Early Breast and Prostate Cancer and Clinical Outcomes (Fracture)
Early Breast and Prostate Cancer and Clinical Outcomes (Fracture)
Osteoporosis is a skeletal disorder characterized by low bone mass that is associated with increased risk of fracture. Nearly 40% of the 12 million cancer survivors in the United States were diagnosed with breast and prostate cancer. Therapy for these two diseases is not uncommonly associated with bone loss related to hormone-ablative therapy. In women, this includes the use of endocrine therapies and chemotherapy-related premature menopause. In men, hormone-ablative therapies include gonadotropin-releasing hormone analogs and bilateral orchiectomy. Fracture risk assessment includes bone mineral density determination in appropriate populations and integration of findings with identified risk factors. Strategies to prevent and treat bone loss include nonpharmacologic and pharmacologic interventions. In the former case, regular weight-bearing and muscle-strengthening exercise is encouraged along with smoking cessation, modulation of alcohol consumption, and fall prevention. Supplementation with calcium and vitamin D decreases fracture risk in subgroups. Pharmacologic interventions include use of oral or intravenous bisphosphonates, selective estrogen receptor modulators, and calcitonin. Estrogen/menopause hormone therapies are not recommended for use in breast cancer survivors related to potential influence on recurrence. Strategies for management of bone loss in breast and prostate cancer are outlined by guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network.
Over 40 million men and women in the United States have osteoporosis and low bone mineral density (BMD), placing them at risk for adverse skeletal events such as fractures and their sequelae. There are over 12 million cancer survivors in this country. Of these, 22% were diagnosed with breast cancer and 17% with prostate cancer.[1,2] Because cancer therapies can adversely influence bone health, these survivors are at particular risk for skeletal complications. Cancer therapies associated with bone loss include hormone deprivation therapies such as aromatase inhibitors, ablative surgical procedures that induce hypogonadal states, and premature menopause induced by chemotherapy.[3,4]
Healthy bone is maintained by a balance between osteoclasts that break down bone and osteoblasts that form new bone. In normal bone, the cycle of resorption and formation is balanced and regulated by complex mechanisms involving systemic and local factors. As one factor, estrogen decreases the formation, activation, and lifespan of osteoclasts. Loss of estrogen from menopause or from iatrogenic causes results in a remodeling imbalance with a prolonged osteoclast-induced resorption phase and a reduced formation phase.[3,4] In addition, loss of androgens also leads to increased bone resorption through decreased aromatization of androgens to estrogens in bone.
Factors involved in the control of bone remodeling include rRANK ligand and osteoprotegerin (OPG). RANK ligand is expressed by osteoblasts and, as a small molecular signal, activates and binds to the RANK receptor on osteoclasts promoting both osteoclast formation and prolongation of the osteoclast lifespan. Osteoprotegerin suppresses the effects of RANK ligand by posing as a RANK ligand decoy receptor, thus reducing RANK receptor binding. Change in the ratio between RANK ligand and OPG balance contributes to bone disease. The currently approved pharmacologic agents used to treat bone loss, bisphosphonates, work by inhibiting osteoclast-mediated bone resorption.
Bone Health in Breast Cancer Survivors
Cancer therapy may be associated with bone loss. The most common cause is the use of hormone-ablative therapy, including endocrine therapies and chemotherapy-related premature menopause in women. In men, hormone-ablative therapies include use of gonadotropin-releasing hormone (GnRH) analogs and bilateral orchiectomy.
The majority of patients with breast cancer have hormone receptor–positive disease and receive adjuvant therapy with either a selective estrogen receptor modulator (SERM) and/or an aromatase inhibitor. In postmenopausal women, SERM reduces bone resorption and fracture risk. In contrast, the aromatase inhibitors, which block conversion of androgens to estrogen, increase bone resorption by prolonging osteoclast-induced resorption. The aromatase inhibitors are increasingly used in the adjuvant setting of hormone receptor–positive breast cancer in postmenopausal women as they significantly improve disease-free survival compared to SERMs and have less risk of venous vascular events. However, aromatase inhibitors are associated with loss of BMD and increased fracture risk.
In substudies of the larger adjuvant breast cancer trials involving postmenopausal women with early-stage breast cancer, higher rates of bone loss have been seen in women receiving aromatase inhibitors compared to women on placebo or SERM. A prospective bone substudy in the ATAC trial (Anastrozole, Tamoxifen, Alone or in Combination) found that, after 5 years, mean BMD decreased by 6.1% in the spine and 7.2% in the hip for patients on the aromatase inhibitor, but increased by 2.8% in the spine and 0.7% in the hip for those receiving the SERM. No women with an initial normal bone density at the start of treatment developed osteoporosis after 5 years of treatment. Those whose baseline T score was less than -1.5 prior to initiation of the aromatase inhibitor were at greatest risk for developing osteoporosis. In similar trials with two other aromatase inhibitors bone loss was consistently higher with the aromatase inhibitor.[9,10] It has become clear that the aromatase inhibitors cause bone loss for the duration of their administration regardless of which aromatase inhibitor is selected. The bone loss seen with aromatase inhibitor use is associated with increased fracture risk;[11,12] without intervening therapy there is about a 10% risk of clinical fracture after 5 years of aromatase inhibitor use (Figure 1).
The majority of the more than 2 million breast cancer survivors in the United States are either postmenopausal at diagnosis or they become menopausal as a result of cytotoxic chemotherapy. Loss of BMD is observed in women undergoing adjuvant chemotherapy due to both treatment-induced premature ovarian failure and possibly direct effects of chemotherapy on bone.
Premenopausal women with early-stage breast cancer who become amenorrheic experience accelerated bone loss of about 6% to 8% in the first year. The loss of bone persists for years after completion of chemotherapy in women who continue to be amenorrheic primarily related to loss of ovarian function.
Prostate Cancer and Bone Health
Men with early-stage prostate cancer are more likely to have low BMD than age-matched controls without prostate cancer. In addition, treatment of prostate cancer with androgen deprivation therapy using a GnRH analog, with or without an antiandrogen, reduces estrogen and testosterone levels with associated increase in bone resorption and decrease in bone formation.
In cross-sectional studies in men diagnosed with nonmetastatic prostate cancer, those treated with GnRH agonists experience significant bone loss after 1 year of about 6% loss in BMD compared to men with prostate cancer who are not receiving systemic therapy. In one study, 5 years after diagnosis, 19.6% of men treated with androgen deprivation therapy sustained fracture compared to 12.6% of men not receiving that treatment (P < .001). The severity of the reduction in BMD correlates with the duration of androgen deprivation therapy. Therapy with a GnRH analog for 4 or more years was associated with a greater fracture risk compared with treatment for 1 year or less (hazard ratio [HR] 1.5 [P < .001]).
Evaluation of Bone Health
The 2003 American Society of Clinical Oncology (ASCO) guidelines published by Hilner and colleagues presented an algorithm for maintenance of bone health in women with breast cancer. Women are at high risk for osteoporosis if they are older than 65, or between the ages of 60 and 65 with risk factors including family history of fracture, body weight less than 70 kg, prior nontraumatic fracture, Asian or White ethnicity, smoking, or having risk factors for falls or an inactive lifestyle. Postmenopausal women treated with aromatase inhibitors and premenopausal women with therapy-related premature menopause are also considered at increased risk. Accordingly, individuals at high risk should undergo DEXA screening with results subsequently guiding therapy.
In both men and women with cancer secondary causes of poor skeletal health have been identified. In addition to age-related bone loss, lifestyle factors such as smoking, exercise habits, poor vitamin D and calcium intake, and alcohol consumption may contribute to poor bone health. Other medical conditions including hypogonadism, growth hormone deficiency, hyperthyroidism, hyperparathyroid issues, hypercalciuria, and glucocorticoid excess can contribute to bone loss. Iatrogenic causes of bone loss in addition to hormone-ablative therapy include prolonged use of an anticoagulant, glucocorticoids, anticonvulsants, and antimetabolite/antifolate agents.