No abstract

In poly-traumatic patients a blunt chest trauma is an important trigger of the posttraumatic systemic inflammatory response. There is clinical evidence that fracture healing is delayed in such patients, however, experimental data are lacking. Therefore, we investigated the influence of a thoracic trauma on fracture healing in a rat model. Male Wistar rats received either a blunt chest trauma combined with a femur osteotomy or an isolated osteotomy. A more rigid or a more flexible external fixator was used for fracture stabilization to analyze whether the thoracic trauma influences regular healing and mechanically induced delayed bone healing differently. The blunt chest trauma induced a significant increase of IL-6 serum levels after 6 and 24 h, suggesting the induction of a systemic inflammation, whereas the isolated fracture had no effect. Under a more rigid fixation the thoracic trauma considerably impaired fracture healing after 35 days, reflected by a significantly reduced flexural rigidity (three-point-bending test), as well as a significantly diminished callus volume, moment of inertia, and relative bone surface (mCT analysis). In confirming the clinical evidence, this study reports for the first time that a blunt chest trauma considerably impaired bone healing, possibly via the interaction of the induced systemic inflammation with local inflammatory processes. ß

Fracture healing is impaired in aged and osteoporotic individuals. Because adequate mechanical stimuli are able to increase bone formation, one therapeutical approach to treat poorly healing fractures could be the application of whole-body vibration, including low-magnitude high-frequency vibration (LMHFV). We investigated the effects of LMHFV on fracture healing in aged osteoporotic mice. Female C57BL/6NCrl mice (n=96) were either ovariectomised (OVX) or sham operated (non-OVX) at age 41 weeks. When aged to 49 weeks, all mice received a femur osteotomy that was stabilised using an external fixator. The mice received whole-body vibrations (20 minutes/day) with 0.3 g peak-to-peak acceleration and a frequency of 45 Hz. After 10 and 21 days, the osteotomised femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, micro-computed tomography (μCT), histology and gene expression analyses. LMHFV disturbed fracture healing in aged non-OVX mice, with significantly reduced flexural rigidity (−81%) and bone formation (−80%) in the callus. Gene expression analyses demonstrated increased oestrogen receptor β (ERβ, encoded by Esr2) and Sost expression in the callus of the vibrated animals, but decreased β-catenin, suggesting that ERβ might mediate these negative effects through inhibition of osteoanabolic Wnt/β-catenin signalling. In contrast, in OVX mice, LMHFV significantly improved callus properties, with increased flexural rigidity (+1398%) and bone formation (+637%), which could be abolished by subcutaneous oestrogen application (0.025 mg oestrogen administered in a 90-day-release pellet). On a molecular level, we found an upregulation of ERα in the callus of the vibrated OVX mice, whereas ERβ was unaffected, indicating that ERα might mediate the osteoanabolic response. Our results indicate a major role for oestrogen in the mechanostimulation of fracture healing and imply that LMHFV might only be safe and effective in confined target populations.

Low-magnitude high-frequency vibration (LMHFV) provokes anabolic effects in non-fractured bone; however, in fracture healing, inconsistent results were reported and optimum vibration conditions remain unidentified. Here, we investigated frequency dependent effects of LMHFV on fracture healing. Twelve-week-old, female C57BL/6 mice received a femur osteotomy stabilized using an external fixator. The mice received whole-body vibrations (20 min/day) with 0.3g peak-to-peak acceleration and a frequency of either 35 or 45 Hz. After 10 and 21 days, the osteotomized femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, m-computed tomography, and histomorphometry. In non-fractured trabecular bone, vibration with 35 Hz significantly increased the relative amount of bone (þ28%) and the trabecular number (þ29%), whereas cortical bone was not influenced. LMHFV with 45 Hz failed to provoke anabolic effects in trabecular or cortical bone. Fracture healing was not significantly influenced by whole-body vibration with 35 Hz, whereas 45 Hz significantly reduced bone formation (À64%) and flexural rigidity (À34%) of the callus. Although the exact mechanisms remain open, our results suggest that small vibration setting changes could considerably influence LMHFV effects on bone formation in remodeling and repair, and even disrupt fracture healing, implicating caution when treating patients with impaired fracture healing. Keywords: whole-body vibration; LMHFV; fracture healing; bone formation Delayed or incomplete fracture healing is a major issue in orthopedic surgery, with an incidence of about 10% of patients and a high socioeconomic burden, implicating the need for effective treatment strategies.1 Because bone metabolism is partly regulated by mechanical factors and suitable mechanical stimuli can improve bone repair, 2,3 non-invasive physical methods, among them low-magnitude high-frequency vibration (LMHFV), 2,4 could provide a readily applicable and cost-effective approach to prevent or treat delayed fracture healing.LMHFV is characterized by a sinusoidal waveform with an acceleration of <1g (g ¼ gravitational acceleration, 1g ¼ 9.81 m/s 2 ) and a frequency range between 20 and 90 Hz, 5 inducing extremely small strains in bone tissue (approximately 10 me), much less than the peak strains generated during locomotion (2,000-3,000 me). 2LMHFV provoked anabolic effects in both healthy and osteoporotic bone in preclinical 6-9 and clinical studies. 11 In both healthy 12 and ovariectomized rats, 13 LMHFV (35 Hz/0.3g) was shown to improve bone repair by inducing a large callus with more bone and improved mechanical quality. The same authors found that LMHFV stimulated callus angiogenesis 14 and, in the late healing phase, bone resorption. 15 In a model of metaphyseal bone healing, vibrations with both high frequency (90 Hz) and acceleration (4g) provoked some positive effects in ovariectomized rats, but resulted in delayed callus bridging in healthy animals, and was therefore consi...