| Part 1.Hyperparathyroidism in X-linked hypophosphatemia:A cohort studyObject:X-linked hypophosphatemia,which is caused by the mutation of human PHEX gene,is the most common form of hereditary hypophosphatemia.Except for the manifestations of bone due to pathological mineralization,hyperparathyroidism is also a common complication.It has long been recognized that tertiary hyperparathyroidism is closely associated with phosphate therapy.Whereas the mechanism of secondary hyperparathyroidism,especially in untreated XLH patients has not been uncovered.At present,research on characteristics of XLH with concurrent HPT is insufficient.We aim to fully evaluate the prevalence and of HPT in Chinese XLH patients and explore its related influencing factors.Methods:A total of 165 patients who were diagnosed with XLH in the Department of Endocrinology of Peking Union Medical College Hospital from 2001 to 2020 were included if having concurrent measurement of intact parathyroid hormone(PTH)and serum calcium.Both adults(age>18 years)and non-adults(age<18 years)were included.The detailed medical history and medications of patient's were collected.We also recorded or examined the laborotary test,the HR-pQCT in part of the adult patients and renal utral sound in newly visit patients.We analyged the proportion of XLH patients with HPT and the characteristics of PTH fluctuations.Besides,patients were divided into HPT group and NHPT group according to the their baseline PTH levels.Moreover,they were divided into treatment and non-treatment group was based on whether they received traditional treatment or not at the very first visit.Biochemical parameters,renal calcification,bone microstructure changes were compared between the HPT and NHPT group.Correlation coefficient,Logistics regression and ROC analysis were performed to explore the potential influencing factors,including conventional therapy,biomarkers and the genotypoe of the occurence of HPT.Results:1.In the present cohort with 165 XLH patients(male:female=1:2,with 79 adults and 86 non-adults),we found that the prevalence of HPT among XLH patients in our center was 62.4%(103/165),1.2%(3/165)of the patients were eligible for tertiary hyperparathyroidism,all of whom were non-adults.SHPT occurred in 70.9%(56/79)of the adults and 52.3%(45/86).The median PTH of all patients was 76.4pg/ml.61.7%(58/94)of patients in the non-treatment group and 63.4%(45/71)patients in the treatment group had HPT.2.Compared to the NHPT group,patients in the HPT group had a higher proportion treatment(68.2%vs 48.1%,P=0.02),and longer duration of previous neutral phosphorus[NHPT group 0(0,18)vs HPT group 0(0,25)],P=0.006).HPT patients had lower median serum calcium level(2.3 1mmol/L vs 2.37mmol/L,P=0.011),a lower but non significant median serum phosphorus level(adults 0.65mmol/Lvs 0.60mmol/L,P=0.777;non-adults 0.80 vs 0.78mmol/L,P=0.842),and lower median 25OHD level(17.50ng/ml vs 28.0ng/ml,P<0.0001).Median FGF23 level was lower but non significant(17.95pg/ml vs 95.39pg/ml,P=0.524).3.The proportion of nephrocalcinosis in HPT patients was not increased compared with NHPT patients(17.9%vs 22.6%).HR-pQCT parameters were different in the distal radius but not in the tibia between the two groups.In the HPT group,Tb.N was much less(0.83 ± 0.16mm-1 vs 1.14±0.24 mm-1,P=0.002),Tb.Sp was much higher(1.24 ± 0.24mm vs 0.89±0.19mm,P=0.002)and Tb.1/N.SD was much higher(0.60±0.14 vs 0.39±0.10,P=0.001)than in the NHPT group.After adjusted for sex,age and BMI,in the distal radius,PTH level was showed a negative correlation between Tb.vBMD(r=-0.637,P=0.006),Tb.BT/TV(r=-0.569,P=0.017)and Tb.N(r=-0.743,P=0.001)in the correlation coefficient analysis.And a positive correlation between the Tb.Sp(r=0.686,P=0.002)and Tb.1/SD(r=0.766,P<0.0001)was observed.In the distal tibia,PTH level was showed a negative correlation between Tb.N(r=-0.521,P=0.039)with sex,age and BMI controlled.4.After adjusted for age and sex,PTH level was negtively correlated with 250HD(r=-0.418,P=0.009;r=-0.421,P=0.001)in the whole population and NHPT group.In the untreated group,PTH level was negtively correlated with serum Pi(r=-0.222,P=0.034)but no corrolation was found after the adjustment.A positively correlation(r=0.402,P=0.004)was observed between PTH and 1,25(OH)2D in the non-treatment group,while he correlation reversed in the treament group(r=-0.385,P=0.025).No correlation was observed in any group between PTH and FGF23 or between PTH and calcium.5.In the ROC analysis,calcitriol dose predicted the occurrence of HPT at 1 year with an AUC of 0.705(95%CI 0.532-0.877,P=0.035),the cut-off point was less than 23.55ng/kg/d(sensitivity 72.7%,specificity 74.0%).6?Correlation coefficient analysis showed a positive correlation between the term of neutral phosphorus therapy(r=0.247,P=0.006)and the occurrence of HPT,while gender and mutation genotype of PHEX played no role.We found that age was a predictor of HPT in the univariant logistics regression model,for a 1-year increase in age,the odds increased by 2.6%(OR 1.026[95%CI 1.001-1.052],P=0.038).In the mutiple logistics regression model,those treated with 30.4%-63.5%of life with neutral phosphorus had higher odds of HPT(OR 14.028[95%CI 1 1.032-190.66],P=0.047).When the 25(OH)D level is above 17.5ng/ml,the odds of HPT was lower then those with 25(OH)D level less than 17.5ng/ml(OR 0.154[95%CI 0.026-0.924],P=0.041).Conclusion:This study is the largest scale cohort study focused on HPT in XLH patients.No such studies has been presented in China.The present research found that a considerable proportion of HPT in Chinese XLH patients.Elevated PTH aggravated the trabecular bone structure,but did not increase the risk of renal calcification.The occurrence of HPT in the non-treatment group may be related to the abnormal regulation of FGF23-1,25(OH)2D and PTH secretion.The increase in PTH of the treatment group is mainly related to phosphate therapy duration and insufficient calcitriol,increasing 25OHD level can improve the situation in our patients.Part 2.The efficacy and safety of different dose of calcitriol combined with neutral phosphate in children with X-linked hypophosphatemia:a prospective studyObject:X-linked hypophosphatemia(XLH)is a rare bone mineral deficits disease due to renal phosphate loss.A combination of calcitriol and neutral phosphate has been the conventional pharmacological treatment for decades and remains the main therapy in China and most developing regions.However,randomized studies are lack for the proper dose of calcitrol in the clinical practice.We aimed to assess the efficacy and safety and in children with X-linked hypophosphataemia,as a solid reference for the clinical work.Methods:The study was a single center,randomized,open-label,prospective trial performed at the Department of Endocrinology,Peking Union Medical College Hospital(PUMCH).Patients of XLH aged 1-12 years of both genders were screened with stict inclusion and exclusion critera from July 2017 to January 2018.A total of 68 patients met the inclusion criteria have been randomizedly assigned into two different calcitriol groups.Calcitriol dose was 40ng/kg per day with a min dose of 0.5 ug/d and a max dose of lug/d in the high dose group.The dose was 20ng/kg per day with a min 0.25 ug/d to a max 0.5ug/d in the low dose group.Oral phosphate receipt was a mix powder of Na2HPO4(29 g)and KH2PO4(6.4 g)melted in 1L distilled water,phosphate content was 779 mg/dl.Dose of calcitriol was adjusted to 40ng/kg/d when serum ALP and PTH level increased over 30%or no improvement in total RSS score compared to the last visit.Dose of calcitriol decreased to 20ng/kg/d when serum calcium level was over the upper limit,24h urine calcium level over 4 mg/kg,newly developed or worsen grade of nephrocalcinosis appeared during visit.Severity of rickets was evaluated by radiograph,laboratory examinations and clinical symptoms.The primary efficacy endpoint was total RSS change from baseline to 24th month.Secondary efficacy endpoints included total RSS change from baseline to 12th month.Change from baseline in fasting serum TALP levels,fasting serum phosphorus levels,body height Z-score,frequency of dental abscess and bone pain.Safety assessments were adverse events occurred at any time during the study.Gastrointestinal adverse reactions,renal ultrasound nephrocalcinosis grades(0-4),fasting serum calcium and PTH level were included.Results:1.During the observation period,65 patients(35 in the high dose group and 30 in the low dose group)finished at least one post baseline visit were included in the modified intention to treat analyasis.The average age of the participants were 6.12±2.83 with a mean RSS of 5.61(lowest 2.5 and highest 10.0)and height Zscore of-2.065±1.05.1 patient in the high dose group and 4 patients in the low dose group had drug adjustment.53 patients(33 in the high dose group and 20 in the low dose group)was included in the PP analysis.2.For the primary endpoint,the decreasing of the total Thatcher rickets severity score(RSS)at 12 months and 24 months from baseline was greater in the high dose group than in the low dose group[12months:mean change from baseline 1.04 vs 0.17,respectively,difference 0.87,P=0.049;24months:mean change from baseline 1.82 vs 0.58,respectively;difference 1.24,P=0.011.For the secondary efficacy points,Z-score of body height improvement showed no difference between groups.But both showed improvement at 24 months within groups[low dose group-1.92±0.94 vs-2.14±1.05,.P=0.021;high dose group-1.96± 1.04 vs-2.17±1.03,P=0.002].Height Z score also showed improvement at 12 months(-1,96±1.04 vs-2.11±1.06,P=0.017).Serum ALP level was significantly lower in the high dose group since month 6 and remained to month 24.Serum Pi level at month 24 improved significantly compared to baseline[high dose group Pi(mmol/L)0.93(0.77,1.24)vs 0.83(0.56,1.44),P=0.001;low dose group Pi(mmol/L)0.83(0.75,1.28)vs 0.83(0.59,1.24),P=0.013)],no great difference was observed between the two groups.Severity of bone pain and the frequence of tooth abscess showed no difference between groups.3.There was no significant difference in the blood calcium during the follow-up period between the two groups.The 24-hour urine calcium at month 24 in the high dose group was higher than that of the low dose group(median level 2.36mg/kg/24h vs1.04mg/kg/24h,respectively,P=0.016).Secondary hyperparathyroidism were observed in both groups,with a lower incidence in the high dose group(20%vs 30.0%,P<0.0001).De novo nephrocalcinosis happened in both groups and the ratio was not significant.Conclusion:The efficacy and safety of the combination of calcitriol and neutral phosphate was well accecpted.Compared with 20ng/kg/d,the 40ng/kg/d dose of calcitriol showed more effective to relief the rickets of XLH in children,with similar safety.In summary,a high dose of calcitriol was recommended in XLH pediatrics. |
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