Introduction: Oncologists' New Focus on Bone Health

Abstract

Oncologists have always been dedicated to fully understanding the toxicities associated with the cancer treatments they administer, and because of this, the bone health of patients undergoing chronic treatment for cancer has become of increasing importance in recent years. It is now clear that evaluation and maintenance of bone health in patients with early-stage and advanced breast cancer is the responsibility of the oncologist because of the growing realization that several cancer treatments induce clinically significant bone loss. The American Society of Clinical Oncology has given credence to this obligation by outlining a management strategy for bone health evaluation and maintenance in breast cancer survivors. Bone mineral density measurement every 1 to 2 years in survivors of breast cancer is warranted because of the clearly increased risk for fragility fractures caused by the loss of bone mineral density and tensile strength. Especially because of the known effectiveness of risk reduction and treatment strategies, regular counseling and follow-up of survivors of breast cancer regarding their bone health is now part of standard practice management of these patients. Total hormonal blockade as treatment of estrogendependent early-stage breast cancer is being increasingly used because of the maturing data on the safety and efficacy of the aromatase inhibitors in postmenopausal women, including those who develop permanent chemotherapy-induced amenorrhea. Estrogen deprivation has profound effects on bone health, decreasing osteoblast activity and disrupting the balance between osteoblast and osteoclast function caused by decreased production of the regulatory protein osteoprotegerin. Estrogen deprivation stimulates osteoclastogenesis, leading to bone turnover, bone resorption, and osteoporosis. In addition to the clinical morbidity that can result from osteoporosis, estrogen deprivation–induced bone resorption results in the production of bone growth factors that may support the growth and survival of bone micrometastases. As the mineralized matrix of bone decreases with estrogen deprivation caused by increased osteoclast function, insulin-like and transforming growth factors are released, stimulating progression of micrometastatic disease as well as attracting and supporting the growth of new metastases. Interrupting the vicious cycle of communication between bone micrometastases and osteoclasts with agents such as the potent bisphosphonates or the receptor activator of nuclear factor–κB ligand inhibitor AMG-162 inhibits osteoclast function and the growth of micrometastases by stimulating apoptosis of osteoclasts. Preclinical animal models demonstrate that maintenance of bone health and inhibition of osteoclast function produce a hostile environment for bone micrometastases, whereas increased bone remodeling, bone turnover, and bone resorption can stimulate the growth of micrometastatic breast cancer. Emerging data in women with early-stage breast cancer suggest that bisphosphonate therapy effectively maintains bone density in women with low estrogen levels. Several oral bisphosphonates, as well as intravenous zoledronic acid given every 6 months, prevent bone density loss in postmenopausal women being treated with aromatase inhibitors or with goserelin plus an aromatase inhibitor in premenopausal patients. Several large international phase III trials are under way to determine the effectiveness of oral and intravenous bisphosphonates in maintaining bone health in survivors of breast cancer, as well as to evaluate whether these therapies can reduce the incidence of bony metastatic disease. This important area of clinical research is part of our growing recognition of the significance of the health of the host in combating breast cancer. Mighty efforts are under way around the globe to understand whether maintaining or enhancing bone health can not only reduce the long-term morbidity of breast cancer treatment, but also halt the progression of or eradicate bone micrometastasis. Address for correspondence: Joyce A. O’Shaughnessy, MD, US Oncology, 3535 Worth St, 5th Floor, Collins Bldg, Dallas, TX 75246 Fax: 214-370-1850; e-mail: joyce.o’shaughnessy@usoncology.com Oncologists’ New Focus on Bone Health