Liver function linked to bone health: A bibliometric of the liver-bone axis

Abstract

BACKGROUND

The liver exerts profound influence on skeletal health, while osseous tissues reciprocally modulate hepatic function. This bidirectional metabolic axis between these two organ systems plays a pivotal role in both physiological homeostasis and pathological states.

AIM

To investigate and analyze the literatures on liver-bone axis using bibliometrics.

METHODS

A comprehensive literature search pertaining to the liver-bone axis was conducted using the Science Citation Index Expanded within the Web of Science Core Collection. Subsequently, visualization and bibliometric analyses were performed utilizing VOSviewer (version 1.6.20), Citespace (version 6.2.R4), and the R programming language.

RESULTS

This comprehensive analysis encompasses 855 publications, comprising 694 articles and 161 reviews, authored by 4988 researchers from 425 institutions across 61 countries. The United States and China emerge as the leading nations in terms of publication volume. The University of California system stands out as the most influential institution in liver-bone axis research. Guanabens N is identified as the most prolific author in this field. The annual increase in publications related to the liver-bone axis underscores its growing prominence as a research focus. The study highlights key areas of investigation, including osteoporosis, bone metabolism, non-alcoholic fatty liver disease, and insulin-like growth factor-1, which represent both current and prospective hot topics within this domain.

CONCLUSION

This investigation employs bibliometric methodologies to conduct a systematic analysis of liver-bone axis literature spanning from 2001 to 2024. The exponential growth in publications over the past two decades underscores the significance of synthesizing research outcomes in this domain. Through rigorous statistical analyses, we delineate fundamental contributions to the field while providing strategic direction for emerging scholars. Furthermore, we illuminate current research trajectories and identify promising future investigative directions. Investigation of the liver-bone axis enhances our comprehension of inter-organ communication networks. Conceptualizing these organs as an integrated system provides profound insights into pathophysiological mechanisms and disease management strategies. This paradigm not only facilitates the development of sophisticated diagnostic modalities but also catalyzes the discovery of novel therapeutic agents targeting these mechanistic pathways, thereby advancing our capacity to diagnose and treat hepatic and skeletal disorders.

Key Words: Non-alcoholic fatty liver disease; Bone metabolism; Liver; Osteoporosis; Citespace; VOSviewer

Core Tip: This investigation employs bibliometric methodologies to conduct a systematic analysis of liver-bone axis literature. Non-alcoholic fatty liver disease demonstrates particularly strong citation, which is poised to remain a central focus in future investigations of the liver-bone axis. Our research offers insights into inter-organ communication, which may inspire new approaches for the diagnosis and treatment of hepatic and skeletal disorders.

INTRODUCTION

The liver is an important metabolic organ that controls human energy metabolism, which acts as a metabolic hub connecting various tissues, including skeletal muscle and adipose tissue[1]. Concurrently, the liver functions as a crucial endocrine organ, secreting hepatokines that modulate the activities of various distal tissues and organs, thereby orchestrating systemic metabolic processes[2]. Hepatic dysfunction specifically leads to alterations in skeletal metabolic homeostasis, thereby underscoring the intricate interplay between these two physiological systems, with a heightened focus on the skeletal system garnering increasing scrutiny. Up to 50% of patients with chronic liver disease (CLD) experience bone loss and fractures, a condition referred to as hepatic osteodystrophy (HOD)[3]. Non-alcoholic fatty liver disease (NAFLD) can lead to a reduction in bone mineral density due to vitamin D deficiency, chronic inflammation, and gut microbiota dysbiosis[4].

Bone performs crucial endocrine functions by secreting factors such as fibroblast growth factor 23, osteocalcin (OCN), lipocalin-2, and other bone-derived factors known as osteokines, which are involved in phosphate and energy metabolism[5]. Serum amyloid A3, a lipid metabolism-related factor secreted by bone, suppresses the expression of cholesterol 7α-hydroxylase and suppresses the conversion of cholesterol to bile acids[6]. OCN, synthesized by osteoblasts during bone formation, plays a role in reducing visceral fat accumulation and decreasing fat storage in the liver[7]. Moreover, osteokines can influence or reflect the progression of liver diseases. Transforming growth factor β (TGF-β) is one of the most abundant factors in bone, secreted by osteoblasts and osteoclasts in its latent form[3]. It has been shown that TGF-β promotes liver fibrosis by activating hepatic stellate cells and facilitating their transformation into myofibroblasts. Moreover, TGF-β exhibits a dual role in hepatocellular carcinoma (HCC), suppressing tumor growth in the early stages while promoting tumor progression at later stages[3,8]. Sclerostin, an inhibitor of the wingless-type signaling pathway that impedes bone formation, is associated with liver function and fat deposition in alcoholics[9]. A signaling axis exists between the liver and bone at both the metabolic and molecular levels, known as the “liver-bone axis”, which may offer novel insights into the prevention, diagnosis, and treatment of liver and bone-related diseases through the investigation of the molecular mechanisms involved[10]. Although extensive studies have been conducted on the liver-bone axis, limitations persist due to an incomplete understanding of the molecular pathways, particularly regarding the relationship between tumor necrosis factor-α, interleukin-6, and osteoporosis, as well as the unclear role of insulin-like growth factor 1 (IGF-1) in liver disease-related bone metabolism[11].

Bibliometrics represents an interdisciplinary methodology that employs mathematical and statistical approaches to quantitatively analyze knowledge dissemination[12]. This analytical framework facilitates visual and performance-based evaluation of field-specific publications, offering researchers profound insights into research trajectories, focal points, and emerging trends. While bibliometric analyses have been extensively deployed across medical disciplines, including investigations of coronavirus disease 2019 (COVID-19), sepsis, and gastric cancer[13-15], no systematic bibliometric assessment has yet been conducted on liver-bone axis research. Thus, this study presents a comprehensive bibliometric analysis of liver-bone axis literature, elucidating the contemporary research landscape and seminal contributions to this field.

MATERIALS AND METHODS

Data sources and collection strategy

The data for this study were obtained from the Science Citation Index Expanded within the Web of Science Core Collection (WoSCC) database, which is one of the first broad-scope international bibliographic databases. To prevent errors from database updates, all article queries and filtering were completed on 30 September 2024. The query word is as follows: TS = “liver” and “bone metabolism” OR TS = “liver” and “bone mineral density” OR TS = “liver” and “bone mass” OR TS = “bone” and “liver” and “crosstalk” OR TS = “bone” and “liver” and “axis”. The time frame was from 1 January 2001 to 30 September 2024, and a total of 2534 publications were obtained. After restricting the language to English and the publication type to reviews and articles, 2404 articles underwent screening. After excluding retractions and duplicates, two reviewers individually examined the abstracts and content of the articles. In case of discrepancies in the screening results, a third reviewer was engaged for further evaluation. Ultimately, 855 eligible articles were included (Supplementary Table 1, Figure 1A).

Figure 1 Flowchart of the paper screening process and the number of papers and citations. A: Flowchart of the process of publication screening; B: Annual number of publications and citations related to the liver-bone axis. WOS: Web of Science.

Statistical analysis

The eligible articles were exported as text files in the “full record and cited references” format and then subjected to bibliometric analysis using Citespace (version 6.2.R4), VOSviewer (version 1.6.20), and Bibliometrix. Citespace is a data analysis tool for interactive and exploratory analysis of the evolution of scientific domains, spanning from single specialties to multiple interrelated scientific frontiers[16]. VOSviewer is a software tool for constructing and visualizing bibliometric maps based on network data[17]. Bibliometrix is an open-source package in the R software environment that supports three phases of bibliometric analysis as a comprehensive mapping tool[18].

RESULTS

Main information about data

This study collected 296 papers from 353 institutions across 61 countries, published in 365 journals, with an average of 35.63 publications per year. A total of 4988 individuals contributed to these papers, averaging 5.83 authors per article. Of the 855 papers analyzed, 694 were original research articles, and 161 were reviews. These publications have received a total of 27485 citations, with an average of 32.15 citations per article, and collectively referenced 18858 articles, averaging 22.06 references per article (Table 1).

Table 1 Main information about data.

Description	Results
Documents	855
Annual growth rate	3.43%
Document average age	35.63
Citations	27485
Average citations per document	32.15
Journals (Sources)	365
References	18858
Average references per document	22.06
Journals (References)	4046
Article	694
Review	161
Authors	4988
Co-authors per document	5.83
International co-authorships	15.91%
Countries	61
Institutions	425

Analysis of annual publication and citation

Temporal publication patterns serve as indicators of a field’s vitality, maturity, and developmental trajectory. Figure 1B delineates the chronological distribution of liver-bone axis publications from 2001 to 2024. Publications in the liver-bone axis field have shown annual growth, with an average growth rate of 3.43% (Table 1). Additionally, from 2001 to 2023, there has been a significant increase in citations for liver-bone axis-related articles, reflecting the growing academic focus in this area (Figure 1B). As of September 30, 2024, the cumulative publication count of 50 manuscripts approaches the entire 2023 output, suggesting that 2024 is poised to exceed the previous year’s publication volume. The period from 2001 to 2009 exhibited oscillatory publication patterns, followed by similar fluctuations during 2010-2020. However, there is a marked acceleration in publication frequency emerged post-2020. The rise be linked to the COVID-19 pandemic, which triggers immune and inflammatory responses that not only affect the lungs but can also impact various systems throughout the body, including the skeletal system. Patients with severe COVID-19 often experience skeletal complications, such as decreased bone density and an increased risk of fractures[19]. Given that the liver plays a crucial role in regulating immune and inflammatory responses, it may contribute significantly to these changes, sparking further investigation into the liver-bone axis. Additionally, severe COVID-19 patients often require prolonged bed rest, leading to bone mass loss and abnormal bone metabolism. This has heightened attention on the relationship between liver function and bone metabolism, facilitating increased research into the liver-bone axis. More importantly, interdisciplinary collaboration across fields such as hepatology, orthopedics, immunology, and endocrinology, along with advances in biomarker technology and high-throughput screening techniques, has enabled researchers to more efficiently identify and validate factors involved in liver-bone axis, thereby contributing to the rapid growth of liver-bone axis research.

Analysis of country

The map in Figure 2A shows that most research on the liver-bone axis is conducted in Europe, North America, and East Asia. Figure 2B illustrates the publication numbers by country. The United States has the highest number of publications (n = 214), followed by China (n = 168), Japan (n = 61), Italy (n = 60), Spain (n = 58), Germany (n = 49), England (n = 41), South Korea (n = 39), Brazil (n = 26), and Sweden (n = 20), indicating that the liver-bone axis has garnered significant attention among scholars in these countries. The United States and China collectively contribute more than 40% of the analyzed literature corpus. While China’s publication volume approximates 80% of United States output, American publications garner substantially higher citation metrics (10836 citations) compared to their Chinese counterparts (2875 citations), representing a nearly fourfold differential. Notably, the United Kingdom, despite ranking seventh in publication quantity, demonstrates superior bibliometric impact with the highest per-article citation rate (Table 2). A country collaboration network was constructed utilizing Citespace (Figure 2C). Chronological publication patterns are represented by colored rings, whose dimensions correlate with publication volume. Purple rings, indicative of high centrality metrics, denote substantial field impact. The United States, Italy, Spain, Germany, England, Sweden, Canada, and France are distinguished by purple rings, signifying their considerable influence and prominence in liver-bone axis research within the global scientific community. Along with the highest number of publications, the United States has the highest centrality in the collaborative network, reinforcing its prominence in the liver-bone axis field. Notably, Canada and France exhibit high centrality despite a relatively limited number of publications (n = 19). In contrast to countries with a high volume of publications, articles on the liver-bone axis emerged later in China and Japan. Furthermore, both countries exhibit low centrality despite their high number of publications.

Figure 2 Analysis of country. A: Map of the world with national publications; B: Bar chart of national publications; C: Country collaboration network. Each circle represents a country and the lines between the circles represent cooperation between countries, the thicker the line the more cooperation. Different colored rings represent different publication years, and the size of the ring represents the number of publications. Purple rings represent countries with high centrality.

Table 2 The top 10 countries in the bone-liver axis.

Rank	Publications, n (%)	Centrality	Country	Citation	AC
1	214 (25.03)	0.53	United States	10836	50.64
2	168 (19.65)	0.05	China	2875	17.11
3	61 (7.13)	0	Japan	1607	26.34
4	60 (7.02)	0.25	Italy	2745	45.75
5	58 (6.78)	0.2	Spain	2119	36.53
6	49 (5.73)	0.34	Germany	1988	40.57
7	41 (4.80)	0.13	United Kingdom	2588	63.12
8	39 (4.56)	0	South Korea	891	22.85
9	26 (3.04)	0.05	Brazil	494	19.00
10	20 (2.34)	0.32	Sweden	881	44.05

AC: Average citation.

Analysis of institution

A total of 425 institutions were involved in publishing articles on the liver-bone axis. The institutions ranked by the number of publications are as follows: University of California System (n = 22), Mayo Clinic (n = 20), Hospital Clinic de Barcelona (n = 17), CIBER - Centro de Investigación Biomédica en Red (n = 16), Shanghai Jiao Tong University (n = 15), University of Barcelona (n = 13), CIBEREHD (n = 12), Icahn School of Medicine at Mount Sinai (n = 11), Harvard University (n = 11), and University of Pennsylvania (n = 11) (Supplementary Table 2, Figure 3A). Half of the top 10 institutions were from the United States, which had the highest number of publications. A network diagram of institutional collaborations created with Citespace demonstrates a large cluster centered on the University of California System and the David Geffen School of Medicine at University of California, Los Angeles (UCLA) (Figure 3B). The University of California System and the David Geffen School of Medicine at UCLA had the highest centrality (0.29) and tied for first place, exerting the greatest influence in the liver-bone axis field (Table 3). The University of California System comprises 10 public universities in California, United States. The University of California, San Francisco is a globally esteemed center for research and education in the life sciences and medicine. The David Geffen School of Medicine is the medical school of the UCLA, which is widely regarded as one of the most prestigious medical schools in the United States. Notably, despite a relatively low number of publications (n = 5), it exhibits a centrality similarly to that observed for the University of California. Additionally, among the top ten institutions in terms of centrality, the top six are located in the United States, highlighting the country’s prominent position in liver-bone axis research (Table 3). By analyzing the papers published by these two institutions, we found that they maintain collaborative relationships with several other universities, including Harvard University in the United States and Aarhus University Hospital in Denmark. Additionally, both institutions, which had the highest centrality, are closely linked with the National Institutes of Health and its affiliated institutes, receiving sponsorship through its funding. It is the advanced research platforms, extensive clinical resources, and adequate funding that have positioned them at the forefront of the liver-bone axis field.

Figure 3 Analysis of institutions and authors. A: Bar chart of the top ten issuing institutions; B: Network diagram of institutional collaborations. The thickness of the line reflects the strength of the collaboration; C: The co-citation network of authors. Each sphere represents one author, and the lines between the spheres represent two co-cited authors. Different colors represent different clusters. The threshold is 40.

Table 3 The top 10 institutions in terms of centrality.

Rank	Publications	Centrality	Institution	Country
1	22	0.21	University of California System	United States
2	5	0.21	David Geffen School of Medicine at University of California, Los Angeles	United States
3	11	0.19	Icahn School of Medicine at Mount Sinai	United States
4	8	0.15	Jackson Laboratory	United States
5	9	0.12	Beth Israel Deaconess Medical Center	United States
6	5	0.09	Boston University	United States
7	15	0.06	Shanghai Jiao Tong University	China
8	3	0.05	CIBEROBN	Spain
9	20	0.04	Mayo Clinic	United States
10	16	0.04	CIBER - Centro de Investigacion Biomedica en Red	Spain

Analysis of author

A critical analysis of the literature’s authors identifies key scholars and delineates core research strengths in this field. The highest number of publications on the liver-bone axis belongs to Guanabens N (n = 18) (Table 4). She is Chair of Medicine at the University of Barcelona and a Senior Consultant in the Rheumatology Department at the Hospital Clínic de Barcelona, with her research focusing on bone turnover markers and bone disease in CLDs. These articles address the relationship between CLD and osteoporosis[20,21], the effects of hepatokines on bone during liver transplantation and biliary cirrhosis[22,23], the roles of osteoprotegerin and sclerostin in metabolic bone disease[24,25]. Among the author’s published articles on the liver-bone axis, the most cited (n = 119) addresses that severity of cholestasis and advanced histological stage are major risk factors for osteoporosis in primary biliary cirrhosis[26]. Albert P and Rosen CJ are tied for second place with the same number of posts (Table 4). Albert P is a co-author with Guanabens N, focusing on gastroenterology and hepatology. He is the Senior Consultant in Hepatology at Hospital Clínic de Barcelona and has contributed to the development of several clinical guidelines on autoimmune hepatitis and cholestatic liver disease, as well as clinical studies on patients with primary biliary cirrhosis. Rosen CJ’s research focuses on the role of IGF-1 and fibroblast growth factor 21 in the liver-bone axis[27,28]. Currently, the central themes of his laboratory include the genetic regulation of insulin-like growth factor in relation to skeletal metabolism, the relationship between marrow adipogenesis and osteoblastogenesis, and the interactions between whole-body and skeletal metabolism. The H-index is a hybrid metric for assessing a researcher’s quantity and quality of scholarly output, proposed by Hirsch JE[29] in 2005. Most of the top ten academics by publication count have an H-index greater than 30, indicating their high influence in the research field. Rosen CJ has the highest H-index of 99 and received a high citation award from WoSCC. He also has the highest average citation of 84.14, largely due to one article on IGF-1, which has 737 citations[30]. To analyze the authors of the journals cited by selected articles, we use VOSviewer to create the co-citation network. The co-citation network includes four clusters, each represented by a different color (Figure 3C). The four clusters comprise three principal clusters and one minor cluster. The blue cluster centers on Guanabens N, the most frequently cited author with 234 citations (Su-pplementary Table 3), and has the highest publication count. The purple cluster centers on Ana Monegal, who has the second highest citation count. Her current focus is on osteoporosis and fragility fractures[31,32]. A significant proportion of the authors in the brown cluster investigate the relationship between fatty liver, hepatokines, and bone metabolism[33]. The yellow cluster contains only one author, Angulo P, whose research focuses on liver fibrosis and NAFLD[34,35].

Table 4 The top 10 authors in terms of number of publications.

Rank	Author	Count	H-index	Citation	HCSA	AC	Country
1	Guanabens N	18	36	877	119	48.72	Spain
2	Albert P	14	61	721	119	51.50	Spain
3	Rosen CJ	14	99	1178	737	84.14	United States
4	Pilar P	13	32	772	123	59.38	Spain
5	Ana M	10	34	528	123	52.80	Spain
6	Emilio GR	10	26	194	60	19.40	United States
7	J. Eileen H	8	36	526	138	65.75	United States
8	Keith D L	8	94	387	128	48.38	Belgium
9	Shoshana Y	8	40	325	84	40.63	United States
10	Francisco SF	8	19	155	60	19.38	United States

HCSA: Highest citation single article; AC: Average citation.

Analysis of journal

The top ten journals by the number of articles related to the liver-bone axis, listed in descending order, are Osteoporosis International [n = 28, impact factor (IF) = 4.2], Journal of Bone and Mineral Research (n = 20, IF = 5.1), Frontiers in Endocrinology (n = 18, IF = 3.9), World Journal of Gastroenterology (n = 18, IF = 4.3), Transplantation Proceedings(n = 17, IF = 0.8), Journal of Hepatology (n = 16, IF = 26.8), Journal of Clinical Endocrinology and Metabolism (n = 15, IF = 5.0), Plos One (n = 15, IF = 2.9), Calcified Tissue International (n = 14, IF = 3.3), Liver Transplantation (n = 14, IF = 4.7). Most of these journals are classified as Q1 or Q2 (Table 5), indicating that articles related to the liver-bone axis are published in high-quality journals. Osteoporosis International, which has the highest number of articles, is an international multidisciplinary journal co-founded by the International Osteoporosis Foundation and the National Osteoporosis Foundation of the United States. This journal publishes articles on the diagnosis and prevention of osteoporosis, as well as the treatment and management of other metabolic bone diseases. It focuses on a wide range of research on osteoporosis and bone metabolism, with the impact of liver disease on bone quality emerging as one of the journal’s key research areas, contributing to its position as the journal with the highest number of publications. Among the top 10 journals, Journal of Hepatology has the highest number of citations (993) and the highest average citations (62.06), and it also has the highest impact factor. Journal of Hepatology is the official journal of the European Association for the Study of the Liver and focuses on clinical and basic research in hepatology. Journal of Hepatology, one of the leading journals in the field of hepatology, has the highest number of citations due to its authority and influence in liver disease research, particularly its leadership in hepatology, clinical interventions, and treatments. Despite its relatively small output of articles, the journal’s impact on the field of liver disease contributes to its high citation count. Many high-impact studies published in Journal of Hepatology explore the interaction between the liver and bone, which has led to increased citations for research related to the liver-bone axis. Figure 4A shows the cumulative occurrence change of the top 5 journals in terms of the number of articles from 2001 to 2024. Except for Frontiers in Endocrinology, the cumulative number of articles in the remaining four journals has shown a consistent upward trajectory from 2001 to 2024. Since 2014, Osteoporosis International has maintained its position as the most prolific journal, publishing the highest number of articles. Frontiers in Endocrinology had no liver-bone axis-related publications from 2001 to 2014; however, after 2014, the number of publications rose rapidly (Figure 4A). Other four journals also experienced a higher growth rate of publications after 2020 compared to before, which aligns with the previous trend of average annual publications (Figure 1B). This indicates that the field of the liver-bone axis began to receive more noticeable attention after 2020. The cited journals were analyzed using the co-citation network created by VOSviewer. The journal co-citation network is illustrated in Figure 4B and consists of three clusters. The journals in the blue and purple clusters primarily focus on clinical and fundamental research. The journals in the brown cluster concentrate on hepatology and gastroenterology. The dual-map overlay analysis illustrates the relationship between references and citations. In the dual-map overlay analysis, the dots and colors on the left represent the citing journals and their topics, indicating the direction of knowledge frontiers. Conversely, the dots and colors on the right represent the cited journals and their topics, indicating the knowledge base. The thickness of the lines represents the number of citations[36]. The fields of molecular biology, genetics, and health, including nursing and medicine, were initially fragmented but later converged to develop molecular biology, immunology, and clinical medicine (Figure 4C).

Figure 4 Analysis of journal and the co-citation network of articles. A: Line chart of journal publications; B: The co-citation network of journals. The size of the spheres reflects the frequency of citations to journals, with different colors representing distinct clusters. The lines represent the co-citation intensity of journals. The threshold is 30; C: Dual-map overlay of articles related to the bone-liver axis. The left side represents the citing literature and the right side represents the cited literature; D: Each sphere represents one article, and the lines between the spheres represent the co-citation of two articles. Different colors represent different clusters. The threshold is 30.

Table 5 The top 10 journals in terms of number of publications.

Rank	Journal	Count, n(%)	Citation	AC	IF (2023)	JCR (2024)	Country
1	Osteoporosis International	28 (3.27)	800	28.57	4.2	Q1	United Kingdom
2	Journal of Bone and Mineral Research	20 (2.34)	771	38.55	5.1	Q1	United States
3	Frontiers in Endocrinology	18 (2.11)	293	16.28	3.9	Q2	United States
4	World Journal of Gastroenterology	18 (2.11)	592	32.89	4.3	Q1	United States
5	Transplantation Proceedings	17 (1.99)	156	9.18	0.8	Q4	United States
6	Journal of Hepatology	16 (1.87)	993	62.06	26.8	Q1	Netherlands
7	Journal of Clinical Endocrinology and Metabolism	15 (1.75)	535	35.67	5.0	Q1	United States
8	Plos One	15 (1.75)	445	29.67	2.9	Q1	United States
9	Calcified Tissue International	14 (1.64)	800	57.14	3.3	Q2	United States
10	Liver Transplantation	14 (1.64)	368	26.29	4.7	Q1	United States

AC: Average citation; IF: Impact factor; JCR: Journal citation reports.

Analysis of references and citations

Further analyses of references and citations were conducted to gain deeper insights into the field. The co-citation network of references, generated using VOSviewer, comprises four distinct clusters (Figure 4D). The articles in the blue and purple clusters examine the interrelationship among liver health status, liver function alterations, and bone metabolism[37,38]. The brown cluster focuses on the role of hepatokines in HOD[39], while the yellow cluster investigates the relationship between NAFLD and bone metabolism[40]. Most of the top 10 co-citation references come from Hepatology, which ranks as the second most cited journal. This reflects the journal’s prominent role and impact in the field, indicating its extensive use and influence within the liver-bone axis field (Table 6). Furthermore, among these articles, the most common type is original research articles. The most frequently cited article is titled “Bone Mineral Density, Serum Insulin-Like Growth Factor I, and Bone Turnover Markers in Viral Cirrhosis”, authored by Gallego-Rojo et al[39] which examines the relationship between IGF-1 and bone metabolism in viral cirrhosis. The article “High Prevalence of Vitamin D Inadequacy and Implications for Health”, authored by Holick[41] published in Mayo Clinic Proceedings, has the highest number of citations and is a review that describes the relationship between vitamin D and bone metabolism (Su-pplementary Table 4).

Table 6 The top 10 co-citation references.

Rank	Title	First author	Source	Citations	TLS	Year	Type
1	Bone mineral density, serum insulin-like growth factor I, and bone turnover markers in viral cirrhosis	Gallego-Rojo FJ	Hepatology	96	787	1998	Article
2	Rates of vertebral bone loss before and after liver-transplantation in women with primary biliary-cirrhosis	Eastell R	Hepatology	74	638	1991	Article
3	AGA Technical Review on osteoporosis in hepatic disorders	Leslie WD	Gastroenterology	74	576	2003	Review
4	Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation	Monegal A	Calcified Tissue International	69	610	1997	Article
5	Bone disorders in chronic liver disease	Collier J	Hepatology	65	484	2007	Review
6	Role of hyperbilirubinemia in the impairment of osteoblast proliferation-associated with cholestatic jaundice	Janes CH	Journal of Clinical Investigation	63	580	1995	Article
7	Bone mineral density before and after OLT: Long-term follow-up and predictive factors	Guichelaar MMJ	Liver Transplantation	61	548	2006	Article
8	Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection	Schiefke I	World Journal of Gastroenterology	59	423	2005	Article
9	Osteoporosis and skeletal fractures in chronic liver-disease	Diamond T	Gut	58	508	1990	Article
10	Association of nonalcoholic fatty liver disease with low bone mass in postmenopausal women	Moon SS	Endocrine	57	299	2012	Article

TLS: Total link strength.

Analysis of key words

Keywords constitute distinctive terms or phrases that encapsulate a study’s primary focus and conceptual framework, facilitating information retrieval and document classification[42]. These indicators serve as valuable tools for identifying current research priorities and emerging trends. Frequency analysis of keywords reveals the following hierarchical distribution: “osteoporosis “(373), “bone mineral density” (151), “disease” (132), “mineral density” (120), “primary biliary-cirrhosis” (97), “metabolism” (85), “postmenopausal women” (76), “risk” (76), “cirrhosis” (74), and “insulin-resistance” (68). The top 20 keywords bifurcate into two distinct categories: Hepatic pathologies, encompassing primary biliary cirrhosis, cirrhosis, and HOD; and skeletal homeostasis parameters, including “osteoporosis”, “bone mineral density”, “osteopenia”, and “vitamin D” (Table 7). Network visualization analysis via VOSviewer reveals five distinct keyword clusters, demarcated by unique chromatic identifiers. The blue, pink, and brown clusters exhibit pronounced consolidation, while yellow and purple clusters demonstrate more diffuse distribution patterns (Figure 5A). The blue cluster encompasses clinical research and hepatic pathologies, including “liver transplantation” and “primary biliary cirrhosis”, predominantly representing pre-2012 literature in the temporal overlay visualization (Figure 5B). Early investigations primarily explored the relationship between hepatic dysfunction and bone mass deterioration[43,44]. The brown cluster aggregates fundamental research and molecular mechanisms within the liver-bone axis, including “metabolism”, “growth factor 1”, “osteoprotegerin”, “OCN”, and “genetic elements”, with most publications emerging post-2015, reflecting intensified investigation into molecular mechanisms and genetic expression patterns[45,46]. The pink cluster concentrates on metabolic disorders, encompassing “fatty liver disease”, “NAFLD”, “obesity”, and “insulin resistance”, with heightened research attention evident from 2018 onward. The yellow cluster comprises foundational disease entities including “osteoporosis”, “osteopenia”, and “HOD”, representing earlier conceptual frameworks[47-49]. The purple cluster, focused on fundamental bone metabolism parameters such as “bone mineral density”, exhibits dispersed distribution across other clusters, reflecting its integral role in liver-bone axis research, analogous to yellow cluster elements.

Figure 5 Analysis of keyword. A: Network visualization of keywords. Each sphere represents one keyword, and the lines between the spheres represent the co-occurrence of two keyword. Different colors represent different clusters. The threshold is 20; B: Overlay visualization of keywords. The different colors represent the mean time the keyword appears. The threshold is 20; C: The timeline of keywords. Each circle represents one keyword. The position on the axis represents the time of the first appearance of the keyword. The colors of the rings represent the different time periods in which the keyword appeared, and the size of the ring represents the frequency of the keyword in a period. The line between two circles represents the co-occurrence of two keywords; D: Top 30 keywords with the strongest citation bursts by year. The yellow bars indicate the beginnings and ends of citation bursts.

Table 7 The top 20 most occurring keywords.

Rank	Keyword	Occurrences
1	Osteoporosis	373
2	Bone mineral density	151
3	Disease	132
4	Mineral density	120
5	Primary biliary-cirrhosis	97
6	Metabolism	85
7	Postmenopausal women	76
8	Risk	76
9	Cirrhosis	74
10	Insulin-resistance	68
11	Osteopenia	65
12	Women	63
13	Expression	61
14	Bone	59
15	Hepatic osteodystrophy	59
16	Fractures	58
17	Liver	58
18	Mass	55
19	Vitamin-D	55
20	Obesity	52

Temporal keyword analysis utilizing Citespace generated timeline and burst visualizations reveals persistent prominence of “osteoporosis “and “bone mineral density”, while “NAFLD”, “insulin resistance”, “adipose tissue”, and “iron overload” represent emerging research frontiers (Figure 5C). Notably, “NAFLD” demonstrates particularly strong citation burst metrics (Figure 5D). Recent scholarly contributions include Vachliotis et al’s study[50] comprehensive review of osteokine involvement in NAFLD pathogenesis and progression, Tao et al’s study[51] exploration of the adiposity-NAFLD-osteoporosis nexus, and Lu et al’s study[52] cross-sectional investigation establishing receptor activator of nuclear factor kappa-B ligand as an independent risk factor for NAFLD in PCOS patients. Despite substantial evidence linking NAFLD to elevated osteoporosis risk, mechanistic understanding remains incomplete, and therapeutic interventions targeting relevant molecular pathways await thorough investigation. Given these research trajectories, NAFLD appears poised to maintain its position as a cardinal focus in future liver-bone axis investigations.

DISCUSSION

With an aging population, osteoporosis has emerged as a prevalent disease, leading to medical and socioeconomic effect. It is estimated that 10.2 million Americans have osteoporosis, and an additional 43.4 million have low bone mass. With one in two White women and one in five men expected to experience an osteoporotic-related fracture in their lifetime, the burden is projected to increase by almost 50%, leading to more than 3 million fractures and dollars 253 billion per year by 2025 in the United States[53]. The current treatment strategies of osteoporosis are inhibiting excessive bone resorption and increasing bone formation[54]. Despite the availability of many promising new treatments, the issue of complications is becoming increasingly urgent. Denosumab, a monoclonal antibody for receptor activator of nuclear factor kappa-B ligan, may cause an atypical femur fracture or an osteonecrosis of the jaw. The incidence of denosumab-related osteonecrosis of the jaw increases with longer follow-up periods: 3% at 1 year, 7% at 2 years, and 8% after 30 months[55]. Teriparatide, a recombinant of human parathyroid hormone, approved by the Food and Drug Administration for the treatment of osteoporosis, may be associated with adverse cardiac events; however, a cardiac safety analysis has not been conducted[56]. HCC is the most common form of primary liver cancer. Despite having the sixth highest incidence among all cancers, it is the third leading cause of cancer-related deaths, following lung cancer and colorectal cancer. Current treatment options include curative categories including resection, liver transplantation, ablation/segmental transarterial radioembolization and noncurative categories including transarterial chemoembolization and systemic therapies[57]. Additionally, the use of modified nanoparticles to target HCC cells presents promising therapeutic strategies[58,59]. However, no sufficiently effective treatment regimen exists for advanced-stage HCC that can significantly reduce mortality and achieve the desired therapeutic outcomes. In this study, we analyzed the liver-bone axis using bibliometric methods and proposed a novel approach to the development of therapeutic drugs for osteoporosis and HCC.

From 2001 to 2024, the number of articles related to the liver-bone axis has steadily increased, indicating a growing interest in this area of research. Among the 61 countries that have published articles on the liver-bone axis, the United States ranks first in both the number of publications and citations, demonstrating its significant influence in the field of liver-bone axis research. Most of the top 10 institutions in the analysis of publication numbers are also located in the United States. In the analysis of author, Guanabens N has the highest number of publications, while Rosen CJ has garnered the most citations, indicating their substantial contributions to liver-bone axis research and understanding the fundamentals of this axis requires a thorough examination of their work. Osteoporosis International has the highest number of publication while Journal of Hepatology has the highest number of citations, both serving as key journals for clinical and basic research in this field. The reference and citation analysis highlight pivotal papers that have advanced research in the liver-bone axis. These articles address the roles of IGF-1 and vitamin D in the liver-bone axis[39,41], previously identified hepatokines involved in regulating bone metabolism. Keyword analysis highlights current and emerging research trends. “Osteoporosis” is the most frequently occurring keyword and treating skeletal diseases such as osteoporosis is also one of the aims of studying the liver-bone axis. Some keywords related to hepatic diseases, such as “primary biliary-cirrhosis” and “liver transplantation”, exhibit a high frequency of occurrence, because patients with primary biliary-cirrhosis or liver transplantation have an increased risk of bone loss and fracture complications[22,25]. This suggests the influence of liver function on bone metabolism, which underlies the study of the liver-bone axis. Emerging keywords such as “NAFLD,” “insulin resistance,” “adipose tissue,” and “iron overload” demonstrate significant research potential. NAFLD, characterized by macrovesicular steatosis, is on the rise globally and is expected to become a leading cause of CLD. The pathogenesis of NAFLD involves several mechanisms, including ectopic lipid accumulation, oxidative stress, endoplasmic reticulum stress, lipotoxicity. Besides, as inflammation and fibrosis worsen, NAFLD can progress to cirrhosis and subsequently elevate the risk of liver cancer. NAFLD has been shown to impact bone mass, in conjunction with type 2 diabetes and vitamin D deficiency, with recognized as a risk factor for postmenopausal osteoporosis[60]. Despite its relevance, research into the mechanisms linking NAFLD to bone health is still limited. As an emerging and highly promising area of research, NAFLD has become a prominent topic within the liver-bone axis field. Insulin resistance is defined as an impaired biological response to insulin stimulation in target tissues and may play a key role in both obesity and type 2 diabetes mellitus T2DM[61]. As a condition affecting metabolic responses, it increases the risk of fractures due to disrupted liver fat and glucose metabolism[62]. Given the increasing prevalence of obesity and type 2 diabetes mellitus, addressing insulin resistance within the liver-bone axis and intervene the progression of insulin resistance by targeting factors present practical implications for treating associated conditions. Adiponectin, the most abundant adipokines in plasma, plays crucial metabolic and anti-inflammatory role and is rapidly emerging as a significant molecular target in treating metabolic disorders. Stimulation of adipo-receptor1 decreases the receptor activator of nuclear factor kappa-B ligand to osteoprotegerin ratio in osteoblasts, thus inhibiting osteoclast differentiation[63]. The association between adiponectin and bone mineralization in NAFLD has garnered significant attention. Additionally, iron overload is known to elevate osteoporosis risk[64], with the liver playing a critical role in systemic iron regulation through factors like ferroportin and transferrin receptor 2. Ferroportin, a hormone abundantly expressed in hepatocytes and integral to iron metabolism, has been demonstrated to influence transferrin, which is the sole exporter of iron from cells, regulates both the uptake and release of this mineral[65]. Transferrin receptor 2, primarily expressed in the liver, regulates iron homeostasis by mediating the transport of iron in plasma through its binding to iron ions[66]. Targeting hepatokines involved in iron metabolism could provide a novel strategy for enhancing bone mass and preventing osteoporosis.

The analysis of the keywords revealed that potential future research hotspots are primarily related to energy metabolism, particularly fat metabolism. This may be linked to metabolic reprogramming, which is a current area of focus in research. Therefore, future research on the liver-bone axis is likely to focus on the regulation of energy metabolism between the liver and bone. Investigating the signaling pathways and key molecules involved in the regulation of hepatic metabolism, as well as bone-related factors influenced by disrupted hepatic energy metabolism, may reveal potential diagnostic and therapeutic targets for related diseases.

Limitations

Several limitations warrant consideration in the present study. Our analysis encompasses publications from January 2001 to September 2024, thus excluding both historical literature and the most recent contributions to the field. Additionally, while the WoSCC served as our primary data source, inherent database limitations may have resulted in minor omissions or selection bias. Nevertheless, these constraints do not substantially impact the robustness or validity of our findings.

CONCLUSION

This investigation employs bibliometric methodologies to conduct a systematic analysis of liver-bone axis literature spanning from 2001 to 2024. The exponential growth in publications over the past two decades underscores the significance of synthesizing research outcomes in this domain. Through rigorous statistical analyses, we delineate fundamental contributions to the field while providing strategic direction for emerging scholars. Furthermore, we illuminate current research trajectories and identify promising future investigative directions. Investigation of the liver-bone axis enhances our comprehension of inter-organ communication networks. Conceptualizing these organs as an integrated system provides profound insights into pathophysiological mechanisms and disease management strategies. This paradigm not only facilitates the development of sophisticated diagnostic modalities but also catalyzes the discovery of novel therapeutic agents targeting these mechanistic pathways, thereby advancing our capacity to diagnose and treat hepatic and skeletal disorders.