BISFOSFONIANY W ZMIANACH KOSTNYCH INDUKOWANYCH CHOROBĄ NOWOTWOROWĄ

liganda aktywatora receptora NF-κ 

L19

Bisphosphonates in cancer-induced bone disease

Misiorowski W.

Klinika Endokrynologii CMKP w Warszawie

Keywords: cancer, multiple myeloma, PTHrP, bisphoshonates

         Cancer affects the skeleton in several ways: bone metastases, hypercalcemia and osteoporosis due to cancer treatment. Bone is one of the most frequent sites of metastasis formation for patients with advanced cancers. Osteolytic metastasis is the site of a vicious cycle wherein bone-residing tumor cells have spread to bone release factors that affect bone cells, resulting particularly in activation of bone-resorbing osteoclasts; these osteoclasts in turn allow the release of bone matrix-derived factors that feed back to the cancer cells, further fueling the latter’s growth. Skeletal-related clinical events (SREs) are a direct result of bone metastasis and include bone pain, pathologic fractures and spinal cord compression. SREs contribute significantly to patient morbidity as up to 75% of advanced prostate and breast cancer and 30-40% of lung cancer patients have bone metastases. Systemic effects of tumor-derived PTHrP and other cytokines (e.g. IL-6, IL-11), which promotes receptor activator of NF-κB ligand (RANKL) production by host osteoblasts resulting in calcium mobilization from bone and renal tubular reabsorbtion of calcium, is a major causal factor in hypercalcemia of malignancy. Multiple myeloma also causes significant osteoclastogenesis, however recently Dickkopf 1 (Dkk1) was reported to be involved in the suppression of osteoblasts in multiple myeloma. Increased production of Dkk1 has been correlated with both the number and severity of resulting bone lesions, SREs and hypercalcemia. Finally, cancer treatments such as estrogen or androgen blockade, chemotherapy and radiation therapy result in bone loss. Inhibiting osteoclast function to reduce bone resorption is paramount in each of these scenarios to reduce these related complications and possibly tumor growth in bone. Bisphosphonates currently represent the standard bone-targeted and approved therapy to treat skeletal complications of cancer and cancer treatment. They effectively inhibit osteoclast function, and decrease the risks of SREs in patients with solid tumor bone metastases. Bisphosphonates have also been shown to reduce bone pain. Bisphosphonates are also effective for treatment of hypercalcemia of malignancy, multiple myeloma-related bone resorption and bone loss during cancer treatment. In addition to their antiresorptive function, bisphosphonates might also exhibit antitumor activity. Recently published study demonstrated that the addition of zoledronic acid to adjuvant endocrine therapies improved disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. There are several limitations to the use of bisphosphonates: 1) association with osteonecrosis of the jaw; 2) long half-life in bone and long-term potential to suppress bone turnover; 3) possible renal toxicity and contraindication in renal failure.

         In summary, many questions are still unanswered about the mechanisms of action of bisphosphonates as anti-tumor agents. Although bisphosphonates have long been used to treat the osteolytic bone disease associated with skeletal metastases, it is only recently, however, that evidence is emerging to suggest that they may also modify the course of the disease when used in the adjuvant setting. Moreover, the RANK/RANKL track has emerged as a very attractive and efficient target to treat patients with malignant diseases that affect bone. Results from clinical trials using denosumab in the context of breast and prostate cancers and in myeloma will likely aid the development of more powerful, safe and versatile therapeutics for cancer patients with bone alterations.