Optimizing bone health and minimizing skeletal morbidity in men with prostate cancer

Abstract

Maintaining bone health is important in the management of men with prostate cancer. Patients receiving androgen deprivation therapy are at increased risk for treatment-related osteoporosis, and patients with bone metastases are at increased risk for skeletal morbidity related to debilitating skeletal-related events (SREs). Optimizing bone health in these patients includes lifestyle modifications, calcium/vitamin D supplementation, and osteoclast-targeted agents in select high-risk patients. No agent is approved for the prevention of bone metastases. Novel systemic agents have shown a beneficial effect bone by directly affecting tumor growth. Integration of these anticancer agents with osteoclast-targeted agents warrants further investigation.

Keywords: Androgen deprivation therapy; Bisphosphonate; Bone metastases; Denosumab; Osteoporosis; Prostate cancer; Skeletal-related events; Zoledronic acid.

Figure 1. Normal bone physiology

The skeleton is a metabolically active organ that undergoes continuous remodeling, a dynamic process of bone resorption by osteoclasts and bone formation by osteoblasts. Osteoblasts and bone marrow stromal cells release RANKL, which binds to RANK on mononuclear osteoclast precursor cells. This process promotes osteoclast differentiation and activation. Mature, multi-nucleated osteoclasts bind to the bone matrix, form a resorption lacunae, into which they secrete acid and lytic enzymes, leading to bone resorption. Osteoblasts, which arise from osteoprogenitor cells, form a cell layer over the bone surface, on which the matrix is formed and subsequently mineralized to become bone.^[2]

Figure 2. The vicious cycles of bone metastases

Interactions between tumor cells and the bone microenvironment cause bone destruction via osteoclast activation and tumor growth. Tumor cells secrete cytokines and factors which activate osteoblasts to produce RANKL and downregulate OPG. This leads to activation of osteoclast precursors and subsequent osteolysis. The process of bone resorption releases TGF-β, PDGF, FGF, BMPs which promote tumor cell proliferation and further production of pro-resorptive factors, including PTHrH, macrophage colony stimulating factor (M-CSF), TNF, IL-6. This leads to a vicious cycles of osteolysis and tumor growth.^[30]

Figure 3. Basic structure of a bisphosphonate

Bisphosphonate are synthetic analogues to naturally occurring inorganic pyrophosphate. The two phosphate groups (PO₃) bound to a carbon determine the name bisphosphonate. The R₁ side chain mainly influences pharmacokinetics of the drug, while the R₂ side chain determines mechanism of action and potency.^[31]