TASK FORCE

Evaluation and Management of Hypoparathyroidism

Summary Statement and Guidelines from the Second
International Workshop
Aliya A. Khan,1 John P. Bilezikian,2 Maria Luisa Brandi,3 Bart L. Clarke,4 Neil J. Gittoes,5
Janice L. Pasieka,6 Lars Rejnmark,7 Dolores M. Shoback,8 John T. Potts,9 Gordon H. Guyatt,10
and Michael Mannstadt9
1
Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON, Canada
2
Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
3
F.I.R.M.O. Foundation, Florence, Italy
4
Mayo Clinic Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Rochester, MN, USA
5
Centre for Endocrinology Diabetes & Metabolism, Queen Elizabeth Hospital, Birmingham, UK
6
Department of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
7
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
8
Endocrine Research Unit, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA, USA
9
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
10
Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada

ABSTRACT
This clinical practice guideline addresses the prevention, diagnosis, and management of hypoparathyroidism (HypoPT) and provides
evidence-based recommendations. The HypoPT task forces included four teams with a total of 50 international experts including rep-
resentatives from the sponsoring societies. A methodologist (GG) and his team supported the taskforces and conducted the system-
atic reviews. A formal process following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE)
methodology and the systematic reviews provided the structure for seven of the guideline recommendations. The task force used
a less structured approach based on narrative reviews for 20 non-GRADEd recommendations. Clinicians may consider postsurgical
HypoPT permanent if it persists for >12 months after surgery. To predict which patients will not develop permanent postsurgical
HypoPT, we recommend evaluating serum PTH within 12 to 24 hours post total thyroidectomy (strong recommendation, moderate
quality evidence). PTH > 10 pg/mL (1.05 pmol/L) virtually excludes long-term HypoPT. In individuals with nonsurgical HypoPT,
genetic testing may be helpful in the presence of a positive family history of nonsurgical HypoPT, in the presence of syndromic fea-
tures, or in individuals younger than 40 years. HypoPT can be associated with complications, including nephrocalcinosis, nephro-
lithiasis, renal insufficiency, cataracts, seizures, cardiac arrhythmias, ischemic heart disease, depression, and an increased risk of
infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory indices. In patients with
chronic HypoPT, the panel suggests conventional therapy with calcium and active vitamin D metabolites as first-line therapy (weak
recommendation, low-quality evidence). When conventional therapy is deemed unsatisfactory, the panel considers the use of PTH. ©
2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone
and Mineral Research (ASBMR).

KEY WORDS: PTH/VIT D/FGF23; CELL/TISSUE SIGNALING—ENDOCRINE PATHWAYS; PARATHYROID-RELATED DISORDERS; DISORDERS OF CALCIUM/
PHOSPHATE METABOLISM

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
Received in original form February 11, 2022; revised form August 18, 2022; accepted August 24, 2022.
Address correspondence to: Aliya A. Khan, MD, Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON L8S 4L8,
Canada. E-mail: aliya@[Link]
Journal of Bone and Mineral Research, Vol. 00, No. 00, Month 2022, pp 1–18.
DOI: 10.1002/jbmr.4691
© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research
(ASBMR).

1 n
SUMMARY OF RECOMMENDATIONS 4. What are the most common symptoms and complications
of chronic HypoPT reported in the literature? (GRADEd
recommendation)
T he following recommendations are intended to guide prac-
tice and are not intended to be used for the development
of reimbursement policies.
Observational studies comparing patients with HypoPT to
controls with normal parathyroid function have identified
the following complications associated with HypoPT
1. How should chronic HypoPT be diagnosed? (un-GRADEd (percentages represent the median among all studies):
recommendation, i.e., not based on Grading of Recom- cataract (17%), infection (11%), nephrocalcinosis/
mendations, Assessment, Development and Evaluation) nephrolithiasis (15%), renal insufficiency (12%), seizures
1.1. Hypocalcemia (low ionized serum calcium or total (11%), depression (12%), ischemic heart disease (7%),
serum calcium adjusted for albumin) in the presence and arrhythmias (7%).
of an undetectable, low or inappropriately normal intact 5. What is the optimal monitoring strategy for chronic
PTH (utilizing either a second- or third-generation assay) HypoPT?
on two occasions at least 2 weeks apart confirms the 5.1. (Systematic Current Practice Survey)*
diagnosis.
1.2. Additional abnormalities caused by low PTH that sup- New Follow-up for
port the diagnosis: Elevation in serum phosphorus, patient stable patients**
reductions in 1,25-dihydroxyvitamin D (1,25(OH)2D) Serum creatinine, estimated √ Every 3–
and elevations in the urinary fractional excretion of glomerular filtration rate 12 months
calcium. (eGFR), calcium (either ionized
1.3. In patients with postsurgical HypoPT, panel members or albumin-adjusted),
regard the condition as permanent if the HypoPT per- magnesium, phosphorus
sists >12 months after surgery. 25-hydroxyvitamin D √ Every 6–
2. How can the risks of chronic postsurgical HypoPT be 12 months
minimized? (un-GRADEd recommendation) 24-hour urine for creatinine and √ Every 6–
The panel proposes avoiding accidental parathyroidectomy calcium 24 months
as well as intraoperative parathyroid autotransplantation dur-
ing neck surgery and only utilizing this in the presence of *These are graded as low-quality recommendations based on the prac-
inadvertent parathyroidectomy. tice of 70% of the respondents completing this at least 70% of the time.
3. What is the value of determining serum calcium **For unstable patients: Frequently measure serum calcium and phos-
phorus as clinically indicated.
and PTH post-thyroidectomy to predict future permanent
postsurgical HypoPT? (GRADEd recommendation)
We recommend using PTH measurements early (12– The panel also proposes the following (non-survey-
24 hours) after total thyroidectomy for predicting which based):
patients will not develop permanent postsurgical 5.2. Complete a baseline assessment for the presence of
HypoPT renal calcification or stones with renal imaging.
(strong recommendation, moderate quality evidence). 5.3. Monitor serum calcium (ionized or albumin-adjusted)
Comments: If PTH values are >10 pg/mL (1.05 pmol/L) within several days of a significant change in medical
12–24 hours post surgery, the development of perma- treatment.
nent HypoPT is unlikely, and therefore there is no 6. How are patients with HypoPT managed?
long-term need for treatment with active vitamin D (GRADEd recommendations)
and calcium supplements above the recommended 6.1. In patients with chronic HypoPT, the panel suggests
daily allowance. Many patients with PTH values conventional therapy as first-line therapy (weak recom-
<10 pg/mL (1.05 pmol/L) 12–24 hours post surgery mendation, low-quality evidence).
may still recover from temporary HypoPT. Comment: When conventional therapy is deemed
What is the role of genetic testing in the diagnosis unsatisfactory, the panel considers the use
and evaluation of chronic HypoPT? (un-GRADEd of parathyroid hormone.
recommendations) un-GRADEd PANEL RECOMMENDATIONS FOR MANAGE-
3.1. In patients with nonsurgical HypoPT who have a posi- MENT
tive family history of nonsurgical HypoPT, present with In patients with HypoPT, the panel proposes:
syndromic features, or are younger than 40 years, panel 6.2. Treat with calcium and an active vitamin D analogue,
members undertake genetic testing. with the goal of raising serum calcium to the target
3.2. In patients with nonsurgical HypoPT who have other range, i.e., the lower half of the normal reference range
clinical features of autoimmune polyendocrinopathy– or just below the normal reference range. At this time, it
candidiasis–ectodermal dystrophy syndrome is not clear how to best balance the doses of calcium rel-
(APECED), panel members undertake genetic testing ative to those of the active vitamin D analogue.
for autoimmune regulator (AIRE) gene variants. 6.3. Alleviate symptomatic hypocalcemia while avoiding
3.3. Panel members avoid the designation of “autoimmune hypercalciuria.
HypoPT” for patients who do not have APECED because 6.4. Avoid hypercalciuria when titrating calcium and active
there are no definitive diagnostic tests for polygenic vitamin D analogue therapy, aiming for low normal
autoimmune HypoPT. plasma calcium levels.

n2 KHAN ET AL. Journal of Bone and Mineral Research

 The panel proposes achieving a 24-hour urinary calcium level updated evidence-based guidelines on the diagnosis, evalua-
of <6.25 mmol/24 hours or 250 mg/24 hours for adult tion, and management of HypoPT. Over the past 5 years, signifi-
women and <7.5 mmol/24 hours or 300 mg/24 hours for cant advances have been made in our understanding of the
adult men. Data from the general population have shown multisystem complications of HypoPT and, in particular, the skel-
a relationship between hypercalciuria and the develop- etal and renal manifestations of this disorder. New treatment
ment of renal stones—such data do not exist in patients options are being developed with improvements in our under-
with HypoPT. However, panel members infer that hyper- standing of calcium homeostasis and pharmacological
calciuria may be associated with a higher risk of renal approaches to intervention.
stones in patients with HypoPT as well and thus seek to The international task force, consisting of 50 international
avoid hypercalciuria. experts in HypoPT and general endocrinologists from 15 coun-
6.5. Avoid hyperphosphatemia. Panel members prescribe cal- tries, met over 24 months to review key issues pertaining to
cium supplements with meals to serve as phosphate the diagnosis, prevention, evaluation, and management of
binders, implement a low-phosphate diet in adults if HypoPT.
needed, and judiciously use active vitamin D analogue ther- A methods team, using the Grading of Recommendations,
apy. No data are available on the use of other types of phos- Assessment, Development and Evaluation (GRADE) methodol-
phate binders in HypoPT. Hyperphosphatemia may be ogy, completed four systematic reviews addressing the
associated with an increased incidence of ectopic calcifica- diagnosis, management, and complications of HypoPT. In addi-
tion, but currently there is no evidence of this in HypoPT. tion, narrative reviews were completed regarding the epi-
6.6. Treat to normalize plasma magnesium levels. Magnesium demiology, financial burden, and etiology of HypoPT. A survey
supplements can be used as tolerated by the patient. of panel members informed the recommendations for monitor-
6.7. Aim to achieve a 25-hydroxyvitamin D (25(OH)D) level ing. The diagnosis and risk factors for the development of post-
in the normal reference range (75–125 nmol/L). surgical HypoPT were reviewed with the development of
6.8. Consider treating hypercalciuria with thiazide diuretics strategies to help minimize postsurgical HypoPT. The role of
in conjunction with a low-sodium diet with careful mon- genetic testing in determining the underlying etiology of
itoring of blood pressure (BP), serum magnesium, HypoPT was highlighted and an approach to establishing the
potassium, and renal function. diagnosis presented. Calcium homeostasis in pregnancy and
6.9. Consider PTH replacement therapy in patients who are lactation was also reviewed with the development of strategies
not adequately controlled on conventional therapy. Inade- to optimize maternal and fetal outcomes. The risks and benefits
quate control is considered to be any one of the following: of PTH replacement therapy in comparison to conventional
(i) symptomatic hypocalcemia, (ii) hyperphosphatemia, therapy were evaluated with application of the GRADE
(iii) renal insufficiency, (iv) hypercalciuria, or (v) poor quality methodology.
of life. These new international guidelines on HypoPT have been
6.10. Individuals with poor compliance or malabsorption or endorsed by over 65 professional medical and surgical societies
who are intolerant of large doses of calcium and active as well as patient advocacy organizations interested in advanc-
vitamin D may also benefit from PTH therapy. Individ- ing the care of individuals with HypoPT. These guidelines also
uals requiring high doses of conventional therapy highlight key areas for future research in HypoPT.
(i.e., calcium >2 g/day or active vitamin D > 2 μg/day)
may also benefit from PTH therapy. Methodology
7. un-GRADEd CONSENSUS MANAGEMENT RECOMMENDA-
TIONS DURING PREGNANCY AND LACTATION A detailed discussion of the methodology is presented in an
In pregnant women with HypoPT, the panel proposes the accompanying report.(1)
following: To summarize, four international task forces were formed with
7.1. Aim to achieve serum calcium (ionized or albumin international experts in HypoPT addressing the following areas
adjusted) in the mid to low normal reference range of review, with each task force publishing its findings as a sepa-
throughout pregnancy. rate manuscript in this issue of the JBMR.
7.2. Aim to achieve serum phosphorus, magnesium, and
25OHD levels in the normal reference range. • Epidemiology and Financial Burden (cochairs BLC and NG)
7.3. Closely monitor serum calcium (ionized or albumin- • Etiologies and Pathophysiology (cochairs JLP and DMS)
adjusted) every 3–4 weeks during pregnancy and lacta- • Genetics and Diagnosis (cochairs MM and MLB)
tion, with increased frequency in the months preceding • Evaluation and Management (cochairs AAK and LR)
and following parturition as well as in the presence of Systematic reviews and narrative reviews were completed
symptoms of hypercalcemia or hypocalcemia. to inform the recommendations. GRADEd recommendations
7.4. Work closely with the obstetrician to optimize preg- followed a structured process that included framing questions
nancy outcomes. Coordinate with the pediatric team in patient/intervention/comparator/outcome format; con-
to ensure appropriate postnatal monitoring for tran- ducting a systematic evidence search and associated sum-
sient neonatal hypo- or hypercalcemia. mary, specifying values and preferences, and classifying and
7.5. Avoid using thiazide diuretics and PTH or PTH ana- presenting recommendations as strong or weak with the
logues during pregnancy. corresponding quality of evidence. A strong recommendation
was made when the desirable effects were much greater
Introduction than undesirable effects or vice versa and is worded as “we
recommend.”(2,3)
An international task force on hypoparathyroidism (HypoPT) was A weak recommendation was made if there was low certainty
convened to review new findings and insights and to develop of evidence or a close balance between desirable and

Journal of Bone and Mineral Research HYPOPARATHYROIDISM SUMMARY STATEMENT AND GUIDELINES 3 n
undesirable effects and is worded as “we suggest.” Each of the Postsurgical HypoPT constitutes approximately 75% of all
systematic reviews has also been published as a separate manu- cases. There are multiple reasons for a variable prevalence of
script in this issue of JBMR. postsurgical HypoPT in the literature, and these include variable
The three systematic reviews evaluated (i) the value of mea- timing of the biochemical monitoring, incomplete follow-up,
suring calcium and PTH 12–24 hours after total thyroidectomy and variable definitions of permanent HypoPT with a lack of con-
for predicting which patient would develop chronic HypoPT, sensus in the literature. The literature is currently of low quality,
(ii) the prevalence of symptoms and complications of HypoPT, with single-institution results and retrospective series. The most
and (iii) the effects of therapy with PTH compared to conven- commonly utilized definition of permanent HypoPT is a contin-
tional therapy. ued requirement for calcium and active vitamin D for 12 months
Ungraded recommendations from the narrative reviews did or more following surgery.
not involve structured approaches and are presented as descrip- The impact of HypoPT on mortality is not clear. Data based on
tions of the practice of the panelists in managing patients with five registries is inconsistent; mortality in HypoPT is reported to
HypoPT. Un-GRADEd recommendations are presented as “we be increased in some studies(5,6) but not in others.(7-9)
propose.” The intent was to achieve consensus on all recommen- HypoPT is associated with a major financial burden owing to
dations. There was no provision for voting. increased healthcare utilization. Individuals with chronic HypoPT
Following completion of the reviews, both systematic and have significant symptoms and comorbidity resulting in
narrative, the findings were presented to all the members of increased healthcare costs and utilize healthcare resources with
the HypoPT task forces and all members of the accompanying increased numbers of outpatient visits and ER visits.(10) This
task forces on primary hyperparathyroidism (approximately was more frequently noted in individuals with poorly controlled
100 members in total) for their perspective and feedback at a HypoPT in a recent retrospective 1-year review.(10)
recorded virtual meeting. The feedback and suggestions from A web-based survey of 374 adult U.S. patients with chronic
these members were incorporated into each of the manuscripts. HypoPT also confirmed significant healthcare utilization with
A second virtual meeting was held at which time the findings of 79% of patients requiring hospitalization or ER visits during the
the task forces were presented to representatives from global year before the survey and 72% having experienced >10 symp-
scientific societies and patient advocacy organizations for their toms during the year before the survey while receiving standard
feedback. medical treatment. Symptoms were experienced for a mean of
All task force members disclosed any potential conflicts of 139 hours each day.(11) HypoPT is associated with a major det-
interest prior to participating in the development of the manu- rimental impact on the lives of patients with HypoPT.(11)
scripts and guidelines.
Funding was received in the form of unrestricted educational
grants from Amolyt, Ascendis, Calcilytix, and Takeda. These com- Etiology
panies had no input in the design of the project, conduct of the
Postsurgical HypoPT
reviews, review of the data, content of the manuscripts, review of
the manuscripts, or forthcoming recommendations. Several risk factors have been identified for the development of
postsurgical HypoPT. They include patient factors (i.e., vitamin D
Results deficiency), the underlying disease (malignancy, thyrotoxicosis,
size of the parathyroid glands identified during thyroidectomy),
Diagnosis and operative factors (reoperation, extent of operation, sur-
geon’s practice volume).
The diagnosis of HypoPT is based on biochemical evaluation and A recent meta-analysis of 25 studies showed an increased risk
is usually straightforward. Low or inappropriately normal PTH of postsurgical HypoPT in those who underwent parathyroid
in the setting of hypocalcemia distinguishes the disease from autotransplantation.(12)
secondary causes of hypocalcemia, in which PTH is elevated. The number of autotransplanted glands correlates positively
with the development of postsurgical HypoPT and may reflect
How should chronic HypoPT be diagnosed? (un-GRADEd the result of removal or devascularization of the glands.(13) It is
recommendation) advisable to leave all viable parathyroid in situ and not proceed
with parathyroid autotransplantation. Autotransplantation
Hypocalcemia (low serum calcium adjusted for albumin or low
should only be performed if parathyroidectomy has inadver-
ionized calcium) in the presence of an undetectable, low, or
tently occurred.(13) Emerging technologies may be of value in
inappropriately normal intact PTH (utilizing either a second- or
reducing the risk of inadvertent damage or removal of the para-
third-generation assay) on two occasions at least 2 weeks apart
thyroid glands and are discussed in detail in an accompanying
confirms the diagnosis.
review.(13)
Additional abnormalities caused by low PTH, which support
the diagnosis:Elevation in serum phosphorus, reductions in
1,25(OH)2D, and elevations in 24-hour urinary calcium. How can the risks of chronic postsurgical HypoPT be minimized?
In patients with postsurgical HypoPT, panel members regard it (un-GRADEd recommendation)
as permanent if the HypoPT persists >12 months after surgery.
The panel proposes avoiding parathyroid autotransplantation
during neck surgery and only utilizing this in the presence of
Epidemiology and Financial Burden inadvertent parathyroidectomy.
Owing to improved surgical techniques, permanent HypoPT is
HypoPT is a rare condition with an estimated prevalence ranging uncommon after neck surgery. However, it would be desirable to
from 6.4 to 37/100,000 person-years and an incidence reported predict postoperatively which patient is more or less likely to
to be 0.8 to 2.3/100,000/person-years.(4) develop chronic HypoPT.

n4 KHAN ET AL. Journal of Bone and Mineral Research

 A systematic review was conducted to address the value of Permanent HypoPT should be differentiated from transient
determining serum calcium and PTH post-thyroidectomy to pre- nonsurgical HypoPT, which can be caused by hypo- or hyper-
dict future permanent postsurgical HypoPT. If PTH values exceed magnesemia.(20-22) Maternal hypercalcemia can result in infantile
10 pg/mL (1.05 pmol/L) 12–24 hours post surgery, the develop- hypocalcemia and infants of mothers with familial hypocalciuric
ment of permanent HypoPT is very unlikely, as is the long-term hypercalcemia can also have HypoPT.(14,23,24)
need for treatment with active vitamin D and calcium supple- Pseudo-HypoPT or vitamin D disorders can also present with
ments above the recommended daily allowance. Management hypocalcemia; however, PTH is elevated. In pseudo-HypoPT
in the immediate postoperative state should continue to be there is a target organ resistance to PTH, resulting in low serum
guided by serum calcium, symptoms, and clinical judgment. calcium and high phosphate with a high PTH.(14) In vitamin D
PTH values <10 pg/mL (1.05 pmol/L) 12–24 hours post sur- deficiency, calcium and phosphate absorption from the bowel
gery have less predictive value. The possibility of developing per- is impaired and PTH is secondarily elevated.(14) These conditions
manent hypoPT still exists but is less than 50% (15). require careful evaluation and close monitoring. If the cause of
HypoPT is not identified, it is classified as idiopathic.(13)
What is the value of determining serum calcium and PTH post-
thyroidectomy to predict future permanent postsurgical HypoPT? What is the role of genetic testing in the diagnosis and evaluation
(GRADEd recommendation)? of chronic HypoPT? (un-GRADEd recommendation)
We recommend using PTH measurements after total thyroidec- In patients with nonsurgical HypoPT who have a positive family
tomy for predicting which patients will not develop permanent history of nonsurgical HypoPT, present with syndromic features,
postsurgical HypoPT (strong recommendation, moderate-quality or are younger than 40 years, the panel advises genetic testing.
evidence). In patients with nonsurgical HypoPT who have other clinical
features of APECED, the panel advises genetic testing for autoim-
Nonsurgical HypoPT mune regulator gene (AIRE) gene variants.
Panel members advise avoiding the designation of “autoim-
The etiology of nonsurgical HypoPT requires careful evaluation mune HypoPT” for patients who do not have APECED because
with identification of the underlying cause. It may be due to a definitive diagnostic test for polygenic autoimmune HypoPT
genetic, autoimmune, and metabolic factors(13) (Table 1).(14) is not currently available.
Genetic disorders can present as isolated HypoPT or as part of
a syndrome. Genetic HypoPT can be due to disorders of parathy-
Autoimmune HypoPT
roid gland formation, PTH secretion, and parathyroid gland dam-
age.(15) Evaluation includes a thorough family history and Autoimmune HypoPT may occur either in isolation or as part of
attention to the presence of features of syndromic forms of APECED, which is also called autoimmune polyglandular syn-
HypoPT. Genetic tests can be employed examining each candi- drome type 1 (APS-1). This syndrome is due to genetic mutations
date gene at a time or a panel of implicated genes at once, or in the autoimmune regulator gene (AIRE).(13) APECED is associ-
genome-wide approaches can be used. ated with HypoPT owing to parathyroid damage by circulating
Autoimmune HypoPT may occur as an acquired disease or as a autoantibodies and infiltration with lymphocytes.(14) The three
component of autoimmune polyendocrinopathy–candidiasis– major clinical features are chronic mucocutaneous candidiasis,
ectodermal dystrophy syndrome (APECED).(16)
Rare etiologies for nonsurgical HypoPT include deposition of
copper, iron, or aluminum in parathyroid tissue or the invasion Table 2. Features of autoimmune polyglandular syndrome
of the parathyroid glands by neoplastic diseases or granuloma- type 1
tous or inflammatory cells or by amyloid protein.(14,17) Major features
Drugs can also rarely result in HypoPT. Cinacalcet, a calcimi- • Mucocutaneous candidiasis
metic agent, increases the sensitivity of the CaSR to extracellular • Hypoparathyroidism
calcium and reduces PTH and also serum calcium.(18) • Adrenal insufficiency
Immune checkpoint inhibitors can also induce HypoPT in Minor features
association with activating autoantibodies to the calcium- • Keratitis
sensing receptor.(19) • Autoimmune hepatitis
• Primary ovarian failure
• Enamel hypoplasia
Table 1. Etiology of hypoparathyroidism • Enteropathy with chronic diarrhea or constipation
• Postsurgical • Periodic fever with rash
• Autoimmune • Pneumonitis
• Genetic variants • Nephritis
• Infiltrative (granulomatous) • Pancreatitis
• Mineral deposition (copper, iron) • Type 1 diabetes
• Metastatic • Functional asplenia
• Radiation • Celiac disease
• Functional (magnesium deficiency or excess) • Thyroiditis
• Transient (severe burns or acute illness) • Retinitis
• Maternal hyperparathyroidism • Pure red-cell aplasia
• Idiopathic • Polyarthritis
Reproduced with permission from Khan et al., EJE 2019.(14) Reproduced with Permission from Khan et al., EJE 2019(14).

Journal of Bone and Mineral Research HYPOPARATHYROIDISM SUMMARY STATEMENT AND GUIDELINES 5 n
HypoPT, and adrenal insufficiency. HypoPT is present in >80% of Renal complications reported in population studies
patients with APECED and may be the only endocrinopathy pre-
sent.(14) Patients may also have minor features of APS1 (Table 2). The prevalence of chronic kidney disease (CKD) in patients with
The diagnosis of APS1 is probable in the presence of at least one HypoPT ranges from 2.5% to 41%, depending on the definition
major feature and positive antibodies to type 1 interferon (pre- (eGFR < 60 mL/min/1.73 m2 International Classification of Dis-
sent in >95% of patients). The presence of auto-antibodies to eases (ICD) codes or self-report).(7,9,11,30-38) Data from a large US
21-hydroxylase correlate with adrenal insufficiency.(16) The pres- managed care claims database (8097 cases, 40,485 controls)
ence of antibodies to the antigen NALP5 correlate with develop- noted an increased risk of CKD (eGFR < 60) in HypoPT.(39)A pop-
ing hypoparathyroidism.(25) A molecular diagnosis can be ulation study from Denmark suggested that a longer disease
confirmed with DNA analysis of the AIRE gene if pathogenic var- duration,(36) higher median calcium-phosphate product
iants are present. (>2.80 mmol2/L2), and a higher frequency of episodes of hyper-
Activating antibodies to the calcium-sensing receptor inhibit- calcemia were associated with an increased risk of CKD.(36)
ing PTH secretion have also been reported in individuals with Patients with nonsurgical HypoPT had an increased risk of
autoimmune HypoPT.(26-28) These antibodies have been CKD stage 4 (eGFR = 15–29 mL/minute) and 5 (eGFR<15 mL/
reported in individuals with APS1 and may also occur in isolation minute) in comparison with matched controls.(38)
without APS1.
Recovery over time has been reported in some individuals as Skeletal complications
the antibody titers decrease. Unfortunately, no standardized HypoPT is associated with bone mineral density (BMD) values
diagnostic tests for the presence of antibodies to the CaSR are that are above average(40-43) in comparison to age, sex, and
currently available. body mass index matched controls. Skeletal microstructure
is abnormal with both cortical and cancellous compartments
affected.(43-46) Transiliac bone biopsies have demonstrated
Functional HypoPT
increased cortical thickness and cancellous bone volume.(47,48)
Both hypomagnesemia and hypermagnesemia can impair para- Bone remodeling is significantly reduced,(47-49) with each remo-
thyroid function, leading to functional HypoPT. Magnesium can deling cycle being associated with a positive bone balance.(13)
activate the calcium-sensing receptor and decrease PTH synthe- Trabecular bone score (TBS) is maintained as noted in a retro-
sis and secretion.(20) Hypomagnesemia also results in a resis- spective cohort study.(50)
tance to PTH because intracellular magnesium is a cofactor for The effects of these changes on bone strength are not
adenylate cyclase.(20) Abnormalities in serum magnesium fully understood at this time. Bone material strength index
require further evaluation to determine the cause, and correction (BMSi) utilizing microindentation was found to be lower in
is necessary in order to improve calcium homeostasis, especially comparison to controls and improved with recombinant
in patients on PTH therapy.(13) human PTH (rhPTH) (1–84) therapy.(51) The effects of HypoPT
on the risk of fracture has been evaluated; however, current data
are limited by small sample sizes and study design. An increase in
Complications the overall risk of fracture incidence has not been consistently
observed.(4,52)
What are the most common complications of HypoPT? There may also be differences in the response of the various
(systematic review) skeletal sites to the effects of HypoPT.(8,9,38,42,52,53) Large fracture
HypoPT is associated with symptoms and complications affect- studies in HypoPT patients compared to controls have not yet
ing multiple organ systems. The methods team conducted a sys- been completed. The effects of HypoPT on the risk of fracture
tematic review investigating the prevalence of symptoms and requires further study.
complications. Ninety-three studies enrolling a total of 18,973
patients proved eligible. The review team developed the follow- Cardiovascular complications
ing two criteria to determine whether the complications and HypoPT can affect the cardiovascular system. Hypocalcemia can
symptoms were caused by chronic HypoPT: (i) they were lead to electrocardiographic abnormalities, including prolonga-
reported by at least three studies and (ii) they had statistically tion of the corrected QT (QTc) interval. The rare occurrence of
significantly greater pooled nonadjusted and adjusted relative cardiomyopathy and congestive heart failure in the setting of
estimates in comparison with individuals with normal parathy- hypocalcemia has been described in case reports. Data from
roid function. We identified the following eight most common the large Danish national registry evaluating180 nonsurgical
complications that met these two criteria and identified their fre- HypoPT patients and 540 controls found an increased risk for car-
quency in the median of all studies in which they were diovascular disease; Hazard Ratio (HR) 1.91, 95% confidence
addressed.(29) interval (CI) 1.29–2.81, p = 0.01), ischemic heart disease (HR
2.01, 95% CI 1.31–3.09, p = 0.01), cardiac arrhythmias (HR 1.78,
95% CI 0.96–3.30, p = 0.03), and stroke (HR 1.84,95% CI 0.95–
Other symptoms and complications
3.54, p = 0.03). Mortality was not increased. These findings are
We identified 51 complications reported by one to two studies supported by a subgroup analysis(36) and by a population study
(see supplemental table), as predefined in the methods. Because from Korea.(8,36) Increased risk of cardiovascular disease in
only limited studies reported these complications and symp- chronic HypoPT was associated with lower time-weighted serum
toms, we are uncertain as to whether they are caused by chronic ionized calcium, increased number of hypercalcemic episodes,
HypoPT or are contributed to by comorbidities of other diseases. and longer duration of HypoPT.(36) Although hypocalcemia is
We therefore did not present these complications/symptoms in the presumed etiological factor in several of these
the main paper. complications,(54-56) it has also been hypothesized that the loss

n6 KHAN ET AL. Journal of Bone and Mineral Research

of PTH action on arterial vascular smooth muscle, endothelial Infections
cells, cardiomyocytes, and the cardiac conducting system may
be implicated.(13) Chronic HypoPT appears to be associated with an increased risk
of infections(81). A higher incidence of all types of infections was
noted in a Danish national cohort study in both nonsurgical and
Cataracts in HypoPT postsurgical patients with hypoparathyroidism.(52) Urinary tract
Cataracts are seen more frequently as a complication of chronic infections and respiratory tract infections were seen more com-
HypoPT(8,38,57) and appear to have a two- to fourfold higher risk monly in comparison to the general population.(52) Risk factors
in chronic HypoPT. Surgery may be required at an earlier mean appear to be increased disease duration, hyperphosphatemia,
age of 35 years.(38,57,58) and increased episodes of hypercalcemia.(36) Infections may be
The mechanisms leading to cataracts are not well established. more prevalent in nonsurgical than in postsurgical HypoPT
Altered electrolyte composition of the aqueous humor may lead (HR 1.87, 95% CI, 1.20–2.92).(4,6,9,36,52) The mechanisms involved
to a change in the solubility of the lens fibers.(59,60) Risk factors for are unclear. Since calcium signaling plays an important role in
the development of cataracts include the nonsurgical form of the production of cytokines by mast cells, T cells and natural
HypoPT as well as a longer duration of HypoPT.(61-63) killer cells, in target cell lysis by cytotoxic T cells, and lymphocyte
differentiation,(81) impaired immune function caused by abnor-
Basal ganglia calcifications mal serum calcium level may be involved. Impaired immune
function in patients with chronic postsurgical hypoparathyroid-
Basal ganglia calcification (BGC) has been noted to occur ism was noted by immune cell profiling,(81) A decrease in mono-
more frequently in HypoPT than in the general population, cytes as well as regulatory, naïve, and total CD4 + T lymphocytes
where the prevalence of BGC appears to be approximately was noted and correlated with total calcium, ionized calcium,
12%.(47,64-68) Studies completed to date have had limited sample and PTH levels in patients with HypoPT.(81)
size, and many have been retrospective. In a Canadian prospec-
tive observational study, BGCs were noted in 37% of nonsurgical
patients and 15% of postsurgical patients with HypoPT.(68) The Evaluation and Management of HYPOPT
median prevalence of BGC was 28% based on 20 studies in a sys-
tematic review of the complications of HypoPT.(29) HypoPT requires careful clinical assessment of the underlying eti-
BGC was, however, not identified as one of the most common ology and for the presence of complications.(82) Because of the
complications among the 14 cohort studies comparing individ- limited number of studies, a systematic review to determine
uals with HypoPT to euparathyroid individuals and is not the optimal monitoring strategy for the avoidance of complica-
included in the eight most common complications of HypoPT. tions from HypoPT was not feasible. Therefore, we conducted a
The consequences of these observed intracranial calcifications survey determining the practice pattern of the 97 experts serving
are unclear at this time. An association with Parkinson’s disease on the parathyroid consensus panel.(82-84) A practice recommen-
has been proposed; however, this requires further evaluation with dation was based on the practice pattern of 70% or more of the
higher-quality evidence in order to determine causality.(69) respondents if the pattern was adopted in at least 70% of their
patients.(85) These recommendations are summarized below
Neuropsychiatric complications and features (Table 3).

Data from national registries as well as population-based cohort

studies support an increased incidence of neuropsychiatric dis- What is the optimal monitoring strategy for chronic
ease.(8,9,38,52) An increased incidence of anxiety, depression, HypoPT? (systematic current practice survey)
and bipolar affective disorder has been observed in patients with
HypoPT.(4) Panel members complete a baseline laboratory profile, including
Neuromuscular manifestations of HypoPT include seizures, calcium adjusted for albumin or ionized calcium, serum magne-
tetany, and muscle stiffness, which are common presenting fea- sium, phosphorus, creatinine and 25(OH)D, as well as 24-hour
tures in 40%–60% of patients with HypoPT.(66) Seizures are com- urine for creatinine and calcium.(85) Stable patients are moni-
mon in young patients, particularly those with nonsurgical tored with repeat laboratory profile every 6–12 months. Unstable
disease.(70) The seizures may be generalized tonic–clonic (80%) patients are followed more closely to ensure that serum calcium
but may also be petit mal, partial, or atonic.(70) Hypocalcemia does not fluctuate widely and to avoid the symptoms and the
leads to a decreased threshold for membrane depolarization, long-term complications of HypoPT. Evaluation for the presence
resulting in increased neuronal excitability.(71) Numbness and
tingling in the face, hands, and feet are recognized as classical
Table 3. Most common complications of chronic hypoparathy-
symptoms of hypocalcemia.
roidism reported in the literature (GRADEd recommendations)
Complication Prevalence (median %)
Neuropsychiatric complications: quality of life
Cataract 17
Reductions in quality of life (QoL) with significant negative
Infection 11
impact on physical, mental, or emotional health have been docu-
Nephrocalcinosis/nephrolithiasis 15
mented in several studies utilizing standardized instruments
Renal insufficiency 12
validated for chronic diseases such as the SF36.(37,62,72-78) A
Seizures 11
disease-specific instrument, the Hypoparathyroid Patient Experi-
Depression 9
ence Scale-Symptom (HPES-Symptom), was developed and vali-
Ischemic heart disease 7
dated for HypoPT.(79,80) Poor health-related QoL has been noted
Arrhythmias 7
in both postsurgical and nonsurgical HypoPT patients.(36,37,62,75)

Journal of Bone and Mineral Research HYPOPARATHYROIDISM SUMMARY STATEMENT AND GUIDELINES 7 n
of nephrocalcinosis or nephrolithiasis can be performed by hypotension may limit its use, and thiazide diuretics are not
either an ultrasound or CT of the kidneys.(82,85) advised in the presence of adrenal insufficiency. Thiazide
Panel members refer patients for slit-lamp examination diuretics should also be used carefully in the presence of autoso-
searching for ocular complications in patients who are mal dominant hypocalcemia as the urinary magnesium losses
experiencing visual symptoms. are further enhanced with thiazide diuretics(14) (Table 4).
The panel proposes the following:

1. Evaluate and monitor the laboratory profile as described Emergency management of severe acute hypocalcemia
previously. Emergency management is advised in the presence of cardiac,
2. Monitor serum calcium (ionized or albumin-adjusted) within respiratory, or significant neurologic symptoms of hypocalcemia
several days of a significant change in medical treatment. or if the albumin-adjusted calcium <7.0 mg/dL (1.75 mmol/L).
3. Complete a baseline assessment for the presence of nephro- Intravenous (iv) calcium bolus administration is given as 90–
calcinosis or nephrolithiasis with renal imaging. 180 mg elemental calcium over 10–20 minutes and requires car-
diac monitoring. This is followed by an iv calcium infusion and
Management initiation of oral therapy with calcium and calcitriol.(14,25) Typi-
cally, the iv calcium bolus is followed by an iv calcium infusion.
Conventional therapy consists of oral calcium and active vitamin This may be prepared with 10 ampules (900 mg elemental cal-
D. In patients with low PTH levels following total thyroidectomy cium) in 1 L of 5% dextrose water or normal saline and initiate
(<10 pg/mL (1.05 pmol/L), medical therapy is advised with 2–3 g infusion at 50 mL/hour and titrate to serum calcium. The goal is
of elemental calcium daily and 0.5–1.5 μg calcitriol/day.(13,86-89) to elevate serum calcium to just below the normal reference
Approximately 70%–80% of individuals with postoperative range. An elemental calcium iv dose of 15 mg/kg over the course
parathyroid failure will recover within a month following of 4–6 hours is expected to elevate serum calcium by approxi-
thyroidectomy,(13,90) and medical therapy can be gradually with- mately 0.5–0.75 mmol/L.(25) Active vitamin D metabolites are
drawn with close monitoring(13) (Table 4). also initiated with calcitriol orally (0.25 μg twice/day to 0.5 μg
Cholecalciferol or ergocalciferol is also often required to main- twice/day) or alfacalcidol, which is less potent than calcitriol.(14)
tain the 25(OH)D level within the normal range. Recommenda-
tions for management are derived from case series, consensus
statements, guidelines, and standards of care.(14,25,91-93) PTH replacement
Thiazide diuretics can be utilized to lower urine calcium losses Clinical trials of human PTH (1–34) in HypoPT have demonstrated
as they enhance distal tubular renal calcium reabsorption when the beneficial effects of PTH replacement therapy. Synthetic PTH
paired with low salt intake.(14) Potential adverse effects include (1–34) was effective in increasing serum calcium, lowering urine
hypokalemia, hypomagnesemia, and hyponatremia. Treatment calcium excretion and increasing phosphate excretion.(94,95)
with thiazides requires monitoring of electrolytes. Postural Twice daily doses were of value because PTH (1–34) has a short
half-life of 1 hour and resulted in improved maintenance of
eucalcemia over 24 hours with a lower total daily dose require-
Table 4. Conventional therapy for hypoparathyroidism ment in comparison to once daily regimens.(96,97) Administration
Medication Dose Comments/half-life of PTH (1–34) by continuous subcutaneous (sc) infusion pump in
comparison to twice daily injections resulted in the normaliza-
Calcium Ranges from 500– Calcium citrate
tion of serum calcium with less fluctuation in serum calcium,
carbonate or 3000 mg three preferred in
phosphorus, and magnesium and reduced urine calcium. Daily
calcium citrate times daily presence of
PTH (1–34) requirements were also lower when administered
preferably with Proton Pump
by pump compared to twice daily sc PTH (1–34) injections.(98,99)
meals to enhance Inhibitor (PPI) use
The full-length molecule, rhPTH (1–84), has been evaluated.
phosphate
The half-life of sc rhPTH (1–84) is longer at 3 hours and can be
binding effects
administered as a once daily dose. rhPTH (1–84) is well tolerated,
Vitamin D3 1000 IU/day to 4–6 hours plasma
reduces the need for calcium and calcitriol, reduces serum phos-
(cholecalciferol) 100,000 IU/day half-life
phorus, and in long-term studies lowered urinary calcium excre-
based on 25-
tion. rhPTH (1–84) and PTH (1–34) have been associated with
hydroxy vitamin
marked initial rises in bone turnover markers (BTMs). After reach-
D level
ing a plateau, BTMs decline but are maintained at a new steady
Vitamin D2 50,000 IU weekly to 4–6 hours plasma
state, higher than pretreatment values and well within the nor-
(ergocalciferol) daily based on half-life
mal reference range.(98-100) BMD appears to be stable at the hip
25-
and spine with decreases observed at the radial site.(82)
hydroxyvitamin D
The REPLACE study was a blinded placebo-controlled Phase 3
levels
study conducted in 134 patients randomized to rhPTH (1–84) or
Calcitriol 0.25–3 μg /day total 5–8 hours plasma
placebo. In this study, 53% of patients receiving rhPTH (1–84)
dose half-life
met the primary endpoint (≥50% reduction in oral calcium and
administered in
calcitriol doses while maintaining normal serum calcium) in com-
divided doses
parison to placebo, in whom only 2% achieved this endpoint.(101)
Alfacalcidol 0.5–6 μg/day 3–6 hours plasma
Reductions in urine calcium were observed in both the rhPTH (1–
half-life
84) and placebo arms and the difference was not statistically sig-
Thiazide diuretics 25–100 mg/day 6–12 hours plasma
nificant. Reductions in the dose of calcium and active vitamin D
half-life
were also noted in other studies using rhPTH (1–84).(102,103)

n8 KHAN ET AL. Journal of Bone and Mineral Research

 In both short-term and long-term studies, renal function was number of patients. Statistically significant reductions in serum
stable with the use of rhPTH (1–84).(101-104) Renal calcifications phosphorus were observed with PTH therapy in comparison to
were not eliminated, and nephrolithiasis was still noted.(102,104) conventional therapy. Reductions in serum phosphorus may be
Hypercalcemia was observed in rhPTH (1–84) studies, with of value in lowering the incidence of ectopic calcification and
18% incidence reported in the REPLACE study.(101) In the Aarhus require further study in individuals with HypoPT. Small but statis-
study, rhPTH (1–84) was given at a fixed dose of 100 μg/day ini- tically significant improvements in physical health related QoL
tiated in addition to existing conventional therapy, and a higher were observed in the meta-analysis evaluating PTH therapy in
incidence of hypercalcemia was observed, as expected, at comparison to conventional therapy.(116) A significant reduction
34%.(103) In the Columbia University studies, hypercalcemia was in pill burden was also noted in this meta-analysis with PTH ther-
observed with rhPTH in 30% of the patients.(102,105) apy(116) PTH therapy may not result in important adverse effects,
Hypocalcemia in patients receiving rhPTH was also noted in but the quality of evidence is low(116) (Table 5).
the randomized control trials (RCTs).(82) TransCon PTH (TC PTH) In these randomized trials, PTH therapy was also associated
is a prodrug consisting of PTH (1–34) transiently conjugated to with increases in the episodes of hypercalcemia in comparison
polyethylene glycol carrier molecule providing stable PTH to conventional therapy. In one of the seven studies, PTH therapy
levels.(91,94,95) The carrier blocks the parent drug from binding was added onto active vitamin D and hypercalcemia was
to the PTH receptor and decreases renal clearance and enzy- expected. Gradual downward titration of the dose of the active
matic degradation.(106) Following sc injection with exposure to vitamin D with cessation of active vitamin D occurred, as
physiologic pH and temperature, the linker is cleaved, releasing planned.(74,103,114,115) PTH therapy was well tolerated with very
PTH (1–34) in a controlled manner.(106) In a Phase 1 study, the infrequent serious adverse effects. The quality of the evidence
effective half-life of TC PTH was approximately 60 hours.(107,108) was, however, low.
In a 4-week blinded Phase 2 trial, TC PTH was compared to con- PTH therapy can be considered in individuals who are inade-
ventional therapy in 59 adults with chronic hypoPT; this was fol- quately controlled with conventional therapy. Individuals with
lowed by a 26-week open-label extension period. TransCon PTH fluctuating serum calcium requiring hospitalization for hypocal-
enabled cessation of active vitamin D with reductions in calcium cemia or hypercalcemia, or those who have hyperphosphatemia,
supplements (≤500 mg/day) in 91% of subjects while achieving renal insufficiency, hypercalciuria, nephrocalcinosis, or nephro-
normal sCa, sP, uCa, and calcium phosphate product and dem- lithiasis may benefit from PTH therapy. Individuals with poor
onstrating improved health-related QoL. TC PTH was well toler- compliance, malabsorption, or gastrointestinal side effects from
ated with no adverse events of hypocalcemia or hypercalcemia large doses of calcium, making it difficult to adhere to large fre-
requiring a visit to hospital, ER or urgent care (96). quent doses of calcium and active vitamin D, may also benefit
A Phase 3 double-blind, placebo-controlled study with Trans- from PTH therapy.
Con PTH 18 μg daily versus placebo recently evaluated safety PTH therapy may also be appropriate in individuals with oste-
and efficacy in 84 patients with chronic HypoPT. At 26 weeks, oporosis who require pharmacological intervention because
cessation of active vitamin D was possible in 93% of participants antiresorptive therapy (i.e., denosumab) may result in significant
while maintaining normal serum calcium. Improvements in QoL hypocalcemia.
as evaluated by the HPES and the SF36 scale were observed. Sta- PTH therapy in the form of rhPTH (1–84) is initiated at 50 μg
tistically significant reductions in 24-hour urine calcium were daily, and the dose is adjusted by 25 μg every 4 weeks up to a
also observed in comparison to placebo. Adverse events were maximum dose of 100 μg daily. PTH (1–34) has not yet been
mild or moderate, and no study drug-related withdrawals approved for use in HypoPT.
occurred. TransCon PTH was safe and effective and well tolerated
over 26 weeks.(109) These results support TransCon PTH as a How are patients with HypoPT managed? (GRADEd
potential hormone-replacement therapy for adults with recommendations)
HypoPT.(106) Open-label trials have reported improvements in
QoL with both rhPTH (1–84)(72,73,110) and PTH (1–34).(111,112) In patients with chronic HypoPT, the panel suggests conven-
PTH (1–84) replacement therapy was approved by the US Food tional therapy as first-line therapy rather than administration of
and Drug Administration (FDA) in 2015 and the European Medi- parathyroid hormone. (weak recommendation, low-quality
cines Agency (EMA) for the management of HypoPT. evidence).
In 2019, the FDA recalled rhPTH (1–84) due to the possibility of Comment: When conventional therapy is deemed unsatisfac-
the presence of rubber particles originating from the cartridge tory, the panel considers the use of parathyroid hormone.
septum. A similar recall has not taken place in Europe.
Pregnancy and Lactation
PTH therapy in comparison to conventional therapy for
Pregnancy is associated with changes in calcium-regulating hor-
managing chronic HypoPT (systematic review)
mones and in calcium homeostasis. These changes may result in
A systematic review and meta-analysis of randomized trials from altered requirements for calcium and active vitamin D during
inception to May 2022 evaluated the benefits and harms of PTH pregnancy.(119) Reductions in the serum albumin in association
therapy in comparison to conventional therapy in managing with volume expansion result in reductions in measured total
patients with chronic HypoPT.(116) Seven studies met the eligibil- calcium and necessitate measurement of calcium adjusted for
ity criteria.(74,94,101,103,106,113-115,117,118) These studies were rela- albumin or ionized calcium.(120-122) Phosphorus and 25(OH)D
tively small and of short duration and did not consistently remain unchanged during pregnancy. Levels of endogenous
report on the eight most common complications of HypoPT 1,25(OH)2D increase by two- to threefold as early as the first tri-
identified earlier in the systematic review.(82) These studies con- mester, resulting in enhanced absorption of calcium from the
firmed that PTH therapy permitted reductions in the dose of cal- bowel and increasing renal filtered calcium load, and urine cal-
cium and active vitamin D metabolites by 50% or more in a large cium (Fig. 1).

Journal of Bone and Mineral Research HYPOPARATHYROIDISM SUMMARY STATEMENT AND GUIDELINES 9 n
n 10KHAN ET AL.
Table 5. Trials included in systematic review of PTH therapy in chronic hypoparathyroidism
Study
Reference study Treatment Control duration Conclusion
(101,113,117)
REPLACE 50–100 μg/day rhPTH (1–84); active vitamin D; Placebo; active vitamin D; calcium 7 months Eucalcemia maintained Calcium-phosphate
calcium product and Serum phosphorus declined with
PTH therapy
Urine calcium declined in both PTH and control
groups
Sikjaer, Recombinant human PTH (1–84) 100 μg/day; Placebo; calcium and alfacalcidol/ 6 months Eucalcemia maintained, Phosphorus declined
2011–2014(74,103,114,115) calcium, alfacalcidol/calcitriol/ergocalciferol calcitriol/ergocalciferol with PTH therapy, no change in calcium
phosphate product, and no change in urine
calcium with PTH therapy
Winer, 2003(94) PTH (1–34) 0.5 μg/kg/dose twice daily; elemental Calcitriol and calcium (0.91  0.2 μg); 36 months Eucalcemia maintained, urine calcium declined
calcium 1000 mg/day calcium (1000 mg/day) with PTH therapy
Winer, 1996(95) PTH (1–34) 0.5–3 μg/kg per day once daily; Calcitriol 0.5–6 μg/day; dietary 2.5 months Eucalcemia maintained, Urine calcium declined
dietary elemental calcium 1–2 g/day elemental calcium 1–2 g/day; with PTH therapy
1000 mg/day of calcium carbonate
Winer, 2010(118) PTH (1–34) 0.4 μg/kg/dose twice daily; dietary Twice-daily calcitriol (initially 0.25 μg/ 36 months Eucalcemia maintained, no change in urine
elemental calcium 1–2 g/day; magnesium dose); calcium (1200 mg/day) and calcium noted with PTH therapy
supplement cholecalciferol (800 IU/d);
magnesium supplement
Khan, 2021(106) TransCon PTH 15–21 μg per day; oral elemental Placebo; oral elemental calcium 1 month Eucalcemia maintained, Fractional excretion of
calcium 1550 mg/day; active vitamin D 1200 mg/day; active vitamin D calcium declined with PTH therapy
Khan, 2022(109) TransCon PTH 18ug daily; calcium and active Placebo; oral calcium; active vitamin D 6.5 months Eucalcemia maintained, 24 hr urine calcium
vitamin D declined, QoL improved, pill burden declined

Journal of Bone and Mineral Research

 evaluated and closely followed to ensure that serum calcium is
normal.
Following delivery, 1,25(OH)2D levels normalize postpartum,
and serum calcium adjusted for albumin should be monitored
closely.
The lactating breast produces PTHrP, and during lactation
PTHrP levels rise and increase maternal bone resorption and
enhance maternal renal calcium reabsorption.(131,132) The eleva-
tions in PTHrP seen during lactation may result in lower require-
ments for calcium and active vitamin D during lactation. If
lactation is stopped, the requirements for calcium and active
vitamin D may rise as PTHrP levels decline, and close follow-up,
particularly during the weaning period, is required to ensure that
hypocalcemia does not develop in the mother.
Calcium, vitamin D, and active vitamin D analogues can be
safely administered during pregnancy.(82) Thiazide diuretics
and PTH therapy are not recommended for use during preg-
nancy due to lack of safety data and are considered FDA preg-
nancy risk category B and C respectively.(133)
During pregnancy and lactation, it is advised to maintain
serum calcium adjusted for albumin in the low to midnormal ref-
erence range. Close monitoring with lab tests every 3–4 weeks is
advised to ensure that hypocalcemia and hypercalcemia are
Fig. 1. Role of PTH-related peptide during pregnancy (reproduced with avoided in the mother to optimize maternal and fetal outcomes.
permission from Khan et al. EJE 2019).(119) Changes in the dose of the calcitriol should be followed by a
repeat serum calcium within 2–3 days.(119) A coordinated
approach to care is advised, with close communication among
the treating endocrinologist, obstetrician, and pediatrician.
PTH-related peptide (PTHrP) is produced by the placenta
and breast tissue and begins to rise from the third to the thir- What are additional recommendations for patients with
teenth week of gestation and increases threefold by term(119) HypoPT during pregnancy and lactation? (un-GRADEd
(Fig. 1). The significant rise in PTHrP may upregulate calci-
recommendation)
triol.(123) Estradiol levels also rise by 100-fold during preg-
nancy and stimulate Cyp27b1, further enhancing the Closely monitor serum calcium (albumin-adjusted or ionized)
formation of 1,25(OH)2D.(119) In women with residual parathy- every 3–4 weeks during pregnancy and lactation, with increased
roid function, PTH is suppressed during pregnancy and subse- frequency in the months preceding and following parturition as
quently rises into the midnormal reference range by the third well as in the presence of symptoms of hypercalcemia or
trimester.(120-122) hypocalcemia.
Due to increased endogenous production of 1,25(OH)2D and Comment: The use of albumin-adjusted or ionized calcium is
PTHrP during pregnancy, the requirements for calcium and essential during pregnancy as total calcium can be misleading.
active vitamin D analogues may decline. However, this may be Close coordination between the obstetrician and pediatrician is
offset by the increased requirements for calcium by the develop- advised in order to optimize pregnancy outcomes. Avoid using
ing fetal skeleton as well as the increased maternal urinary cal- thiazide diuretics and PTH or analogues during pregnancy.
cium losses. In the presence of inadequate dietary calcium
intake, active vitamin D requirements may increase during preg-
Approach to the Pediatric Patient with HypoPT
nancy. Thus, it is necessary to closely monitor serum calcium
adjusted for albumin during pregnancy as the requirements for
Children with HypoPT require careful evaluation to determine its
calcium and active vitamin D may increase, remain stable, or
underlying cause. A high prevalence of renal and basal ganglia
decline.(82) In a recent case series, the dose of the calcium and
calcification has been observed with conventional ther-
active vitamin D required adjustments by more than 20% in
apy.(82,134,135) Treatment with calcium and active vitamin D sup-
more than 50% of patients during pregnancy in order to main-
plements are recommended as first-line therapy. If these options
tain eucalcemia.(124)
are not effective or practical, then PTH therapy can be consid-
Hypocalcemia during pregnancy is associated with uterine
ered.(82) PTH (1–34) has been associated with improved meta-
contractions and an increased risk of preterm labor or
bolic control, and lower doses are required if administered as a
miscarriage.(125) Maternal hypocalcemia is also associ-
continuous sc infusion.(100,136-138) Clinical trials examining rhPTH
ated with stimulation of the fetal parathyroid glands and
(1–84) excluded children.
the development of secondary hyperparathyroidism in the
fetus.(126-129) Fetal secondary hyperparathyroidism can be
associated with demineralization of the fetal skeleton and Emerging Therapies
fractures in utero.(119)
Maternal hypercalcemia can suppress the development of the New therapies are being developed targeting the PTH receptor
fetal parathyroid glands and result in transient hypocalcemia in (PTH1R) as well as the calcium sensing receptor, as summarized
the neonate.(130) Following birth, the neonate should be below.

Journal of Bone and Mineral Research HYPOPARATHYROIDISM SUMMARY STATEMENT AND GUIDELINES 11 n
 1. Transcon PTH (1–34), discussed earlier, is in Phase 3 long- • Prospective controlled studies on the determinants of nephro-
term extension clinical trials at this time. calcinosis and renal insufficiency in HypoPT are needed.
2. Long-acting PTH analogue (LA-PTH) is a hybrid molecule • A controlled study should be conducted on phosphate restric-
with both PTH and PTHrP homology and has been effective in tion in children with severe hyperphosphatemia: Does dietary
increasing serum calcium and reducing serum phosphorus in phosphate restriction do more harm than good?
animal studies.(139,140) Preliminary results from a Phase 1 trial • Prospective long-term large trials are needed to evaluate the
with this drug (AZP-3601) showed dose-dependent increases in risks and long-term complications of chronic HypoPT and
albumin-adjusted serum calcium.(141) impact on QoL.
3. PTHR1 agonist, an orally available agonist of PTHR1
(PCO371), was being evaluated in HypoPT patients in a Phase
1 study. The study was terminated due to increases in liver Summary
enzymes (AAK, personal communication with Chugai).
4. Oral PTH molecule with hPTH (1–34) complexed with excip- HypoPT is a rare disease associated with significant morbidity,
ients to facilitate small bowel absorption was evaluated in a poor QoL, and increased healthcare utilization. We have pro-
16-week open-label pilot study.(142) Early data indicate that it vided updated recommendations regarding the diagnosis
can maintain serum calcium and phosphorus in the target range. and management of HypoPT. Careful evaluation to determine
5. Calcilytics are antagonists of the calcium-sensing receptor the underlying etiology is essential for optimal management.
and appear to be an attractive treatment option for individuals Early identification of HypoPT with initiation of effective con-
with autosomal dominant hypocalcemia type 1 (ADH1) due to ventional therapy with calcium and active vitamin D metabo-
gain-of-function mutations in the calcium-sensing receptor lites is helpful in improving symptoms. However, QoL
gene. The calcilytic NPSP795 was shown to result in a dose- remains poor in individuals receiving conventional therapy
dependent increase in PTH in patients with ADH1.(143) The cal- with significant complications. Unfortunately, conventional
cilytic encaleret was recently shown to normalize serum cal- therapy is also associated with wide fluctuations in serum cal-
cium, phosphorus, and magnesium as well as urine calcium in cium. In these individuals, management may improve with
an early Phase 2 study.(144) PTH therapy. Pregnant and lactating women require close
follow-up because their requirements for calcium and active
vitamin D may change due to changes in calcium homeostasis
Knowledge Gaps and Future Research Directions during pregnancy and lactation. To achieve optimal maternal
and fetal outcomes, it is important to monitor patients closely
• Studies of the epidemiology of HypoPT published to date and work effectively in a multidisciplinary team with an obste-
show that patients with nonsurgical HypoPT appear to have trician and pediatrician. Emerging therapies show great prom-
higher risks of complications than patients with postsurgical ise in terms of refining and further improving the management
HypoPT. Future studies should address whether the differ- of HypoPT in the near future.
ences seen are due to the longer duration of disease in those
with nonsurgical disease or other factors that differ between
these types of patients. Disclosures
• Future studies on the complications of HypoPT, including car-
diovascular disease, cataracts, BGCs, infections, malignancy, AAK: Grants and/or Speaker for Alexion, Amgen, Amolyt, Ascen-
and neuropsychiatric disorders, are needed. dis, Chugai, Radius, Takeda, and Ultragenyx; consultant for Alex-
• Large multicenter prospective studies in pregnant patients ion, Amgen, Amolyt, Ascendis Takeda, and Ultragenyx
with HypoPT are needed to better understand the impact of JPB: Consultant for Amgen, Radius, Ascendis, Calcilytix,
pregnancy on calcium homeostasis in HypoPT as well as Takeda, Amolyt, Rani Therapeutics, MBX, Novo-Nordisk, and
requirements of conventional therapy and maternal and fetal Ipsen
outcomes. MLB has received honoraria from Amgen, Bruno Farmaceutici,
• Further studies are needed to establish the financial burden of Calcilytix, Kyowa Kirin, and UCB; grants or speaker: Abiogen,
HypoPT, given that healthcare resource utilization appears to Alexion, Amgen, Bruno Farmaceutici, Echolight, Eli Lilly, Kyowa
be increased in these patients. Kirin, SPA, Theramex, and UCB; consultant: Alexion, Amolyt,
• The effects of HypoPT on skeletal health and bone strength Bruno Farmaceutici, Calcilytix, Kyowa Kirin, and UCB.
need to be evaluated. BLC: Consultant for Takeda/Shire, Amolyt Pharma, and
• Validated assays are needed to diagnose non-APECED-related Calcilytix; grants from Takeda/Shire and Ascendis.
autoimmune HypoPT, including the detection of antibodies LR: Speaker for Amgen, Lilly, Takeda, Alexion, Kyowa Kirin,
against CaSR. Amolyt, Ascendis, and Ultragenyx; consultant for Amgen, Lilly,
• The impact of genetic testing on management/outcomes Takeda, Alexion, Kyowa Kirin, Amolyt, Ascendis, and Ultragenyx;
needs to be evaluated. grants from Takeda and Kyowa Kirin.
• The best genetic testing modality needs to be determined. JTP: Consultant for Radius Pharma.
• Postsurgical diagnosis requires RCTs to test the utility of early MM: Consultant for Takeda, Amolyt, and Chugai; grants from
predictors of permanent HypoPT. Takeda and Chugai.
• Future trials should include patients with genetic disorders to We acknowledge unrestricted financial support from Amo-
clarify best management. lyt, Ascendis, Calcilytix, and Takeda. They had no input into
• Prospective studies are needed in HypoPT in pregnancy to the planning or design of the project, the conduct of the
evaluate optimal management strategies. reviews, evaluation of the data, or the writing or review of
• Prospective controlled studies are needed to evaluate PTH ver- the manuscript, its contents, conclusions, or recommendations
sus conventional therapy on patient-important outcomes. contained herein.

n 12 KHAN ET AL. Journal of Bone and Mineral Research

Acknowledgments Peer Review

Author Roles: The peer review history for this article is available at https://
Conceptualization, visualization: AAK, JPB, MLB, BLC, NJG, JLP, [Link]/publon/10.1002/jbmr.4691.
LR, DMS, JTP, GHG, MM. Data curation, formal analysis, investiga-
tion, methodology, validation, software: AAK, JPB, MLB, BLC, NJG,
JLP, LR, DMS, JTP, GHG, MM. Project administration, funding acqui- Data Availability Statement
sition, resources: AAK, JPB, MLB, BLC, JTP, MM. Supervision: AAK,
JPB, MM. Writing—original draft: AAK. Writing—review and edit- The data that support the findings in this study are openly
ing: AAK, JPB, MLB, BLC, NJG, JLP, LR, DMS, JTP, GHG, MM available in PubMed, MEDLINE, EMBASE, and the Cochrane
In addition to the coauthors, the International Workshop on databases.
HypoPT was composed of the following individuals, whose
major contributions are most appreciated and gratefully
acknowledged: Dalal S. Ali, S Bjornsdottir, Luisella Cianferotti, References
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Journal of Bone and Mineral Research HYPOPARATHYROIDISM SUMMARY STATEMENT AND GUIDELINES 17 n
 Hellenic Society of Endocrine Surgeons Lebanese Society of Endocrinology Diabetes and Lipids
Hong Kong Society of Endocrinology, Metabolism and Parathyroid UK
Reproduction Peruvian Diabetes Association
Hungarian Society for Endocrinology and Metabolism Peruvian Society of Endocrinology
HypoPara Support & Advocacy Philippine Society of Endocrinology Diabetes and Metabolism
HypoPARAthyroidism Association, Inc. Qatar Osteoporosis Association
International Association of Endocrine Surgeons Romanian Society of Endocrinology
Indonesian Society of Endocrinology Russian Association of Endocrine Surgeons
International Society of Endocrinology Russian Association of Endocrinologists
Israel Endocrine Society Russian Association on Osteoporosis
Italian Society for Osteoporosis, Mineral Metabolism and Bone Sociedad Argentina de Endocrinología
Diseases South Asian Federation of Endocrine Society
Italian Society of Endocrinology Sociedad Argentina de Osteoporosis
Italian Society of Orthopedics, Medicine and Rare Skeleton Saudi Osteoporosis Society
Diseases Sociedad Chilena de Osteología y Metabolismo
Japan Association of Endocrine Surgery Mineral
Japan Endocrine Society Sociedad Mexicana de Endocrinología Pediatrica
Japanese Society for Bone and Mineral Research Sociedad Mexicana de Nutricio n y Endocrinología
Japanese Society for Pediatric Endocrinology Society for Endocrinology
Jordanian Osteoporosis Society Society for Endocrinology and Metabolism of Turkey
Korean Endocrine Society WORLDMEN Int’l Conf Committee
Kuwait Osteoporosis Society

n 18 KHAN ET AL. Journal of Bone and Mineral Research