Multiple cytokines have been implicated in the causation, development, or neural sensitization of bone cancer pain. Nerve growth factor (NGF) modulates inflammatory and neuropathic pain states. In chronic pain, NGF levels are elevated in peripheral tissues and neutralizing antibodies against NGF are effective in reducing or preventing cancer-related bone pain [20]. In vitro studies have shown that neutralizing antibodies can inhibit growth and differentiation of NGF-dependent sensory nerve cell lines. More recently, these same antibodies have been shown to inhibit the in vitro migration and metastasis of prostate cancer cells [21]. In addition, pathological sprouting of nerve fibers in a prostate cancer model is modulated in an NGF-dependent fashion (Fig. 3.4) [15]. In animal models, anti-NGF antibodies reduce continuous and breakthrough pain by blocking the nociceptive stimuli associated with the sensitization in the peripheral or central nervous system [22].

Endothelins are a family of vasoactive peptides that are expressed by several tumors, with levels that appear to correlate with pain severity. Direct application of endothelin to peripheral nerves induces activation of primary afferent fibers and pain-specific behaviors. It is hypothesized that endothelins contribute to cancer pain by directly sensitizing nociceptors [23]. Selective blockade of endothelin receptors blocks bone cancer pain-related behaviors and spinal changes indicative of peripheral and central sensitization [24]. Brain-derived growth factor (BDNF) is involved in central sensitization as its expression is increased in nociceptive neurons in models of chronic neuropathy. BNDF sensitizes C fiber activity resulting in hyperalgesia and allodynia. Inhibition of BNDF and its cognate receptor, TrkB, results in decreased C fiber firing and a reduction in pain behaviors [25]. Glial-derived growth factor (GDNF) is important in the survival of sensory neurons and supporting neural cells. Neuropathic pain behaviors commonly observed in animal models of chronic pain are prevented or reversed following GDNF administration and these analgesic effects of GDNF show strong temporal and molecular regulation. Specifically the timing of administration of GDNF directly determines whether analgesia effects are observed [25, 26].

The transient receptor potential V1 (TRPV1) family of ion channels is located on unmyelinated C fibers and spinal nociceptive neurons that mediate pain transmission. TRPV1 channels can be activated by heat, capsaicin, and acid. Activation of TRPV1 initially provokes a powerful afferent nerve irritant effect, followed by desensitization and long-term analgesia. As TRPV1 is only expressed on nociceptive peripheral terminals, selective blockade of TRPV1 may provide analgesia with a limited side effect profile [27]. Mice that lack the channel are unable to develop chronic pain states while antagonists to TRPV1 significantly decrease chronic pain [28]. In a canine model of bone cancer, intrathecal administration of TRPV1 antagonist resulted in pain reduction and selective destruction of small sensory neurons [29]. Recent work has focused on the role of TRPV1 in the acidic microenvironment of bone metastasis that mediates pain. Specifically, acid signals received by the sensory nociceptive neurons innervating bone stimulate intracellular signaling pathways of sensory neurons. Molecular blockade of the activated intracellular transcription factors in these signaling pathways has served as a method to inhibit pain transmission [7, 30].

Most metastatic skeletal malignancies are destructive in nature and produce regions of significant osteolysis via activation, recruitment, and proliferation of osteoclasts at tumor-bearing sites [31]. This activation and proliferation of osteoclasts are mediated by the interaction between receptor activator for nuclear factor κB (RANK) expressed on osteoclasts with RANK ligand (RANKL) expressed on osteoblasts. Increased expression of both RANK and RANKL has been found in tumor-bearing sites. Selective inhibition of osteoclasts using either bisphosphonates or the soluble decoy receptor for RANKL, osteoprotegerin (OPG), results in inhibition of cancer-induced osteolysis, cancer pain behaviors, and neurochemical markers of peripheral and central sensitization [32, 33].

Bisphosphonates have shown clinical success in treatment of both osteoporosis and tumor-induced osteolysis. Administration of bisphosphonates has shown a positive impact on overall skeletal health and quality of life in patients with breast and prostate skeletal metastasis [34, 35]. The long-term beneficial effects of bisphosphonate treatment in reducing bone pain and skeletal related events (e.g., pathologic fractures) and the patient-reported improvement in overall quality of life are clear from clinical trials in lung, breast, and prostate cancer [36–38]. In addition, one recent meta-analysis has shown that initiation of therapy with the bisphosphonates prior to the development of skeletal metastasis improves quality-of-life scores and decreases clinical pain and skeletal events in patients with prostate cancer [39].