The Most Cited Papers in Osteoporosis and Related Research

Osteoporosis is a systemic disease of the bone that affects millions of people and causes burden for both the affected individual and health systems and societies worldwide. Since the 1970s much research has been done in the field of osteoporosis. The number of citations of a paper reflects its influence and importance to the field. Thomson ISI Web of Science database was searched to retrieve a list of the fifty most cited articles related to osteoporosis and its research. The fifty most cited articles in absolute numbers in the field of osteoporosis were cited from 877 to 3056 times (mean 1141 ± 537). Most papers were published in the basic science category (n = 23). 395 authors contributed; a single paper had between one and 62 authors (mean: 10.02 ± 9.9 authors). 12 authors (3.04%) contributed between 7 and 4 papers; 340 authors (86.1%) were at least named once. Corresponding authors were from eight countries with most contributions from the United States (n = 34, 68%). The majority of papers were published in the 1990s (n = 29). The list of 50 most cited papers presents citation classics in the field of osteoporosis and related research.


Introduction
Osteoporosis is a systemic disease of the bone that affects millions of people and causes burdens for both the affected individual and health systems and societies worldwide [1]. Osteoporosis is a multidisciplinary disease and therefore relevant to different medical specialities, for example, general medicine, internal medicine, endocrinology, gynaecology, orthopaedic surgery, and traumatology, but also to preclinical and basic disciplines such as physiology, pathology, and biomechanics.
Since the 1970s much research has been done in the field of osteoporosis. Research in osteoporosis poses a wide field and includes basic, clinical, and translational studies in the above mentioned specialities. Meanwhile several journals have been established that are dedicated to publishing articles related to the disease.
A citation is a quotation or a reference of published scientific work in books, book chapters, or articles [2]. The number of citations of published scientific work has been used as a marker to evaluate the level of its influence and importance. However, the number of citations may not be the only factor in determining the importance of scientific work in the field, but allows defining "citations classics" that could be used, for example, for educational purposes. Furthermore, the number of citations directly influences the impact factor of a journal, a generally accepted factor that determines its quality and importance [2].
The purpose of the present study is to determine scientific articles in the field of osteoporosis and related research that have been cited most frequently by other authors and to establish a ranking of the fifty most cited papers in the field by using the Thomson ISI Web of Science database. "osteoporosis, " "fracture, " "bone mineral density, " "bone density, " "bone mass, " "BMD, " "dual energy X-ray absorptiometry, " "DXA, " "DEXA, " "osteoclast, " "osteoblast, " "osteocyte, " "bone formation, " "bone resorption, " "hormone replacement therapy, " "estrogen replacement therapy, " "bisphosphonate, " "teriparatide, " "denosumab, " and "SERMs. " All papers with the main focus of their research on osteoporosis and related basic, clinical and translational research were included in this study. Papers including the above used terms, but focusing on other research areas were excluded. The search output was then recorded and ranked according to the absolute number of highest citations. In cases with an identical absolute number of citations, the papers that had a higher citation density (see below) were ranked higher. A list of the fifty most cited articles was established.
Searches and analyses were done by individuals with a long-time experience in both basic and clinical research in osteoporosis.

Data Analyses.
Each of the fifty most cited articles was reviewed and the following data was extracted: number of citations, authors, article title, journal title, publication year, and origin of corresponding author. Each paper was assigned to a single country in accordance with the corresponding author's address because the corresponding author is usually primarily and mainly responsible for the whole study project [18]. To evaluate the relative impact of a published paper, the citation density ("number of citations/years since publication") was calculated as described before [12]. Furthermore, each article was analyzed and in case of a clinical study a level of evidence was attributed to the paper based on the guidelines for clinical articles by Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence (Oxford, UK: http://www.cebm.net/) [19]. Three categories were established: basic science, clinical science, and reviews and guidelines. The papers were analyzed and attributed to one of these categories.

Results
The fifty most cited articles on osteoporosis and related research were cited from 877 to 3056 times (mean 1141±537), the top ten papers at least 1741 times. For the whole list see Table 1. The most frequently cited paper was by Lacey et al. published in 1998 with a mean number of 184,5 citations per year. The top ten papers according to citation density can be seen in Table 2. The majority of articles could be attributed to the basic science category ( = 23). The distribution of the other categories can be seen in Figure 1. Level of evidence could be analyzed in 17 clinical papers (from the Clinical Science category) and can be seen in Table 1. The majority of papers ( = 13) were level of evidence I, one paper was level of evidence II, and three papers level of evidence III (see Figure 2).
Eleven search terms were found in the title of the papers; altogether these terms were found 70 times (mean: 6.4 ± 5.5 times). For the list of all search terms found see Table 3. Search terms "fracture" ( = 18) and "osteoporosis" ( = 14)  were found most frequently (45.7% of all terms searched).
Other terms searched were found between one and nine times (mean: 4.2 ± 2.9 times). More search terms were found in the abstract and the keywords of the papers. All together 395 authors contributed to the papers of the top 50 list. A single paper had between one and 62 authors (mean: 10.02 ± 9.9 times). 12 authors (3.04%) contributed to between seven and four papers, 13 authors (3.3%) to three, and 30 twice (7.6%). 340 authors (86.1%) were named at least once. The top 12 authors are presented in Table 4.
Eight countries contributed to the Top 50 list (see Figure 3). Authors from the United States contributed most frequently as a corresponding author ( = 34, 68%), followed             paper each. The distribution of the most cited papers in the various journals can be seen in Figure 4. The number of most cited papers according to the decade of publication can be found in Figure 5. The majority of papers were published since 1990 ( = 39), whereas there is just one in the 1960s. Eight of the top 10 papers according to the citation density were published in the 1990s.

Discussion
In this study, Thomson ISI Web of Science was searched to analyze the most cited papers on osteoporosis and related research and to define a list of "citation classics" in this field.
In order to identify the most cited papers and cover all aspects and the whole field of osteoporosis and related research not only the term "osteoporosis" per se, but also processes involved in the biology and pathology of bone and bone metabolism as well as risk factors and the consequences of the disease were used. Furthermore, diagnostic and therapeutic options were considered. Altogether 20 search terms were used. The majority of articles could be attributed to "fractures" and "osteoporosis" (45.7% of papers altogether). This underlines the magnitude of osteoporosis and osteoporotic fractures. Eleven out of 20 search terms were found in the title of the papers, others in the abstract and     keywords. All keywords were found, but some papers did not reach enough citations to be put onto the list of the Top 50. Articles on osteoporosis and related research were cited up to 3056 times; the top ten papers according to absolute numbers were cited at least 1744 times. This fact shows the importance of osteoporosis as it affects a large number of patients worldwide and being of interest for many different medical specialities. Papers on other conditions such as acute pancreatitis had a maximum of 1281 citations [13]; the highest cited papers on septic conditions reached 2932 [14], whereas papers on epilepsy were cited even more frequently than osteoporosis (3749 citations) [15]. Top ranked articles in other fields such as papers on arthroscopic surgery or trauma reached about 500 citations [9,10]. In orthopaedic paediatrics just four papers reached 100 citations [11].
The most cited paper in the present list was cited 3056 times. It is the oldest in the list and was published by a single author in 1956. The reason why this paper has been cited so often could be that "bone morphogenetic proteins" were described and for years their existence seemed to be the core of possible solutions for all aspects in bone metabolism [20].
395 authors contributed to the papers of the top 50 list. This reflects the wide range of osteoporosis and related research. Some authors contributed more than once; one author contributed seven times (Steven C. Cummings).
All papers were published in English. This clearly demonstrates the predominance of the English language in publications on osteoporosis and related research.
The spectrum of osteoporosis is also expressed in the large number of journals in which results of osteoporosis research are published. Papers were published in 18 different journals. Although there are journals focusing on osteoporosis itself and, more generally, on bone and bone metabolism, studies are also published in journals with a wide spectrum and more general medical background as such.
Papers were attributed to three different categories. Their distribution can be seen in Figure 1. Most papers were focusing on basic science.
Evidence Based Medicine has been introduced just recently using levels of evidence. Level of evidence could be analyzed in 17 clinical papers (from the Clinical Science category). According to the guidelines of the Oxford Centre for Evidence-Based Medicine the majority of articles ( = 13) were level of evidence I, one paper was level of evidence II, and three papers level of evidence III. This points to the fact that there is a high quality of study design and evidence in clinical osteoporosis research.
Interestingly, the majority of papers were published since 1990 ( = 39), whereas there is just one from the 1960s. Although bone changes were recognized quite early many significant advancements have been made in recent years.
Considering this trend further developments in the field are to be expected.
This study has limitations. Identifying the 50 most cited papers they still remain a selection although using well defined criteria. So, important and influential papers with lower citation frequency might have been missed. In some cases the value of contribution to the field cannot be quantified by the number of citations. However, with respect to the aim of this study a bottom line is drawn. This approach seems to be more objective. Any other selection based on the importance of papers would depend on personal favour. The absolute or relative number of citations of articles can be influenced by several factors and does not necessarily reflect the importance of research that has been performed or has been published [12], nor does it directly translate into clinical practice changes. The search was performed in the Thomson ISI Web of Science database. Therefore citations of articles from other sources, such as textbooks, lectures, or digital media could not be considered. Another weakness might be the cross-sectional study design and research at a single point in time with focus on the absolute number of citations.
A list of 50 most cited papers in osteoporosis and related research covers a broad range of medical subspecialities. This is reflected by the number of journals and decades. Studies focusing on basic and clinical science of osteoporosis mainly dominate the literature in respect to absolute citations numbers. Considering the high number of high impact papers in the last two decades further developments in the field are to be expected.