The Muscle-Bone Relationship in X-Linked Hypophosphatemic Rickets.
ABSTRACT Context:We recently found that patients with X-linked hypophosphatemic rickets (XLH) have a muscle function deficit in the lower extremities. As muscle force and bone mass are usually closely related, we hypothesized that patients with XLH could also have a bone mass deficit in the lower extremities.Objective:The study objective was to assess the muscle-bone relationship in the lower extremities of patients with XLH.Setting:The study was carried out in the outpatients department of a pediatric orthopedic hospital.Patients and Other Participants:Thirty individuals with XLH (6 to 60 y; 9 male patients) and 30 age- and gender-matched controls participated.Main Outcome Measures:Calf muscle size and density as well as tibia bone mass and geometry were assessed by peripheral quantitative computed tomography. Muscle function was evaluated as peak force in the multiple 2-legged hopping test.Results:Muscle force was significantly lower in XLH patients than in controls but muscle cross-sectional area did not differ (after adjustment for tibia length). External bone size, expressed as total bone cross-sectional area, was higher in the XLH group than in controls. The XLH cohort also had statistically significantly higher bone mineral content.Conclusions:Patients with XLH have increased bone mass and size at the distal tibia despite muscle function deficits.
- The Lancet 08/2013; 382(9894):767. · 39.21 Impact Factor
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ABSTRACT: In children, hypophosphatemic rickets is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogues (alfacalcidol or calcitriol) to counter the 1,25-dioH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of hypophosphatemic rickets. Besides vitamin D analogues and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical and contributions of various expertises to the treatment of hypophosphatemic rickets are described, with an effort to highlight the importance of coordinated care.Endocrine connections. 02/2014;
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ABSTRACT: In recent years, as knowledge regarding the etiopathogenetic mechanisms of bone involvement characterizing many diseases has increased and diagnostic techniques evaluating bone health have progressively improved, the problem of low bone mass/quality in children and adolescents has attracted more and more attention, and the body evidence that there are groups of children who may be at risk of osteoporosis has grown. This interest is linked to an increased understanding that a higher peak bone mass (PBM) may be one of the most important determinants affecting the age of onset of osteoporosis in adulthood. This review provides an updated picture of bone pathophysiology and characteristics in children and adolescents with paediatric osteoporosis, taking into account the major causes of primary osteoporosis (PO) and evaluating the major aspects of bone densitometry in these patients. Finally, some options for the treatment of PO will be briefly discussed.Italian journal of pediatrics. 06/2014; 40(1):55.
The Muscle-Bone Relationship in X-Linked
Louis-Nicolas Veilleux, Moira S. Cheung, Francis H. Glorieux, and Frank Rauch
Shriners Hospital for Children and Department of Pediatrics, McGill University, Montréal, Québec,
Context: We recently found that patients with X-linked hypophosphatemic rickets (XLH) have a
muscle function deficit in the lower extremities. As muscle force and bone mass are usually closely
related, we hypothesized that patients with XLH could also have a bone mass deficit in the lower
Objective: The study objective was to assess the muscle-bone relationship in the lower extremities
of patients with XLH.
and gender-matched controls participated.
Main Outcome Measures: Calf muscle size and density as well as tibia bone mass and geometry
were assessed by peripheral quantitative computed tomography. Muscle function was evaluated
as peak force in the multiple 2-legged hopping test.
Results: Muscle force was significantly lower in XLH patients than in controls but muscle cross-
sectional area did not differ (after adjustment for tibia length). External bone size, expressed as
total bone cross-sectional area, was higher in the XLH group than in controls. The XLH cohort also
had statistically significantly higher bone mineral content.
function deficits. (J Clin Endocrinol Metab 98: 0000–0000, 2013)
ing, resulting in rickets, deformities of the lower extrem-
ities, and short stature (1, 2). The condition is most com-
monly caused by mutations in the phosphate-regulating
endopeptidase gene (PHEX), which leads to X-linked hy-
pophosphatemic rickets (XLH; OMIM 307800) (1, 2).
Autosomal-dominant (OMIM 193100) and autosomal-
recessive (OMIM 241520) forms of the disease have also
been reported and are caused by mutations in fibroblast
(1, 2). However, these latter forms are much rarer than
ereditary hypophosphatemic rickets is characterized
phate supplementation and calcitriol; the latter aims at
preventing secondary hyperparathyroidism that other-
tation (2). This regimen corrects the mineralization defect
at the level of the growth plates and thus heals the rickets,
but some degree of mineralization defect persists in the
bone tissue despite treatment (4).
Muscle force is strongly correlated with measures of
bone strength in healthy subjects (5). For example, it has
been shown that the maximal ground reaction force dur-
ing hopping on the forefoot predicts as much as 84% of
bone mineral content (BMC) of the tibia in healthy chil-
ISSN Print 0021-972X
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
Received December 8, 2012. Accepted February 22, 2013.
ISSN Online 1945-7197 Abbreviations: BMC, bone mineral content; CSA, cross-sectional area; M1LH, multiple
puted tomography; XLH, X-linked hypophosphatemic rickets.
O R I G I N A LA R T I C L E
E n d o c r i n eR e s e a r c h
doi: 10.1210/jc.2012-4146 J Clin Endocrinol Metabjcem.endojournals.org
J Clin Endocrin Metab. First published ahead of print March 22, 2013 as doi:10.1210/jc.2012-4146
Copyright (C) 2013 by The Endocrine Society
dren, adolescents, and adults (5). We recently found that
XLH patients have muscle function deficits as compared
to age- and gender-matched controls (6). If the muscle-
bone relationship follows the same pattern in patients as
cle function deficit in XLH will lead to weaker bones in
To test this hypothesis, we used a recently established
approach to assess specifically muscle-bone interaction in
the lower leg (5). Muscle size, bone mass, and bone ge-
ometry at the lower leg are assessed by peripheral quan-
titative computed tomography (pQCT), and muscle func-
tion is evaluated by jumping mechanography.
Subjects and Methods
The patient population comprised 30 individuals with a di-
agnosis of XLH who were at least 6 years of age, the lower age
for reliably performing pQCT and jumping mechanography as-
sessments. The XLH population consisted of the following 2
subgroups: patients under 21 years of age who were actively
followed at the Shriners Hospital for Children in Montreal, and
participants aged 21 years or older, who were former patients
invited to the clinic for the purpose of the present study. Exclu-
sion criteria were fractures of the lower limbs in the past 6
months or lower limb surgery in the past 12 months. Thirty
patients with XLH (age 6 to 60 y; 9 male patients) agreed to
participate in this study.
The diagnosis was based on the presence of low serum phos-
phorus and normal results for serum calcium and parathyroid
hormone levels, plus radiological evidence of rickets or a family
history of XLH. In 25 of the 30 study patients, PHEX mutation
analysis had been performed and revealed disease-causing mu-
tations in 19 patients. Regarding treatment status at the time of
this study, 14 patients were actively being treated with calcitriol
and phosphate supplementation and had been receiving this
treatment for 1.1 to 15.9 years (mean ? SD: 8.5 ? 4.0 y). Ten
patients had received the same therapy in the past and had dis-
continued treatment when they had reached final height (ie, 2.9
to 18.6 y) prior to the present testing (mean ? SD: 8.9 ? 5.7 y).
Six patients had never received phosphate supplementation. Re-
sults in this population were compared with those of 30 healthy
age- and gender-matched control subjects (age range: 6 to 55 y)
who were recruited among hospital staff and their children as
well as among healthy siblings of patients. The study was ap-
proved by the Institutional Review Board of McGill University.
Informed consent was provided by participants or, for minors,
their parents. Assent was provided by participants aged 7 to 17
The patient and control populations included in the current
study were drawn from the same cohort as that of our previous
study (6), with the exception of 4 patients and their respective
matched controls who were excluded from the present study
ping (n ? 2) or because they did not have valid pQCT measure-
ments due to movements artifacts (n ? 2).
pQCT was performed on the left tibia using the Stratec
XCT2000 (Stratec Inc, Pforzheim, Germany). Tibia length was
the foot and lower leg was set at 120°. The scanner was posi-
open growth plate, the reference line was drawn through the
most distal portion of the growth plate. When the growth plate
was no longer visible, the reference line was drawn through the
middle of the medial border of the articular cartilage. The lower
leg was scanned at 4, 14, and 66% of tibia length, measured as
the distance from the reference line. At each of the 3 measure-
at a voxel size of 0.4 mm ? 0.4 mm ? 2 mm. The speed of the
translational scan movement was set at 20 mm/s.
Image acquisition, processing, and the calculation of numer-
ical values were performed using the manufacturer’s software
site (metaphysis, trabecular bone) and 14% site (metaphyseal-
diaphyseal transition site, cortical bone), whereas muscle size
was determined at the 66% site. The 14% site was selected be-
shown the strongest correlation between BMC and maximal
muscle force during multiple 1-legged hopping (5). This is also
the location where BMC of the tibial cross-section is at its min-
imum (7). The 66% site was selected to obtain calf muscle phys-
At the 4% site, the outer bone contour was detected at the
using the software’s CALCBD routine. The cortical bone at the
14% site was analyzed at a threshold of 710 mg/cm3using the
software’s CORTBD routine. At the 66% site, the combined
cross-sectional area (CSA) of muscle and the 2 bones (fibula and
tibia) was determined at a threshold of 40 mg/cm3, and the CSA
of the 2 bones was determined with the threshold set at 280
mg/cm3. Muscle CSA was calculated by subtracting the bone
CSA from the combined muscle and bone CSA. Muscle density
in the measurement of muscle CSA.
The main parameters of pQCT analysis at the tibia are as
follows: BMC, corresponding to the amount of mineral per mil-
at the 4 and 14% sites); total bone CSA, the surface area of the
entire bone cross-section, including cortex and marrow space
(unit: mm2; 4 and 14% sites); cortical CSA, the surface area of
the cortical bone cross-section excluding marrow space (unit:
mm2; 14% site); total volumetric bone mineral density (vBMD;
bone mineral density averaged across the entire bone cross-sec-
tion; unit: mg/cm3; 4 and 14% sites); trabecular vBMD, the av-
erage mineral density in the trabecular compartment, deter-
mined in the central 45% of the tibial cross-section (unit: mg/
determined from total and cortical CSA using the ring model
(unit: mm; 14% site).
Veilleux et alMuscle-Bone Interaction in XLHJ Clin Endocrinol Metab
A force plate (Leonardo Mechanograph Ground Reaction
used to measure vertical ground reaction forces. The force plate
was connected to a laptop computer and force measurements
were sampled at a frequency of 800 Hz. As described in detail
elsewhere, all muscle function parameters reported here were
derived from these force-time data using proprietary software
(Leonardo Mechanography GRFP Research Edition software,
version 4.2-b05.53-RES; Novotec Medical GmbH) (9).
hopping (M2LH) rather than multiple 1-legged hopping
(M1LH) was selected for the present study. The main reason for
M1LH test. The M2LH test results in a slightly lower force per
close to maximal voluntary force contractions (2.7 times their
body weight vs 3.1 times for the M1LH in healthy children and
adults) (6, 9). The M2LH has also been investigated in detail in
11). The test consists of jumping on the forefeet with stiff knees
and without the heels touching the ground (similar to skipping
the highest peak force (FM2LH) (9). The main parameter to in-
vestigate the muscle-bone interaction is peak force (5). Because
mechanography assesses maximal muscle performance, partic-
ipants were excluded from the hopping test if they reported any
disorder that might interfere with their ability to perform the
Height was measured using a Harpenden stadiometer (Hol-
tain, Crymych, United Kingdom). Weight was determined using
the Leonardo Mechanograph GRFP (Novotec Medical GmbH).
Height and weight measurements were converted to age- and
gender-specific z-scores on the basis of reference data published
by the Centers for Disease Control and Prevention (12). Lower
extremities were classified as straight legs, genu varum, or genu
valgum. Legs were considered straight if the intercondylar and
the intermalleolar distances were less than 4 cm. Genu varum
was classified as mild when the intercondylar distance was be-
severe when the intermalleolar distance was more than 8 cm (6).
were 2-tailed and throughout the study P ? .05 was considered
significant. Paired t tests were used to detect significant differ-
ences between XLH patients and controls for anthropometric
data. Data on muscle characteristics (force, cross-section, and
density) represent a subset of previously reported results (6). To
avoid redundancy, muscle characteristics are shown in the Sup-
plemental data section, published on The Endocrine Society’s
Journals Online web site at http://jcem.endojournals.org.
To compare bone parameters between the XLH and control
groups, we first computed the percentage difference between
each XLH patient and the matched control for each bone pa-
rameter. This new variable was used for ANOVAs, with treat-
ment status (currently treated, previously treated, never treated)
and leg deformities as the between-subjects factors. Additional
covariates were age, tibia length, and height z-scores. It was
found that tibia length and leg deformities were the only cova-
riates significantly impacting bone parameters. Therefore, sim-
parameter, in which the disease status (XLH vs control group)
was set as the between-subjects factor and tibia length and leg
deformities were used as covariates (ie, data adjusted for tibia
length and presence of deformities).
Independent stepwise regression analyses were used to assess
predictors of BMC and total bone CSA. Independent predictors
Table 1. Anthropometric data
(n ? 30)
(n ? 30)P
Tibia length (mm)
Results are given as mean (SD).
Table 2. Bone Characteristics at the Tibia as Measured by pQCT
(n ? 30)
(n ? 30)%?
Metaphysis (“4% site”)a
Total CSA, mm2
Total BMC, mg/mm
Total vBMD, mg/cm3
Trabecular vBMD, mg/cm3
Transition site (“14% site”)
Total CSA, mm2
Total BMC, mg/mm
Cortical vBMD, mg/cm3
Cortical thickness, mm
Cortical CSA, mm2
Results are given as mean (SD). All values are corrected for tibia length.
aData of one participant removed because of movement artifacts.
were muscle force (FM2LH; muscle function model) or its phys-
iological surrogates (muscle CSA and muscle density that make
up the muscle anatomy model), disease status (Control ? 0;
XLH ? 1), leg deformity (straight legs ? 0; mild deformities ?
1; severe deformities ? 2), age, and tibia length. These calcula-
18.0 (SPSS Inc, Chicago, Illinois).
Compared with age- and gender-matched controls, pa-
tients with XLH were shorter and had shorter tibias but
leg deformities (genu varum or valgum); 9 had mild leg
deformities and 13 had straight legs.
External bone size, expressed as total bone CSA, and
sites (Table 2). Trabecular vBMD was similar between
in controls. The patient group had higher cortical CSA,
whereas cortical thickness was similar between groups.
Stepwise regression analyses were performed to deter-
mine predictors of BMC at the 4 and 14% sites (Table 3).
rameters of either muscle function (FM2LH; Supplemental
data) or of muscle anatomy (muscle
the muscle function model (Figure
1A), FM2LH, leg deformity, and tibia
length were significant predictors of
BMC at both bone sites, whereas dis-
ease status was a significant predic-
tor at the 4% site only. In the muscle
anatomy model (Figure 1B), muscle
CSA but not muscle density, leg de-
formities, and tibia length were sig-
nificant predictors of BMC at the 2
measurement locations (Table 3).
also computed to determine predic-
tors of total bone CSA (Table 4).
Muscle force (Figure 1C), muscle
CSA (Figure 1D), and tibia length
were predictors of total bone CSA at
both sites. Disease status was a sig-
nificant predictor of total bone CSA
at both the 4% and the 14% sites
with greater CSA in XLH. Leg de-
formity was not a significant predic-
tor of total bone CSA.
Figure 1. A, Relationship between BMC (mg/mm) and muscle force (FM2LH; kN) at the 14% site
as a function of the disease status and leg deformity status (XLH group). B, Relationship between
BMC (mg/mm) and muscle cross-sectional area (mCSA; mm2) at the 14% site as a function of
the disease status and leg deformity status (XLH group). C, Relationship between total bone CSA
(mm2) and muscle force (FM2LH; kN) at the 14% site as a function of the disease status and leg
deformity status (XLH group). D, Relationship between mCSA (mm2) and total bone CSA (mm2)
at the 14% site as a function of the disease status and leg deformity status (XLH group).
Table 3. Predictors of BMC (mg/mm) at the 4 and 14% Tibia Sites
Muscle function model
?18 ? 50 ? (FM2LH; kN) ? 50 ? (Leg deformity; 0, 1, 2)
? 34 ? (Disease status; 0, 1) ? 0.52 ? (Tibia length;
?21 ? 36 ? (FM2LH; kN) ? 34 ? (Leg deformity; 0, 1, 2)
? 0.41 ? (Tibia length; mm)
Muscle anatomy model
?99 ? 0.020 ? (Muscle CSA; mm2) ? 0.70 (Tibia
length; mm) ? 53 ? (Leg deformity; 0, 1, 2)
?58 ? 0.022 ? (Muscle CSA; mm2) ? 0.41 (Tibia
length; mm) ? 25 ? (Leg deformity; 0, 1, 2)
The muscle function model tested the following predictors: muscle force, disease status, leg deformity, tibia length, and age. The muscle anatomy
model tested the following predictors: muscle CSA, muscle density, disease status, leg deformity, tibia length, and age.
Veilleux et alMuscle-Bone Interaction in XLHJ Clin Endocrinol Metab
hypothesis, patients with XLH had higher BMC in the
distal tibia than healthy controls, even though muscle
function was clearly lower in the XLH group (6). The
higher BMC in XLH was mostly explained by larger bone
size (higher total bone CSA), whereas trabecular vBMD
was similar between groups and cortical vBMD was even
lower in XLH patients than in controls.
Our regression analyses shed some light on the muscle-
bone relationship in XLH. First of all, our data showed
that the age factor did not make an independent contri-
bution to the disease effect on bone parameters and the
muscle-bone relationship. As the age range of the study
no indication that the study results depend on develop-
mental stages. In contrast, leg deformity had a significant
deformity) had a significant independent influence on the
relationship between muscle size or force and bone size.
The “muscle anatomy model” indicated a leg deformity
that patients and controls had the same tibia length and
results (Table 2) XLH patients with mild leg deformities
bled in those patients with severe leg deformities. Simi-
larly, XLH patients had a 32% larger bone CSA than
controls with the same tibia length and muscle CSA.
This was a clinical observational study that was not
designed to provide mechanistic data. Nevertheless, it is
possible to interpret these results in the framework of the
to muscle forces in a manner that maintains bone tissue
deformation caused by mechanical muscle loads within
safe limits (13). In XLH, the bone matrix is presumably
softer than normal, due to the mineralization defect that
may persist despite current standard therapy with phos-
phate supplementation and calcitriol (14). The observa-
that a mineralization defect was indeed present in this
population. At a given force level, undermineralized bone
should deform more than normally mineralized bone,
which, according to the mechanostat model, should lead
to higher than normal bone mass. If this interpretation is
correct, treatment approaches that normalize bone min-
eralization in XLH during bone development should lead
to smaller bones and lower BMC in such patients. This
hypothesis can be tested in ongoing treatment trials.
Other explanations for the increased bone mass and
size in XLH patients are also possible. For example,
PHEX is expressed in osteoblasts and mutations in that
cells (15). It has also been reported that mice with PHEX
mutations have decreased expression of sclerostin (16),
which would lead to increased production of bone tissue.
Another possibility is that hypophosphatemia alters the
secretion of muscle-derived hormones (myokines) that
might have an effect on bone metabolism (17).
In the present study we used both muscle anatomy
(muscle size and density) and muscle function (peak force
in M2LH) to assess the muscle-bone relationship. Muscle
force as measured by mechanography (kN) and muscle
cross-sectional area (mm2) are known to be highly corre-
lated (18) (R2? 0.53 P ? .001; R2? 0.75, P ? .001, for
the XLH and control participants, respectively). Never-
muscle force in the M1LH than it is by muscle CSA (5).
This means that the influence of muscle on bone strength
should be analyzed through measurements of dynamic
force surrogates. At present it is unknown if this remains
Table 4. Predictors of Total Bone CSA (mm2) at the 4 and 14% Tibia Sites
Muscle function model
?413 ? 109 ? (FM2LH; kN) ? 298 ? (Disease status; 0, 1)
? 2.72 ? (Tibia length; mm)
?80 ? 55 ? (FM2LH; kN) ? 120 ? (Disease status; 0, 1) ?
0.82 ? (Tibia length; mm)
Muscle anatomy model
?530 ? 0.054 ? (muscle CSA; mm2) ? 280 ? (Disease
status; 0,1) ? 2.9 ? (Tibia length; mm)
?104 ? 0.039 ? (Muscle CSA; mm2) ? 107 ? (Disease
status; 0, 1) ? 0.65 ? (Tibia length; mm)
The muscle function model tested the following predictors: muscle force, disease status, tibia length, and age. The muscle anatomy model tested
the following predictors: muscle CSA, muscle density, disease status, tibia length, and age.
reached with the two approaches were identical and the
correlation coefficients between muscle and bone param-
eters tended to be higher when using muscle CSA than
when using FM2LH. This indicates that the muscle-bone
interaction can simply be assessed through these 2 pQCT
measurements (ie, at 14% [cortical bone] and 66% [mus-
served in the muscle anatomy model might simply reflect
range than muscle CSA data. Therefore, although func-
tional testing using jumping mechanography does not
seem to be essential for such studies, it nevertheless pro-
vides unique information with regard to muscle force.
In conclusion, this study found that patients with XLH
have increased bone mass and size at the distal tibia even
though they have some muscle function deficits. The
mechanisms leading to higher bone mass in XLH warrant
Address all correspondence and requests for reprints to: Louis-
Nicolas Veilleux, Shriners Hospital for Children, 1529 Cedar
Avenue, Montréal, Québec, Canada H3G 1A6. E-mail:
This work was supported by the Shriners of North America,
the Fonds de la Recherche en Santé du Québec (FRSQ), the
MENTOR-Réseau de recherche en santé buccodentaire et os-
seuse (RSBO) program supported by the Canadian Institute for
Health Research (CIHR), and the FRSQ.
Disclosure Summary: The authors have nothing to disclose.
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