Hypoparathyroidism : epidemiological studies from prevalence to mortality

<p dir="ltr"><b>Background</b><br>Chronic hypoparathyroidism (hypoPT) is a rare endocrine disorder caused by insufficient parathyroid hormone (PTH) secretion, leading to hypocalcemia and hyperphosphatemia. Postsurgical damage to the parathyroid glands is the most common cause, while nonsurgical hypoPT may arise from autoimmune or genetic disorders. Standard treatment with active vitamin D and calcium supplements normalizes serum calcium but does not restore the physiological actions of PTH. Emerging evidence indicates that patients with chronic hypoPT are at risk of multiple long-term complications. The underlying mechanisms remain incompletely understood, and it is uncertain to what extent these outcomes relate to the disease itself, treatment-related factors, or in the case of nonsurgical hypoPT, diagnostic delay. In Sweden, neither population-based prevalence data nor validation of diagnostic coding for chronic hypoPT had previously been performed.</p><p dir="ltr"><br></p><p dir="ltr"><b>Objective</b><br>This thesis aimed to advance knowledge on chronic hypoPT by (study I) validating diagnostic coding in the Swedish registers; (study II) assessing fracture risks, osteoporosis diagnoses, and osteoporosis medication use; (study III) estimating prevalence and mortality; and (study IV) evaluating neuropsychiatric outcomes, including diagnoses, hospitalization, and medication use.</p><p dir="ltr"><br></p><p dir="ltr"><b>Methods</b><br><b>Study I</b> validated register diagnoses through medical record review of 120 patients with ICD-10 codes for hypoPT, receiving conventional treatment (2004- 2016).</p><p dir="ltr"><br></p><p dir="ltr"><b>Studies II-IV</b> were nationwide cohort studies using the Swedish National Patient Register, Prescribed Drug Register, Cause of Death Register, and Total Population Register. Patients with chronic hypoPT were identified through ICD-10 codes combined with dispensations of active vitamin D. Ten population-based controls matched by age, sex, and county of residence were selected for each case. Subgroup analyses were performed by sex and etiology.</p><p dir="ltr">In <b>study II</b>, the outcomes included fractures, osteoporosis diagnoses, and osteoporosis medication use.</p><p dir="ltr"><b>Study III</b> estimated the prevalence of chronic hypoPT and assessed all-cause and cause-specific mortality, stratified by sex, and etiology.</p><p dir="ltr"><b>Study IV</b> included patients with chronic hypoPT diagnosed in 2005-2018. Dispensed medications were extracted from the Prescribed Drug Register, and neuropsychiatric morbidity was assessed using diagnoses, hospitalizations, and drug dispensations.</p><p dir="ltr"><b>Results</b><br><b>In</b> <b>study I</b>, the positive predictive value of the hypoPT diagnosis was 91%, based on review of 120 medical records, confirming high diagnostic accuracy in the National Patient Register. <b>In study II</b>, 1,915 patients and 15,838 controls were included. The overall fracture risk was not increased (HR 0.93, 95% CI 0.69-1.26). However, the risk of vertebral fractures was higher (HR 1.55, 95% CI 1.12-2.14), and the risk of hip fractures was lower in patients compared with controls (HR 0.70, 95% CI 0.50-0.98). <b>In study III</b>, the prevalence was estimated at 19.4 per 100,000 inhabitants. Postsurgical cases accounted for 72% of all patients. All-cause mortality was significantly higher in patients compared to controls (HR 1.55, 95% Cl 1.40-1.72), with an observed excess risk particularly in nonsurgical hypoPT (HR 2.16, 95% CI 1.76-2.65) compared with postsurgical hypoPT (HR 1.39, 95% CI 1.23- 1.58). <b>In study IV</b>, patients with chronic hypoPT had higher use of antiepileptics (OR 1.68, 95% CI 1.35-2.08), hypnotics/sedatives (OR 1.28, 95% CI 1.11-1.47), and opioids (OR 1.21, 95% CI 1.05-1.40). No significant differences were observed for neuropsychiatric diagnoses or hospitalizations.</p><p dir="ltr"><br></p><p dir="ltr"><b>Conclusions</b><br>Chronic hypoPT is associated with multiple long-term health risks, including increased mortality, a higher risk of vertebral fractures and a lower risk of hip fractures compared to population controls. Furthermore, patients with chronic hypoPT had greater use of antiepileptics, hypnotics/sedatives, and opioids compared to controls. These findings highlight the importance of improved clinical awareness and structured long-term follow-up. Further research is needed to clarify the mechanisms behind the observed complications and to explore whether modifications in long-term management could mitigate comorbidity burden and improve quality of life.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Kamal W,</b> Björnsdottir S, Kämpe O, Trolle Lagerros Y. Concordance Between ICD-10 Codes and Clinical Diagnosis of Hypoparathyroidism in Sweden. Clin Epidemiol. 2020 Mar 24;12:327-331. PMID: 32273771; PMCID: PMC7102876. <a href="https://doi.org/10.2147/CLEP.S242528">https://doi.org/10.2147/CLEP.S242528</a></p><p dir="ltr">II. Björnsdottir S, <b>Kamal W,</b> Mannstadt M, Mäkitie O, Spelman T, Kämpe O, Langdahl BL. Increased risk of vertebral fractures and reduced risk of femur fractures in patients with chronic hypoparathyroidism: a Nationwide cohort study in Sweden. J Bone Miner Res. 2025 Jun 25;40(7):860-867. PMID: 40324207; PMCID: PMC12188750. <a href="https://doi.org/10.1093/jbmr/zjaf061">https://doi.org/10.1093/jbmr/zjaf061</a></p><p dir="ltr">III. <b>Kamal W,</b> Trolle Lagerros Y, Mannstadt M, Spelman T, Kämpe O, Björnsdottir S. Increased Mortality in Chronic Hypoparathyroidism: A Nationwide Cohort Study in Sweden. [Submitted] </p><p dir="ltr">IV. <b>Kamal W,</b> Mannstadt M, Trolle Lagerros Y, Spelman T, Husebye ES, Mäkitie O, Kämpe O, Björnsdottir S. Psychiatric drug use in patients with chronic hypoparathyroidism: A nationwide cohort study in Sweden. [Manuscript]</p>