The skeletal and immune systems have a complex relationship. Both systems are 
intimately coupled, with osteoclastogenesis and hematopoiesis occurring in the 
bone marrow. Bone and immune cells also share common hematopoietic precursors. 
Furthermore, the skeletal and immune systems share various cytokines, receptors, 
and transcription factors that regulate signal transduction pathways involved in 
osteoclastogenesis and immune system activation, including the receptor 
activator of nuclear factor-κΒ ligand/receptor activator of nuclear 
factor-κΒ/osteoprotegerin (RANKL-RANK-OPG) pathway. Cancer cells can disrupt 
both the skeletal and immune systems. Interaction between cancer and bone cells 
results in a vicious cycle of bone destruction and cancer growth. Bone 
remodeling generates a growth-factor-rich environment that attracts cancer cells 
and promotes their proliferation. In turn, cancer cells stimulate osteoclast 
formation and activity, resulting in additional bone resorption that further 
stimulates cancer cell growth. Currently available bone-targeted therapies may 
also modulate the immune system. Bisphosphonates such as zoledronic acid exert 
stimulating effects on the immune system, resulting in possible anticancer 
activity against malignant cells. Denosumab, an anti-RANKL monoclonal antibody 
with proven antiosteoclast activity, may suppress immune responses. This may 
result in the reported association with an increased risk of neoplasms, as well 
as serious skin and other infections as reported in some studies, mainly in the 
postmenopausal setting. When assessing bone-targeted therapies, it is important 
to consider the shared signaling pathways between bone and the immune system, as 
well as the clinical risk:benefit ratio.