Therapeutic Irradiation: Consequences for Bone and Bone Marrow Adipose Tissue

Abstract

Radiotherapy continues to be one of the most accepted medical treatments for cancer. Localized irradiation is the most common treatment for prostate, pancreatic, rectal, cervical and endometrial malignancies. Conventional localized fractions are total doses of 30-62Gy at 1.8-2Gy per fraction, with administration of ~60Gy often used for tumor ablation. However, even the lowest dose of localized irradiation exposure can result in adverse complications to adjacent organs, tissues, and vessels, which absorb a portion of the treatment. Skeletal complications are common amongst cancer patients undergoing these localized treatments. Irradiation exposure causes deterioration to the overall quantity and quality of bone by interfering with the trabecular architecture through increased osteoclast activity and decreased osteoblast activity. Irradiation-induced bone damage parallels adipocyte infiltration of the bone marrow (BM) resulting in compositional alterations of the microenvironment that may further affect bone quality and disease state. There may also be direct effects of irradiation on the BM adipocyte/pre-adipocyte, although in vitro findings do not always agree and cellular response is dependent on irradiation dosage. Hematopoietic cells also become apoptotic upon irradiation, which causes a range of skeletal effects. Bone loss leaves patients at a greater risk for osteopenia, osteoporosis, osteonecrosis, and skeletal fractures that drastically reduce quality of life. Osteoanabolic agents stimulate bone formation and reduce fracture risk in patients with low bone density; thus, osteoanabolic or anti-resorptive agents may be useful co-treatments with irradiation. This review discusses these topics and proposes further research directions using novel or combination therapies to enhance bone health during irradiation.

Adipogenesis in Different Body Depots and Tumor Development

“…Tumor cells can induce the phosphorylation of hormone-sensitive lipase and activate lipolysis in BMAT, allowing the transfer of fatty acids from adipocytes to tumor cells in AML (Shafat et al, 2017;Tabe et al, 2020), multiple myeloma (Morris et al, 2020), and prostate tumor (Herroon et al, 2019). Importantly, after chemotherapy, marrow necrosis and the loss of myeloid tissue may result in a BMAT expansion (Hwang and Panicek, 2007;Costa and Reagan, 2019), which might create a favorable niche for tumor cells.…”

Erythropoietin-Induced Changes in Bone and Bone Marrow in Mouse Models of Diet-Induced Obesity

“…In the bone marrow, BMAT originates from a subset of bone marrow stromal cells (BMSCs) called skeletal stem cells, which are also the precursors of osteoblasts that form the mineralized bone matrix [4]. Conditions of excessive marrow adiposity, such as ageing [5], estrogen deficiency, osteoporosis [6], obesity [7], caloric restriction [8], radiation and chemotherapy [9] are associated with bone loss and skeletal fragility, suggesting an inverse relationship between BMAT and bone remodeling. Specifically, the role of obesity in skeletal health has been contradictory with early observations that were suggestive of the protective role of obesity in bone health [10].…”

Osteogenic Effects of IL-12 on Bone Marrow Mesenchymal Stem Cells Facilitates Its Irradiation Hematopoiesis Recovery

“…Radiotherapy is considered to be one of most accepted medical and widely used treatments for tumor and cancer. However, even the lowest dose of localized irradiation exposure can result in adverse complications to adjacent organs, tissues, especially irradiation-sensitive organizations, such as hematopoietic and gastrointestinal system, gonads tissues [1]. The irradiation caused myelosuppression and hematopoietic dysfunction [1,2] have become common side effects and obstacles in radiotherapy patients[3-7].…”

“…However, even the lowest dose of localized irradiation exposure can result in adverse complications to adjacent organs, tissues, especially irradiation-sensitive organizations, such as hematopoietic and gastrointestinal system, gonads tissues [1]. The irradiation caused myelosuppression and hematopoietic dysfunction [1,2] have become common side effects and obstacles in radiotherapy patients[3-7]. As we known, hematopoiesis is a complex and multistep developmental process involves pluripotent hematopoietic stem and progenitor cells (HSPCs),varies supportive cells in the hemopoietic microenvironment (HM) and terminating erythrocytes.…”

“…In irradiation, HSPCs were seriously damaged but for more importance the hemopoietic microenvironment (HM) which regulates the hematopoietic process, including maintenances and regulation of HSPCs quiescence, self-renewal and differentiation were also damaged. Then the demaged HM resulted its ineffective supporting in hematopoiesis recovery [1]. Preserving and promoting HM physiological function gradually become the target of hematopoietic reconstitution and rescuing hematopotic injury [6][7][8] .…”