Journal of the Endocrine Society, 2023, 7, 1–16

https://doi.org/10.1210/jendso/bvad043
Advance access publication 4 April 2023
Clinical Research Article

Long-Term Safety and Efficacy of Recombinant Human

Parathyroid Hormone (1-84) in Adults With Chronic
Hypoparathyroidism
Nelson B. Watts,1 John P. Bilezikian,2 Henry G. Bone,3 Bart L. Clarke,4 Douglas Denham,5
Michael A. Levine,6 Michael Mannstadt,7 Munro Peacock,8 Jeffrey G. Rothman,9

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Tamara J. Vokes,10 Mark L. Warren,11 Shaoming Yin,12 Nicole Sherry,12
and Dolores M. Shoback13,14
1
Osteoporosis and Bone Health Services, Mercy Health, Cincinnati, OH 45236, USA
2
Division of Endocrinology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
3
Michigan Bone and Mineral Clinic, PC, Detroit, MI 48236, USA
4
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN 55905, USA
5
Clinical Trials of Texas, Inc., San Antonio, TX 78229, USA
6
Division of Endocrinology and Diabetes and Center for Bone Health, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
7
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
8
Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
9
UPG-Endocrine (Research Division), Staten Island, NY 10301, USA
10
Section of Endocrinology, University of Chicago Medicine, Chicago, IL 60637, USA
11
Endocrinology and Metabolism, Physicians East, PA, Greenville, NC 27834, USA
12
Takeda Pharmaceuticals USA, Inc., Lexington, MA 02421, USA
13
Endocrine Research Unit, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121, USA
14
Department of Medicine, University of California, San Francisco, CA 94143, USA
Correspondence: Nelson B. Watts, MD, Mercy Health Osteoporosis and Bone Health Services, 4760 East Galbraith Road, Suite 212, Cincinnati, OH 45236, USA.
Email: nelson.watts@hotmail.com.

Abstract
Context: Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum
calcium and phosphorus levels, but some patients remain inadequately controlled.
Objective: To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment.
Methods: This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The
intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices.
Results: Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to
2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were
normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month
72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients
(n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74%
± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1
collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites.
Conclusion: 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the
percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no
new safety signals were identified.
Key Words: recombinant human parathyroid hormone (1-84), hypoparathyroidism, active vitamin D, calcium, bone turnover, mineral homeostasis
Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; BAP, bone alkaline phosphatase; BMD, bone mineral density; BTM, bone
turnover marker; CKD, chronic kidney disease; CTX, cross-linked C-telopeptide of type 1 collagen; eGFR, estimated glomerular filtration rate; EOT, end of
treatment; ITT, intent-to-treat; PTH, parathyroid hormone; P1NP, aminoterminal propeptide of type 1 collagen; rhPTH(1-84), recombinant human parathyroid
hormone (1-84); TEAE, treatment-emergent adverse event.

Hypoparathyroidism is a rare endocrine disorder characterized parathyroid hormone (PTH) despite low circulating concentra­
by absent or inappropriately low circulating concentrations of tions of calcium [1]. The consequences of loss of PTH action on

Received: 30 November 2022. Editorial Decision: 24 March 2023. Corrected and Typeset: 21 April 2023
© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.
org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered
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2 Journal of the Endocrine Society, 2023, Vol. 7, No. 5
the skeleton, kidney, and gastrointestinal tract typically mani­
fest as hypocalcemia, hyperphosphatemia, hypercalciuria, de­
creased bone turnover, and increased bone mineral density
(BMD) [2, 3]. Management goals for patients with hypopara­
thyroidism include maintenance of serum calcium in the lower
part of or slightly below the reference range, control of urinary
calcium excretion to within normal limits, normalization of se­
rum phosphorus levels, and improved quality of life [4-6].
Conventional therapy for hypoparathyroidism includes oral
calcium and active vitamin D (eg, calcitriol) [1, 7]. In addition,
thiazide diuretics are sometimes prescribed for hypercalciuria
[2, 8]. Conventional therapy increases serum calcium through
enhanced gastrointestinal absorption but does not replace other
actions of PTH, including control of renal tubular reabsorption
of calcium, excretion of phosphorus and regulation of bone
turnover [2, 9]. When hypoparathyroidism is not adequately
controlled by conventional therapy, chronic hypocalcemia, hy­
perphosphatemia, and hypercalciuria can become troubling
clinical issues [10-12] and may increase the risk of complica­
tions, including central nervous system calcifications, nephro­
calcinosis and nephrolithiasis, and impaired renal function
[10, 13-16].
Recombinant human parathyroid hormone (1-84),
rhPTH(1-84), is full-length PTH approved in the United
States and Europe as an adjunct to calcium and active vitamin
D for adults with hypoparathyroidism. Safety and efficacy of
rhPTH(1-84) for patients with hypoparathyroidism have been
evaluated in several prospective clinical studies [17-20].
RACE (ClinicalTrials.gov identifier, NCT01297309) was an
open-label extension study of the REPLACE (NCT00732615)
[18, 21] and RELAY (NCT01268098) [17] studies and was de­
signed to assess long-term safety and efficacy of rhPTH(1-84).
An analysis of 5-year results from RACE demonstrated a safety
profile consistent with those of REPLACE and RELAY. In add­
ition, mean serum calcium levels remained within the target
range, mean 24-hour urinary calcium declined to within the ref­
erence range, and skeletal catabolic and anabolic activity, as
measured by levels of bone turnover markers (BTMs), stabilized
within reference ranges after an initial increase; however, ami­
noterminal propeptide of type 1 collagen (P1NP) levels re­
mained above the reference range [22]. In another long-term,
open-label study [20], treatment with rhPTH(1-84) over 8 years
led to sustained reduction in requirements for oral calcium and
calcitriol and decreases in urinary calcium, while serum calcium
levels were maintained slightly below the lower limit of the ref­
erence range in accordance with current guidelines [4-6]. In
addition, BTMs increased during the first 12 months of treat­
ment, then declined to new steady-state levels that were above
pretreatment values [23, 24].
Because rhPTH(1-84) therapy for hypoparathyroidism is a
chronic, life-long treatment, assessment of long-term safety
and efficacy is important. In addition, the collection of detailed
and granular data on biochemical parameters enables a deeper
understanding of the impact of treatments on the disease course.
Here we report final, 6-year safety- and efficacy-related out­
comes of treatment with rhPTH(1-84) from the RACE study.
Materials and Methods
Study Design
The open-label RACE extension study was conducted between
April 2011 and February 2018 and enrolled patients from 12
centers in the United States. The primary objective was to assess
the long-term safety and tolerability of rhPTH(1-84) for the
treatment of adult patients with chronic hypoparathyroidism.
The secondary objectives were (1) to evaluate the impact of dif­
ferent preparations of calcium on the response to rhPTH(1-84);
(2) to establish whether dosing with rhPTH(1-84) across a
range of 25 to 100 μg could be implemented safely and effect­
ively and maintained throughout long-term treatment; and
(3) to evaluate the impact of thiazide diuretics on serum and
urinary calcium in response to rhPTH(1-84). Detailed study
methods for the assessment of safety and biochemical parame­
ters have been reported previously [22].
Participants
Patients were eligible to participate in RACE if they completed
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the 24-week REPLACE study and/or the 8-week RELAY study.
Daily subcutaneous injections of rhPTH(1-84) were self-
administered. The starting dose of rhPTH(1-84) was 50 µg for
patients with total serum calcium ≤2.37 mmol/L (≤9.5 mg/dL)
and for patients with total serum calcium >2.37 mmol/L
(>9.5 mg/dL) taking ≥500 mg of supplemental calcium and/or
any calcitriol. Starting dose was 25 µg for patients with total se­
rum calcium >2.37 mmol/L taking <500 mg of supplemental
calcium and no calcitriol. Investigators could increase or de­
crease the dose of rhPTH(1-84) at any time during the study in
stepwise adjustments of 25 µg, to a maximum of 100 µg, with
the goal of achieving or maintaining total serum calcium levels
in the target range of 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL).
Patients not on thiazide diuretics at baseline were allowed
to initiate treatment with a thiazide diuretic after week 16
to manage hypercalciuria if they were on a stable dose of
rhPTH(1-84) and had a 24-hour urine calcium >7.5 mmol
(>300 mg) for men or >6.25 mmol (>250 mg) for women.
Compliance with dosing was assessed using patient diary
data. Patients were considered compliant if they reported
taking ≥80% of their expected doses.
The study was conducted in accordance with International
Council for Harmonisation guidelines, Good Clinical Practice,
and the World Medical Association Declaration of Helsinki; it
was approved by local institutional review boards or ethics
committees. All patients provided written informed consent.
Outcome Measures and Safety Evaluations
Outcome measures included albumin-adjusted serum cal­
cium, 24-hour urinary calcium and phosphorus excretion, se­
rum phosphorus, serum creatinine, treatment-emergent
adverse events (TEAEs), prescribed doses of oral calcium
and calcitriol, serum 25-hydroxyvitamin D (25[OH]D) and
1,25-dihydroxyvitamin D (1,25[OH]2D), BTMs, and BMD.
Samples for serum albumin, calcium, phosphorus, and cre­
atinine were collected under fasting conditions. Calcium-
phosphorus product, estimated glomerular filtration rate
(eGFR), rhPTH(1-84) dosing, and urinary calcium normal­
ized to body weight were evaluated in post hoc analyses.
eGFR was calculated using the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) equation [25]. The
composite efficacy outcome was the proportion of patients
who met all of the following 3 criteria: ≥ 50% reduction
from baseline in oral calcium dose (or calcium ≤500 mg/
day), ≥ 50% reduction from baseline in calcitriol dose (or cal­
citriol ≤0.25 μg/day), and normalized or maintained
albumin-adjusted serum calcium compared with baseline val­
ue and not exceeding the upper limit of normal for the central
Journal of the Endocrine Society, 2023, Vol. 7, No. 5
laboratory (2.55 mmol/L; 10.2 mg/dL). TEAEs were defined
as any unfavorable and unintended sign (including an abnor­
mal laboratory finding), symptom, or disease that occurred
during rhPTH(1-84) treatment, whether or not the event
was considered by the investigator to be related to
rhPTH(1-84). TEAEs were classified as mild, moderate, or se­
vere in intensity. TEAEs classified as severe were those that re­
quired vigorous therapeutic intervention and interrupted
usual activities. Serious TEAEs were defined as any medical
event that required hospitalization or prolonged hospitaliza­
tion, caused persistent or significant disability, was life-
threatening, resulted in death, or was judged by the investigator
as an important medical event.
All assessments were carried out as reported previously to
month 60 [22]. From month 60 onward, the same schedule of
assessments and procedures was applied. Total serum calcium,
serum phosphorus, and serum 25-hydroxyvitamin D (25(OH)
D) were evaluated every 2 months. Twenty-four–hour urine cal­
cium and phosphorus, serum creatinine, eGFR, and BTMs were
measured every 4 months and serum 1,25-dihydroxyvitamin D
(1,25(OH)2D) every 6 months. BMD was assessed annually
and reported as percentage change from baseline. BMD was ac­
quired using Hologic (Marlborough, MA, USA) and GE Lunar
(Madison, WI, USA) dual-energy x-ray absorptiometry instru­
ments. No weight adjustment was made to z scores calculated
on GE instruments.
The analysis populations were the safety population, which
included all patients who received ≥1 dose of rhPTH(1-84),
and the intent-to-treat (ITT) population, which included all
patients who received ≥1 dose of rhPTH(1-84) and had ≥1 ef­
ficacy measurement. In addition, in post hoc analyses, data
were generated for the subset of patients who completed 72
months of rhPTH(1-84) treatment (completer population).
In this study, the safety and ITT populations were identical.
Baseline values for this study were defined as follows: for pa­
tients who completed REPLACE and RELAY, or only com­
pleted REPLACE, the baseline value of REPLACE was used.
For patients who only completed RELAY, the baseline value
of RELAY was used. For patients who enrolled in
REPLACE and dropped out during optimization and for those
new to rhPTH(1-84) treatment, the baseline visit of this study
was used. Patients whose hypoparathyroidism was not
adequately controlled at baseline were defined as those
with ≥1 biochemical parameter outside the following refer­
ence ranges: albumin-adjusted serum calcium, 2.13 to
2.63 mmol/L (8.5-10.5 mg/dL); serum phosphorus, 0.81 to
1.45 mmol/L (2.5-4.5 mg/dL); calcium-phosphorus product,
<4.4 mmol2/L2 (<55 mg2/dL2); serum creatinine, 51.3 to
112.3 µmol/L (0.58-1.27 mg/dL); eGFR, 15 to 150 mL/min/
1.73 m2; 24-hour urinary calcium, men <7.5 mmol
(<300 mg), women <6.25 mmol (<250 mg).
The end-of-treatment (EOT) visit was defined as the last
available measurement during the treatment period. Patients
received rhPTH(1-84) until January 2018 or completion of
the last study visit at month 72, whichever came later.
Therefore, some patients completed the study with more
than 72 months of rhPTH(1-84) and so had their final visit
after month 72 labeled as the EOT visit. Data for EOT out­
comes were summarized and are reported separately.
Patients were contacted by phone 4 weeks after the EOT or
early termination visit to monitor for and follow up on any
serious TEAEs or TEAEs that were considered by the investi­
gator to be related to rhPTH(1-84) treatment.
3
Statistical Analyses
SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) was used
for all statistical analyses. Because no formal hypothesis test­
ing was performed, the sample size of this extension study was
not a consideration. Statistical testing was precluded by the
open-label study design and lack of comparator. Continuous
variables were summarized using descriptive statistics, includ­
ing number of patients, mean, and SD; categorical variables
were summarized with the number of patients and percen­
tages. Visits were summarized based on the analysis visit win­
dows. If more than 1 nonmissing observation was recorded
within the same analysis visit window, the value of the obser­
vation closest to the target day was used. If observations were
equidistant in days from the target day, the later measurement
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based on measurement date and time was used. Responder
rate and calcium and calcitriol supplementation endpoints
were based on investigator-prescribed data. Missing safety
and efficacy parameters were not imputed. For some parame­
ters, patient numbers reported here differ from those reported
previously [22] because data were not stable at the 5-year
mark and were subsequently updated before database lock
for the 6-year analysis. Data are presented as mean ± SD un­
less otherwise specified.
Results
Patient Population
We enrolled a total of 49 patients in the RACE extension study,
including 48 patients who completed the RELAY and/or
REPLACE studies. In addition, 1 patient who enrolled in
REPLACE but discontinued during optimization met the eligi­
bility criteria and participated in RACE. Of the 49 patients
treated with rhPTH(1-84), 38 patients (77.6%) completed
the study (Fig. 1). One patient discontinued within the analysis
visit window for the month 72 visit and was therefore consid­
ered to have completed the study; however, this patient did
not contribute data to all study outcomes at month 72.
Therefore, the ITT and safety populations consist of all 49 en­
rolled patients, and the completer population comprised 37 pa­
tients (75.5%) who completed 72 months of rhPTH(1-84)
treatment and had month 72 endpoint data available.
The mean duration of rhPTH(1-84) exposure was 2038 ±
675 days (∼5.6 years; median 2333 days; range 41-2497
days; n = 49). Eleven patients withdrew from the study. Six
discontinued based on the patient’s decision: 2 patients were
able to receive rhPTH(1-84) by prescription (1437 and 1996
days in study, respectively), 2 were tired of daily injections
of study medication (393 and 1393 days in study), 1 found
the number of pills inconvenient (107 days in study), and 1
had difficulty swallowing calcium supplements and maintain­
ing study drug compliance (68 days in study). Two patients
discontinued based on the investigator’s decision: 1 patient
was unable to attend clinic visits (750 days in study), and
the second experienced health deterioration in conjunction
with difficulty traveling to the study site (1698 days in study).
The remaining 3 patients discontinued for the following rea­
sons: 1 patient had a TEAE of metastatic lung carcinoma
that was considered unrelated to treatment (study 618 days
in study), 1 patient died from cardiac arrest that was consid­
ered unrelated to treatment (2015 days in study), and 1 de­
clined to continue the extension study after the first 12
months (347 days in study).
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Figure 1. Flow diagram showing patients enrolled in the study. *One patient dropped out during optimization in REPLACE but met inclusion and
exclusion criteria for RACE. †Among enrolled patients, 48 of 49 had chronic hypoparathyroidism that was not adequately controlled at baseline for RACE
based on biochemical measurements. ‡One patient discontinued at around month 72; however, the patient’s last study visit fell within the analysis visit
window for the month 72 visit, and the patient was therefore deemed to have completed the study. ITT = intent to treat.

The demographic and baseline clinical characteristics of the
patients were reported previously [22]. The study population
was primarily female (n = 40; 81.6%) and White (n = 46;
93.9%). At baseline, mean age was 48.1 ± 9.78 years, dur­
ation of hypoparathyroidism was 15.9 ± 12.49 years and
55% (n = 27) of patients had a history of thyroid surgery.
Biochemical Parameters
Biochemical parameters are reported for the ITT population
(n = 49) and for patients who completed 72 months of treat­
ment with rhPTH(1-84) (completer population; n = 37).
Overall, outcomes for these 2 study populations were similar.
Mean albumin-adjusted serum calcium concentration was
within the target range at baseline and through month 72
for both the ITT and completer populations (Fig. 2A).
We defined hypercalciuria as ≥6.25 mmol/24 hours
(250 mg/24 hours) for women and ≥7.5 mmol/24 hours
(300 mg/24 hours) for men. In the ITT population, for pa­
tients with available data, at baseline, 27 of 39 women
(69.2%) and 6 of 9 men (66.7%) had hypercalciuria; the pro­
portions had reduced by more than half by month 72 (n = 9/
27 [33.3%] for women and n = 2/5 [40.0%] for men, n =
11/32 [34%] overall).
A similar pattern was observed in the completer population,
18 of the 28 women (64.3%) and 6 of the 9 men (66.7%) for
whom data were available had hypercalciuria at baseline, and
8 of 26 women (30.8%) and 2 of 5 men (40%) for whom data
were available had hypercalciuria at month 72. Among the 24
completers with hypercalciuria at baseline, 7 (29.2%) re­
mained hypercalciuric at month 72 (data were missing for 3
patients [12.5%]).
At baseline, mean 24-hour urinary calcium excretion was
10.3 ± 6.67 mmol/24 hours (412 ± 267 mg/24 hours) for
men (n = 9) and 8.6 ± 4.60 mmol/24 hours (344 ± 184 mg/
24 hours) for women (n = 39). At month 72, mean urinary
calcium had declined to 6.9 ± 4.66 mmol/24 hours (276 ±
186 mg/24 hours) for men (n = 5) and 5.4 ± 2.93 mmol/
24 hours (216 ± 117 mg/24 hours) for women (n = 27).
When adjusted for body weight, mean urine calcium excretion
at baseline was higher than desirable, 0.11 ± 0.061 mmol/kg/
24 hours (4.3 ± 2.44 mg/kg/24 hours; n = 48), and gradually
decreased to 0.07 ± 0.039 mmol/kg/24 hours by month 72
(2.7 ± 1.55 mg/kg/24 hours; n = 32) (Fig. 2B). Data for pa­
tients who completed the study were almost identical: 0.11
± 0.066 mmol/kg/24 hours (4.3 ± 2.64 mg/kg/24 hours; n = 37)
at baseline and 0.07 ± 0.039 mmol/kg/24 hours (2.7 ±
1.57 mg/kg/24 hours; n = 31) at month 72 (Fig. 2B).
Twelve patients used thiazide diuretics. Mean serum cal­
cium concentrations and mean 24-hour urinary calcium ex­
cretion at baseline were higher in patients using thiazide
diuretics than in patients not using them (Table 1). At month
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Figure 2. Change over time in (A) albumin-adjusted serum calcium, (B) 24-hour urinary calcium excretion corrected for body weight, (C) serum
phosphorus, and (D) 24-hour urinary phosphorus excretion for the ITT and completer populations. Completers are patients who completed 72 months of
treatment. ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

72, the absolute change from baseline in serum and urinary
calcium was larger in patients receiving than not receiving
thiazide diuretics.
At baseline, mean serum phosphorus concentration was
1.6 ± 0.19 mmol/L (4.8 ± 0.58 mg/dL; n = 49), above the ref­
erence range (0.81-1.45 mmol/L [2.5-4.5 mg/dL]). After initi­
ation of treatment with rhPTH(1-84), mean serum
phosphorus levels declined and then remained at a lower level
through month 72 (Fig. 2C). At month 72, mean change from
baseline in serum phosphorus was −0.3 ± 0.22 mmol/L (−1.0
± 0.70 mg/dL; n = 36). At baseline, 31 of 49 patients (63.3%)
were hyperphosphatemic (ie, serum phosphorus >1.45 mmol/L
[>4.5 mg/dL]). Of the 24 patients who were hyperphosphate­
mic at baseline and had month 72 data available, 18 (75%)
had normal serum phosphorus and 6 (25%) had high serum
phosphorus at month 72. Mean 24-hour urinary phosphorus
level also trended downward from baseline over the course of
the study (Fig. 2D), consistent with a reduced renal filtered
load of phosphorus due to the decrease in serum phosphorus
levels.
In concert with declines in serum phosphorus, mean cal­
cium-phosphorus product also declined from baseline with
rhPTH(1-84). Calcium-phosphorus product was 3.4 ±
0.51 mmol2/L2 at baseline (n = 49) and decreased to 2.7 ±
0.41 mmol2/L2 at month 72 (n = 36). The mean change
from baseline in calcium-phosphorus product was −0.8 ±
0.50 mmol2/L2 at month 72 (n = 36). For the completer popu­
lation, calcium-phosphorus product was 3.5 ± 0.51 mmol2/L2
at baseline (n = 35) and 2.7 ± 0.41 mmol2/L2 at month 72
(n = 35).
Renal Function
Mean serum creatinine level was steady and remained within
the reference range throughout the study (Fig. 3). Mean
eGFR was stable over 72 months of treatment; mean values
were 78.1 ± 17.75 mL/min/1.73 m2 at baseline (n = 49) and
81.5 ± 18.27 mL/min/1.73 m2 at month 72 (n = 38). For
the completer population, mean eGFR was 75.16 ±
17.05 mL/min/1.73 m2 at baseline (n = 37) and 84.39 ±
6 Journal of the Endocrine Society, 2023, Vol. 7, No. 5

Table 1. Change in serum calcium and 24-hour urinary calcium excretion among patients using and not using thiazide diuretics

Parameter Baseline Month 72

n Value n Value

Serum calcium, mmol/L (mg/dL), mean ± SD

Patients receiving thiazide diuretics
Absolute value 12 2.3 ± 0.18 (9.2 ± 0.71) 11 2.1 ± 0.13 (8.4 ± 0.53)
Change from baseline − 11 −0.21 ± 0.232 (−0.84 ± 0.930)
Patients not receiving thiazide diuretics
Absolute value 37 2.1 ± 0.17 (8.5 ± 0.67) 26 2.2 ± 0.19 (8.6 ± 0.76)
Change from baseline − 26 0.02 ± 0.164 (0.08 ± 0.658)
24-hour urinary calcium, mmol (mg), mean ± SD

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Patients receiving thiazide diuretics
Absolute value 12 10.2 ± 4.78 (409.2 ± 191.03) 10 6.4 ± 3.60 (254.3 ± 143.98)
Change from baseline − 10 −4.6 ± 4.91 (−181.90 ± 196.38)
Patients not receiving thiazide diuretics
Absolute value 36 8.5 ± 5.07 (339.2 ± 202.93) 22 5.3 ± 3.04 (212.0 ± 121.71)
Change from baseline − 22 −2.4 ± 5.39 (−94.0 ± 215.45)

Figure 3. Change over time in serum creatinine for the ITT and completer populations. Completers are patients who completed 72 months of treatment.
ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

19.00 mL/min/1.73 m2 at month 72 (n = 37). At baseline, 2
of 41 patients (4.9%) had CKD stage 3a (eGFR 45-59 mL/
min/1.73 m2), and none had CKD stages 3b (eGFR 30−44
mL/min/1.73 m2), 4 (eGFR 15–29 mL/min/1.73 m2), or 5
(end-stage renal disease; eGFR <15 mL/min/1.73 m2 or dia­
lysis). Both patients with CKD stage 3a at baseline completed
the study. At month 72, 4 of 38 patients (10.5%) had CKD
stage 3a, but no patients had progressed to CKD stage 3b,
4, or 5.
Adverse Events
Overall, TEAEs were reported in 48 patients (98.0%) and are
summarized in Table 2. In addition, nephrolithiasis was
Journal of the Endocrine Society, 2023, Vol. 7, No. 5 7

Table 2. Treatment-emergent adverse events occurring in ≥20% of Based on patient diary data, 48 patients (98.0%) had ≥80%
patients treatment compliance during the first 12 months of the study,
as did 42 patients (85.7%) between 12 months and EOT.
TEAE, preferred term, n (%) Patients treated Events, n As shown in Fig. 4, doses of oral calcium and calcitriol sup­
with rhPTH(1-84)
plements were reduced rapidly during the first year of
(n = 49)
rhPTH(1-84) treatment. Thereafter, oral calcium supplement
Hypocalcemia 19 (38.8) 51 doses showed an upward trend from month 12 through
Muscle spasms 19 (38.8) 46 month 72, whereas calcitriol doses remained stable. The
Sinusitis 16 (32.7) 31 mean percentage change in oral calcium supplementation
was −69%±34.1% at month 12 (n = 46), and −45%
Paresthesia 15 (30.6) 38
±113.6% at month 72 (n = 37). The mean percentage change
Nausea 15 (30.6) 20
in calcitriol supplementation was −72%±44.6% at month 12
Headache 13 (26.5) 22 (n = 46) and −74%±39.3% at month 72 (n = 37).
Arthralgia 13 (26.5) 19 Reflecting the action of rhPTH(1-84) on the conversion of

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Bronchitis 12 (24.5) 16
Nasopharyngitis 11 (22.4) 22
Back pain 11 (22.4) 16
Pain in extremity 10 (20.4) 17
Urinary tract infection 10 (20.4) 14
Constipation 10 (20.4) 11
Diarrhea 10 (20.4) 11
Influenza 10 (20.4) 11
Abbreviations: rhPTH(1-84), recombinant human parathyroid hormone
(1-84); TEAE, treatment-emergent adverse event.
reported in 6 patients (12.2%); nephrocalcinosis was not re­
ported. TEAEs assessed by the investigator as related to treat­
ment with rhPTH(1-84) were reported in 25 patients (51.0%);
all were mild or moderate in severity except for 1 event of se­
vere lower back pain. The most common TEAEs that were
considered to be related to treatment were nausea (n = 7,
14.3%), hypercalcemia (n = 6, 12.2%), hypocalcemia (n = 5,
10.2%), tetany (n = 4, 8.2%), constipation (n = 3, 6.1%),
and paresthesia (n = 3, 6.1%). Thirty serious TEAEs were re­
ported in 13 patients (26.5%); none were reported in more
than 1 patient, and none were assessed by the investigator as
related to treatment with rhPTH(1-84). Nine events of bone
fracture were reported in 8 patients during the study: 3 events
of ankle fracture; 1 event each of fibula, radius, rib, thumb,
and ulna fracture; and 1 event of stress fracture of the foot.
None of the fracture events were considered by the investiga­
tor to be related to treatment. No cases of osteosarcoma were
reported. Two deaths occurred during the study; neither was
considered by the investigator to be related to rhPTH(1-84)
treatment. As reported previously, a 52-year-old woman
with a history of hyperlipidemia, diabetes mellitus type 2, car­
diomyopathy, and hypertension died of congestive heart fail­
ure [22]. In addition, a 65-year-old woman with a history of
beta-thalassemia and mitral valve prolapse died from cardiac
arrest. There were no clinically significant changes in vital
signs or electrocardiogram parameters over the treatment
period.
rhPTH(1-84) Dosing, Oral Supplement Dosing, and
Serum 25(OH)D and 1,25(OH)2D Levels
Most patients (n = 46; 93.9%) initiated the study on 50 µg per
day of rhPTH(1-84), but by month 72, most (n = 26/37;
70.3%) were receiving 100 µg per day of rhPTH(1-84).
Administration of rhPTH(1-84) was generally well tolerated.
25(OH)D to 1,25(OH)2D, serum concentrations of
1,25(OH)2D increased over the course of the study. Mean se­
rum 1,25(OH)2D concentration was 30.6 ± 12.21 pg/mL at
baseline (n = 29) and increased to 45.0 ± 25.94 pg/mL at
month 12 (n = 44), and 44.3 ± 17.37 pg/mL at month 72
(n = 37). Mean change from baseline was 17.0 ± 29.62 pg/
mL at month 12 (n = 27) and 11.6 ± 16.34 pg/mL at month
72 (n = 24). Mean serum 25(OH)D concentration declined
from a baseline value of 45.7 ± 16.86 ng/mL (n = 49) to
33.4 ± 10.24 ng/mL at week 24 (n = 47) and then remained
relatively stable over the remainder of the study (Fig. 5). Per
protocol, supplements of ergocalciferol and cholecalciferol
could be altered at any time during the study, which would
likely influence the serum 25(OH)D results; however, data re­
garding changes in doses of these supplements are not
available.
Composite Efficacy Outcome
The composite efficacy outcome was defined as a ≥50% re­
duction in oral calcium (or ≤500 mg/day) and calcitriol (or
≤0.25 μg/day) doses and albumin-adjusted serum calcium
concentration that were normalized or maintained compared
with baseline and did not exceed the upper limit of normal.
The composite efficacy outcome was achieved by 35 of 46 pa­
tients (76.1%; 95% CI 61.2-87.4%) at month 12 and by 25 of
38 patients (65.8%; 95% CI 48.6-80.4%) at month 72. The
composite efficacy response rate was similar regardless of
the source of the oral calcium supplementation. Among pa­
tients who were prescribed calcium as calcium citrate, the
composite efficacy response rate was 75.0% at month 12
(n = 21 of 28 patients) and 75.0% at month 72 (n = 18 of
24 patients). Among patients who were prescribed calcium
as calcium carbonate, the composite efficacy response rate
was 77.8% at month 12 (n = 7 of 9 patients) and 66.7% at
month 72 (n = 4 of 6 patients).
Bone Turnover Markers, Bone Mineral Density, and
Z Score
For both the ITT and completer analysis populations, levels of
BTMs initially increased with rhPTH(1-84) treatment and
then declined by month 32 to steady-state values that re­
mained above pretreatment levels (Fig. 6). For the ITT popu­
lation, mean percentage change in BMD at month 72 was less
at lumbar spine (−1.9% ± 9.30%; n = 32), total hip (−2.8%
± 7.09%; n = 31), and femoral neck (−3.1% ± 8.01%; n =
31) than at one-third radius (−7.5% ± 9.04%; n = 32), which
declined progressively from baseline (Fig. 7). Baseline mean z
scores were well above average at all sites (lumbar spine, +2.1
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Figure 4. Percentage change from baseline in dose of oral calcium and calcitriol over time for the ITT and completer populations. Completers are patients
who completed 72 months of treatment. ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84). *n = 38 for the overall study
(ITT) population.

± 1.47 [n = 40]; total hip, +1.6 ± 1.12 [n = 40]; femoral neck,
+1.4 ± 1.24 [n = 40]; one-third radius, +0.9 ± 0.83 [n = 40]).
At month 72, mean z scores were slightly better than baseline
in the lumbar spine and stable at the total hip and femoral
neck. Mean change of z score at the one-third radius was a de­
crease of 0.5 z score units (Fig. 7). Similar results were ob­
tained when BMD and z scores were determined for the
completer population (Fig. 7).
Summary of Efficacy Endpoints, rhPTH(1-84)
Dosing, Biochemical Parameters, and Bone Indices
Data collected at the last study visit (ie, at EOT) for study out­
comes reported in the ITT population were collated and are
summarized in Tables 3 and 4. At EOT, the composite efficacy
outcome was achieved by 30 of 49 patients (61.2%; 95% CI
46.2–74.8%), which was similar to the response rate at month
72. In addition, there was no substantial difference in the re­
sponse rate between patients prescribed calcium citrate and
those prescribed calcium carbonate (Table 3). At EOT, 30
of 49 patients (61.2%) were receiving 100 µg per day of
rhPTH(1-84) as their final dose level. Results for composite
efficacy endpoint and rhPTH(1-84) dosing values at EOT
may be less robust than values at month 72 because patients
could have discontinued treatment before escalation to full
dose occurred.
Discussion
Outcomes of this study confirm and extend results of previous
analyses of the safety and efficacy of rhPTH(1-84) for chronic
hypoparathyroidism and demonstrate that beneficial treat­
ment effects were maintained over 6 years. All but 1 study pa­
tient (48 of 49) had chronic hypoparathyroidism that was not
adequately controlled at baseline of RACE, as defined by key
biochemical measurements. Over 72 months of treatment
with rhPTH(1-84), biochemical parameters improved or
were maintained within reference ranges, and mean urinary
calcium excretion decreased to within the reference range
for men and women. These outcomes demonstrate that
patients treated long-term with rhPTH(1-84) can achieve im­
portant management goals for hypoparathyroidism as out­
lined in treatment guidelines [4, 5, 26]. The safety profile of
rhPTH(1-84) was consistent with results of the shorter-term
Journal of the Endocrine Society, 2023, Vol. 7, No. 5
Figure 5. Change over time in serum 25(OH)D for the ITT and completer populations. Completers are patients who completed 72 months of treatment.
ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84).
antecedent studies REPLACE and RELAY, as well as the
5-year analysis of data from RACE, and another long-term,
single-center study of rhPTH(1-84) [17, 18, 22, 24]. No cases
of osteosarcoma were reported during the study, and no new
safety signals were identified. Although a small number of
fractures occurred, none were considered related to
rhPTH(1-84). Overall, 76% of patients completed 72 months
of rhPTH(1-84) treatment, and 86% maintained ≥80% treat­
ment compliance between month 12 through EOT, indicating
that the dosing regimen can be sustained over long-term
treatment.
Based on several retrospective studies, chronic hypopara­
thyroidism has been associated with an increased risk of renal
complications, including nephrolithiasis, nephrocalcinosis,
eGFR decline, and CKD [10, 15, 27-29]. In RACE, renal func­
tion was preserved throughout the 6 years of treatment with
rhPTH(1-84). Mean serum creatinine and eGFR were stable,
and no patients experienced substantial eGFR decreases, end-
stage renal disease, or the need for renal replacement therapy.
The prevalence of nephrolithiasis in this study (12.2%) was
within the wide range (0-35.5%) reported in the literature
for patients with chronic hypoparathyroidism [29-31]. In add­
ition, no events of nephrocalcinosis were reported; however,
routine ultrasound imaging was not mandated in the protocol,
therefore the rate of asymptomatic nephrocalcinosis could not
be ascertained. Furthermore, hypocitraturia, which was not
recorded in this study, has been associated with renal stone
formation in patients with hyperparathyroidism [32] and
has been reported in patients with hypoparathyroidism who
received synthetic rhPTH (rhPTH[1-34]) [33]. Mean
24-hour urinary calcium levels were reduced from above the
reference range at baseline to within the normal range over
9
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72 months, although considerable interpatient variability
was observed. Among patients who had hypercalciuria at
baseline, 39.4% achieved normal urine calcium excretion at
month 72. Similar beneficial effects on urinary calcium excre­
tion and preservation of renal function were also seen in an­
other open-label, long-term extension study of rhPTH(1-84)
[20]. Furthermore, in retrospective analyses, patients treated
with rhPTH(1-84) in clinical trials (including patients from
RACE) had a lower annual rate of eGFR decline and a lower
risk of developing CKD compared with a historical control co­
hort not treated with rhPTH(1-84) [34-36]. Cumulatively,
these data suggest that therapy with rhPTH(1-84) may miti­
gate some of the risks of adverse renal outcomes for patients
with chronic hypoparathyroidism. Nonetheless, for patients
with hypercalciuria, nephrocalcinosis, and/or kidney stones,
it would be advisable to follow 24-hour urine calcium excre­
tion during rhPTH(1-84) treatment.
Mean serum phosphorus level was above the upper limit of
the reference range at baseline, consistent with the absence of
the phosphaturic effect of endogenous PTH [9]. With
rhPTH(1-84) treatment, serum phosphorus declined to within
the reference range by week 4 and was maintained at lower
levels throughout the remainder of the study. Notably, the de­
crease in serum phosphorus was not accompanied by a corre­
sponding increase in urine phosphorus, possibly because of
the establishment of a new rhPTH(1-84)-driven steady state
in which the renal filtered load of phosphorus was reduced,
or to individual dietary changes in phosphorus content not
captured in the trial. It is also possible that the daily injection
of rhPTH(1-84), by promoting increased renal clearance of
phosphorus during the initial hours after an injection (when
the circulating levels of PTH are high), reduces serum
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Figure 6. Change over time in serum bone turnover markers (A) BAP, (B) P1NP, and (C) CTX for the ITT and completer populations. Completers are
patients who completed 72 months of treatment. BAP, bone alkaline phosphatase; CTX, cross-linked C-telopeptide of type 1 collagen; ITT, intent to treat;
P1NP, aminoterminal propeptide of type 1 collagen; rhPTH(1-84), recombinant human parathyroid hormone (1-84).

phosphorus levels sufficiently that the overall renal filtered
load of phosphorus is decreased over the 24-hour treatment
period, as was seen in the pharmacokinetics/pharmacodynam­
ics study by Clarke et al [37]. In addition, treatment with
rhPTH(1-84) may help restore the complex series of interac­
tions among PTH, fibroblast growth factor 23, and
1,25(OH)2D that together act to regulate serum and urine
phosphorus levels [38, 39]. Indeed, we note that during the
study, serum concentrations of 1,25(OH)2D increased while
serum concentrations of 25(OH)D decreased, a physiological
response that is typical of PTH exposure [40]. This effect is the
result of induction of CYP27B1 by PTH, which increases con­
version of 25(OH)D to 1,25(OH)2D, and induction of
CYP24A1 by 1,25(OH)2D, which increases inactivation of
25(OH)D [40, 41].
In this study, long-term daily treatment with rhPTH(1-84)
improved important measures of bone health for patients
with hypoparathyroidism. As expected, BTMs were in the
lower part of the reference range at baseline because of low
bone turnover in this condition [1]. With rhPTH(1-84) treat­
ment, bone formation and resorption markers increased in
parallel, peaked at 9 to 16 months, and then declined by
month 32 but remained above pretreatment values at a
new steady state that continued through 72 months of ther­
apy. Rubin and colleagues reported a similar pattern of
change in bone formation and resorption markers in another
long-term study of rhPTH(1-84) in patients with chronic
hypoparathyroidism [24]. The time course of changes in
BTM levels with rhPTH(1-84) treatment may have impacted
patients’ oral supplement requirements. As BTM levels
Journal of the Endocrine Society, 2023, Vol. 7, No. 5
Figure 6. Continued
decline and less calcium is released into the blood in the latter
part of the rhPTH(1-84) treatment period, dosages of oral
calcium were increased.
It is important that the long-term implications of PTH re­
placement on bone are well established. A case study regard­
ing a patient with hypoparathyroidism treated with
rhPTH(1-34) for 3 years reported upregulated bone uptake
in the peripheral joints and in the axial skeleton [42], and
an increase in BMD was reported in a patient with autosomal
dominant hypoparathyroidism secondary to calcium recep­
tor mutation who received rhPTH(1-34) for 13.5 years
[43]. Furthermore, diffuse calvarial thickening was observed
in a patient with chronically elevated PTH levels, with the ac­
tivation of cyclic adenosine monophosphate signaling path­
ways proposed as a plausible mechanism [44]. Although
BMD decreased at all sites measured over the course of the
study, changes in the spine and hip were no more than ex­
pected for age, race, and sex. BMD decline was somewhat
greater at the one-third radius. At least part of the decrease
at the one-third radius was due to treatment. In a study of
11
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postmenopausal women in Norway, elevated endogenous
PTH concentration was associated with increased cortical
porosity in the proximal femur [45], while iliac crest bone bi­
opsy data from a study of 5 patients with hypoparathyroid­
ism showed a significant increase in cortical porosity after 12
months of treatment with rhPTH(1-34), with no correspond­
ing increase in cortical thickness [46]. The modest change in z
score (−0.5) observed in this study; however, suggests that
most of the decrease at one-third radius observed in this
study was expected. It should be noted that the patients in
this study had longstanding hypoparathyroidism, and their
BMD was better than expected for age, race, and sex.
Furthermore, the radius is a known site of catabolic actions
of PTH [47] and a site where endosteal resorption and perios­
teal apposition of new bone could maintain skeletal strength
despite the decline in BMD. Further and more detailed
assessments of this site would shed light on those possibilities.
BMD changes over time at the spine and hip were much
smaller quantitatively and are unlikely to be clinically con­
cerning in the majority of patients. Moreover, rhPTH(1-84)
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Figure 7. Change from baseline in z score over time. Filled symbols with solid lines represent the ITT population, and open symbols with dashed lines
represent the completer population. The table below the graph reports percentage change from baseline in BMD at month 72 and z score at baseline and
month 72. Completers are patients who completed 72 months of treatment. BMD, bone mineral density; ITT, intent to treat; rhPTH(1-84), recombinant
human parathyroid hormone (1-84). *Excludes results from 6 patients who were assessed by different dual-energy x-ray absorptiometry machines at
baseline vs month 72 (Hologic and GE Lunar instruments, respectively).

Table 3. Summary of efficacy endpoints and rhPTH(1-84) dosing (ITT population))

Parameter rhPTH(1-84)
(n = 49)

Composite efficacy outcome n Value at EOT

Composite efficacy outcome, % (95% CI) 30 61.2 (46.2-74.8)
Patients prescribed calcium citratea 20 69.0 (49.2-84.7)
Patients prescribed calcium carbonateb 7 63.3 (30.8-89.1)
rhPTH(1-84) dose n Value at EOT
rhPTH(1-84) dose level, %
25 µg 1 2.0
50 µg 10 20.4
75 µg 8 16.3
100 µg 30 61.2

Abbreviations: EOT, end of treatment; ITT, intent to treat; rhPTH(1-84), recombinant human parathyroid hormone (1-84).
a
Among 29 patients.
b
Among 11 patients.

administration in hypoparathyroidism is known to affect in life may already have low BMD or osteoporosis by the
skeletal microstructure in ways that could mitigate concerns time they develop hypoparathyroidism. How treatment
that are typically associated with reductions in BMD [41]. with rhPTH(1-84) would affect BMD in these situations is
However, patients who develop hypoparathyroidism later unknown.
Journal of the Endocrine Society, 2023, Vol. 7, No. 5 13

Table 4. Summary of biochemical parameters, oral supplementation, and bone indices (ITT population)

Biochemical parameters

Parameter, mean ± SD Baseline EOT

n Value n Value

Serum calcium, mmol/L (mg/dL) 49 2.1 ± 0.17 (8.4 ± 0.70) 49 2.0 ± 0.18 (8.1 ± 0.71)
Change from baseline, mmol/L (mg/dL) − 49 −0.1 ± 0.19 (−0.2 ± 0.75)
Change from baseline, % − 49 −2.5 ± 8.90
Patients receiving thiazide diuretics
Absolute value, mmol/L (mg/dL) 12 2.3 ± 0.18 (9.2 ± 0.71) 12 2.1 ± 0.13 (8.4 ± 0.51)
Change from baseline, mmol/L (mg/dL) − 12 −0.2 ± 0.19 (−0.9 ± 0.78)

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Patients not receiving thiazide diuretics
Absolute value, mmol/L (mg/dL) 37 2.1 ± 0.17 (8.5 ± 0.67) 37 2.1 ± 0.21 (8.4 ± 0.84)
Change from baseline, mmol/L (mg/dL) − 37 −0.04 ± 0.200 (−0.2 ± 0.80)
Urinary calcium, mmol/24 hours (mg/24 hours) 48 8.9 ± 5.01 (356.7 ± 200.37) 48 6.5 ± 3.71 (258.2 ± 148.23)
Change from baseline, mmol/24 hours (mg/24 hours) − 47 −2.4 ± 5.81 (−94.7 ± 232.36)
Patients receiving thiazide diuretics
Absolute value 12 10.2 ± 4.78 (409.2 ± 191.03) 12 6.2 ± 2.24 (246.5 ± 89.56)
Change from baseline − 12 −4.1 ± 6.00 (−162.7 ± 240.00)
Patients not receiving thiazide diuretics
Absolute value 36 8.5 ± 5.07 (339.2 ± 202.93) 36 6.6 ± 4.10 (262.1 ± 164.08)
Change from baseline − 35 −1.8 ± 5.71 (−71.4 ± 228.53)
Serum phosphorus, mmol/L (mg/dL) 49 1.6 ± 0.19 (4.8 ± 0.58) 49 1.3 ± 0.24 (4.0 ± 0.74)
Change from baseline, mmol/L (mg/dL) − 49 −0.3 ± 0.29 (−0.8 ± 0.91)
Change from baseline, % − 49 −15.2 ± 18.90
Urinary phosphorus, mmol/24 hours (mg/24 hours) 48 31.9 ± 14.50 (1.0 ± 0.45) 48 24.6 ± 10.80 (0.8 ± 0.33)
Change from baseline, mmol (mg/dL) − 47 −7.6 ± 14.14 (−0.2 ± 0.44)
Change from baseline, % − 47 −13.8 ± 44.32
Creatinine, µmol/L (mg/dL) 49 84.7 ± 18.16 (1.0 ± 0.21) 48 79.8 ± 21.60 (0.9 ± 0.24)
Change from baseline, µmol/L (mg/dL) − 48 −5.3 ± 16.88 (−0.1 ± 0.19)
Change from baseline, % − 48 −5.6 ± 19.60
eGFR, mL/min/1.73 m2 49 78.1 ± 17.75 48 80.3 ± 20.55
25(OH)D, ng/mL 49 45.7 ± 16.86 49 38.2 ± 10.58
Change from baseline, ng/mL − 49 −7.6 ± 18.53
1,25(OH)2D, pg/mL 29 30.6 ± 12.21 46 36.2 ± 13.66
Change from baseline, pg/mL − 28 6.4 ± 17.62

Oral supplementation

Baseline EOT

Parameter, mean ± SDa n Value n Value

Oral calcium, mg/day 49 2194 ± 1732.3 49 1032 ± 1352.8

Change from baseline, % − 49 −40.4 ± 106.98
Oral calcitriol, µg/day 49 0.67 ± 0.446 49 0.18 ± 0.414
Change from baseline, % − 49 −73.7 ± 39.35
Supplement use at EOT, %
Patients off oral calcium − 14 28.6
Patients off calcitriol − 32 65.3
Patients with oral calcium <600 mg/day and off calcitriol − 19 38.8
Patients off oral calcium and calcitriol − 10 20.4

(continued)
14 Journal of the Endocrine Society, 2023, Vol. 7, No. 5

Table 4. Continued

Bone indices

Baseline EOT

Parameter, mean ± SD n Value n Value

Bone indices

Baseline EOT

Parameter, mean ± SD n Value n Value

BAP, µg/L 48 9.6 ± 3.32 48 14.6 ± 11.54

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Change from baseline, µg/L − 47 5.3 ± 11.16
P1NP, µg/L 49 33.7 ± 19.72 48 124.9 ± 104.44
Change from baseline, µg/L − 48 91.9 ± 104.33
CTX, ng/L 48 213.0 ± 172.34 48 422.8 ± 282.83
Change from baseline, ng/L − 47 224.2 ± 295.86
BMD, change from baseline, %b
Lumbar spine − 39 −2.2 ± 8.83
Total hip − 39 −2.9 ± 6.55
Femoral neck − 39 −4.4 ± 7.76
One-third radius − 39 −6.9 ± 9.94
z scoreb
Lumbar spine 40 2.1 ± 1.47 42 2.2 ± 1.56
Total hip 40 1.6 ± 1.12 42 1.6 ± 1.10
Femoral neck 40 1.5 ± 1.24 42 1.4 ± 1.17
One-third radius 40 0.9 ± 0.83 42 0.5 ± 1.22

Abbreviations: BAP, bone alkaline phosphatase; BMD, bone mineral density; CTX, cross-linked C-telopeptide of type 1 collagen; eGFR, estimated glomerular
filtration rate; EOT, end of treatment; ITT, intent to treat; P1NP, aminoterminal propeptide of type 1 collagen; rhPTH(1-84), recombinant human parathyroid
hormone (1-84).
a
Unless otherwise indicated.
b
Excludes results from 6 patients who were assessed by different dual-energy x-ray absorptiometry machines at baseline vs month 72 (Hologic and GE Lunar
instruments, respectively).

In contrast to the decline in BMD at all sites in the current
study, another long-term study of rhPTH(1-84)-treated pa­
tients with hypoparathyroidism by Tay et al showed an in­
crease in BMD from baseline at the lumbar spine, total hip,
and femoral neck [20]. In both the current study and the
Tay et al study, BMD decreased at the one-third radius, but
the magnitude of the decline was less in the analysis by Tay
et al [20]. Patients in the study by Tay et al had a longer dur­
ation of hypoparathyroidism (29.9 ± 3.3 years for patients in
Tay et al vs 15.9 ± 12.5 years in RACE) and used a lower dose
of rhPTH(1-84) (50 µg daily was the most frequent dose in the
Tay study vs 100 µg daily in RACE) [20], either of which
could affect the BMD response to rhPTH(1-84) treatment.
Together, the available bone-related data suggest that long-
term rhPTH(1-84) treatment may help restore the skeleton
closer to the euparathyroid state without an associated in­
crease in fracture risk.
A major strength of this study was that the cohort of patients
was followed longitudinally for 6 years, with few discontinua­
tions due to TEAEs. Long-term follow-up enabled the collec­
tion of an extensive biochemical and safety data set for this
rare disease population. Limitations include the open-label de­
sign and lack of control cohort. In addition, the protocol did
not specify that serum samples for 25(OH)D, 1,25(OH)D2,
or BTMs were collected at prescribed times or under fasting
conditions, which may limit data interpretation.
Conclusions
Continuous use of rhPTH(1-84) over 6 years is an effective
long-term treatment for chronic hypoparathyroidism and
has a safety profile consistent with previous studies.
Treatment with rhPTH(1-84) permitted reductions in oral
calcium and calcitriol, while albumin-adjusted serum cal­
cium was maintained in the target range. Improvements in
efficacy-related biochemical parameters were sustained, re­
nal function was preserved, and mean urinary calcium excre­
tion declined to within the reference ranges for men and
women.
Acknowledgments
Under the direction of the authors, editorial support in the
preparation of this manuscript was provided by Alan Storey,
PhD, an employee of ICON (Reading, Berkshire, UK), and
funded by Takeda Development Center Americas Inc.,
Lexington, MA, USA.
Journal of the Endocrine Society, 2023, Vol. 7, No. 5
Funding
The clinical trial was funded by Takeda Pharmaceuticals
U.S.A., Lexington, MA, USA.
Disclosures
N.B.W. has served as research investigator and speaker for
and received honoraria and research support from Takeda
Pharmaceuticals USA, Inc. J.P.B. has served as advisory board
member, research investigator, and speaker for and has re­
ceived consulting fees, research support, and honoraria from
Takeda Pharmaceuticals USA, Inc. H.G.B. has served as re­
search investigator for and received research support from
Takeda Pharmaceuticals USA, Inc. and has served as consult­
ant for Entera Bio and BridgeBio Pharma. B.L.C. has served
as consultant and research investigator for Takeda
Pharmaceuticals USA, Inc., and has received research grant
funding from Takeda Pharmaceuticals USA, Inc., Ascendis
Pharma, and Chugai Pharmaceutical Co., Ltd. D.D. has re­
ceived research support from Takeda Pharmaceuticals USA,
Inc. MAL has served as advisory board member, consultant,
and research investigator for Takeda Pharmaceuticals USA,
Inc. and as a consultant for Ascendis Pharma and Calcilytix.
M.M. has served as an advisory board member, consultant,
and research investigator for Takeda Pharmaceuticals USA,
Inc.; as a consultant and research investigator for Chugai
Pharmaceutical Co., Ltd; and as a consultant for
Amolyt Pharma. M.P. has received research support from
Takeda Pharmaceuticals USA, Inc. J.G.R. has served as a re­
search investigator for and received research support from
Takeda Pharmaceuticals, USA, Inc. T.J.V. has served as advis­
ory board member, consultant, and research investigator for
and received consulting fees and research support from
Takeda Pharmaceuticals USA, Inc. M.L.W. has served as
speaker for and has received honoraria and research support
from Takeda Pharmaceuticals USA, Inc. S.Y. is an employee
and N.S. is a former employee of Takeda Pharmaceuticals
USA, Inc., Lexington, MA, USA. D.M.S. has served as advis­
ory board member, consultant, and research investigator for
and received consulting fees and research support from
Takeda Pharmaceuticals USA, Inc. and has received institu­
tional research support from and served as a consultant for
Ascendis Pharma.
Data Availability
Some or all data sets generated during and/or analyzed during
the current study are not publicly available but are available
from the corresponding author on reasonable request.
Clinical Trial Information
NCT01297309, registered February 11, 2011.
Current Affiliation
Nicole Sherry, Freeline Therapeutics, Boston, MA, USA.
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