This study analyzed patient data from the SUNFLOWER study to investigate the treatment status and prevalence of comorbid hyperparathyroidism and its association with renal dysfunction in patients with XLH in Japan and South Korea. This analysis is important because the prevalence of hyperparathyroidism and its association with renal dysfunction in Japan and South Korea have been unknown for patients with XLH.

The median age was the highest in the patient group with tertiary hyperparathyroidism, followed by secondary hyperparathyroidism and then non-hyperparathyroidism (aged 45, 34, and 30, respectively). The year from diagnosis of XLH was 50.63 years in patients with tertiary hyperparathyroidism, which was longer than 10.84 years in patients with secondary hyperparathyroidism and 13.18 years in patients without hyperparathyroidism.

This study showed that 53.6% of patients with XLH in Japan and South Korea have hyperparathyroidism. The prevalence of secondary hyperparathyroidism was 47.8%, and that of tertiary hyperparathyroidism was 5.8%. At the time of informed consent, most patients were receiving conventional treatments such as oral phosphate therapy or active vitamin D. Patients with tertiary hyperparathyroidism had a lower eGFR and higher prevalence of nephrocalcinosis and tended to have a more advanced CKD stage than patients in the other two groups.

In the past, several studies have suggested a relationship between the risk of developing secondary/tertiary hyperparathyroidism in patients with XLH with or without conventional therapy [1, 14,15,16,17,18,19, 21,22,23]. In the present study, it is possible that the difference in the duration of treatment led to the risk of tertiary hyperparathyroidism because many patients were receiving conventional therapy with oral phosphate or active vitamin D at the time of informed consent.

In a previous study by DeLacey et al. [22], it was found that hyperparathyroidism can increase the risk of renal dysfunction. Our study also supports this finding, as we observed a similar trend. Our results suggest that patients with tertiary hyperparathyroidism have a higher prevalence of nephrocalcinosis and tend to have a higher CKD stage than those without tertiary hyperparathyroidism. Additionally, we found that renal function (based on eGFR) significantly differed according to hyperparathyroidism status, and patients with tertiary hyperparathyroidism had a lower eGFR than those without it. The study by DeLacey et al. also revealed that a patient with tertiary hyperparathyroidism tended to relapse to the same condition after parathyroidectomy. Still, this tendency was not confirmed because of the small numbers in the current study. These findings indicate that tertiary hyperparathyroidism may be the underlying cause of renal dysfunction in patients with XLH.

In addition to CKD, there are other factors contributing to hyperparathyroidism. Among them, the present study focused on (1) vitamin D deficiency, (2) the use of medications that significantly affect mineral metabolism, such as loop diuretics, (3) the use of antiresorptive drugs such as denosumab or bisphosphonates, and (4) primary or secondary aldosteronism. In this study, no patients had severe vitamin D deficiency (25(OH)D level < 5 ng/mL). Of note, there are two definitions for “severe vitamin D deficiency”: one is 25(OH)D level < 5 ng/mL, and the other is 25(OH)D level < 10 ng/mL. Although the second definition may be more common, we adopted the first definition according to Gani et al. [33]. Among the non-hyperparathyroidism, secondary hyperparathyroidism, and tertiary hyperparathyroidism groups, there were no notable differences in the prevalence of vitamin D deficiency, defined as 25(OH)D levels < 20 ng/mL. These results suggest that the impact of low 25(OH)D levels on the outcomes might be small. We also evaluated the prescription of loop diuretics or thiazide diuretics and confirmed that none of the patients were prescribed these medications. Unfortunately, information regarding antiresorptive drugs was not obtained in the present study. Additionally, primary or secondary aldosteronism, which is not a known complication associated with XLH, could not be evaluated or excluded in this study owing to a lack of relevant data.

The relationship between conventional therapy and the risk of developing secondary/tertiary hyperparathyroidism in patients with XLH may be related to a mechanism of secondary hyperparathyroidism caused by oral phosphate in which PTH rises to suppress a temporary increase in serum phosphate levels, resulting in secondary hyperparathyroidism [18]. If this stimulation of parathyroid glands by oral phosphate is repeated, the parathyroid tissue gradually alters to adenomas, and the patient develops tertiary hyperparathyroidism, a condition similar to primary hyperparathyroidism characterized by continuous inappropriate PTH secretion despite high serum calcium concentration.

Tertiary hyperparathyroidism is the same condition as primary hyperparathyroidism, except that the phase of secondary hyperparathyroidism is identified before the onset of the disease. It is known that renal dysfunction sometimes occurs in primary hyperparathyroidism secondary to excess calcium and phosphate urinary excretion [34]. Therefore, in treating patients with XLH, the dosage of oral phosphate should be adjusted within an appropriate range when using conventional therapy, based on calcium and PTH levels, to avoid progression from secondary hyperparathyroidism to tertiary hyperparathyroidism. Some physicians tend to increase oral phosphate too much to normalize serum phosphate levels. It should be noted that serum phosphate levels only increase for 1–2 h after administration of oral phosphate and that serum phosphate levels before oral administration are trough values [35].

Conventional therapy should not be used to normalize serum phosphate levels. Instead, it should be used to improve actual pseudo-fractures or improve biochemical markers (alkaline phosphatase or bone-specific alkaline phosphatase) to indicate treatment efficacy [1].

In cases where tertiary hyperparathyroidism does occur, parathyroidectomy should be undertaken. Furthermore, as mentioned above, patients with XLH who develop tertiary hyperparathyroidism once are prone to recurrent tertiary hyperparathyroidism after parathyroidectomy, and if conventional therapy is continued thereafter, the dosage should be carefully re-set, and calcium, PTH, and creatinine should be carefully monitored [22].

This study had some limitations. As this was a non-randomized observational study, the results may be influenced by selection bias and confounding variables. Although statistical methods were used to adjust the results, only measurable items can be controlled. There were not enough data available to assess the impact of active vitamin D and oral phosphate doses and the duration of this conventional treatment on the development of secondary and tertiary hyperparathyroidism and nephrocalcinosis. Compliance with the prescribed treatment and dosage is crucial for managing hyperparathyroidism. However, although dosing data were collected as far back as possible, the analysis was challenging because of the limited availability of clinical records and lack of precise information on the exact dose and duration of administration for many of the patients. Some patients had received treatment from multiple medical institutions for decades, making it challenging to obtain comprehensive records. As a result, we were unable to determine whether the development of hyperparathyroidism and nephrocalcinosis was related to the doses of oral phosphate and active vitamin D or the duration of administration. The present study was based on data collected at the time of enrollment, with hyperparathyroidism criteria also determined using test values obtained at that time. Consequently, the persistence of elevated iPTH levels over time is unknown. Because the SUNFLOWER study is a 10-year observational study running from 2018 to 2028, future analyses related to drug dosages and hyperparathyroidism may be considered. In addition, all patients with tertiary hyperparathyroidism in this study had previously undergone parathyroidectomy (specific details regarding the procedures were not obtained), and it was difficult to obtain data before the procedure. Therefore, to avoid misunderstanding, alkaline phosphatase and bone-specific alkaline phosphatase were not included.

In conclusion, among this cohort of patients with XLH, the prevalence of secondary hyperparathyroidism was 47.8%, and that of tertiary hyperparathyroidism was 5.8%. Ongoing treatment status showed that patients with secondary hyperparathyroidism and tertiary hyperparathyroidism were primarily treated with active vitamin D and oral phosphate. Calcimimetics were seldom used, with only two patients receiving cinacalcet. In contrast with non-hyperparathyroidism and secondary hyperparathyroidism groups, patients diagnosed with XLH and tertiary hyperparathyroidism exhibited a lower eGFR, a higher prevalence of nephrocalcinosis, and a tendency towards a higher CKD stage. Our study highlights the prevalence of comorbid hyperparathyroidism and its association with renal dysfunction in patients with XLH through a large-scale observational study in Asia. Despite some limitations, the findings can be useful for clinicians to provide a better clinical procedure for patients with XLH.