The antineoplastic role of bisphosphonates: from basic research to clinical evidence

Abstract

Bisphosphonates are now well established as successful agents for the prevention and treatment of postmenopausal osteoporosis, corticosteroid-induced bone loss and Paget's disease. Bisphosphonates have also recently become important in the management of cancer-induced bone disease, and they now have a widely recognized role for patients with multiple myeloma and bone metastases secondary to breast cancer and prostate cancer. Recent studies suggest that, besides the strong antiosteoclastic activity, the efficacy of such compounds in the oncological setting could also be due also to direct antitumor effect, exerted at different levels. Here, after a brief analysis of the chemical structure, we will review the antineoplastic and biological properties of bisphosphonates. We will start from well estabilished mechanisms of action and go on to discuss the latest evidence and hypotheses. In particular, we will review the antiresorptive properties in malignant osteolysis and the recent evidence of a direct antitumor effect. Furthermore, this review will analyze the influence of bisphosphonates on cancer growth factor release, their effect on cancer cell adhesion, invasion and viability, the proapoptotic potential on cancer cells, the antiangiogenic effect, and, finally, the immunomodulating properties of bisphosphonates on the gammadelta T cell population.

Systematic Review: Bisphosphonates and Osteonecrosis of the Jaws

“…Aminobisphosphonates exert several antitumor effects, including induction of tumor cell apoptosis, inhibition of tumor cell adhesion to the extracellular matrix, and inhibition of tumor invasion (4,7). Bisphosphonates also have antiangiogenesis properties (8,9) and can activate ␥␦ T cells (10,11).…”

Bisphosphonate osteonecrosis of the jaws; an increasing problem for the dental practitioner

“…3 The antitumour effect of bisphosphonates is thought to be due to induction of tumour cell apoptosis, and inhibition of tumour cell adhesion and invasion. 4 Absorption of bisphospho nates from the gastrointestinal tract is variable, but generally poor with only 1-5% of ingested preparation becoming bioavailable. The bisphosphonates are excreted from the body unchanged, via the kidneys.…”

“…9 Osteonecrosis associated with the use of bisphosphonates was fi rst described by Marx in 2003, 10 since which there have been a multitude of case series published. 4 The link between osteonecrosis and dental treatment is deduced from the data that between 33 and 86% of reported cases had undergone surgical treatment in the period before their diagnosis and the fact that the area of osteonecro sis was co-incident with the area of treatment. 2 Why bisphosphonates have a predilec tion for causing osteonecrosis in the jaws is not yet fully understood.…”

“…12 Multi focal involvement has been described, mostly in the maxilla. 4 The maxilla is therefore affected more commonly than in osteoradionecrosis, as would be expected from the understanding that radiotherapy has a direct action on bone, and the mandible is more commonly irradiated than the maxilla, whereas bisphosphonates have a systemic effect.…”

Zoledronate can induce colorectal cancer microenvironment expressing BTN3A1 to stimulate effector γδ T cells with antitumor activity

“…[3][4][5][6][7][8] Different drugs can be utilized to improve the mechanisms of gd T cell activation: 2,3,8 in particular, synthetic pyrophosphate-containing compounds have been proposed for cancer immunotherapy on the basis of their ability to stimulate gdT cells. [9][10][11][12] Moreover, aminobisphosphonates (N-BPs), in addition to their effect of inhibiting osteoclastic bone resorption, 13 lead to gd T cell activation and proliferation, with a consequent increased number of gd T cells in peripheral blood, displaying antitumor activity [14][15][16][17][18] Indeed, N-BPs, such as zoledronate (Zol), are chemically stable analogs of inorganic pyrophosphate (IPP) that inhibit the mevalonate pathway and upregulate IPP accumulation, promoting antitumor Vg9Vd2 T cells in vitro and in vivo. [15][16][17][18][19][20] For this reason, different N-BPs have been used in anticancer clinical trials.…”