Elsevier

Nitric Oxide

Volume 20, Issue 4, 1 June 2009, Pages 298-303
Nitric Oxide

The effects of shockwave on bone healing and systemic concentrations of nitric oxide (NO), TGF-β1, VEGF and BMP-2 in long bone non-unions

https://doi.org/10.1016/j.niox.2009.02.006Get rights and content

Abstract

This study investigated the effects of extracorporeal shockwave treatment (ESWT) on bone healing and the systemic concentrations of nitric oxide (NO), TGF-β1, VEGF and BMP-2 in long bone non-unions. Forty-two patients with 42 established non-unions of the femur and tibia were enrolled in this study. Each long bone non-union was treated with 6000 impulses of shockwave at 28 kV in a single session. Ten milliliters of peripheral blood were obtained for measurements of serum NO level and osteogenic growth factors including TGF-β1, VEGF and BMP-2; serum levels of calcium, alkaline phosphatase, calcitonin and parathyroid hormone before treatment and at 1 day, 1, 3 and 6 months after treatment. The evaluations for bone healing included clinical assessments and serial radiographic examinations. At 6 months, bony union was radiographically confirmed in 78.6%, and persistent non-union in 21.4%. Patients with bony union showed significantly higher serum NO level, TGF-β1, VEGF and BMP-2 at 1 month after treatment as compared to patients with persistent non-union. Shockwave-promoted bone healing was associated with significant increases in serum NO level and osteogenic growth factors. The elevations of systemic concentration of NO level and the osteogenic factors may reflect a local stimulation of shockwave in bone healing in long bone non-unions.

Introduction

Non-union of long bone is defined when new bone fails to bridge the fracture gap within 6 months from the initial fracture [1], [2]. Many procedures are attempted to prevent the occurrence of non-union including bone grafting, distraction osteogenesis, electrical magnetic field stimulation, low-intensity pulsed ultrasound, gene therapy with BMP-2 and implantation of mesenchymal stem cells [3], [4], [5], [6], [7], [8], [9], [10]. Some achieved limited success in selected series, but none showed universal results. Many procedures are invasive and may incur certain risks and complications, and they are costly. Therefore, the development of an effective and safe method of treatment for long bone non-union appears to be very attractive.

Extracorporeal shockwave treatment (ESWT) was shown effective to accelerate bone healing with increased callus formation and to prevent delayed or non-union of long bone fractures [11], [12], [13], [14], [15], [16], [17]. Despite the good clinical results, the exact mechanism of shockwave in bone healing remains unknown. Some studies demonstrated shockwave treatment rapidly induces elevation of systemic nitric oxide (NO) level and subsequent increases in systemic osteogenic factors, but not prostaglandin E2 (PGE2) in non-union of long bone [18], [19], [20], [21]. Others reported that NO as the mediator in callus formation in fracture healing after mechanical stimulation [22], [23]. We hypothesized that local stimulation with ESWT in bone may result in systemic elevations in NO and osteogenic factors. The specific aim of this study was to investigate the effects of shockwave treatment on bone healing and the systemic concentrations of NO level, TGF-β1, VEGF and BMP-2 in long bone non-unions.

Section snippets

Patients and procedures

Institutional Review Board approval was obtained and written informed consent obtained from study subjects. The studies were in compliance with the Declaration of Helsinki ethical principles for medical research involving human subjects. The inclusion criteria comprised of patients with non-unions of diaphyseal fractures of femur and tibia. Non-union was evaluated by history and physical examination, and confirmed by X-rays of the affected bone when the fracture failed to heal in 6 months from

Results

The results of clinical assessment are summarized in Table 2. There were significant time-dependent improvements in pain score, weight bearing and work ability after shockwave treatment (P < 0.05).

The results of radiographic evaluation are summarized in Table 3. There were progressive improvements in fracture gap, the size of callus and fracture healing, and such changes were time dependent and became significant after 3 months (P < 0.05). The rate of bony union was 12% (5 of 42) at 1 month, 43% (18

Discussion

Fracture healing is a complex phenomenon involving the growth and differentiation of mesenchymal stem cells, regulation of inflammatory cytokines, synthesis and resorption of extracellular matrix [24], [25], [26], [27]. Some studies showed gene expressions of BMP-2, 3, 3B, 4, 6, 7, GDF-5, 7, and BMP antagonists noggin, drm, screlostin, and BAMAI were significantly lower in non-unions compared to standard healing fractures, and concluded that down-regulation in expression of osteogenic BMPs may

Acknowledgments

The authors declared that they did not receive any honoraria or consultancy fees in writing this manuscript. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support for the research or clinical study presented in this article. The funding source was from National Health Research Institute (NHRI-EX96-9423EP).

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