Sepsis Reduces Bone Strength Before Morphologic Changes Are Identifiable

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Abstract

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.

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