Systematic Review With Meta-analysis

Non-alcoholic Fatty Liver Disease Is Associated With a History of Osteoporotic Fractures but Not With Low Bone Mineral Density

Alessandro Mantovani; Marco Dauriz; Davide Gatti; Ombretta Viapiana; Giacomo Zoppini; Giuseppe Lippi; Christopher D. Byrne; Fabrice Bonnet; Enzo Bonora; Giovanni Targher


Aliment Pharmacol Ther. 2019;49(4):375-388. 

In This Article

Abstract and Introduction


Background: Several studies have explored the effect of non-alcoholic fatty liver disease (NAFLD) on bone mineral density (BMD) and risk of osteoporotic fractures in adults. However, the extent to which NAFLD adversely affects bone health remains uncertain.

Aim: To provide a quantitative estimation of the magnitude of the association of NAFLD with BMD or history of osteoporotic fractures in adults.

Methods: We searched PubMed, Web of Science, and Scopus using predefined keywords to identify all observational studies, published up to 31 August 2018, in which NAFLD was diagnosed by imaging or histology; BMD was measured by dual energy X-ray absorptiometry; and a self-reported history of osteoporotic fractures was collected with interviewer-assisted questionnaires. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling.

Results: Twelve cross-sectional or case-control studies with aggregate data on 30 041 adults of predominantly Asian ethnicity (30% with NAFLD) were included in the final analysis. No significant differences in BMD at different skeletal sites (whole body, lumbar spine, or femur) were observed between individuals with and without NAFLD. Conversely, NAFLD was associated with increased odds of osteoporotic fractures, especially in older Chinese men (n = 2 studies; random-effects odds ratio 2.10, 95% CI 1.36-3.25; I 2 = 0%). Sensitivity analyses did not alter these findings. The funnel plot and Egger test did not reveal significant publication bias.

Conclusions: This meta-analysis suggests that imaging-defined or biopsy-proven NAFLD is associated with a self-reported history of osteoporotic fractures (principally in Chinese men), but not with low BMD, in middle-aged and elderly individuals.


Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in both developed and developing countries, and is estimated to affect at least 25%-30% of adults in the general population and up to 70%-90% of persons with type 2 diabetes or obesity.[1] NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and other extrahepatic diseases (eg, type 2 diabetes, chronic kidney disease, and colorectal cancer).[2–6]

Osteoporosis is a skeletal disease characterised by low bone mineral density (BMD) and microarchitectural disruption, with a resulting increase in bone fragility and susceptibility to fractures.[7] Osteoporosis is a public health problem due to the high cumulative rates of fractures with advancing age. For example, in the Global Longitudinal Study of Osteoporosis in Women, involving 60 393 non-institutionalised women aged ≥55 years, the proportion of incident osteoporotic hip fractures increased more than fivefold with age, from ~7% among women aged 55–59 years to ~35% among those aged ≥85 years.[8] Notably, hip fractures are the most serious of all osteoporotic fractures, as they are strongly associated with an increased risk of morbidity and mortality, as well as with high healthcare costs.[9] Identification of novel and potentially modifiable risk factors for osteoporosis is therefore a key issue in clinical practice.

Recently, the existence of a possible association between NAFLD and osteoporosis has created considerable scientific interest.[10] Several observational cross-sectional or case-control studies have examined the association between imaging-defined or biopsy-proven NAFLD and BMD measurement in middle-aged and elderly individuals.[11–22] However, the findings from such studies have been inconsistent or conflicting so far, with some studies reporting a significant association between NAFLD and reduced BMD, especially in Chinese men,[13,15,18] some studies reporting a significant association between NAFLD and increased BMD,[12,16,19] and with others failing to find any significant association between NAFLD and BMD.[11,14,17,20] Moreover, it remains uncertain whether an association also exists between low BMD and severity of NAFLD. Recently, some large cross-sectional studies of Chinese middle-aged and elderly individuals also showed that ultrasound-diagnosed NAFLD was significantly associated with a self-reported history of osteoporotic fractures in older men, but not in women.[21,22] Similar to observations in patients with obesity or type 2 diabetes,[23] these latter findings raise the possibility that BMD might underestimate the long-term risk of osteoporotic fractures in individuals with NAFLD (who are often obese or have diabetes).

Therefore, we herein report the results of a comprehensive systematic review and meta-analysis of observational studies that have examined the association of NAFLD (as detected by imaging or histology) with either BMD measurements at different skeletal sites or a history of osteoporotic fractures in middle-aged and elderly individuals. Given the clinical and cost-effectiveness impact of osteoporosis, clarification of the magnitude of the potential adverse effect(s) of NAFLD on bone health might have relevant clinical implications for the prevention, diagnosis, and treatment of this common skeletal disease.