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Sepsis Reduces Bone Strength Before Morphologic Changes Are Identifiable

Puthucheary, Zudin A. MBBS, PhD1,2,3; Sun, Yao BSc, M.Eng4; Zeng, Kaiyang PhD4; Vu, Lien Hong PhD1; Zhang, Zhi Wei BSc1; Lim, Ryan Z. L. BSc1; Chew, Nicholas S. Y. MBChB, PhD1; Cove, Matthew E. MBChB1

doi: 10.1097/CCM.0000000000002732
Online Laboratory Investigations
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Objectives: Survivors of critical illness have an increased prevalence of bone fractures. However, early changes in bone strength, and their relationship to structural changes, have not been described. We aimed to characterize early changes in bone functional properties in critical illness and their relationship to changes in bone structure, using a sepsis rodent model.

Design: Experimental study.

Setting: Animal research laboratory.

Subjects: Adult Sprague-Dawley rats.

Interventions: Forty Sprague-Dawley rats were randomized to cecal ligation and puncture or sham surgery. Twenty rodents (10 cecal ligation and puncture, 10 sham) were killed at 24 hours, and 20 more at 96 hours.

Measurements and Main Results: Femoral bones were harvested for strength testing, microCT imaging, histologic analysis, and multifrequency scanning probe microscopy. Fracture loads at the femoral neck were significantly reduced for cecal ligation and puncture–exposed rodents at 24 hours (83.39 ± 10.1 vs 103.1 ± 17.6 N; p = 0.014) and 96 hours (81.60 ± 14.2 vs 95.66 ± 14.3 N; p = 0.047). Using multifrequency scanning probe microscopy, collagen elastic modulus was lower in cecal ligation and puncture–exposed rats at 24 hours (1.37 ± 0.2 vs 6.13 ± 0.3 GPa; p = 0.001) and 96 hours (5.57 ± 0.5 vs 6.13 ± 0.3 GPa; p = 0.006). Bone mineral elastic modulus was similar at 24 hours but reduced in cecal ligation and puncture–exposed rodents at 96 hours (75.34 ± 13.2 vs 134.4 ± 8.2 GPa; p < 0.001). There were no bone architectural or bone mineral density differences by microCT. Similarly, histologic analysis demonstrated no difference in collagen and elastin staining, and C-X-C chemokine receptor type 4, nuclear factor kappa beta, and tartrate-resistant acid phosphatase immunostaining.

Conclusions: In a rodent sepsis model, trabecular bone strength is functionally reduced within 24 hours and is associated with a reduction in collagen and mineral elastic modulus. This is likely to be the result of altered biomechanical properties, rather than increased bone mineral turnover. These data offer both mechanistic insights and may potentially guide development of therapeutic interventions.

1Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore.

2Adult Intensive Care Unit, Royal Brompton Hospital, London, United Kingdom.

3Centre for Human Health and Performance, Division of Medicine, University College London, London, United Kingdom.

4Department of Mechanical Engineering, National University Singapore, Singapore.

Drs. Chew and Cove contributed equally and are joint senior authors. Dr. Puthucheary contributed to conceptual design, analysis, interpretation, article drafting, and final approval and accountable for accuracy of data presented. Drs. Sun, Vu, Zhang, and Lim contributed to data acquisition, analysis, article revising, and final approval and accountable for accuracy of data presented. Drs. Chew and Cove contributed equally to the article. Drs. Zeng, Chew, and Cove contributed to conceptual design, analysis, interpretation, article drafting, and final approval and accountable for accuracy of data presented.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by Medicine-Engineering seed grant from National University Health System and Faculty of Engineering at National University Singapore (R-265-000-532-112) (to Drs. Puthucheary, Zeng, and Cove). Singapore National Medical Research Council Transitional Award funding, NMRC/TA/0015/2013 (to Dr. Cove). Ministry of Education (Singapore) Academic Research Grant (R-265-000-495-112) (to Dr. Zeng and Ms. Sun).

Drs. Vu, Zhang, Lim, Chew, and Cove’s institution received funding from National University Health System Medicine-Engineering grant—Seed Grant. Dr. Cove’s institution received funding from the National Medical Research Council, and he received honorarium and travel support from Covidien/Medtronic. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: Zudin.puthucheary.09@ucl.ac.uk

Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.