Phosphate is the most abundant anion, consisting of phospholipids and other intracellular compounds (1). Approximately 85% of total body phosphate is localized in the bones and teeth, 14% in the cells, and only 1% in the serum and extracellular fluids (2). It helps in energy storage and metabolism, regulates many coenzymes and oxygen transport, and performs other important biological functions for the immune and clotting systems (3). Therefore, its depletion can cause a broad spectrum of complications, including musculoskeletal, cardiovascular, neurologic, and hematologic disorders, through decreased intracellular adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) (4). However, studies on the prognosis and long-term adverse events of chronic hypophosphatemia are limited.

Even though phosphate homeostasis is finely mediated by three main regulators such as vitamin D, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23), hypophosphatemia (<0.80 mmol/L or <2.48 mg/dL) can occur owing to decreased intestinal absorption, internal redistribution, and increased renal loss (5). Among them, FGF-23-related hypophosphatemic diseases, where elevated levels of FGF-23 inhibit proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D (1,25D) are rare, including X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO) (6, 7). XLH is a form of heritable rickets caused by mutations in the PHEX gene (8, 9). TIO is an acquired paraneoplastic ricket induced by small, slowly growing tumors of mesenchymal origin or other rare tumors (10). Unfortunately, there have not been many studies or guidelines on either disease; thus, delayed diagnosis and treatment can contribute to increased risks of adverse outcomes and socioeconomic burdens (4).

Notably, epidemiological studies on chronic hypophosphatemia are still limited worldwide, with a focus primarily on the pediatric population and little emphasis on its long-term prognosis in adulthood (11). Furthermore, although burosumab, a recombinant human IgG1 monoclonal antibody against FGF-23, has been approved as a treatment for hypophosphatemic rickets in children and adults, patients in Korea are less likely to participate in randomized controlled trials than other ethnicities owing to a lack of epidemiologic research in the country (12).

Therefore, using the well-established Korean National Health Insurance Service (NHIS) database, this study aimed to explore the epidemiology of chronic idiopathic hypophosphatemia (CIH) in South Korea and investigated related complications and prognoses compared to the general population, regardless of exact etiologies.

This was the first nationwide population-based epidemiological study of CIH in South Korea, providing an overall age-standardized incidence rate of 0.28 cases per million. We observed a bimodal age distribution and no sex difference in the hypophosphatemic group. The complication risks for composite cardiovascular outcomes, heart failure, CKD, hyperparathyroidism, MOF, hip fracture, periodontitis, and depression were higher in hypophosphatemic patients than in age- and sex-matched controls. We also observed that hypophosphatemic patients had higher risks of mortality and hospitalization than the controls.

Phosphate homeostasis is maintained by a harmonized hormonal triad consisting of FGF23, PTH, and 1,25D (14). FGF23, primarily secreted by osteocytes, plays a critical role in this regulatory system (15). Prolonged increases in extracellular fluid phosphate levels stimulate FGF23 production, which subsequently reduces renal phosphate reabsorption, effectively counteracting hyperphosphatemia (16). Concurrently, a decrease in renal 1,25D production reduces phosphate absorption in the gastrointestinal tract (17). Overall, this endocrine regulation is to prevent hyperphosphatemia and maintain normophosphatemia. In contrast, lower extracellular phosphate concentrations lead to FGF23 downregulation, resulting in increased renal phosphate reabsorption and intestinal absorption, counteracting hypophosphatemia (18). FGF23 primarily modulates phosphate metabolism, while both PTH and 1,25D regulate phosphate and calcium homeostasis. These hormones exhibit reciprocal modulation of each other’s secretion. Hypophosphatemia arising from an intrinsic increase in FGF23 secretion is characterized by reduced phosphate reabsorption, low 1,25D, and high-normal PTH (19). Within the chronic idiopathic hypophosphatemia spectrum, two conditions, X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), are notably distinct (20).

Although a few epidemiologic studies have been conducted in other countries, their results should be interpreted with caution because of differences in their cohort populations. In southern Denmark, 112 patients with nutritional rickets were identified, indicating that the prevalence of hypophosphatemic rickets was 4.3 per million (21). A recent population-based study conducted in Norway identified only 28 patients with hereditary hypophosphatemia, among whom 21 children were confirmed to have XLH with a prevalence of 16.6 per million (22). Furthermore, an analysis of real-world data from the United Kingdom showed an increasing trend in the prevalence of XLH, from 3.0 per million in 1995–1999 to 8.1 per million in 2012–2016 by using the conservative definition (23). In the case of TIO, the incidence had been reported to be much lower than that of XLH, which estimates that the incidence of TIO in Denmark was below 0.13 per 100,000 person-years (24). In Japan, the first epidemiologic study regarding FGF23-related hypophosphatemic diseases, including both XLH and TIO, revealed that the estimated annual incidence rate was 117 cases (11). In this study, we could not distinguish each cause of CIH because specific ICD-10 codes for either XLH or TIO do not exist as diagnostic gold standards and orphanet codes are also not available in this cohort. However, we reported a total of 154 patients with CIH, providing an overall incidence rate of 0.28 per million. The etiology behind the lower incidence rate of CIH in Korea in comparison to other countries remains unclear. Setting operational definitions for CIH that are too conservative to accurately detect cases might contribute to missing more cases. Nevertheless, this was the first epidemiological study in South Korea on hypophosphatemia, possibly including XLH and TIO. Further nationwide cohort studies are needed to accurately identify the epidemiology of both diseases.

Few studies have reported the risks of long-term complications in patients with CIH. A Norwegian study reported that patients with hereditary hypophosphatemia, especially those who initiated early treatment and took higher daily doses of phosphate, were at high risk of developing nephrocalcinosis (22). However, our findings showed that the risk of renal stones was not increased in patients with CIH. Although higher risks of CKD and hyperparathyroidism, both of which are associated with renal stones, were observed in patients with CIH compared to their controls, monitoring of renal stones might not be performed owing to a lack of awareness of these diseases (4). Disruption of the physiological regulation of PTH secretion in CIH patients has been described in previous studies, although the interactions between phosphate, FGF23, and PTH remain unclear (1). Additionally, oral phosphate supplementation as a treatment for CIH can cause secondary hyperparathyroidism (25), which was also observed in our study. Interestingly, our study showed an increased risk of heart failure (approximately 6.1-fold) in patients with CIH compared with controls. The decline in 2,3-DPG in erythrocytes and the depletion of ATP in myocardial cells could both be contributing factors to hypophosphatemia-induced cardiomyopathy (26). Musculoskeletal complications related to hypophosphatemia included osteomalacia (MOF and hip fracture) and dental anomalies (periodontitis), which were also observed in our study. Regarding the higher risks of hip fractures than other sites, lifelong hypophosphatemia induces deterioration in the microarchitecture of the cortical bone, which causes osteomalacia in combination with skeletal deformities from childhood (27–29). Herrou et al. also found that adult XLH patients have a high prevalence of dental diseases because of the severity of osteomalacia (30). The association between hypophosphatemia and mood disorders has not been presented in previous studies. Suffering from chronic pain and taking multiple drugs lifelong can cause depression in CIH patients. Further studies are needed to clarify the direct association between CIH and psychiatric disorders. This higher risk of complications might contribute to an increased risk of hospitalization.

Additionally, we identified a higher risk of mortality in CIH patients. The association between hypophosphatemia and mortality among hospitalized patients has been consistently shown; however, the possible cause has never been clarified (31). According to the results of the study conducted in the United Kingdom, an unexpected increase in mortality in later life was observed in patients with XLH (23). The mechanism underlying the association between CIH and mortality is unknown; nonetheless, a higher risk of complications indirectly induces higher mortality. Furthermore, elevated levels of FGF23 are associated with increased vascular calcification and higher mortality, although future studies are needed to confirm these associations (32).

To our knowledge, this is the first Korean study to investigate the epidemiology and long-term events in CIH patients of all ages. Furthermore, our analysis of the risks of different complications in CIH patients can enrich the scope of research in this field. However, our study had several limitations. First, we used an operational definition for CIH based on diagnostic and prescription codes rather than the results of genetic testing for XLH and pathological findings for TIO. Additionally, the diagnosis of CIH may not be accurate since this cohort did not have data on phosphate and FGF23 for evaluating the state of hypophosphatemia. However, we have attempted to exclude patient groups, such as those with CKD or hyperparathyroidism that could develop the condition secondarily as possible to focus on the specific patient group with CIH. Second, the number of outcomes was small, which might limit the statistical analysis. Lastly, detection bias might contribute to more complications in patients compared to their controls.

In conclusion, our nationwide population-based study showed a small number of CIH patients in South Korea, which may be an underestimation. However, the risks of long-term adverse events and mortality were higher in these patients than in the control group. Therefore, early detection and an ideal treatment approach are needed to improve long-term adverse events of patients. Moreover, considering the limited information owing to its rarity, further studies with constant attention are required.

Publicly available datasets were analyzed in this study. This data can be found here: https://nhiss.nhis.or.kr/bd/ab/bdaba021eng.do. (The Korean National Health Insurance Service).

The studies involving humans were approved by Institutional Review Board of Severance Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because The requirement of informed consent was waived because All data were anonymized.

KK, NH and YR conceived and designed the study. KK, JS, JK, JL, and YR analyzed and verified the data. KK and YR wrote the manuscript. NH, SK, and JLperformed the critical reviews. All the authors contributed to the review and revision of the manuscript. The corresponding author attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted. All authors contributed to the article and approved the submitted version.