NRDP 201755

PRIMER
Hypoparathyroidism
Michael Mannstadt1, John P. Bilezikian2, Rajesh V. Thakker3, Fadil M. Hannan3,4,
Bart L. Clarke5, Lars Rejnmark6, Deborah M. Mitchell1, Tamara J. Vokes7,
Karen K. Winer8 and Dolores M. Shoback9
Abstract | Hypoparathyroidism is a disease characterized by inadequately low circulating
concentrations of parathyroid hormone (PTH) resulting in low calcium levels and increased phosphate
levels in the blood. Symptoms of the disease result from increased neuromuscular irritability caused
by hypocalcaemia and include tingling, muscle cramps and seizures. The most common cause of the
disease is inadvertent removal of, or injury to, the parathyroid glands during neck surgery, followed
by genetic, idiopathic and autoimmune aetiologies. Conventional treatment includes activated
vitamin D and/or calcium supplements, but this treatment does not fully replace the functions of PTH
and can lead to short-term problems (such as hypocalcaemia, hypercalcaemia and increased urinary
calcium excretion) and long-term complications (which include nephrocalcinosis, kidney stones and
brain calcifications). PTH replacement has emerged as a new treatment option. Clinical trials using
human PTH(1–34) and PTH(1–84) showed that this treatment was safe and effective in studies lasting
up to 6 years. Recombinant human PTH(1–84) has been approved in the United States and Europe for
the management of hypoparathyroidism; however, its effect on long-term complications is still being
evaluated. Clinical practice guidelines, which describe the consensus of experts in the field, have
been published and recognize the need for more research to optimize care. In this Primer,
we summarize current knowledge of the prevalence, pathophysiology, clinical presentation
and management of hypoparathyroidism.
Hypoparathyroidism is a disease characterized by conventional treatment with activated vitamin D and

absence or inappropriately low concentrations of cir oral calcium is currently the standard of care, it does not
culating parathyroid hormone (PTH), leading to hypo fully replace the functions of PTH and is associated with
calcaemia, hyperphosphataemia and elevated fractional long-term complications, such as extraskeletal calcifi
excretion of calcium in the urine1,2. The most common cations. Of particular concern are the calcium losses
aetiology of the disorder is the removal of, or injury to, in the urine in the absence of PTH, which are associ
the parathyroid glands during neck surgery, for exam ated with nephrocalcinosis (renal parenchymal calcifi
ple, total thyroidectomy or radical neck dissection for cation) and impaired renal function in the long term.
head and neck malignancies; other aetiologies include Several clinical studies have also reported reductions
autoimmune, genetic and, very rarely, infiltrative dis in the quality of life (QOL) of patients with hypopara
orders (such as haemochromatosis, Wilson disease and thyroidism. Novel treatments are therefore needed and,
metastasis)3,4. The discovery of numerous genetic defects until recently, hypoparathyroidism was one of the few
responsible for hypoparathyroidism has enhanced our classic endocrine deficiency states not treated by replace
Correspondence to M.M. understanding of parathyroid gland physiology. These ment of the missing hormone. However, clinical trials
Endocrine Unit,
Massachusetts General
defects include gain‑of‑function mutations affect demonstrating the efficacy of PTH for the treatment
Hospital and Harvard Medical ing extracellular calcium-sensing receptor (CaSR) of hypoparathyroidism have led to the approval of full-
School, 50 Blossom St., or guanine-nucleotide-binding protein 11α (G 11α) length recombinant human PTH (rhPTH(1–84)) for the
Boston, and loss‑of‑function mutations affecting essential treatment of hypoparathyroidism in the United States
Massachusetts 02114, USA.
transcription factors or PTH itself 2. and the European Union, and stimulated research into
[email protected]
The clinical presentation varies from mild disease new treatment modalities and novel PTH analogues5,6.
Article number: 17055 with paraesthesia (burning or tingling sensation) and As new therapies become more widely used, evaluation
doi:10.1038/nrdp.2017.55
Published online 31 Aug 2017; muscle cramps to severe symptoms such as laryngo of their effectiveness on disease control, long-term
corrected online 5 Oct 2017 spasm (spasm of the voice box) and seizures2. Although complications and QOL will be critically important.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17055 | 1

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PRIMER
Author addresses with hypoparathyroidism of any cause since 1945.

54 cases of hypoparathyroidism were found, which led
1
Endocrine Unit, Massachusetts General Hospital to a calculated prevalence of 37 per 100,000 residents.
and Harvard Medical School, 50 Blossom St., Boston, This prevalence projected to an estimated 115,000
Massachusetts 02114, USA. individuals with hypoparathyroidism from any cause in
2
Division of Endocrinology, College of Physicians and
the United States. In this database, hypoparathyroidism
Surgeons, Columbia University Medical Center, New York,
New York, USA. resulted from neck surgery in 78% of cases, other
3
Academic Endocrine Unit, Radcliffe Department secondary causes in 9%, familial disorders in 7%, and
of Medicine, University of Oxford, Oxford, UK. was idiopathic in 6%.
4
Department of Musculoskeletal Biology, Institute of
Ageing and Chronic Disease, Faculty of Health & Life Europe
Sciences, University of Liverpool, Liverpool, UK. The prevalence of hypoparathyroidism in Denmark
5
Division of Endocrinology, Diabetes, Metabolism, and was estimated using the Danish National Patient
Nutrition, Mayo Clinic, Rochester, Minnesota, USA. Registry 8,9,13. These studies also assessed mortality and
6
Department of Endocrinology and Internal Medicine, comorbidities by comparing patients with hypopara
Aarhus University Hospital, Aarhus, Denmark.
thyr oidism with age-matched and sex-matched
7
Section of Endocrinology, University of Chicago Medicine,
Chicago, Illinois, USA. population-based controls. A total of 1,849 individuals
8
Pediatric Growth and Nutrition Branch, The Eunice with post-surgical hypoparathyroidism and 180 individ
Kennedy Shriver National Institute of Child Health and uals with non-s urgical hypoparathyroidism were
Human Development, Bethesda, Maryland, USA. identified. The estimated prevalence of post-surgical
9
Endocrine Research Unit, San Francisco Department of hypoparathyroidism was 22 per 100,000 individuals
Veterans Affairs Medical Center, University of California, and non-surgical hypoparathyroidism was 2.3 per
San Francisco, California, USA. 100,000 individuals. The incidence of post-surgical
hypoparathyroidism was estimated to be 0.8 per 100,000
person-years13. Of the post-surgical cases, indications
Epidemiology for surgery included malignancy (primarily thyroid
The available estimates of the prevalence of hypopara cancer) in 30%, non-toxic goitre (normally active,
thyroidism in the United States, Denmark and Italy non-cancerous thyroid hypertrophy) in 37%, toxic
are relatively close, in the range of 23–37 per 100,000 goitre (overactive thyroid hypertrophy) in 25% and pri
individuals3, but the prevalence in some other countries mary hyperparathyroidism in 8%13. The prevalence of
is reported to be lower 7. The variation between hypoparathyroidism in Norway is about half that of the
countries might be explained by differences in surgical estimates for Denmark, at 10.2 per 100,000 individuals5.
outcomes, as the majority of cases are the consequence of The mean hospitalization rate for hypoparathyroidism
surgery. Further research is needed to define the preva in Italy was 5.9 per 100,000 person per year 14.
lence and incidence of hypoparathyroidism outside the
United States and Europe, as no such studies have been Mechanisms/pathophysiology
reported from South America, Asia, Africa or Australia. Hypoparathyroidism is characterized by absence or
Although the prevalence of inherited causes of hypopara inappropriately low levels of circulating PTH, a key
thyroidism is similar between men and women8, post- hormone involved in mineral homeostasis. The most
surgical hypoparathyroidism is more common in women common cause is surgical destruction or injury to the
than in men9 because women are more likely to have parathyroid glands; other causes are autoimmune dis
thyroid disease and hence undergo thyroidectomy 10. eases or genetic disorders affecting parathyroid gland
development or the biosynthesis or release of PTH.
North America
The best estimate of the prevalence of hypopara PTH and mineral homeostasis
thyroidism in North America is based on analysis of a The parathyroid glands control extracellular calcium
large US health plan claims database over a 12‑month homeostasis by secreting PTH (FIG. 1). In the para
period from 2007 to 2008 (REF. 11). Population prevalence thyroid cell, PTH is synthesized as a 115‑amino-acid
of hypoparathyroidism is estimated at 59,000 adults precursor peptide (pre-proPTH(1–115)), which later
with health insurance and 77,000 adults in total in the matures into full-length PTH containing 84 amino
United States. An alternative approach based on the inci acids (PTH(1–84)). PTH is stored in secretory granules
dence of neck surgeries and the incidence of chronic and released by the parathyroid glands when circulat
hypoparathyroidism as a surgical complication using ing ionized calcium concentrations are reduced. These
the same database led to similar estimates11. Another changes in serum calcium levels are detected by CaSR,
estimate of the prevalence of hypoparathyroidism was a G protein‑coupled receptor that is highly expressed
presented as an abstract 12 and is based on the longitudi on the surface of parathyroid cells15. A decrease in the
nal population-based Rochester Epidemiology Project, levels of extracellular calcium reduces CaSR signalling
in which medical records linkage resources were used via G11α and Gqα, which induces a marked increase
to identify all individuals residing in Olmsted County, in PTH release from the parathyroid glands. The
Minnesota, USA, in 2009 (mean age and standard devi secreted PTH circulates in the bloodstream and acts
ation = 58 ± 20 years; 71% women) who were diagnosed on the G protein-coupled PTH1 receptor (PTH1R)16
2 | ARTICLE NUMBER 17055 | VOLUME 3 www.nature.com/nrdp

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PRIMER
in bone and the kidneys to increase serum calcium PTH is also involved in magnesium homeostasis.
levels, which leads to feedback inhibition of PTH PTH increases magnesium reabsorption in the kidney 21,
secretion from the p arathyroid glands15. whereas severe and prolonged hypomagnesaemia results
PTH also regulates circulating phosphate levels. in hypocalcaemia through inhibition of PTH secretion
Indeed, a rise in circulating phosphate levels stimu and PTH end-organ resistance22,23. Hypermagnesaemia
lates the secretion of PTH, which in turn acts on the may also inhibit PTH release through activation of
kidneys to inhibit tubular phosphate reabsorption17. CaSR, thus promoting hypocalcaemia24,25.
Phosphate homeostasis is further regulated by fibro
blast growth factor 23 (FGF23), an osteocyte-derived Post-surgical hypoparathyroidism
hormone that inhibits renal tubular phosphate reabsorp Neck surgery is the most common cause of acquired
tion and the renal synthesis of calcitriol (also known as hypoparathyroidism and accounts for ~75% of all cases
1,25‑dihydroxyvitamin D (1,25(OH)2D))18. of hypoparathyroidism3. Surgeries associated with the
In the setting of hypoparathyroidism, absence or development of hypoparathyroidism are total thyroid
low circulating levels of PTH lead to hypocalcaemia ectomy or radical neck dissection for head and neck
by impairing osteoclast activity, which diminishes the malignancies; the causes of hypoparathyroidism are
efflux of calcium from bone, by enhancing urinary inadvertent gland removal, intraoperative trauma to
calcium excretion and by inhibiting the renal synthe the parathyroid glands or gland devascularization.
sis of calcitriol, which impairs the intestinal absorption Parathyroidectomy aimed at removing, for exam
of dietary calcium19. Deficiency of PTH also causes ple, one or more parathyroid tumours, can also lead
hyperphosphataemia, owing to an increase in the to hypoparathyroidism1,3,26.
renal tubular reabsorption of phosphate, and chronic Transient post-surgical hypoparathyroidism, which
hyperphosphataemia has been shown to be associ is defined as absence of PTH or low PTH levels last
ated with increases in serum FGF23 levels in patients ing <6 months, affects up to 25–30% of patients
with hypoparathyroidism20. following total thyroidectomy, whereas permanent
post-surgical hypoparathyroidism (hypoparathyroidism
for >6 months) affects only up to 3% of patients27. Low
↓Ca2+ preoperative levels of serum calcium and 25-hydroxy
vitamin D (25(OH)D), low intraoperative PTH con
CaSR centrations, autotransplantation (parathyroid gland
reimplantation in the neck or forearm following neck
Parathyroid surgery) of one or more parathyroid glands and longer
gland
duration of surgery have been identified as indepen
dent predictors of transient hypoparathyroidism
post-thyroidectomy 28. Risk factors for permanent
PTH
hypoparathyroidism following thyroid surgery include
Phosphate
extent of the surgery; a preoperative diagnosis of Graves
PTH1R PTH1R excretion disease (an autoimmune disease causing thyroid over
Intestine
activity); failure to identify ≥2 parathyroid glands dur
Osteoblast Osteoclast 25(OH)D ing surgery; serum calcium levels of ≤1.88 mmol per l
Kidney
(7.5 mg per dl (normal range: 2.12–2.62 mmol per l or
CYP27B1 8.5–10.5 mg per dl) at 24 hours post-surgery; and reoper
Bone VDR
ation for bleeding 28. Rarely, post-surgical hypopara
Bone resorption Ca2+ reabsorption Calcitriol Ca2+ absorption thyroidism can present years after neck surgery 29. The
mechanism underlying this delayed presentation is
unclear, but may be caused by the effects of age-related
↑Ca2+ changes to the vasculature of the marginally functional,
Figure 1 | Regulation of extracellular calcium homeostasis. residual parathyroid tissue present post-surgery 1.
Nature Reduced
Reviews |activation of
Disease Primers
the extracellular calcium-sensing receptor (CaSR) owing to a reduction in extracellular
calcium levels results in a rapid increase in parathyroid hormone (PTH) secretion. Genetic causes of hypoparathyroidism
PTH acts on the PTH1 receptor (PTH1R) in the kidneys and bone. In bone, PTH1R Hypoparathyroidism has a genetic aetiology in <10%
activation in osteoblasts (bone-forming cells) and osteocytes (differentiated osteoblasts of cases3. However, chromosomal microdeletions and
that have become embedded in the bone matrix and are involved in the regulation of monogenic abnormalities represent the major cause
osteoblast and osteoclast (bone-resorbing cell) activity and phosphate homeostasis) of hypoparathyroidism in children30. Genetic forms of
results in the release of cytokines that stimulate osteoclast activity, thereby enhancing hypoparathyroidism occur as a component of syndromic
bone resorption and the release of calcium from the skeleton16. In the kidney, PTH disorders, as a solitary endocrinopathy, which is referred
increases tubular calcium reabsorption, phosphate excretion and stimulates the
to as isolated hypoparathyroidism, or as autos omal
25‑hydroxyvitamin D 1‑α‑hydroxylase (CYP27B1) enzyme, which promotes the
conversion to active 1,25‑dihydroxyvitamin D (also known as calcitriol) metabolite from dominant hypocalcaemia, which can be considered a
its precursor (25(OH)D). Calcitriol acts on the intestine to increase the absorption of distinct type of hypoparathyroidism (TABLE 1). Genetic
dietary calcium via the vitamin D receptor (VDR)19. The increase in calcium and calcitriol forms of PTH resistance (BOX 1) — a distinct set of dis
levels mediated by PTH act on the parathyroid glands to induce feedback inhibition of eases that are referred to as pseudohypoparathyroidism
further PTH secretion (indicated by the dashed arrow)15. — are not covered in detail in this Primer.

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PRIMER
Table 1 | Inherited types of hypoparathyroidism

Disorder Inheritance Chromosomal Gene
location
Syndromic hypoparathyroidism
DiGeorge syndrome type 1 (also known as 22q11.2 deletion AD 22q11.2 TBX1
syndrome)
DiGeorge syndrome type 2 AD 10p13–14 NEBL
CHARGE syndrome AD 8q12.2 CHD7
Autoimmune polyendocrine syndrome type 1 AR 21q22.3 AIRE
Hypoparathyroidism, sensorineural deafness and renal disease AD 10p15 GATA3
(HDR) syndrome
Kearns–Sayre syndrome Maternal NA Mitochondrial DNA
Mitochondrial encephalomyopathy with lactic acidosis and Maternal NA Mitochondrial DNA
stroke-like episodes (MELAS) syndrome
Mitochondrial trifunctional protein (MTP) deficiency syndrome AR 2p23 HADHB
Kenny–Caffey syndrome type 1* AR 1q42.3 TBCE
Kenny–Caffey syndrome type 2* AD 11q12.1 FAM111A
Sanjad–Sakati syndrome* AR 1q42.3 TBCE
Gracile bone dysplasia* AD 11q12.1 FAM111A
Autosomal dominant hypocalcaemia
Autosomal dominant hypocalcaemia type 1 and Bartter AD 3q21.1 CASR
syndrome type 5‡
Autosomal dominant hypocalcaemia type 2 AD 19p13.3 GNA11
Isolated hypoparathyroidism
Autosomal hypoparathyroidism AD or AR 6p24.2 and GCM2 and PTH
11p15
X‑Linked hypoparathyroidism XR Xq26–27 SOX3?§
AD, autosomal dominant; AR, autosomal recessive; NA, not applicable; PTH, parathyroid hormone; XR, X‑linked recessive. *Bone
dysplasia and short stature. ‡Bartter syndrome type 5 is a variant of autosomal dominant hypocalcaemia type 1. §The causative role
of SOX3 in X‑linked hypoparathyroidism is uncertain.
DiGeorge syndrome. DiGeorge syndrome has been structures), heart abnormalities, choanal atresia (a con
reported in ~60% of children with hypoparathyroid genital nasal airway abnormality), growth retardation
ism30. The syndrome presents with hypoparathyroidism, and genitourinary and/or ear anomalies35. CHARGE
cardiac outflow tract malformations, facial dysmorphia, syndrome is caused by heterozygous mutations in
psychiatric illness, palatal dysfunction and thymic chromodomain helicase DNA‑binding 7 (CHD7) 35
hypoplasia31. DiGeorge syndrome is most commonly (TABLE 1), which is expressed within the pharyngeal
caused by a heterozygous 3‑Mb microdeletion of ectoderm36 and may play a part in the development of
chromosome 22q11.2 (REF. 31), which is referred to as the pharyngeal region.
DiGeorge syndrome type 1 (also known as 22q11.2
deletion syndrome) (TABLE 1) . The deleted region Autoimmune polyendocrine syndrome type 1. Auto
encompasses TBX1, which encodes T box protein 1, immune polyendocrine syndrome type 1, which is
a transcription factor involved in the development of also referred to as autoimmune polyendocrinopathy–
the parathyroid glands and thymus from the embry candidiasis–ectodermal dystrophy syndrome, is an
onic pharyngeal region32 (FIGS 2,3). Abnormalities in the autosomal recessive disorder characterized by immune
function of TBX1 explain all of the main phenotypical deficiency and autoimmune destruction of endocrine
features of DiGeorge syndrome type 1 (REF. 33). organs, such as the parathyroid glands, adrenal cortex
Some patients harbour chromosome 10p dele and ovaries37 (FIG. 2; TABLE 1). Autoimmune polyendo
tions 19, referred to as DiGeorge syndrome type 2. crine syndrome type 1 is caused by mutations in auto
Deletion of the gene encoding the actin-binding pro immune regulator (AIRE). AIRE is expressed in thymic
tein n ebulette (NEBL) is probably responsible for this medullary epithelial cells38 and promotes immuno
disorder 34 (TABLE 1), but how deficiency in NEBL causes logical tolerance to self-antigens by deleting clones of
hypoparathyroidism is currently unclear. autoreactive T cells within the thymus39. Autoimmune
In addition, some patients with DiGeorge syn polyendocrine syndrome type 1 is clinically defined by
drome have features of CHARGE syndrome, which is the presence of at least two components of a triad that
characterized by coloboma (a hole in one or more ocular consists of mucocutaneous candidiasis (a Candida spp.

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PRIMER
infection of the skin, mucous membranes or nails), transcription factor mediates PTH expression (FIG. 2)
hypoparathyroidism and adrenal insufficiency 40. How and is involved in the embryonic development of the
ever, the disorder can also be associated with various common parathyroid–thymus primordia47–50 (FIG. 3).
other autoimmune disorders, such as gonadal failure,
alopecia, pernicious anaemia, vitiligo and type 1 dia Mitochondrial disorders associated with hypopara
betes mellitus, and can present with isolated hypopara thyroidism. Hypoparathyroidism has been reported
thyroidism41. Patients can have ectodermal dystrophies, to occur in three disorders associated with mitochon
such as hypoplasia of tooth enamel42, and are at higher drial dysfunction: Kearns–Sayre syndrome, mito
risk of developing oral cancer 43. chondrial encephalomyopathy with lactic acidosis and
stroke-like episodes (MELAS) syndrome, and mito
Hypoparathyroidism, sensorineural deafness and chondrial trifunctional protein (MTP) deficiency syn
renal disease syndrome. Hypoparathyroidism, drome51–53 (FIG. 2; TABLE 1). Kearns–Sayre syndrome is
sensorineural deafness and renal disease (HDR) syn characterized by progressive external ophthalmoplegia
drome is an autosomal dominant disorder in which (paralysis of the eye muscles) and pigmentary retino
patients often have hypocalcaemia and undetectable, pathy occurring at <20 years of age52. Deletions, dupli
low or inappropriately normal serum PTH concen cations and missense substitutions in mitochondrial
trations44,45. Moreover, HDR syndrome is associated DNA cause Kearns–Sayre syndrome and MELAS syn
with bilateral symmetrical sensorineural deafness and drome19,30,51, whereas MTP deficiency syndrome, which
renal abnormalities consisting mainly of cysts that is a disorder of fatty acid oxidation in the mitochondria
compress the glomeruli and tubules, thereby leading associated with cardiomyopathy, peripheral neuro
to renal impairment 45. HDR syndrome is caused by pathy, pigmentary retinopathy and liver dysfunction,
germline heterozygous mutations in GATA-binding is caused by mutations in HADHB, which encodes
factor 3 (GATA3) 46 (TABLE 1). This dual zinc-finger the trifunctional enzyme β-subunit 53. The mechanism
(or mechanisms) leading to hypoparathyroidism in these
mitochondrial disorders is currently not understood.
Box 1 | Pseudohypoparathyroidism
Inherited bone dysplasias associated with hypopara
Pseudohypoparathyroidism is a disorder associated with parathyroid hormone (PTH) thyroidism. Hypoparathyroidism occurs in >50% of
resistance. Although it also leads to hypocalcaemia and hyperphosphataemia, patients with Kenny–Caffey syndrome19, which is also
circulating PTH concentrations are increased in pseudohypoparathyroidism, which characterized by short stature and osteosclerotic bone
differentiates this condition from hypoparathyroidism. The primary causes of pseudo
dysplasia. Kenny–Caffey syndrome can be inherited as
hypoparathyroidism are genetic or epigenetic mutations in GNAS, the imprinted gene
an autosomal recessive (type 1) or dominant (type 2) dis
encoding the guanine-nucleotide-binding stimulatory protein (Gs) α‑subunit (Gsα) and
splice variants thereof167 (FIG. 2). Gsα is encoded by GNAS exons 1–13 and is biallelically order 19. Sanjad–Sakati syndrome, which is also known
expressed in most tissues, but expression from the maternal allele is reduced or absent as the hypoparathyroidism–retardation–dysmorphism
in tissues including the proximal renal tubule, the thyroid gland and few other tissues. syndrome, affects Middle Eastern populations and has a
Heterozygous inactivating mutations on the maternal GNAS allele cause pseudohypo similar phenotype to that of Kenny–Caffey syndrome54.
parathyroidism type 1a. In addition to PTH resistance, patients with pseudohypopara Sanjad–Sakati syndrome and Kenny–Caffey syndrome
thyroidism type 1a exhibit features of Albright hereditary osteodystrophy (AHO), type 1 are caused by mutations in tubulin-specific
including short stature, obesity, round facies, subcutaneous calcifications and chaperone E (TBCE)55, which encodes a chaperone pro
brachydactyly (shortening of fingers or toes)167. Resistance to other hormones that signal tein required for the correct folding of α‑tubulin sub
through Gsα may occur, for example, to thyroid-stimulating hormone (TSH) and growth
units55 and is postulated to have a role in parathyroid
hormone-releasing hormone. Conversely, mutations on the paternally inherited GNAS
gland migration56. Kenny–Caffey syndrome type 2 is
allele cause pseudopseudohypoparathyroidism, which is characterized by the AHO
phenotype but without obesity, neurocognitive abnormalities and hormonal resistance. caused by heterozygous missense mutations of family
Pseudohypoparathyroidism type 1b is characterized by GNAS methylation defects that with sequence similarity 111 member A (FAM111A),
lead to resistance to PTH and sometimes to TSH167–169. Autosomal dominant pseudo which encodes a protein involved in DNA replication
hypoparathyroidism type 1b can be caused by maternal deletions involving the GNAS and chromatin maturation and may be involved in
exons AS3–4 and/or NESP (which encodes the neuroendocrine secretory protein 55 embryonic development 57,58. A FAM111A mutation,
(NESP55; part of the complex GNAS locus)) or the nearby gene syntaxin 16 (STX16), Ser342del, has been shown to cause gracile bone dys
but the molecular defect of the more-common sporadic form of the disease is still plasia, which occurs in association with hypopara
unresolved. Coding-region GNAS abnormalities also cause pseudohypoparathyroidism thyroidism and r epresents a perinatally lethal condition58
type 1c, which is clinically similar to type 1a, although Gsα activity is not affected
(FIG. 2; TABLE 1).
in vitro170. In contrast to patients with pseudohypoparathyroidism type 1a and type 1b,
in which cAMP responses to PTH are blunted, patients with pseudohypoparathyroidism
type 2 demonstrate conserved responses; pseudohypoparathyroidism type 2 may, Autosomal dominant hypocalcaemia. Autosomal
in some cases, be explained by vitamin D deficiency171. As Gsα is expressed from both dominant hypocalcaemia type 1 and type 2 are geneti
alleles in the distal renal tubule where it is not imprinted, urinary calcium reabsorption cally distinct disorders that were found to be associated
is normal in the distal tubule, and patients with pseudohypoparathyroidism are not at with germline gain‑of‑function mutations of CaSR and
increased risk for nephrocalcinosis. Treatment of PTH resistance in pseudohypopara G11α proteins, respectively 15,59,60 (FIG. 2; TABLE 1). Type 1,
thyroidism consists of activated vitamin D and calcium, but therapeutic goals differ from which is the most common type of autosomal domin
those of hypoparathyroidism treatment, that is, normalization of blood calcium levels ant hypocalcaemia, is associated with hypocalcaemia,
and maintenance of PTH levels in the normal-to-mildly elevated range. Blood chemistries PTH levels ranging from undetectable to normal and
should be monitored frequently and urinary calcium excretion monitored occasionally.
elevated fractional excretion of calcium, which can

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PRIMER
lead to frank hypercalciuria even in the setting of low a Bartter-like syndrome (Bartter syndrome type 5)
serum calcium concentrations15,60–62. Ectopic calcifi characterized by hypokalaemic alkalosis, renal salt wast
cations of the kidneys or basal ganglia affect ~35% ing and hyperreninaemic hyperaldosteronism, in addi
of patients with autosomal dominant hypocalcaemia tion to hypocalcaemia and hypoparathyroidism15,64.
type 1 (REFS 15,60,63). Some patients with autosomal Autosomal dominant hypoc alcaemia type 2 has a
dominant hypocalcaemia type 1 associated with severe similar serum biochemical phenotype to that of type 1
gain‑of‑function mutations of CASR may also have (REFS 59,65,66) but usually a milder renal phenotype,
CaSR
Ca2+ Ca2+ Autosomal dominant hypocalcaemia
Parathyroid cell type 1 and Bartter syndrome type 5 Autosomal
dominant
hypocalcaemia
Giα Gq/11α Autosomal dominant hypocalcaemia
type 2
ATP AC PLC PtdIns(4,5)P2
–
cAMP DAG + Ins(1,4,5)P3 Ca2+ Kearns–Sayre syndrome,
MELAS syndrome and
Tubulin MTP deficiency syndrome
Mitochondrion Kenny–Caffey syndrome type 1 and
TBCE Sanjad–Sakati syndrome
DiGeorge syndrome and
Syndromic
Transcription factors and CHARGE syndrome
hypoparathyroidism
chromatin-remodelling proteins Autoimmune polyendocrine
TBX1 and CHD7 syndrome type 1
AIRE (thymus) HDR syndrome
GATA3 Kenny–Caffey syndrome type 2 and
FAM111A Gracile bone dysplasia
GCM2
Nucleus
PTH synthesis Isolated
hypoparathyroidism
PTH secretion
Target cell PTH PTH1R
Gq/11α Gsα Pseudohypoparathyroidism

PtdIns(4,5)P2 PLC AC ATP
Ca2+ Ins(1,4,5)P3 + DAG cAMP
Gq/11α Autosomal dominant hypocalcaemia

type 2
Autosomal
dominant
Autosomal dominant hypocalcaemia hypocalcaemia
type 1
Ca2+ Ca2+ Bartter syndrome type 5
Figure 2 | Overview of the regulation of PTH synthesis, secretion and action and associated genetic|disorders.
Nature Reviews Disease Primers
Variations in the levels of extracellular calcium are detected by the calcium-sensing receptor (CaSR), which is expressed
by cells in the parathyroid gland, kidney and bone. CaSR signals via the guanine-nucleotide-binding protein q/11α (Gq/11α)
to stimulate phospholipase C (PLC), which catalyses the hydrolysis of phosphatidylinositol 4,5‑bisphosphate (PtdIns(4,5)P2)
to inositol 1,4,5‑trisphosphate (Ins(1,4,5)P3), thereby increasing the levels of intracellular calcium. CaSR also signals via the
Giα protein, which inhibits adenylyl cyclase (AC), thereby leading to a reduction in the formation of cAMP from ATP.
In parathyroid cells, these proximal signals modulate downstream pathways, which lead to alterations in the synthesis
and secretion of parathyroid hormone (PTH). Secreted PTH acts on the PTH1 receptor (PTH1R) in target tissues, which
mediates signalling via the Gsα and Gq/11α proteins. Abnormalities in several genes and encoded proteins in these
pathways involved in calcium-sensing and G protein function, mitochondrial activity and tubulin formation, as well as in
gene transcription and chromatin remodelling have been identified in patients with genetic hypoparathyroid disorders19.
AIRE, autoimmune regulator; CHD7, chromodomain helicase DNA‑binding 7; DAG, diacylglycerol; GATA3, GATA-binding
factor 3; GCM2, glial cells missing homologue 2; HDR, hypoparathyroidism, sensorineural deafness and renal disease;
MELAS, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; MTP, mitochondrial trifunctional
protein; TBCE, tubulin-specific chaperone E; TBX1, T box 1.

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In utero and
In utero postnatal
Pharyngeal Formation of common Separation of parathyroid Upregulation

Parathyroid
pouch parathyroid–thymus glands from thymus and of PTH
organogenesis
development primordia migration to the thyroid expression
TBX1, EYA1, GATA3,

HOXA3, PAX1, GCM2 and
PAX9, SIX1 or SIX4 GATA3 GCM2 MAFB MAFB
Figure 3 | Transcription factors involved in parathyroid gland development and function. Nature Reviews
The | Disease
parathyroid Primers
glands
in humans are derived from the endoderm of the third and fourth pharyngeal pouches48, whereas the glands develop
together with the thymus from the endoderm of the third pharyngeal pouch in mice48,50. Studies using mouse models have
shown that a network of transcription factors mediates patterning of the third pharyngeal pouch and the formation of the
common parathyroid–thymus primordia48,50. These transcription factors act in a spatiotemporal manner. For example,
T box 1 (TBX1), expressed in the pharyngeal endoderm, is required for the development of the third pharyngeal pouch32,
whereas GATA-binding factor 3 (GATA3), which is expressed later than TBX1 in the common parathyroid–thymus
primordia, mediates the differentiation and survival of parathyroid and thymus progenitor cells47,48. Moreover, GATA3
regulates the expression of glial cells missing homologue 2 (GCM2), which is expressed in the parathyroid domain of
the common primordia and mediates the initial stages of parathyroid organogenesis47,48. MAFB is also expressed in the
parathyroid domain and facilitates the separation of the parathyroid glands from the thymus and the migration of
the parathyroid glands towards the thyroid50. GATA3, GCM2 and MAFB act synergistically to upregulate the expression
of parathyroid hormone (PTH)49. As the expression of GATA3, GCM2 and MAFB persists into adulthood, these
transcription factors are probably required for the postnatal expression of PTH49. EYA1, eyes absent homologue 1;
HOXA3, homeobox A3; PAX, paired box; SIX, Sine oculis homeobox homologue.
with considerably less urinary calcium excretion67. against PTH(1–34) and PTH(13–34) fragments, thus
Moreover, some patients have short stature caused by explaining why some assays were unable to detect the
postnatal growth insufficiency 67,68. mutant PTH peptide75.
Autosomal forms of hypoparathyroidism. Glial X‑Linked recessive hypoparathyroidism. X‑Linked

cells missing homologue 2 (GCM2) is a parathyroid- recessive hypoparathyroidism only affects men and
specific transcription factor (FIG. 2) that has a crucial is associated with infantile hypocalcaemic seizures76.
role in extracellular calcium homeostasis by promot Molecular deletion–insertions involving chromosome
ing development of the parathyroid glands47,48,69 and by 2p25 and Xq27 have been identified, and these struc
interacting with the GATA3 and MAFB transcription tural alterations may alter the expression of the nearby
factors to increase PTH expression49,50 (FIG. 3). Germline gene SOX3 (REFS 77,78) (TABLE 1) . SOX3 encodes a
GCM2 mutations (TABLE 1) are often associated with high-mobility group box transcription factor, which is
severe hypocalcaemia and low or undetectable serum expressed in the parathyroid glands during embryo
PTH concentrations 70. Homozygous GCM2 muta genesis and may a play a part in the development of the
tions cause an autosomal recessive form of isolated parathyroid glands from the pharyngeal pouches77 (FIG. 3).
hypoparathyroidism by impairing nuclear localiza
tion, DNA binding and/or transactivation activity of Other causes of hypoparathyroidism
the GCM2 transcription factor 70, whereas heterozygous Some cases of isolated hypoparathyroidism, in which no
GCM2 mutations cause autosomal dominant hypopara other cause can be identified, are also presumed to be
thyroidism by exerting a d ominant-negative effect on caused by autoimmune destruction of the parathyroid
GCM2 transactivation activity 71,72. glands. No formal diagnostic criteria and no established
Germline PTH gene abnormalities are a rare cause laboratory tests are available to confirm this diagnosis.
of autosomal dominant and recessive forms of isolated Severe and prolonged hypomagnesaemia can lead to
hypoparathyroidism (TABLE 1). These abnormalities, functional hypoparathyroidism79,80. Rarely, infiltrative
which comprise missense, nonsense or splice-site muta diseases such as haemochromatosis, Wilson disease and
tions, mainly affect exon 2 (encoding the signal peptide metastasis can cause hypoparathyroidism2. The mech
region of the pre‑proPTH(1–115) peptide) and are pre anism for this is thought to involve inhibition of para
dicted to impair PTH biosynthesis and secretion19,73–75 thyroid cellular function by iron (primary iron excess in
(FIG. 2). A mutation affecting the mature PTH(1–84) haemochromatosis and secondary iron overload owing
peptide was recently identified in a family with an auto to blood transfusions in thalassaemia (a group of inheri
somal recessive form of hypocalcaemia and was shown ted blood disorders associated with abnormal haemo
to impair binding of PTH to PTH1R75. Affected family globulin production)), copper (in Wilson disease) and
members showed either high or low plasma PTH levels replacement of functional parathyroid tissue by tumour
depending on the type of PTH assay used. The mutation cells. Parathyroid tissue is relatively radiation-resistant.
(Arg25Cys) was subsequently revealed to interfere with Although cases of radiation-induced hypoparathyroidism
some PTH immunoassays that used antibodies raised have been reported, this aetiology is very rare2.

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PRIMER
Central nervous system Neuropsychiatric system

observed in the past, prevalence rates of seizures in
• Seizures • Symptoms of anxiety patients with hypoparathyroidism were only 4–8% in
• Calcifications and depression two recent studies13,85. Possible explanations might be
• Parkinsonism or dystonia selection bias of the earlier studies or better control of
serum calcium levels in the later studies.
Ophthalmological system Central nervous system calcifications (FIG. 5a,b) are a
Cardiovascular system • Cataracts common finding in patients with hypoparathyroidism,
• Cardiac arrhythmias • Papilloedema
• Hypocalcaemia-associated
with prevalence rates of 52–74% in two moderate-size
dilated cardiomyopathy cohorts from the United States and India85,86. The calcifi
Dental system cations are most commonly seen in the basal ganglia but
• Altered tooth
morphology
can also occur in the grey and white matter junction,
Respiratory system the cerebellar parenchyma, the thalamus and the dentate
• Laryngospasm nucleus. Although the exact cause of these calcifications
Dermatological system is unclear, increased progression of calcifications over
• Dry skin time was independently associated with a decreased
Renal system • Onycholysis ratio of calcium to phosphate in serum, which suggests
• Nephrocalcinosis* • Coarse, thin hair that altered phosphate metabolism may play a key part
• Kidney stones* • Pustular psoriasis
• Chronic kidney disease* in ectopic calcifications86. Notably, two genes (sodium-
dependent phosphate transporter 2 (PIT2; also known
as SLC20A2) and xenotropic and polytropic retrovirus
Musculoskeletal system
Peripheral nervous system • Myopathy receptor 1 (XPR1)) found to be associated with famil
• Paraesthesia • Spondyloarthropathy ial idiopathic basal ganglia calcification (also known as
• Muscle cramp Fahr syndrome) encode proteins involved in phosphate
• Tetany transport, which supports the hypothesis that abnormal
phosphate homeostasis has a role in ectopic calcifica
Figure 4 | Clinical manifestations of hypoparathyroidism. Common and rare
Nature Reviews | Disease Primers tions in chronic hypoparathyroidism87,88. The clinical
manifestations are shown. *These manifestations are mostly the result of treatment with
calcium and activated vitamin D rather than of the disorder itself. relevance of the central nervous system calcifications
seen in patients with longstanding hypoparathyroidism
is unclear. Symptoms including parkinsonism (a neuro
Diagnosis, screening and prevention logical movement disorder characterized by tremor,
Clinical manifestations bradykinesia, rigidity and postural instability) and dys
The clinical manifestations of hypoparathyroidism are tonia (a neurological movement disorder associated with
variable and can involve almost any organ system (FIG. 4). twisting or abnormal fixed postures) have been reported
The classic symptom of hypoparathyroidism is neuro in hypoparathyroidism, but at a much lower prevalence
muscular irritability owing to hypocalcaemia. Other than basal ganglia calcifications 85,86,89. In addition,
manifestations can be due to episodes of hypercalcaemia the relationship between the extent and location of
and hyperphosphataemia (for example, extraskeletal calci calcification with neurological findings is conflicting 90,91.
fication), but the cause of some symptoms (for example,
neuropsychiatric symptoms) remains poorly understood2. Cardiovascular system. Cardiac arrhythmias are rare
in hypoparathyroidism. Some patients with chronic
Peripheral nervous system. Hypocalcaemia partially hypocalcaemia associated with hypoparathyroidism
depolarizes the resting membrane potential of a neuron, showed prolongation of the corrected QT interval
thereby increasing the probability of triggering action on electrocardiogram, along with prominent U wave
potentials81. This leads to neuromuscular irritability and T wave abnormalities92. However, most of these
— the hallmark symptom of hypocalcaemia from any symptoms resolve promptly after treatment of hypo
cause. Sensory neuron irritability manifests as para calcaemia. Hypocalcaemia-associated dilated cardio
esthesia in the extremities and in the peri-oral and oral myopathy, which can occur during chronic severe
area. Motor neuron irritability can manifest as m uscle hypocalcaemia, is typically reversible with treatment 93.
spasms or t etany, ranging from the classic carpopedal However, a recent case report of an infant with severe
spasm (spasmic muscle contractions of the forearm, hypocalcaemia suggested a non-reversible component
hand, lower leg and/or feet) to life-threatening laryngo in hypocalcaemia-associated dilated cardiomyopathy 94.
spasm82,83. Increased neuromuscular irritability can be Despite the numerous case reports, the prevalence of
detected using the Chvostek sign (ipsilateral twitching cardiomyopathy is very low in cohorts of patients with
of facial muscles when tapping on the area of the facial hypoparathyroidism, suggesting that there is a subset of
nerve) and the Trousseau sign (muscular contraction of vulnerable patients with as yet undefined risk factors13,85.
the hand when inflating a blood pressure cuff on the arm
above systolic blood pressure for 3 minutes)84. Renal system. Hypoparathyroidism per se is usually not
associated with renal disease, even among those with
Central nervous system. Severe hypocalcaemia can gain‑of‑function mutations of CASR who are most likely
precipitate seizures, which can be focal or generalized to have hypercalciuria without treatment 63,95. However,
(tonic–clonic type). Although seizures were frequently conventional treatment of hypoparathyroidism with

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PRIMER
calcium and activated vitamin D metabolites leads to in reductions in mineralizing surface and mineral
increased excretion of calcium into the urine because apposition rate. In hypoparathyroidism, the decrease in
of the lack of PTH-mediated reabsorption in the bone turnover leads to a situation where more bone is
distal nephron. The resulting hypercalciuria can lead deposited than removed after each remodelling cycle
to nephrocalcinosis and kidney stones (FIG. 5c). The is completed99. This observation explains the increase
reported prevalence rates of nephrocalcinosis in patients in bone mineral density and cortical thickness that has
with hypoparathyroidism who are treated with calcium been reported in some studies. These skeletal abnor
and activated vitamin D is 12–57%63,96,97. The hazard malities are detected in trabecular and cortical bone,
ratio of developing kidney stones was 4.82 (95% CI: and these changes are confirmed by micro‑CT of the
2.00–11.64) in a large Danish case–control study of bone biopsies103,104. Dentition can be affected in patients
patients with post-surgical hypoparat hyroidism 13. with non-surgical hypoparathyroidism, with symptoms
Patients with hypoparathyroidism on conventional including shortened roots, hypoplastic enamel and
treatment have a significantly increased risk of chronic hypoplastic or absent teeth105,106.
kidney disease. In a US cohort 85, 41% of patients had The impact, if any, of the skeletal abnormalities
an estimated glomerular filtration rate (eGFR) of associated with hypoparathyroidism on osteoporosis
<60 ml/min/1.73 m2 (an eGFR of ≥90 ml/min/1.73 m2 and fracture risk remains unclear. In the Danish case–
is considered normal), which was 2–17‑fold higher control studies8,13, no differences in overall fracture rate
than age-adjusted normal values. In two Danish case– compared with the general population were detected.
control studies8,13, the hazard ratios for diagnosed renal Analyses of specific fracture types showed that
insufficiency were 3.10 (95% CI: 1.73–5.55) and 6.01 patients with non-surgical hypoparathyroidism had
(95% CI: 2.45–14.75) for patients with surgical and non- an increased hazard ratio for upper extremity fractures
surgical hypoparathyroidism, respectively, compared (1.94; 95% CI: 1.31–2.85) compared with controls and
with age‑matched controls. that patients with post-surgical hypoparathyroidism
had a lower hazard ratio for the same fracture (0.69;
Musculoskeletal and dental system. Hypopara CI: 0.49–0.97)9. In several case reports, hypopara
thyroidism is associated with low bone turnover (the thyroidism has also been associated with a spondylo
active process of coupled bone formation and bone arthropathy characterized by ligament ossification and
resorption), which is linked to normal or increased syndesmophyte formation107. One small case series
bone mineral density and distorted bone micro reported the presence of clinically overt spondylo
architecture98,99. The reduction in bone formation is arthropathy in 3 out of 40 patients with hypopara
demonstrated by the profound reduction of tetracycline thyroidism, with radiological changes being identified
labelling in bone biopsies compared with controls100–102. in 14 out of 40 (REF. 108).
The activation frequency (a marker for the number Myopathy of the skeletal muscles, characterized by
of times per year a specific bone site undergoes bone increased serum levels of creatine phosphokinase and
formation) is decreased by 50–80% in patients with histological abnormalities in muscle biopsies, is also
hypoparathyroidism compared with controls. In addi seen in hypoparathyroidism and seems to relate to the
tion to the overall reduction in bone remodelling, severity of hypocalcaemia109,110. Compared with age-
the depth and number of resorption pits are reduced, matched and sex-matched controls, patients with
suggesting a reduction in bone resorption. Bone forma hypoparathyroidism have a significant reduction in
tion rate, osteoid (unmineralized bone matrix) surface muscle strength and maximal force production, and
and osteoid width are consistently and substantially they also require a longer time to complete tests of
reduced. The reduction in bone formation is reflected physical function111.
a b c
Figure 5 | Extraskeletal calcifications. Coronal (part a) and sagittal (part b) CT images ofNature Reviews
the head | Disease with
of an individual Primers
hypoparathyroidism show extensive symmetrical calcifications involving the subcortical white matter, basal ganglia
(arrows) and cerebellar hemispheres. An abdominal CT (part c) of an individual with longstanding idiopathic
hypoparathyroidism shows large bilateral stone fragments in the kidney, the largest being a staghorn calculus in the
interpolar region of the right kidney. Images in part a and part b are courtesy of J. Warshauer, University of California,
San Francisco, USA.

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PRIMER
Ophthalmological system. Hypoparathyroidism is Neuropsychiatric system. Hypoparathyroidism is

associated with an increased risk of cataracts, with associated with an increased risk of neuropsychiatric
reported prevalence rates of 27–55%112–114. In the Danish diseases120. In the Danish cohort, the risk of being hospi
case–control studies, non-surgical hypoparathyroidism talized due to neuropsychiatric diseases, such as depres
was associated with an increased hazard ratio of 4.21 sion or bipolar affective disorders, was significantly
(95% CI: 2.13–8.34) compared with controls, but the increased in post-surgical (hazard ratio: 2.01; 95% CI:
risk of cataracts in patients with post-surgical hypopara 1.16–3.50) and non-surgical hypoparathyroidism
thyroidism was not significantly different from that in (hazard ratio: 2.45; 95% CI: 1.78–3.35) compared with
the general population, suggesting that age of onset age‑matched and sex-matched controls9.
and/or duration of hypoparathyroidism are impor
tant contributing factors8,13. In a recent case–control Diagnosis
study of patients with cataracts, those with hypopara Biochemical investigations are required to confirm
thyroidism were significantly younger than typical the clinical diagnosis of hypoparathyroidism. The
patients with cataracts who did not have hypopara combination of levels of albumin-corrected or ionized
thyroidism and had evidence of more-severe posterior calcium in serum below the laboratory normal range
capsule (the m embrane that surrounds the lens) disease (<8.5 mg per dl or 2.12 mmol per l) and absent, low
and a higher rate of anterior capsule disease114. In addi or inappropriately normal PTH levels at the time of
tion, hypoparathyroidism is predominantly associated hypocalcaemia is the hallmark of hypoparathyroidism
with cortical cataracts (gradual clouding starting in and helps to differentiate hypoparathyroidism from
the periphery of the lens), whereas typical age-related other diso rders associated with hypocalcaemia,
cataracts are more likely to be nuclear (gradual clouding such as pseudohypoparathyroidism (BOX 1). Hence, a
of the central portion of the lens)113. The aetiology of reliable assay for measuring PTH in serum is crucial
the cataract formation is unclear, although preclinical for diagnosis (BOX 2).
studies suggest that it may be a consequence of chronic The biochemical diagnosis of hypoparathyroidism
hypocalcaemia115. Papilloedema (swelling of the optic in the right clinical setting is usually straightforward.
disc caused by increased intracranial pressure) can For example, when a patient with a prior history of neck
also be seen in patients with hypoparathyroidism and surgery presents with symptoms of hypocalcaemia and
typically improves with correction of hypocalcaemia116. has low PTH levels, hypoparathyroidism can be inferred.
However, circulating PTH levels in these patients can
Dermatological system. Skin and skin appendages also be within the normal range. Similarly to diagnos
are affected by hypoparathyroidism; dry, scaly skin is ing patients with hyperparathyroidism, for diagnosing
commonly reported, and nails are often brittle and sub patients with hypoparathyroidism, the PTH value has
ject to onycholysis (separation of the nail from the nail to be considered in relation to the serum calcium value
bed)117. Scalp, axillary and pubic hair can be coarse and drawn simultaneously. In patients with hypocalcaemia,
thin117. A rare and severe type of psoriasis (generalized PTH levels that are within normal laboratory range are
pustular psoriasis associated with pus-filled blisters) inappropriate, as they would be elevated if the func
has been described in numerous case reports; in all tion of the parathyroid gland was intact. In patients
cases, pustular psoriasis was associated with profound with a positive family history of hypoparathyroidism
hypocalcaemia and improved with treatment 118,119. and in children with non-surgical hypoparathyroid
ism, a search for a possible genetic defect should be
considered, with appropriate pretest counselling and
Box 2 | Measurement of serum PTH levels informed consent.
Circulating parathyroid hormone (PTH) peptides include full-length, active PTH(1–84)
peptides and several forms of truncated, mostly carboxyl-terminal fragments, the Monitoring
majority being PTH(34–84) and PTH(37–84)172,173. These truncated fragments cannot At regular intervals, patients should be monitored
bind to and activate the classic PTH1 receptor (PTH1R). Although the plasma half-life for potential complications of hypoparathroidism5,6
of intact PTH(1–84) is only a few minutes, renal clearance of PTH fragments is slower. (TABLES 2,3) . In addition to measuring the levels of
Thus, under normocalcaemic conditions, only about 20% of the PTH peptides are intact, total calcium and albumin, or ionized calcium, bio
biologically active PTH174. chemical tests should include measuring serum phos
To improve the clinical performance of the first-generation PTH assay175, which phate levels (to detect hyperphosphataemia), creatinine
detected not only intact PTH but also truncated fragments, the two-site
levels in the blood, with calculation of eGFR to detect
immunoradiometric assay (IRMA) was introduced in 1987 (REF. 164). This sandwich
assay uses a C-terminal capture antibody linked to a solid phase and an amino-terminal
renal impairment, and serum magnesium concentra
detection antibody, making the measurement of PTH(1–84) more accurate. This tions, particularly in patients with autosomal domin
second-generation assay, which does not detect the majority of C-terminal fragments, ant hypocalcaemia. The calcium–phosphate product
is the most widely used intact PTH assay to date. should be kept below 55 mg 2 per dl2 to avoid renal
In 1999, a third-generation PTH assay was introduced176, called the ‘whole PTH’ or calcifications1,5. This target calcium–phosphate prod
‘biointact PTH’ assay. This assay uses a C‑terminal capture antibody similar to that of uct is used by nephrologists in patients with chronic
the second-generation test but an N-terminal detection antibody that detects only the kidney disease to reduce the risk of arterial calcifica
extreme N-terminal region of PTH (that is, PTH(1–6)). Interestingly, although this test is tion. However, the value of using the calcium–phosphate
theoretically better, it has not been proven to be superior in clinical practice, although product level in hypoparathyroidism to predict the risk
studies are limited177,178.
of calcifications that may lead to renal insufficiency

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PRIMER
Table 2 | Goals of management of hypoparathyroidism according to the European Society of Endocrinology

Therapeutic Parameter to Complications to Frequency of Level of Level of Comment
goal monitor be prevented monitoring recommendation recommendation
for the goal of for the frequency
management of monitoring
(quality of (quality of
evidence)* evidence)*
Serum calcium • Albumin-corrected • Hypocalcaemia: Every Suggested (+) Recommended During active
in the low to total serum for example, 3–6 months (evidence not adjustments of
low-normal range calcium levels of symptomatic graded) treatment with
8.0–8.5 mg per dl tetany and mental calcium and vitamin D
(2.0–2.12 mM) status changes analogues, clinical
• Serum ionized • Hypercalcaemia: assessments and serum
calcium levels in for example, biochemistry should
the lower part of, dehydration, be done frequently
or slightly below, renal dysfunction (weekly or every other
the reference and mental status week)
range changes
Prevent Urinary calcium Hypercalciuria, Once a year or Suggested (+) Suggested NA
hypercalciuria levels corrected nephrocalcinosis, every second (evidence not
for BSA below the kidney stones and year graded)
sex-specified normal renal insufficiency
range (<250 mg daily
for women; <300 mg
daily for men; <4 mg
per kg per day for
both sexes)
Serum phosphate Serum phosphate Ectopic soft tissue Every Suggested (+) Recommended After a change in
levels within levels within or close calcifications in 3–6 months (evidence not therapy, monitor
reference range to age-adjusted the brain, kidney, graded) weekly or every
reference range‡ vascular system other week
and other tissues
Control calcium– Serum calcium– Ectopic soft tissue Every Suggested (+) Recommended Monitor weekly or
phosphate phosphate levels calcifications in the 3–6 months (evidence not every other week after
product levels of <55 mg2 per dl2 brain, kidneys and graded) a change in treatment
(<4.4 mmol2 per l2) vascular system
Serum magnesium Serum magnesium Hypomagnesaemia Every Suggested (+) Recommended NA
levels within levels within 3–6 months (evidence not
reference range reference range‡ graded)
eGFR within Creatinine levels in Renal insufficiency Every NA Recommended Monitor weekly or
reference range serum and urine; an 3–6 months (evidence not every other week after
eGFR of 90–120 ml/ graded) a change in treatment
min/1.73 m2 should
be aimed for
Vitamin D Serum 25(OH)D of Non-skeletal Yearly Suggested (+) NA Vitamin D levels should
adequacy >20 ng per ml effects of vitamin D be maintained within
(>50 nmol per l) deficiency, the normal range
including myopathy
Prevention of Urine levels of Flank pain If symptoms Recommended Recommended Renal imaging is also
kidney stone kidney stone risk infection and or kidney (evidence not (evidence not recommended if
formation and/or markers and renal renal insufficiency, stones occur graded) graded) symptoms of renal stone
nephrocalcinosis imaging (mainly among others or if renal disease are present or
ultrasonography) function starts serum creatinine levels
to decline start to increase
Improved QOL QOL, well-being and Impaired QOL Every Recommended Personalized No specific instrument
and absence of symptoms 3–6 months (evidence not treatment used to assess QOL
symptoms of graded) recommended,
hypocalcaemia focused on overall
well-being and
QOL (evidence not
graded)
Maintain bone Bone mineral density Osteoporosis or Not routinely NA NA NA
mass by dual energy X‑ray fractures recommended
absorptiometry
25(OH)D, 25‑dihydroxyvitamin D; BSA, body surface area; eGFR, estimated glomerular filtration rate; NA, not applicable; QOL, quality of life.*Recommendations
are graded as recommended (strong recommendation) and suggested (weak recommendation), with grading of evidence as ‘strong (++++), moderate (+++), low (++)
and very low (+) according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) principles5. ‡Reference range might differ
slightly between laboratories.

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Table 3 | Goals of management according to the First International Conference on the Management of Hypoparathyroidism
Therapeutic goal Parameters to monitor Complications to be Frequency of Comment
prevented monitoring
Prevention of • Clinical symptoms and Tetany, seizures, muscle Every 6 months During active adjustments of
hypocalcaemia signs of hypocalcaemia cramps, paraesthesia, (when stable treatment with calcium and
using patient history and other neuromuscular dosing has been vitamin D analogues, clinical
physical examination complications, fatigue, achieved) assessments and serum
• Laboratory tests (serum poor concentration, biochemistry should be done
calcium and albumin levels) memory and cognitive frequently (several times per week,
function, impaired quality weekly or monthly), depending on
Maintain serum calcium • Total serum calcium levels of life, and congestive Yearly or more the circumstances
level slightly below the of no more than 0.5 mg per heart failure (if severe and frequently per
normal range dl below the lower limit of chronic) clinical situation
normal (with normal being
8.5 mg per dl)
• Serum phosphate,
magnesium, creatinine,
blood urea nitrogen levels
and eGFR
Prevent or minimize 24‑hour urine calcium Kidney stones, At least once a If thiazide diuretics are used, monitor
hypercalciuria excretion, creatinine levels nephrocalcinosis, renal year (consider serum potassium and magnesium
and eGFR dysfunction and end-stage remeasuring with levels; volume status should be
renal disease dose adjustments) monitored clinically and by physical
examination; if patients have normal
urinary calcium levels for several
years without renal complications,
physicians may opt not to measure
urinary calcium levels annually
Keep the calcium– Serum calcium and Ectopic calcifications in Every 6 months Consider reassessing with dose
phosphate product <55 mg2 phosphate levels the brain, kidneys, vascular (yearly if very changes
per dl2 (or 4.4 mmol2 per l2) system and soft tissues stable)
Maintain fasting serum Serum phosphate levels Extraskeletal calcifications Every 6 months Phosphate binders or a
phosphate within the (more often low-phosphate diet are generally
normal range or only during treatment used only when serum phosphate
slightly elevated dose adjustments) levels are very high
Avoid hypercalcaemia Serum calcium, phosphate, Symptomatic Twice a year During active adjustments of
urea nitrogen, creatinine hypercalcaemia (weakness, (yearly if very calcium and vitamin D analogues,
and electrolyte levels altered mental status, stable) clinical assessments and serum
nausea and abdominal biochemistry should be done
pain) and increased risk of frequently (several times per week,
renal calcification weekly or monthly)
Decrease potential Renal imaging Renal dysfunction and At baseline, and It is unclear whether basal ganglia
for renal and other (ultrasonography or CT), progression to dialysis to be considered or other central nervous system
extraskeletal calcifications brain calcifications (CT) or transplantation, every 5 years (or calcifications should be monitored
and cataracts (slit lamp central nervous system more frequently and at what frequency if detected at
examination) calcifications and possible if signs of renal the baseline or interval examination;
dysfunction (for example, stones or renal the frequency of cataract monitoring
seizures, altered mental dysfunction will depend on results of baseline
activity and movement develop) ophthalmological examination and
disorder), and visual loss the current status of the patient
Guidelines from the First International Conference on the Management of Hypoparathyroidism6. eGFR, estimated glomerular filtration rate.
remains controversial121,122 and awaits further evalu of hypercalciuria. Patients with a greater tendency to
ation. Nevertheless, most experts are mindful of the hypercalciuria might require more frequent monitor
calcium–phosphate product in hypoparathyroidism ing. In children, 24‑hour urine calcium measurements
and will endeavour to lower it, particularly if it exceeds should be adjusted for body surface area or body weight.
the threshold that has been set, however uncertain that Renal imaging should be considered periodically 123
threshold may be. or if a patient has symptoms of renal stone disease or if
Patients should be asked whether they have experi serum creatinine levels start to rise5. Renal ultrasono
enced symptoms such as flank pain or haematuria graphy is a safe modality to detect the presence of early-
(to detect kidney stones), blurred vision (to detect catar stage nephrocalcinosis and was shown in one study to
acts) and neuropsychiatric symptoms (to detect, for be superior to CT124. As hypoparathyroidism treated
example, depression and anxiety), among others; by conventional therapy is associated with low bone
if symptoms are present, patients should be referred for turnover, patients are not especially prone to develop
proper evaluation. Measurement of 24‑hour urinary cal ing osteoporosis. Dual energy X‑ray absorptiometry
cium once a year should be considered for monitoring (DXA) scans to determine bone mineral density are

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PRIMER
not needed specif ically for patients with hypopara or are on concomitant proton-pump inhibitor therapy.
thyroidism, but may be performed according to guide Acute severe hypocalcaemia is treated with intravenous
lines for the diagnosis and monitoring of osteoporosis calcium gluconate5,6.
(for example, screening in populations at risk). Owing Various vitamin D metabolites and analogues (BOX 3)
to the uncertain clinical relevance of calcifications have been used to treat hypoparathyroidism. Although
in the central nervous system, brain imaging using a high dose of the vitamin D precursors ergocalciferol
CT should be performed only in case of unexplained (vitamin D2) and cholecalciferol (vitamin D3) can be
neurological manifestations5,123. used126, such treatment is not common and can lead to
prolonged hypercalcaemia owing to the long half-life
Screening of these precursors. The use of activated vitamin D —
As most cases of hypoparathyroidism are post-surgical, calcitriol (1,25(OH)2D) or alphacalcidol (1α(OH)D3)
patients should be evaluated for hypocalcaemia follow — is favoured, because of its direct action on the
ing neck surgeries, but no guidelines exist with regard gastrointestinal tract to increase intestinal calcium
to the diagnostic tests and timing. In familial forms of absorption and its shorter onset of action and half-
hypoparathyroidism, biochemical screening of first- life127. Both alphacalcidol and calcitriol are titrated to
degree relatives may be offered. In several patients with achieve desired serum calcium concentrations within
seizures, including children presumed to be suffering or slightly below the low-normal range.
from febrile convulsions, not measuring serum cal Infants and young children should receive calcitriol
cium concentrations can cause a delay in the diagnosis (weight-based dosing, 0.01–0.04 μg per kg per day);
of hypoparathyroidism125. some centres will also give calcium carbonate supple
ments (20–40 mg per kg per day), divided into two or
Prevention three doses. Older children usually receive adult doses
To avoid post-surgical hypoparathyroidism, surgical of activated vitamin D128.
experience in neck surgery is crucial. In non-surgical
hypoparathyroidism with a known genetic aetiology, PTH analogues
genetic counselling should be offered. To avoid lengthy Although conventional therapy with activated vit
episodes of hypocalcaemia or hypercalcaemia, patients amin D and calcium supplements can restore serum
with hypoparathyroidism should be aware of the symp calcium levels, it does not restore other actions of PTH,
toms of low and high circulating calcium concentra such as bone turnover or renal calcium reabsorption.
tions, to allow for early detection and adjustment of In addition, conventional treatment is associated with
treatment. Of note, serum calcium levels may fluctuate hypercalciuria, which increases the risk of develop
without obvious reasons in patients being treated for ing nephrocalcinosis and kidney stones. To establish a
chronic hypoparathyroidism. Likewise, patients should more physiological alternative to conventional therapy,
be familiar with potential complications of their disease studies aimed at PTH replacement were first initiated
to enable early detection. with synthetic human PTH(1–34) (hPTH(1–34)),
the biologically active amino-terminal fragment of the
Management full-length PTH peptide. Both the active N-terminal
Conventional therapy fragment and the full-length 84‑amino-acid peptide
Conventional treatment of adults with hypopara bind to and a ctivate PTH1R.
thyroidism involves calcium supplementation or activ
ated vitamin D supplementation (using calcitriol or
alphacalcidol (1α(OH)D3); BOX 3), or a combination of Box 3 | Vitamin D metabolism
both. Treatment is aimed at increasing intestinal calcium Vitamin D precursors are derived from the conversion
absorption to increase serum calcium concentrations of cholesterol to cholecalciferol (vitamin D3) through a
(FIG. 1). Goals of chronic management include prevent chemical reaction that takes place in the skin and requires
ing signs and symptoms of hypocalcaemia and redu UVB radiation. Cholecalciferol or ergocalciferol
cing the risk of long-term complications5,6 (TABLES 2,3). (vitamin D2) can be ingested through the diet, but only
Treatment is adjusted to achieve low to low-normal very few foods (such as fatty fish) contain adequate levels.
serum calcium (~8.0–8.5 mg per dl (2.0–2.12 mM) and The biologically inactive cholecalciferol or ergocalciferol
normal urine calcium levels. is activated by two hydroxylation steps. Hydroxylation in
the liver to either calcifediol (25(OH)cholecalciferol) or to
Patients often require a minimum of 1 g of elemen
25(OH)ergocalciferol — together known as 25(OH)D —
tal calcium in doses divided throughout the day. produces the stable precursor of the active hormone,
Calcium carbonate (40% calcium by weight) is the which is typically measured in clinical practice to assess
least expensive formulation. As it depends on an acidic vitamin D status. Further hydroxylation of 25(OH)D in
gastric pH for efficient absorption, it should be taken the kidney to calcitriol (also known as 1,25‑dihydroxy
with meals. Calcium citrate, calcium gluconate or vitamin D (1,25(OH)2D) — the active form of vitamin D —
calcium lactate are alternatives for calcium carbon is the rate-limiting step that is enhanced by parathyroid
ate, but more tablets are needed for these, owing to hormone and blocked by fibroblast growth factor 23.
their relatively low content of elemental calcium. Treatment of hypoparathyroidism often involves calcitriol
Calcium citrate is recommended for patients who or alphacalcidol (1α(OH)D3), the latter of which requires
hepatic 25‑hydroxylation for bioactivation.
have achlorhydria (impaired gastric acid secretion)

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hPTH(1–34). Synthetic hPTH was used in the first To further improve metabolic control, pump delivery
clinical trials testing hormonal replacement therapy of of hPTH(1–34) was studied in adults and children with
hypoparathyroidism. In these studies, the biologically various hypoparathyroidism aetiologies and compared
active fragment hPTH(1–34) was formulated in the with twice-daily injections61,133. hPTH(1–34) micro
pharmacy at the study site, as there was no commer boluses (0.1 μg) were delivered at intervals ranging
cially available hormone when the studies were initiated from 2 to 8 pulses per hour and corresponded to a dose
in 1992. Synthetic hPTH(1–34) was given alone, with range of 4.8–19.2 μg daily, which is approximately one-
out calcitriol, thiazide diuretics or phosphate binders, third of the average daily hPTH(1–34) dose required
and titrated to maintain serum calcium levels within during twice-daily injection therapy. Pump delivery of
or slightly below the low-normal range and normal hPTH(1–34) led to less fluctuation of serum calcium
urine calcium excretion. Various hPTH(1–34) regi levels and a >50% reduction in urine calcium levels in
mens were evaluated in short-term or long-term stud adults with post-surgical hypoparathyroidism compared
ies61,62,129–133. Initial studies confirmed the advantages of with twice-daily delivery 133. Serum magnesium con
once-daily subcutaneous hPTH(1–34) injection over centrations were higher and bone resorption markers
conventional therapy 132. The phosphaturic and calcium- lower in the pump group133. Although pump delivery
retaining effects of hPTH(1–34) on the kidney reduced has clinical advantages, it requires a skilled provider with
serum phosphate levels and urinary calcium excretion expertise in the management of hypoparathyroidism
compared with conventional therapy over a period of and in pump devices. In children with congenital
10 weeks132. hPTH(1–34) replacement compared with hypoparathyroidism (autoimmune polyendocrine syn
conventional therapy was further investigated in a drome type 1 or a mutation in CASR), pump delivery
randomized controlled study over a 3‑year period in of hPTH(1–34) compared with twice-daily injections
both adults and children129,131. resulted in near normalization of mean serum calcium
Comparisons of once-daily and twice-daily levels (2.02 ± 0.05 mmol per l versus 1.88 ± 0.03 mmol
h PTH(1–34) therapy in both adults and children per l; P < 0.05), a nonsignificant reduction of mean
demonstrated that an increased frequency of injections urine calcium excretion (5.17 ± 1.10 mmol per 24 h ver
significantly reduced the total daily dose needed62,130. sus 6.67 ± 0.76 mmol per 24 h; P = 0.3) and a significant
Twice-daily injections resulted in lower markers of reduction in the levels of bone turnover markers61. Pump
bone turnover and more physiological serum cal therapy increased serum magnesium levels, lowered
cium and magnesium profiles with less fluctuation in the urinary magnesium excretion and permitted the
the later portion of the day compared with once-daily reduction in magnesium supplements61,133.
hPTH(1–34) injections. A 3‑year randomized controlled Three children with hypoparathyroidism (two
trial in children compared conventional therapy to siblings with autoimmune polyendocrine syndrome
twice-daily subcutaneous hPTH(1–34) injection therapy, type 1 and one child with idiopathic hypopara
with doses titrated to specific target serum and urine thyroidism) refractory to conventional therapy were
levels131. In both treatment groups, mean serum calcium successfully treated with continuous subcutaneous
levels were slightly below the normal range; mean urine administration of hPTH(1–34) over a 3‑year period. The
calcium excretion, lumbar spine and whole-body bone two patients with autoimmune polyendocrine syndrome
mineral density, as well as height and weight percen type 1 required substantially higher doses than the child
tiles, were within the normal range and did not differ with idiopathic hypoparathyroidism134.
between groups129,131. Serum calcitriol levels were higher Sudden discontinuation of treatment with
in children receiving twice-daily hPTH(1–34) injections hPTH(1–34) may lead to hypocalcaemia, and patients
than in those receiving conventional therapy 131. This may require significantly higher than baseline doses
study shows that treatment with hPTH(1–34) is safe of calcium and calcitriol135. Weaning hPTH(1–34)
and effective in maintaining stable calcium homeostasis may be a safe approach for patients transitioning to
in c hildren with hypoparathyroidism and allowed for conventional therapy.
normal linear growth over a 3‑year period. hPTH(1–34) was approved by the US FDA in 2002
In 27 adults with hypoparathyroidism, conventional for the treatment of osteoporosis in adults. The restric
treatment was compared with twice-daily injections of tions on the length of treatment to 2 years and the
hPTH(1–34) in a 3‑year randomized open-label trial129. exclusion of its use in children render this peptide not
Serum calcium levels were maintained slightly below practicable for use in long-term replacement therapy of
the normal range in both groups. Although mean urin hypoparathyroidism as an ‘off-label’ drug.
ary calcium excretion was consistently within normal
range in the hPTH(1–34) group and above the nor rhPTH(1–84). Full-length rhPTH(1–84) is associ
mal range in the conventional treatment arm, the levels ated with a longer calcaemic effect when injected into
were not significantly different between groups. Bone the thigh than when injected into the abdomen 136;
mineral content and bone mineral density, measured hPTH(1–34) for osteoporosis is subcutaneously injected
twice yearly, were not different between the groups129. into either the thigh or the abdomen. One single-centre
Treatment with hPTH(1–34) for 3 years was safe and study tested subcutaneous rhPTH(1–84) injection in the
effective in maintaining serum calcium at the slightly thigh in 33 patients over a 6‑year period compared with
low to low-normal range without hypercalciuria in baseline137. The initial dose was 100 μg subcutaneously
adults with hypoparathyroidism. every other day, but most patients transitioned later to

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PRIMER
once-daily injections, with doses ranging from 25 μg to in trabecular number 101. Intratrabecular tunnelling
100 μg daily. Compared with baseline, serum calcium (bone resorption in trabecular packets) was demon
levels were stable over 6 years, and serum phosphate strated in more than half of the biopsies104. These micro
and urinary calcium levels decreased significantly at sev structural changes demonstrate that one of the functions
eral of the measured time-points. Bone mineral density of PTH in bone is to maintain ongoing turnover and
at the spine mildly increased, whereas it decreased at repair bone.
the hip and the distal radius. The required calcium The FDA approved rhPTH(1–84) in 2015 as an
dose was reduced by 53% and calcitriol dose by 67%. adjunct to calcium and vitamin D for the treatment
Adverse events included hypercalcaemia (12 episodes of adults with hypoparathyroidism who cannot be
in 9 patients), hypocalcaemia (5 episodes), musculo well-controlled on conventional therapy. In 2017, the
skeletal symptoms, infections, fractures (8 fractures in European Commission granted Conditional Marketing
6 patients), and renal stones (3 patients). This study Authorization for rhPTH(1–84) in Europe.
concluded that treatment with rhPTH(1–84) is safe and
effective for at least 6 years and allows a reduction in the Thiazide diuretics
dose of conventional therapy. Thiazide diuretics can reduce urinary calcium excre
In another single-centre study, 62 patients with tion141–144 and are prescribed as an adjunct therapy.
hypoparathyroidism were randomized (1:1) to either A study in dogs with hypoparathyroidism treated with
placebo or rhPTH(1–84) (100 μg daily) for 24 weeks as chlorothiazide demonstrated a progressive decrease in
an add‑on to conventional therapy 138. Supplements were the fractional clearance of calcium, with increased clear
titrated to achieve normal serum calcium levels and ance of sodium145. Thus, a high-salt diet would override
24‑hour urine calcium excretion. Daily doses of calcium any reduction in calciuria associated with thiazides, and
and activated vitamin D decreased by 75% and 73%, dietary restriction of sodium is required. Indeed, a study
respectively, in patients randomized to rhPTH(1–84) in seven patients with mild post-surgical hypopara
compared with placebo. Bone turnover markers thyroidism reported that oral chlorthalidone in combin
increased, and bone mineral density of the hip and ation with a low-salt diet was effective in lowering urinary
spine decreased, with rhPTH(1–84) therapy compared calcium levels146. Thiazides lead to urinary magnesium
with placebo. losses. Thus, patients with autosomal dominant hypo
In a double-blind, multinational, randomized con calcaemia type 1, who have abnormally high urinary
trolled trial (REPLACE), 134 patients with hypopara magnesium excretion and hypomagnesaemia, should
thyroidism were randomized (2:1) to rhPTH(1–84) avoid thiazide diuretics147. Likewise, patients with auto
or placebo for 24 weeks139,140. When rhPTH(1–84) was immune polyendocrine syndrome type 1 and adrenal
initiated at 50 μg daily, activated vitamin D (calcitriol insufficiency should not take thiazide diuretics, to avoid
or alphacalcidol) and/or calcium supplements were the resulting increase in urinary sodium excretion148.
reduced by ~50%. At subsequent 2‑week intervals, doses
of rhPTH(1–84) were increased and supplements were Diet
reduced. The primary end point was defined as >50% Treatment of hypoparathyroidism is facilitated by a
reductions of activated vitamin D and calcium supple diet rich in calcium. To manage hyperphosphataemia,
ments at 24 weeks, while maintaining serum calcium con dietary phosphate restriction and phosphate bind
centrations within the target range (equal to baseline and ers are sometimes prescribed in hypoparathyroidism.
less than the upper limit of normal). This was achieved in Simply avoiding foods with phosphate additives and
53% of patients treated with rhPTH(1–84) versus 2% of limiting commercially prepared foods, which are often
patients treated with placebo (P < 0.001). Urinary calcium high in sodium and phosphate, effectively limits phos
levels did not change with rhPTH(1–84) therapy 140, but phate intake but enables dairy intake, which provides
serum phosphate levels decreased significantly compared important nutrients, especially in children. All patients,
with placebo139. Adverse events were similar between particularly if risk factors for kidney stone formation are
both groups and included hypocalcaemia, muscle spasm, present, should be counselled regarding adequate fluid
paraesthesia, headache and nausea. After the end of treat intake to decrease the risk of renal calcifications.
ment with rhPTH(1–84), hypocalcaemia was reported
in a higher proportion of patients in the rhPTH(1–84) Complications
group than in the placebo group140. Conventional therapy is often associated with hyper
Conventional treatment does little to alter the marked calciuria even when the serum calcium levels are in the
static and dynamic abnormalities of bone in hypopara low-normal or slightly below the normal range. Although
thyroidism123. By contrast, use of rhPTH(1–84) has PTH therapy has the potential to reduce urine calcium
shown reversal and recovery of many of these abnormal excretion compared with conventional therapy, only a few
ities. Transiliac crest bone biopsies have demonstrated studies demonstrate such a reduction, possibly because
a rapid and marked increase in tetracycline-labelled of an insufficient duration of action of once-daily PTH
surfaces, representing an increase in bone formation, as injections on the kidneys132,137,138. To avoid renal damage
early as 3 months after rhPTH(1–84) administration101. from recurrent transient hypercalcaemia and concur
Within 1 year of treatment, improvements in both corti rent hypercalciuria, close monitoring of serum calcium
cal and trabecular bone were observed, including, for levels should occur after each medication adjustment 5,6
example, a reduction in trabecular width and an increase (TABLES 2,3).

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PRIMER
The effects of hPTH injections on bone depend to focus, often described as ‘brain fog’; and emotional
on the size and frequency of the dose. Once-daily or difficulties, which are variable but encompass, among
twice-daily hPTH(1–34) injections62 and alternate-day others, anxiety, depression and personality disorders.
or once-daily rhPTH(1–84) injections produced persis Recent studies have attempted to define the nature
tently increased levels of bone turnover markers, with and prevalence of QOL impairments in hypopara
varying long-term effects on bone mineral density thyroidism7,111,113,120,157. When compared with healthy
measured by DXA129,137. Pump delivery of hPTH(1–34) controls or with patients who have had thyroid surgery
normalized the levels of bone turnover markers in a but retained normal parathyroid function, patients with
12‑week study 61, but further studies of pump delivery post-surgical hypoparathyroidism had significantly
of hPTH(1–34) are required to determine its long-term higher global complaint scores113, lower physical sum
effects on bone. mary scores on the 36-Item Short Form Health Survey
Potential carcinogenic effects underlie the cur (SF‑36) and decreased muscle function 111. Lower
rent FDA black box warning on hPTH(1–34) and QOL scores have also been observed in patients with
rhPTH(1–84) use. In 1998, Eli Lilly released its 2‑year hypoparat hyroidism in registries and surveys from
rat carcinogenicity data in connection with the new Norway 7, Denmark8,9 and the United States120. Finally,
drug application of hPTH(1–34) to the FDA 149–151. patients who developed post-surgical hypopara
Osteosarcomas developed in these rats exposed to thyroidism had lower QOL scores than anticipated by
3–58 times the human equivalent dose over a period of healthy individuals given the description of the disease
18–24 months (about 75 years of a human life). The osteo and by experienced (endocrine) surgeons157.
sarcomas were dose-dependent and duration-dependent When hPTH(1–34) and rhPTH(1–84) became
and most evident in animals receiving the highest dose available, there was a hope that replacing the missing
(75 μg per kg). Similar rodent carcinogenicity studies hormone would restore QOL in patients with hypopara
demonstrated an increased osteosarcoma risk associ thyroidism. Indeed, many patients treated with synthetic
ated with pharmacological doses of subc utaneous hPTH report improved well-being compared with base
rhPTH(1–84) injections152. Subsequent data in non- line (conventional treatment). However, despite such
human primates receiving high doses of hPTH(1–34) laudable anecdotal reports, findings from the studies
(5 μg per kg) for 18 months showed increased bone mass, of synthetic hPTH on QOL have been inconsistent.
but no osteosarcoma or bone proliferative lesions were In an open-label, uncontrolled study from Columbia
evident after the therapy was discontinued or during a University, New York, USA, QOL, as assessed by SF-36,
subsequent 3‑year observation period153. Despite the rat was low in all domains at baseline despite acceptable
toxicity data, an important observation in humans is that control of serum calcium levels through conventional
longstanding hyperparathyroidism is not associated with therapy 158,159. All domains improved significantly in
the development of osteosarcomas despite chronically response to rhPTH(1–84) at 1 and 2 years158. In individ
elevated PTH levels154. Furthermore, no increased rate uals who completed 5 years of therapy, QOL improved
of osteosarcoma has emerged despite extensive use of for the duration of the study 159. Similar improvements
hPTH(1–34) in patients with hypoparathyroidism or were reported in an Italian study that used twice-daily
osteoporosis over >20 years, although most of the latter injection of hPTH(1–34)160. However, many patients in
were treated for only 2 years155,156. this study had hypocalcaemia at baseline, which was
Recently, two guidelines were developed to assist clin corrected during the study 160. Thus, it is possible that
icians treating chronic hypoparathyroidism in adults5,6 improved well-being may be at least in part due to better
(TABLES 2,3). The data on which these guidelines are based calcaemic control.
are from relatively small trials, with mainly biochemical In contrast to the strikingly positive results of the
as opposed to clinical end points (such as disease pro open-label studies described above, a Danish double-
gression and survival). The guideline sponsored by the blind, placebo-controlled study that enrolled relatively
European Society of Endocrinology 5 was based on a sys well-controlled patients with hypoparathyroidism
tematic review of the literature, and the guideline from found that patients receiving rhPTH(1–84) had less
the First International Conference on the Management improvement in SF-36 scores than those who received
of Hypoparathyroidism was based on both a literature placebo and actually had worse performance on at least
review and expert opinion6. Both guidelines recom some muscle function tests161. However, many patients
mend intervals for monitoring for possible complica treated with rhPTH(1–84) in that study developed
tions of the condition, such as renal insufficiency, soft hypercalcaemia, which may have negatively affected
tissue c alcifications and h
ypercalciuria, as detailed in their well-being. Preliminary analysis of the REPLACE
TABLES 2,3. study revealed improved QOL scores (SF-36) with
rhPTH(1–84) treatment but not with placebo. However,
Quality of life the between-group differences were not significant 162.
Patients with hypoparathyroidism on conventional Further studies are needed to better understand the
therapy with calcium and activated vitamin D often nature and the degree of QOL impairments, individual
have complaints suggestive of reduced QOL1,2,4. These differences, and the relationship to biochemical variables
complaints include physical symptoms, such as fatigue; (if any) and treatment modalities. Developing better and
neuromuscular complaints, such as weakness, cramps, hypoparathyroidism-specific instruments to assess QOL
paraesthesia and seizures; inability to concentrate or will be crucial in achieving this goal.

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Box 4 | Indication for considering the use of rhPTH(1–84) therapy As we look to the future, several issues require greater
insight and knowledge, including questions related to
Expert opinion of the First International Conference on the Management of which patients should be considered for treatment with
Hypoparathyroidism to guide the use of full-length recombinant human parathyroid the newly approved rhPTH(1–84) therapy. Although
hormone (rhPTH(1–84))6 patients with mild disease can often be managed with
• Inadequate control of serum calcium with hypocalcaemia, or erratic swings to oral calcium and/or activated vitamin D, patients
hypocalcaemia or hypercalcaemia on conventional therapy with more-severe manifestations require higher doses
• Doses of supplemental calcium of >2.5 g, or of activated vitamin D of >1.5 μg calcitriol of calcium and activated vitamin D, which raises con
or >3.0 μg alphacalcidol daily needed cerns about long-term sequelae, such as soft tissue
• Evidence for renal involvement with hypercalciuria, nephrocalcinosis, nephrolithiasis calcifications in the kidneys, brain and joints. Moreover,
or reduced creatinine clearance on conventional therapy conventional therapy does not restore the underlying
• Hyperphosphataemia or a calcium–phosphate product of >55 mg2 per dl2 hormonal deficiency. Some experts also consider the
(or >4.4 mmol2 per l2) on conventional therapy reduced QOL, now substantiated in many studies using
• A gastrointestinal disorder or post-bariatric surgery, associated with malabsorption generic metrics, such as the SF‑36 QOL scale, as being
• Reduced quality of life on conventional therapy due, at least in part, to the lack of PTH.
Adapted with permission from Brandi, M. L. et al., Management of hypoparathyroidism: The indications for the use of FDA-approved
summary statement and guidelines, J. Clin. Endocrinol. Metab., 2016, 101 (6), 2273–2283, rhPTH(1–84) target patients with hypoparathyroidism
by permission of Oxford University Press. who cannot be well-controlled on conventional therapy.
Although the wording of the FDA term ‘well-controlled’
is subject to interpretation, the First International
Outlook Conference on the Management of Hypoparathyroidism
In the past 25 years since the first studies of syn considered six specific situations, any one of which could
thetic hPTH therapy were initiated, our knowledge of lead to rhPTH(1–84) therapy 123 (BOX 4). These guidelines
hypoparathyroidism has increased markedly. For a rare will evolve over time and are not meant to be rules but
disease, the stimulus to conduct further research is due instead guidance for the clinician to help to decide the
to the fact that hypoparathyroidism was one of the last best course of action for an individual patient. Data on
of the classic endocrine deficiency diseases for which the the efficacy of rhPTH(1–84) therapy in preventing long-
replacement hormone was not available. This is an ironic term complications of hypoparathyroidism are sparse,
historical note, as the primary amino acid sequence of and safety data in large cohorts of patients, especially in
PTH was delineated in the late 1960s163 and it was the children, are missing. The current costs of rhPTH(1–84)
second peptide hormone, after insulin, for which a sand therapy and compliance with the injectable form are
wich immunoassay was developed164. Almost 50 years potential hurdles for its use. Long-term, multicentre,
later, we now have an approved replacement therapy controlled trials are necessary to determine the best
for hypoparathyroidism. possible treatment for patients with hypoparathyroidism.
The recent interest in this disorder has resulted in In addition, more-detailed analysis of the skeleton
more information about the incidence, prevalence and with newer technologies, such as high-resolution periph
natural history of hypoparathyroidism. Our understand eral quantitative CT, trabecular bone score and reference
ing of the underlying genetics of many of the rare vari point indentation, might yield insights into altered bone
ants has been enhanced greatly. Such insights not only quality in hypoparathyroidism. To understand the long-
have added to our knowledge of rare genetic mutations term impact of rhPTH(1–84), more insight into the
that cause hypoparathyroidism but also have given us natural history of hypoparathyroidism, skeletal dynamics,
insight into the molecular actions of PTH and its cellular bone quality, renal function, QOL and known complica
functions under normal circumstances. tions of the disease is needed. With regard to long-term
The experience with rhPTH(1–84) as a treatment studies, the idea that rhPTH(1–84) might have an effect
of hypoparathyroidism provides evidence for the to reverse or mitigate ectopic calcifications in soft t issues
maintenance of the serum calcium levels, at doses of is worthy of study. Another direction that is likely to
supplemental calcium and activated vitamin D that be of importance is the feasibility and applicability of
are substantially lower than pretreatment values. Only new delivery systems (including the transdermal patch,
modest effects on urinary calcium excretion, restor continuous infusion pump and oral hPTH formulations),
ation of abnormal skeletal histomorphometric para as well as PTH analogues and mimetics165,166.
meters and QOL have been observed. Experts have With the advances over the past decade and the
galvanized new knowledge of hypoparathyroidism by marked interest in this orphan disease, we are likely to
offering guidelines for the diagnosis and management learn more, not only about the disease itself but also
of this disease5,6. about the many important and varied actions of PTH.
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cardiomyopathy as initial presentation of primary A blind panic. Lancet 357, 1262 (2001). synthetic parathyroid hormone 1–34 (hPTH 1–34)
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(2014). Mucocutaneous manifestations of acquired J. Bone Miner. Res. 30, 2112–2118 (2015).

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PRIMER
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persistent efficacy and apparent safety of this & Bilezikian, J. P. A 10‑year prospective study terminal peptide fragments of parathyroid hormone
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146. Porter, R. H. et al. Treatment of hypoparathyroid models of acquired hypoparathyroidism and treatment M.M. has received consulting fees and a research grant from
patients with chlorthalidone. N. Engl. J. Med. 298, with a long-acting parathyroid hormone analog. Shire Pharmaceuticals. J.P.B. is a consultant for Shire
577–581 (1978). J. Bone Miner. Res. 31, 975–984 (2016). Pharmaceuticals. R.V.T. has received grant funding from NPS/
147. Sato, K. et al. Hydrochlorothiazide effectively reduces 166. Tamura, T. et al. Identification of an orally active Shire Pharmaceuticals, GlaxoSmithKline, Novartis Pharma
urinary calcium excretion in two Japanese patients small-molecule PTHR1 agonist for the treatment of AG and the Marshall Smith Syndrome Foundation, and he is
with gain‑of‑function mutations of the calcium-sensing hypoparathyroidism. Nat. Commun. 7, 13384 (2016). a medical adviser for the patient charity HypoPara UK. F.M.H.
receptor gene. J. Clin. Endocrinol. Metab. 87, 167. Lemos, M. C. & Thakker, R. V. GNAS mutations has received grant funding from NPS/Shire Pharmaceuticals
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148. Breslau, N. A., McGuire, J. L., Zerwekh, J. E. disorders. Hum. Mutat. 36, 11–19 (2015). from Shire Pharmaceuticals and has received honoraria from
& Pak, C. Y. The role of dietary sodium on renal 168. Linglart, A., Gensure, R. C., Olney, R. C., Jüppner, H. Amgen. L.R. has received honoraria and speaker fees from
excretion and intestinal absorption of calcium and & Bastepe, M. A novel STX16 deletion in autosomal Amgen, Eli Lilly, Novo Nordic, Takeda Pharmaceuticals, NPS
on vitamin D metabolism. J. Clin. Endocrinol. Metab. dominant pseudohypoparathyroidism type Ib Pharmaceuticals, Shire, Bristol-Myers Squibb, Abbott,
55, 369–373 (1982). redefines the boundaries of a cis-acting imprinting and Boehringer Ingelheim Denmark. T.J.V. is a consultant and
149. Vahle, J. L. et al. Bone neoplasms in F344 rats given control element of GNAS. Am. J. Hum. Genet. 76, investigator for Shire Pharmaceuticals. D.M.S. is a consultant
teriparatide [rhPTH(1–34)] are dependent on duration 804–814 (2005). for Shire Pharmaceuticals and Ascendis Pharmaceuticals.
of treatment and dose. Toxicol. Pathol. 32, 426–438 169. Richard, N. et al. A new deletion ablating NESP55 D.M.M. and K.K.W. declare no competing interests.
(2004). causes loss of maternal imprint of A/B GNAS and
150. Vahle, J. L., Sato, M. & Long, G. G. Variations in autosomal dominant pseudohypoparathyroidism Publisher’s note
animal populations over time and differences in type Ib. J. Clin. Endocrinol. Metab. 97, E863–E867 Springer Nature remains neutral with regard to jurisdictional
diagnostic thresholds used can impact tumor (2012). claims in published maps and institutional affiliations.
incidence data. Toxicol. Pathol. 35, 1045–1046 170. Brix, B. et al. Different pattern of epigenetic changes
(2007). of the GNAS gene locus in patients with How to cite this article
151. Vahle, J. L. et al. Skeletal changes in rats given daily pseudohypoparathyroidism type Ic confirm the Mannstadt, M. et al. Hypoparathyroidism. Nat. Rev. Dis.
subcutaneous injections of recombinant human heterogeneity of underlying pathomechanisms in this Primers 3, 17055 (2017).

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CORRECTION
CORRECTION
Hypoparathyroidism
Michael Mannstadt, John P. Bilezikian, Rajesh V. Thakker, Fadil M. Hannan, Bart L. Clarke, Lars Rejnmark,
Deborah M. Mitchell, Tamara J. Vokes, Karen K. Winer and Dolores M. Shoback
Nature Reviews Disease Primers 3, 17055 (2017)
In the version of the article originally published, Lars Rejnmark was incorrectly stated as Lars Reijnmark. The article has
now been corrected.
NATURE REVIEWS | DISEASE PRIMERS www.nature.com/nrdp

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PRIMER

Hypoparathyroidism is a disease characterized by conventional treatment with activated vitamin D and

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17055 | 1

Author addresses with hypoparathyroidism of any cause since 1945.

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Table 1 | Inherited types of hypoparathyroidism

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Target cell PTH PTH1R

Gq/11α Gsα Pseudohypoparathyroidism

Ca2+ Ins(1,4,5)P3 + DAG cAMP

Gq/11α Autosomal dominant hypocalcaemia

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Pharyngeal Formation of common Separation of parathyroid Upregulation

TBX1, EYA1, GATA3,

Autosomal forms of hypoparathyroidism. Glial X‑Linked recessive hypoparathyroidism. X‑Linked

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Central nervous system Neuropsychiatric system

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Ophthalmological system. Hypoparathyroidism is Neuropsychiatric system. Hypoparathyroidism is

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Table 2 | Goals of management of hypoparathyroidism according to the European Society of Endocrinology

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