Bisphosphates for Osteoporosis: A Bibliometric Analysis of the Most Cited Articles

Osteoporosis has become a major public health problem and bisphosphates treatment for osteoporosis is a rapidly developing research field. Every year, plenty of studies devoted to the treatment of osteoporosis are published, giving clinicians a new perspective on bisphosphates treatment for osteoporosis. However, the quality of the scientific papers in this area is unclear. The aim of the present study was to characterize the 100 top-cited articles regarding bisphosphates treatment for osteoporosis. This analysis provides an accessible list for practitioners of endocrinology, pharmacy, epidemiology, imaging, surgery, and scientific research to identify the most frequently cited literature and better understand the future direction.


Introduction
Osteoporosis is a common metabolic bone disease, which is related to the decrease of bone mineral density (BMD) and bone mass and increase of bone fragility [1][2][3]. e distribution of osteoporosis is different in different populations. In the United States, 10 million people over the age of 50 suffer from osteoporosis, and another 34 million people are at risk [4]. It is reported that the incidence of osteoporosis in Europe in 2010 was 27.6 million [5]. According to the national statistical yearbook, the number of people aged over 60 in China has exceeded 210 million. By the end of 2015, the number of elderly patients with osteoporosis has exceeded 75 million [6]. e most serious consequence of osteoporosis is fracture, which causes a significant economic burden on health care systems around the world [7,8].
At present, the drug treatment for osteoporosis can be divided into two categories: anti-resorption drugs which slow down bone resorption, and synthetic metabolic drugs which stimulate bone formation [9]. Bisphosphonates are the backbone of anti-resorption drugs, which show high affinity to bone and long-term safety and can be taken orally or intravenously [10][11][12]. Bisphosphates binds to the free hydroxyapatite that can be obtained on the bone surface, has a strong affinity with bone tissue, and resists enzyme digestion. In the process of bone resorption, bisphosphate will be desorbed from hydroxyapatite and absorbed by osteoclasts, reducing the metabolic activity of osteoclasts, weakening the bone resorption capacity of osteoclasts, preventing osteoblasts and osteocytes from apoptosis, and increasing the number and function of osteoblasts [13,14]. e anti-apoptotic effect of bisphosphates is separated from the effect of drugs on osteoclasts, protecting the bone formation function of mature osteoblasts and maintaining the osteocyte network, coupled with the lack of anti-catabolism. us, bisphosphonates are the most widely used anti-resorption drugs for osteoporosis mainly in post-menopausal women. Every year, plenty of studies devoted to the treatment of osteoporosis are published, giving clinicians a new perspective on bisphosphates treatment for osteoporosis. e quality of scientific studies in this field, however, is uncertain. Identifying the most influential pieces remains a difficulty. e citation can be used as an indicator of the scientific influence of an article in its field [15,16]. Bibliometric analysis is an important tool to help quantify the number of articles in disciplines and provide a comprehensive overview of the literature [17,18]. Bibliometric analysis is now widely used in many disciplines, including anesthesiology [19], orthopedics [20], endocrinology [21], oncology [22], obstetrics, and gynecology [23]. e purpose of this study was to identify and analyze the 100 most-cited literature related to bisphosphate treatment for osteoporosis through extensive literature search methods. Appreciating and learning from these influential publications can help clinicians better make treatment decisions and understand the future direction.

Materials and Methods
Our study was a retrospective assessment of the public data, so the approval of the institutional review committee is not required. A bibliometric analysis of bisphosphates treatment for osteoporosis was performed on August 5th, 2021, using the Web of Science (WOS). No restrictions were placed on country of origin or medical specialty. As in other documents, England, Wales, Northern Ireland, and Scotland were classified as the United Kingdom. First, osteoporosis and bisphosphate were used as search terms. To ensure the breadth and relevance of the search scope, the keywords were constantly filtered. And then, the final set of search terms were 'osteoporosis' AND ('bisphosphonate' or 'BPs' OR 'alendronate' or 'risedronate' or 'etidronate' or 'ibandronate' or 'clodronate' or 'pamidronate' or 'zoledronate' or 'zoledronic acid') included in the "Title" search. e search results were sorted by the times cited in the WOS, and the 100 most-cited articles on bisphosphates for osteoporosis were derived. Again, the search time was set from 2019 to 2021, and the search results were sorted by the times cited in the WOS; the 50 most cited articles on bisphosphates for osteoporosis were derived. e citations per year index (CPYI) was introduced to eliminate the tendency of older articles to accumulate more citations. Two independent authors (Zhang and Hu) performed the search, screened the articles, and extracted the information. e third author (Zhang) was consulted if differences arise. e number of citations, authorship, journal of publication, year of publication, and country were extracted. VOS viewer software 1.6.16 (Van Eck and Waltman, Leiden University, Leiden, e Netherlands) was used for network visualization analysis of keywords [24]. e terms are used more frequently as when the circle grows larger. is article ranked fourth in annual citations (69.78 per year). Of the top 10 articles in terms of total citations, 5 articles were published in the New England Journal of Medicine. Four articles were cited more than 1000 times and 15 articles were cited more than 500 times (Table 1).

Analysis of Country and Publishing
Trend. According to the affiliation of the first author, the 100 most-cited articles in bisphosphates for osteoporosis were from 16 countries, with most publications from the United States (52 articles), followed by Italy (7 articles), Belgium (6 articles), Denmark, United Kingdom and Canada (5 articles each), France (4 articles), New Zealand, Japan, and Germany (3 articles each), and Switzerland and Netherlands (2 articles each). e remaining countries (Israel, Spain, and Australia) published one article each in the top 100 cited list ( Figure 1).

Journal Analysis.
Twenty-nine journals contributed to the top 100 articles with 12 contributing two or more articles (Table 2). e most published journals were the New England Journal of Medicine and Journal of Bone and Mineral Research, with 16 articles, respectively. Moreover, the total number of citations and impact factors in the New England Journal of Medicine was also the highest. e Journal of Clinical Endocrinology and Metabolism ranked second with 14 articles.

Highly Contributive Authors.
According to the ranked of the total number of co-authors published, 20 authors contributed 5 or more of the top 100 papers. Miller PD published the most articles, with 15 items. e main contributors to an article are usually the first and the last authors. Among the first authors, Black, DM published the most articles (n � 7), and the last author Delmas, PD published the most articles (n � 4) ( Table 3).

Analysis of Study Types, Patients, Drugs, and
Complications.
e 100 most-cited articles were categorized as original studies (n � 89), systematic review/meta-analysis (n � 5), reviews (n � 5), and editorial material (n � 1). e treatment patients mainly included post-menopausal women and glucocorticoid-induced patients. Alendronate and risedronate were the two most used drugs. Four articles Evidence-Based Complementary and Alternative Medicine 3     (Table 4).
To further determine the change of research topic over time, the evolution of the highest frequency keywords was evaluated using VOS viewer (Figure 2(b)). e blue color means the keyword appears early and yellow-colored keywords appear later. In the early stage of bisphosphate therapy for osteoporosis, most studies focused on "drug and imaging examination of bone mineral density". e latest trends indicated that "basic research" on bone turnover markers and "clinical fracture and risk" clusters may receive widespread attention in the future.

e Most Cited Papers and Keyword Analysis in the Recent 2 Years.
e most productive period was 2019 (n � 30) and the most published author was Sugimoto T (n � 4). e United States published (n � 10) the most articles, followed by Japan (n � 9) and China (n � 7). According to the network co-occurrence analysis of keywords, it was found that osteoporosis (n � 24) was the most common keyword, followed by bisphosphate (n � 18), zoledronic acid (n � 16), and alendronate (n � 15) (Figure 2(c)).

Discussion
Osteoporosis has become a major public health problem and bisphosphates treatment for osteoporosis is a rapidly developing research field. Bibliometrics analysis is a form of statistical analysis of published papers. Although it is not the only symbol of the scientific quality of an article, it can be used to quantify the citation frequency of a paper and be used as an alternative sign of influence in its field [17,18,26]. e present study was the first to conduct a bibliometric and keyword co-occurrence analysis of the 100 most influential articles on bisphosphates treatment for osteoporosis. At the same time, we also studied the bibliometric analysis of the most frequently cited latest literature in the recent 2 years to understand the current trends and hotspots. e results of this study may help to collate data and easily obtain the highest yield data of bisphosphates treatment for osteoporosis, thus helping clinicians better make a treatment decision and understand the future direction of this discipline. e 100 most-cited articles published from 1976 to 2018 were cited 102 to 1884 times. e list of the articles identified topics that reflect changing trends in bisphosphates treatment for osteoporosis over the past 42 years. Although it was impossible to analyze all 100 highly cited articles in detail, we can find some important results. We found that the most cited publications in the field were mainly from the United States. e United States published 52 articles, followed by Italy and Belgium. e top countries are mainly distributed in North America and Europe, which are all developed countries. us, there is still a significant gap in the output of articles between developed countries and developing countries.
We found that the top 100 most-cited articles were mainly published before 2018. rough the further time limit of 2019-2021, there was no doubt that the country with the most published papers was still the United States, but the difference was that the second and third most cited publications in this field were Japan and China. is was roughly the same as the citation analysis of articles related to postmenopausal women with osteoporosis in the top countries [27,28]. Similarly, in the dental and osteoporosis analysis studied by Qiu et al. Japan was found to be the most frequently cited publication country in this field [29]. e principles and concepts of anti-osteoporosis treatment in developed countries have been fully affirmed and established based on scientific research. In many aspects, it showed that China and Japan were two Asian countries that attach importance to the study of osteoporosis and become important participants in the treatment of osteoporosis. Bisphosphate therapy for osteoporosis will continue to attract medical researchers around the world to promote further research on the treatment of osteoporosis and bring new perspectives in this regard.
In terms of the most published journals, we found that the New England Journal of Medicine and Journal of Bone and Mineral Research are the most productive journals with the highest average number of citations. ese results are in line with Bradford's law as if the researchers deviate from these core journals, their citation frequency will decrease [30]. us, researchers tend to cite papers from several core journals in their professional fields.
As is known to all, the date of publication can affect the number of citations. Older studies may have a higher Evidence-Based Complementary and Alternative Medicine    [31,32]. But in this analysis, the period from 2000 to 2009 was the most frequently cited period, with more than half of the articles. One possible explanation was that the intensification of global aging may lead to an increased incidence of osteoporosis [33,34]. e other important reason might be the popularity of bisphosphate therapy and the promotion of imaging methods and basic research [8].
Among the multi-author papers, the first and the last authors usually contributed the most. To better clarify the contribution of researchers in this field, we collected the number of papers that the author participated in and counted the number of papers published by the first and the last authors. Miller PD was the co-author of all 15 articles, making him the most published researcher in the top 100. Dr. Miller and his team put more emphasis on individualized treatment which is found as effective as daily medication based on patients' compliance. Black, DM was another pioneer of bisphosphates for osteoporosis research who had the most first-author publications (n � 7). By analyzing the main authors in this field, we can identify the main contributors and look for opportunities for further cooperation. e keyword co-occurrence analysis found that the most popular keywords were fracture, lumbar spine, alendronate, and incidence. Individuals with osteoporosis are at an increased risk of fragility fracture [35]. e fracture site often occurs in the lumbar vertebrae [36,37]. us, routine DXA examination of lumbar BMD is necessary for osteoporosis patients in the clinical diagnosis. For the prevention, postmenopausal osteoporosis women and glucocorticoid-dependent osteoporosis patients routinely take bisphosphate drugs after being diagnosed by BMD examination. Bisphosphonates can significantly increase BMD of the whole body such as spine and hip and thus significantly reduce the risk ratio of a new spine fracture. e visual map drawn by the VOS viewer was used to find the changing trend of keywords with time. A total of 39 included keywords was divided into clinical study, drug and imaging study, and basic research. In the initial study, we found that the study focuses gradually shifted from x-ray diagnosis and treatment to basic research, which was consistent with the trend reported by Qiu et al. [27]. By grasping the changing trend in this field, we can reduce resource waste and better understand the future direction.
Early keyword co-occurrence analysis found that alendronate was the most frequently used in clinical use. According to the most citations of 50 articles in recent 2 years, zoledronic acid was used most frequently, which was consistent with the results of Gao et al. [38]. After long-term bisphosphonate medication, patients with osteoporosis will re-evaluate the appropriate response. e curative impact will be influenced by patient compliance and varying drug absorption. e research trend shows that more and more studies turn to basic research, and more drugs may be used to treat osteoporosis in the future. Timely bibliometrics and global analysis of all bisphosphates treatment for osteoporosis not only reveal the main countries, authors, and research impacts of the study but also provide information on the main research directions and trends, which will enable researchers to better understand the future direction. Predicting the fracture risk of osteoporosis patients in the future is still critical. More research into the usage of bisphosphonates in combination with other anti-osteoporosis treatments is needed in the future. Future study will focus on determining how to make the best use of existing treatments and develop better drugs.

Limitation.
Although bibliometrics is an effective method to evaluate article influence, there are still several limitations in our current research. First, only WOS was used to search the literature, not the existing Google academic, Medline, or other databases [39]. e number of citations of the report may be slightly different. Second, the main language of WOS is English, which may lead to the omission of relevant articles in other countries [40]. ird, the number of citations may be higher for the older research, but the older articles may not keep up with current research hotspots [41,42]. Newly published articles need more time to accumulate citations, and their influence may be underestimated [43]. With the continuous updating of the database, the bibliometrics analysis data may be different from the actual research situation, but the overall trend does not change much. Finally, one of the reasons for a high number of citations may be self-citation, including authors citing their own articles and authors citing more articles from the journals they want to publish [44]. Further research is needed to analyze the frequency of self-citation and its influence on the article. Despite these limitations, bibliometric analysis remains a valuable method for quantifying the number of articles published in various fields and providing a comprehensive overview of the literature. Our study is the first bibliometric analysis of bisphosphate for the treatment of osteoporosis. Moreover, our analysis can help clinicians better make treatment decisions and understand the future direction.

Conclusion
In summary, our study provides a detailed list and characteristics of the first 100 articles on bisphosphate for the treatment of osteoporosis. is analysis provides an accessible list for practitioners of endocrinology, pharmacy, epidemiology, imaging, surgery, and scientific research to identify the most frequently cited literature and better understand the future direction.

Data Availability
All data generated or analyzed during this study are included in this published article.

Ethical Approval
Our study was a retrospective assessment of the public data, so the approval of the institutional review committee is not required.

Conflicts of Interest
All the authors declare that no conflicts of interest exist and the manuscript is approved by all authors for publication.

Authors' Contributions
Yu Zhang and Man Hu contributed to protocol/project development, data analysis, and manuscript writing. Bo Meng, Junwu Wang, Pingchuan Wang, Pengzhi Shi, Xinmin Feng, and Yongxiang Wang contributed to data collection or management and data analysis. Lei Zhu, Wenjie Zhao, Xin Liu, Qing Peng, and Chen Chen assisted in the literature searching based on WOS and data analysis. Liang Zhang contributed to protocol/project development, data analysis, and manuscript editing. All the authors agreed on and approved the final manuscript for publication. e authors Yu Zhang and Man Hu contributed equally to this work and share the first authorship.