Breast cancer bone metastasis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-In-Chief: Jack Khouri, B.S.

Overview

Bone is the most common site of breast cancer distant spread. Bone metastases due to breast cancer cause major morbidity, decrease survival and reduce quality of life of many patients. Cancer influence on the skeleton results in two main negative consequences: pain and Skeletal-Related events (SREs), defined as any of the following:

• pathologic fracture,
• a requirement for surgical intervention and palliative radiotherapy to bone lesions,
• spinal cord compression,
• hypercalcemia of malignancy .

In fact, SREs constitute readily measured clinical parameters that are employed in clinics and clinical trials.

Many disciplines should be involved in the management of breast cancer bone metastases, including medical oncology, pain and palliative care, radiation oncology, orthopedic surgery and neurosurgery. Systemic therapy delays the progression of bone metastases and provides palliation; it includes endocrine therapy, biologic agents, chemotherapy, bisphosphonate therapy and the new osteoclast inhibitors.

Pathogenesis

A thorough knowledge of the molecular basis of bone metastasis caused by breast cancer is essential for the understanding of the therapeutic approach. As a matter of fact, The normal balance between bone resorption and deposition is significantly affected by cancer. Bone metastases due to breast cancer are mostly osteolytic lesions, though predominant osteoblastic disease can occur . The breast cancer cells and the bone microenvironment interact extensively through many chemical mediators resulting in bone destruction and tumor growth. These molecular mediators (pimarily Osteopontin, CXCR4, CTGF and Interleukin-11) exert their effect on osteoclasts which in turn cause bone resorption. This osteoclast-mediated bone resorption is thought to be the product of the action of numerous molecules including: PTHrP (Parathyroid Hormone–related Peptide), Tumor Necrosis Factor α (TNF-α), and cytokines such as Interleukin-1, Interleukin-6, Interleukin-8, and interleukin-11. These facors signal osteoblasts (the bone-building cells) to induce osteoclast differentiation through the RANKL (the ligand for the receptor activator of nuclearfactor-κB [RANK])- RANK signaling. When Osteoclasts lyse bone, they cause the release of growth factors such as bone morphogenetic proteins (BMPs), IGF-I and TGF-β from the bone matrix which stimulate and maintain tumor cell proliferation and induce further release of PTHrP .

Systemic Therapy

Bisphosphonates

Bisphosphonates constitute a mainstay therapy for patients with bone metastases, they can prevent skeletal complications and palliate bone pain. It should be noted that there are no proven survival benefit. Therapy with high dose bisphosphonates should be initiated after a documented diagnosis of osseous metastases, because it has been shown that they do not decrease the incidence of skeletal events in women without metastatic disease.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption through multiple mechanisms, including downregulation of osteoclast activity, promotion of osteoclast apoptosis and inhibition of osteoclast maturation and differentiation . Furthermore, they may trigger the apoptosis of cancer cells, inhibit matrix metalloproteinase 1 ( an enzyme that degrades extracellular matrix proteins), reduce angiogenesis and disturb the adhesion of tumour cells to bone .

The bisphosphonates are analogs of pyrophosphate, with carbon replacing the central oxygen. Their affinity for hydroxyapatite, the main bone mineral, is made possible by the side chains (R1 and R2) from the central carbon . There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, that are different in their action on the osteoclasts. The nitrogen containing bisphosphonates ( pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid) are more potent osteoclast inhibitors than the non-nitrogen containing bisphosphonates which include Etidronate, clodronate, and tiludronate.

In the United States, only the intravenous pamidronate and zoledronic acid are approved by the FDA for treatment of osseous metastases. The American Society of Clinical Oncology (ASCO) recommends that osteoclast inhibitors including bisphosphonates be initiated in the management of patients with metastatic breast cancer and evidence of bone destruction on plain radiographs, CT, or MRI ( but not bone scans) even if asymptomatic. The ACSO guidelines regarding bisphosphonates administration are the following: Intravenous pamidronate 90 mg over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks. There is no clear difference between oral or intravenous formulations of bisphosphonates and no clear superiority of either zoledronic acid or pamidronate . Another important concept is that bone modifying agents including bisphosphonates and other agents discussed below should be adjunctive for bone pain control and not a replacement for analgesics, radiotherapy, or surgery .