title: Long-term loss of osteoclasts and unopposed cortical mineral apposition following limited field irradiation.
abstract: 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.
authors.affiliation: Department of Orthopedic Surgery, Upstate Medical University, Syracuse, New York.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Oest
authors.forename: Veerle
authors.initials: V
authors.lastname: Franken
authors.forename: Timothy
authors.initials: T
authors.lastname: Kuchera
authors.forename: Judy
authors.initials: J
authors.lastname: Strauss
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Damron
mesh_terms: D000818:Animals; D015519:Bone Density / Q000528:radiation effects*; D005260:Female; D005269:Femur / Q000528:radiation effects; D050723:Fractures, Bone / Q000209:etiology*; D006614:Hindlimb / Q000528:radiation effects; D051379:Mice; D010010:Osteoclasts / Q000528:radiation effects*; D011878:Radiotherapy / Q000009:adverse effects*
keywords: bone morphology; fracture; mineral apposition; osteoclast; radiation