Cisplatin inhibits bone healing during distraction osteogenesis

Abstract

Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five dose CDP regimen (2mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (P<0.001). Further, no significant inhibitory effects from the 5 dose CDP regimen were observed in TNFR1KO mice. The two dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP.

Cisplatin chemotherapy impairs the peri‐implant bone repair around titanium implants: An in vivo study in rats

“…These data confirm that CIS showed a severe impairment over differentiation and maturation of the osteoblastic lineage and justifies the lower peri‐implant bone formation, corroborating Stine et al. ().…”

“…As chemotherapy increases severity and accelerates the progression of experimental periodontitis (Garcia et al., ; Theodoro et al., ), clinically, exposure of these implants to plaque can lead to impairment of osseointegration due to severe peri‐implantitis. As CIS develops hazardous effect over bone repair and bone formation (Stine et al., , ), more studies are needed for proper and secure rehabilitation of patients previously submitted to chemotherapy. Moreover, circulating levels of CIS have been shown up to 20 years after therapy; thus, long‐term renal effects (Gietema et al., ; Orchard et al., ) and its impairment over bone growth can be expected.…”

“…The treatment of cancer (Al‐Mahalawy et al., ; Nack, Raguse, Stricker, Nelson, & Nahles, ) is among the innumerous conditions (Brink, Meraw, & Sarment, ; Duarte et al., ; Franchi et al., ; Fujimoto, Niimi, Sawai, & Ueda, ; Keller & Steiger, ; Ma, Zwahlen, Zheng, & Sham, ; Sakakura, Marcantonio, Wenzel, & Scaf, ; Siqueira, Cavalher‐Machado, Arana‐Chavez, & Sannomiya, ) capable to interfere with osseointegration. Cisplatin chemotherapy can be clearly defined as a potential agent to jeopardize the peri‐implant bone repair, as its severe inhibitory effect over bone formation has already been described (Stine et al., , ). This damage can be suggested by phosphate and magnesium urinary losses due to its nephrotoxic effects (Jiménez‐Triana et al., ).…”

The best of both worlds — managing the cancer, saving the bone

“…However, the need to maintain bone homeostasis and overall mass and strength of the skeleton during the necessary treatments to successfully kill tumour cells is critical. Indeed, several studies have indicated a lack of bone regeneration and/or healing after treatment of osteolytic metastases or following chemotherapy, which suggests that cancer cells (and specific treatments) might have altered the behaviour and/or differentiated activity of osteoclasts, osteoblasts and/or osteocytes 67,68 .…”

The influence of Cisplatin‐based chemotherapy on the osseointegration of dental implants: An in vivo mechanical and histometrical study

“…Among the most recently used chemotherapeutic drugs, Cisplatin stands out because it has a marked antitumor activity against various types of cancer (Almeida et al, ; Mitin et al, ). However, one of its side effects is a reduction in bone remodeling (Al‐Mahalawy et al, ; Kovács, ; Matheus et al, ; Stine et al, ; Young, Shih, et al, ; Young, Virolainen, et al, ), which may hamper the patients' bone metabolism and, consequently, impair their rehabilitation with osseointegratable implants. Thus, this study assessed the bone quality and the osseointegration of dental implants after exposure to the chemotherapeutic drug Cisplatin.…”