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Meta-Analysis
. 2023 Jan;38(1):198-213.
doi: 10.1002/jbmr.4740. Epub 2022 Dec 5.

Lipopolysaccharide-Induced Bone Loss in Rodent Models: A Systematic Review and Meta-Analysis

Kirsten N Bott  1   2 , Evelyn Feldman  3 , Russell J de Souza  4   5 , Elena M Comelli  1   6   7 , Panagiota Klentrou  1   2 , Sandra J Peters  1   2 , Wendy E Ward  1   2   6   8
Affiliations
Meta-Analysis

Lipopolysaccharide-Induced Bone Loss in Rodent Models: A Systematic Review and Meta-Analysis

Kirsten N Bott et al. J Bone Miner Res. 2023 Jan.

Abstract

Osteoporosis has traditionally been characterized by underlying endocrine mechanisms, though evidence indicates a role of inflammation in its pathophysiology. Lipopolysaccharide (LPS), a component of gram-negative bacteria that reside in the intestines, can be released into circulation and stimulate the immune system, upregulating bone resorption. Exogenous LPS is used in rodent models to study the effect of systemic inflammation on bone, and to date a variety of different doses, routes, and durations of LPS administration have been used. The study objective was to determine whether systemic administration of LPS induced inflammatory bone loss in rodent models. A systematic search of Medline and four other databases resulted in a total of 110 studies that met the inclusion criteria. Pooled standardized mean differences (SMDs) and corresponding 95% confidence intervals (CI) with a random-effects meta-analyses were used for bone volume fraction (BV/TV) and volumetric bone mineral density (vBMD). Heterogeneity was quantified using the I2 statistic. Shorter-term (<2 weeks) and longer-term (>2 weeks) LPS interventions were analyzed separately because of intractable study design differences. BV/TV was significantly reduced in both shorter-term (SMD = -3.79%, 95% CI [-4.20, -3.38], I2 62%; p < 0.01) and longer-term (SMD = -1.50%, 95% CI [-2.00, -1.00], I2 78%; p < 0.01) studies. vBMD was also reduced in both shorter-term (SMD = -3.11%, 95% CI [-3.78, -2.44]; I2 72%; p < 0.01) and longer-term (SMD = -3.49%, 95% CI [-4.94, -2.04], I2 82%; p < 0.01) studies. In both groups, regardless of duration, LPS negatively impacted trabecular bone structure but not cortical bone structure, and an upregulation in bone resorption demonstrated by bone cell staining and serum biomarkers was reported. This suggests systemically delivered exogenous LPS in rodents is a viable model for studying inflammatory bone loss, particularly in trabecular bone. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords: BIOCHEMICAL MARKERS OF BONE TURNOVER; BONE HISTOMORPHOMETRY; DUAL-ENERGY X-RAY ABSORPTIOMETRY (DXA); MICRO-COMPUTED TOMOGRAPHY; PRECLINICAL STUDIES.

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Conflict of interest statement

E.M.C. received research support from Lallemand Health Solutions and Ocean Spray and consultant fees or speaker and travel support from Danone and Lallemand Health Solutions. (All are outside of this study.)

R.J.d.S. has served as an external resource person to the World Health Organization's (WHO) Nutrition Guidelines Advisory Group on trans fats, saturated fats, and polyunsaturated fats. The WHO paid for his travel and accommodations to attend meetings from 2012–2017 to present and discuss this work. He presented updates of this work to the WHO in 2022. He has also done contract research for the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism, and Diabetes, Health Canada, and the WHO, for which he received remuneration. He has received speaker's fees from the University of Toronto and McMaster Children's Hospital. He has held grants from the Canadian Institutes of Health Research, Canadian Foundation for Dietetic Research, Population Health Research Institute, and Hamilton Health Sciences Corporation as a principal investigator and is a co‐investigator on several funded team grants from the Canadian Institutes of Health Research. He has served as an independent director of the Helderleigh Foundation (Canada). He serves as a member of the Nutrition Science Advisory Committee to Health Canada (Government of Canada) and a co‐opted member of the Scientific Advisory Committee on Nutrition (SACN) Subgroup on the Framework for the Evaluation of Evidence (Public Health England). (All are outside of this study.)

Figures

Fig. 1
Fig. 1
Flow chart of study screening and selection process.
Fig. 2
Fig. 2
Duration of lipopolysaccharide (LPS) administration in included studies (n = 110). Given the clustering of studies with LPS administration less than 2 weeks with more homogeneous study design compared to studies with LPS administration greater than 2 weeks, this 2‐week cutoff was used for analysis.
Fig. 3
Fig. 3
Results of the risk of bias for 110 studies according to the SYRCLE risk of bias tool. “Yes” indicates low risk of bias, “no” high risk of bias, and “unclear” an unclear risk of bias. The stacked bars represent the percentage of studies, and the numbers within each bar represent the number of studies.
Fig. 4
Fig. 4
Effect of lipopolysaccharide (LPS) on BV/TV of femur and tibia in studies lasting less than 2 weeks. LPS, lipopolysaccharide; BV/TV, bone volume fraction; CI, confidence interval; SD, standard deviation; IV, weighted mean difference.
Fig. 5
Fig. 5
Effect of lipopolysaccharide (LPS) on vBMD of femur and tibia in studies lasting less than 2 weeks. LPS, lipopolysaccharide; vBMD, volumetric bone mineral density; CI, confidence interval; SD, standard deviation; IV, weighted mean difference.
Fig. 6
Fig. 6
Effect of lipopolysaccharide (LPS) on BV/TV of femur, tibia, and lumbar vertebra in studies lasting more than 2 weeks. LPS, lipopolysaccharide; BV/TV, bone volume fraction; CI, confidence interval; SD, standard deviation; IV, weighted mean difference.
Fig. 7
Fig. 7
Effect of lipopolysaccharide (LPS) on vBMD of femur and lumbar vertebra in studies lasting more than 2 weeks. LPS, lipopolysaccharide; vBMD, volumetric bone mineral density; CI, confidence interval; SD, standard deviation; IV, weighted mean difference.
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