A delicate balance: the challenges of hypoparathyroidism

Vignette

A 38-yr-old woman with chronic non-surgical hypoparathyroidism, managed elsewhere, presented to our practice with symptomatic hypocalcemia. At the age of 17, she began to suffer from muscle cramps, paresthesia, and ongoing diffuse pain. It took years before she was correctly diagnosed with hypoparathyroidism. Her symptoms were severe enough that she required emergency room visits several times a year. After she was properly diagnosed and started on calcium and calcitriol therapy, she continued to experience frequent episodes of severe hypocalcemia. She saw multiple healthcare providers who each introduced a new regimen. In addition, poor communication led to her discontinuing her medications altogether. As a result, her calcium levels remained consistently low, and she lost confidence in her prospect for better health. At the time of her visit to our clinic, she had discontinued calcitriol, was taking a large amount of oral calcium daily all at once, and had hypocalcemia. We addressed her concerns, and the challenges she faces with adherence to her medication regimen. We provided her with detailed information about the disease and the reasoning behind her treatment plan. Treatment was initiated with calcium carbonate 600 mg 3 times daily and calcitriol 0.5 mcg once daily. One week after treatment initiation, her test results showed improvement in her albumin-adjusted calcium, phosphorus, and 24-h urine calcium which were all within target range.

Case description

A 38-yr-old woman with chronic non-surgical hypoparathyroidism presented to our clinic for initial consultation. Her symptoms, which included muscle cramps, paresthesia, and generalized fatigue, started when she was 17 yr old. One particular morning, she experienced severe diffuse body pain, muscle spasms, weakness, and difficulty breathing prompting her to seek emergency care at an outside hospital. Spiral CT scan raised the possibility of bilateral pulmonary embolisms and anticoagulation was started. Despite this, her symptoms of muscle spasms and chest discomfort worsened, prompting her to return to the hospital. Her albumin-adjusted calcium was found to be critically low at 4.8 mg/dL (normal: 8.5–10.5 mg/dL) and intravenous calcium gluconate was administered with rapid improvement of her symptoms. With an undetectable PTH and no history of neck surgery or other apparent causes, she was diagnosed with idiopathic hypoparathyroidism. A re-evaluation of her initial CT reversed the initial interpretation, attributing her initial symptoms to the hypocalcemia. She was discharged home on a treatment plan with calcium and calcitriol. Over the next 8 yr, she struggled to keep her calcium within range (Figure 1) and her symptoms controlled. She moved cities multiple times for training and her career, which left her often without consistent medical supervision. She self-modified her medications according to what she thought would help, resulting in several emergency room (ER) visits due to severe hypocalcemia. Her distrust in the medical system likely began with the initial misdiagnosis and gradually grew over the years.

Figure 1.

Albumin-adjusted serum calcium levels before optimization. Normal range 8.5–10.5 mg/dL (shaded band).

Additional history includes depression and anxiety on fluoxetine and lorazepam, a history of C-section due to intrauterine growth retardation, and tobacco use of about 10 cigarettes daily. Of note, she had no history of kidney stones. Patient is unaware of a family history of hypoparathyroidism or other calcium-related disorder though no calcium measurements of first-degree members were provided.

At the time of her visit to our clinic, she was taking 5 pills of calcium carbonate 600 mg (total 3000 mg), all at bedtime. She had discontinued calcitriol due to fear that it will worsen her bone pain. Physical exam revealed a blood pressure of 98/65 mmHg, and positive Chvostek and Trousseau signs.

Lab results revealed albumin-adjusted calcium of 6.6 mg/dL (normal 8.5–10.5 mg/dL), ionized calcium 0.91 mmol/L (normal 1.09–1.33 mmol/L), 25OH-vitamin D of 25 ng/mL (normal 20–80 ng/mL), phosphorus 6 mg/dL (normal 2.6–4.5 mg/dL), creatinine 0.7 mg/dL (normal 0.4–1 mg/dL), magnesium 2 mg/dL (normal 1.8–2.5 mg/dL). Cosyntropin stimulation tests to rule out adrenal insufficiency and thyroid-stimulating hormone were normal, and thyroid peroxidase antibodies were negative. Renal ultrasound to assess for the presence of nephrolithiasis or nephrocalcinosis was unremarkable.

We addressed her concerns regarding treatment adjustments and the challenges she faces with medications adherence. Additionally, we provided information about the disease and the rationale for her treatment. Our initial medical management included calcium carbonate 600 mg 3 times daily taken with meals and calcitriol 0.5 mcg once daily with a goal to achieve low to low-normal calcium levels of around 8.0–8.5 mg/dL to minimize the risk of hypercalciuria. One week after treatment initiation, her test results showed improvement: albumin-adjusted calcium 8.4 mg/dL, phosphorus 4.5 mg/dL, 24-h urine calcium 204 mg/24 h. We discussed with the patient the option of PTH replacement treatment. Since she appeared well-controlled on conventional treatment, and rhPTH(1-84) was only available through a Special Use Program, PTH replacement was not further pursued at that time.

She was pleased to report only minimal symptoms. Her serum calcium levels mostly remained within the desired target range (Figure 2), and her 24-h urine remained below 250 mg/d, allowing us to maintain her medication regimen with only minor adjustments over the years.

Figure 2.

Albumin-adjusted serum calcium levels after optimization. Normal range 8.5–10.5 mg/dL (shaded band).

Of note, patient’s depression showed improvement, as she could find more joy in life and reported higher energy levels than before. She also appeared in a better mood during the office visit and endorsed an overall enhancement in her mood.

Clinical problem

Hypoparathyroidism is characterized by undetectable or inappropriately low PTH levels, resulting in hypocalcemia, hyperphosphatemia, and tendency toward elevated 24-h urine calcium. Symptoms of hypocalcemia vary from mild, including paresthesia and muscle cramps, to severe symptoms, such as laryngospasm, cardiac arrhythmias, and seizures. Adverse outcomes of hypoparathyroidism include kidney stones, nephrocalcinosis, CKD, central nervous system calcifications, cataracts, and mood disorder including anxiety.¹ The symptoms and comorbidities of hypoparathyroidism lead to a high utilization of healthcare resources and a poor quality of life (QOL) of patients.

When the disease is caused by neck surgery, the diagnosis of hypoparathyroidism is usually straightforward. However, the diagnosis of idiopathic hypoparathyroidism is often delayed, since it is a rare disease (in one estimate comprising 6% of patients with hypoparathyroidism)¹ and therefore frequently not considered by physicians.

The management of hypoparathyroidism can be challenging. Calcium and calcitriol are the standard of care, but this regimen does not always provide optimal levels of serum and urine calcium. Calcium and calcitriol do not replace the functions of PTH; they do not address hyperphosphatemia, hypercalciuria, and low bone turnover leading to abnormal bone microstructures.

Differential diagnosis and investigations

The differential diagnosis of hypocalcemia is wide and includes vitamin D-related disorders (eg, vitamin D deficiency from low intake or treatment with specific antiepileptic drugs), PTH-related disorders (hypoparathyroidism, hypo- or hypermagnesemia, pseudohypoparathyroidism), and others (drugs that block bone resorption or chelate calcium, critical illness, and renal disease). Our patient did not take any drugs that lower calcium, had normal kidney function, magnesium, and 25OH-vitamin D but undetectable PTH, therefore a diagnosis of hypoparathyroidism was confirmed. Hyperphosphatemia, a consequence of the lack of the phosphaturic effect of PTH, is commonly seen.¹

The most common cause of hypoparathyroidism is surgical injury to or removal of the parathyroid glands during neck surgery, accounting for about 75% of cases; other causes include genetic disorders impairing parathyroid gland development, PTH biosynthesis or release, or autoimmune parathyroid gland destruction, seen in Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).¹ Infiltrative disorders can very rarely be responsible for hypoparathyroidism. In our patient, given the lack of neck surgery, the absence of an infiltrative disease and other autoimmune diseases, a diagnosis of idiopathic hypoparathyroidism was made. Genetic testing for hypoparathyroidism is recommended in patients with a positive family history of non-surgical hypoparathyroidism or who develop nonsurgical hypoparathyroidism at an age younger than 40, but our patient declined.² Suitable laboratory tests for diagnosing autoimmune hypoparathyroidism are currently not available except for the type associated with APECED.

Diagnosis

Idiopathic hypoparathyroidism.

Treatment and progression

According to the 2022 International Task Force guidelines for chronic hypoparathyroidism,³ the recommended management consists of calcium and an active vitamin D analog, with the target range for albumin-adjusted serum calcium in the lower half of the normal range or just below normal. The goal here is to avoid hypercalciuria by targeting a low to low-normal serum calcium, which effectively lowers the renal filtered load of calcium improving hypercalciuria. However, serum calcium should not be so low that patients have significant symptoms. This fine balance works in some, but not all patients on standard of care. The goal for the 24-h urine calcium excretion is less than 250 mg for adult women and 300 mg for men. Thiazide diuretics combined with a low sodium diet can improve hypercalciuria but requires monitoring of serum magnesium and potassium, and, at initiation, of serum sodium. Population-wide and case–control studies revealed a slight rise in the incidence of cutaneous squamous cell cancer associated with the use of thiazide diuretics, leading some experts to advise the use of sun protection measures.

Hyperphosphatemia can be another challenge because current standard of care does not replace the function of PTH. Calcium supplements, when taken with meals, can bind some of the dietary phosphate, reduce phosphate absorption, and alleviate hyperphosphatemia. Calcium acetate has been shown to bind phosphorus when given with meals in normal subjects. Serum phosphate could also be reduced by using phosphate binders and avoiding phosphate rich diets.

Serum magnesium levels, when very low, can cause symptoms similar to hypocalcemia and should be corrected. 25OH-vitamin D levels should be kept in the normal range.

Our patient was treated with a classic regiment of calcitriol and 3 times daily calcium with meals, which achieved serum calcium within the target range of around 8–8.5 mg/dL while maintaining 24-h urine calcium below 250 mg. When these goals cannot be achieved, experts recommend the consideration of PTH or PTH analogs.

The biggest challenge was the patient’s limited understanding of her condition and understanding of the rationale for its treatment, possibly compounded by inadequate communication with her healthcare providers.

The goal for dividing the calcium supplements into 3 times a day is to avoid peaks in serum and urine calcium and to bind phosphorus from the meals. For patients who take proton pump inhibitors or have otherwise low stomach acidity, calcium citrate should be given instead of calcium carbonate.

Serum ionized or albumin-adjusted calcium, phosphorus, magnesium, creatinine, and eGFR should be measured every 3–12 mo in stable patients. Additionally, serum 25OH vitamin D should be measured every 6–12 mo, 24-h urine calcium, and creatinine every 6–24 mo. In unstable patients, the assessment should be performed more frequently as clinically indicated.

Discussion

The 2 main challenges that our patient with idiopathic hypoparathyroidism faced were (1) the delay in the diagnosis and (2) finding a satisfactory treatment regimen and adhering to it.

Although the diagnosis of postsurgical hypoparathyroidism is often straightforward and quick, it can be delayed in the idiopathic forms. Classical symptoms of hypocalcemia are not always present leading to an atypical presentation like in our patient whose chief complaint at her initial presentation was chest pain. This led to a misdiagnosis at her initial visit to the ER and subsequent visits, triggering a cardiovascular workup instead. Many symptoms of hypoparathyroidism are nonspecific, such as the decrease in mental acuity and inability to concentrate, characterized as “brain fog,” fatigue, anxiety and altered mood, muscle weakness, and stiffness.

The problem of patients with hypoparathyroidism feeling misunderstood has been previously documented. A web-based survey conducted among 374 adults with hypoparathyroidism revealed that, on average, patients consulted with 6 ± 8 physicians before and after their diagnosis.⁴ Nearly half of them (48%) believed that they had received inadequate care, and a significant majority (79%) strongly agreed that most physicians lacked a proper understanding of hypoparathyroidism. Our patient expressed similar sentiments and perceptions, which contributed to her non-adherence to treatment, resulting in many years of severe symptoms and poorly controlled disease.

A retrospective online chart review conducted across multiple countries found that 59.4% of patients experienced hypoparathyroidism-related symptoms. When hypoparathyroidism was inadequately controlled, patients exhibited a higher number of comorbidities and required more hospitalizations, ER visits, and outpatient visits.⁵ Another study involving 82 adult patients with chronic hypoparathyroidism highlighted suboptimal treatment outcomes, with only 34% of them achieving all the target ranges of calcium, phosphate, and urine calcium levels. Approximately 14% had calcium levels below the desired range, and 30% of patients experienced nephrolithiasis.⁶

A questionnaire survey asking about medication adherence revealed that about one-third of 64 patients with post-operative hypoparathyroidism were taking less than the recommended doses of oral calcium and calcitriol. Adherence was lower in patients with longer disease duration. Common reasons for non-adherence to calcium and calcitriol were patients’ concerns about potential kidney damage and experiencing polyuria related to the pills.⁷

A study investigating adherence to treatment and the impact of suboptimal management of hypoparathyroidism on the QOL of patients was conducted with patients from 20 different endocrinology clinics who were taking conventional treatment.⁸ Among the 300 patients included in the study, only 60.7% adhered to their treatment. Non-adherent patients exhibited higher levels of anxiety and depression compared to treatment-adherent counterparts, and these scores were negatively correlated with calcium concentrations. Furthermore, these non-adherent patients reported lower QOL scores.

Taking calcium and activated vitamin D multiple times daily can be more challenging than it may seem. Many patients do not fully understand the rationale behind splitting their calcium doses. It becomes apparent that managing multiple pills daily can be a burden to the individual. The situation becomes even more daunting when the calcium levels remain uncontrolled or when symptoms persist. In our patient’s case, she began associating some or her symptoms to the treatment itself, which led to a decline in her adherence. Identifying barriers to achieving optimal adherence is critical for any chronic disease, including hypoparathyroidism.

Patients with hypoparathyroidism on conventional treatment have consistently been shown to have reduced QOL. Hypoparathyroidism etiology, gender, comorbidities, and medication are among factors that influence QOL. In addition to general tools that assess QOL, several disease-specific questionnaires for hypoparathyroidism have been developed such as the Hypoparathyroidism Symptom Diary, and the Hypoparathyroid Patient Questionnaire (HPQ 40/28). The accessibility of these questionnaires for researchers should be improved, and the potential for their application in routine patient care should be investigated.⁹

The replacement of conventional therapy with PTH or PTH analogs has shown improvements in QOL in some but not all studies.

The conventional treatment with calcium and activated vitamin D, that is currently the standard of care, does not replace the actions of PTH. Standard treatment can increase the risk for extraskeletal calcifications and kidney stones. In addition, patients frequently need to take several pills daily, a requirement that can diminish their QOL. The use of full length recombinant human PTH (rhPTH(1–84)) is approved for the treatment of hypoparathyroidism and has shown promising results in clinical trials and postmarketing use but unfortunately it is not currently available for patients.

Patients with chronic hypoparathyroidism have been found to have increased risk of CKD in several retrospective and prospective cohort studies. In a recent retrospective cohort study, the risk of CKD was reduced in patients with chronic hypoparathyroidism who were treated with rhPTH(1-84), compared to historical controls who were not treated with PTH (but had been prescribed calcitriol).¹⁰ Cardiovascular manifestations such as hypotension, arrhythmias, bradycardia, and congestive heart failure due to cardiomyopathy have been observed in patients with hypoparathyroidism and hypocalcemia.¹

Unanswered questions for future research

Emerging treatment options with PTH or PTH analogs have the potential to change our management of hypoparathyroidism (see Table 1 for a current list of PTH analogs). Hormone replacement with PTH or PTH analogs is a logical proposition and aligns with the standard practice for most other classical endocrine disorders. However, many questions remain. Will PTH replacement effectively reduce the long-term risk of nephrocalcinosis, nephrolithiasis, and CKD? Do these novel treatments have beneficial effects on skeletal health? Can patients gain access to point-of-care calcium measurements, enabling them to monitor their calcium levels at home? Addressing these and other questions requires continued collaborations among endocrinologists, patients, and the pharmaceutical industry, all working toward the common goal of improving the QOL for individuals with hypoparathyroidism.

Table 1.

Overview of PTH analogs and other emerging therapies in clinical trials for hypoparathyroidism treatment.

Analog	Description	Use in patients with hypoparathyroidism
hPTH(1-34)	Synthetic or recombinant human PTH(1-34) (hPTH(1-34)) is the biologically active fragment of PTH peptide and can bind and activate the PTH receptor. Approved for osteoporosis. Short plasma half-life (1 h approximately).	Needs to be administered more frequently than once a day or even continuously to exert effects over 24 h. Not approved for hypoparathyroidism in the US.
rhPTH(1-84)	Recombinant full-length PTH	Daily injection can reduce the need for calcium and active vitamin D. Approved for hypoparathyroidism in the US, but product recalled due to rubber particulates in the cartridge.
Transcon PTH (Palopegteriparatide)	Investigational once-daily prodrug with sustained release of active PTH(1-34). Consists of a parent drug, PTH(1-34), transiently conjugated to a branched methoxypolyethylene glycol (mPEG) carrier through a proprietary linker. Administered as a once-daily SC injection designed to provide stable PTH levels, calcium and phosphate within the normal physiological range over 24 h/d.	PaTHway Trial: patients maintained normocalcemia while permitting independence from conventional therapy and being well-tolerated. This drug is awaiting approval.
AZP-3601 (eneboparatide)	Injectable PTHR agonist (PTH/PTHrP hybrid) with prolonged intracellular signaling.	Currently in clinical trial phase 3 (NCT05778071)
PCO371	Oral small-molecule agonist of PTHR1.	Clinical trial (NCT04209179) terminated due to unexplained adverse effects.
Encaleret	Oral calcilytic for the treatment of autosomal-dominant hypocalcemia 1	Currently in phase 3 clinical trial (NCT05680818)
MBX2109	Once-weekly injectable PTH prodrug with release of the active PTH(1-34)	Phase 1 clinical trial completed (NCT05158335)
EXT608	Once-weekly injectable PTH attached to the vitamin D-binding protein.	Phase 1 clinical trial completed (NCT05408663)

Conclusions and future directions

The management of hypoparathyroidism is complex. Shared decision making between physicians and their patients plays a crucial role for ensuring adherence and achieving favorable outcomes including the patients’ QOL. There is an urgent need for improved disease education for both patients and healthcare providers. Distributing printed resources and directing patients to relevant medical information including those from patient organization such as the Hypoparathyroidism Association can be beneficial.

Although conventional treatment for hypoparathyroidism may raise serum calcium levels and relieve symptoms associated with hypocalcemia in some patients, improvements in the management of this condition are needed. Indications for considering PTH replacement therapy include symptomatic hypocalcemia, hyperphosphatemia, renal insufficiency, hypercalciuria, or poor QOL despite maximal optimization of conventional therapy. Recent developments have deepened our understanding of PTH pharmacology, leading to innovative approaches to treating hypoparathyroidism.

Key points

• Chr onic hypoparathyroidism causes typical symptoms of hypocalcemia such as paresthesia, muscle cramps, and seizures. Atypical complaints, which can lead to missing the diagnosis, include mood disorders, fatigue, and lack of concentration.

• Conventional management of hypoparathyroidism includes calcium taken in divided doses and active vitamin D.

• Management of hypoparathyroidism with conventional treatment can be challenging due to lack of adequate serum und urine calcium control and complications of chronic treatment such as nephrocalcinosis and nephrolithiasis.

• Reduced patient quality of life, the feeling of being misunderstood, and not understanding the rationale for the burdensome treatment can contribute to poor patient adherence to treatment. Shared decision-making is crucial to ensure the patient's active involvement.

• Novel treatments that reduce the need for multiple daily pills and achieve better control of calcium and phosphate homeostasis are promising.

Author contributions

Garyfallia Papaioannou (Conceptualization, Data curation, Investigation, Methodology, Writing – original draft, Writing – review & editing) and Michael Mannstadt (Conceptualization, Project administration, Supervision, Writing – review & editing).

Funding

G.P. was supported by the T32 NIH training grant T32DK007028 to the MGH Endocrine Division.

Conflicts of interest

MM: Principal investigator/Advisory board/Consultant for Takeda, Amolyt and Bridgebio. GP has no conflicts of interest to declare.

Data availability

None declared.