Original Article
ADULT HYPOPHOSPHATASIA TREATED WITH TERIPARATIDE:
REPORT OF 2 PATIENTS AND REVIEW OF THE LITERATURE
Pauline M. Camacho, MD, FACE1; Alaleh M. Mazhari, DO1; Cory Wilczynski, MD1;
Ruth Kadanoff, MD2; Steven Mumm, PhD3,4; Michael P. Whyte, MD3,4
ABSTRACT
Objective: Hypophosphatasia (HPP) is a rare inher-
ited metabolic bone disease from deficient activity of the
tissue-nonspecific isoenzyme of alkaline phosphatase
(TNSALP). Reportedly, teriparatide (parathyroid hormone
1-34) can benefit the adult form of HPP, including fracture
healing. We studied 2 women with adult HPP given teripa-
ratide and reviewed the reports of 6 additional patients.
Methods: A 68-year-old black woman (patient 1)
described low-trauma fractures and had subnormal serum
alkaline phosphatase (ALP) activity. Biochemical find-
ings were consistent with HPP. Mutation analysis revealed
a heterozygous defect in exon 10 of TNSALP (ALPL).
Teriparatide was injected daily for 2 years. Four years
later, she fractured her right hip. Treatment was resumed
for 8 months without further fractures. A 53-year-old white
woman (patient 2) reported low-trauma fractures and
had subnormal serum ALP. Mutation analysis revealed a
heterozygous defect in exon 8 of TNSALP. She injected
teriparatide daily for 2 years. One year later, bone mineral
density (BMD) declined and treatment was resumed for 3
Submitted for publication June 22,2015
Accepted for publication January 24, 2016
From the 1Division of Endocrinology and Metabolism, Loyola University
Medical Center, Maywood, Illinois, 2Division of Rheumatology, Loyola
University Medical Center, Maywood, Illinois, 3Center for Metabolic Bone
Disease and Molecular Research, Shriners Hospital for Children, St. Louis,
Missouri, and 4Division of Bone and Mineral Diseases, Department of
Internal Medicine, Washington University School of Medicine at Barnes-
Jewish Hospital, St. Louis, Missouri.
Address correspondence to Dr. Pauline Camacho, 2160 South First Avenue,
Maywood, IL 60153.
E-mail: pcamach@lumc.edu
Published as a Rapid Electronic Article in Press at http://www.endocrine
practice.org on April 4, 2016. DOI: 10.4158/EP15890.OR
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright © 2016 AACE.
Copyright © 2016 AACE
months. When she sustained a sacral fracture, teriparatide
was administered for a further 18 months.
Results: Patient 1’s serum ALP increased while
receiving teriparatide and returned to baseline after its
discontinuation. BMD remained unchanged, but no frac-
tures were sustained. Patient 2’s serum ALP increased, but
the improvement was not sustained. Femoral neck BMD
increased significantly during the first cycle, declined
significantly afterwards, and was regained during a second
course of teriparatide.
Conclusion: Teriparatide shows some benefit for adult
HPP. (Endocr Pract. 2016;22:941-950)
Abbreviations:
ALP = alkaline phosphatase; BMD = bone mineral
density; BSAP = bone-specific alkaline phosphatase;
CTX = C-telopeptide; DXA = dual-energy X-ray
absorptiometry; FN = femoral neck; HPP = hypophos-
phatasia; LS = lumbar spine; PEA = phosphoethanol-
amine; PLP = pyridoxal 5'-phosphate; PTH = parathy-
roid hormone; SQ = subcutaneous; TNSALP = tissue-
nonspecific isoenzyme of alkaline phosphatase; TPTD
= teriparatide
INTRODUCTION
Hypophosphatasia (HPP) is a rare inherited metabolic
bone disease characterized by low serum alkaline phospha-
tase (ALP) activity (hypophosphatasemia), setting it apart
from other forms of rickets or osteomalacia (1-5). As a
consequence of the underlying loss-of-function mutation(s)
in the gene that encodes the tissue-nonspecific isoenzyme
of alkaline phosphatase (TNSALP), the enzyme’s natural
substrates accumulate extracellularly, including inorganic
pyrophosphate (PPi), a potent inhibitor of mineraliza-
tion, pyridoxal 5'-phosphate (PLP), the principal circulat-
ing form of vitamin B6, and phosphoethanolamine (PEA)
(1). TNSALP is a cell-surface enzyme, and the excess PPi
ENDOCRINE PRACTICE Vol 22 No. 8 August 2016 941
942 Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8)
in the bone milieu in HPP interferes with hydroxyapa-
tite crystal formation for deposition into the skeleton and
leads to rickets or osteomalacia (1,6). Autosomal reces-
sive and autosomal dominant inheritance from among at
least 300 predominantly missense mutations throughout
TNSALP (ALPL) largely explain the broad expressivity of
HPP, which ranges from death in utero from an unminer-
alized skeleton to problems with dentition or arthropathy
beginning in adult life (1-5,7). HPP presenting in adult-
hood commonly features recurrent low-trauma metatarsal
fractures and/or femoral pseudofractures that may begin a
debilitating clinical course (1,2).
Asfotase alfa, a mineral-targeted recombinant human
TNSALP, was approved multinationally in 2015 for the
treatment essentially of pediatric-onset HPP; however,
there is as yet no approved medical therapy for adult-onset
HPP in Europe or North America. Teriparatide (TPTD:
parathyroid hormone [PTH] 1-34), an anabolic agent for
bone given daily as a 20-μg subcutaneous (SQ) injection,
increases bone formation, bone mineral density (BMD),
and reduces fractures in postmenopausal women with
osteoporosis (8). Within 3 to 6 months of beginning TPTD
treatment, patients with osteoporosis can significantly
increase circulating bone-specific ALP (BSAP) and then
markers of bone resorption (9).
Beginning in 2007, a total of 6 case reports evaluated
TPTD given for HPP to adults, but only 4 of the publi-
cations provided the underlying TNSALP defect to help
understand their responses (8,10,11). Here, we describe
2 women with the adult form of HPP caused by different
heterozygous missense defects in TNSALP who seemed to
benefit from TPTD therapy.
METHODS
Case Reports
Patient 1
This 68-year-old black woman was referred to Loyola
University Osteoporosis and Metabolic Bone Disease
Center in April 2006 for low-trauma fractures, low BMD,
and hypophosphatasemia. She reported a low-trauma frac-
ture of a femur resulting from slipping on ice at age 27
years. A low-trauma fracture of a first metatarsal occurred
in her 50s. She did not recall the duration for fracture heal-
ing. At age 64 years, a dental crown was placed, but she
reported no other dental abnormalities. Her family history
revealed “osteoporosis” and fractures in her mother, but
the details were unknown.
Before referral, she had taken prednisone for approxi-
mately 3 years for polymyositis, initially considered fibro-
myalgia. However, in 2002, she manifested diplopia and
collagen vascular disease and was diagnosed with poly-
myositis by her rheumatologist. Prednisone was started in
2003 and continued with doses ranging from 2.5 mg daily
to her current dose of 10 mg daily. Hypophosphatasemia
Copyright © 2016 AACE
with serum ALP of 15 U/L (normal, 30 to 110 U/L) (Table
1) was, however, evident in 2002 at 63 years of age before
the prednisone therapy.
Ibandronate had been given for approximately 7
months (September 2005 to April 2006) for low BMD.
Serum ALP before ibandronate was 19 U/L (normal, 30 to
110 U/L). and then ranged from 14 to 18 U/L. When HPP
was diagnosed, ibandronate was discontinued due to fear it
could exacerbate her HPP skeletal disease (12).
Height was 170 cm (67 inches) and weight was 83 kg
(183 pounds). Physical exam was unremarkable except for
grade 1 kyphosis, without muscle weakness or limitations
in range-of-motion. No dental abnormalities were noted.
Dual-energy X-ray absorptiometry (DXA, Lunar Prodigy,
Madison, WI) revealed “osteopenia” in January 2003 after
beginning prednisone. In 2005, after varying doses of pred-
nisone, her femoral neck (FN) T-score had decreased to
−2.9 (Table 2).
We diagnosed adult HPP in July 2006 based on her
typical clinical and biochemical findings, including low-
trauma fractures, hypophosphatasemia with serum ALP
ranging from 11 to 20 U/L (normal, 30 to 110 U/L), serum
BSAP of 3.4 µg/L (normal, 4.5 to 22.4 µg/L), and a high
serum PLP level of 95 ng/mL (normal, 5 to 30 ng/mL)
(Table 1). Subsequently, TNSALP gene analysis supported
the diagnosis (See “TNSALP Mutation Analysis” section
below). At HPP diagnosis in 2006, serum ionized calcium,
PTH, and creatinine levels were normal, and the serum
phosphorus (inorganic phosphate) level was slightly
elevated, at 4.8 mg/dL (normal, 2.6 to 4.4 mg/dL), consis-
tent with HPP (Table 1) (1). Concurrent hypovitaminosis
D was treated with ergocalciferol 50,000 IU weekly for 12
weeks, followed by 50,000 IU monthly. TPTD was given
as 20 µg SQ injections daily beginning 5 months after the
discontinuation of ibandronate and continued for 2 years
(from September 2006 to September 2008). She report-
ed being compliant with the TPTD therapy for the entire
duration.
While receiving TPTD, serum ALP and BSAP and
urinary N-telopeptide (NTX) increased (Fig. 1 A, B, and
C). Her elevated serum PLP level initially declined slightly
from 95 to 77.9 ng/mL, but without any vitamin B6 supple-
mentation increased after 19 months of TPTD adminis-
tration to just below the baseline value (Fig. 1 D). With
vitamin D administration, serum 25-hydroxyvitamin D
transiently increased to above the target level, but subse-
quently normalized with a lower dose of vitamin D (Table
1). We worried that hypervitaminosis D could suppress any
TPTD-mediated increase in serum ALP.
One month after stopping TPTD, serum ALP was 25
U/L and serum BSAP was 5.6 µg/L. Eleven months after
TPTD discontinuation, these values had returned to base-
line levels, and the PLP level had increased to above the
baseline level (Fig. 1 A, B, and D).
Copyright © 2016 AACE Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8) 943

Table 1
Biochemical Studies of Bone and Mineral Metabolism in Patient 1

Serum Urine
Total Ionized NTX
ALP Phos PLP calcium 25-OHD Creatinine (17-124
Date (30-110 Bone-specific ALP (2.6-4.4 (5-30 ng/ (1.1-1.3 (30-80 ng/ (0.7-1.5 mg/ BCE/mmol
(Mo/Yr) U/L) (4.5-22.4 μg/L)a mg/dL) mL) mmol/L) mL) dL) creatinine)b
9/02 15
12/02 16 4.8 1.0
5/04 20
5/05 11
9/05
Ibandronate
Started
10/05 14
1/06 18
4/06
Ibandronate 16 3.4 4.2 95 1.22 67 1.1 32
Stopped
6/06 16 1.4
9/06 2.9 38
TPTD Started
10/06 17
12/06 24
4/07 25 5.0 78 1.23 139 1.01
10/07 26 7.0 1.14 43 1.35
4/08 21 4.5 93 1.13 47 1.13 79
6/08 25 1.27
9/08
TPTD Stopped
10/08 25 5.6 >100 48 1.19
12/08 20
8/09 19 3.7 45 1.26
10/09 19 1.22
12/09 19 1.45
6/10 15 2.7 >100 66 1.47
9/10 20 1.49
12/10 20 3.8 157 70 1.45
6/11 19 4.1 1.85
11/11 20 3.4 70 1.61
6/12 16 2.9 5.1 81 1.41
9/13 12 2.59
TPTD Resumed
10/13 20 5.9 78 3.13
2/14 15 2.51
5/14 3.4 108 2.78
TPTD Stopped
6/14 14 2.97
Abbreviations: 25-OHD = 25-hydroxyvitamin D; ALP = alkaline phosphatase; BCE = bone collagen equivalents; NTX = N-telopeptide; PLP =
pyridoxal 5’-phosphate; Phos = phosphorus; TPTD = teriparatide.
Note: All studies were performed at the same laboratory (Maywood, IL) between 2002 and 2014.
aPremenopausal female: 4.5-16.9 μg/L; postmenopausal female: 7.0-22.4 μg/L.
bPremenopausal: 17-94 BCE/mmol creatinine; postmenopausal: 26-124 BCE/mmol creatinine.
Normal ranges provided in parentheses.
944 Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8) Copyright © 2016 AACE

Table 2
Dual-Energy X-ray Absorptiometrya Results Before and After Treatment With Teriparatide in Patient 1
% Change Mean femoral % Change
L2-4 BMD compared to neck BMD compared to
Date (g/cm2) T-score Z-score previous study (g/cm2) T-score Z-score previous study
1/03 1.159 −0.3 0.807 −1.4
9/05
1.006 −1.6 −1.4 −13.1b 0.693 −2.9 −2.8 −14.1b
Ibandronate started
4/06
Ibandronate stopped
9/06
TPTD started
10/07 1.012 −1.6 −1.4 +0.6 0.714 −2.3 −2.1 +3.1
9/08
TPTD stopped
4/10 1.035 −1.4 −0.7 +2.2 0.708 −2.4 −1.8 −1.0
Abbreviations: BMD = bone mineral density; TPTD = teriparatide.
aLunar Prodigy (Madison, WI).
bSignificant change.

Fig. 1. Trend of biochemical findings before and after teriparatide (TPTD) was given (September 2006 to
September 2008 and September 2013 to May 2014). Shaded areas represent the normal reference ranges.
X-axis documents the month and year laboratory studies were obtained. (A) Serum alkaline phosphatase
measurements from 2001 until 2014. The only sustained increases were seen while the patient was receiv-
ing TPTD from September 2006 to September 2008 (area denoted with open squares) and June 2013 to May
2014 (area denoted with open triangles). (B and C) Similarly, serum bone-specific alkaline phosphatase and
urinary N-telopeptide (NTX) increased while TPTD was administered. (D) Pyridoxal 5'-phosphate (PLP)
initially declined but later increased while on TPTD, and returned to a level higher than baseline levels after
discontinuation.
Copyright © 2016 AACE Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8) 945
DXA T-scores were calculated using the combined
National Health and Nutrition Examination Survey popu-
lation for the femur and the Lunar AP spine database (ver.
112). From October 2007 to April 2012, DXA showed
stable BMD of the lumbar spine (LS) and FN despite her
prednisone therapy (Table 2). While receiving TPTD for
2 years, and during follow-up lasting until 2014, there
were no fractures and no adverse effects related to TPTD.
Radiographs of her hands and left knee after a fall in 2009
showed no fracture, but in the left femur there was focal
distal lateral diaphyseal periosteal changes indicating new
bone formation in response to recent injury versus delayed
healing in areas of prior fracture over 10 years previously.
However, the absence of prior radiographs prohibited a
comparison.
In July 2013, 4 years after discontinuing TPTD, she
fell down steps and fractured her right hip, which required
surgical repair. Bone was not examined histologically.
TPTD was resumed September 2013. Four months later
(February 2014), another fall did not cause fracture. Serum
ALP, 12 U/L prior to this second course of TPTD, increased
but then decreased to 15 U/L 4 months later (Table 1).
TPTD was continued until May 2014.
Patient 2
This 53-year-old white woman was referred to Loyola
University Osteoporosis and Metabolic Bone Disease
Center in October 2009 for HPP diagnosed from her medi-
cal history, laboratory data, and TNSALP mutation analy-
sis. She recollected multiple fragility fractures, including
of a wrist and radius at ages 4 and 5 years, respectively,
rib fractures in 1994, 1996, 2007 (falling down stairs), and
2009 (when hugged), and a foot fracture in 2008 (strik-
ing the foot on a cabinet). She did not report childhood
dental abnormalities. Cluster headaches had been treated
intermittently with prednisone, but she had not received
glucocorticoids since 2002, 7 years before referral.
Her mother had breast cancer with skeletal metastasis
(serum ALP data not available) and sustained a pathologic
hip fracture. No other family member was known to have
bone disease.
Height was 159 cm (62 inches) and weight was 47 kg
(102 pounds). Physical exam was unremarkable. No dental
abnormalities were observed.
Hypovitaminosis D was treated with ergocalciferol
50,000 IU weekly for 12 weeks, which increased her serum
25-hydroxyvitamin D level from 9 to 62 ng/mL (Table 3).
DXA prior to TPTD treatment reported “osteoporo-
sis,” with a LS T-score of −3.9 and FN T-score of −2.6
(Table 4).
Baseline serum ALP and BSAP were in the low-
normal range. Serum PLP level was elevated at 32 ng/mL
(normal, 2.1 to 21.7 ng/mL), and phosphorus was high at
4.8 mg/dL (normal, 2.6 to 4.4 mg/dL) shortly after begin-
ning TPTD.
She was compliant with the TPTD injections (20 μg
SQ daily) prescribed for 2 years (September 2009 until
September 2011). Two months after starting TPTD, a
metatarsal fracture showed no delayed healing. Serum
ALP increased to 36 U/L and peaked at 41 U/L (normal,
20 to 132 U/L) (Fig. 2 A). Serum BSAP initially increased
but subsequently dropped to 8.0 μg/L despite continuing
TPTD therapy (Fig. 2 B). Although she did not have serum
C-telopeptide (CTX) measured before TPTD treatment, it
increased from 338 pg/mL after 1 month of treatment to
599 pg/mL 4 months later (Fig. 2 C). Serum PLP at base-
line was 32 ng/mL and then dropped to 22.4 ng/mL (Fig.
2 D). One month after TPTD discontinuation, serum ALP
decreased to 33 U/L (Fig. 2 A; Table 3).
Due to a decline in LS and FN BMD (Table 4), the
patient resumed TPTD from October 2012 to January
2013 (second cycle). In April 2013, 4 months after TPTD
was discontinued, she fell, and radiographs in June 2013
confirmed a sacral fracture. A third cycle of TPTD was
given until January 2015. Repeat DXA showed improve-
ments in both LS and FN BMD (Table 4).
TNSALP Mutation Analysis
After informed consent, TNSALP mutation analysis
was performed for both patients. Patient 1’s leukocyte
DNA was obtained using a Gentra Puregene DNA extrac-
tion kit (Invitrogen, Carlsbad, CA) for peripheral blood
sent air express to St. Louis, Missouri. In our research labo-
ratory (S.M. and M.P.W., Washington University School of
Medicine, St. Louis, MO), we sequenced all 11 TNSALP
coding exons and adjacent mRNA splice sites using previ-
ously described polymerase chain reaction and sequencing
primers and conditions (12). For patient 2, a commercial
laboratory (Connective Tissue Gene Tests, Allentown, PA)
performed TNSALP mutation analysis.
RESULTS
For patient 1, we identified a single (heterozygous)
TNSALP mutation involving exon 10: c.1133A>T,
p.Asp378Val. This is a common mutation in the United
States, which we have thus far found only in patients of
white ethnicity (7). Upon further questioning, the patient
reported that her great grandfather was white.
For patient 2, mutation analysis revealed a hetero-
zygous c.818C>T, p.Thr273Met mutation within exon 8
of TNSALP. Though this mutation has not been reported
previously, we have detected it in the heterozygous state in
2 individuals with adult HPP (Mumm and Whyte, unpub-
lished data).
DISCUSSION
Here, we report clinical, biochemical, and DXA find-
ings from 2 women with adult HPP presenting with recurrent
946 Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8) Copyright © 2016 AACE

Table 3
Biochemical Studies of Bone and Mineral Metabolism in Patient 2
Serum Serum Ionized Serum Serum
total ALP BSAP Phos PLP calcium 25-OHD creatinine CTX
Date (30-110 (4.5-22.4 (2.6-4.4 mg/ (5-30 ng/ (1.1-1.3 (30-80 ng/ (0.7-1.5mg/ (104-1,008
(Mo/Yr) U/L) µg/L)a dL) mL) mmol/L) mL) dL) pg/mL)b
31 0.5
OSH
[20-132 [0.5-1.5 mg/
3/06
U/L] dL]
26
OSH
[20-132 0.5
9/06
U/L]
26
OSH
[20-132 9
12/08
U/L]
OSH
32
1/09
9.32
OSH
[5.6-29.0 62
5/09
µg/L]
32
OSH
[2.1-21.7
7/09
ng/mL]
9/09
10/09
TPTD 36 9.6 4.8 22.4 1.16 43 0.58 338
started
41
OSH
[20-132
12/09
U/L]
2/10 13.8 1.16 30 0.53 599
6/10 9.2
12/10 8.9 33
10/11-
TPTD
stopped
11/11 33 8.0 29 0.84
10/12
TPTD
started
1/13
TPTD 6.1
stopped
6/13
TPTD 6.8 62
started
1/2015
TPTD 37 7.4 59
stopped
Abbreviations: 25-OHD = 25-hydroxyvitamin D; ALP = alkaline phosphatase; BSAP = bone-specific alkaline phosphatase; CTX =
C-telopeptide; OSH = outside hospital (Chicago, IL); Phos = phosphorus; PLP = pyridoxal 5'-phosphate; TPTD = teriparatide.
aPremenopausal female: 4.5-16.9 μg/L; postmenopausal female: 7.0-22.4 μg/L.
bPremenopausal: 17-94 bone collagen equivalents (BCE)/mmol creatinine; postmenopausal: 26-124 BCE/mmol creatinine.

[ ] = outside lab reference ranges.

Copyright © 2016 AACE Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8) 947

Table 4
Dual-Energy X-ray Absorptiometrya Results Before and After Treatment With Teriparatide in Patient 2
% Change Mean % Change
compared femoral compared
L2-4 BMD to previous neck BMD to previous
Date (g/cm2) T-score Z-score study (g/cm2) T-score Z-score study
2/2009
0.714 −3.9 0.686 −2.6
OSH
9/09
TPTD
started
5/10 0.794 −3.4 −2.2 NA 0.614 −3.1 −1.9 NA
10/11
TPTD 0.808 −3.3 −1.9 +2.0 0.661 −2.7 −1.4 +7.7b
stopped
6/12 0.745 −3.8 −2.4 −7.8b 0.635 −2.9 −1.6 −3.9
10/12
TPTD
restarted
6/13 0.735 −3.9 −2.4 −3.5 0.613 −3.1 −1.7 −1.4
1/13
TPTD
stopped
10/13
TPTD
restarted
6/14 0.754 −3.7 −2.1 +2.7 0.667 −2.6 −1.1 +8.8b
Abbreviations: BMD = bone mineral density; OSH = outside hospital; TPTD = teriparatide.
NA = not applicable, as the imaging was not performed on the same machine.
aLunar Prodigy (Madison, WI).
bSignificant change.

fractures and then given multiple cycles of TPTD. Because
both individuals were prescribed TPTD cumulatively for
longer than the 2-year approval duration for osteoporosis,
they were informed about a rare risk of osteosarcoma and
advised to report any unusual pain, swelling, etc. Each
carried a heterozygous missense mutation in TNSALP.
We also assessed the data in the medical literature from
all 6 such adult HPP patients treated with TPTD or PTH
1-84 (8-11,13).
The first use of TPTD for HPP were reported by Whyte
et al (8) in 2007 concerning a 56-year-old white woman
with adult HPP who seemed to benefit symptomatically,
biochemically, and radiographically from TPTD admin-
istered for 18 months. The second patient, a 75-year-old
white woman given TPTD for 24 months, was reported by
Camacho et al (9) in 2008. Additional reports by Doshi et al
(13) in 2009 and Gagnon et al (10) in 2010 described indi-
vidual patients who received TPTD for 34 and 13 months,
respectively. Two siblings with HPP reported by Schalin-
Jäntti et al (11) in 2010 received PTH 1-84 for 7 and 18
months. Notably, all 8 HPP patients treated with PTH 1-34
or 1-84 have been women in the fifth to eighth decade of
life. All were probably white (8-10,13), since the report of
Schalin-Jäntti et al (11) without this information was from
Finland. All showed a modest biochemical improvement
(8,13). Two of the reports described subjective improve-
ment of bony pain while on treatment.Though serum ALP
activity did not normalize in most cases, improvement in
BSAP suggested that persistently low ALP activity from
the liver due to the HPP prevented correction of the total
ALP level. We also found a consistent increase in the bone
resorption markers urinary NTX and serum CTX while our
patients received TPTD, suggesting bone resorption and
perhaps remodeling had activated, but this was not studied
by bone histology.
In 2010, Gagnon et al (10) reported that their patient’s
serum ALP initially doubled, urine PEA and serum
PLP decreased, and other markers of bone remodeling
increased during TPTD treatment. Yet, between months 8
and 13 of therapy, serum ALP, serum PLP, and urine PEA
all returned to baseline, suggesting possible resistance
to, versus noncompliance for, the TPTD treatment. The
pattern of this patient’s biochemical changes was perhaps
from poor compliance with administration of TPTD, as
948 Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8) Copyright © 2016 AACE

Fig. 2. Biochemical testing of patient 2 before and after teriparatide (TPTD) treatment was given October
2009 to October 2011 (open squares), October 2012 to January 2013 (open diamonds) and October 2013 to
January 2015 (open triangles). Shaded areas represent the normal reference ranges. Times off TPTD are in
blue diamonds. X-axis documents the month and year laboratory testing was performed. (A) Serum alkaline
phosphatase measurements from 2006 until 2015. The sustained increases occurred while the patient was
receiving TPTD from October 2009 to December 2009 and a smaller rise in January 2015 after the third trial
of TPTD. (B-D) Similarly, bone-specific alkaline phosphatase (BSAP), C-telopeptide (CTX), and pyridoxal
5'-phosphate (PLP) initially increased while on treatment. BSAP and PLP later decreased, even below base-
line levels in the case of BSAP (B) while on TPTD.

she had missed at least 9 doses according to the dispen-
sary history. We confirmed by pharmacy refill history that
our 2 patients were likely compliant with dosing of TPTD
for at least the first full 2 years of treatment. Patient 2 had
an initial rise in serum BSAP, which was inexplicably not
sustained, yet serum ALP continued to increase with TPTD
administration. Her largest increases in serum ALP and
BSAP occurred in the first cycle of treatment.
The serum PLP response to treatment with TPTD has
been variable in the literature. The PLP level declined in
the patient reported by Camacho et al (9), similar to our
patient 2, whose PLP level dipped from 32 to 22.4 ng/dL
(Table 3). In contrast, the patients described by Whyte et al
(8) and Doshi et al (13) had relatively unaltered serum PLP
levels. It may be that changes in the TNSALP substrate
levels occurring within the skeleton are not closely reflect-
ed by the circulating PLP level.
Similar to the experience of Doshi et al (13), patient 1
was treated for 7 months with a bisphosphonate (ibandro-
nate) prior to TPTD. Its impact, including on her biochemi-
cal profile, is uncertain. Serum ALP was low prior to iban-
dronate exposure and was unchanged throughout the thera-
py. Nevertheless, she had a favorable response to treatment
with TPTD, showing improvement in bone turnover mark-
ers despite her prior bisphosphonate treatment. Doshi et al
(13) reported widening of femur fractures seen radiologi-
cally, and BMD declined after treatment with risedronate.
While patient 1 received TPTD, BMD values were main-
tained in both her spine and hip. This experience empha-
sized the importance avoiding bisphosphonates for patients
with HPP (12). Also, patient 1’s hypophosphatasemia was
not likely due to prednisone therapy. Her serum ALP levels
were low prior to starting prednisone in 2002. However,
likely impaired bone mineralization in HPP and enhanced
bone resorption may have been exacerbated by prednisone,
as evidenced by the BMD decline while she was taking
prednisone.
Radiographic improvement characterized by bony
bridging, reduction of fracture lines (8), periosteal callus
formation (11), increased bone mineralization (10), and
Copyright © 2016 AACE Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8) 949
complete healing of fractures (8-11,13) was reported
for TPTD treatment for 5 of the 6 adults with HPP who
presented with nonhealing fractures. Except for their DXA
findings, limited radiologic studies were available for our 2
patients. Patient 1 had no follow-up imaging, but her bone
markers improved, and no further fractures occurred after
TPTD therapy began and for almost 2 years after stopping
TPTD treatment. Patient 2 sustained a metatarsal fracture
early (2 months) into the TPTD treatment, but there was no
evidence of delayed healing that is common in adult HPP
(4,8). A radiograph of her fingers showed a healing fracture
in August 2006. Her bone marker response was more vari-
able, initially exhibiting an increase in serum ALP (with a
corresponding increase in CTX), followed by a decline.
With the addition of our 2 new patients, results from
TNSALP mutation analysis are now available for 6 of
the 8 patients with adult HPP given TPTD or PTH 1-84.
Mutation analysis was not performed for the patients report-
ed by Camacho et al (9) or Doshi et al (13). The patient
reported by Whyte et al (8) was heterozygous for a single
TNSALP missense mutation (c.1133A>T, p.Asp378Val)
within exon 10. The patient reported by Gagnon et al
(10) was compound heterozygous for 2 missense muta-
tions occurring within exon 6 (p.Ala176Thr) and exon
11 (p.Val423Ala) and also carried a single polymorphism
at exon 12. Both siblings reported by Schalin-Jäntti et al
(11) were compound heterozygotes for a p.Gly339Arg and
p.Glu191Lys mutation but seemed to benefit from PTH
1-84 treatment.
Patient 1’s heterozygous TNSALP mutation in exon
10, 1133A>T, p.Asp378Val, is common in our HPP experi-
ence (Mumm and Whyte, unpublished). Patient 2’s hetero-
zygous c.818C>T, p.Thr273Met change within exon 8
has not been reported in HPP but has been considered a
“rare variant” of TNSALP associated with low serum ALP
and low BMD (14). In fact, we have encountered this as a
heterozygous mutation in 2 adult HPP patients (Mumm and
Whyte, unpublished).
The presence of one normal TNSALP allele in both
of our patients (therefore likely having some wild type
TNSALP activity) perhaps helps to explain why they
responded to TPTD. There are no reports of TPTD or PTH
1-84 given for the more severe pediatric forms of HPP,
likely because the “black box” warning proscribes TPTD
when growth plates are open. Furthermore, these severe
forms of HPP typically involve the likely disadvantage of
compound heterozygous TNSALP defects (1).
BMD data, available for 4 of the total of 8 HPP
patients treated by TPTD or PTH 1-84, do not show consis-
tent results from the therapy. However, interpretation of
DXA BMD could be difficult when osteomalacia is present
at baseline (15). In fact, Whyte et al (8) observed in 2007
an elevated T-score in the spine and normal T-score in the
total hip prior to TPTD treatment. Two years later, DXA
showed a 4.3% decline in spine BMD, 4.1% increase in left
total hip BMD, and stable right total hip BMD. Camacho
et al (9) observed low BMD prior to TPTD treatment. Four
months after TPTD began, they found an 8.6% increase
in spine BMD and stable hip BMD. No change in BMD
occurred after 17 months of treatment. Patient 1’s BMD
remained stable during and after TPTD treatment, similar
to previous cases (8,9,13). In contrast, repeated courses of
TPTD for patient 2 significantly increased her FN BMD,
with BMD loss both in the spine and FN after TPTD
stopped. Some of the 8 HPP patients had hypovitaminosis
D. In the initial phase of vitamin D replacement, increases
in BMD can reflect mineralization of accumulated osteoid.
Then, as skeletal remodeling is restored, excess osteoid
may be removed, which can then decrease BMD. Perhaps
this partly explains the variable DXA responses reported
with TPTD treatment of adult HPP.
To date, only Gagnon et al (10) has provided bone
histology data for TPTD given for HPP. At baseline from
their adult patient, a femur fracture site specimen, obtained
without prior tetracycline labeling, revealed changes
consistent with a mineralization defect. A second speci-
men, from biopsy of an iliac crest 5 months after TPTD
therapy began and following tetracycline labeling, did not
reveal fluorescent labels. However, the presence of resorp-
tion lacunae, increased numbers of osteoblasts, and greater
extent of the bone surface covered by osteoid suggested
active remodeling had occurred. However, no tetracycline
labeling was seen in a third specimen, from a femur frac-
ture site, after discontinuation of TPTD. It was not clear if
the method of bone labeling using different tetracyclines
affected the observations. While no tetracycline labels
were seen by Gagnon et al (10), favorable responses seem-
ingly from TPTD therapy included higher markers of bone
turnover, evidence of fracture healing on imaging, and
the bone histology changes summarized above. Why no
sustained response to TPTD was observed by Gagnon and
colleagues is not clear, but compound heterozygosity for
the presence of 2 TNSALP mutations in their patient may
have been a factor. Clearly, further data, preferably from
iliac crest biopsy with nondecalcified histomorphometry
following tetracycline labeling is needed from adults with
HPP treated with TPTD.
CONCLUSION
TPTD or PTH 1-84 has now been given “off label”
and assessed for 8 patients with adult HPP. Notably, all
were women. Schalin-Jäntti et al (11) reported the only
patient for whom PTH 1-84 was administered. In general,
this treatment approach seems to have some benefit clini-
cally, biochemically, for bone healing, and perhaps for
fracture prevention (8,9,11,13). Neither of our patients
sustained a significant fracture while receiving TPTD.
However, the beneficial effects seem to decrease within
months after TPTD is stopped. In 2015, recombinant,
950 Hypophosphatasia & Teriparatide, Endocr Pract. 2016;22(No. 8)
mineral-targeted, TNSALP enzyme replacement therapy
was approved in Japan, Canada, Europe, and the United
States essentially for HPP of pediatric-onset that would
therefore include some affected adults (1). Further infor-
mation from TNSALP gene analysis and bone histology is
needed to better understand TPTD’s potential role in the
treatment of adults with HPP.
ACKNOWLEDGMENT
This work was supported by the Shriners Hospitals for
Children, The Clark and Mildred Cox Inherited Metabolic
Bone Disease Research Fund, The Hypophosphatasia
Research Fund, and The Barnes-Jewish Hospital
Foundation.
DISCLOSURE
Dr. Whyte is a study site investigator for Alexion
Pharmaceuticals Inc. and has received research grants,
honoraria, and travel support from Alexion Pharmaceuticals
Inc.
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