Endocrine

https://doi.org/10.1007/s12020-020-02324-2

REVIEW

Diagnosis and management of hypocalcemia

Jessica Pepe1 Luciano Colangelo 1 Federica Biamonte1 Chiara Sonato1 Vittoria Carmela Danese1
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Veronica Cecchetti1 Marco Occhiuto1 Valentina Piazzolla1 Viviana De Martino1 Federica Ferrone1
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Salvatore Minisola1 Cristiana Cipriani1

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Received: 15 February 2020 / Accepted: 18 April 2020

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
The aim of this clinical narrative review is to summarize and critically appraise the literature on the differential diagnosis of
hypocalcemia and to provide its correct management. Calcium is essential for muscle contraction and neurotransmitter
release, but clinical manifestations of hypocalcaemia (serum calcium level <8 mg/dl; 2.12 mmol/L) may involve almost any
organ and system and may range from asymptomatic to life-threating conditions. Disorders causing hypocalcemia can be
divided into parathyroid hormone (PTH) and non-PTH mediated. The most frequent cause of hypocalcemia is postsurgical
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hypoparathyroidism, while a more comprehensive search for other causes is needed for appropriate treatment in the non
PTH-mediated forms. Intravenous calcium infusion is essential to raise calcium levels and resolve or minimize symptoms in
the setting of acute hypocalcemia. Oral calcium and/or vitamin D supplementation is the most frequently used as treatment
of chronic hypocalcemia. In hypoparathyroidism, providing the missing hormone with the use of the recombinant human
(rh) PTH(1–84) has been recently approved both by the Food and Drug Administration (FDA) and the European Medicines
Agency (EMA). This new therapy has the advantage of being effective for correcting serum calcium levels and significantly
reducing the daily requirements of calcium and active vitamin D supplements. However, due to the high cost, a strict
selection of candidates to this therapy is necessary. More challenging is the long-term hypocalcemia treatment, due to its
associated complications. The development of long-acting recombinant human PTH will probably modify the management
of chronic hypoparathyroidism in the future.
Keywords Hypocalcemia Diagnosis Treatment Calcium Hypoparathyroidism
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Introduction diagnosis [3, 4] if measured within 2 h of sampling and

Hypocalcemia is one of the most common electrolytic dis-
orders whose diagnosis and management need careful
evaluation by clinicians. It is defined as corrected serum
total calcium levels <2.12 mmol/l (8.5 mg/dl). For clinical
practice purposes, correction of serum calcium levels for
serum albumin concentration is useful in many, but not all,
cases, being less accurate in patients with perturbation of
the acid-base balance or of the serum proteins concentration
[1, 2]. In those cases, measurement of ionized calcium
(normal values 1.17–1.33 mmol/L) is the gold standard for
* Luciano Colangelo
luciano.colangelo@hotmail.it
1
Department of Clinical, Internal, Anesthesiology and
Cardiovascular Sciences, Sapienza University, Rome, Italy
maintaining room temperature at 4 °C [5].
The formula for albumin-corrected serum calcium is as
follows: total serum Ca concentration (mmol/L) + 0.02 ×
[40 – serum albumin concentration (g/L)] [4].
Patients with hypocalcemia may present with a variety of
symptoms and signs, as the low serum calcium levels may
potentially impact virtually any organ and system. New
onset hypocalcemia may represent a life-threatening situa-
tion requiring immediate intervention, while the chronic
reduction in serum calcium levels is sometimes asympto-
matic or slightly symptomatic. In all cases, the identifica-
tion, clinical assessment and management of hypocalcemia
are key points that need to be addressed simultaneously, as
soon as possible. In particular, the evaluation of the causes
of hypocalcemia is the main determinant in the diagnostic
workup and to guide successful therapeutic interventions.
Hypocalcemia is reported in both genetic and acquired
disorders of several organs and systems. In particular,
 Endocrine

diseases that may alter the parathyroid glands, skeleton, gut,
kidneys axis, all of which are responsible for the fine reg-
ulation of serum calcium levels, may cause hypocalcemia
[3].
The focus of this review is to update the evidence on the
diagnostic assessment and clinical management of hypo-
calcemia with the aim of providing a useful algorithm for
clinical practice.
Causes of hypocalcemia
Disorders causing hypocalcemia can be divided into para-
thyroid hormone (PTH) and non-PTH mediated, as
summarized in Table 1. In the first group, are included all
cases of impaired parathyroid gland function leading to
absent or reduced PTH production, while in the second
group other organs and systems are involved. As illustrated
in Table 1, the kidneys, the liver, the skeleton, the gut, and
the vitamin D metabolism play a major role in these cases
that are commonly associated with secondary increase of
PTH levels.
Hypoparathyroidism is classified as a rare disease, with a
prevalence ranging from 5.3/100,000 to 37/100,000 inha-
bitants per year depending on the population studied [6, 7].
Hypocalcemia is associated with hyperphosphatemia and
inappropriately low or low-normal serum PTH levels. Post-
surgical hypoparathyroidism is the most common form of

Table 1 Causes of
PTH—mediated causes
hypocalcemia.
Genetic disorders Acquired disorders

Familial isolated hypoparathyroidism Post-surgical Hypoparathyroidism

Syndromes associated with hypoparathyroidism: Hypomagnesemia
−22q11.2 deletion (DiGeorge) syndrome Hypermagnesemia
−Hypoparathyriodism, Sensory Neural Deafness, Renal
Dysplasia Syndrome (HDR) Autoimmune polyendocrine syndrome
−Kearns–Sayre syndrome type 1 (APS1)
−Kenny–Caffey syndrome type 1 and 2 Blood transfusion (haemosiderosis)
−Mitochondrial encephalomyopathy with lactic acidosis and Radiation therapy
stroke-like episodes (MELAS) syndrome
Sclerotic metastases
−Sanjad Sakati syndrome (SSS)
−Mitochondrial trifunctional protein (MTP) deficiency
syndrome
Autosomal Dominant Hypocalcemia (ADH) 1 and 2
Pseudohypoparathyroidism 1A and 1B
Wilson’s disease
Hemochromatosis

Non PTH—mediated causes

Genetic Acquired

Vitamin D dependent rickets (VDDR) type 1 and 2 Vitamin D deficiency

Hypocalcemic vitamin D-resistant rickets (HVDRR) Malabsorption
Osteopetrosis Chronic kidney disease
Maternal hyperparathyroidism “Hungry bone” syndrome
End-stage liver disease
Critical illness
Acute pancreatitis
Citrate (blood trasfusion)
Drugs:
−Loop diuretics
−Phosphate
−Foscarnet
−EDTA
−Anti-convulsants
−Magnesium sulfate
−Calcitonin, bisphosphonates, denosumab
−Cinacalcet
Endocrine

the disease, and it may be transient when it recovers in the
first days-months after surgery or chronic (or permanent),
when it lasts more than 6 months after surgery [8]. In this
context, early measurement of serum calcium and PTH
levels after neck surgery demonstrated to be good predictors
of permanent post-surgical hypoparathyroidism [9, 10].
Prevalence of post-surgical hypoparathyroidism is
described in a figure of 1.4–22/100,000 inhabitants per year,
while the non-surgical causes are reported in 1.3 to 2.3/
100,000 per year [7, 11].
Hypomagnesemia is a relatively common cause of
functional hypoparathyroidism, while hypermagnesemia is
less common in clinical practice. Both disorders lead to
reduction of PTH secretion by parathyroid glands pre-
sumably through the stimulation of the Calcium Sensing
Receptor (CASR) [8].
Pseudohypoparathyroidism is a rare disorder character-
ized by peripheral resistance to PTH action; hypocalcemia,
hyperphosphatemia and high serum PTH levels are the main
biochemical findings [8].
Drug-induced hypocalcemia is not an uncommon con-
dition in clinical practice and can be associated with
increase in renal calcium excretion (loop diuretics), altered
vitamin D metabolism (anticonvulsants), calcium pre-
cipitation (citrate, phosphate, EDTA), or inhibition of bone
resorption (bisphosphonates, denosumab) (Table 1).
Severe vitamin D deficiency may cause hypocalcemia
that is usually associated with hypophosphatemia and high
serum PTH. Malabsorption syndromes (e.g., celiac disease;
complication of bariatic surgery; inflammatory diseases,
etc.) are typically associated with hypocalcemia and vitamin
D deficiency. In addition, some forms of autoimmune
hypoparathyroidism may be associated with celiac disease
with consequent further reduction in serum calcium levels
due to the perturbation of calcium absorption.
Finally, hypocalcemia may be induced by perturbation of
the PTH-vitamin D axis during critical illness or after major
surgery or by calcium saponification of fatty acids released
during acute pancreatitis [8, 12].
Clinical presentation
Factors influencing the clinical presentation of hypocalce-
mia are severity and timing of serum calcium reduction
(acute vs chronic), patient’s age, complications, and
comorbidities. For the purposes of this review, we present
the signs and symptoms of acute and chronic hypocalcemia
in two different sections, but it is important to bear in mind
that many of the signs and symptoms may be present in
both conditions, as summarized in Table 2. In these cases, it
is usually the severity of the signs and/or symptoms

Table 2 Clinical manifestations

Organ/System Acute Chronic
of hypocalcaemia [6, 8, 30]
Cardiovascular Prolongation of QTc interval
2:1 atrioventricular block or 2nd/3rd degree atrioventricular blocks
Hypotension
Cardiomyopathy
Heart failure
Respiratory Laryngeal stridor, bronchospasm
Nervous system Seizures
Paresthesias (perioral and extremities)
(Chvostek’s sign and Trousseau’s sign)
Tetany
Coma
Extrapyramidal disorders (Fahr’disease)
Pseudotumor cerebri
Neuropsychiatric manifestations (anxiety, depression, bipolar disorders)
Ophthalmology Cataracts
Calcification of cornea
Papilledema
Renal Hypercalciuria
Reduced filtration rate
Kidney stones
Nephrocalcinosis
Dental Alterated tooth morphology
Dental enamel hypoplasia
Dermatological Alopecia
Xeroderma

presentation that marks the real difference between acute vs
chronic hypocalcemia.
Acute hypocalcemia
Acute hypocalcemia may present with severe symptoms,
but there is a large interindividual threshold that can influ-
ence the clinical response to low serum calcium levels
[8, 13, 14]. This point explains why epidemiological data
showing the prevalence of symptoms of acute hypocalcemia
are difficult to collect.
Calcium is essential for muscle contraction and neuro-
transmitter release, and the clinical manifestations of
hypocalcaemia may involve almost any organ system [15],
as summarized in the Table 2.
The most frequent clinical manifestations are the neu-
romuscular irritability, which ranges from paresthesia,
numbness or tingling sensation in the perioral area, hands or
feet, as well as carpopedal spasms, seizures, tetany and
rarely laryngospasm. It should be noted that hypocalcemia
may be asymptomatic. In these cases, latent tetany may be
elicited by the assessment of two clinical signs. They are the
Chvostek sign and Trousseau sign and should always be
checked in hypocalcemic patients [5, 15]. Positive Chvostek
sign can be observed in 25% of healthy individuals, while
29% of patients with hypocalcemia have no positive sign.
For every 1 g/dL increase in serum calcium level, the odds
for a positive Chvostek sign increases by 4% (95% CI
0.00–8%) [16]. Conversely, the Trousseau sign is reported
to be more specific, as it is positive only in 1% of healthy
individuals [8].
Acute and severe hypocalcemia frequently require
admission to the emergency department. Data gleaned from
case reports of acute hypocalcemic patients reveal arrhyth-
mias, such as: torsades of pointes, ventricular tachycardia
and ventricular fibrillation, often due to prolongation of the
QT interval that triggers the arrhythmias [15]. A recent
retrospective study of approximately 40.000 patients (mean
age 65 years, 48% male) showed that calcium levels below
1.69 mmol/l were associated with a 20.4-millisecond pro-
longed QTc interval [17]. A three-year retrospective
observational study including 41,823 patients admitted to
the adult emergency department reported calcium levels <
2.2 mmol/l in 8.3% of the subjects. Among hypocalcemic
subjects, 2.2% had a life-threating cardiac presentation.
However, authors concluded that other comorbidities and
electrolyte abnormalities contributed to the clinical pre-
sentation [18].
Interestingly, Jentzer et al. have recently theorized an
addicting role of calcium in the regulation of smooth vessels
function, and suggested that hypocalcaemia may be impli-
cated in the pathogenesis of the refractory vasodilatory
shock [19]. However, more studies are needed to provide a
Endocrine
better framework for the role of reduced serum calcium
levels in this particular context [20].
Hypocalcemia is a very rare cause of dilated cardio-
myopathy, a condition associated with high mortality rate.
Although this association has been reported only by case
reports, in patients with unexplained left ventricular dis-
function serum calcium should be measured, because its
correction ameliorates the cardiomyopathy [21].
Seizures are usually mentioned as a life-threating con-
dition in relation to severe hypocalcemia [22, 23], but evi-
dence are conflicting [24]. Indeed, calcium ions play a
crucial role in neurotransmission [25], but the mechanisms
associated with the pathogenesis of seizures remain elusive
[24]. It was proposed that low calcium levels, through a
modulation effect mediated by CASR signalling [26], could
shift channels and surface charge [24]. This enhances
sodium influx through the voltage-gated sodium channels
and results in glutamate release with a secondary increase of
burst firing activity of neuronal cells, that may enhance
epiletogenesis [24]. Life-threating neurological conditions
are reported in a figure of 2% (coma) and 8% (seizures)
[27]. A study conducted in US children (aged 0–5 years)
showed an incidence of hypocalcemia associated with
potentially life-threatening complication defined as seizures,
arrhythmias and laryngospasm in 6.1 per 100,000 person-
years (95% CI, 3.5–10.0) [27].
In adults, laryngospasm is not frequently observed. There
are no prospective nor retrospective studies on the pre-
valence of laryngospasm in hypocalcemic adults and evi-
dence are supported only by case reports. Moreover,
laryngospasm has been described usually only in the con-
text of hypoparathyroidism following neck surgery [28] or
structural laryngeal abnormalities [29]. This point suggests
the possibility of a combination of factors, in association
with hypocalcemia, that triggers the pathogenesis of lar-
yngospasm. In any case, the possibility of electrolyte (par-
ticularly calcium) abnormalities should be explored in cases
of laryngospasm of unknown etiology [29].
Chronic hypocalcemia
Paresthesia, numbness and tingling sensation are the most
frequent clinical manifestations of chronic hypocalcemia,
particularly in the setting of chronic postsurgical hypopar-
athyroidism [20, 21]. In these cases, low serum calcium
levels and low PTH are the hallmark of the disease and
calcium and active vitamin D are usually prescribed. Hence,
clinical manifestations are associated with both hypocalce-
mia and low PTH levels, as well as with therapy. The lack
of PTH enhances urinary calcium excretion and a high
calcium x phosphate product may cause ectopic calcifica-
tions. Underbjerg et al. [11] found that patients with post-
surgical hypoparathyroidism have a four time increased risk
Endocrine
of renal complications in terms of calcification or renal
injury. Brain calcifications [30] may develop during long-
standing hypocalcemia and be incidentally detected in
asymptomatic patients. They could have a role in the epi-
letogenesis [31]. The prevalence of seizures in patients with
chronic hypoparathyroidism ranges from 30 to 70%
(regardless of the presence of calcifications) [32, 33].
Neuropsychiatric disorders, such as depression and
bipolar disorder, were reported, as well [34] in postsurgical
hypoparathyroidism [11].
Cataracts has also been observed in association with
chronic hypocalcemia. Specific bilateral lens abnormalities,
consisting of punctate, iridescent opacities in the anterior
and posterior cortex lying beneath the lens capsule are
characteristic [35].
In the Danish study comprising 431 hypoparathyroid
patients, ionized calcium in the lowest tertile (<1.15 mmol/
L) was associated with an increased risk of cardiovascular
disease compared with the mid-tertile (1.16–1.19 mmol/L)
(OR adj 3.01; 95% CI, 1.03 to 8.82) [36]. In addition, the
impairment in the cardiovascular autonomic system causing
elevated mortality was found in 59.1% of hypoparathyroid
patients compared to 2.4% in the control group [37].
Congestive heart failure may rarely occur during long-
standing hypocalcemia [38]. A few cases of hypocalcemia-
associated cardiomyopathy that resolved after serum cal-
cium normalization have been described [39, 40].
The overall data have shown that clinical presentation of
both acute and chronic hypocalcemia may vary and result in
considerable increase in patients’ admission to hospital, as
well as reduced quality of life [7, 41].
Differential diagnosis
The primary step in the differential diagnosis of hypo-
calcemia is its confirmation by the assessment of calcium
corrected for serum albumin levels through the formula (see
“Introduction”; Fig. 1). Whenever available, and particu-
larly in patients with acid-base disorders, it is essential to
measure ionized calcium.
Once hypocalcemia is confirmed, the approach to
patients includes the simultaneous evaluation of clinical and
laboratory findings that are necessary to guide the differ-
ential diagnosis and the therapeutic interventions (Fig. 1).
Clinicians need to evaluate timing and severity of hypo-
calcemia, while assessing specific clinical and subclinical
signs and symptoms. This approach is of utmost importance
in order to differentiate between acute vs chronic cases of
hypocalcemia and to identify the specific management.
The required laboratory exams are serum phosphate,
magnesium, PTH, and GFR. Perturbation of the renal
function is usually associated with elevated serum
phosphate levels that need specific management [42]. Sec-
ondary hyperparathyroidism is frequent, but patients may
also present with adynamic bone disease and/or osteoma-
lacia [42].
Assessment of serum magnesium is needed in every
patient, as hypomagnesemia is a frequent cause of reduced
PTH secretion [8]. Correction of hypocalcemia, without
magnesium supplementation, would, therefore, never
reverse the reduction in parathyroid function. In addition,
the cause of hypomagnesemia needs be identified and
managed [43]. The most common causes of hypomagne-
semia are those associated with reduced gastrointestinal
absorption (low dietary intake, diarrhea, steatorrhea, alco-
holism), sequestration by organs or cells (acute pancreatitis,
hungry bone syndrome, refeeding syndrome, massive blood
transfusion) and renal loss (Fanconi syndrome, tubular
necrosis, diabetes, drug toxicity) [43]. Hypermagnesemia is,
in most of the cases, associated with renal failure. As high
serum magnesium levels could be the cause of reduced PTH
production and secretion, its correction is mandatory to
correct hypocalcemia.
The assessment of medical, family and pharmacological
history, as well as physical examination are of utmost
importance in patients with hypocalcemia (Fig. 1). Identi-
fication of drug inducing hypocalcemia (Table 1) and
eventually its discontinuation will resolve the disorder. In
this context, careful evaluation needs to be done in every
patient. It is important to assess the risk/benefit ratio of
continuing vs discontinuing the drug or reducing vs not
increasing its dose and/or frequency of administration (e.g.
loop diuretics in heart failure). In some cases, whenever
possible, a switch to other drugs that do not induce hypo-
calcemia, needs to be considered (e.g. anticonvulsants,
foscarnet, etc.), in accordance with the specialist in charge
of the patient. Regarding bone-active agents, attention is
needed when deciding to stop denosumab, because of the
well-known rebound of bone turnover and associated bone
loss and increase in vertebral fractures [44]. A single infu-
sion of 5 mg of zoledronic acid demonstrated to be effective
in preventing bone loss associated with denosumab dis-
continuation [45]. Management of eventual hypocalcemia
associated with zoledronic acid administration should be
carried out in these cases. In any case, the assessment of
vitamin D status and the correction of hypovitaminosis D is
a preventive strategy to avoid hypocalcemia induced by
both denosumab and bisphosphonates [46, 47].
With reference to comorbidities, a positive history of
adrenal insufficiency in patients with hypocalcemia and low
serum PTH levels defines the diagnosis of autoimmune
polyendocrine syndrome type 1 (APS1). The presence of at
least two of the three components of the disease (mucocu-
taneous candidiasis, Addison's disease, and hypoparathyr-
oidism) is necessary for the diagnosis [8].
 Endocrine

Hypocalcemia

Correct for serum albumin*

and/or measure Ca2+

Confirmed
hypocalcemia

Evaluate Evaluate
Timing and severity Check GFR, serum phosphate, medical, family and
Symptoms and signs magnesium, PTH pharmacological history
Physical exam

Reduced GFR:
Acute Chronic Manage renal Low/high magnesium
failure levels: correct and
identify the cause**

See specific treatment Consider

discontinuing drugs
inducing
hypocalcemia**
High PTH Low PTH

Positive family history and/or

phenotypic abnormalities or
Hypoparathyroidism comorbidities:
Low phosphate Normal phosphate High phosphate
Consider genetic syndromes*** or
APS1

Check alkaline phosphatase, Pseudohypoparathyroidism

25(OH)D

High alkaline Normal alkaline History of neck surgery/radiation:

phosphatase and low phosphatase and low Post-surgical/post-radiation
25(OH)D 25(OH)D hypoparathyroidism

High alkaline
phosphatase and
normal 25(OH)D
Osteomalacia/ Vitamin D deficiency
rickets Malabsorption

VDRR/HVDRR**

Fig. 1 Differential diagnosis of hypocalcemia. *See text for the for- hormone, APS1 autoimmune polyendocrine syndrome type 1, 25(OH)
mula of corrected calcium; **See text for details; ***See Table 1 Ca2+ D, 25-hydroxy-vitamin D; VDRR Vitamin D dependent ricketsm,
ionized calcium, GFR glomerular filtration rate, PTH parathyroid HVDRR Hypocalcemic vitamin D-resistant rickets

Instead, the simultaneous presence, in young patients, of
hypoparathyroidism, autoimmune disease, cognitive and/or
psychiatric disorders, gastrointestinal and renal abnormal-
ities characterizes the more rare 22q11.2 deletion (former Di
George) syndrome [48].
Physical examination could reveal not only the presence
of comorbidities that characterize the genetic disorders
associated with hypoparathyroidism, but also features of
pseudohypoparathyroidism (Fig. 1). The last is a genetic
disorder characterized by resistance to PTH action [8]. Short
stature, round facies, brachydactyly, ectopic ossifications,
obesity and cognitive impairment are commonly observed,
while hypocalcemia, hyperphosphatemia and high serum
PTH levels are the main laboratory findings [49].
Finally, cases of hypocalcemia associated with reduced
serum phosphate levels, mostly in the setting of elevated
alkaline phosphatase and severe 25-hydroxy-vitamin D [25
(OH)D] reduction (serum levels < 10 ng/ml), configure the
diagnosis of osteomalacia/rickets (Fig. 1). When 25(OH)D
is normal in children presenting with hypocalcemia, hypo-
phosphatemia, elevated PTH and features of rickets, vitamin
D dependent rickets (VDDR) or hypocalcemic vitamin D-
resistant rickets (HVDRR) should be suspected [50, 51].
Treatment
In both acute and chronic hypocalcemia, the aim of treat-
ment is to raise serum calcium to the normal range, in order
to resolve or minimize symptoms. Identifying the etiology
of hypocalcemia is of major importance to establish the
optimal therapy.
Endocrine
For example, magnesium should be administered in
cases of hypomagnesemia-associated hypocalcemia [52].
Mild hypomagnesemia can be treated with oral supple-
ments, whereas parenteral magnesium is indicated in severe
hypomagnesemia (<0.05 mmol/L). The administration of
1 g (8 mEq) of intravenous magnesium increases serum
magnesium concentration by 0.15 mEq/L within 18–30 h.
Magnesium supplementation is usually done with a bolus of
2 g followed by continuous infusion with a maximum of
16 g (130 mEq) over 24 h until normal serum magnesium
level is reached [53].
Hypocalcemia related to severe vitamin D deficiency,
(i.e. osteomalacia) should be treated with vitamin D sup-
plements together with calcium supplements [54]. In case of
calcium intestinal malabsorption, treating the cause of
malabsorption is necessary.
Acute treatment
In acute hypocalcemia, intravenous calcium is usually
administered if the serum calcium level falls below
1.9 mmol/L, or the ionized calcium level is <1 mmol/L, or if
patients are symptomatic [52]. Intravenous calcium solu-
tions are hyperosmolar and should be administered through
a large central vein, whenever possible, considering that 1 g
of calcium gluconate contains 93 mg of elemental calcium,
while 1 g of calcium chloride contains 273 mg of elemental
calcium. In adults, 100 to ~300 mg of elemental calcium
(1–3 g calcium gluconate or 0.5–1 g calcium chloride), in
100 mL dextrose over 10 min is administered over a 10 to
20-minute infusion followed by continuous infusion of
0.5–1.5 mg of elemental calcium/kg per hour.
A periodic monitoring of the blood calcium levels is
necessary until a stable oral calcium regimen is achieved
[12]. Timing of calcium measurements is driven by
patients’ symptoms. In patients receiving digoxin calcium,
infusion may provoke life-threatening cardiac arrhythmias,
and ECG monitoring is suggested [55].
Long-term treatment
The goal of long-term therapy is to control hypocalcemia-
related symptoms while minimizing complications. A recent
meta-analysis demonstrated that routine supplementation
with calcium plus vitamin D3 is associated with lower risk
of hypocalcemia in patients undergoing thyroid surgery,
compared to the approach based on measurements of cal-
cium levels [56].
A sufficient dietary calcium intake is recommended, with
the aim of at least 1 g of calcium daily. However, this
approach is rarely sufficient to avoid hypocalcemia in
hypoparathyroid patients, thus an oral supplementation is
suggested. Doses of calcium usually indicated in patients
with chronic hypoparathyroidism are 1–3 g of oral ele-
mental calcium in 3–4 doses. The most frequently admi-
nistered forms are calcium citrate and calcium carbonate.
Calcium carbonate should be taken during or after meals to
ensure the optimal absorption. Calcium carbonate may
interfere with the absorption of other drugs, for example of
L-thyroxine, thus specific instruction should be provided to
patients in this case. Calcium citrate had the advantage of an
optimal absorption independent of food intake, and also in a
case of gastric achlorhydria.
In order to minimize hypocalcemic symptoms, in the
cases of concomitant hypomagnesemia, oral magnesium
supplementation should be given.
Calcitriol is administered over a wide dosing range
(0.25–2.0 μg/day) [57]. Thiazide diuretics, that increase
renal calcium reabsorption, may be needed to achieve a
urinary calcium level of <4 mg/kg/day. Starting with a
lower dose of hydrochlorothiazide, 12.5 mg once daily, up
to the doses need to achieve a urinary calcium level of
<4 mg/kg/day, which is usually not higher than 12.5 mg
twice daily. In patients with 25(OH) insufficiency, chole-
calciferol could be also added. The rationale is that several
human tissues to provide 1,25-dihydroxyvitamin D and
other metabolites of vitamin D that may have also beneficial
non-skeletal effects.
Recently, different guidelines for the management of
postsurgical hypoparathyroidism have been published,
mostly focused on treatment of chronic hypocalcemia [58–
60]. Unfortunately, the majority of these recommendations
are based on small studies rather than long-term controlled
trials, as they are the only currently available.
One of the he aims of chronic management of hypo-
calcemia is to avoid hypercalciuria, and maintain the cal-
cium phosphate product below 55 mg2/dL2 (4.4 mmol2/L2)
to avoid complications such as nephrolithiasis and other
extra-skeletal calcifications [61].
To achieve a successful treatment, a routine biochemical
check is recommended every 6 months [59]. Indeed, there is
an association between biochemical indices and risk of
complications. A positive association between a relatively
high plasma phosphate level and/or a high calcium ×
phosphate product and mortality, as well as risk of renal
diseases and infections were observed [36].
An advance in the chronic management of hypopar-
athyroidism is the administration of the PTH peptides
[62–64]. Before the approval by FDA of the rhPTH
(1–84), teriparatide was utilized in hypoparathyroid
patients not responding to conventional therapy [65].
Teriparatide is a PTH analog (PTH 1–34) produced by
recombinant technology and it is usually prescribed for
osteoporosis treatment at the dose of 20 μg as a daily
injection for a maximum of 2 years [66]. While for
chronic hypoparathyroidism, the dosage in adults ranged

from 20 mcg twice daily for 2 years [61], to 40 mcg twice
daily for 3 years [59].
A systematic review demonstrated that both rhPTH
(1–84) and teriparatide were effective in correcting serum
calcium levels and significantly reduced daily requirements
of calcium and active vitamin D supplements compared to
placebo [67]. Urinary calcium excretion was reduced with
teriparatide compared to conventional therapy, but
unchanged with PTH 1–84. Teriparatide had also positive
data on its long-term efficacy and safety in a cohort of
children with genetic hypoparathyroidism [68]. Finally,
teriparatide discontinuation was associated with transient
increase in calcium and calcitriol requirements [69].
Recombinant human PTH(1–84) may theoretically be
administered as life-long treatment of hypoparathyroidism.
It is administered subcutaneously every day at different
doses. So far, data from retrospective analysis of patients
treated for 10 years showed stable restoration of serum
calcium, and an ~50 and a 75% reduction of calcium and
calcitriol supplements [70], with significant improvement in
quality of life [41].
Both standard therapy with calcium and calcitriol, as well
as the new therapy with rhPTH, had side effects. Calcium
supplements may have a low gastrointestinal tolerance in
long-term treated subjects. Also, thiazides have side effects
that should be monitored, such as hypokalemia and the rise
in serum levels of uric acid. The possible drawbacks/side
effects reported for rhPTH are mainly related to hypercal-
ciuria with controversy in the literature [58–61, 66] and to
the reported risk of hypocitraturia with rhPTH 1–34 [71].
Concerning the long-term safety issue of the develop-
ment of bone neoplasm using PTH peptides, so far in the
literature no cases of osteosarcoma in hypoparathyroid
patients have been reported for PTH 1–34 and PTH 1–84.
However, studies for PTH 1–84 have a follow-up of no
longer than 10 years [38].
The high cost of the rhPTH(1–84) therapy imposes the
identification of to hypoparathyroid patients who would
benefit from this therapy. Recent guidelines recom-
mended that rhPTH(1–84) therapy is prescribed only in
patients unresponsive to conventional treatment, with
inconstant control of serum calcium and frequent epi-
sodes of hypo- or hypercalcemia [59]. Patients with
nephrolithiasis or nephrocalcinosis or eGFR < 60 mL/min
or hypercalciuria and/or other biochemical indices of risk
for kidney stones are also candidates. Moreover, elevated
serum phosphate and/or calcium-phosphate product
(higher than 55 mg2/dL2 or 4.4 mmol2/L2) are considered
as indications for rhPTH(1–84) therapy. Finally, high
dose of calcium and/or vitamin D (i.e., >2.5 mg of cal-
cium and/or >1.5 μg of active vitamin D daily), in asso-
ciation with malasbsorption or other gastrointestinal
disease, are potential indications.
Endocrine
The main limitation of teriparatide and rhPTH(1–84) is
their short-acting nature and the consequent need for a
twice-day injection. A small 6-month randomized trial, was
carried out with the use of teriparatide delivered by pump
and compared to the twice-daily s.c injection [72]. Data
showed fewer fluctuations in serum calcium levels with the
use of the pump. In addition, a new sustained-release pro-
drug of PTH(1–84), namely the TransCon PTH, was tested
in phase I trial and are now under phase II investigation
[73]. In animals, the once-daily subcutaneous administra-
tion of TransCon PTH maintained a steady systemic con-
centration of PTH, which mimic an infusion-like profile
of PTH.
In conclusion, acute hypocalcemia can be safely cured by
the administration of intravenous calcium infusion. We
suggest the ECG monitoring during the infusion, that
should be continued until the oral therapy is possible. More
challenging is the long-term treatment, especially when it is
life-long, due to the associated complications. Development
of new drugs and long-term randomized trials (longer than
10 years) will probably modify the management of chronic
hypocalcemia in the future.
Conclusions
Assessment of hypocalcemia needs careful evaluation by
clinicians. After confirming the reduction in serum calcium
levels, attention needs to be paid to the definition and
management of the specific causes. Knowledge of the main
genetic and acquired causes of hypocalcemia, together with
the specific clinical and laboratory evaluations, are of
utmost importance in the management and follow-up of
hypocalcemic patients. From a clinical point of view, the
differences in the time of hypocalcemia onset usually define
the clinical presentation of the disease. Indeed, acute cases
of hypocalcemia are typically associated with more severe
signs and symptoms and a higher risk of acute complica-
tions, while chronic hypocalcemia may be less symptomatic
or asymptomatic. In any case, the major goals of treatment
for both acute and chronic hypocalcemia are to increase
serum calcium levels, as soon as possible, to control
symptoms and to avoid complications, although with dif-
ferent timing between the two forms. The administration of
calcium, active and native vitamin D, magnesium and
thiazide diuretics are the mainstream treatment of hypo-
calcemia. The administration of the missing hormone in
hypoparathyroidism, in the form of rhPTH (1–84), has been
recently approved both by the FDA and the EMA [74]. The
use of rhPTH (1–84) has demonstrated to be associated with
stabilization of the disease, both from the laboratory and the
clinical point of view. The idea of treating not only the
serum calcium levels, but all the aspects related to the
Endocrine
disease, is now emerging as an interesting crucial point in
the treatment of hypoparathyroidism. This approach leaves
room for future improvement in the knowledge and man-
agement of all forms of hypoparathyroidism, as well as all
diseases associated with hypocalcemia.
Compliance with ethical standards
Conflict of interest S.M. served as speaker for Abiogen, Amgen,
Bruno Farmaceutici, Diasorin, Eli Lilly, Shire, Sandoz, Takeda. He
also served in advisory board of Abiogen, Kyowa Kirin, Pfizer, UCB.
All other authors declare no competing interests.
Ethical approval All procedures performed in studies involving human
participants were in accordance with the ethical standards of the
institutional and/or national research committee and with the 1964
Helsinki declaration and its later amendments or comparable ethical
standards.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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