Abstract
Fragility fractures are a well-known complication following oncologic radiotherapy, and it is suspected that radiation-induced embrittlement of bone within the treatment field may contribute to fracture risk. To explore this phenomenon, a mouse model (BALB/cJ) of fractionated, limited field, bilateral hindlimb irradiation (4x5 Gy) was used. The effects of radiation on femoral (cortical) bone fracture toughness, morphology, and biochemistry—including advanced glycation end products (AGEs)—were quantified and compared to Sham group samples prior to irradiation and at 0, 4, 8, and 12 weeks post-irradiation. Additionally, alterations to bone fracture toughness mediated directly by radiation (independent of cellular mechanisms) were determined using devitalized mouse cadaver femurs. Finally, the contribution of AGEs to reduced fracture toughness was examined by artificially ribosylating mouse femurs ex vivo. These data demonstrate that in vivo irradiation results in an immediate (-42% at 0 weeks, p < 0.001) and sustained (-28% at 12 weeks, p < 0.001) decrease in fracture toughness with small changes in morphology (-5% in cortical area at 12 weeks), and minimal changes in bone composition (tissue mineral density, mineral:matrix ratio, and AGE content). Irradiation of devitalized femurs also reduced fracture toughness (-29%, p < 0.001), but to a lesser extent than was seen in vivo. While artificial ribosylation decreased fracture toughness with time, the extent of glycation needed to induce this effect exceeded the AGE accumulation that occurred in vivo. Overall, hindlimb irradiation induced a substantial and sustained decrease in bone fracture toughness. Approximately half of this decrease in fracture toughness is due to direct radiation damage, independent of cellular remodeling. Collagen glycation in vivo was not substantially altered, suggesting other matrix changes may contribute to post-radiotherapy bone embrittlement.
Highlights
Fragility fractures are a well-known complication following oncologic radiotherapy, occurring in up to one third of cancer survivors in certain groups [1,2,3,4,5,6,7,8]
Analysis of covariance (ANCOVA) was used to test whether changes in fracture toughness over time differed between RTx and Sham femuprs (Table 1)
This work provides direct and definitive evidence that radiotherapy results in diminished bone fracture toughness
Summary
Fragility fractures are a well-known complication following oncologic radiotherapy, occurring in up to one third of cancer survivors in certain groups [1,2,3,4,5,6,7,8]. Murray endowment has no url The funders had no role in study design, data, collection and analysis, decision to publish, or preparation of the manuscript
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