**5. Conclusion**

Cancer-induced bone pain (CIBP) causes life-altering pain in 75 to 90% of the advanced stage cancer patients. The movement-induced incident and breakthrough events cause a severe impairment of the quality of life of patients and explain the difficulty to treat this unique type of pain. There remains a high unmet medical need for CIBP treatment since around one-third of the advanced cancer patients

**13**

**Author details**

Sonny Hermanus Johannes Sliepen

provided the original work is properly cited.

Dutch Independent Researcher, Hamburg, Germany

\*Address all correspondence to: sonny.sliepen@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Bone Cancer Pain, Mechanism and Treatment DOI: http://dx.doi.org/10.5772/intechopen.95910*

analgesic compounds.

is still undertreated [90]. Apparent from the mechanism of actions is that CIBP concerns distinct processes and could be treated by pharmacological and non-pharmacological options. Strategies are to combine therapies, such as co-administration of zoledronate via a new innovative nano-agent with cisplatin and alendronate for breast cancer metastases and bone resorption, showing remarkable inhibition of tumor cell proliferation, osteoclast activation and bone pain relief [134]. Mixed ligands are another strategy, such as Cebranopadol, a mixed NOP/Opioid receptor ligand, indicating antinociceptive and antihypersensitive effects in a rat model of CIBP [135]. A meta-analysis comparing the efficacy of NSAID, opioids and monoclonal NGF antibodies indicate the latter provide superior pain relief, noteworthy is that this was in osteoarthritis [136]. As new strategies are arising, bisphosphonates and denosumab are the first-line therapies for bone metastases [38] and continuing research is warranted to elucidate the CIBP mechanism for identifying novel

#### *Bone Cancer Pain, Mechanism and Treatment DOI: http://dx.doi.org/10.5772/intechopen.95910*

*Recent Advances in Bone Tumours and Osteoarthritis*

growth of tumors occurs [32, 126, 127]. Next came the technique of injecting osteosarcoma-derived mesenchymal cells (NCTC-2472) directly into the long bones of mice [128]. This technique indicates good face and predictive validity, resulting in a controlled late-phase CIBP model, reflecting the clinical course with a comparable responsiveness to systemic opioid treatment [32, 128]. Finally, construct validity had been optimized using syngeneic cell lines (originating from the same species). The first example was rat mammary gland carcinoma cells (MRMT-1 cell line) inoculation into the tibia of rats [129]. The main characteristics after inoculation of cancer cells are: development of allodynia and hyperalgesia, progressive tumor growth, profound destruction and rebuilding of bone and no external tumor growth into other organs. In addition, upregulation of TNF-α, Interferon- γ (IFN-γ), IL-1β, IL-4, IL-10 and IL-6 occurs in tumor-bearing animals [49, 130]. Fine-tuning occurred with another rat breast cancer cell line (Walker 256 cells) inoculated into the tibia [131]. This model has been reviewed extensively and develops spontaneous pain, hyperalgesia, allodynia as well as ambulatory pain, indicates progressive tumor growth with osteolysis and no external growth, including upregulation of IL-1β, NGF, PGE2, IL-6 and TNFα [132]. This model has been subjected to a detailed pharmacological profiling using standard analgesic drugs for CIBP in a clinical setting and is suggested to be one of the most suitable preclinical models for novel compound identification and assessment [132, 133]. No study has been conducted comparing the Walker 256 model with the MRMT-1 model

*A representation of the different in vivo models to study cancer induced bone pain.*

Cancer-induced bone pain (CIBP) causes life-altering pain in 75 to 90% of the advanced stage cancer patients. The movement-induced incident and breakthrough events cause a severe impairment of the quality of life of patients and explain the difficulty to treat this unique type of pain. There remains a high unmet medical need for CIBP treatment since around one-third of the advanced cancer patients

**12**

(**Figure 2**).

**Figure 2.**

**5. Conclusion**

is still undertreated [90]. Apparent from the mechanism of actions is that CIBP concerns distinct processes and could be treated by pharmacological and non-pharmacological options. Strategies are to combine therapies, such as co-administration of zoledronate via a new innovative nano-agent with cisplatin and alendronate for breast cancer metastases and bone resorption, showing remarkable inhibition of tumor cell proliferation, osteoclast activation and bone pain relief [134]. Mixed ligands are another strategy, such as Cebranopadol, a mixed NOP/Opioid receptor ligand, indicating antinociceptive and antihypersensitive effects in a rat model of CIBP [135]. A meta-analysis comparing the efficacy of NSAID, opioids and monoclonal NGF antibodies indicate the latter provide superior pain relief, noteworthy is that this was in osteoarthritis [136]. As new strategies are arising, bisphosphonates and denosumab are the first-line therapies for bone metastases [38] and continuing research is warranted to elucidate the CIBP mechanism for identifying novel analgesic compounds.
