Hypoparathyroidism

Abstract

Background

Hypoparathyroidism is a rare endocrine disorder characterized by hypocalcemia and low or undetectable levels of parathyroid hormone.

Methods

This review is an evidence-based summary of hypoparathyroidism in terms of relevant pathophysiological, clinical, and therapeutic concepts.

Results

Many clinical manifestations of hypoparathyroidism are due to the lack of the physiological actions of parathyroid hormone on its 2 major target organs: the skeleton and the kidney. The skeleton is inactive, accruing bone without remodeling it. The kidneys lose the calcium-conserving actions of parathyroid hormone and, thus, excrete a greater fraction of calcium. Biochemical manifestations, besides hypocalcemia and low or undetectable levels of parathyroid hormone, include hyperphosphatemia and low levels of 1,25-dihydroxyvitamin D. Calcifications in the kidney, brain, and other soft tissues are common. Removal of, or damage to, the parathyroid glands at the time of anterior neck surgery is, by far, the most likely etiology. Autoimmune destruction of the parathyroid glands and other genetic causes represent most of the other etiologies. Conventional treatment with calcium and active vitamin D can maintain the serum calcium level but high doses may be required, adding to the risk of long-term soft tissue calcifications. The advent of replacement therapy with recombinant human PTH(1-84) represents a major step in the therapeutics of this disease.

Conclusions

Advances in our knowledge of hypoparathyroidism have led to greater understanding of the disease itself and our approach to it.

I have recently reviewed for this journal primary hyperparathyroidism (PHPT), a common endocrine disorder (1). In this issue, I review hypoparathyroidism (HypoPT), its pathological counterpart. In contrast to PHPT, HypoPT is a rare endocrine disorder that is seen infrequently among practicing endocrinologists. As a rare bone disease, it has been relegated, until recently, to that of an oddity, often leading general endocrinologists to refer these patients to specialists in metabolic bone diseases. Times, however, have changed, not in terms of the incidence of this disease but rather in our interest. A casual sampling of publications in PubMed indicates that two-thirds of all peer-reviewed papers on HypoPT have occurred within the past decade. Over an 85-year period, from 1925 to 2010, about 2000 papers were published using the search term “hypoparathyroidism.” In the 10-year period, starting in 2010, more than 4000 papers have been published. This dramatic change is due not only to our burgeoning interest in the disease itself because of new concepts and therapeutic alternatives, but also to the expanding interest in rare bone diseases in general. A sampling of the last 2 Annual Meetings of the American Society of Bone and Mineral Research substantiates this point with an overrepresentation of oral abstracts being presented on rare bone diseases (2, 3). In this review, I summarize our current state of knowledge of the pathophysiology, diagnosis, clinical presentations, complications, and therapy of HypoPT.

Diagnosis

The diagnosis of HypoPT is made when the corrected serum calcium or ionized calcium concentration is below the normal range and is accompanied by undetectable or inappropriately low levels of PTH (4). Typically, these indices are confirmed at least twice over a 6-month period for the condition that we recognize as chronic HypoPT to be established. The so-called second-generation assay for PTH, introduced in the 1980s, is still the most widely used measurement technology (5). Although this assay detects inactive fragments of PTH along with the active, full-length 84-amino acid peptide, and, thus, theoretically could be improved upon by the third-generation assay that measures only intact PTH(1-84) (6), clinical experience has not borne this out. The second-generation assay has stood the test of time and continues to be the preferred PTH assay.

The combination of a low PTH level and a low serum calcium concentration is decidedly abnormal because under physiological conditions, hypocalcemia will lead to an increase in PTH. The expected increase in PTH from the parathyroid glands in the context of hypocalcemia is due to the calcium sensing receptor (CaSR) (7). The reduced occupancy of the CaSR by its preferred divalent ligand, calcium, generates the signal to increase the synthesis and secretion of PTH. Secreted PTH binds to its G-protein coupled PTH1 receptor in bone and kidney to raise the serum calcium level under normal circumstances (8). Without PTH, the skeleton and kidneys do not provide a source of calcium by mobilizing the skeleton or enhancing renal tubular calcium reabsorption or, indirectly, by facilitating vitamin D-mediated absorption of calcium in the gastrointestinal tract by increasing the synthesis of 1,25-dihydroxyvitamin D (5). As a result, 1,25-dihydroxyvitamin D is usually low (9, 10). The lack of PTH also leads to hyperphosphatemia because the phosphaturic actions of PTH are lost. There is relative hypercalciuria for the level of the serum calcium.

Causes of hypoparathyroidism.

The diagnostic combination of hypocalcemia and low PTH levels leads to a discussion of the causes of “irreversible” hypoparathyroidism. First, however, it is important to ascertain that the serum magnesium level is normal. Both hypermagnesemia and severe hypomagnesemia can lead to functional hypoparathyroidism (11). Low calcium and PTH resulting from hypermagnesemia is readily understood by virtue of its actions, as a divalent cation, to bind to the CaSR, albeit not as well as calcium, to reduce PTH synthesis and secretion. Severe hypomagnesemia is actually a more common clinical entity (11, 12). Other pathophysiologies of this form of reversible HypoPT include the requirement of magnesium to activate adenylate cyclase, one of PTH’s messengers (13), and peripheral resistance to the actions of PTH.

After neck surgery

By far, the most common cause of HypoPT is after neck surgery, with 75% of all cases falling into this category. The incidence of HypoPT after neck surgery is about 8%, but 75% of these cases are transient, with recovery within 6 months (4, 5, 14). Thus, the incidence of chronic HypoPT after neck surgery is <2%. It is even lower in the hands of experienced, high-volume neck surgeons. They are less likely to see this complication (15). HypoPT can occur years to decades after neck surgery (16), but if it is to occur, it is more likely to develop soon after neck surgery. A clinical pearl is always to check for a neck scar in someone with HypoPT even if the patient does not acknowledge or recall previous neck surgery. Risk factors for the development of postoperative HypoPT include: extensive neck surgery, total thyroidectomy, bilateral neck exploration for PHPT, repeated neck surgery, a history of Graves’ disease, failure to identify >2 PTH glands during surgery, a serum calcium <7.5 mg/dL 24 hours after neck surgery, and postoperative complications like bleeding (15, 17–20).

Genetic

Although genetic causes constitute fewer than 10% of all cases of HypoPT, they have generated great interest because of the pathophysiological insights they have provided (21).

DiGeorge syndrome.

The most common genetic cause is DiGeorge syndrome, representing about 60% of children with HypoPT (22, 23). The type 1 form of DiGeorge syndrome is due to a microdeletion in chromosome 22q11.2 (24). The importance of this deletion rests in the lack of T box protein 1 that is necessary for the development of the thymus and the parathyroids. The phenotypia of DiGeorge syndrome (facial abnormalities, cardiovascular malformations, and thymus underdevelopment) are explained by this deletion (25).

Autoimmune polyendocrine syndrome type 1.

Another well-recognized genetic cause of HypoPT is autoimmune polyendocrine syndrome type 1. The autosomal recessive disorder is due to mutations in the autoimmune regulator gene, known as AIRE (26–28). The mutation in AIRE leads to lack of self-immunotolerance and, as a result, destruction of the parathyroids, adrenals, and other endocrine glands. Two of 3 components of the classical triad (mucocutaneous candidiasis, HypoPT, adrenal insufficiency) must be present to consider the diagnosis (29).

Autosomal dominant hypocalcemia (ADH).

Another interesting genetic form of HypoPT is ADH from gain-of-function mutations of the CaSR (type 1) or G11alpha (type 2) proteins (7, 30–32). The hypocalcemia of this disorder is not always accompanied by low PTH levels. Even if PTH levels are normal, though, they are not normal for the presence of hypocalcemia. Hypercalciuria is a common feature (7, 31), with renal calcifications being recognized often (31). The type 2 variant of ADH is similar biochemically but the renal features are not as prominent (33).

Other genetic syndromes associated with HypoPT include syndromes associated with deafness and renal disease (hypoparathyroidism-deafness-renal syndrome (34, 35)); mitochondrial disorders (e.g., MELAS syndrome (36–38)); bone dysplastic syndromes (e.g., Kenny-Caffey syndrome (39)); genetic abnormalities of parathyroid-specific transcription factors GCM2 (40); or SOX3 (41, 42); and disorders of intracellular PTH processing (39, 43–45). These very rare genetic etiologies are covered in more detail elsewhere (4, 5, 9, 11, 21).

Other causes

The parathyroid glands can be infiltrated by iron (hemochromatosis), copper (Wilson disease), and certain metastases (46). Even more rarely, HypoPT can be due to external or internal radiation. Because the parathyroid glands are notoriously resistant to radiation damage, one rarely implicates this as a cause (46). Finally, HypoPT can occur without any clear etiology. It is likely that these patients have an autoimmune form of the disease.

Epidemiology

HypoPT clearly fits the criterion of a rare or orphan disease in the United States with fewer than 200 000 in the population. Its prevalence has been estimated in the United States to be 37/100 000 (4, 5). In Denmark, the incidence is about 22/100 000 (47, 48). It is less common in other countries, such as Norway, where the estimated prevalence is 9.4/100 000 (49). In Italy, reports range from 5.3 to 27 per 100 000 (50, 51). Despite the variability within and between countries, it is clear that HypoPT is a rare disorder of calcium homeostasis. Long-term complications associated with HypoPT include renal dysfunction, kidney stones, posterior subcapsular cataracts, and intracerebral calcifications (4). There does not appear to be an increase in overall mortality, cardiovascular disease, fractures, or mortality, although Vadiveloo et al. have presented evidence against this impression (52).

Clinical Features of HypoPT

Neuromuscular

The major symptomatic features of HypoPT relate to neuromuscular irritability. These features, however, are greatly variable and depend, in part, upon the rate of change of the serum calcium, the actual degree of hypocalcemia, and variability among patients. For the same serum calcium level, the patient can be markedly symptomatic or asymptomatic. Other variables include alkalosis, which can worsen symptoms because the partition between albumin-bound and free calcium favors the bound fraction. Hypomagnesemia can also be associated with more symptoms (53). The enhanced neuromuscular excitability is governed by the hypocalcemia, which stimulates spontaneous high-frequency discharges, leading to muscle spasm (54). Classically, the Chvostek sign is elicited by tapping the facial nerve at the ear and seeing an ipsilateral upturn twitch of the facial muscles. Although the Chvostek sign is helpful, it can be seen in as many as 10% to 25% of the normal population and can be absent in as many as 30% of hypocalcemic individuals (55). Thus, it is neither sensitive nor specific. On the other hand, the Trousseau sign is more sensitive and specific with >90% of hypocalcemic individuals and only about 1% of normocalcemic individuals displaying this sign (56, 57). The Trousseau sign is positive if carpal spasm is elicited upon inflating the blood pressure cuff to slightly above systolic for up to 3 minutes. Other manifestations of neuromuscular irritability are paresthesias of the extremities and around the mouth, laryngospasm, and frank seizures.

Neurological/Neuropsychiatric

Although seizures can be seen as an acute manifestation of hypocalcemia, it is also a major risk in general. Basal ganglia calcifications are a classic manifestation of chronic HypoPT. In the study of Mitchell et al. (58), 52% of those studied had evidence for basal ganglia calcifications. Although an elevated Ca × P product has been implicated as an etiology for this site of ectopic calcification in HypoPT, elevated phosphorus, per se, has also been implicated (59). Basal ganglia calcifications are not unique to HypoPT: other intracerebral sites of calcifications can be seen in HypoPT (60). Although motor dysfunction such as parkinsonism and cerebellar dysfunction have been described (61, 62), they have been seen in a relatively small number of patients in most series. The incidence of depression and other psychiatric diseases has been reported to be twice as high in HypoPT, from any etiology (48). Infection risk also appears to be higher (48). Cognitive function, as reported by Aggarwal et al. (63) can also be affected with patients showing greater impairment as a function of duration of disease, calcium-phosphate product, and the serum calcium concentration (64).

Renal

The lack of PTH’s calcium-conserving properties leads to an increase in the fraction of filtered calcium at the glomerulus (65). The presence of frank hypercalciuria, however, is a function of the level of the serum calcium, the level of renal function, and the amount of supplementation calcium being used in management. In ADH, hypercalciuria is likely to be a more common feature. Although renal function can be intact, the kidneys are a major target organ for complications. The work of Mitchell and colleagues (58) is an informative cross-sectional sampling of more than 100 patients with HypoPT with regard to renal and other organ systems. That study reported a substantial 40% who demonstrated chronic renal dysfunction, between stages 3 and 5. This extent of renal dysfunction was seen at virtually every decade and was more prevalent than a control population. Of those who had renal imaging, one-third showed evidence by ultrasound and/or computed tomography of renal calcification. A similar but larger cross-sectional cohort from Denmark (48, 66) confirms the essential features of the Mitchell et al. study with regard to the extent of renal dysfunction and calcifications. The risk of kidney stones was almost 5-fold greater than the case controls. Those with nonsurgical HypoPT appeared to have more renal dysfunction than the postsurgical cohort, perhaps because they had lived with the disease for a longer period.

Skeletal

Dynamics

PTH is required in the adult for normal skeletal remodeling, the process by which mature bone is replaced by younger, more resilient bone. PTH participates in this process of biomechanical renewal. Without PTH, skeletal dynamics are affected, with low bone turnover being a cardinal feature (67). Low bone turnover can be measured by circulating markers of bone formation such as procollagen type 1 amino-terminal propeptide, osteocalcin, or bone-specific alkaline phosphatase and by circulating markers of bone resorption such as tartrate-resistant acid phosphatase 5b and serum C-telopeptide. These markers are generally in the lower half of the normal range (68). Given that these markers are usually not frankly low, they are not particularly helpful in terms of ascertaining bone turnover status in HypoPT. More revealing are studies by dynamic histomorphometry in which tetracycline labeling of bone formation surfaces and osteoclast numbers can be delineated. Obtaining a representative sample of bone by the percutaneous iliac crest bone biopsy, uniform reductions with prolonged quiescent periods, reduced bone formation, and bone resorption rates are evident (68–70). All 3 envelopes of bone, namely cancellous, endocortical, and intracortical sites are affected. These results have been confirmed by microcomputed tomography (71).

Micro- and material structure

Data from the iliac crest bone biopsy have also been helpful in understanding microstructure in this disease. Uniformly increased are trabecular bone volume and trabecular thickness, along with greater trabecular numbers and connectivity (72). Bone mineralization density, as determined by backscatter electron microscopy, is not increased but there is greater inter-individual variability (73).

Bone Mineral Density

As a low bone turnover state, it is not surprising that bone mineral density (BMD) as determined by dual energy X-ray absorptiometry is generally higher than age- and sex-matched controls (74–76). Expected postmenopausal bone loss from estrogen deficiency does not occur at the same rate as postmenopausal women without HypoPT (77). However, an exception to the rule that BMD is uniformly above average is seen, at times, in postmenopausal women whose HypoPT occurred well after the menopause. The reduced BMD, particularly at the lumbar spine, can be explained by the effects of the menopause on BMD occurring before the development of HypoPT. By peripheral quantitative computed tomography, trabecular volumetric BMD (vBMD), cortical vBMD and cortical thickness are all greater in HypoPT than controls (78). Higher cortical vBMD is also seen by high-resolution peripheral quantitative computed tomography (79).

Fracture risk

One of the challenges in any rare disease is amassing a sufficiently large number of subjects to ascertain the extent to which the rare disease is more or less likely to cause specific harm. When that harm is also a rare event, like a fracture, gaining this information is even more challenging. Therefore, information about fracture risk in HypoPT is sparse. One could speculate that fracture risk would be greater than normal because bone is generally hypermature and more brittle than tough. On the other hand, the increased BMD could argue that fracture risk would be reduced. By finite element modeling, biomechanical strength appears to be normal (80). Consistent with finite element modeling, with singular exceptions, case-control studies have not confirmed an increase or decrease in fracture risk (47, 66, 81). With specific reference to the upper extremity, however, the hazard ratio has been reported to be increased among those with nonsurgical HypoPT and lower among those with postsurgical HypoPT (48).

Quality of Life

One of the most prototypical elements of HypoPT is the complaint of “brain fog” often spontaneously volunteered by patients. This complaint references the patient’s perception that thinking has been clouded generally and pervasively (82). The complaint has been quantified by metrics such as the generic Short Form 36 (SF-36) scale (83–85) and shown to be below control groups even when the serum calcium is managed well by calcium and vitamin D. The categories defined by the SF-36 scale include both physical and mental domains, virtually all of which are adversely affected. Reduced quality of life is not as readily perceived by health care professionals, like surgeons, as they are by their patients (86). Also of interest is the work of Vokes et al., in which quality of life at baseline levels of calcium and vitamin D replacement may also be a function of perception by the patient. In Hungary, for example, quality of life scored consistently higher than countries in Western Europe and in the United States (87, 88).

Cardiovascular

The classical cardiovascular manifestation of hypocalcemia is a prolonged QT interval on the electrocardiogram resulting from prolongation of phase 2 of the action potential. This feature is seen more often in the setting of an acute fall in the serum calcium (89). A certain kind of polymorphic ventricular arrhythmia, known as torsades de pointes, can be seen but it is rare. In view of the importance of calcium in excitation-contraction coupling, cardiac failure has been reported particularly among children (90). It is rarely seen in adults in the absence of underlying heart disease. Cardiovascular autonomic neuropathy has been reported recently in which symptoms are related to the extent of hypocalcemia (91).

Other clinical manifestations

Cataracts

Cataracts are more likely to occur in HypoPT with a suggestion that the duration of disease confers greater risk (92). The cataracts are more likely to be posterior and begin in the periphery of the lens.

Skin

Various dermatological manifestations include dry, scaly skin, brittle nails, coarse and thin hair, and, rarely, a pustular psoriasis (93–95). Candidiasis is a specific manifestation of the autoimmune form of the disease (as previously discussed).

Evaluation

Table 1 summarizes current recommendations for the evaluation of a patient with HypoPT (96). The evaluation of a patient with HypoPT follows from the discussion of its many different clinical features. Confirmation of the hypocalcemia, either determined by correcting for the serum albumin, or by the ionized calcium concentration is important. The correction factor for the ambient albumin concentration is to increase the measured calcium by 0.8 mg/dL for a decline in the serum albumin by 1 g/dL. In settings where an accurate and reliable ionized calcium can be obtained, this is theoretically more accurate because it measures only the physiologically active partition of the total calcium value. However, if the ionized calcium to be measured, it is important to make sure that the venous site is “free-flowing,” namely that it is not restricted by a tourniquet. Anaerobic sample handling and a calibrated instrument are additional requirements (96). The PTH level is undetected or clearly inappropriately low for the hypocalcemic state. As noted previously, the second-generation assay is sufficient in most situations. Chronic HypoPT is established by the copresence of hypocalcemia and low PTH at least twice over a 6-month period.

Table 1.

Evaluation of Hypoparathyroidism

Family history

Parathyroid disease

Other endocrine disease

Autoimmune disorders

Personal history

Prior anterior neck surgery for parathyroid or thyroid disease.

Other endocrine disease.

Kidney stones or fractures

Dietary and supplemental intake of calcium, vitamin D

Physical examination

Chvostek or Trousseau sign

Eyes: cataracts

Neck: signs of previous surgery

Skin: mucocutaneous candidiasis, other fungal infection, vitiligo

Joints: arthritis

Biochemical evaluation

Biochemical screen with total calcium, albumin, blood urea nitrogen, and creatinine

Parathyroid hormone

Ionized calcium (see text)

25-hydroxy- and 1,25-dihydroxyvitamin D

Estimated glomerular filtration rate

24-hour urine for creatinine, calcium, and biochemical stone risk profile

Target organ imaging

Bone mineral density

Abdomen: ultrasound or computed tomography

Skull (optional)

Genetic: only if family or personal history of other information leads to this possibility

Historical

Family history, perceived duration of the symptoms and/or presence of hypocalcemia, kidney stones, fractures, cataracts, quality of life, medications, and supplements all follow from the classic clinical manifestations of the disease. In young individuals, one is more attuned to the possibility of a genetic form of the disease. A dietary history with specific reference to intake of dairy products is important.

Physical examination

Signs of neuromuscular irritability are noted, either spontaneously or elicited by the Chvostek or Trousseau sign. The eyes are examined for lens opacities. The neck should always be inspected, even in patients who have no history or recollection of anterior neck surgery. The skin is noted for depigmentation, if any, as well as for fungal infection, such as candidiasis. Joints with stiffness should be noted.

Biochemical

The standard biochemical screen will include a serum calcium, blood urea nitrogen/creatinine but typically will not include a serum phosphate or magnesium, both essential measurements. They should be measured. The 25-hydroxy and 1,25-dihydroxyvitamin D also should be measured. This is one of the few instances where the active metabolite of vitamin D is appropriate to measure because the lack of PTH along with the high phosphate, which is typically present, will suppress the renal activating 1-alpha hydroxylase, thus leading to a low value for 1,25-dihydroxyvitamin D. A 24-hour urine should be obtained for volume, creatinine, and calcium. Because many of these patients will have either frank hypercalciuria or an elevated fractional excretion of calcium, many clinicians will also obtain a stone risk profile along with the urinary calcium determination.

Imaging

I always obtain 3-site dual energy X-ray absorptiometry, although it could be argued that this is not generally helpful in view of the fact that most patients have bone density that is above average. However, if the lumbar spine measurement, for example, is low, this might indicate in a postmenopausal woman that the HypoPT developed years after the menopause. Additionally, if the distal one-third radius site is low, particularly in those who have had PHPT, this will indicate that there was substantial skeletal disease because of PHPT before the onset of the HypoPT. This also provides a baseline that can be more or less helpful depending upon what plan for management is pursued. Abdominal imaging is a key element of the evaluation. Ultrasound or computed tomography can be used, looking for renal stones and/or nephrocalcinosis. Imaging of the skull for basal ganglia or other intracerebral calcifications can help to date the duration of the HypoPT but per se is not helpful in terms of management plans. If the patient has an involuntary movement disorder, brain imaging is clearly indicated.

Genetic studies

The typical adult with HypoPT will have developed it after anterior neck surgery. Genetic studies are clearly not indicated in these and, thus, the vast majority of patients. In other patients, particularly those who are young and have a family history, and/or if there is other endocrine disease, genetic studies can be helpful.

Management of HypoPT

Acute management

Patients with HypoPT can become acutely hypocalcemic either in the immediate aftermath of neck surgery or in patients whose chronic replacement regimen has been perturbed by gastrointestinal illness or other extenuating factors. When symptoms are present, they can be life-threatening, and rapid action is needed (97). The first step, to quickly restore serum calcium levels, can be accomplished by intravenous infusion of 1 to 2 ampules of 10% calcium gluconate (93 mg of elemental calcium/10 mL) in 50 mL of 5% dextrose over 15 to 30 minutes. The second step is a slower, more prolonged infusion of calcium gluconate, 0.5–1.5 mg/kg body weight/hour, over an 8- to 10-hour period. In both cases, continuous electrocardiogram monitoring is recommended. Calcium should be monitored every 4 to 6 hours.

Chronic management

The major goals for chronic management are to keep patients from experiencing symptomatic hypocalcemia as well as to ameliorate the complications of the disease (97, 98). Conventional management can generally accomplish the first goal, namely to raise the serum calcium concentration to levels that are not symptomatic. Conventional management typically cannot lessen the complications of the disease and may increase risk in this regard because of the high doses of calcium, vitamin D, and vitamin analogues that are often necessary. The natural history of HypoPT has not been prospectively ascertained and cross-sectional studies are complicated by the fact that these patients are being treated. Some of the complications of HypoPT that are well described can, therefore, be related to conventional therapeutic approaches as well as to the disease per se (5, 99). Table 2 provides a summary of the goals of ideal management.

Table 2.

Goals of Management

1. Avoid symptomatic hypocalcemia

2. Maintain the serum calcium in the lower range of normal or slightly below. It is generally not recommended to exceed the middle of the population range for the normal serum calcium concentration

3. Keep the serum phosphate as close to normal as possible

4. Maintain a normal serum magnesium concentration

5. Maintain the calcium × phosphate product as close to normal as possible and always <55 mg2/dL2 [4.4 mmol2/L2]

6. Avoid hypercalciuria

7. Prevent extraskeletal complications, like nephrocalcinosis and nephrolithiasis

8. Improve quality of life

Conventional management

The mainstay of conventional management is supplemental calcium and vitamin D. Management styles differ with respect to emphasizing active vitamin D with as little calcium supplementation as possible or vice versa (97). In either case, the goal should be to keep the serum calcium within the low normal reference range, namely 8.0 to 8.5 mg/dL or even somewhat below the lower limit for a normal population as long as the patient is asymptomatic.

Calcium supplements

It is virtually impossible to management HypoPT by providing sufficient calcium through the diet. Also, dairy products, the major source of calcium in the diet, are rich in phosphate. Thus, calcium supplements are essential. Typically, patients will require 1 to 2 g of supplemental calcium given in divided doses of 500 mg at a time. Calcium carbonate is generally preferred because 40% of this calcium salt is elemental calcium by molecular weight, making it a more efficient source. Calcium carbonate has to be given with a source of acid, either naturally in someone with normal gastric acid and/or with a protein-based meal (100). Calcium carbonate is not always well tolerated, with some patients complaining of bloating and constipation. The use of calcium carbonate preparations that contain magnesium can ameliorate these complaints. Alternatively, calcium citrate can be used. Its advantage is that it does not require a source of acid and is not generally associated with constipation. The disadvantage of calcium citrate is that it is only 21% calcium by molecular weight and thus requires more pills to achieve the same goals as would be the case with calcium carbonate. In my experience, amounts as much as 9 g of calcium have been required by patients to control the serum calcium (101). Although there has been much discussion about whether calcium supplementation is harmful with regard to long-term cardiovascular risk (102–106), such studies are not directly relevant to HypoPT. First, these patients typically require doses that are higher than recommended, >2.5 g/day (107). Second, increased cardiovascular risk has not been substantiated (66).

Vitamin D supplements

The need for the active form of vitamin D, 1,25(OH)D, calcitriol, or an active analogue, 1-alpha hydroxycholecalciferol, is self-evident. In HypoPT, active vitamin D formation is impaired in the kidney because of the lack of PTH and hyperphosphatemia. Because the biological half-life of active vitamin D is only 4 to 6 hours, daily or twice-daily administration is needed. The average daily dose of calcitriol is about 0.5 to 1.0 mcg or 1.0 to 2.0 mcg of the 1-alpha analogue. Titration upwards can reduce the amount of supplemental calcium required. Although active vitamin D or its analogues is virtually always needed, the need for cholecalciferol (vitamin D₃) or ergocalciferol (vitamin D₂) is less clear. The argument that these patients cannot easily activate the 25-hydroxyvitamin D formed in the liver to the active metabolite formed in the kidney leads to the sense that parent vitamin D is not an important therapeutic adjunct. On the other hand, there are arguments for using a parent form of vitamin D. First, we define vitamin D sufficiency by the level of 25-hydroxyvitamin D (107, 108). In HypoPT are we content with low levels of 25-hydroxyvitamin D if the 1,25 (OH)D level is normal? Many experts are uncertain because the putative extraskeletal benefits of vitamin D may or may not be associated with other metabolites of vitamin D formed in the liver (96). There may be other advantages to using parent vitamin D with less hypocalcemia as noted by Streeten et al. (109). It seems reasonable to maintain levels of 25-hydroxyvitamin D at > 20 ng/mL (50 nmol/L). Recent studies have emphasized the advantages of vitamin D₃ over vitamin D₂ as a supplement (110).

Thiazide diuretics

In patients who have marked hypercalciuria, thiazide diuretics can be used (96). Drawbacks to thiazide diuretics include renal potassium and magnesium losses (46). They are contraindicated in autoimmune polyendocrine syndrome type 1 and in ADH when accompanied by Bartter syndrome (96). I try to avoid thiazide diuretics.

Parathyroid hormone

Although management approaches with calcium and vitamin D can usually deal with the hypocalcemia of HypoPT, large doses are often needed, raising long-term concerns about renal function and extraskeletal calcifications. In addition, conventional management with calcium and active vitamin D does not solve the basic problem in HypoPT, namely the hormone is missing. Without PTH, normal calcium homeostasis cannot be restored either at the skeleton, the kidneys, or other sites such as the central nervous system that have been implicated in the nontraditional aspects of PTH action (111, 112). HypoPT is the last classical endocrine deficiency disease for which the missing hormone has become available. The quest to institute PTH replacement therapy in HypoPT can be traced to Fuller Albright, who treated a patient with a bovine extract of PTH in 1929 (113). More than 60 years later, Winer and colleagues demonstrated that PTH(1-34), an active fragment of PTH, could be used effectively in children and in adults with HypoPT (114). The short half-life of PTH(1-34) was given as the reason why twice- and thrice-daily dosing seemed to be more effective in controlling the serum calcium over a 24-hour period of time than single daily dosing (115–118). Studies by other investigators have also been supportive (119, 120). PTH(1-34) improved control of the serum calcium with smaller amounts of supplemental calcium and vitamin D. Bone turnover increased (114–116) but BMD did not differ from conventional approaches (116, 121) and urinary calcium excretion did not consistently fall. Studies by several laboratories, directed at quality of life measures, demonstrated improvement in most the mental and physical domains of the SF-36 scale (119, 120).

Recombinant human PTH(1-84)

The use of the native human hormone, recombinant human PTH(1-84) (rhPTH(1-84)) ushered in the official therapeutic era of full hormone replacement therapy (122, 123). The pivotal REPLACE study (124) used a double blind, placebo-controlled randomized design of 134 patients in a 2:1 ratio of drug:placebo over 24 weeks. The triple end points were maintenance of the serum calcium and 50% or greater reduction in starting oral calcium dose and in active vitamin D. The dose of rhPTH(1-84) was titrated up, as needed, from 50 mcg to 100 mcg per day as a single dose. The trial unequivocally demonstrated efficacy with 53% taking rhPTH(1-84) reaching the endpoint versus only 2% on placebo (P < 0.001). A secondary prospective endpoint, defined as the number of subjects who could eliminate active vitamin D entirely while reducing the calcium supplement to 500 mg or less per day, was met by a highly significant 43% of subjects (P < 0.001). Other observations of this trial included a reduction of the serum phosphorus into the normal range as well as a reduction in the calcium-phosphate product (125). The REPLACE trial was followed by REPEAT that confirmed and extended these results (126).

Long-term studies of rhPTH(1-84)

The observational work from the Columbia group and others has given insight into some of the long-term benefits and safety of rhPTH(1-84) (127, 128). Over an 8-year period, Tay et al. showed a progressive reduction in supplemental calcium needs by 57% and active vitamin D by 76% (127). The serum calcium was maintained in the low normal range throughout the 8 years of therapy. Although early studies did not show major effects of rhPTH therapy on urinary calcium, time-related changes were evident with a 38% overall reduction in urinary calcium. In the 5-year follow-up study of the REPLACE trial, Mannstadt et al. also showed a reduction in urinary calcium excretion (128). Renal function was stable, which is noteworthy particularly in reference to other studies that have associated long-term conventional management of HypoPT with declining renal function (47, 58, 66, 127). Also noteworthy are long-term effects on quality of life. Although many patients report improved quality of life (“the brain fog has lifted”), Tabacco et al. have shown this to be the case over an 8-year observational period (129). The work from REPLACE, a much shorter term study, also showed improvements in quality of life, particularly with reference to baseline metrics (87-88, 129). In both the long-term studies and the REPLACE trial, the extent of improvement was related to the baseline measures of quality of life. The worse the baseline measures, the greater the improvements with rhPTH(1-84). This observation was highlighted in the REPLACE study, showing that participants from Hungary, the country that had essentially normal quality of life at baseline, did not show any improvement. Improvement in quality of life was not corroborated by the Danish group but that study was short term and did not have the flexibility to adjust the dose of rhPTH(1-84) which was fixed at 100 mcg. The appreciable incidence of hypercalcemia was a limiting confounding variable (84, 87).

The skeletal effects of PTH in HypoPT

The effect of rhPTH(1-84) and human PTH(1-34) [hPTH(1-34)] is to stimulate bone turnover as measured by circulating markers of bone turnover and circulating osteogenic cells (67, 116, 130–133). The exuberant response highlighted by rapid increases in both bone formation and bone resorption markers is tempered over time. Eventually, usually within 1 to 2 years, bone turnover markers fall, returning to a new baseline state, which is higher than the untreated baseline values and more comfortably within the normal euparathyroid range. By histomorphometry, these indications of increased bone turnover are substantiated with marked changes being evident as early as 3 months (68). BMD results have been variable with hPTH(1-34) not being associated with an increase (131) but with rhPTH(1-84), a decline (132) or an increase in the lumbar spine and hip regions and decline in the distal forearm (127). Microstructural studies show trabecular thinning, tunneling, and increased trabecular connectivity (132, 134). Cortical porosity appears to increase (133, 134). The 2-year study of Rubin et al. (67, 68) showed an early anabolic effect with initial increases in mineralizing surface, osteoid surface, and bone formation rate peaking at 12 months. Trabecular width was reduced while trabecular number increased, along with cortical porosity. This work has been extended to patients who were treated with rhPTH(1-84) for an average of 8.3 years (135). The increases in bone remodeling in the short-term biopsies were sustained over time. Early changes in microstructure featured by intra-trabecular tunneling, increases in cancellous bone volume and trabecular number, along with an increase in cortical porosity were all sustained. The results argue for a salutary effect of PTH replacement therapy on the skeleton. The direction toward normalization might be expected to be associated with a reduction in fracture incidence but the paucity of baseline data on fracture incidence in HypoPT and the small number of subjects treated with PTH preclude any conclusions in this regard.

Safety of rhPTH(1-84)

All PTH and PTH-related protein (PTHrP) molecules, when tested in rats at high doses for prolonged periods, will cause osteosarcoma (136, 137). Thus, all PTH and PTHrP-like molecules approved for human use carry with them a black-box warning from the US Food and Drug Administration (FDA). The longest experience is with teriparatide [rhPTH(1-34)] an approved therapy for osteoporosis. With nonhuman primate studies and more than 17 years of human surveillance, no safety signals are evident (138, 139). It would appear that osteosarcoma is not a safety concern in human subjects. To this point, the FDA has approved rhPTH(1-84) in HypoPT with no restrictions as to duration of use, although the black-box warning persists. Other safety concerns specifically related to PTH are those associated with hypercalcemia and hypercalciuria but the safety profile on long-term use is most favorable (127).

Indications for the use for rhPTH(1-84) in HypoPT

The FDA approved rhPTH(1-84) for patients with HypoPT who cannot be well-controlled on conventional therapy. Although it was not clear what the FDA meant by “well-controlled” expert opinion has offered several examples of poor control and, thus, situations where rhPTH(1-84) would be considered (Table 3). Several groups, considering the evidence that is available, have offered management guidelines (96, 140, 141). Two of these reports deal specifically with rhPTH(1-84) (96, 141). A prime indication is someone with symptomatic hypocalcemia who cannot be adequately controlled or in someone whose serum calcium is chronically below a critical value such as 7.5 mg/dL. A second indication is the amount of calcium and active vitamin D required to control the serum calcium. rhPTH(1-84) would be considered if the amount of oral calcium supplementation exceeds 2.5 g/d or if the amount of active vitamin D exceeds 1.5 mcg/day or the 1-alpha analog exceeds 3.0 mcg/d. A third indication is hypercalciuria, kidney stones, nephrocalcinosis, increased stone risk, or reduced creatinine clearance (< 60 mL/min). Other indications include elevated serum phosphorus or calcium-phosphate product (>55 mg²/dL²), any gastrointestinal tract associated with malabsorption. Of particular note are those who have had bypass bariatric surgery. Finally, in view of the data arguing for an improvement in quality of life, many experts feel that this is another guideline for instituting rhPTH(1-84) therapy in HypoPT.

Table 3.

Indications for Considering the Use of rhPTH(1-84) in Hypoparathyroidism^a

1. Poor control of the serum calcium (serum corrected calcium (<7.5 mg.dL) or clinical symptomatology

2. Oral calcium supplementation > 2.5 g/d or 1,25-(OH)D > 1.5 mcg/d or 1-alpha vitamin D > 3.0 mcg/d

3. Hypercalciuria, nephrolithiasis, nephrocalcinosis, reduced creatinine clearance or eGFR (<60 mL/min) or increased stone risk by urinary biochemical analysis

4. Hyperphosphatemia or calcium-phosphate product > 55 mg2/dL2 (4.4 mmol2/L2)

5. Gastrointestinal dysfunction resulting from intrinsic disease or after bariatric surgery

6. Reduced quality of life

^aBased on data derived from reference 96.

Patients who are to begin rhPTH(1-84) therapy should start with 50 mcg/day and simultaneously reduce the dose of active vitamin D or calcium by 50%. Administration should be in the thigh because uptake kinetics are beneficially slower at this site, as opposed to the abdomen. The serum calcium is monitored with gradual reductions in active vitamin D and calcium in stepwise fashion to achieve the optimal goal, elimination of active vitamin D and reduction of supplemental calcium to 500 mg/d or lower. Increases in rhPTH(1-84) are in 25-mcg steps. If therapy is to be discontinued for any reason, such as the current, temporary hold on the availability of rhPTH(1-84) in the United States, it is important to appreciate that the skeleton is now active and will continue to accrue calcium, which could lead to dangerous hypocalcemia (96). Thus, patients who stop therapy should be carefully instructed to increase their calcium and active vitamin D to levels that match or are even higher than the amounts they were taking before starting rhPTH(1-84) therapy.

Future directions

Although the advent of an approved form of PTH, namely rhPTH(1-84), was a signal event in the therapeutic history of HypoPT, several approaches, currently under active investigation, could represent an improvement (122, 142). They are all under development at this time and, thus, it is too soon to know how and whether they will become available. Nevertheless, they do represent potential improvements over the once-daily regimen of rhPTH(1-84) as approved by the FDA and the European Medicines Agency.

Infusion pump

The secretory dynamics of PTH secretion include tonic secretion with circadian excursions and stochastic pulsatility (143). Continuous infusion of PTH would mimic the tonic secretory dynamics that represent the majority of secreted PTH under normal circumstances. The only experience so far, in this regard, is with hPTH(1-34) as reported by Winer et al (144). When compared with a twice-daily injection regimen, the infusion approach resulted in 65% less hPTH required to control the serum calcium along with a 50% lower urinary calcium excretion.

Trans-Con PTH

This approach takes advantage of linking hPTH(1-34) to a polymer that slowly releases the peptide over a prolonged period. The conditions of the formulation can be adjusted to provide for continuous release for 24 hours. A recent study by Holten-Andersen et al (145). demonstrated that this formulation of hPTH(1-34) in both rats and monkeys has a prolonged effect on the serum calcium along with a reduction in urinary calcium excretion.

Pegylated PTH

The effective half-life of PTH can also be extended by attaching PTH to a polyethylene glycol moiety (146). The larger molecular size of hPTH(1-34) with this formulation is associated with prolonged increase in the serum, for up to 48 hours under the conditions of the mouse experiments. The half-life of the pegylated PTH was 24 hours, much longer than the half-life of hPTH(1-34), which is only 2 to 4 hours.

Long-acting PTH

An analogue of hPTH, based on placing different amino acids in the linear sequence of the native peptide, has been shown in thyroparathyroidectomized rats that become acutely hypocalcemic, to be more effective than hPTH(1-34) or hPTH(1-84) (147, 148). The peptide is thought to bind to a configuration of the PTH1 receptor, the Ro state, that is associated with a more prolonged effect. Another PTH peptide that has been altered in its primary sequence might have promise (149).

Other creative approaches to replacement therapy include an oral formulation of a molecule that binds to the PTH1 receptor (150) and in ADH the use of calcilytics (151).

Summary

The explosion of knowledge and interest in hypoparathyroidism is a confluence of burgeoning interest in rare diseases, per se, greater understanding of the pathophysiology of PTH deficiency, clinical experience with conventional management, and new optimism about how to best approach these patients therapeutically with rhPTH(1-84).

Glossary

Abbreviations

ADH

autosomal dominant hypocalcemia

BMD

bone mineral density

CaSR

calcium sensing receptor

FDA

US Food and Drug Administration

HypoPT

hypoparathyroidism

PHPT

primary hyperparathyroidism

PTHrP

parathyroid hormonerelated protein

SF-36

Short Form 36

vBMD

trabecular volumetric BMD

Additional Information

Disclosure Summary: The author has served as a consultant for Takeda.

Data Availability: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.