Clinic Rev Bone Miner Metab (2013) 11:78–83

DOI 10.1007/s12018-013-9141-6

ORIGINAL PAPER

Hypophosphatasia: The Disease in Adults

Geneviève Baujat • Valérie Cormier-Daire •

Martine Le Merrer

Published online: 7 June 2013

Ó Springer Science+Business Media New York 2013

Abstract Hypophosphatasia is an inherited skeletal dis- non-steroidal anti-inflammatory agents and teriparatide
order due to mutations within the ALPL gene that encodes may improve the symptoms. Enzyme replacement therapy
the ‘‘tissue-nonspecific isoenzyme of alkaline phospha- is currently evaluated in phase II clinical trials in children
tase’’. This disease is characterized by a low serum alkaline and infants and will, hopefully, be soon discussed in some
phosphatase. If the severe paediatric forms are quite rare adults presenting with a significant and progressive disease.
(\1/100,000 births), the prevalence of moderate form is
theoretically estimated at 1/6,370, suggesting some unrec- Keywords Hypophosphatasia
TNSALP
Alkaline
ognized cases. This condition is inherited in an autosomal phosphatase
Fractures
Osteoporosis
Pseudofractures
recessive manner for a majority of cases, but some mod-
erate adult phenotypes and odonto-hypophosphatasia are Abbreviations
autosomal dominant. In adult, the presentation is highly AP Serum alkaline phosphatase
variable, being either manifestations of HPP diagnosed in BPs Bisphosphonates
paediatric age or adult-onset HPP. Adult HPP typically DXA Dual-energy X-ray absorptiometry
manifests during middle age, as variable osteoarticular pain ERT Enzyme replacement therapy
and recurrent slowly healing fractures of metatarsal bone HPP Hypophosphatasia
and proximal femur. The presence of chondrocalcinosis NSAID Non-steroid anti-inflammatory drugs
and ectopic calcifications around joints and tendon PEA Urinary phosphorylated enzyme substrates
attachments to bone are also reported. Biochemically, this phosphoethanolamine
disease is characterized by an excessive urinary excretion PLP Plasma pyridoxical 5’-phosphate
of phosphoethanolamine and elevated serum pyridoxical PPi Inorganic pyrophosphate
5’-phosphate. Elevated serum calcium and phosphorus may TNSALP ‘‘Tissue-nonspecific’’ isoenzyme of alkaline
be found. The molecular diagnosis is today easily per- phosphatase
formed, by ALPL gene analysis. Adult patients have to be
referred in consultation with a genetics professional, to
discuss the related genetic counselling issues with the Introduction
potential risks to offspring, and depending on the individ-
ual case, the possibility of prenatal diagnosis. There is no Hypophosphatasia (HPP, OMIM 171760) is a rare skeletal
curative treatment, but symptomatic treatments such as disorder due to defective mineralization of bone and teeth,
and characterized by an extreme variability range, from
lethal forms to quasi-asymptomatic disease, with only
G. Baujat (&)
V. Cormier-Daire
M. Le Merrer dental symptoms. It is caused by the deficient activity of
Département de génétique, Institut Imagine, Hôpital Necker the tissue-nonspecific isoenzyme of alkaline phosphatase
Enfants-malades, Assistance Publique des Hôpitaux de Paris,
(TNSALP). The presence of low activity of serum alkaline
INSERM U781, Université Paris Descartes, 149 rue de Sèvres,
75743 Paris cedex, France phosphatase (AP) is the hallmark of the disease. Elevation
e-mail: genevieve.baujat@nck.aphp.fr of plasma pyridoxical 5’-phosphate (PLP) and urinary

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Clinic Rev Bone Miner Metab (2013) 11:78–83
phosphorylated enzyme substrates phosphoethanolamine
(PEA) are additional biochemical features supporting the
diagnosis. Consequently, inorganic pyrophosphate (PPi)
accumulates extracellularly and inhibits bone and dental
mineralization. The prevalence is estimated between
1/100,000 and 300,000 for severe forms but about 1/6,500
for moderate forms, which occur more frequently than
often thought [1]. This disease is inherited in an autosomal
recessive manner for a majority of cases. Some moderate
adult phenotypes and/or odonto-hypophosphatasia are
autosomal dominant inherited. The diagnosis is usually
confirmed by molecular testing of TNALPL, gene encoding
the TNSALP, and the detection of either one or two
pathologic mutation(s) [2].
Conventionally, six clinical forms are distinguished,
based on the severity and the age at diagnosis. They
include (1) lethal perinatal form leading to spontaneous
foetus abortion or perinatal death by respiratory insuffi-
ciency and hypercalcemia; (2) benign perinatal form with
prenatal skeletal manifestations but improvement after
birth or in childhood; (3) infantile hypophosphatasia, the
onset of which is between birth and 6 months; (4) child-
hood hypophosphatasia; (5) juvenile form; and (6) odonto-
hypophosphatasia characterized by premature exfoliation
of primary teeth and severe dental caries [3, 4]. However,
the disease spectrum plays a continuum of severity leading
to some degree of confusion within this classification.
While mild adult forms are probably more common than
severe paediatric forms, the disease in adults is much less
described than in children, as shown in the few literature
existing on the field. The clinical manifestations in adults
vary widely with age, gender, diagnosis and onset age, and
the management of the disease. In adults, it may be indeed
distinguished as (1) late manifestations of HPP discovered
in paediatric age; (2) adult-onset hypophosphatasia where
HPP symptoms and diagnosis first occur at [18 years of
age and may include osteomalacia; (3) odonto-hypophos-
phatasia, characterized by an isolated dental phenotype but
without osteomalacia. We will focus particularly on the
adult-onset HPP; the adult dental aspects are deeply
detailed elsewhere in this special issue. There are no adult
HPP management guidelines, but various medical treat-
ment options are being developed. Lastly, the genetic
counselling and prenatal diagnosis discussions take an
important place in adult hypophosphatasia follow-up.
Diagnosis
Adult hypophosphatasia is usually recognized in middle
age, the cardinal features being recurrent fractures, mus-
culoskeletal pain, chondrocalcinosis and dental
abnormalities.
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HPP diagnosed in adult age may be associated with a
history of bowed legs or transient rickets in childhood, and/or
premature loss of teeth, before 3 years of age. In a recent and
interesting retrospective study on 22 adults diagnosed with
HPP, the mean age for diagnosis was 49 years and the onset
of the first symptoms was at 44 years. Only 9 % reported a
history of childhood rickets, unrecognized as HPP, and 4 %
reported history of premature loss of deciduous teeth. Two-
thirds of this series appeared asymptomatic, the HPP diag-
nosis being identified on routine laboratory anomalies or
family history [5].
As previously described, characteristic fracture types in
adults with HPP are recurrent (and slowly healing) frac-
tures of the lower limbs. These fractures are usually first
repeated stress fractures of the lower extremities (meta-
tarsal fractures) followed by painful non-healing proximal
femur fractures [6] or pseudofractures (Fig. 1). The
pseudofractures of the proximal femur are often the first
specific symptoms that evoke the diagnosis of HPP. The
adult fracture burden was recently studied by Whyte et al
[7]. They collected details of fractures for 125 adults with
HPP. The mean of self-reported fracture numbers was 13.9
(range 1–100). For adult-onset HPP, 43/44 (98 %) experi-
enced at least one fracture. Of these, 75 % were lower
extremity fractures and 28/44 required surgical fixation of a
fracture. One-third presented a substantial burden conse-
quently to fracture, pain and immobility. In the Berkseth’s
study, fractures were reported in about half of the adults:
they occurred mainly in hip femora, feet (23 %) and rarely
in wrist (18 %). Vertebral fractures were rarely reported
and occurred in men (9 %), while subtrochanterian frac-
tures were more frequent in women [5]. Lower legs and
vertebral static deformations (genu valgum, genu varum,
kyphoscoliosis) may be sequelae of HPP paediatric forms.
Bowing deformities are rare, also particularly appanage of
patients with HPP diagnosed in infancy. X-rays and den-
sitometry may show variable degree of osteopenia.
Abnormal crystal deposition leading to ectopic calcifi-
cations is another characteristic feature of the disease.
Spinal ligament calcification, in the lumbar or cervical area,
like those reported in adults with hypophosphatemic rickets
or in Forestier’s disease are described [8]. Chondrocalci-
nosis defined by premature intra- and peri-articular calcifi-
cations of several joints, including hands, feet, knees, hips
and shoulder, and due to calcium pyrophosphate dehydrate
(CPPD) deposition is inconstant in adult-onset HPP, as
shown by Berkseth with only 27 %, women exclusive,
presenting with in their series [5]. Radiographs may show
unilateral or bilateral nummular calcifications, localized in
tendons and entheses (wrist triangular ligament, symphysis
pubis, patella, Achilles tendon insertions, plantar fascia
insertions), peri-articular area (hips, carpus, knee, wrist) or
close to some soft tissues (greater trochanters, intervertebral
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Fig. 1 Radiographic finding in HPP diagnosed in a woman adult
aged 53, with pseudofracture of the proximal femur (arrow)
disc calcification of the nucleus pulposis), leading to
inflammatory symptom onset. Needle aspiration of the joint
shows material positive on alizarin red staining, confirmed
as hydroxyapatite by spectroscopy [8]. The term ‘‘pseudo-
gout’’, sometimes used to describe acute inflammatory
onset in variable feet joints secondary to this calcium
pyrophosphate deposition, is noted in 14 % of the Berketh
series, still only in women [5].
Multiple causes are responsible of chronic and acute
variable pain in HPP adults, including chronic osteoar-
thritis, microfractures, chondrocalcinosis and the pseudo-
gout attacks described above. Foot pain is common, due to
compression microfractures of lower-limb bones. Slow-to-
heal fatigue fractures of the metatarsals are sometimes
reported. Patients also reported chronic diffuse muscular
pain. Chronic thigh and hip suffering may reflect femora
pseudofractures, but also hip chondrocalcinosis and/or
osteoarthropathy that will tend to increase with age [9].
The dental phenotype includes early decidual tooth loss,
thin enamel, multiple dental cavities, and dental fracture,
requiring the frequent use of dental prosthesis.
The radiological features include under-mineralized
bones, osteomalacia with rickets sequelae features, namely
flared metaphyses, poorly ossified epiphyses, and enlarged
wrists, knees, ankles, and bowed legs. Skull X-rays might
show copper-beaten appearance. Ectopic calcifications are
showed on the radiographs, performed according to the
symptomatology.
The biology will show the hallmarks of the diagnosis,
namely low serum alkaline phosphatase, elevated urinary
phosphoethanolamine (PEA) and increased circulating
concentrations of pyridoxal-5-prime phosphate (PLP).
Urine PEA excretion may be normal in some case of HPP
[10] and is not regularly performed since the advent of the
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Clinic Rev Bone Miner Metab (2013) 11:78–83
molecular screening. As previously shown by Whyte et al.
[7, 11], Berkseth et al. [5] found a correlation between
clinical severity (fractures rate, chondrocalcinosis) and
lower AP and higher PLP and PEA. Hypercalcemia and
hyperphosphatemia are usually associated with severe
forms but may also be found in adult-onset HPP: hyper-
calcemia was found in 13 % and hyperphosphatemia in
18 % of the adult-onset HPP in the Berkseth’s study [5].
Osteopenia or low bone mineral content for age is
detected by dual-energy X-ray absorptiometry (DXA) and
is the expected consequence of abnormal mineralization in
paediatric HPP [12]. Bone mineral content will increase
with age. Few absorptiometry data have been published in
adult HPP: bone mineral density is usually decreased [13,
14], but may be normal [8], and also, in a few cases, is
reported with elevated Z-score (and higher in lumbar spine
than in femoral neck) consistent with hyper-osteoidosis
[15, 16].
Bone histomorphometric measures after iliac crest bone
biopsy may demonstrate mineralization defects, abnormal
bone volumes with patchy osteoid accumulation, abnormal
trabecular microarchitecture and decreased calcium content.
Alteration in double-tetracycline labelling with abnormal,
little uptake is usually noted. Heterogeneity in bone histol-
ogy in 16 patients with adult HPP has been described with
some patients without any sign of osteomalacia [17, 18].
There could be a correlation between the presence of
osteomalacia features and the severity of the disease [5].
Intrafamilial heterogeneity has been demonstrated and
may be explained by additional factors, including genetic
modifiers, gender, management and environmental factors
[19]. The main differential diagnoses in adult HPP are
X-linked hypophosphatemic rickets, Paget’s disease, osteo-
genesis imperfecta and classical postmenopausal osteopo-
rosis, sometimes leading to inadequate treatment. For
instance, a 55-year-old woman was recently reported, suf-
fering atypical subtrochanteric femoral fractures after
4 years of bisphosphonates (BPs) given for ‘‘osteoporosis’’.
She did not present any medical history. Metatarsal stress
fractures began after several months of therapy, and her
osteoporosis course became worse under BPs. Adult HPP
was diagnosed from low ALP and a heterozygous TNSALP
mutation [14].
Pregnancy
There is no consensual guideline on pregnancy in woman
affected by hypophosphatasia, but many paediatric HPP
cases are born from HPP heterozygous mothers, possibly
undiagnosed. In case of symptomatic mothers, they will be
helped during pregnancy by moderate physical exercises
and resting, and by peripheral analgesics. Even if
Clinic Rev Bone Miner Metab (2013) 11:78–83
asymptomatic, mothers will be followed carefully, with
particular attention to fatigue and pain. Non-steroidal anti-
inflammatory agents are contraindicated during the first
term of pregnancy. The mode of delivery will depend on
the baby’s status. Caesarean section will be discussed if
there are any signs of severe disease in the foetal ultra-
sound and/ or 3D CT-scan. There is no official recom-
mendation for breast-feeding, but by analogy with
osteogenesis imperfecta, long-term breast-feeding will
probably not be encouraged [20]. Serum ALP activity
improves classically during the 3rd term of pregnancy. This
was suggested as a possible explanation for the improve-
ment of symptoms in affected foetuses at the end of
pregnancy, leading to the ‘‘HPP benign form’’ [4].
Genetic Counselling and Antenatal Diagnosis
Testing ALPL alterations and appropriate genetic counsel-
ling must be provided by referring the patient in a special-
ized genetic clinic. Perinatal and infantile hypophosphatasia
are inherited in an autosomal recessive manner. But the
milder phenotypes, particularly in adult HPP and in odonto-
hypophosphatasia, may be inherited in an autosomal
recessive or autosomal dominant manner, depending on the
effect the ALPL mutation has on TNSALP activity [21].
Fifty percentage of the offspring of patients with dominant
HPP will be affected. The offspring of a patient with
recessive HPP are obligate heterozygotes for a disease-
causing mutation in the ALPL gene. Testing the patient’s
relatives may be useful as heterozygotes may express a mild
form of the disease. Regarding the frequency of the disease,
testing patient’s spouses is not relevant unless there is a
history of consanguinity [10].
Genetic counselling has been modified by the possibility
of early detection of the molecular alteration during preg-
nancy. ALPL testing for the homozygous lethal form, in case
of two affected parents, allows them to consider having
children. Interest and possibilities in using prenatal diagnosis
in dominant HPP is variably perceived and have to be cor-
related with individual experiences and perceptions of the
condition, and according to the laws of the country.
Therapeutic Strategies
Management focuses essentially on supportive treatments
to limit pain and minimize disease-related complications.
Physical activity adaptation and moderate but regular
exercises may improve general bone health. Coaching by a
physiotherapist, familiar with bone fragility, is suggested.
Bone pain and osteoarthritis may respond to non-steroid
anti-inflammatory drugs (NSAID) [22]. The surgical
81
management of pseudofractures and stress fractures may be
delicate. Permanent internal fixation has been suggested for
recurrent long bone fractures, and for feet fractures, foot
orthotics may help in healing management.
PTH analogues are bone-forming agents, used to treat
various osteoporosis at high risk of fracture, stimulating
osteoblast precursor cells. Five reports, on six cases, are
published since 2007, on recombinant human PTH expe-
rienced in HPP. Globally, beneficial effects of PTH 1-34
(teriparatide) or PTH 1-84 (Preotact) were demonstrated in
5/6 cases. The patients, all women, were aged between 56
and 75. It induced prompt pain relief and improved
mobility and radiological response, facilitating fracture
healing [13, 16, 23–25]. Serum ALP increased and all the
biochemical levels of other markers of bone turnover were
enhanced, as long as the therapy continued, that is, 18 and
24 months [16, 23]. In Doshi’s paper, teriparatide treat-
ment was given to a 53-year-old HPP woman, previously
exposed to bisphosphonates for 2.5 years with excellent
clinical benefit. During the 34 months of treatment, levels
of 1, 25(OH) D increased and PTH levels decreased, but
bone-specific alkaline phosphatase did not increase as
expected [13]. Interestingly, in Gagnon’s report, in a
recessive HPP diagnosed in adult age, after a first clinical
and biological positive improvement, the biochemical
results were unsustained after 8 months of teriparitide
treatment, and bone biopsy performed before, during and
after treatment, showed increased amount of osteoid and
osteoblast numbers, but absence of tetracycline labelling
[13, 24]. The way through which teriparatide improves
ALP activity remains unclear. It is suggested that teri-
paritide may stimulate ALP production by osteoblast. The
phosphaturic effect of this drug may also increase ALP
catalytic activity by reducing extracellular inorganic
phosphate, which is a known inhibitor of APL activity [26].
It was suggested that response to teriparitide treatment
might differ depending on the TNSALP gene mutation.
The molecular analysis was not performed systematically
in the cases described above.
Bisphosphonates are not recommended in HPP because of
their potential deleterious effects on bone formation and
mineralization. As previously said, in female adults suffering
from mild HPP, osteoporosis and fragility fractures may
mimic classic primary osteoporosis, which may be mistreated
when using standard bisphosphonates treatment. Since the
skeletal disease of HPP results from extracellular accumula-
tion of the TNSALP substrate, inorganic pyrophosphate (PPi)
and its inhibitory effect on mineralization BPs are analogues of
PPi and may get the bone turnover suppression worse. As
already noticed above, it was reported last year that a 55-year-
old woman suffered atypical subtrochanteric femoral fractures
after 4 years of exposure to alendronate then zoledronate
given for ‘‘osteoporosis’’, leading to disease aggravation [14].
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In the near future, the causal treatment of this disease is
enzyme replacement therapy with asfotase alpha, a bone-
targeted, human recombinant TNSALP fusion protein,
currently developed by Alexion Pharmaceutical (Cheshire,
Connecticut) [27]. This ERT is being evaluated for the
treatment of severe forms in infants and children in a
clinical phase II study: the first evaluation in adolescents
and adults was reported last year, with inclusion of 6
adolescents and 13 adults with HPP (mean age 42 years
(14–68 years) in a randomized open-label, multicenter
study, with either asfotase alpha or placebo. Asfotase alpha
significantly decreases TNSALP substrates and improves
function in patients after 24 weeks of treatment. No serious
adverse events were observed [28].
Upcoming anabolic treatment modalities are anti-scle-
rostin antibodies, anti-DKK1 antibodies and activin
antagonists. A phase II clinical trial is already ongoing
using an anti-sclerostin antibody, in mildly affected HPP
adult, which will demonstrate to what extent this molecule
is capable of stimulating bone formation in this disease.
Furthermore, the cathepsin K antagonist ‘‘Odanacatib’’ is
being developed as an ‘‘osteoclast-friendly’’ antiresorptive
[29].
In summary, hypophosphatasia, even in adults, remains
a disease with a wide spectrum of severity from asymp-
tomatic patients to disabled patients with the accumulation
of slow-healing fractures, pain and impaired mobility
leading to wheelchair. Several elements, including gender
and environment, may modify the clinical features. Under-
diagnosed mild forms are not so rare and may mimic
classic osteoporosis. Polyarticular chondrocalcinosis and
tendons hyperostosis may be the first and inaugural mani-
festation of the disease. The diagnosis is now more easily
confirmed by biological and molecular studies. Further
randomized and crossover studies with the emergent’s
therapeutics (teriparatide, ERT and others) will be needed
to better assess the relatives benefits, risks and costs,
probably complemented by TNSALP mutation analysis,
histomorphometry and bone remodelling markers.
Disclosures
Conflict of interest Genevieve Baujat, Valerie Cormier-Daire and
Martine Le Merrer declare that they have no conflict of interest.
Animal/Human Studies This article does not contain any studies
with human or animal subjects performed by any of the authors.
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