Global current research status and future hotspots in osteoporotic fracture based on bibliometric assessment and visualization techniques

Abstract

BACKGROUND

In the past decade, the evolution of themes in the field of osteoporotic fractures has changed from epidemiology and prediction of long-term morbidity, risk assessment of osteoporotic fractures, and zoledronic acid and denosumab in the treatment of osteoporosis to treatment guidelines for osteoporosis and the side effects caused by anti-osteoporotic drugs.

AIM

To understand the trends and hotspots in osteoporotic fracture research.

METHODS

Original articles were retrieved between January 1, 2010, and December 31, 2019, from the Web of Science Core Collection database. CiteSpace software facilitated the analysis and visualization of scientific productivity and emerging trends.

RESULTS

Nine studies were identified using bibliometric indices, including citation, centrality, and sigma value, which might indicate a growing trend. Through clustering, we identified six major hot subtopics. Using burst analysis, top-5 references with the strongest bursting strength after 2017 were identified, indicating a future hotspot in this field.

CONCLUSION

Current hot subtopics in osteoporotic fracture research include atypical femoral fractures, androgen deprivation therapy, denosumab discontinuation, hip fractures, trabecular bone score (TBS), and bone phenotype. Management and prevention of secondary fractures in patients with osteoporotic fractures, TBSs, and long-term administration strategy for zoledronic acid are expected to become research hotspots.

Key Words: Osteoporotic fracture, Bibliometrics, Trabecular bone score, Co-occurrence analysis, Co-citation analysis, Clustering

Core Tip: The evolution process of the research focus in the field of osteoporosis fractures in the past decade has changed from epidemiological statistics and long-term incidence prediction to osteoporosis fracture risk assessment and significant effects of zoledronic acid and denosumab on reducing fracture risk in osteoporosis treatment to the proposal of osteoporosis treatment guidelines and the adverse reactions caused by anti-osteoporosis drugs such as zoledronic acid. Current hot topics in the treatment of osteoporosis fractures include atypical femoral fractures, osteoporosis fractures caused by androgen deprivation, increased fracture risk due to denosumab discontinuation, hip fractures, trabecular bone scores, and genes related to bone density or osteoporosis fracture phenotypes.

INTRODUCTION

Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and strength, and an increased risk of fragility fractures. Previous studies have shown that more than 33% of women and 20% of men aged > 50 years suffer from fragility fractures[1]. The current annual number of osteoporotic fractures is estimated to be approximately 3.2 million, and this number is expected to increase to 4.6 million by 2035. The annual medical expenditure for treating osteoporotic fractures, including numerous implants, is expected to exceed 18 billion United States dollars and reach 25.43 billion US dollars by 2050[2]. Hip and vertebral compression fractures are the most common osteoporotic fractures, with high mortality and disability rates, which seriously affect the quality of life of patients and become a heavy economic burden for society and families[3].

CiteSpace is an information visualization software based on the co-citation analysis theory and the pathfinder network algorithm, which can measure the literature of a specific field, filter out key research results and evolution trends, and predict potential future hotspots[4,5]. This method can provide a perspective that traditional systematic reviews do not have and has been widely used in the field of tissue engineering at home and abroad[6]. Currently, there are few bibliometric studies on the clinical diagnosis and treatment of osteoporotic fractures[7]. This study aimed to apply bibliometrics and use CiteSpace software for visualizing information to provide researchers with a clearer presentation of the current situation and possible future research hotspots of clinical diagnosis and treatment of osteoporotic fractures.

MATERIALS AND METHODS

Literature data were derived from the core database (Science Citation Index Expanded) of the Web of Science (WoS) retrieval platform (Clarivate, United States).

Search strategy

Keywords "osteoporosis" and "fracture" were searched in the WoS database, and the document type was limited to articles. The database retrieval time span was limited from January 1, 2010 to December 31, 2019.

Data processing and analysis

Full literature records (including title, publication year, author name, nationality, journal name, keywords, and abstract) and reference information were obtained from the WoS database. All literature data were exported in .txt format source files, and then imported into CiteSpaceV.5.5.R2 analysis software. A total of 14479 articles from the WoS database were included in this study.

Institutional and author collaboration network analyses indicates the scientific output of different institutions and authors as well as their cooperative relationships. Literature keyword co-occurrence analysis understands keywords with high frequency in the current research field and use a clustering algorithm to calculate the co-occurrence frequency of keywords and obtain the research hotspots in the current field[8]. The citation frequency, betweenness centrality, and sigma value of the reference literature in the research field are calculated through a co-citation analysis of the literature citation information, and the key literature in the research field development process are found. Citation frequency refers to the situation in which literature is cited in the relevant research field. Betweenness centrality refers to the ratio of the shortest path passing through a certain point and connecting these two points to the total number of shortest paths between them. Nodes with a high betweenness centrality are regarded as key nodes, indicating important development signs in the research field[9]. The sigma value is a comprehensive evaluation index that considers both citation frequency and betweenness centrality[10]. Burstiness is the rate of change in frequency within a given period. High burstiness indicates breakthrough progress in research[11]. Literature with high burstiness in different time periods are found through the burstiness time distribution, which indicates the developmental trends of the research field and predicts potential research hotspots.

Software parameter settings: Time zone segmentation (Time Slicing) was set from 2010 to 2019, with an interval of "1" year. The node screening criteria selected the top 50 nodes (TOP N) according to the research-level value. The pruning strategy selected the pathfinder network (Pathfinder) and the overall network pruning (Pruning the merged networks), and the visualization (Visualization) selected the static cluster view (Cluster View-Static) and displayed the merged network (Show Merged Network).

For the WoS data, the node types were selected as institution (Institution) and author (Author) for cooperative network analysis. Then, the reference (Reference) was selected for co-citation analysis, and the key literature was screened by citation frequency, betweenness centrality, and sigma value. Then, the citations were clustered, hot keywords were extracted using the log-likelihood rate (LLR algorithm), and a cluster knowledge map was drawn. Simultaneously, the burstiness of the references was calculated, and finally, a burstiness literature table was drawn according to the burstiness size and time distribution.

RESULTS

Globally, the annual scientific output of osteoporosis fracture-related research has increased compared to a decade ago, and the overall trend has remained stable since 2011 (Figure 1). In terms of national scientific output, the top five countries were the United States, China, the United Kingdom, Germany, and Canada. In terms of annual scientific output, China's annual research quantity had a clear increasing trend, while that of the United States had declined slightly compared to a decade ago, and other countries had remained unchanged. The H-index is a hybrid quantitative indicator that is used to evaluate the quantity and level of academic output of researchers and institutions. The number of citations and H-index reflect the quality of articles. Table 1 shows that the United States remained in the world's leading position in terms of research quality, whereas China lagged behind other countries, such as the United Kingdom, Germany, and Canada.

Figure 1 Annual publication trend of osteoporosis fracture-related research and the top 5 countries. The left ordinate represents the total annual publication from 2010 to 2019 worldwide; the right ordinate represents the annual publication of different countries.

Table 1 Statistics of research quantity and quality for the top 5 countries in global publication volume.

Country	Research quantity	Total citation frequency	H index
United States	4107	99638	120
China	1756	18871	52
The Great Britain	1376	40580	89
Germany	1247	22494	65
Canada	1111	28347	75

Author institution analysis

The author co-occurrence analysis of the WoS data showed that among the top ten authors in terms of the number of osteoporosis fracture studies, seven scholars were from the United Kingdom, the United States, and Canada. Among them, there were three teams from the University of Sheffield, led by John A Kanis, Richard Eastell, and Helena Johansson respectively, indicating the outstanding achievements of this institution in the research field of osteoporosis fracture (Table 2). The results of the institution co-occurrence analysis showed (Figure 2) that the cross-institutional collaboration research on osteoporosis fractures was relatively close worldwide.

Figure 2  Global collaboration among institutions in the field of research related to osteoporotic fractures.

Table 2 Statistics of the top 10 authors' research output in studies related to osteoporotic fracture.

Author	Research Quantity	Institution
Cyrus Cooper	184	University of Southampton
Christian Roux	161	Paris Descartes University
William D Leslie	157	University of Manitoba
John A Kanis	140	University of Sheffield
Jonathan D Adachi	136	McGill University
Richard Eastell	105	University of Sheffield
Helena Johansson	89	University of Sheffield
Jane A Cauley	84	University of Pittsburgh
Steven Boonen	83	Catholic University of Leuven (Belgium)
Jean Yves Reginster	75	King Saud University (Saudi Arabia)

Key literature in the field of osteoporosis fracture

The WoS data included 199563 citations for co-citation analysis, and the top five studies were ranked by citation frequency, betweenness centrality, and sigma value, and nine key node studies were identified (Table 3).

Table 3 Top five publications ranked by number of citations, intermediary centrality, and sigma values.

Author	Journal	Top 5 in citation count	Top 5 in centrality	Top 5 in sigma value
Johnell and Kanis[3],2006	Osteoporos Int			Yes
Burge et al[12], 2007	J Bone Miner Res	Yes		Yes
Black et al[14], 2007	N Engl J Med	Yes
Lyles et al[15], 2007	N Engl J Med		Yes
Cummings et al[16], 2009	N Engl J Med	Yes	Yes
Kanis et al[17], 2013	Osteoporos Int		Yes	Yes
Cosman et al[18], 2014	Osteoporos Int	Yes	Yes	Yes
Shane et al[19], 2014	J Bone Miner Res			Yes
Kanis et al[36], 2008	Osteoporos Int	Yes	Yes

Current hot topics in the clinical diagnosis and treatment of osteoporosis fracture

The co-citation network of the WoS data was clustered. The results showed (Figure 3) that the current global research hot topics in the field of osteoporosis fracture include "atypical femoral fracture", "osteoporosis fracture caused by androgen deprivation therapy", "increased fracture risk due to denosumab discontinuation", "hip fracture", "trabecular bone score", and "genes related to bone density or osteoporosis fracture phenotype".

Figure 3  Hot topics in osteoporotic fracture research in the Web of Science database.

Potential research hotspots in the clinical diagnosis and treatment of osteoporosis fracture

The co-citation network of the WoS data was analyzed for citation burstiness, and the results showed that 59 articles had burstiness. Based on the time distribution of burstiness, five articles with the highest burstiness after 2017 were selected that may indicate future research hotspots (Table 4).

Table 4 Articles with significant breakthroughs since 2017.

Author	Journal	Breakthrough time	Top 5 breakthrough
Silva et al[31], 2015	J Clin Densitom	2017	24.6367
Harvey et al[32], 2015	Bone	2017	25.6491
McCloskey et al[33], 2016	J Bone Miner Res	2017	36.2806
Ganda et al[34], 2013	Osteoporos Int	2017	24.095
Adler et al[35], 2016	J Bone Miner Res	2017	20.5926

DISCUSSION

This study found that research on osteoporosis fractures had grown slowly in the past decade globally, with the United States leading worldwide in terms of overall scientific quantity and quality, but with a decline in annual scientific output compared to previous years. In contrast, China had been in a state of continuous growth in annual scientific output over the past decade, indicating the significant progress China had made in the field of osteoporosis fractures in recent years. However, in terms of research quality, China still lagged behind traditional scientific powers, such as the United States and the United Kingdom.

Author institution analysis

The top ten authors in terms of the number of osteoporosis fracture studies mainly came from countries such as the United Kingdom, the United States, and Canada. Among them, there were three research teams from the University of Sheffield in the United Kingdom (John A Kanis, Richard Eastell, and Helena Johansson), indicating that the University of Sheffield is in a leading position in the related research field of osteoporosis fractures worldwide. The results of the inter-institutional collaboration research analysis showed that cross-institutional collaboration research on osteoporosis fractures was relatively close worldwide, while inter-institutional collaboration research within China was less, suggesting that domestic author institutions can conduct more extensive cooperation and communication in research.

Node literature and research focus development trend

Nine-node studies were screened using citation frequency, betweenness centrality, and sigma values as parameters. The development trend of the research focus in this field can be indicated according to the chronological order of literature publications. Johnell and Kanis[3] published an article in Osteoporosis International in 2006 that statistically analyzed the incidence and prevalence of osteoporosis fractures worldwide and found that > 9 million people suffer from osteoporosis fractures every year, with a high mortality and disability rate. The authors believe that this will become a significant disease burden worldwide. Burge et al[12] published a study in the Journal of Bone and Mineral Research in 2007 that used a Markov model to predict the incidence of osteoporosis fractures in the United States from 2005 to 2025. The results showed that by 2025, the incidence of osteoporosis fractures in the United States will increase by > 50% compared to 2005, reaching > 3 million people, and the total annual cost will be as high as 25.3 billion United States dollars. Osteoporosis fractures will increase more rapidly in the 65-74-year age group and in non-white populations. The results of this study provide important references for formulating overall health policies. Kanis et al[13] published a study in Osteoporosis International in 2008 that proposed a tool (Fracture Risk Assessment Tool, FRAX) that combines clinical risk factors with bone density to predict the risk of osteoporosis fractures in patients. The clinical risk factors included seven items: history of fragility fracture, family history of hip fracture, smoking history, long-term oral hormone history, rheumatoid arthritis, other risk factors for secondary osteoporosis, and daily alcohol consumption of more than three units. Original data were obtained from 11 independent prospective cohort studies from different countries and regions with a cumulative follow-up period of more than 1 million patient-years. This study laid the foundation for the subsequent intervention and treatment of patients based on fracture risk. Black et al[14] published a randomized controlled study in the New England Journal of Medicine in 2007 that showed that zoledronic acid injection once a year can significantly reduce the risk of fracture in patients during a three-year follow-up period. The authors also recommended that intravenous administration once a year is better than oral administration to eliminate the influence of medical compliance on the final treatment effect. Lyles et al[15] published a randomized controlled study in the New England Journal of Medicine in 2007 that showed that zoledronic acid injection within 90 days after hip fracture surgery can significantly reduce the risk of refracture and improve the survival rate. The results of this study provide an important reference for combined treatment and improvement in the treatment effects of hip fractures. Cummings et al[16] published a randomized controlled study in the New England Journal of Medicine in 2009 that proved that denosumab can effectively reduce the occurrence of osteoporosis fracture in perimenopausal women, and provided a basis for the application of the drug in clinical practice. The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, in collaboration with the International Osteoporosis Foundation[17] and the Expert Committee of the National Osteoporosis Foundation (NOF)[18], published clinical guidelines for the prevention and treatment of osteoporosis in Osteoporosis International in 2013 and 2014, respectively, which provided detailed recommendations for the diagnosis, treatment, prevention, and risk assessment of osteoporosis. In particular, the NOF guidelines also proposed the following criteria for starting drug intervention: (1) History of hip or vertebral fractures; and (2) bone density T values ≤ -2.5, (3) for postmenopausal women or men aged > 50 years with low bone mass and FRAX risk assessment of hip fracture risk > 3% within 10 years or osteoporosis fracture risk > 20%. Shane et al[19] published an article in the Journal of Bone and Mineral Research in 2014 that reviewed the epidemiology, pathophysiology, and treatment of atypical femoral fractures. The authors believe that the long-term use of bisphosphonates can increase the risk of atypical femoral fractures, and the mechanism may be that bisphosphonates accumulate at the site of stress fractures, inhibit bone remodeling, and thus affect fracture healing. Discontinuation of bisphosphonate drugs can reduce the risk of atypical femoral fracture and lower limb force line abnormalities, and Asian ethnicity may also be a risk factor. This study provides a direction for subsequent research on the association between bisphosphonate and atypical femoral fractures.

Current hot topics in clinical diagnosis and treatment of osteoporosis fracture

An atypical femoral fracture refers to a fracture that occurs in the subtrochanteric or femoral shaft with specific clinical manifestations after a low-energy injury. Although the evidence for a causal relationship between bisphosphonate use and fractures is still insufficient, most studies still tend to believe that long-term bisphosphonate use is a risk factor[20]. Current research mainly focuses on identifying the risk factors for atypical femoral fracture, and the treatment effects of surgery or drugs[21,22].

Androgens play an important role in bone growth and the maintenance of bone mass; therefore, androgen deficiency caused by prostate cancer castration therapy often leads to significant bone loss and increased fracture risk[23]. The specific mechanism of androgen regulation of bone formation and cell activity remains unclear, but studies have shown that androgens have a synthetic-promoting effect after fractures[24]. Future studies revealed that the role of androgens in precursor stem cells in the bone microenvironment may have broad application prospects for the clinical promotion of bone healing.

Denosumab is a monoclonal antibody drug that competes with the receptor activator for nuclear factor-κB (RANK) to bind to the RANK ligand (RANKL), thereby inhibiting the differentiation and activation of osteoclasts mediated by the RANKL-RANK-osteoprotegerin signaling pathway, reducing osteoclastic activity, and treating osteoporosis patients[25]. However, denosumab does not bind and store with its receptor for a long time, and its effects on bone density and improvement in bone turnover indicators are reversible[26]. Currently, the literature regarding whether osteoporosis fractures occur after denosumab discontinuation is still controversial, and further studies are needed to confirm this.

Hip fracture is one of the most common osteoporosis fractures, which seriously affects the quality of life of patients, has a high mortality rate, and places a heavy economic burden on society. Common research topics include fracture classification, comparison of the treatment effects of proximal femoral anti-rotation intramedullary nail and dynamic hip screw, joint replacement, fast recovery treatment after surgery, prevention and treatment of perioperative complications, risk factors, and surgical treatment methods for refracture. In addition, some studies such as Takeshima et al[27] in 2017 have also conducted genetic-level research, which found that the aldehyde dehydrogenase gene locus missense mutation was associated with hip fracture.

The trabecular bone score (TBS) is a gray-scale texture index derived from dual-energy X-ray absorptiometry images and can be used to assess fracture risk in clinical practice. Current dual-energy X-ray bone density and quantitative computed tomography measurement results have certain limitations in the assessment of osteoporosis fracture risk. The emergence of the TBS has provided a new direction for research. Currently, the TBS can be used in combination with FRAX and bone density to guide treatment decisions; however, further evaluation of the association between TBS changes and fracture risk reduction is needed in the future[28].

Literature shows that genetic factors account for 60%-80% of the occurrence of osteoporosis, and there have been many studies on gene sequencing of osteoporosis and osteoporosis fracture phenotypes, such as Styrkarsdottir et al[29] in 2016 that found that the PTCH1 gene was associated with spine bone density and osteoporosis fracture and Li et al[30] in 2014 that found that GALNT3 gene polymorphism was associated with bone density in postmenopausal Chinese women.

Potential research hotspots

This study extracted burstiness information from the co-citation network of WoS data, and articles with burstiness after 2017 indicate potential hotspots for osteoporosis fracture research in the future. The top five articles in terms of burstiness intensity included Silva et al[31] published in the Journal of Clinical Densitometry in 2015, Harvey et al[32] published in Bone in 2015, and McCloskey et al[33] published in the Journal of Bone and Mineral Research in 2016, all of which affirmed the ability of TBS to independently predict fracture risk. More applications are needed in the future to determine the correlation between TBS reduction and fracture risk reduction, as well as the threshold for clinical intervention. Ganda et al[34] published a systematic review of the management model for preventing recurrent osteoporosis fracture in Osteoporosis International in 2013, which showed that simple health education had little effect on urging patients to start anti-osteoporosis treatment; the current better model involve establishing an electronic medical record network, having dedicated staff regularly conducting remote supervision, and providing feedback treatment results through the database. Future research requires more data on medical compliance and further improvements to the patient management model. Adler et al[35] published an article in the Journal of Bone and Mineral Research in 2016, reviewing the long-term use of bisphosphonate treatment for osteoporosis, and suggested that for women with a high risk of osteoporosis fracture, after oral bisphosphonate for 5 years or intravenous bisphosphonate for 3 years, the duration of medication can be extended to 10 years and 6 years, respectively. For women with no high risk of fracture, bisphosphonates can be discontinued for 2-3 years after 3-5 years of use and then re-evaluated. The efficacy of bisphosphonate treatment for osteoporosis is definite, but an understanding of its side effects, especially the increased risk of fracture after long-term use, has always existed. More high-quality prospective randomized controlled studies are needed to provide more evidence in the future.

The reason for using WoS literature data in this study is mainly because its data can cover domestic and foreign research more comprehensively, and its format is compatible with CiteSpace; however, there is also the possibility of missing high-quality literature data from other databases. In future, a more comprehensive analysis of literature data from more sources can be achieved by updating the software functions.

CONCLUSION

The United States continues to lead the world in research on osteoporotic fractures. China's related research shows an increasing trend annually, but there is still a gap between research quality as compared to Europe and America. The University of Sheffield in the United Kingdom has more scientific output in this field and there is more joint research among institutions worldwide, whereas there is less cooperative research among domestic institutions. The evolution process of the research focus in the field of osteoporosis fractures in the past decade has changed from epidemiological statistics and long-term incidence prediction to osteoporosis fracture risk assessment and significant effects of zoledronic acid and denosumab on reducing fracture risk in osteoporosis treatment to the proposal of osteoporosis treatment guidelines and the adverse reactions caused by anti-osteoporosis drugs such as zoledronic acid. Current hot topics in the clinical diagnosis and treatment of osteoporosis fractures include atypical femoral fractures, osteoporosis fractures caused by androgen deprivation, increased fracture risk due to denosumab discontinuation, hip fractures, TBS scores, and genes related to bone density or osteoporosis fracture phenotypes. The management model of osteoporosis fracture patients and the prevention of secondary fractures, TBS scores, and the administration strategy of long-term use of zoledronic acid to prevent osteoporosis fractures are expected to become future research hotspots.

ACKNOWLEDGEMENTS

I would like to express my gratitude to all those who helped me during the writing of this thesis.