Chronic kidney disease (CKD) is defined by abnormalities in the kidney structure or function that present for 3 months or longer. A new classification system was proposed by the Kidney Disease Improving Global Outcomes (KDIGO), called CGA staging (cause, GFR, and albuminuria), which incorporated the glomerular filtration rate (GFR) and urine albumin-to-creatinine ratio (1).

CKD affects approximately 10% of the general population worldwide, and diabetes and high blood pressure are the most common causes of the disease (2). CKD–mineral bone disorder (CKD-MBD) is a complex syndrome defined by the KDIGO as a term used to collectively describe the mineral [e.g., phosphorus, calcium, parathyroid hormone (PTH)], bone (osteodystrophy), and soft tissue calcification abnormalities that develop as a complication of CKD. MBDs represent a clinical condition that, when present and not sufficiently controlled, is predictive of a very high risk of death and cardiovascular (CV) events (3).

Secondary hyperparathyroidism (SHPT) is a common complication of CKD and is a component of CKD-MBD that results from hyperphosphatemia, hypocalcemia, and the trade-off between hyperparathyroidism, decreased production of active vitamin D, and resistance to vitamin D (4).

The management of CKD, generally, should be based on the KDIGO clinical guidelines. Pharmacologic management of PTH, phosphorus, and calcium balance is essential in preventing the development of SHPT and in slowing down CKD and its associated consequences (1, 5).

In patients with stage 5 CKD who require PTH-lowering therapy, KDIGO suggests calcimimetics, calcitriol, or vitamin D analogs, or a combination of calcimimetics with calcitriol or vitamin D analogs (6).

The discovery of extracellular calcium-sensing receptors (CaSR) has prompted research on calcimimetic agents that allosterically modulate CaSR. CaSR have been identified in the parathyroid gland, thyroid, nephron, brain, intestine, bone, lung, and other tissues.

Calcimimetic agents increase the sensitivity of CaSR to extracellular calcium ions and inhibit the release of PTH, lowering its levels within hours of administration (7).

A few examples of calcimimetics include cinacalcet, etelcalcetide, evocalcet, and upacicalcet (8).

The term “calcimimetics” was coined by Nemeth et al. in 1990 and appeared in the public domain at the annual meeting of the American Society of Bone Mineral Research in 1993. The definition of “calcimimetics” is broad, representing all types of ligands that mimic the effects of extracellular calcium (Ca²⁺) on CaSR and inhibit the secretion of PTH.

Nemeth et al. classified calcimimetics into two pharmacological types: type I and type II. Type I calcimimetics act as agonists on the parathyroid cell CaSR. They do not require the presence of extracellular Ca²⁺ to affect PTH secretion. On the other hand, type II calcimimetics have no effects on the PTH secretion at very low or high concentrations of extracellular Ca²⁺, but shift the concentration–response curve for extracellular Ca²⁺ to the left, thereby lowering the half maximal effective concentration (EC₅₀) for extracellular Ca²⁺. This mode of action suggests that type II calcimimetics function as positive allosteric modulators of CaSR rather than simple agonists (9).

Calcimimetics reduce the serum levels of PTH and calcium, with a leftward shift in the set point for calcium-regulated PTH secretion. Calcimimetics are a potential alternative for patients contraindicated for parathyroidectomy (PTX) or those who had a failed previous PTX and have recurrent primary HPT. SHPT develops early in CKD and is present virtually in all patients with end-stage renal disease (ESRD). SHPT is a progressive disease and is associated with several systemic complications, including renal osteodystrophy, soft tissue and vascular calcifications, and adverse cardiovascular outcomes (10, 11).

In renal allograft recipients with tertiary HPT and hypercalcemia, calcimimetics comprise a promising treatment option to control the parameters of calcium phosphate metabolism and may be a valid alternative to PTX. Based on its unique mechanism of action, the calcimimetic cinacalcet may play a role in the medical treatment of the primary and tertiary forms of HPT, in addition to its registered indication for the treatment of SHPT.

One study revealed that calcimimetics have had no impact on the indications for surgery of tertiary hyperparathyroidism (12–14).

A lot of studies have investigated the use and effectiveness of calcimimetics in the management of electrolyte abnormalities in different diseases (15–18). The calcimimetic cinacalcet is the first agent in this class to be approved by the Food and Drug Administration (FDA) in March 2004 for the treatment of SHPT in end-stage kidney disease.

Etelcalcetide, another calcimimetic agent owned by Amgen and Ono Pharmaceuticals (Japan), was approved in February 2017. It is administered intravenously. While cinacalcet is an allosteric modulator of CaSR, etelcalcetide acts as a direct CaSR agonist (19). Cinacalcet has been demonstrated to be an effective agent for reducing and sustaining intact parathyroid hormone (iPTH) within target concentrations in hemodialysis (HD) patients. Cinacalcet offers an additional therapeutic option for lowering the iPTH when vitamin D cannot be increased due to elevated calcium or phosphorus. Cinacalcet is not FDA-approved for use in patients with CKD not receiving dialysis as it is associated with frequent hypocalcemic episodes (20). Nausea and vomiting are the most common adverse events associated with cinacalcet. Moreover, 66% of patients administered cinacalcet experience at least one episode of hypocalcemia (serum calcium <8.4 mg/dl) (21, 22).

Evocalcet, which has been approved by the Pharmaceutical Affairs Act in Japan, is another calcimimetic that has been proven effective in the management of SHPT, with lower incidence of gastrointestinal side effects compared with cinacalcet (23). Evocalcet has fewer gastrointestinal-related adverse events while suppressing PTH at a lower dose than cinacalcet. These data suggest that evocalcet may contribute to better adherence and sufficient dose escalation in patients with SHPT (24).

Upacicalcet is a novel SHPT drug that targets the amino acid binding site of CaSR. It is an intravenous calcimimetic agent developed by Sanwa Kagaku Kenkyusho (Nagoya, Japan) for the treatment of SHPT in patients undergoing HD. Upacicalcet received its first approval on June 23, 2021, in Japan (25, 26).

Over the past two decades, there has been an increased scholarly focus on calcimimetics in terms of quantitative data, but scarcely in qualitative aspects.

Africa, particularly Sub-Saharan Africa, faces major challenges with respect to CKD. There is an increasing prevalence due to the combined effects of hypertension, diabetes, and human immunodeficiency virus (HIV). Two systematic reviews that determined the prevalence of CKD in the general African population found a prevalence of 13.9% (27). African scholars need to be abreast of the latest management measures and updated guidelines for CKD treatment.

This study examines the implications of systematic and thematic trends through bibliometric analysis to assess the growth and evaluation of research across various scientific fields. The data from these studies were interpreted using various metrics to assess impacts and the performance indicators within research policies and the broader research ecosystem. Given the rising demand for these types of analyses, in particular among policymakers and funding agencies, they are becoming increasingly crucial for the evaluation of research productivity and impact within many scientific communities.

Bibliometric studies effectively track the overall research trends and analyze the connections between authors and research institutions. Therefore, this study aimed to examine the characteristics of the top articles on calcimimetics indexed in the Web of Science (WoS) and Scopus databases, employing both systematic and thematic analyses as approaches, which have gradually emerged as valuable methods in the professional community. The current investigation aimed to answer the following scientific inquiries.

In this review, we visualize the results obtained from the WoS and Scopus databases and summarize the research hotspots and development trends, as well as the research gaps. Building upon the practical consistency in exploring global trends in calcimimetic research using systematic and thematic analyses, this study examines the collection of comprehensive body of literature published over the past year. The goal was to contribute to the growing scientific body of evidence in the field of calcimimetics by tracking the growth of research on calcimimetics, understanding the key contributions of authors and the corresponding authorship countries, and exploring changes in the identification, analysis, and interpretation of the pattern themes, emerging topics, and authorship over time within qualitative data accessed in the field.

Since its introduction into the market, various quantitative systematic analyses have been published with regard to the use of calcimimetics. However, only a few qualitative analyses have been conducted to explore the literature on these issues. This bibliometric analysis provided an overview of the scientific publications, identified emerging trends and research topics on the use of calcimimetics, analyzed research collaborations, and highlighted influential research groups and collaborative clusters, as well as previous studies in different scientific fields. It also helps lay the groundwork for new or emerging aspects of topics within the area of calcimimetic research. The citation analysis of the published articles determined the most highly cited articles, emphasizing their great importance among scholars. The articles, published between 1997 and 2024, received 27.29 average citations per document and 10.23% international co-authorships. International co-authorships are widely encouraged by research funders in the belief that these are beneficial to scientific progress (30, 31).

M. Fukagawa from Tokai University, Japan, was the most prolific and active author, with 97 articles, total citation counts of 2,658, and an h_index of 25. M. Fukagawa also had the longest duration of research activity on calcimimetics (1999–2024). However, it is J. Bilezikian from Columbia University who had the highest number of publications calcimimetics per one year (n = 28) in 2003.

W. Goodman had the highest h_index (27), with 45 publications and 4,768 TNC. The h_index is an author-level metric that measures both the productivity and citation impact of a publication.

However, G. Chertow from Stanford University had the highest g_index (50), with 50 TNP and 3,740 citations. The high g_index reflects the depth of the impact of the articles published by this author, giving greater weight to highly cited papers. However, this author had fewer published articles than M. Fukagawa from Tokai University, Japan.

Based on research evidence, the most highly cited papers were published by G. Block. in 2004 in the New Engl J Med (853 citations), which explored the use of cinacalcet for SHPT in patients receiving HD. The study concluded that cinacalcet lowers the PTH levels and improves the calcium–phosphorus homeostasis in patients with uncontrolled SHPT receiving HD (32).

Among the hugely popular topics and highly cited articles published by Glenn M. Chertow in 2012, also in the New Engl J Med (with 687 citations), is the EVOLVE trial, which investigated the effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. The results of cinacalcet hydrochloride therapy for lowering cardiovascular events (EVOLVE) trial were inconclusive, and the study failed to show any statistically significant effect on its primary outcome, a composite of cardiovascular events and death. However, predefined secondary and post-hoc analyses of the EVOLVE trial suggested beneficial effects both in general and in subgroups. As a consequence of these mixed results, it was proposed that while cinacalcet could be used as one of several drugs to improve the achievement of biochemical control in CKD-related MBD as recommended by international guidelines, it should not be used with the purpose of decreasing the cardiovascular outcomes and/or improving survival (33).

After the EVOLVE trial, the focus moved to the impact of cinacalcet on hard clinical outcomes to assess its effects on cardiovascular calcification and the risk of cardiovascular events and mortality (34–36).

Two highly influential journals that significantly advanced research on calcimimetics were Nephrology Dialysis Transplantation and the Clinical Journal of the American Society of Nephrology, which received 5,568 and 4,251 citations, respectively. These most highly cited publications played a crucial role in broadening scholarly evidence with regard to the application of calcimimetics.

Most of the publications on calcimimetics were from the USA, Japan, and China. The USA was the most productive in single-country production with 841 articles, followed by Japan and China. In the top country categories, there were massive research contributions from developed countries. The findings of this retrospective study highlight the geographic distribution of the research contributions to the global research on calcimimetics. Notably, North America, Europe, and Asia emerged as the leading regions across all examined categories, including authorship, institutional affiliation, and funding sources in the publications indexed by WoS and Scopus. Calcimimetic documents received significantly more citations in countries such as the USA, Spain, and Japan compared with others, leading to improved research outcomes and journal metrics for both the authors and journals involved.

In contrast, regions with lower levels of contribution, Africa being one of them, require substantial support to enhance their research productivity, particularly in resource-limited settings. To enhance the research progress in other countries, we recommend breaking down barriers, encouraging both national and international fostering and both national and international collaborations, and fostering exchanges between various nationals and international organizations.

The large number of scientific institutions or affiliations involved (3,931) provided evidence that research institutions play a crucial role in driving the research productivity on calcimimetic-associated publications from the WoS and Scopus databases over the past years. Of these institutions, Amgen had greater influence with contributions in 245 articles, making it more likely to foster outstanding researchers and to make exceptional contributions in relevant calcimimetic-associated publications. This could be explained by Amgen being the first company to license cinacalcet. Cinacalcet is the first calcimimetic approved for clinical use under the brand name Mimpara^® in 1996 in Europe. In March 2004, the FDA also approved cinacalcet, which is marketed as Sensipar^® in the USA. Cinacalcet remains the most prescribed calcimimetic drug (37).

A significant correlation between the number of articles [the journal impact factor (JIF, 2023)] and the h_index was observed for the journals that published articles on calcimimetics from 1997 to 2024. For example, Nephrology Dialysis Transplantation published 112 articles (h_index = 43), followed by the Clinical Journal of the American Society of Nephrology and Kidney International [n = 56 (h_index = 34) and n = 49 (h_index = 31), respectively]. The Journal of the American Society of Nephrology had the least number of articles published [n = 31 (h_index = 21].

Across all branches of science in calcimimetic research published in the WoS and Scopus databases, all of the top 10 most cited articles were published in 1998–2011. Overall, these articles received more than 24,144 citations from global researchers.

“Cinacalcet” was the most explored calcimimetics by authors according to the keyword and KeyWords Plus analysis, in addition to PTH and hyperparathyroidism. This finding reflects the authors’ concern about the effect of calcimimetics on the management of hyperparathyroidism, which can result in extremely serious complications particularly for patients with CKD.

However, the research gap concerning the clinical usefulness of calcimimetics remains unaddressed, with the keyword and KeyWords Plus analysis failing to highlight this critical issue—particularly in light of the disappointing results from the EVOLVE trial in 2012 and the subsequent controversy.

The thematic evolution analysis showed that the research on calcimimetics evolved from fundamental studies on CaSR mechanisms and hyperparathyroidism treatment to new areas such as AI-based drug response predictions and novel calcimimetic formulations in light of the evidenced high adverse effect profile of many calcimimetics. Emerging themes in the phase of authors’ keywords suggest future research directions focusing on calciphylaxis, bisphosphonates, hypercalcemia, drug repurposing, kidney, and cardiovascular disease. Emerging themes in the phase of KeyWords Plus show new and growing topics by scholars such as research focused on SHPT, CKD, vascular calcification, and primary hyperparathyroidism.

The results of this study offer a summary of the global landscape, key research areas, and possible future directions in calcimimetic research. This information can assist researchers in exploring the knowledge structure and understanding future trends in calcimimetic research. Bibliometric studies such as this are valuable for researchers and policymakers, helping them evaluate and understand the knowledge structure and guide future development trends in calcimimetic research.

The strengths of this study include its provision of a qualitative and thematic analysis of the most comprehensive literature on calcimimetic research globally, highlighting how far scientific research and scholars have contributed over the past decades. We also recognize certain limitations of our study. We relied solely on the WoS and Scopus databases for identifying publications, which meant that studies indexed in other databases (e.g., PubMed, Medline, and Google Scholar) may have been overlooked. However, we believe that using the Science Citation Index Expanded of the WoS and the Scopus databases offers a strong foundation for the analysis of research performance in calcimimetics. In addition, we suggest that incorporating data from other sources would have introduced more diversity, leading to a more comprehensive bibliometrix analysis.

This study highlighted the extent of calcimimetic use and expanded the knowledge on the most prominent articles, authors, publishing journals, and countries. Support should be accorded to increase the publication and funding in low-resource settings with low publications. Furthermore, the collaboration analysis showed that there is a need for scientific health policies to promote international partnerships toward enhancing research infrastructure and to increase participation in global scientific collaborations. The aggregate response toward the collaboration issue can help in further understanding the global collaboration dynamics and improving the scientific cooperation between countries working in the field.

In terms of institution or university collaboration in global research productivity, there is a need for future research that could explore how these institutions’ varying centralities influence collaborative efforts and scientific advancements toward global calcimimetic-associated publications.