Examination of the mechanisms of osteolysis in patients with metastatic breast cancer

Abstract

Abstract. The benefits of bisphosphonates (BPs) in reducing skeletal-related events (SREs) in patients with bone metastases has mainly been attributed to their potent osteoclast inhibiting effect. However, despite the use of modern systemic anticancer therapy including potent BPs, many patients with bone metastases continue to have SREs. An improved understanding of the fundamental mechanisms of bone destruction allows for further development of appropriate targeted treatments. In this study, archival paraffin-embedded bone metastases specimens from patients with metastatic breast cancer were examined for the presence of osteoclasts, expression of the receptor activator of nuclear factor κB (RANK), RANK Ligand (RANKL), osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF). Histological specimens were available for primary breast cancer, lymph node metastases, normal breast and normal bone tissues for comparison. Bone metastasis specimens were available for 20 BP naïve patients and two BP-treated patients. Osteoclasts were significantly increased in the bone metastases of the BP naïve group compared to normal bone. No osteoclasts were detected in the BP-treated group. RANKL was predominantly expressed in osteoblasts and in the stromal elements of metastatic tissue. Conversely, RANK was present in osteoclasts of bone metastases and normal bone, as well as in tumor cells of metastatic lymph nodes and bone metastases. VEGF was strongly expressed in the control bone and bone metastases regardless of BP treatment. In summary, osteoclasts may not be the singular obligatory factor for osteolysis in bone metastases. An increased expression of RANKL in stromal tissue surrounding bone metastases, RANK in osteoclasts and VEGF may serve as future targeted therapies possibly in conjunction with bisphosphonates. The mechanisms for osteoclast expression and the expression of RANKL, RANK, OPG and VEGF merit further prospective analysis, particularly in the context of BP treatment and progressive bone metastases. IntroductionBreast cancer continues to be the most commonly diagnosed cancer in women in the developed world (1). Bone metastases are the most common site of metastatic recurrence (2) and are a major cause of morbidity for patients. Complications resulting from bone metastases include pain, reduced mobility and a reduced quality of life. In addition, patients are at a considerable risk of, so-called skeletal related events (SREs) such as the requirement for surgery and/or radiotherapy, pathological fractures, spinal cord compression and hypercalcaemia (3). Characteristically, patients with bone as the predominant site of metastatic spread tend to have a protracted disease course when compared to those patients with visceral metastases (4). Furthermore, patients with the disease confined to the skeleton have been found to be most likely to develop skeletal-related complications and hence derive the most benefit from treatment with bone-specific therapies (5).Bone resorption is dependent on a cytokine known a...