Long-term loss of osteoclasts and unopposed cortical mineral apposition following limited field irradiation.

Late-onset fragility fractures are a common complication following radiotherapy for metastatic disease and soft tissue sarcomas. Using a murine hindlimb focal irradiation model (RTx), we quantified time-dependent changes in osteoclasts and mineral apposition rate (MAR). Mice received either a single, unilateral 5 Gy exposure or four fractionated doses (4 × 5 Gy). Osteoclast numbers and MAR were evaluated histologically at 1, 2, 4, 8, 12, and 26 weeks post-RTx. Radiation induced an early, transient increase in osteoclasts followed by long-term depletion. Increased osteoclast numbers correlated temporally with trabecular resorption; the resorbed trabeculae were not later restored. Radiotherapy did not attenuate MAR at any time point. A transient, early increase in MAR was noted in both RTx groups, however, the 4 × 5 Gy group exhibited an unexpected spike in MAR eight weeks. Persistent depletion of osteoclasts permitted anabolic activity to continue unopposed, resulting in cortical thickening. These biological responses likely contribute to post-radiotherapy bone fragility via microdamage accumulation and matrix embrittlement in the absence of osteoclastic remodeling, and trabecular resorption-induced decrease in bone strength. The temporal distribution of osteoclast numbers suggests that anti-resorptive therapies may be of clinical benefit only if started prior to radiotherapy and continued through the following period of increased osteoclastic remodeling.