J Pediatr Endocrinol Metab 2021; 34(6): 791–798

Daisuke Harada*, Kaoru Ueyama, Kyoko Oriyama, Yoshihito Ishiura, Hiroko Kashiwagi,
Hiroyuki Yamada and Yoshiki Seino

Switching from conventional therapy to

burosumab injection has the potential to prevent
nephrocalcinosis in patients with X-linked
hypophosphatemic rickets
https://doi.org/10.1515/jpem-2020-0734 intact parathyroid hormone during conventional therapy
Received December 23, 2020; accepted March 8, 2021; was increased within the normal range by switching
published online April 12, 2021 treatments.
Conclusions: Our results suggest that a high dose of alfa-
Abstract
calcidol was needed to control the disease, but it caused
hypercalciuria and NC. We concluded that switching
Objectives: X-linked hypophosphatemic rickets (XLH) is a
treatments in relatively well-controlled XLH children
congenital fibroblast growth factor (FGF)23-related meta-
improved renal phosphate reabsorption and decreased
bolic bone disease that is treated with active vitamin D and
urine calcium extraction, and may have the potential to
phosphate as conventional therapies. Complications of
prevent NC.
these therapies include nephrocalcinosis (NC) caused by
excessive urine calcium and phosphate concentrations. Keywords: burosumab; hypercalciuria; nephrocalcinosis;
Recently, an anti-FGF23 antibody, burosumab, was devel- neural phosphate; vitamin D; X-linked hypophosphatemic
oped and reported to be effective in poorly-controlled or rickets.
severe XLH patients. This study aimed to reveal the impact
of switching treatments in relatively well-controlled XLH
children with the Rickets Severity Scale less than 2.0.
Introduction
Methods: The effects of the two treatments in eight rela-
tively well-controlled XLH children with a mean age of
X-linked hypophosphatemic rickets (XLH) [OMIM#307800]
10.4 ± 1.9 years were compared retrospectively for the same
is a congenital metabolic bone disease characterized by
treatment duration (31 ± 11 months) before and after the
short stature, genu varum/valgum, fraying, or cupping in
baseline.
the metaphysis, and increased serum alkaline phosphatase
Results: Actual doses of alfacalcidol and phosphate as
(ALP), caused by hypophosphatemia [1–3]. XLH is caused
conventional therapy were 150.9 ± 43.9 ng/kg and 27.5 ± 6.3
by mutations in the phosphate regulating neutral endo-
mg/kg per day, respectively. Renal echography revealed
peptidase (PHEX) gene [OMIM*300550] and is inherited as
spotty NC in 8/8 patients, but no aggravation of NC was
an X-chromosomal dominant trait [4]. Although the path-
detected by switching treatments. Switching treatments
ogenic mechanisms are not understood completely, the
increased TmP/GFR (p=0.002) and %TRP (p<0.001), and
hypersecretion of fibroblast growth factor 23 (FGF23) in
improved the high urine calcium/creatinine ratio to the
XLH patients decreases vitamin D activation and sup-
normal range (p<0.001) although both treatments
presses the reabsorption of phosphate (P) in renal tubules,
controlled disease markers equally. Additionally, low
leading to hypophosphatemia [5, 6].
Active vitamin D and phosphate are administrated to
*Corresponding author: Daisuke Harada, MD, PhD, Department
XLH patients as conventional therapies to improve hypo-
of Pediatrics, Osaka Hospital, Japan Community Healthcare phosphatemia and rickets [7]. In adulthood, nephrocalci-
Organization (JCHO), 4-2-78 Fukushima, Fukushima-ku, Osaka nosis (NC), nephrolithiasis, and impaired renal function
553-0003, Japan, Phone: +81 6 6441 5451, Fax: +81 6 6445 8900, occur in XLH patients as complications related to conven-
E-mail: harada-d@nifty.com tional therapy [8, 9]. NC is caused by hypercalciuria and
Kaoru Ueyama, Kyoko Oriyama, Yoshihito Ishiura, Hiroko Kashiwagi,
excessive urine P concentration [10–12]. Because NC can
Hiroyuki Yamada and Yoshiki Seino, Department of Pediatrics, Osaka
Hospital, Japan Community Healthcare Organization (JCHO), Osaka, cause nephrolithiasis, careful follow-up is essential [13, 14].
Japan Although conventional therapy is moderately effective for

Open Access. © 2021 Daisuke Harada et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0
International License.
792 Harada et al.: Burosumab does not develop hypercalciuria and nephrocalcinosis

XLH, oral active vitamin D and phosphate, or both, can this study. Informed consent was obtained from all individual par-
promote or worsen NC related to drug-induced hyper- ticipants included in this study.

calciuria in addition to the impaired reabsorption of phos-

phate by the disease itself [7, 15, 16]. Treatments
Recently, an anti-FGF23 antibody, burosumab, was
developed as a fundamental treatment for FGF23-related For conventional therapy, 50–100 ng/kg per day of alfacalcidol
hypophosphatemic diseases [17–19]. Compared with con- (Alfarol®, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan, or Onealfa®,
Teijin Pharmaceutical Company, Tokyo, Japan) and/or 20–40 mg/kg
ventional therapy, burosumab improved disease symp-
per day of neural phosphate (Phosribbon® Combination granule,
toms and clinical data in severe or poorly-controlled XLH ZERIA Pharmaceutical Co., Ltd., Tokyo, Japan) were administered at
patients, with the Rickets Severity Scale (RSS) of 2.0 or diagnosis. We set the most important clinical goal as to control rickets.
more, in a randomized controlled clinical trial (RCT) [20]. We adjusted the doses of the drugs monitoring bone X-rays and
However, the effect of burosumab in relatively well- biochemical data particularly the serum ALP concentration. We also
monitored the urine Ca/Cre ratio not to exceed about 0.3–0.4 mg/mg.
controlled XLH patients, with RSS below 2.0, by conven-
Burosumab (CRYSViTA® Subcutaneous Injection, Kyowa Kirin
tional therapy has not been evaluated thoroughly and the Co., Ltd, Tokyo, Japan) was administrated by subcutaneous injection
benefits of switching treatments are key clinical issues to at doses of 0.8–1.2 mg/kg every two weeks, adjusting in relation to
be elucidated. serum P concentrations above 3.0 mg/dL which was the criterion of
the clinical trials.

Data analysis
Patients and methods
Biochemical analyses and bone X-rays were performed every 3–4 months
Study design
and every six months, respectively, in the RCT (UX023-CL301) [20], in the
following continuous administration trial (KRN23-004), in the self-
This study aimed to reveal the impact of switching treatments from injection trial (KRN23-003), or within clinical practice in our hospital. The
conventional therapy to burosumab in relatively well-controlled XLH RSS was used to evaluate rickets status as previously reported [21].
children with RSS below 2.0. Briefly, rickets status in the metaphysis of four long bones (distal femur,
We retrospectively analyzed the clinical data of pediatric XLH proximal tibia, distal radius, and distal ulna) was scored from 0 (normal)
patients during conventional therapy and burosumab injection to 10 (most severe). RSS was evaluated blindly by three specialists.
(Figure 1). Before initiating burosumab injection, we set the baseline Renal echography was performed and the severity of NC was
after four weeks as the washout period for conventional therapy. assessed as previously described on a scale of 0–4, with 0 indicating
Because the clinical severity or control status of XLH patients varies, normal, 1 indicating mild echogenicity around the medullary pyra-
the effects of the two treatments were compared for the same treatment mids border, 2 more intense echogenic rims with echoes faintly filling
duration (31 ± 11 months) in each patient before and after the baseline. the entire pyramid, 3 uniformly intense echoes throughout the pyra-
mid, and 4 indicating stone formation [7, 11, 22]. In a kidney indicating
all severity including grade 0, high echoic dots may be detected
Patients (Figure 2). In this study, we diagnosed over three dots less than 3 mm
in diameter in a kidney as mild spotty NC [23]. The severity of NC was
Overall, 28 XLH patients, 13 children, and 15 adults were treated with also evaluated blindly by three specialists.
conventional therapy in our hospital. Because clinical trials for Genetic analysis of the PHEX gene was performed by direct
switching treatments to burosumab was for only pediatric patients, of sequencing.
these, informed consent was obtained from the parents of 13 pediatric Blood and urine tests were performed in a fasting state. Urine
XLH patients at enrollment to the RCT (UX023-CL301) [20] in December samples were the second urination of the day. Serum/urine con-
2016, at enrollment to the self-injection trial (KRN23-003) in July 2017, centrations of calcium (Ca) and creatinine (Cre) were measured in or
and/or after burosumab approval in Japan in November 2019. Poorly- after the clinical trials by Arsenazo III, an enzymatic method
controlled XLH patients, with RSS of 2.0, participated in the RCT [20] (sarcosine oxidase–peroxidase) (Aqua Auto Kinos Ca reagents,
and patients and/or parents/family members chose their own treat- Kainos Laboratories, Inc., Tokyo, Japan; Serotec Ca-AL, Serotec Co.,
ments. Two patients were enrolled in the RCT, five participated in the Ltd., Sapporo, Japan), and electrochemiluminescence immuno-
self-injection trial, and one initiated burosumab after its approval. assay (ECLIA) (L system CRE, Sysmex Corporation, Kobe, Japan;
Consequently, eight patients treated with burosumab were enrolled in Determiner L CRE, Hitachi Chemical Diagnostics Systems Co., Ltd.,

Figure 1: Schematic representation of study

design.
 Harada et al.: Burosumab does not develop hypercalciuria and nephrocalcinosis 793

Figure 2: Echographic analysis of kidney.

(A) Grade 1 of nephrocalcification in patient 1. (B) High echoic dots (arrows) considered as mild nephrocalcinosis in patient 5 grading 0.

Tokyo, Japan), respectively. Serum intact parathyroid hormone between the two methods (spot sample and 24 h sample) for urine Ca
(iPTH) and 1,25-dihydoxy vitamin D [1,25(OH)2D], and FGF23 were extraction. All statistical analyses were performed using SPSS soft-
measured by ECLIA (ECLusys PTH-intact: Roche Diagnostics K.K., ware V23.0 (IBM, Japan, Tokyo). A p-value <0.05 was considered
Tokyo, Japan), double-antibody radioimmunoassay (RIA2) statistically significant.
(1,25(OH)2D RIA kit, Immunodiagnostic Systems Limited, Boldon,
UK), and chemiluminescent enzyme immune assay (Determiner CL
FGF23, Hitachi Chemical Diagnostics Systems Co., Ltd., Tokyo, Ethical approval
Japan), respectively. Serum ALP activities were detected using the
International Federation of Clinical Chemistry and Laboratory Med- This study was approved by the Medical Ethic Committee of JCHO
icine (IFCC) method (ALP2 Reagents, Roche Diagnostics Corporation, Osaka Hospital (ID: 2020-04) for collection and analysis of the clinical
IN, USA) in the RCT [20] and the modified Japan Society of Clinical data. All procedures performed in studies involving human partici-
Chemistry Reference (JSCC) method for other data (CicaLiquid ALP, pants were in accordance with the ethical standards of the institu-
Kanto Kagaku Co. Inc., Tokyo, Japan) [24]. These methods cannot be tional and/or national research committee and with the 1964 Helsinki
directly compared, but the formula x = 2.84 × y (x = JSCC, y = IFSS) declaration and its later amendments or comparable ethical stan-
established by the Japan Society of Clinical Chemistry was used dards. Written informed consent was obtained from all individuals
to estimate and compare values [25]. Serum and urine P were included in this study.
detected with different methods but the reference ranges were the
same and considered comparable. Phosphate concentrations were
measured by the molybdic acid direct method (IP-HR II, Fujifilm
Wako Pure Chemical Corporation, Osaka, Japan) (reference range:
2.5–4.5 mg/dL) and the enzymatic method (UV-end) (IP reagent L
Results
“Kokusai”, Sysmex Corporation, Kobe, Japan) (reference range:
2.5–4.5 mg/dL), respectively, in the clinical trials and in our hospital. The backgrounds of the patients are summarized in Table 1.
Urine calcium extractions were analyzed in all patients using the Two male patients were included in the eight participants
spot urine Ca to urine Cre ratio (u-Ca/Cre) constantly, and by 24 h urine (25%). Clinical diagnosis of XLH was determined at infancy
Ca extraction during the clinical trials. Consequently, the 24 h urine Ca (0.5 ± 0.2 years of age) and later it was confirmed by
extraction was evaluated total of 34 times in 7/8 patients. The maximal
mutational analysis of the PHEX gene in all patients. The
tubular reabsorption of phosphate per glomerular filtration rate
(TmP/GFR) and tubular reabsorption of phosphate (%TRP) were duration of conventional therapy was 9.8 ± 2.1 years and
calculated as follows: serum P − (urine P × serum Cr)/urine Cr (mg/dL), burosumab injection was started at 10.4 ± 1.9 years of age.
and {1 − (urine P × serum Cr/serum P × urine Cr)} × 100 (%), respectively. At baseline, the mean height and BMI were −1.41 ± 0.75 SD
(range: −0.64 to −2.52) and −0.84 ± 0.58 SD (range: −0.32
to −1.82), respectively. Patients were administrated alfa-
Statistical analysis
calcidol and phosphate as conventional therapies. The
actual dose of alfacalcidol was 150.9 ± 43.9 ng/kg per day
The mean values of biochemical data and RSS were calculated for each
patient during conventional therapy and burosumab treatment. To through the analysis period (range: 85–227). Oral phos-
evaluate the course of serum and urine biochemical data, and X-rays, phate was prescribed at 27.5 ± 6.3 mg/kg per day
one-way analysis of variance (ANOVA) for repeated measures and throughout the analysis period (range: 14.6–40.5) 3–4
general linear model repeated measures were performed. The mean times a day.
values for baseline, conventional therapy, and burosumab were
At baseline after four weeks of the washout period, the
compared. Mauchly’s sphericity test was applied and, if necessary,
technical corrections were made using the Greenhouse–Geisser test.
serum P and FGF23 concentrations were 2.3 ± 0.3 mg/dL
Multiple comparisons were analyzed by Bonferroni’s test. Pearson’s and 247.8 ± 157.1 pg/mL, respectively (Table 2). Serum Ca,
correlation coefficient was calculated to compare the correlation ALP, and 1,25(OH)2D were 9.8 ± 0.2 mg/dL, 1,564 ± 177 U/L,
Table : Backgrounds of the patients at initiation of burosumab.
794

Case no. Gender Age at diagnosis, years Conventional therapy Age, years Height, SD BMI, SD Alfacalcidol, ng/kg/day Phosphate, mg/kg/day
duration, years

 M . . . −. −.  (–) . (.–.)

 F . . . −. −.  (–) . (.–.)
 F . . . −. −.  (–) . (.–.)
 F . . . −. −.  (–) . (.–.)
 F . . . −. −.  (–) . (.–.)
 F . . . −. −.  (–) . (.–.)
 F . . . −. −.  (–) . (.–.)
 M . . . −. −.  (–) . (.–.)

Average ± SD (range) . ± . . ± . . ± . −. ± . −. ± . . ± . (–) . ± . (.–.)

Table : Clinical data at baseline.

Case no. Ca, mg/dL P, mg/dL ALP, U/L ,-(OH)D, pg/mL iPTH, pg/mL FGF, pg/mL u-Ca/Cre, mg/mg TmP/GFR, mg/dL %TRP, % RSS Echography

NC grade Spotty NC

 . . , .  . . . . .  +

Harada et al.: Burosumab does not develop hypercalciuria and nephrocalcinosis

 . . , .  . . . . .  +

 . . , .  . . . . .  +
 . . , .  . . . . .  +
 . . , .  . . . . .  +
 . . , .  . . . . .  +
 . . , .  . . . .   +
 . . , . . . . . . .  +

Average ± SD . ± . . ± . , ±  . ± . . ± . . ± . . ± . . ± . . ± . . ± .

SD, standard deviation; Ca, calcium; P, phosphate; ALP, alkaline phosphatase; ,(OH)D, ,-dihydroxyvitamin D; iPTH, intact parathyroid hormone; FGF, fibroblast growth factor ; u-Ca/
Cre, urine calcium/creatinine ratio; TmP/GFR, Maximal tubular reabsorption of phosphate per glomerular filtration rate; %TRP, tubular reabsorption of phosphate; RSS, rickets severity scale; FTA,
fibra-tibia angle; NC, nephrocalcinosis.
 Harada et al.: Burosumab does not develop hypercalciuria and nephrocalcinosis 795

and 36.9 ± 29.5 pg/mL, respectively. Urine extraction of Ca Discussion

and renal reabsorption of P were assessed as the u-Ca/Cre
(0.055 ± 0.041 mg/mg), and the TmP/GFR (2.1 ± 0.5 mg/dL) In the present study, burosumab improved the renal reab-
and %TRP (87.6 ± 6.1%), respectively. Bone X-rays to sorption of P (TmP/GFR and %TRP) compared to that at the
determine rickets status were analyzed by RSS as 1.1 ± 0.8 baseline, which was unchanged by conventional therapy.
(range: 0.0–2.0). Abdominal echography revealed low- These data demonstrate burosumab is a useful treatment for
grade NC in four of eight patients (50%) and spotty calci- XLH and reproduced the results of a previous RCT [20].
fications were observed in all patients (Figure 2). Burosumab also tended to improve rickets in partly-
Burosumab was injected at 1.09 ± 0.38 mg/kg every controlled XLH children. A statistical difference was not
two weeks (range: 0.64–2.04). Mean RSS scores tended to detected in our study possibly because disease in our
be improved by switching treatment from conventional patients was already partly controlled. Indeed, RSS and
therapy to burosumab, but this did not reach statistical
height SD scores were relatively good during conventional
significance (F(2,12)=3.54, p=0.062) (Figure 3). After
therapy. To treat XLH children, we believe the most
switching treatments, renal echography was performed
important goal is not to control biochemical defects but to
regularly and showed no aggravation of NC in any patients.
control rickets in growing bones. Improved rickets should
In both conventional therapy and burosumab
lead to good growth minimizing deformity of legs or short
injection, serum P (F(2,14)=8.768, p=0.003), ALP
stature. Thus we adjusted doses of the drugs referring to
(F(2,14)=4.385, p=0.033), and 1,25(OH)2D (F(2,14)=20.983,
X-rays paying attention to side effects including urine Ca
p<0.001) were improved from baseline, but were not
extraction. Consequently, rickets in our patients were
different between treatments (Supplementary Material).
controlled with the conventional therapy instead of over-
TmP/GFR and %TRP were unchanged by conventional
dose active vitamin D. Large doses of active vitamin D
therapy when compared with baseline, but they were
increase the risk of hypercalciuria [15]. Although initial
significantly increased by burosumab injection: 78.4 ± 9.4
dose of alfacalcidol was recommended 30–50 ng/kg/day
to 91.6 ± 5.6% (F(2,12)=10.501, p=0.002) and from 2.5 ± 0.6
[26], actual clinical dose was reported 110 ± 0.04 ng/kg/day
to 3.0 ± 0.4 mg/dL (F(2,12)=15.452, p<0.001), respectively.
[27]. Overdoses of alfacalcidol in our patients may be in a
Switching treatments decreased serum Ca (F(2,12)=
gap between the recommendation and the clinical neces-
4.536, p=0.034) within the normal range and increased
sity. From this report, we could say that burosumab
u-Ca/Cre to the normal range (F(2,14)=28.639, p<0.001)
injection therapy dissolves this dilemma and is worth to be
(Figure 4). Furthermore, suppressed serum iPTH during
switched from the conventional therapy beyond the cost.
conventional therapy was increased within the normal
range by washing out the treatment and during burosumab At baseline, frequent NC, increased serum Ca, and
injection (F(2,14)=0.548, p<0.001) (Figure 4). increased u-Ca/Cre were observed as possible side effects
To analyze the reliability of spot urine samples, a com- of the conventional therapy. Burosumab did not develop or
parison of spot u-Ca/Cre to 24 h urine Ca extraction was worsen NC. Because the cutoff value of hypercalciuria in
performed (Figure 5). Calcium extraction of spot urine sam- spot u-Ca/Cre has been reported to be 0.13–0.18 [28, 29],
ples correlated with that of 24 h urine samples (r=0.61, u-Ca/Cre during conventional therapy was often diagnosed
p<0.001). as hypercalciuria. Switching treatments dissolved hyper-
calciuria to the normal range and may be useful for the
reduction of side effects caused by conventional therapy
although both treatments controlled disease markers
equally (serum P, ALP, and 1,25(OH)2D).
Intact PTH was increased within normal range after
switching treatments. Because iPTH was already increased
by washout of alfacalcidol administration, one possible
cause may be a direct effect of hypervitaminosis D [30]. As
the other possibility, endogenous PTH secretion may have
been suppressed by excess serum Ca concentration prov-
ably because of the high dose of alfacalcidol. This
assumption is partially supported by consequent hyper-
calciuria during the therapy. Through these ways, switching
Figure 3: Rickets severity scale (RSS) in bone X-rays. treatments can normalize serum iPTH levels.
796 Harada et al.: Burosumab does not develop hypercalciuria and nephrocalcinosis

Figure 4: The impact of switching treatments on calcium metabolism.

Switching treatments decreased serum Ca (A, B) and u-Ca/Cre (C, D) from 9.7 ± 0.4 to 9.5 ± 0.3 mg/dL (p=0.015), and from 0.359 ± 0.195 to
0.056 ± 0.044 mg/mg (p=0.003), respectively. On the other hand, iPTH (E, F) was increased from 25.9 ± 10.9 to 55.9 ± 15.3 pg/mL by switching
treatments (p<0.001).

Hypercalciuria and high levels of urine P cause NC,

and therefore oral vitamin D and phosphate may be major
causes for developing NC in XLH patients treated with
conventional therapy [12, 31–33]. The degree of NC varies
from histologically subtle forms such as NC or Randall’s
plaque, which may not be detected by echography to
advanced NC that is visible by X-rays [12, 34]. High echoic
dots in the renal medulla should be assessed as mild NC
although the echographic grading scale of NC judges them
0 (no abnormalities). To assess them in an objective
Figure 5: Correlation analysis of spot u-Ca/Cre and 24 h Ca extraction.
manner, we set diagnostic criteria as over three dots less
Spot u-Ca/Cre were correlated with urine Ca extraction in 24 h than 3 mm in diameter in a kidney. Several pathways for
samples (r=0.608, p<0.001). developing nephrolithiasis have been suggested and some
 Harada et al.: Burosumab does not develop hypercalciuria and nephrocalcinosis 797

forms of NC lead to nephrolithiasis [12, 35, 36]. Consistent References

with our data, no past clinical studies have reported that
burosumab induced or aggravated NC [37–39]. Thus, 1. Albright F, Butler AM, Bloomberg E. Rickets resistant to vitamin D
switching treatments, which decreased urine Ca and P therapy. Arch J Dis Child 1937;54:529–47.
extraction, is expected to decrease the risk of NC and 2. Lobaugh B, Drezner MK. Abnormal regulation of renal
25-dihydroxyvitamin D-1α-hydroxylase activity in the X-linked
nephrolithiasis.
hypophosphatemic mouse. J Clin Invest 1983;71:400–3.
In conclusion, this study demonstrated that burosumab
3. Endo I, Fukumoto S, Ozono K, Namba N, Inoue D, Okazaki R, et al.
improved renal P reabsorption in partly-controlled XLH Nationwide survey of fibroblast growth factor 23 (FGF23)-related
children compared with conventional therapy. Because hypophosphatemic diseases in Japan: prevalence, biochemical
high doses of alfacalcidol and phosphate as conventional data and treatment. Endocr J 2015;62:811–6.
therapy were needed to control rickets in XLH children, 4. Francis F, Hennig S, Korn B, Reinhardt R, de Jong P, Poustka A,
et al. A gene (PEX) with homologies to endopeptidases is mutated
switching treatments to burosumab injection can dissolve
in patients with X-linked hypophosphatemic rickets. Nat Genet
side effects associated with conventional therapy. More- 1995;11:130–6.
over, switching treatments decreased urine Ca extraction 5. Gattineni J, Bates C, Twombley K, Dwarakanath V, Robinson ML,
indicating it may have the potential to prevent NC. Goetz R, et al. FGF23 decreases renal NaPi-2a and NaPi-2c
expression and induces hypophosphatemia in vivo
predominantly via FGF receptor 1. Am J Physiol Ren Physiol 2009;
Acknowledgments: Part of this study was included in phase 297:F282–91.
III clinical trial and the following KRN23-004 and KRN23- 6. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y,
et al. FGF-23 is a potent regulator of vitamin D metabolism and
003 studies conducted by Kyowa-Kirin Ltd. Kyowa-Kirin
phosphate homeostasis. J Bone Miner Res 2004;19:429–35.
Ltd. provided biochemical data within the clinical trials. We 7. Costa T, Marie PJ, Scriver CR, Cole DE, Reade TM, Nogrady B, et al.
would like to thank our patients and their families for X-linked hypophosphatemia: effect of calcitriol on renal handling
agreeing to participate and for providing data through their of phosphate, serum phosphate, and bone mineralization. J Clin
medical records. We appreciate Dr. Noriyuki Namba and the Endocrinol Metab 1981;52:463–72.
8. Skrinar A, Dvorak-Ewell M, Evins A, Macica C, Linglart A, Imel EA,
clinical trial coordinators for translation among clinical
et al. The lifelong impact of X-linked hypophosphatemia: results
staff, patients, and the pharmaceutical company. We also
from a burden of disease survey. J Endocr Soc 2019;3:1321–34.
express our gratitude to the clinical staff of Osaka Hospital, 9. Chesher D, Oddy M, Darbar U, Sayal P, Casey A, Ryan A, et al.
JCHO. We thank J. Ludovic Croxford, PhD, from Edanz Outcome of adult patients with X-linked hypophosphatemia
Group (https://en-author-services.edanzgroup.com/ac) for caused by PHEX gene mutations. J Inherit Metab Dis 2018;41:
editing a draft of this manuscript. 865–76.
10. Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M,
Research funding: This study was funded in part by a grant
et al. Effects of therapy in X-linked hypophosphatemic rickets. N
from the Foundation for Growth Science 2020 (receipt Engl J Med 1991;325:1843–8.
number: 32) (D.H.). 11. Shavit L, Ferraro PM, Johri N, Robertson W, Walsh SB, Moochhala
Author contributions: All the authors were involved in the S, et al. Effect of being overweight on urinary metabolic risk
clinical management of the patients and reviewed the data factors for kidney stone formation. Nephrol Dial Transplant 2015;
30:607–13.
and the manuscript. DH and YS designed the study. DH
12. Pozdzik A, Maalouf N, Letavernier E, Brocheriou I, Body JJ, Vervaet
obtained and analyzed most of the data. DH wrote the paper.
B, et al. Meeting report of the “symposium on kidney stones and
All authors have accepted responsibility for the entire mineral metabolism: calcium kidney stones in 2017”. J Nephrol
content of this manuscript and approved its submission. 2019;32:681–98.
Competing interests: The authors declare that they have 13. Habbig S, Beck BB, Hoppe B. Nephrocalcinosis and urolithiasis in
no conflict of interest. children. Kidney Int 2011;80:1278–91.
14. Hoppe B, Kemper MJ. Diagnostic examination of the child with
Informed consent: Written informed consent was obtained
urolithiasis or nephrocalcinosis. Pediatr Nephrol 2010;25:
from all individuals included in this study. 403–13.
Ethical approval: This study was approved by the Medical 15. Carpenter TO, Imel EA, Holm IA, de Beur SMJ, Insogna KL. A
Ethic Committee of JCHO Osaka Hospital (ID: 2020-04) for clinician’s guide to X-linked hypophosphatemia. J Bone Miner
collection and analysis of the clinical data. All procedures Res 2011;26:1381–8.
16. Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E.
performed in studies involving human participants were in
Early treatment improves growth and biochemical and
accordance with the ethical standards of the institutional
radiographic outcome in X-linked hypophosphatemic rickets. J
and/or national research committee and with the 1964 Clin Endocrinol Metab 2003;88:3591–7.
Helsinki declaration and its later amendments or 17. Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA,
comparable ethical standards. Wooddell MM, et al. Randomized trial of the anti-FGF23 antibody
798 Harada et al.: Burosumab does not develop hypercalciuria and nephrocalcinosis

KRN23 in X-linked hypophosphatemia. J Clin Invest 2014;124: 30. Coe FL, Evan AP, Worcester EM, Lingeman JE. Three pathways for
1587–97. human kidney stone formation. Urol Res 2010;38:147–60.
18. Imel EA, Zhang X, Ruppe MD, Weber T, Klausner MA, Ito T, et al. 31. Shavit L, Jaeger P, Unwin RJ. What is nephrocalcinosis? Kidney Int
Prolonged correction of serum phosphorus in adults with 2015;88:35–43.
X-linked hypophosphatemia using monthly doses of KRN23. J Clin 32. Taylor A, Sherman NH, Norman ME. Nephrocalcinosis in X-linked
Endocrinol Metab 2015;100:2565–73. hypophosphatemia: effect of treatment versus disease. Pediatr
19. Cheong HI, Yoo HW, Adachi M, Tanaka H, Fujiwara I, Hasegawa Y, Nephrol 1995;9:173–5.
et al. First-in-Asian phase I study of the anti-fibroblast growth 33. Hu H, Zhang J, Lu Y, Zhang Z, Qin B, Gao H, et al. Association
factor 23 monoclonal antibody, burosumab: safety and between circulating vitamin D level and urolithiasis: a systematic
pharmacodynamics in adults with X-linked hypophosphatemia. review and meta-analysis. Nutrients 2017;9:301.
JBMR Plus 2019;3:e10074. 34. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ.
20. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, Comparison of dietary calcium with supplemental calcium and
et al. Burosumab versus conventional therapy in children with other nutrients as factors affecting the risk for kidney stones in
X-linked hypophosphataemia: a randomised, active-controlled, women. Ann Intern Med 1997;126:497–504.
open-label, phase 3 trial. Lancet 2019;393:2416–27. 35. Wiener SV, Ho SP, Stoller ML. Beginnings of nephrolithiasis:
21. Thacher TD, Pettifor JM, Tebben PJ, Creo AL, Skrinar A, Mao M, insights into the past, present and future of Randall’s plaque
et al. Rickets severity predicts clinical outcomes in children with formation research. Curr Opin Nephrol Hypertens 2018;27:
X-linked hypophosphatemia: utility of the radiographic rickets 236–42.
severity score. Bone 2019;122:76–81. 36. Insogna KL, Briot K, Imel EA, Kamenický P, Ruppe MD, Portale AA,
22. Boyce AM, Shawker TH, Hill SC, Choyke PL, Hill MC, James R, et al. et al. A randomized, double-blind, placebo-controlled, phase 3
Ultrasound is superior to computed tomography for assessment trial evaluating the efficacy of burosumab, an anti-FGF23
of medullary nephrocalcinosis in hypoparathyroidism. J Clin antibody, in adults with X-linked hypophosphatemia: week 24
Endocrinol Metab 2013;98:989–94. primary analysis. J Bone Miner Res 2018;33:1383–93.
23. Evan AP, Lingeman J, Coe F, Shao Y, Miller N, Matlaga B, et al. 37. Portale AA, Carpenter TO, Brandi ML, Briot K, Cheong HI, Cohen-
Renal histopathology of stone-forming patients with distal renal Solal M, et al. Continued beneficial effects of burosumab in adults
tubular acidosis. Kidney Int 2007;71:795–801. with X-linked hypophosphatemia: results from a 24-week
24. Ichihara K, Yomamoto Y, Hotta T, Hosogaya S, Miyachi H, Itoh Y, treatment continuation period after a 24-week double-blind
et al. Collaborative derivation of reference intervals for major clinical placebo-controlled period. Calcif Tissue Int 2019;105:271–84.
laboratory tests in Japan. Ann Clin Biochem 2016;53:347–56. 38. Martín Ramos S, Gil-Calvo M, Roldán V, Castellano Martínez A,
25. Committee on Enzyme and Reagent & Japan Society of Clinical Santos F. Positive response to one-year treatment with
Chemistry. About modified methods of measuring ALP and LD: for burosumab in pediatric patients with X-linked
medical staff (ver.1.0) [in Japanese]. Available from: http://jscc- hypophosphatemia. Front Pediatr 2020;8:48.
jp.gr.jp/file/2019/alpld2.pdf [Accessed 08 Oct 2019]. 39. Amir E, Simmons CE, Freedman OC, Dranitsaris G, Cole DEC, Vieth
26. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, R, et al. A phase 2 trial exploring the effects of high-dose
Schnabel D, et al. Clinical practice recommendations for the (10,000 IU/day) vitamin D(3) in breast cancer patients with bone
diagnosis and management of X-linked hypophosphataemia. Nat metastases. Cancer 2010;116:284–91.
Rev Nephrol 2019;15:435–55.
27. Miyamoto J, Koto S, Hasegawa Y. Final height of Japanese
patients with X-linked hypophosphatemic rickets: effect of Supplementary Material: The online version of this article offers
vitamin D and phosphate therapy. Endocr J 2000;7:163–7. supplementary material (https://doi.org/10.1515/jpem-2020-0734).
28. Marwaha RK, Garg MK, Dang N, Mithal A, Narang A, Chadha A, Serum and urine biochemical outcomes before and after
et al. Reference range of random urinary calcium creatinine ratio switching treatments. Serum P (a, b), ALP (c, d), and 1,25-(OH)2D (e, f)
in North Indian children and adolescents. Ann Pediatr Endocrinol concentration were not changed 3.2 ± 0.7 vs. 3.2 ± 0.4 mg/dL,
Metab 2019;24:34–40. 1,229 ± 371 vs. 1,191 ± 327 IU/L, and 70.3 ± 24.1 vs. 65.0 ± 16.3 pg/mL
29. Quiñones-Vázquez S, Liriano-Ricabal MDR, Santana-Porbén S, in both the conventional therapy and burosumab, respectively, but
Salabarría-González JR. Calcium-creatinine ratio in a morning improved comparing to baseline (BL). Renal P reabsorption were
urine sample for the estimation of hypercalciuria associated with analyzed by TmP/GFR (g, h) and %TRP (i, j), and improved with bur-
non-glomerular hematuria observed in children and adolescents. osumab from 2.5 ± 0.6 to 3.0 ± 0.5 mg/dL, and from 77.9 ± 9.3 to
Bol Med Hosp Infant Mex 2018;75:41–8. 90.6 ± 5.3%, respectively.