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J Obes Metab Syndr 2024; 33(2): 108-120

Published online June 30, 2024 https://doi.org/10.7570/jomes24004

Copyright © Korean Society for the Study of Obesity.

Effects of Metabolic Dysfunction-Associated Steatotic Liver Disease on Bone Density and Fragility Fractures: Associations and Mechanisms

Shaghayegh Khanmohammadi1,2, Mohammad Shafi Kuchay3,*

Author Affiliations

1Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Science, Tehran; 2School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; 3Division of Endocrinology and Diabetes, Medanta The Medicity Hospital, Gurugram, India

Correspondence to:
Mohammad Shafi Kuchay
https://orcid.org/0000-0003-3933-6137
Division of Endocrinology and Diabetes, Medanta The Medicity Hospital, Sector 38, Gurugram 122001, Haryana, India
Tel: +91-9717390365
E-mail: drshafikuchay@gmail.com

Received: January 24, 2024; Reviewed : February 23, 2024; Accepted: February 27, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Metabolic dysfunction-associated steatotic liver disease (MASLD) has profound adverse effects on bone health and homeostasis. MASLD appears to be associated with changes in bone mineral density (BMD) and fracture rate. However, the data are ambiguous and conflicting. Although several studies have shown that children and adolescents with MASLD have decreased BMD, the data on the prevalence of fragility fractures among children are scarce. In adults, increasing evidence suggests that MASLD decreases BMD and increases the risk of fragility fractures, which appears to be due to deterioration of bone architecture in addition to a decrease in BMD. Effects of MASLD on bone health may also be age- and race-specific. MASLD does not seem to increase fracture risk in children and adolescents but increases the risk of fractures in elderly men, especially those of Asian origin. From a mechanistic perspective, bone remodeling is a continuous process between osteoblasts (bone-forming) and osteoclasts (bone-resorbing), with any imbalance resulting in metabolic bone disease. In individuals with MASLD, loss of anabolic insulin receptor signaling (insulin resistance) in osteoblasts and increased receptor activator of nuclear factor κB (RANK)/RANK ligand signaling in osteoclasts (proinflammatory cytokines) swings the pendulum toward accelerated bone loss. These processes are further complicated by the concomitant presence of obesity, type 2 diabetes mellitus, or sarcopenia in individuals with MASLD. This study reviews the current literature associated with the effects of MASLD on BMD and fragility fractures in children/adolescents and adults. This review also discusses the pathomechanisms that link MASLD with changes in BMD and fragility fractures.

Keywords: Metabolic dysfunction associated steatotic liver disease, Bone density, Fracture, Osteoporosis

INTRODUCTION

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Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic condition that affects approximately one-quarter of the global population.1 MASLD encompasses a wide range of liver disorders characterized by excessive accumulation of fat in the liver. The spectrum varies from simple steatosis (fatty liver) to metabolic dysfunction-associated steatohepatitis (MASH) and, in severe cases, cirrhosis.2 Several mechanisms, such as insulin resistance, dysregulated lipid metabolism, oxidative stress, low-grade inflammation, altered gut microbiota, and increased intestinal permeability, are involved in the pathogenesis of MASLD.3,4 MASLD is closely associated with several diseases, such as type 2 diabetes mellitus (T2DM), obesity, and cardiovascular diseases. A growing body of evidence suggests that MASLD may affect bone health both quantitatively and qualitatively, increasing the risk of fractures.5,6

Osteoporosis is characterized by low bone mineral density (BMD) and microarchitectural deterioration, which is a substantial public health concern due to its association with increased risk of fragility fractures and mortality. Low BMD has emerged as a significant public health concern since it has imposed a substantial burden on global economic, social, and health development.7 Based on a meta-analysis conducted in 2021, approximately 23% of women are affected by osteoporosis worldwide.8 Several factors, such as age, hormonal changes, and inadequate nutrition, are associated with osteoporosis.9 However, MASLD may also play a role in the pathogenesis of osteoporosis.

Several systematic reviews and meta-analyses have demonstrated that MASLD is associated with osteoporosis and osteoporotic fractures in children and adult populations.5,10,11 Chronic low-grade inflammation, altered levels of adipokines and hormones, and vitamin D deficiency are among the suggested mechanisms through which MASLD may contribute to osteoporosis.12 However, there is controversy surrounding the association between MASLD and changes in BMD,5 which could stem from study populations, study designs, and the heterogeneity of MASLD itself. Therefore, additional longitudinal and large studies with diverse cohorts are required.

Understanding the association between MASLD and bone health is important because of the substantial clinical implications. Furthermore, understanding the role of MASLD in the pathogenesis of osteoporosis could contribute to the development of new treatments. Thus, in this review, we aimed to evaluate the association between MASLD and bone health and discuss the main pathomechanisms using the current literature. When MASLD is severe, such as decompensated cirrhosis and end-stage liver disease, bone is affected significantly, leading to osteoporosis and increased fracture risk, known as hepatic osteodystrophy. Although MASLD is a continuum, encompassing steatosis, MASH, and compensated cirrhosis, in this review we will discuss its association with bone health rather than its effects in individuals with end-stage liver disease.

MASLD AND BMD IN CHILDREN/ADOLESCENTS

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BMD measures the amount of bone minerals in a certain bone volume, which can be used to evaluate fragility-fracture risk. The T-score compares the bone density of the patients with healthy, young individuals of the same sex. Osteoporosis is defined by a negative T-score of 2.5 or less at the femoral neck. In contrast, the Z-score compares the bone density of the patient with people of the same age and sex. A negative Z-score of 2.5 or less should increase suspicion of secondary osteoporosis.13

The prevalence of obesity and its consequences, such as T2DM and MASLD, is increasing in children and adolescents. Recent studies suggest that children and adolescents with MASLD may have lower BMD.14,15 A meta-analysis conducted by Mantovani et al.10 in 2019 on 632 children showed that those with MASLD have lower BMD than the non-MASLD group, and the severity of MASLD was also associated with reduced BMD. Another meta-analysis conducted by Sun et al.11 on 453 obese adolescents in 2019 showed that BMD and Z-score were lower in obese adolescents with MASLD than in the control group. Most studies on obese children/adolescents have shown that BMD was lower in individuals with MASLD compared to the non-MASLD group (Table 1).16-19 Some studies have demonstrated that simple steatosis might not affect BMD, while those with MASH might have reduced BMD.17,18 However, in a cross-sectional study conducted in Korea, the age-matched BMD Z-scores did not exhibit significant differences among simple steatosis, MASH, and control groups.20 There is no evidence that MASLD in children and adolescents increases fracture rate. One of the main limitations of the studies on the association between MASLD and BMD in children with or without obesity is their design. All studies on children have been conducted as cross-sectional or case-control studies, which are unable to establish causality. Additionally, the studies had small sample sizes; therefore, more studies with larger sample sizes and cohort designs are required.

MASLD AND BMD IN ADULTS

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Compared to studies on children/adolescents, a higher number of studies has investigated the association between MASLD and reduced BMD or osteoporosis in adults. In 2019, Mantovani et al.5 conducted a meta-analysis on 30,041 individuals to evaluate the association between MASLD and BMD. Their results showed that there was no association between BMD at different skeletal sites and MASLD. However, higher odds (2.10; 95% confidence interval [CI], 1.36 to 3.25) of osteoporotic fractures, especially in older Chinese men, were seen in individuals with MASLD compared to the non-MASLD group.5 This meta-analysis indicates that MASLD may affect bone quality (deteriorate architecture) rather than bone quantity (BMD). Furthermore, the meta-analysis suggested that the effect of MASLD on the skeleton may be sex- and race-specific. The meta-analysis did not report increased odds of osteoporotic fractures in Chinese women and individuals of other races. In another meta-analysis with a larger sample size of 281,136 individuals conducted by Su et al.21 in 2023, MASLD was associated with increased odds of osteoporosis (risk ratio [RR], 1.28) and osteoporotic fractures (RR, 1.17), especially in Asian populations. However, in non-Asian populations, no association between MASLD and osteoporosis or osteoporotic fractures was found.21

Among cohort studies, all except one showed that MASLD was associated with low BMD and a higher incidence of osteoporosis.22-24 Also, the difference was more noticeable in women compared to men.23,24 In a retrospective cohort study by Sung et al.,25 the presence of MASLD in females was associated with a reduced risk of decrease in BMD, even after accounting for confounding factors through adjustment. However, because most patients included in their study were early-diagnosed MASLD patients, it would have been difficult to detect the unfavorable effect of MASLD on BMD.25 In case-control studies, MASLD,26 notably MASH27,28 but not simple steatosis,28 was associated with low BMD. Among cross-sectional studies (Table 2), there are controversial results regarding the association of MASLD with BMD score. In two studies, BMD was not associated with MASLD.29,30 Also, a large study in the general United States population failed to demonstrate any association between steatosis and liver fibrosis with reduced BMD.31 But in other studies, MASLD patients had lower BMD scores than non-MASLD patients.32-37 Interestingly, in one study, MASLD had a beneficial effect on lumbar BMD in postmenopausal women.38 Yoon et al.39 showed that, among men with MASLD, those with a high or intermediate probability of advanced fibrosis, according to the fibrosis-4 (FIB-4) score, exhibited a significantly higher rate of decline in total hip BMD compared to those with low scores. Differences in race, sample size, confounding factors, and MASLD severity could explain this controversy. Several studies have demonstrated that the association between MASLD and BMD was confounded by other factors. In a large community-based cohort of 2,253 participants, an inverse association existed between liver fat (as measured by computed tomography scan) and BMD. However, the association was no longer significant after adjusting for body mass index or visceral adiposity.40 Studies on patients with T2DM showed no association between MASLD and BMD after adjustment for confounding factors.41,42 However, in a study by Yu et al.,41 postmenopausal women with advanced liver fibrosis (increased FIB-4 score) showed an increased risk of osteoporosis compared to those with no liver fibrosis.

MASLD AND FRAGILITY FRACTURES

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Emerging evidence suggests a potential association between MASLD and osteoporotic fractures (Tables 2 and 3). Research with different study designs has demonstrated a significant association between MASLD and bone fracture.5,21,23,43-48 A large cross-sectional study showed that MASLD with fibrosis was significantly associated with a higher 10-year major osteoporotic and hip fracture probability in Korean men aged ≥50 years. It also demonstrated that the positive association was more profound in individuals with sarcopenia.45 In a nationwide population-based cohort study of 10,678 NAFLD patients and 99,176 non-MASLD controls by Wester and Hagström,47 the risk of fracture in the MASLD group was higher than in the non-MASLD group (hazard ratio, 1.11; 95% CI, 1.05 to 1.19). However, the 5-year risk of fracture was comparable in the two groups. The association between MASLD and osteoporotic fractures is multifactorial and influenced by various factors, including age, obesity, lifestyle factors, and comorbidities. Notably, gender differences have been observed in the association between MASLD and osteoporotic fractures. Some studies suggest a stronger association in men,46 while others report no significant gender-specific differences or a stronger association in women.23 However, in a meta-analysis conducted in 2018, the association between MASLD and bone fractures in older Chinese men was prominent,5 and in a more recent meta-analysis conducted in 2023, the association between MASLD and osteoporotic fractures was only detected in an Asian population.21 These discrepancies highlight the need for further research to improve understanding of the complex interplay between MASLD, gender, race, and osteoporotic fracture risk.

MECHANISM OF MASLD AFFECTING BONE INTEGRITY

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MASLD affects bone through several mechanisms. The effect of MASLD on skeletal integrity may vary as the MASLD progresses from simple steatosis to advanced fibrosis and cirrhosis. The net effect of MASLD on bone mass is the sum total of its effects on the two basic bone processes: osteoblastic activity leading to bone formation and osteoclastic activity leading to bone loss. Insulin receptor (InsR) signaling is an anabolic signal in bone, increasing osteoblastic activity and, consequently, bone mass.49,50 On the other hand, increased circulatory and tissue proinflammatory cytokines, especially interleukin (IL)-1α, IL-6, and tumor necrosis factor α (TNF-α), released by adipose tissue and MASLD-related fibrosed liver increase osteoclastic activity by modifying the receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL)/osteoprotegerin pathway, decreasing bone mass.51-53 The duration and predominance of one process or the other determines the net bone mass. This basic equation of osteoblastic and osteoclastic activity is further influenced by a myriad of factors. For instance, insulin resistance in bone results in the loss of this anabolic stimulus and decreases bone mass. The development of insulin resistance (or loss of insulin sensitivity) is a gradual process that progresses at different paces in different organs. Therefore, at a given time, an individual may have mild to moderate to severe insulin resistance in bone. The amount of proinflammatory cytokines, which determines osteoclastic activity, also varies. Although it appears to be a continuum, three scenarios may be proposed for simplicity. (1) In a given individual, at a particular time, when insulin resistance is mild, and the proinflammatory cytokine level is low, anabolic InsR signaling predominates, resulting in increased bone mass. (2) When insulin resistance and proinflammatory cytokines are moderate, anabolic InsR signaling and osteoclastic activity are balanced, resulting in no net bone change. (3) When insulin resistance is severe, leading to almost complete loss of anabolic InsR signaling, and proinflammatory cytokines are in excess, exaggerated osteoclastic activity occurs and results in accelerated bone loss (Fig. 1). Indeed, a cross-sectional study of a nationally representative population (Korea) demonstrated that in the lowest quartile of homeostatic model assessment for insulin resistance, the fasting insulin level was positively associated with BMD. However, as the insulin resistance increased, the fasting insulin was inversely associated with BMD, and this relationship became more significant as the degree of insulin resistance increased.54 In a recent study, Shieh et al.55 demonstrated that the longitudinal associations of insulin resistance with BMD are nonlinear. They demonstrated that low, decreasing insulin resistance might be beneficial for BMD preservation (attenuates BMD loss). In contrast, high, increasing insulin resistance might be deleterious to BMD (accelerates BMD loss).55 The basic equation of anabolic InsR signaling and proinflammatory cytokine-induced osteoclastic activity is further influenced by a number of conditions, such as obesity, T2DM, sarcopenia, and the diminished growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. These conditions are commonly associated with MASLD. Obesity, on the one hand, may increase bone mass by mechanical loading and increased amounts of estrogen in the adipose tissue,56 but, on the other hand, may cause bone loss by increasing the amount of proinflammatory substances.57,58 Among several proinflammatory cytokines, TNF-α is a pivotal cytokine that contributes to the development and progression of MASH.59 Plasma TNF-α concentrations are elevated in individuals with MASH. TNF-α also induces osteoclastogenesis and bone loss through pathways that are RANKL-dependent or -independent.60,61 T2DM may not affect bone mass but impairs bone quality due to the accumulation of advanced glycation end-products, leading to increasing fracture risk at a relatively higher BMD compared to people without T2DM.62,63 Sarcopenia (loss of skeletal muscle mass and strength) is associated with MASLD-related fibrosis.64-66 Fibrotic liver fails to dispose of ammonia efficiently, which then is diverted to the skeletal muscle for disposal.65 The skeletal muscle controls this excess ammonia using alpha-ketoglutarate (AKG), causing its relative deficiency. The deficiency of AKG leads to mitochondrial dysfunction, the generation of reactive oxygen species, and muscle breakdown.65 Sarcopenia increases fracture risk by increasing the risk of falls in older individuals. GH and IGF-1 levels are reduced in obesity and are also associated with MASLD, especially when MASLD progresses to advanced fibrosis and cirrhosis (Fig. 2).67-70 In that scenario, bone osteoclastic activity further increases and InsR signaling further decreases, leading to further bone loss.71 In conclusion, in a particular individual with MASLD, net bone change depends on several factors, such as degree of insulin resistance, amount of proinflammatory cytokines, and the presence or absence of other comorbid conditions, such as obesity, T2DM, or sarcopenia. Therefore, at the epidemiological level, it may be safe to conclude that MASLD affects bone health negatively; this conclusion is not as clear at the individual level.

CONCLUSION

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Although a large body of evidence suggests that MASLD is associated with reduced BMD and increased fragility fractures in adults, data involving children and adolescents are scarce. Even in adults, newer and well-designed clinical studies are required to further establish the association between MASLD and reduced BMD and increased fractures. Some evidence indicates that the association between MASLD and increased fracture rate might be sex- and race-dependent, as shown by an increase in fracture rate among Asian men with MASLD. Mechanistically, several factors deteriorate bone integrity. On the one hand, there is a progressive increase in insulin resistance, leading to loss of anabolic InsR signaling. On the other hand, a progressive increase in proinflammatory cytokines increases RANK/RANKL signaling, leading to accelerated bone resorption. In addition, obesity, T2DM, and sarcopenia, common accompaniments of MASLD, further impair bone quantity and quality. Future research should delineate the exact effects of loss of insulin signaling (insulin resistance) in individuals with MASLD on bone mass and fracture risk. Another area to explore is whether cytokines elaborated from fibrosed livers in MASLD can directly affect bone RANK/RANKL signaling and bone resorption.

AUTHOR CONTRIBUTIONS

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Study concept and design: MSK; acquisition of data: SK and MSK; drafting of the manuscript: SK and MSK; critical revision of the manuscript: MSK; administrative, technical, or material support: MSK; and study supervision: MSK.

Figures

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Fig. 1. Anabolic insulin receptor (InsR) signaling in osteoblasts versus proinflammatory cytokine-induced osteoclastic activity. In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), the major forces determining bone formation and bone resorption are anabolic InsR signaling in osteoblasts and proinflammatory cytokine-induced osteoclastic activity, respectively. In early MASLD (steatosis stage), mild insulin resistance and low levels of proinflammatory cytokines may cause the anabolic InsR signaling to predominate in osteoblasts, resulting in net bone gain. When insulin resistance (leading to moderate loss of anabolic InsR signaling) and the level of inflammatory cytokines (leading to increased osteoclastic activity) are moderate, the two processes may balance each other, resulting in no net bone change. Last, when insulin resistance worsens (mild/no anabolic InsR signaling) and higher amounts of proinflammatory cytokines are present, osteoclastic activity may predominate, resulting in net bone loss. Advanced fibrosis and cirrhosis stages are associated with predominant osteoclastic activity. GH, growth hormone; IGF-1, insulin-like growth factor-1; MASH, metabolic dysfunction-associated steatohepatitis.
Fig. 2. Shared risk factors for metabolic dysfunction-associated steatohepatitis (MASH) and osteoporosis. Adipose tissue dysfunction (adiposopathy) gives rise to adipose tissue insulin resistance and proinflammatory cytokines. Excess free fatty acids (FFAs) from dysfunctional adipose tissue are diverted to the liver, which ultimately is overwhelmed. This results in the storage of excess FFAs as triglycerides in hepatocytes (steatosis) and gives rise to hepatic insulin resistance and MASH. Proinflammatory cytokines (from adipose tissue and fibrosed liver) also result in muscle loss (sarcopenia) and bone loss (osteoporosis). T2DM, type 2 diabetes mellitus.

Tables

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A summary of studies on the association between MASLD and BMD in children/adolescents


Author (year) Country Study design Sample size (F) Age (yr) NAFLD diagnosis Findings
Pirgon et al. (2011)19 Turkey Cross-sectional 82 (45) 12.3±1.7 US The NAFLD group had lower BMD-SDS scores than the non-NAFLD group.
In the group of obese individuals with NAFLD, there was a positive correlation between BMD-SDS and BMI-SDS and a negative correlation between BMD-SDS and HOMA-IR.
Pardee et al. (2012)18 USA Case-control NAFLD: 38 (5);
non-NAFLD: 38 (5)		 13±2 Liver biopsy Obese children with NAFLD had a lower BMD Z-score than the control group.
Among NAFLD children, the BMD Z-score was significantly lower in the NASH group than in the non-NASH group.
Pacifico et al. (2013)17 Italy Case-control NAFLD: 44 (20);
non-NAFLD: 44		 12.5±1.8 Liver biopsy In comparison to non-NAFLD obese children, obese children with NAFLD exhibited a significantly lower lumbar spine but not whole-body BMD Z-score.
Comparing NAFLD children with NASH to those without NASH, significantly lower BMD Z-scores at the lumbar spine, as well as whole-body BMD Z-scores, were observed in the NASH group.
Chang et al. (2015)20 Korea Cross-sectional 94 (28) 11.3±2.9 (6.6–19.3) US There was no significant difference in levels of vitamin D between study groups (control, NASH, and simple steatosis).
While significant differences in BMDs were observed, the age-matched BMD Z-scores did not exhibit significant differences among the three groups.
Labayen et al. (2018)15 Spain Cross-sectional 115 (64) 10.6±1.1 MRI BMD was lower in children with NAFLD compared to the control group.
Higher liver fat was correlated with lower BMD without regard to confounders.
Mosca et al. (2018)16 Italy Cross-sectional 34 13.8±1.1 (11.0–16.8) Liver biopsy Individuals with NASH had lower BMD than individuals without NASH.
The PNPLA3 CG+GG genotypes were found to have independent associations with NASH.
Additionally, low BMD was found to be associated with both the PNPLA3 CG+GG genotypes and the steatosis, activity, and fibrosis score.
Mantovani et al. (2019)10 Italy Meta-analysis 632 12.8 - In children/adolescents with NAFLD, lumbar or whole-body BMD was reduced compared to the non-NAFLD group.
Sun et al. (2019)11 China Meta-analysis 453 - - BMD and Z-score were lower in obese children with NAFLD than the control group.
Chun et al. (2021)14 USA Cross-sectional 235 (81) 12.5±2.5 (8–17) MRI Lower BMD Z-score was associated with higher liver fat (hepatic steatosis).

Values are presented as mean±standard deviation or mean±standard deviation (range) unless otherwise indicated.

MASLD, metabolic dysfunction-associated steatotic liver disease; BMD, bone mineral density; NAFLD, nonalcoholic fatty liver disease; US, ultrasonography; SDS, standard deviation score; BMI, body mass index; HOMA-IR, homeostatic model assessment for insulin resistance; NASH, nonalcoholic fatty liver disease; MRI, magnetic resonance imaging; PNPLA3, patatin-like phospholipase domain-containing protein 3; CG, heterozygous variant; GG, homozygous variant.

A summary of studies on the association between MASLD and BMD in adults


Author (year) Country Study design Sample size (F) Age (yr) NAFLD diagnosis Findings
Yang et al. (2016)33 Korea Cross-sectional 859 (0) 45±7 (20–69) US After adjusting for BMI and HOMA-IR, NAFLD demonstrated a negative association with right-hip BMD (OR, 0.797; 95% CI, 0.645–0.984) and serum osteocalcin (OR, 0.948; 95% CI, 0.910–0.988).
Lee et al. (2016)38 Korea Cross-sectional 6,634 (3,328) >40 US Moderate or severe NAFLD exhibited a harmful effect on femoral neck BMD in men.
Moderate or severe NAFLD had a beneficial effect on lumbar spine BMD in postmenopausal women.
Xia et al. (2016)32 China Cross-sectional 1,659 (904) 62 (56–72) US After accounting for confounding factors, the association between liver fat content and ALT with BMD and bone formation biomarkers persisted in men but not in postmenopausal women.
However, in cases where both NAFLD and elevated ALT were present, a notable synergistic effect was observed, leading to a significant deterioration of BMDs across all bone sites.
Chen et al. (2018)22 Taiwan Retrospective cohort NAFLD: 4,318; control: 17,272 44.94 (IQR, 35.60–54.94 and 35.60–54.92) Mixed (defined by ICD-9-CM code 571.8) NAFLD group had a 1.35-fold increased likelihood of developing subsequent osteoporosis compared to those without NAFLD (95% CI, 1.20–1.53).
Lee et al. (2018)37 Korea Cross-sectional 3,739 (3,739) 50–59 US Women with NAFLD had significantly lower mean BMD than women without NAFLD in the lumbar spine and femur neck.
Mantovani et al. (2019)42 Italy Cross-sectional 77 (77) 72±8 US The three patient groups (fibrosis, NAFLD without fibrosis, and control) exhibited similar values of BMD after adjustments.
Patients diagnosed with NAFLD and significant fibrosis demonstrated significantly elevated sclerostin levels and decreased levels of DKK-1, RANKL, and sCTX in comparison to the other groups.
Umehara (2018)29 USA Cross-sectional 6,089 (4,131) 40–75 US After adjustments, there was no association between NAFLD and BMD. Among the NAFLD group, higher ALT was associated with lower BMD scores.
Mantovani et al. (2019)5 Italy Meta-analysis 30,041 (19,353) - - There was no association between BMD at different skeletal sites and NAFLD.
Higher odds (2.10; 95% CI, 1.36–3.25) of osteoporotic fractures, especially in older Chinese men, were seen in patients with NAFLD compared to the non-NAFLD group.
Shen et al. (2020)24 China Longitudinal cohort study 1,064 (313) 51.2±9.9 US NAFLD is associated with an elevated risk of low BMD (HR, 2.30; 95% CI, 1.81–2.91).
Non-invasive fibrosis markers of NAFLD were positively associated with an escalating incidence of low BMD.
Individuals who were obese and women with NAFLD at the initial assessment exhibited a higher likelihood of low BMD.
Sung et al. (2020)25 Korea Retrospective cohort 4,536 (3,530) - US In females, the presence of NAFLD was associated with a reduced risk of a decrease in BMD, even after accounting for confounding factors through adjustment (in certain BMI groups).
Ciardullo et al. (2021)31 USA Cross-sectional 1,784 (859) ≥50 VCTE Liver steatosis and fibrosis had no significant association with the femoral DXA-based diagnosis of osteopenia or osteoporosis in the United States population aged 50 years and older.
Li et al. (2021)40 USA Cross-sectional 3,462 (1,177) 51.2±10.7 CT The relationships between NAFLD, BMD, and vertebral strength were influenced by factors such as BMI and VAT, confounding the results. However, NAFLD and vertebral cross-sectional area had an association in adjusted models.
Yoon et al. (2021)39 Korea Cross-sectional NAFLD: 888;
non-NAFLD: 1,735;
total: 2,623 (1,801)		 58.7±7.3 US At baseline, the total hip BMD in NAFLD men was higher than that in the non-NAFLD group, but no difference was seen in women.
In the propensity score-matched cohort, the longitudinal analysis revealed no significant difference in the rate of BMD decline between the two groups.
Among men with NAFLD, those with a high or intermediate probability of advanced fibrosis, according to the FIB-4 score, exhibited a significantly higher rate of decline in total hip BMD compared to those with low scores.
Yu et al. (2022)41 China Cross-sectional 1,243 (589) >50 US After adjusting for age, BMI, and gender, BMD between the NAFLD group and the non-NAFLD group was comparable.
However, in postmenopausal women, the FIB-4 high-risk group showed an increased risk of osteoporosis (OR, 4.41; 95% CI, 1.04–18.70) compared to the low-risk group.
Women with high-risk NFS also had an elevated risk of osteoporosis (OR, 5.98; 95% CI, 1.40–25.60) compared to the low-risk group.
Loosen et al. (2022)23 Germany Retrospective cohort NAFLD: 50,689 (23,114);
control: 50,689		 59.5±13.9 Mixed (diagnosed in general practices) The incidence of osteoporosis and bone fracture was higher in patients with NAFLD than in the control group.
The difference was particularly noticeable among women as opposed to men, and it was observed across all age groups over 50 years old.
Xie et al. (2022)34 China Cross-sectional 1,980 20–59 VCTE In individuals aged 20 to 59, a detrimental association was found between NAFLD and BMD.
A positive correlation was observed between BMD and advanced fibrosis and cirrhosis.
Barchetta et al. (2023)35 Italy Cross-sectional 1,872 (1,483) 44.6±14.1 (18–65) Proton magnetic resonance spectroscopy FIB-4 was higher in obese patients with osteopenia/osteoporosis than those with normal BMD.
FIB-4 was negatively associated with osteocalcin and IGF-1 levels, which were decreased in the presence of low BMD.
Association of FIB-4 with bone fragility: OR, 3.8; 95% CI, 1.5–9.3; AUROC, 0.842; 95% CI, 0.795–0.890.
Hansen et al. (2023)30 Denmark Cross-sectional 147 (108) 45.3±12.5 (18–76) Liver biopsy There was no association between NAFLD and BMD of the lumbar spine and hip.
Hassan et al. (2023)36 Egypt Cross-sectional 100 (40) ≥18 US BMD was decreased in NAFLD patients compared to the control group.
Su et al. (2023)21 Taiwan Meta-analysis 281,136 - - NAFLD was associated with decreased BMD and increased risks of osteoporosis (RR, 1.28; 95% CI, 1.08–1.52) and osteoporotic fractures (RR, 1.17; 95% CI, 1.00–1.37).
In non-Asian populations, no association between NAFLD and BMD, osteoporosis, or osteoporotic fracture was found.

Values are presented as mean±standard deviation (range), median (range), range, or mean±standard deviation unless otherwise indicated.

MASLD, metabolic dysfunction-associated steatotic liver disease; BMD, bone mineral density; NAFLD, nonalcoholic fatty liver disease; US, ultrasonography; BMI, body mass index; HOMA-IR, homeostatic model assessment for insulin resistance; OR, odds ratio; CI, confidence interval; ALT, alanine aminotransferase; IQR, interquartile range; ICD-9-CM, International Classification of Disease; DKK-1, dickkopf related protein 1; RANKL, receptor activator of nuclear factor κB ligand; sCTX, secreted C-telopeptide of type 1 collagen; HR, hazard ratio; VCTE, vibration controlled transient elastography; DXA, dual-energy X-ray absorptiometry; CT, computed tomography; VAT, visceral adipose tisssue; FIB-4, fibrosis-4; NFS, NAFLD fibrosis score; IGF-1, insulinlike growth factor-1; AUROC, area under the ROC curve; RR, risk ratio.

A summary of studies on the association between MASLD and bone fractures


Author (year) Country Study design Sample size (F) Age (yr) Findings
Li et al. (2012)46 China Cross-sectional 7,797 (5,356) 58.4±9.8 Osteoporotic fractures were more common in men (OR, 2.53; 95% CI, 1.26–5.07) but not in women with NAFLD compared to the control group.
Wang et al. (2018)48 China Cross-sectional 3,657 (1,709) 55–85 In multivariate analysis, NAFLD was associated with risk of fracture in men (OR, 1.86; 95% CI, 1.06–3.27) but not in women (OR, 1.05; 95% CI, 0.74–1.48).
NAFLD was significantly associated with osteoporotic fracture risk in men without high TG, low HDL-C, and high LDL-C.
Mantovani et al. (2019)5 Italy Meta-analysis 30,041 (19,353) - There was no association between BMD at different skeletal sites and NAFLD. Higher odds (2.10; 95% CI, 1.36–3.25) of osteoporotic fractures, especially in older Chinese men, were seen in patients with NAFLD compared to the non-NAFLD group.
Lee et al. (2021)45 Korea Cross-sectional 2,525 (0) ≥50 The risk of 10-year major osteoporotic and hip fracture was higher in the NAFLD group with fibrosis compared to the non-NAFLD group. This association was more profound in patients with sarcopenia.
Kim et al. (2023)44 Korea Cohort (health check-ups) 180,519 (78,255) ≥20 Higher fatty liver index was associated with a higher risk of fracture.
Loosen et al. (2022)23 Germany Retrospective cohort NAFLD: 50,689 (23,114);
control: 50,689		 59.5±13.9 The incidence of osteoporosis and bone fracture was higher in patients with NAFLD than in the control group.
The difference was particularly noticeable among women as opposed to men, and it was observed across all age groups over 50 years old.
Wester et al. (2022)47 Sweden Cohort NAFLD: 10,678 (5,125);
non-NAFLD: 99,176 (48,024)		 55 The risk of fracture in the NAFLD group was higher than in the non-NAFLD group (HR, 1.11; 95% CI, 1.05–1.19). However, the 5-year risk of fracture was comparable in the two groups.
Chung et al. (2023)43 Korea Cohort (Korean health insurance system) 3,384,457 (1,699,901) ≥50 Higher fatty liver index was associated with a higher risk of hip and vertebral fracture.
Su et al. (2023)21 Taiwan Meta-analysis 281,136 - NAFLD was associated with decreased BMD and increased risks of osteoporosis (RR, 1.28; 95% CI, 1.08–1.52) and osteoporotic fractures (RR, 1.17; 95% CI, 1.00– 1.37).
In non-Asian populations, no association between NAFLD and BMD, osteoporosis, or osteoporotic fracture was found.

Values are presented as mean±standard deviation or range unless otherwise indicated.

MASLD, metabolic dysfunction-associated steatotic liver disease; OR, odds ratio; CI, confidence interval; NAFLD, nonalcoholic fatty liver disease; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; BMD, bone mineral density; HR, hazard ratio; RR, risk ratio.

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