British Journal of Clinical Br J Clin Pharmacol (2019) 85 1188–1198 1188

Pharmacology

REVIEW-THEMED ISSUE
Pharmacological management of X-linked
hypophosphataemia
Correspondence Erik A. Imel, MD, Gatch Hall, Suite 380 F, 1120 W. Michigan St. Indianapolis, IN 46202-5111. Tel.: +1 317 274 1339;
Fax: +1 317 278 0658; E-mail: eimel@iu.edu

Received 17 July 2018; Revised 5 September 2018; Accepted 5 September 2018

Erik A. Imel1,2 and Kenneth E. White3,4

1
Department of Medicine, Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, IN, USA, 2Department of
Pediatrics, Section of Endocrinology and Diabetology, Indiana University School of Medicine, Indianapolis, IN, USA, 3Department of Medical and
Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA, and 4Department of Medicine, Division of Nephrology, Indiana
University School of Medicine, Indianapolis, IN, USA

Keywords burosumab-twza, fibroblast growth factor 23, PHEX, X-linked hypophosphataemia

The most common heritable disorder of renal phosphate wasting, X-linked hypophosphataemia (XLH), was discovered to be
caused by inactivating mutations in the phosphate regulating gene with homology to endopeptidases on the X-chromosome
(PHEX) gene in 1995. Although the exact molecular mechanisms by which PHEX mutations cause disturbed phosphate handling
in XLH remain unknown, focus for novel therapies has more recently been based upon the finding that the bone-produced
phosphaturic hormone fibroblast growth factor-23 is elevated in XLH patient plasma. Previous treatment strategies for XLH were
based upon phosphate repletion plus active vitamin D analogues, which are difficult to manage, fail to address the primary
pathogenesis of the disease, and can have deleterious side effects. A novel therapy for XLH directly targeting fibroblast growth
factor-23 via a humanized monoclonal antibody (burosumab-twza/CRYSVITA, henceforth referred to just as burosumab) has
emerged as an effective, and recently approved, pharmacological treatment for both children and adults. This review will provide
an overview of the clinical manifestations of XLH, the molecular pathophysiology, and summarize its current treatment.

Introduction Genetic cause

X-linked hypophosphataemia (XLH) is a rare metabolic
bone disease with significant clinical consequences in both
children and adults, due largely to fibroblast growth
factor 23 (FGF23) excess and resulting chronic
hypophosphataemia. In the past, treatment has been re-
stricted to administering phosphorus and activated vitamin
D, with limitations in effectiveness, and significant risk for
important adverse events. Over the past 2 decades research
into XLH mechanisms has generated novel potential targets
for treatment, including the recent regulatory approvals of
burosumab-twza/CRYSVITA (henceforth referred to just
as burosumab) for clinical use in patients with XLH. This pa-
per will review the clinical consequences of XLH, the patho-
physiology involved and various approaches to its medical
management.
XLH is a rare bone disease affecting an estimated 1:20–
25 000 persons [1, 2] (OMIM no. 307800). Deleterious mu-
tations in the phosphate regulating gene with homologies
to endopeptidases on the X chromosome (PHEX) [3] cause
this X-linked dominant condition. The female to male ratio
is about 2:1. Sporadic cases frequently occur. Other genes
having different inheritance patterns cause phenotypically
similar disorders. PHEX mutations cause increased plasma
FGF23 concentrations, leading to impaired renal reabsorp-
tion of phosphorus, hypophosphataemia and impaired acti-
vation of vitamin D [2, 4].
Clinical manifestations
XLH typically presents in early childhood with manifesta-
tions of rickets, although family history may lead to testing

DOI:10.1111/bcp.13763 © 2018 The British Pharmacological Society

 Pharmacological management of X-linked hypophosphataemia
before visible features appear. Unfortunately, clinical labora-
tories often fail to report age-appropriate normal ranges, lead-
ing to missed diagnoses, since adult normal phosphorus
values are much lower than paediatric (especially infant)
values [2]. Both children and adults with XLH have low phos-
phorus concentrations for age, and impaired renal tubular
phosphorus reabsorption, typically assessed as a low
transport maximum for phosphorus adjusted for glomerular
filtration rate (TmP/GFR) [2, 4]. Serum alkaline phosphatase
activity is typically increased for age in children, although
this is more variable in adults [2, 4].
At birth, length is usually normal and legs are not usually
bowed [5–7]. Bowing and impaired linear growth become
more evident with weight bearing, especially between ages 1
and 2 years [2, 5, 6, 8, 9]. Childhood features include bowing
of the femora and tibiae leading to genu varus or sometimes
valgus appearance, widening of the growth plates at the end
of long bones, abnormalities of the skull shape, sometimes
bone pain and occasionally delays in gross motor milestones
(such as difficulties in walking or running) [2, 9, 10].
Radiographic growth plate abnormalities are similar to nutri-
tional rickets, along with diaphyseal bowing, often with me-
dial cortical thickening, and torsion of weight-bearing long
bones. Skeletal severity and the response to medical
management are highly variable [2, 6, 10]. Patients often re-
quire corrective surgical procedures to straighten lower ex-
tremities. Short stature and gait abnormalities persist into
adulthood [2, 6, 8, 10, 11].
Cranial bones are also affected in XLH, most notably with
frontal bossing and dolicocephally [12–14]. Flattening of the
cranial base leads to decreased depth of the posterior fossa
predisposing to Chiari malformations [13], occurring in up
to 44% of XLH patients [12]. For some patients, craniosynos-
tosis of the sagittal suture requires craniotomy [14].
XLH predisposes to dental abscesses due to a combination
of intrinsic effects of Phex deficiency and associated
hypophosphataemia leading to under-mineralized dentin
and cementum [15–18]. Severe dental disease (abscesses and
periodontitis) affects 61–78% of patients with XLH [19, 20].
Retrospective studies suggest that treating XLH with phos-
phate salts and active vitamin D decreases the occurrence of
dental abscesses and periodontitis [19, 20].
XLH does not negatively influence lifespan, so one would
expect at least three quarters of XLH patients to be adults. As
such, although commonly thought of as a paediatric bone
disease, adults bear a considerable burden of the conse-
quences of this lifelong condition. The most debilitating fea-
tures of XLH are experienced by adults: bone pain,
pseudofractures, enthesopathy and osteoarthritis [11, 21, 22].
Osteomalacic bone pain is common [22] and debilitating.
Although complete fractures are not more common in XLH,
patients with XLH are prone to pseudofractures [11].
Pseudofractures occasionally occur in children, but are seen
in up to half of adults in cross sectional studies [21, 22],
although the lifetime incidence might be higher.
Pseudofractures may progress to complete fractures and may
require surgical intervention. Skeletal healing after fracture or
surgery may be delayed.
Enthesopathy involves the calcification of tendons and
ligaments, typically beginning near the bony attachment
sites, and progressing to enthesophyte or osteophyte
formation. The pathophysiology of enthesopathy in XLH is
uncertain, although it may be due to direct effects of FGF23.
Enthesopathy occurs in multiple hypophosphataemic mouse
models having FGF23 excess [23, 24]. FGF receptor 3 and
klotho expression in fibrocartilage of the entheses make di-
rect signalling at least theoretically possible [24].
Enthesopathy causes joint stiffness and limitations in
range of motion which may be extreme. When involving
the anterior and posterior spinal ligaments, patients lose flex-
ion, extension and rotational movement of the neck and
spine. Sometimes patients develop spinal nerve or spinal cord
compression requiring surgical intervention, although the
incidence of this is uncertain. Enthesopathy is more common
in men, and with increasing age and BMI [19], affecting be-
tween 30 and 100% of adults [10, 11, 19, 21, 22, 24].
Osteoarthritis is probably a consequence of chronic ab-
normalities in joint alignment and gait causing degenerative
changes in joint cartilage and bony articulation surfaces. Os-
teoarthritis might be exacerbated by enthesopathy. Joint re-
placements are common surgeries in XLH patients,
although the frequency of such procedures is uncertain [25].
Up to 82% of adults with XLH complain of joint pain and
stiffness, and about 50% report using pain medications
weekly to daily [19, 22].
Muscle weakness, a feature of hypophosphataemia, is
present in both the Hyp mouse and patients with XLH
[22, 26, 27]. However, in XLH patients it is difficult to
separate the effects on mobility from skeletal deforma-
tion, joint abnormalities, and bone pain from those due
to muscle weakness.
Overall, the lifetime burden of illness is high in XLH,
complicated often by a lack of understanding of the disease
and its management by both patients and clinical providers.
Not surprisingly, with the growth abnormalities, skeletal de-
formities, muscle weakness, and bone and joint pain, quality
of life impairments are documented in both children and
adults with XLH [28–30].
Molecular pathophysiology
XLH is fully penetrant with highly variable severity. The
Hyp Consortium determined that XLH is caused by
inactivating mutations in the PHEX gene [3]. PHEX en-
codes a protein that structurally resembles the M13 family
of membrane-bound metalloproteases. Members of this en-
zyme class include single transmembrane proteins with
large extracellular domains such as neutral endopeptidase
and endothelin converting enzymes 1 and 2 (ECE-1 and
ECE-2) [3, 31]. This family is known to cleave small pep-
tides, although the endogenous PHEX protein’s substrate
has yet to be fully confirmed. Close to 300 inactivating
PHEX mutations have been described from XLH patients,
including variations that lead to missense, nonsense, frame
shift, and exon splicing alterations. PHEX shows the
highest expression in bone cells including osteoblasts and
osteocytes, and odontoblasts in teeth, as well as lower ex-
pression in the parathyroid glands, lung, brain and skeletal
muscle [31, 32].
Although the PHEX mutations are predicted to cause loss
of function, the mechanisms whereby this leads to changes
in bone function remain elusive. The Hyp mouse model of
Br J Clin Pharmacol (2019) 85 1188–1198 1189
 E. A. Imel and K. E. White
XLH, has a 30 deletion in PHEX, and has been a very useful
tool for the in vivo study of the XLH phenotype [31]. Similar
to XLH patients, this model has approximately a 10-fold in-
crease in serum FGF23 (although in patients with XLH, serum
FGF23 is typically less severely elevated), and manifests the
XLH biochemical syndrome including hypophosphataemia
with inappropriately normal 1,25-dihydroxyvitamin D3
[1,25(OH)2D] and normocalcaemia [33]. Like patients, the
Hyp mice display growth retardation and bone mineraliza-
tion defects. Interestingly, loss of Phex protein function
was associated with a differentiation defect in osteocytes
from Hyp mice [34]. This mouse line had altered develop-
mental transitions from osteoblasts to osteocytes, with in-
appropriate expression of cell matrix genes [34]. Indeed
Hyp bones had over-expression of type I collagen, as well
as altered expression of matrix proteins such as bone
sialoprotein [34]. Fgf23 mRNA is elevated in Hyp bone
[33] and in isolated Hyp osteoblasts/osteocytes [35]. These
cultures also fail to mineralize fully, consistent with an in-
trinsic cell defect. However, the cellular pathophysiological
mechanisms caused by Phex deficiency that result in al-
tered FGF23 gene expression and sustained FGF23 protein
elevation remain elusive.
FGF23 control of phosphate and active
vitamin D
The primary kidney transport protein responsible for phos-
phate reabsorption in the proximal tubule is the type II
sodium-phosphate cotransporter, or NaPi-IIa. Transgenic
FGF23 mice had dramatic decreases in protein expression of
NaPi-IIa and a related transporter, NaPi-IIc [36]. The Hyp
mouse has a 50% reduction in proximal tubule NaPi-IIa ex-
pression [37]. In normal individuals, phosphate depletion is
a strong stimulus for increasing serum 1,25(OH)2D [38].
However, in XLH patients, hypophosphataemia is accom-
panied by low or inappropriately normal 1,25(OH)2D
concentrations, due to effects of FGF23. In mice implanted
with cells expressing FGF23, or injected with FGF23 itself,
mRNA and protein expression levels of the activating enzyme
25-hydroxyvitamin D3 1-α-hydroxylase (Cyp27b1) was de-
creased, while the catabolic 1,25-(OH)2D 24-hydroxylase
(Cyp24a1) is increased with high FGF23 [39–41]. Thus, the
effects of FGF23 on the renal vitamin D metabolic enzymes is
responsible for the reductions in serum 1,25(OH)2D concen-
trations observed in XLH patients.
Patients with autosomal dominant hypophosphataemic
rickets (ADHR) also have elevated FGF23 but some patients
display waxing and waning of the disease symptoms [42].
Studying a large ADHR kindred, we documented that the
ADHR disease state and circulating levels of intact FGF23 cor-
related strongly with iron deficiency and were reciprocal to
serum iron concentrations [43], which was borne out in an
ADHR knock in animal model to be due to increased bone
Fgf23 mRNA production during experimental iron depletion
[44, 45]. However, intact FGF23 levels in XLH patients were
unrelated to serum iron concentration [46]. A clinical trial is
underway to place ADHR patients on low-dose oral iron
repletion (ClinicalTrials.gov NCT02233322), thus this regi-
men may be the optimal treatment for ADHR, but not XLH
(see below).
1190 Br J Clin Pharmacol (2019) 85 1188–1198
Medical management
Phosphate salts and active vitamin D
For about 4 decades, children and adults with XLH have been
medically managed using pharmacological doses of phos-
phate salts and active vitamin D, attempting to counter the
effects of FGF23 excess. Doses reported vary widely in the
literature [2]. A US-based group of experts recommended tar-
get doses of calcitriol 20–30 ng kg–1 daily and phosphate
20–40 mg kg–1 daily, each in divided doses [2]. European
experts recommended 1–3 μg day–1 of alfacalcidiol or
0.5–1.5 μg day–1 of calcitriol, and 40–60 mg kg–1 daily of
phosphate [10]. However, no study has systematically evalu-
ated the optimal target dose ranges. Clinicians start at lower
doses and titrate to target doses primarily based on gastroin-
testinal tolerance, with frequent laboratory monitoring to
avoid hypercalciuria, hypercalcaemia, hyperphosphataemia
or impairments in renal function. This strategy does not ef-
fectively normalize the serum phosphorus. In fact, attempts
to target normal phosphorus concentrations might be a con-
tributing reason for the high risk of hyperparathyroidism and
nephrocalcinosis with these agents [2]. Monitoring patients
on treatment is complicated by many factors, and most labo-
ratory monitoring addresses safety (serum calcium, phospho-
rus, creatinine, PTH, urine calcium, urine creatinine).
Treatment with active vitamin D and phosphate decreases
alkaline phosphatase and, in bone biopsy studies, improves
the osteomalacia of XLH [47, 48]. However, the skeletal re-
sponse varies widely. Some children straighten leg deformi-
ties and improve their growth, while others persist in
skeletal deformities and short stature. The reason for good re-
sponders vs. poor responders is not solely an issue of compli-
ance [49]. Treating XLH with vitamin D analogues and
phosphate also increases plasma FGF23 concentrations [50–
52], which theoretically could blunt therapeutic effective-
ness, although the true consequences remain unknown.
Many children with XLH have a variable but progressive
decline in height Z-scores, often worsening during puberty
despite therapy with vitamin D analogues and phosphate
[8]. Studies suggest that beginning treatment prior to age
1 year improves height outcomes [6].
When leg deformities persist, the optimal timing of cor-
rective surgery remains uncertain. In a retrospective study,
29% of XLH patients had recurrence of deformity after their
first corrective surgery [53]. Although the differences were
not significant, those having earlier corrective procedures
were more likely to require additional procedures. This find-
ing may be confounded by more severely affected patients
having earlier surgeries.
Unlike nutritional rickets, which is truly cured by adequate
vitamin D repletion, the homeostatic defect in phosphorus
handling is lifelong in XLH. However, because of the known
risks of XLH therapy with active vitamin D and phosphate,
general practice has been to stop treatment at the end of
growth, and restart if developing clinical issues associated
with active osteomalacia [2]. This has led to some confusion
over whether or not adults benefit from treatment, and mis-
interpretation of XLH as a childhood disease. Although some
adults tolerate stopping treatment with few symptoms, at
least for a time, many develop active osteomalacic symptoms,
 Pharmacological management of X-linked hypophosphataemia
bone pain, muscle weakness and pseudofractures, which
demonstrate varying degrees of improvement during treat-
ment with active vitamin D and phosphate [22].
Important side effects limit this therapy. Doses of phos-
phate may be limited by gastrointestinal symptoms,
nephrocalcinosis, ectopic calcification and hyperparathy-
roidism, while active vitamin D may also contribute to
nephrocalcinosis or other ectopic calcification. Nephro-
calcinosis is reported in 50–80% of XLH patients receiving
active vitamin D and phosphate, and appears to relate to
episodes of hypercalciuria [54–57]. Most nephrocalcinosis is
mild, but occasionally patients develop chronic kidney dis-
ease (CKD), the prevalence of which is uncertain, but progres-
sion to end-stage renal disease is rare. Hypertension has been
reported in 27% of XLH patients and may relate in part to
nephrocalcinosis and CKD [58].
Hyperparathyroidism in XLH is complex. Nearly half of
treatment naïve children with XLH have elevated serum
PTH [59], which often decreases after starting active vitamin
D. Serum PTH correlates with FGF23 concentrations in un-
treated patients [52]. However, phosphate doses also lead to
secondary hyperparathyroidism, probably through transient
decreases in serum calcium following every dose. Some pa-
tients with secondary hyperparathyroidism progress to ter-
tiary hyperparathyroidism with multigland hyperplasia and
require surgical intervention to control hypercalcaemia [60,
61]. Prior to the development of parathyroid autonomy, ade-
quate doses of active vitamin D and lowering doses of phos-
phate may combat the rise of PTH.
Novel targets
Given the limitations of effect and the significant risks of
treating XLH with active vitamin D and phosphate salts, the
need for improved treatment options has led to development
of other strategies. We will focus on those targets that have
some clinical/translational data in humans.
Calcimimetics. PTH stimulates FGF23 expression in
osteocytes [62], which could exacerbate
hypophosphataemia in XLH. Since hyperparathyroidism
also complicates XLH treatment, cinacalcet, a tive of the TIO tumour or is a consequence of the
calcimimetic, has been used to manage hyperparathyroidism
in cases of XLH [63, 64]. Short term studies of cinacalcet in
children with XLH demonstrated suppression of the PTH
surge that follows doses of phosphate [65], and improved
TmP/GFR and serum phosphorus. In a case report, one
child developed a severe aversion to, and refusal of, his
oral phosphate doses. Although he did not have
hyperparathyroidism, treatment with cinacalcet, calcitriol
and calcium led to improvements in serum phosphorus
and rickets, although serum FGF23 still increased [66].
Further studies are needed to determine what role
cinacalcet should play, although it may be useful in
tertiary hyperparathyroidism.
Calcitonin. Calcitonin stimulates 1α-hydroxylase in the
proximal renal tubule in Hyp mice [67], and transiently
increases 1,25(OH)2D in subjects with XLH after a single
injection [68]. Osteocytes also express the calcitonin
receptor [69], and as such, calcitonin could influence FGF23
secretion. Calcitonin decreased serum FGF23 in a patient
with tumour-induced osteomalacia (TIO) [70]. A single
calcitonin injection decreased serum FGF23 and increased
serum phosphorus transiently in patients with XLH,
although not in healthy controls [71]. To make the
calcitonin story more confusing, case reports indicate
calcitonin increases urinary phosphorus excretion in
hyperphosphatemic tumoural calcinosis (a condition of
FGF23 deficiency rather than excess) [72], which would be
opposite of the goal of XLH management. A 3-month-long
blinded randomized controlled clinical trial of monotherapy
with nasal calcitonin 400 units daily for XLH failed to
demonstrate improvements in serum phosphorus, TmP/GFR
or FGF23 [73]. Given the current lack of data indicating
benefit, calcitonin should not be used for XLH.
Fibroblast growth factor receptor antagonism in
TIO
TIO (OMIM 605380) is another syndrome of excess fibro-
blast growth factor receptor (FGF23) [39, 74]. These tu-
mours are classified under the collective term of
phosphaturic mesenchymal tumour, mixed connective tissue var-
iant (PMTMCT) or phosphaturic mesenchymal tumour [75].
Complete tumour resection is the most straight forward
cure for TIO. For tumour localization, imaging techniques
using radiolabelled octreotide [76] as well as magnetic reso-
nance imaging [77], computed tomography [78], whole
body sestamibi scanning [79], and Ga68-DOTA-octreotide
positron emission tomography/computed tomography imag-
ing [80] may be useful. Selective venous sampling for FGF23
levels has been attempted to locate tumours as well [77, 81].
Unfortunately, many PMTMCTs are small in size and remain
difficult to localize, necessitating medical management.
In a group of 15 TIO tumours analysed through next-
generation sequencing, a fibronectin (FN1)-FGFR1 fusion
gene was detected in 60% of the tested samples [82]. The fu-
sion protein is predicted to express portions of the three ex-
tracellular FGF-binding (Ig-like) domains [82], therefore
ligand-activated receptor signalling could perhaps occur. It
is not established however, whether the fusion gene is causa-
tumourigenesis. Activating FGFR1 mutations are associated
with osteoglophonic dysplasia, a disease of dwarfism as well
as craniosynostosis [83]. Some osteoglophonic dysplasia
patients also have significantly elevated FGF23 and
hypophosphataemia. Thus, inhibitors of FGF binding or
FGFR activity could be useful pharmacological treatments
for TIO. Such inhibitors may block FGFR auto- and ligand-
and Klotho-dependent FGFR dimerization, and may reduce
signalling through FGFRs along with directly inhibiting
FGF23 bioactivity. However, the ubiquitous nature of FGFR1
could lead to off-target effects. Considering the difficulty with
targeting FGFR inhibitors to a specific tissue, another plausi-
ble approach for treating TIO patients until the tumour is
found may be monotherapy with anti-FGF23 antibody (see
below) as is currently being tested in TIO and XLH
(ClinicalTrials.gov NCT02304367).
FGF23-blocking antibodies. Investigators at Kirin Pharma
developed murine anti-FGF23 monoclonal antibodies that
Br J Clin Pharmacol (2019) 85 1188–1198 1191
 E. A. Imel and K. E. White
bind separate isotopes on either the C-terminal or N-terminal
portions of FGF23 [84], providing information on the
structural interactions of FGF23 with its receptor/co-
receptor. Both antibodies interfered with FGFR signalling as
indicated by declines in Egr-1 reporter activity (a molecular
marker for MAPK activation). The N-terminal antibody
interfered with binding of FGF23 to the FGFR, while the C-
terminal antibody interfered with binding to the coreceptor
klotho. Injecting either antibody into mice produced
generally similar effects: transient increases in 1,25(OH)2D
beginning within 3–5 hours, and in TmP/GFR and serum
phosphorus after 16 h [84]. Combining the antibodies was
synergistic.
Hyp mice receiving subcutaneous injection of these anti-
bodies in combination demonstrated a similar biochemical
response and time course after a single dose [85]. When juve-
nile, 4-week-old Hyp mice were treated with weekly injections
for 5 weeks, renal sodium phosphate cotransporter expres-
sion increased on immunohistochemistry, and serum phos-
phorus improved in a dose-dependent manner along with
increases in Cyp27b1 mRNA expression and serum
1,25(OH)2D. As a result, mice had bone histomorphometric
improvements, including decrease in osteoid thickness and
volume toward normal, as well as increased mineral apposi-
tion rate, bone formation rate, and bone volume/total vol-
ume (BV/TV). This translated into improvements in the
rachitic growth plate morphology, the growth and shape of
their tails, femora and tibiae, and in overall size of the mice
[26, 85]. Treating adult Hyp mice with anti-FGF23 antibodies
also improved osteomalacia on histology, and increased mus-
cle grip strength toward normal without changing muscle
weight [26].
Based on successes in the Hyp mouse, a fully human IgG1
monoclonal antibody to bind FGF23 was developed for hu-
man trials (KRN23, now called burosumab or CRYSVITA).
Table 1 summarizes key findings from the published clinical
trials. In the initial dose finding study, single doses of intrave-
nous or subcutaneous burosumab (or placebo) were adminis-
tered to adults with XLH after stopping phosphate or active
vitamin D [86]. Burosumab increased TmP/GFR, serum phos-
phorus and 1,25(OH)2D in a dose dependent manner. The
half-life was longer for subcutaneous dosing (13–19 days)
than with intravenous dosing (8–12 days). Baseline FGF23
concentration did not predict AUC changes for any pharma-
codynamic parameter.
Twenty-eight adults with XLH stopped all XLH medica-
tions and enrolled in a Phase 2 dose-escalating multidose trial
of burosumab administered subcutaneously every 4 weeks,
with doses ranging from 0.05 to 0.6 mg kg–1 and 22 subjects
continued in a 12-month extension with doses ranging from
0.1–1 mg kg–1 [87]. During the multidose trial, burosumab ex-
hibited first-order absorption and elimination kinetics, simi-
lar to other monoclonal antibody therapies, with an
elimination half-life of 17.8 days [88].
The peak value of 1,25(OH)2D and serum phosphorus oc-
curred about 3–7 days after injection, while peak TmP/GFR
occurred about 7 days after injection [87]. After each peak,
the TmP/GFR, serum phosphorus and 1,25(OH)2D decreased
toward a trough level 4 weeks after injection that remained
generally above the baseline values. Peak and trough values
increased during the dose escalation phase, then remained
1192 Br J Clin Pharmacol (2019) 85 1188–1198
generally stable through the 12 month extension, except for
the peak of 1,25(OH)2D, which decreased in magnitude over
later doses [87]. Most subjects at least transiently achieved
normal serum phosphorus concentrations.
Despite the transient increase in 1,25(OH)2D during each
cycle, there was no systematic change in serum or urine cal-
cium or in PTH. Kidney function also remained stable. Ten
subjects had baseline nephrocalcinosis or nephrolithiasis,
and no subject had worsening nephrocalcinosis [87].
Although this first multidose trial did not assess clinical
bone outcomes, the bone biomarkers P1NP, osteocalcin and
bone alkaline phosphatase increased during the study period.
Quality of life instruments (SF-36v2 and WOMAC) indicated
baseline impairments in bodily pain, physical function and
role limitations, along with stiffness. After 4 months there
were improvements in the patients’ perception of their phys-
ical functioning and stiffness [28].
In a recently published, open-label, phase 2 trial, 52 chil-
dren aged 5–12 years with XLH in Europe and the USA were
randomized to receive burosumab subcutaneously every
2 weeks or every 4 weeks for 64 weeks [29]. Patients were
mostly prepubertal, although Tanner stage 2 subjects were
allowed. All patients stopped phosphate and vitamin D ana-
logues 2 weeks prior to screening. Since this was the first trial
conducted in children, the initial cohort started at very low
burosumab doses and titrated upwards targeting serum phos-
phorus levels between 3.2 and 6.1 mg dl–1 (1.0–2.0 mmol l–1).
Rickets was assessed using a rickets severity score (RSS) that
rated radiographic appearance at the wrist and knee on a scale
from 0–10 (10 being the worst). Differences between baseline
and follow-up radiographs were also assessed using a seven-
point ordinal Radiographic Global Impression of Change
(RGI-C) scale (ranging from –3 severe worsening, to 0 no
change, to +3 complete healing) [89].
One limitation of this paediatric study was its lack of a
control group. However, all but one subject had been receiv-
ing standard treatment with active vitamin D analogues and
phosphate salts up to the time of enrolment (for a mean of
6.9 years prior treatment). Thus, the baseline rickets severity
at enrolment (ranging from RSS 0–4.5, mean 1.8 ± 1.1) repre-
sents residual rickets despite prior treatment. Any improve-
ments seen in trial occurred in the setting of switching from
prior standard therapy to burosumab.
At week 40 the mean burosumab dose had been titrated to
0.98 mg kg–1 every 2 weeks or 1.5 mg kg–1 every 4 weeks [29].
Children receiving every 4 weeks dosing had pharmacody-
namic profiles of serum phosphorus, 1,25(OH)2D and
TmP/GFR similar to that seen in adults [29]. However, the ev-
ery 2 weeks dosing group had more sustained improvements
in these parameters, with less pronounced biochemical
trough effects, and serum phosphorus values more consis-
tently in the normal range. Alkaline phosphatase is com-
monly elevated in XLH patients (mean 459 ± 105 units l–1 at
baseline of this trial), which decreased by 20% at week 64.
Both groups demonstrated improvements in rickets by week
40 that were sustained at week 64. Rickets improvements
were numerically greater in those receiving every 2 weeks in-
jections and also in those having worse baseline rickets sever-
ity. Total RSS score decreased from mean 1.9 to 0.8 after every
2 weeks dosing, and from 1.7 to 1.1 after every 4 weeks dos-
ing. The mean total RGI-C was +1.57 at the end of study,
 Pharmacological management of X-linked hypophosphataemia

Table 1
Key findings from the primary burosumab clinical trial publications in X-linked hypophosphataemia (XLH) to datea

Imel et al. JCEM 2015 [87],

Carpenter et al. Ruppe et al. Carpenter et al. Insogna et al.
Study [ref] / JCI 2011 [86] Bone Reports 2016 [28] NEJM 2018 [29] JBMR 2018 [21]
ClinicalTials.gov number NCT00830674 NCT01340482, NCT01571596 NCT02163577 NCT02526160

Population Adults with XLH Adults with XLH Children with XLH, Adults with XLH
ages 5–12 years at and Brief Pain Inventory
enrollment worst pain score ≥ 4

Treatment arms Single dose Multidose for 16 months: Multidose for 64 weeks, Multidose for 24 weeks:
with dose titration period c
Intravenous 4-month dose escalation phase Every 2 weeks burosumab Every 4 weesk burosumab
–1
burosumab Every 4 weeks burosumab (mean dose at week 40 was 1 mg kg (n = 68)
–1 –1
0.003–0.3 mg kg (n = 17) 0.05–0.6 mg kg
–1
(n = 28), 0.98 mg kg ) (n = 26)
vs. placebo (n = 5)
or followed by or or

Subcutaneous 12-month extension phase Every Every 4 weeks burosumab Every 4 weeks placebo
burosumab 4 weeks burosumab (mean dose at week 40 was (n = 66)
–1 –1
0.1–1 mg kg (n = 12) 0.1–1 mg kg
–1
(n = 22) b 1.5 mg kg ; n = 26)
vs. placebo (n = 4)
Primary outcome Safety and tolerability Proportion of subjects achieving Change in RSS from Percent of subjects achieving
maximum fasting serum Pi in baseline to week 40 and 64 mean serum Pi in the normal
normal range range across the midpoint of
dosing intervals

Biochemical findings Increased serum Pi, serum
1,25(OH)2D3, and TmP/
GFR
Increased serum Pi, serum
1,25(OH)2D3, and TmP/GFR
Increased serum Pi, serum Increased serum Pi, serum
1,25(OH)2D3, and TmP/ 1,25(OH)2D3, and TmP/GFR
GFR;
decreased serum alkaline
phosphatase.

Radiographic outcomes Improved rickets by RSS Improved healing of active

and RGI-C.
Greater changes seen with
every 2-week dosing, and in
those with higher baseline
RSS
fractures/pseudofractures
from baseline:
burosumab (43.1% of
fractures healed) compared
to placebo (7.7%)

Other outcomes At baseline: Increased standing height WOMAC:

Impairment of physical function z-score; Decreased stiffness scores

Over 4 months of treatment: Among those with baseline

Improved role limitations due to impairments in 6MWT, the
physical health (SF-36v2), distance walked improved
physical functioning and stiffness
(WOMAC) On PODCI, among those
with impairments,
burosumab improved:
Sports and physical
functioning domain,
Pain and comfort domain,
Global functioning
a
In each of these trials, subjects had a washout period from phosphate salts and active vitamin D analogues, and burosumab (or placebo) was given as
monotherapy. Dose titration was based on serum phosphorus concentration, targeting normal serum phosphorus ranges
b –1
During the extension phase over 80% of subjects received doses of 0.6–1 mg kg [87]
c
Children in this trial started initially at very low doses, which were titrated based on serum phosphorus concentration, and sequential entry cohorts
began at higher doses [29]
Pi, phosphorus; PODCI, Pediatric Outcomes Data Collection Instrument; RGI-C, Radiographic Global Impression of Change scale for rachitic features
(positive scores indicate improvement); RSS, Thacher Rickets Severity Score; Sf-36v2, Medical Outcomes Study Short Form Health Survey version 2;
TmP/GFR, transport maximum phosphorus adjusted for glomerular filtration rate; WOMAC, Western Ontario and McMaster Osteoarthritis Index;
1,25(OH)2D3 1,25-dihydroxyvitamin D3; 6MWT, 6-min walking test

Br J Clin Pharmacol (2019) 85 1188–1198 1193

 E. A. Imel and K. E. White

indicating healing of rickets. Substantial healing of rickets

(RGI-C ≥ +2) occurred in approximately half the patients in
each group, but in 94% of those with baseline RSS ≥1.5 that
received burosumab every 2 weeks. In addition, small im-
provements in standing height Z-score were observed
(+0.15 ± 0.04). Additional functional improvements were
noted. Impairments in 6-min walking distance were present
at baseline in 46% of patients, and among these the 6-min
walking distance improved by 10% of the predicted normal
range for age. Similarly, baseline scores indicated impair-
ments for sports and physical functioning, and in pain and
comfort domains in 54% of the children using the paediatric
outcomes data collection instrument, which were seen to im-
prove during treatment.
In a Phase 2 trial, 13 children with XLH, age 1–4 years, were
enrolled to receive open-label burosumab 0.8 mg kg–1 every
2 weeks. This trial indicated similar improvements in serum
phosphorus, alkaline phosphatase and rickets severity to that
seen in the 5–12-year-old children [90, 91]. Some details of
this trial have been presented at scientific meetings and are
indicated in the Food and Drug Administration (FDA) drug
label [90, 91], but have not yet been fully published.
The pivotal Phase 3 adult trial randomized 134 adults with
XLH to receive burosumab at doses of 1 mg kg–1 (maximum
90 mg) every 4 weeks vs. a placebo for 24 weeks (without an ac-
tive comparator treatment), after which all subjects received
burosumab for the subsequent 24 weeks [21]. Subjects were re-
quired to have a brief pain inventory worst pain ≥4 to enrol.
Nearly all subjects (99%) had radiographic evidence of
enthesopathy, half had nephrocalcinosis, while 47% in the
burosumab group and 57% in the placebo group had
pseudofractures/fractures with several subjects having multi-
ple pseudofractures. The primary endpoint (the percent of pa-
tients achieving mean serum phosphorus concentrations in
the normal range across the midpoint of dosing intervals) Figure 1
was achieved in 94% of subjects after burosumab vs. 7.6% af- Data from a 24-week randomized, placebo-controlled trial of
ter placebo (Figure 1A). Trough serum phosphorus remained –1
burosumab 1 mg kg vs. placebo in adults with X-linked
in the normal range in 67.6% of burosumab treated subjects. hypophosphataemia are shown. (A) Mean serum phosphorus is
The burosumab group had improvements at week 24 in within the normal range at the midpoint of dosing interval during
the brief pain inventory worst pain score, and WOMAC phys- treatment with burosumab, compared with placebo treated sub-
ical function and stiffness subscales compared to placebo, but jects, whose phosphorus remained low. (B) Active fractures or
only stiffness remained significant after adjustment for multi- pseudofractures were more likely to heal during 24 weeks of
burosumab compared with placebo. Adapted and reproduced from
ple comparisons. Most importantly 43.1% of baseline
Figures 1A and 3A of Insogna et al. J Bone Miner Res 2018;33:1383–
fractures/pseudofractures were healed after 24 weeks in the
1393; (Reference [21]); Wiley Publishers, https://doi.org/10.1002/
burosumab group vs. 7.7% in the placebo group (Figure 1B). jbmr.3475. Creative Commons Attribution License (CC BY 4.0,
Regarding safety, the most common drug-related adverse https://creativecommons.org/licenses/by/4.0)
events have been local injection site reactions that were often
characterized as welts, and usually lasted a few to several
hours, resolving without treatment. Injection site reactions treated subjects in the placebo controlled adult study (8/68
occurred in 57.7% of children [29] and 11.8% of adults [21], or 11.8%) but was also present to some degree in the placebo
although, interestingly, injection site reactions also occurred arm (5/66 or 7.6%) [21]. No serious adverse events were attrib-
in 12.1% of placebo treated adults. Additional adverse events uted to burosumab itself.
occurring in ≥25% of children included headache, vomiting, There has been no systematic evidence of change in PTH,
pyrexia, extremity pain and decrease in vitamin D. Addi- serum calcium or urine calcium excretion in any trials.
tional adverse events occurring in ≥10% of adults included Nephrocalcinosis was present at baseline in 35% of children
back pain, tooth abscess, nasopharyngitis, headaches, nausea in the Phase 2 trial [29] and 54% of adults in the Phase 3 trial
and dizziness. However, most listed adverse events were not [21]. So far, there has been no clear indication of either wors-
considered drug related, while some are consistent with ening or improvement of nephrocalcinosis overall with
symptoms common to XLH patients. Restless legs syndrome burosumab treatment. In fact, similar numbers of patients
was noted in the initial multidose trial (5/28 or 17.9%) [87]. had increases in nephrocalcinosis score in the burosumab
Restless legs syndrome occurred more often in burosumab- and placebo groups, while similar numbers also had decreases

1194 Br J Clin Pharmacol (2019) 85 1188–1198

 Pharmacological management of X-linked hypophosphataemia
in nephrocalcinosis scores in each group [21]. No significant
changes in echocardiograms were reported.
An advantage of burosumab is that it achieves normalization
of serum phosphorus through improvements in TmP/GFR, in
contrast to standard therapy with active vitamin D and
phosphate salts. One hopes that this will translate into lower
long-term risk of nephrocalcinosis and hyperparathyroidism,
provided that episodes of hyperphosphataemia are avoided. In
the phase 3 placebo controlled adult trial, five patients (7.4%)
had dose reductions according to protocol, due to serum
phosphorus above the target range, four of which were classified
as hyperphosphataemic [21]. These subjects maintained in the
trial on smaller doses. Thus, some patients may respond well to
smaller doses to manage XLH.
Conceptually, anti-drug antibodies could bind and inter-
fere with the action of burosumab. The initial multidose
trial in adults, and the Phase 2 trial in children did not find
anti-drug antibody development [29, 87]. However, one
published trial (and the drug labels) notes that anti-drug
antibodies have been detected in small numbers of subjects
at baseline before burosumab administration [21, 91].
Anti-drug antibodies persisted in some subjects, but further
development of antibodies during trial participation, was
not seen. To date, there is no evidence for neutralizing
anti-drug antibodies attenuating effect of burosumab in
human subjects.
Patients with moderate to severe CKD were excluded from
the burosumab trials. In a rat model of severe CKD, treatment
with a different FGF23 antibody hastened death, probably
due to the frank hyperphosphataemia that developed [92].
Thus, the use of burosumab in severe kidney disease is not
recommended, and hyperphosphataemia should be avoided.
The safety of burosumab (or for that matter of phosphate and
active vitamin D) in pregnancy has not been established.
Burosumab was approved as monotherapy in 2017 by the
European Medicines Agency (EMA; conditionally) and in
2018 by the FDA (fully). The EMA conditionally approved
use of burosumab in children aged 1 year and older with ra-
diographic evidence of bone disease, through adolescence
during skeletal growth. The EMA approved starting dose is
0.4 mg kg–1 subcutaneously every 2 weeks in children with
0.8 mg kg–1 as typical maintenance dosing, and a maximum
dose of 90 mg [93]. The FDA approved starting dose is
0.8 mg kg–1 every 2 weeks in children aged 1 year and older,
and 1 mg kg–1 every 4 weeks in adults with a maximum dose
of 90 mg [91]. Doses are titrated on the basis of peak and
trough serum phosphorus concentrations.
Several questions remain. A true active comparator study in
growing children aged 1–12 years is underway (ClinicalTrials.
gov NCT02915705). This trial will identify the effect of 64 weeks
of burosumab vs. phosphate and active vitamin D on multiple
clinical parameters with a primary outcome of differences in
healing of radiographic rickets. The effect on adult height in
growing children is unknown. However, this will take years to
evaluate, given the mean ages of children enrolled in the clinical
trials. Since enthesopathy and other joint related complications
develop and progress slowly, many years of treatment with
burosumab will be necessary to interpret whether or not these
outcomes are altered. Similarly, years of treatment are likely to
be necessary to determine whether the chronic risk of
nephrocalcinosis changes.
Conclusion
XLH is a complex musculoskeletal condition, requiring
careful medical and surgical management. Recent approval
of burosumab represents a substantial advancement in
management of XLH, directed at its pathophysiology of
FGF23 excess. Further studies are needed to fully characterize
long-term risks and benefits of this drug, especially regarding
disease features that take years to develop.
Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked
to corresponding entries in http://www.guidetophar-
macology.org, the common portal for data from the
IUPHAR/BPS Guide to PHARMACOLOGY [94], and are
permanently archived in the Concise Guide to PHARMA-
COLOGY 2017/18 [95, 96].
Competing Interests
E.A.I. receives research funding that contributes to this work
from the NIH/NIAMS 1P30AR072581. K.E.W. would like to
acknowledge support by NIH grants DK063934, DK095784,
and AR059278. E.A.I. has received research funding and fees
for consulting with Kyowa Hakko Kirin and Ultragenyx,
Pharmaceuticals. K.E.W. receives royalties from Kyowa
Hakko Kirin Co. Ltd for licensing FGF23.
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