The efficacy and safety of different doses of calcitriol combined with neutral phosphate in X-linked hypophosphatemia: a prospective study

X-linked hypophosphatemia (XLH) is recognized as the most common genetic cause for the rickets. Loss-of-function of PHEX (phosphate-regulating endopeptidase homologue, X-linked) gene causes the elevated levels of Fibroblast growth factor 23 (FGF23) [1, 2]. Most manifestations of XLH are caused by FGF23-induced hypophosphatemia leading to downregulation of sodium-phosphate transporters in the renal distal tubule along with the repression of serum 1,25OH₂D [3]. The features of XLH is more apparent in the first or second year of life. However, early treatment for the disease is related to the better outcomes [4, 5], and therefore, pharmaceutical therapy in pediatrics patients play a key role. Since the 1980s [6], conventional therapy for XLH have been associated with the multiple daily doses of oral phosphate and one or more daily doses of active vitamin D (calcitriol or alfacalcidol). Although conventional therapy leads to variable improvement in the clinical features of rickets, it is also associated with the adverse effects such as nephrocalcinosis and hyperparathyroidism. Hence, standardized drug application along with the close monitoring for adverse events are highly warranted. The published guidelines recommends 20–30 ng/kg body weight daily dose of calcitriol in XLH children [7, 8]; however,other reported doses of calcitriol vary widely, ranging from 10 to 80 ng/kg/day. Moreover, there is a lack of randomized controlled trials for assessing the clinical evidence for the efficacy and safety of calcitriol in Chinese XLH patients or any other population. We previously reported that in the largest XLH cohort (N = 261), less than 50% had previous treatment of oral phosphate and calcitriol, out of which 34% patients had received irregular treatment prior the confirmation of the diagnosis [4]. In addition, the XLH children response to treatment varies greatly among individuals. Therefore, systemic evaluation of the drug therapy is very essential.

Calcitriol promotes the absorption of calcium and phosphorus in the intestines and reabsorption in the renal tubules. It directly participates in the regulation of osteogenesis and osteoclast activity, further improving the skeletal microarchitecture and bone strength in the absence of phosphate in XLH [9]. Therefore, a higher dose of calcitriol may better improve bone rickets and promote growth in children. On contrary, excessive use of calcitriol increases the risk of hypercalcemia, and nephrocalcinosis. In 2018, burosumab (a fully human monoclonal antibody against FGF23) was approved for the treatment of X-linked hypophosphatemia, which showed effective and promising results in children and adults, especially a superior efficacy compared to conventional therapy in phase 2 and 3 trials [10‐13]. However, an extended observation period is required prior to the burosumab general use in XLH patients, still, it cannot be used widely owing to its high price. Therefore, conventional therapy remains the primary choice in China’s population. Therefore, this prospective, randomized, open-label trial was conducted to observe the effects of higher and lower doses of calcitriol combined with neutral phosphate solution in the early treatment of XLH patients.

Although XLH has been recognized for decades, due to the disease’s rarity and the diversity of clinical manifestations, diagnosis is often delayed, and therefore treatment can be challenging [8]. This present study conducted the first prospective study on large cohort to explore the efficacy as well as the safety of high-/low-dose calcitriol combined with neutral phosphorus in treating children with XLH.

At baseline, patients in these two groups shared same severity of rickets and other clinical features. Although more girls were included in the low-dose group than in the high-dose group (70% vs. 40%), patients were enrolled and assigned randomly with no sexual preference. All patients reported good drug adherence during the entire study. Notably, at the time of enrolment, participant’s baseline total RSS (5.13 ± 1.75) was much higher than the previous study, although a majority (87.6%) of patients were previously treated. In a prior study, mean total RSS scores of 1.8 and 3.0 were reported by Carpenter et al. and Imel, E. A. et al., respectively [10, 13]. As treatment initiation at early infancy (< 1.0 year) results in improved outcomes in patients with XLH [5], we assumed that the relatively late diagnosis and treatment in our cohort (median age of 2.19), might have contributed to the relatively severe disease burden.

The ALP levels are reported marker reflecting the bone mineralization status in rickets. A previous study has reported decreased ALP concentrations to the upper limit of normal in one year for the conventional therapy [17]. We observed that the ALP level in the high-dose group was significantly lower than the low-dose group after 6 months of treatment. In the 24th month, the average ALP level in the high-dose group almost comparable to the normal range. In line with Thacher et al., who reported an improvement in RSS correlated with decreased serum ALP (r = 0.47) in 5- to 12-year-old patients [15], our study has also observed a mild correlation at 24 months. However, the ALP activity had an increase in the low-dose group, which was not found in the previous study [13]. This might be due to the insufficient efficacy of low-dose calcitriol for improving the rickets severity. Besides, the control of the ALP level in the high-dose group were far from satisfactory, which also might be a limitation of the conventional therapy.

Consistent with the previous study, improvement of height Z-score was observed at 24 months in both groups (Fig. 3C) [18, 19], whereas no difference was observed between the groups. Low dentin mineralization, abnormal pulp, and periodontitis are common the abnormalities associated with the X-linked hypophosphatemia, though severity might vary among the patients. Previous reports have suggested that conventional therapy can improve the dentin mineralization as well as decreases the risk of dental abscesses and severe periodontal disease over the years [20, 21]. In the present study, the frequency of dental abscesses was measured by three degrees. Interestingly, the ratio of aggravated dental abscesses was higher in the high-dose group at 24 month, though the ratio could not be correlated with the improvement of rickets or the correction of the serum phosphate. As dental development and abnormalities acquired in utero may alter the response of dental anomalies in children, more extended observation is required for the proper explanation of such incidences.

In safety events, conventional treatment with phosphate supplementation and active vitamin D might increase calcinuria risk and promote nephrocalcinosis in 60% of children with XLH [22]. In our study, the percentage was much low, where both treatment groups shared a similar ratio of de novo nephrocalcinosis. Additionally, urinary calcium at 24 h was also not different between the two groups. Hyperparathyroidism is another commonly reported adverse event observed in adult and pediatric XLH patients during conventional treatment [23, 24]. Recently, a retrospective study reported an 81.8% secondary hyperparathyroidism ratio in 44 XLH children [25]. In addition, we previously reported elevated serum PTH levels in 59.2% of XLH patients (N = 61/103) [4]. In the current study, some patients in both groups developed secondary hyperparathyroidism; however, serum PTH levels varied among these patients. Six patients (4 in the high-dose group) had continuously excessive PTH levels, and the others had intermittently elevated PTH levels. No patients had hypercalcemia and hyperparathyroidism. It could be specifically related to oral phosphate, since a recent study demonstrated that phosphate directly regulates PTH secretion through calcium-sensing receptors on parathyroid cells [26]. To understand this further, we compared PTH value in patients who have or have not demonstrated increased serum phosphate values (Supplementary Table S4). Although PTH levels were higher, no significance observed in patients with increasing Pi value. We previously published that higher PTH level were more persistent in the hypophosphatemic patients than the control group after the oral phosphate loading test [27, 28]. Thus, it was reasonable to correlate the occurrence of hyperparathyroidism with oral phosphate usage, as we presumed that in hypophosphatemic patients, parathyroid might react more sensitively to the phosphate load. Nevertheless, hyperparathyroidism prevalence can be reversed by a higher compensation of 1,25(OH)₂D.

The present study had several limitations. First, the trial was open-label; thus, the adjustment upon the occurrence adverse drug reactions was done. It was done to ensure the therapeutic effect and avoid further aggravated adverse reactions. Moreover, to make the results reliable, two different physicians independently assessed the rickets severity score, and a central laboratory assessed pharmacodynamic measures. Another limitation was that we did not compare the FGF23 level before and after the treatment, which might be one of the reasons for increasing level of the serum FGF23, which may further diminish therapeutic effect or contribute to the complications of therapy. It is well established that calcitriol increases osteoblastic production and the serum levels of FGF23, even in healthy individuals [29‐31]. However, in our previous study, which included 261 Chinese XLH patients, serum iFGF23 levels did not correlate with serum phosphate/upper limit ratio, age at which disease symptom developed, height SDS, or RSS [4]. This result could provide us with evidence that might be helpful to interpret the severity of the disease from the level of FGF23. Further studies are expected to validate and interpret these findings. As we used fixed dose of phosphate in both groups, more systematic evaluation on both conventional drugs could not be performed. Further studies are required on varied drug doses to provide more robust evidence.

For the first time, the current study compared the different doses of calcitriol in a relatively large cohort of Chinese XLH patients. The higher doses of calcitriol (40 ng/kg/day) in the treatment of children with XLH tend to have better efficacy within the acceptable safety. This study provides evidence-based medical evidence for the optimal therapeutic dose of calcitriol for treating children with XLH. Moreover, the study results can be used as an essential theoretical support for clinical guidelines and consensus in this field. Further studies are required on the larger sample size and extended follow-up time for validating the findings of this study.