy in premenopausal women, rapid bone loss occurred. After 3 years, BMD of the lumbar spine and trochanter were reduced by 11.3% and 7.3%, respectively, with the most rapid loss occurring in patients treated with goserelin and anastrozole. Most patients regained menses after 3 years of endocrine treatment was stopped, and this was associated with partial recovery of BMD at both of the aforementioned skeletal sites 2 years thereafter. We now know that, for premenopausal women at high risk of recurrence, initiation of ovarian suppression therapy along with administration of an aromatase inhibitor is a more effective adjuvant endocrine strategy than treatment with tamoxifen, so the results of ABCSG-12 are of direct clinical relevance to current patient care.
For more than a decade, aromatase inhibitors have been established as the endocrine treatment of choice for postmenopausal women with breast cancer. They reduce endogenous serum estrogen to almost undetectable levels. However, when compared with tamoxifen, aromatase inhibitors are associated with accelerated bone loss leading to a decrease in BMD and a 40% to 50% increase in fracture risk,[3,4] thus presenting an important clinical challenge that must be addressed as part of breast cancer care.
Prevention of Cancer Treatment-Induced Bone Loss
Management of bone loss associated with cancer therapies includes both lifestyle recommendations and pharmacologic intervention. All patients at risk for bone loss should be advised to engage regularly in weight-bearing exercise and reduce smoking and alcohol consumption.[5-7]
Pharmacologic intervention includes vitamin D supplementation (1,000-2,000 IU daily), since many breast cancer patients do not have adequate serum levels of vitamin D, and calcium supplementation (at 1,000 mg daily) if dietary intake is inadequate. Antiresorptive therapies have been proven to be effective in preventing cancer treatment-induced bone loss, although their efficacy is influenced by menopausal status and the rate of bone loss.[5,7]
In premenopausal women, administration of the intravenous bone-targeted bisphosphonate zoledronic acid at a dose of 4 mg every 6 months has been shown to prevent the significant bone loss associated with treatment consisting of goserelin plus tamoxifen or anastrozole. This schedule of zoledronic acid has also been shown to prevent bone loss associated with ovarian failure caused by chemotherapy. Other bisphosphonates have shown some ability to prevent the marked bone loss associated with ovarian suppression and ovarian failure but do not have a sustained effect on BMD in this setting.
In postmenopausal women, the choice of bisphosphonate is broader, with evidence that ibandronate (at 150 mg orally monthly), clodronate (at 1,600 mg orally daily), risedronate (at 35 mg orally weekly), alendronate (at 70 mg orally weekly), and zoledronic acid (at 4 mg IV every 6 months) all prevent the bone loss associated with aromatase inhibitor treatments.[1,7,9,10] Although these trials were not designed to evaluate a fracture-prevention endpoint, results from studies of osteoporosis have consistently demonstrated a good correlation between BMD improvement and fracture prevention.
Denosumab is a monoclonal antibody that selectively targets the receptor activator of nuclear factor ÎºB ligand (RANKL), thereby inhibiting osteoclast formation, function, and survival. In patients with postmenopausal osteoporosis, denosumab at 60 mg administered by subcutaneous injection every 6 months was approved by the US Food and Drug Administration based on the results of FREEDOM, the largest single trial to have assessed denosumab (n = 3,702) vs placebo (n = 3,691) for fracture prevention in primary osteoporosis. In the ABCSG-18 trial, 3,425 women with stage I-III breast cancer were randomized to receive either denosumab, using the dose and schedule recommended for treatment of osteoporosis, or placebo. At study entry, 1,548 participants had a BMD T-score of -1.0. At 3 years after randomization, 9.6% of patients in the placebo arm reported a fracture. Treatment with denosumab significantly delayed the time to first fracture (hazard ratio [HR], 0.50 [95% CI, 0.39-0.65]; P < .0001) and reduced the total number of fractures by about one-half, irrespective of baseline BMD. BMD improved following treatment with denosumab, with a difference in mean BMD at 3 years of 10% between patients treated with denosumab vs placebo.
Treatment guidelines have been produced by expert groups in both Europe and North America.[5-7,14] These guidelines all include the following recommendations:
• An assessment of overall fracture risk using a risk score assessment tool.
• BMD assessment.
• Laboratory assessment to exclude secondary causes of osteoporosis.
• Treatment of patients at high risk of fracture.
In terms of treatment choices, the recent data from the ABCSG-18 trial have not yet been incorporated into most of the guidelines. Clearly the fracture-prevention data on denosumab are impressive and support its use as the treatment of choice. However, as will be discussed in this review, the effects of bone-targeted agents on disease recurrence may trump additional benefits related to prevention of bone loss, and instead argue for use of a bisphosphonate as the preferred therapy.
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2. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, 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;9:840-9.
3. Eastell R, Adams J, Clack G, et al. Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Ann Oncol. 2011;22:857-62.
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22. Early Breast Cancer Trialistsâ€™ Collaborative Group (EBCTCG); Coleman R, Powles T, Paterson A, et al. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386:1353-61.
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