Skeletal Complications of Breast Cancer Therapies

Abstract

Nonsurgical treatment options, such as hormonal therapy, chemotherapy, radiation, and bisphosphonate therapy, are undoubtedly improving outcomes for women with breast cancer; however, these therapies also carry significant skeletal side effects. For example, adjuvant hormonal treatments, such as aromatase inhibitors that disrupt the estrogen-skeleton axis, have the potential to cause decreased bone mineral density. Similarly, chemotherapy often induces primary ovarian failure in premenopausal women, resulting in decreased levels of circulating estrogen and subsequent osteopenia. In both cases, women receiving these therapies are at an increased risk for the development of osteoporosis and skeletal fracture. Furthermore, women undergoing radiation therapy to the upper body may have an increased incidence of rib fracture, and those receiving bisphosphonates may be vulnerable to the development of osteonecrosis of the jaw. Therefore, women with breast cancer who are undergoing any of these therapies should be closely monitored for bone mineral loss and advised of skeletal health maintenance strategies. Hormonal TherapyIn adults, the skeleton undergoes complete turnover every 10 years. Bone mass maintenance is a balance between the activity of osteoblasts, which form bone, and osteoclasts, which resorb it. Estrogen plays a key regulatory role in this cycle of bone remodeling by mediating effects through the estrogen receptor (ER) present on several cell types in the bone. Estrogen stimulates osteoblasts to produce osteoprotegerin, a decoy receptor for the receptor of activated nuclear factor-nB (1). Osteoprotegerin blocks the binding of receptor of activated nuclear factor-nB ligand to receptor of activated nuclear factornB on osteoclasts, leading to impaired osteoclast activity and decreased bone resorption. Additionally, estrogen is believed to directly induce apoptosis of bone-resorbing osteoclasts (2, 3). Thus, in premenopausal women, estrogen both inhibits bone remodeling and suppresses bone resorption, contributing to bone strength (Fig. 1). As estrogen levels decline in postmenopausal women, this regulation diminishes and bone resorption increases out of proportion to bone formation, leading to a net loss in bone and weakened bony microarchitecture. Despite the persistence of low levels of circulating estrogen in the postmenopausal state (produced by the conversion of peripheral tissue androgens to estrogen by the aromatase enzyme), bone mass can decrease by as much as 3% yearly in the first 5 years after menopause (4).The ER is expressed by 70% of breast tumors (5), and circulating estrogen can promote the growth of ER-positive tumors. Current breast cancer therapies exploit this relationship either by decreasing circulating estrogen levels or by blocking or down-regulating the receptor itself. Although some of the estrogen-mimicking agents seem to be bone sparing, others that disrupt the estrogen-skeleton axis cause adverse effects on bone remodeling, leading to decreased bone mineral density (BMD)...

Magnetic resonance imaging of bone marrow in oncology, Part 2

“…In children, methotrexate can cause osteopenia, severe bone pain and metaphyseal insufficiency fracture (described as methotrexate osteopathy) [37]. In breast cancer treatment, both hormonal therapy with aromatase inhibitors in postmenopausal women and chemotherapy-induced ovarian failure in premenopausal women can cause significant loss of bone mass, increasing the risk of fractures [38].…”

Pharmacologic inhibitors of IκB kinase suppress growth and migration of mammary carcinosarcoma cellsin vitroand prevent osteolytic bone metastasisin vivo

“…The major clinical manifestations of metastases are bone pain, pathologic fractures, and spinal cord compression (1,2). Most bone metastases are osteolytic and are caused by release of factors by the invading tumor, which cause osteoclast activation and bone resorption (1,4,5). Inhibitors of bone resorption such as bisphosphonates have been shown to significantly reduce skeletal complications in patients with breast cancer, myeloma, and other tumor types but they are incompletely effective, indicating the need to identify new strategies for the prevention and treatment of patients with bone metastases (2).…”

Osteonecrosis Mandibular y Maxilar Secundaria a Bifosfonatos: Presentación de Tres Nuevos Casos

“…Los bifosfonatos constituyen una herramienta fundamental en el manejo de las lesiones secundarias a patologías tan complejas como son las metástasis óseas, en el caso de ciertos tipos de cáncer (Powles et al, 2006;Hirbe et al, 2006). Su frecuente uso en la terapéutica del cáncer durante los últimos años, ha provocado un repunte en el número de pacientes que asociado a su tratamiento con bifosfonatos presentan cuadros de osteonecrosis avascular en las regiones maxilar y mandibular (Merigo et al, 2006).…”