Radiation-Induced Osteoporosis in Women with Cancer: Mechanisms and Prevention

Research project

Description

Pelvic tumors account for 25% of the 700,000 annual cancer diagnoses in women. Radiotherapy for soft-tissue tumors in the pelvic region increases hip-fracture risk, resulting in substantial patient morbidity and mortality: Treatment for rectal, cervical, and anal cancers in postmenopausal women significantly increases fracture rates by 66%, 65%, and 214%, respectively. In our preclinical models, ionizing radiation rapidly activated osteoclastic bone resorption and caused a decline in trabecular-bone volume fraction of 20-30% that occurred from 7-14 days after exposure. Increased expression of proinflammatory cytokines in the marrow preceded activation of osteoclasts, which was followed by evidence (indicated by phosphoSmad2)of activated transforming growth factor-beta (TGF-beta) signaling. In companion studies, the loss in trabecular-bone volume fraction was prevented by the bisphosphonate risedronate. Ongoing clinical collaborations confirm rapid bone loss in patients during radiation therapy for cervical cancer and indicate that older patients experience a greater degree of bone loss. No prophylactic treatment exists for radiation-induced bone loss; moreover, molecular mechanisms for this rapid loss of bone mass and strength and the resultant increased fracture risk are unknown.

We propose that radiation therapy in women with pelvic tumors causes a rapid decline in bone mass that leads to increased fracture risk. We hypothesize that the causal mechanism for this radiation-induced deficit in bone quality is rapid activation (from bone-marrow’s early inflammatory response to radiation damage) of osteoclasts via the cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1). Estrogen suppression enhances this inflammatory response. Furthermore, the subsequent release of TGF-beta from resorbed bone matrix propagates and accelerates bone loss by accelerating osteoclastic bone resorption and inhibiting osteoblast differentiation. Existing therapies for osteoporosis and other disorders (e.g., the antiresorptive zoledronate, RANKL-blocking osteoprotegerin (OPG), TNF-alpha binding protein [TNFbp], IL-1 receptor antagonist [IL-1ra], and a TGF-beta receptor I kinase inhibitor) may prevent this bone loss and could be rapidly translated. To test this causal-mechanism hypothesis, the following specific Aims will determine 1) If osteoclast-inhibiting therapies preserve bone mass in a mouse model for radiation-induced bone loss in the setting of estrogen deficiency; 2) The role of inflammatory cytokines TNF-alpha and IL-1 in acute radiation-induced activation of osteoclastic bone resorption; 3) If greater levels of activated TGF-beta exacerbate radiation-induced bone loss.

Studying the activation of osteoclasts by ionizing radiation is novel, and ongoing clinical trials confirm the resultant profound decline in bone mass. Osteoclast-inhibiting compounds that are already approved by the FDA could prevent radiotherapy-related fractures. The overall goal of this research is to rapidly translate our ongoing preclinical and clinical research in radiation-induced bone loss into a treatment regimen that reduces fracture risk in women who receive ionizing radiation for soft-tissue pelvic tumors.
StatusFinished
Effective start/end date4/1/113/31/16

Funding

  • NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMSD)

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Osteoporosis
Radiation
Bone and Bones
Neoplasms
Osteoclasts
Therapeutics
Bone Resorption
Radiotherapy
Ionizing Radiation
Transforming Growth Factor beta
Tumor Necrosis Factor-alpha
Cytokines
Interleukin-1
Uterine Cervical Neoplasms
Estrogens
Bone Marrow
Research
zoledronic acid
Beta Particles
Anus Neoplasms