Abstract
Introduction
Hypoparathyroidism (HypoPT) is an endocrine disease caused by insufficient levels of parathyroid hormone and is associated with impaired health-related quality of life. This study assessed the clinical burden among individuals with postsurgical chronic HypoPT in Medicare Fee-For-Service.
Methods
Adults (aged ≥ 18 years) with newly diagnosed HypoPT (N = 1166) were identified from the Medicare 100% Limited Data Set between July 1, 2017, and March 31, 2020. All had a confirmed diagnosis within 6–12 months after index diagnosis and were required to be continuously enrolled for ≥ 6 months pre index and ≥ 12 months post index. A random sample of non-HypoPT controls (N = 11,258) was synthetically assigned an index date of diagnosis to ensure similar baseline and follow-up periods as individuals with postsurgical chronic HypoPT. The two cohorts were compared before and after matching with respect to the risk of cardiovascular (CV) events, renal complications, urinary tract infections (UTIs), upper respiratory tract infections (URTIs), and mortality.
Results
Individuals with postsurgical chronic HypoPT were older than non-HypoPT controls (mean age 69 vs. 64 years), more were female (76% vs. 57%), had higher Charlson Comorbidity Index scores (3.24 vs. 0.73), and a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75). The incident risks of composite CV events (HR 1.35), renal complications (HR 4.92), UTIs (HR 2.09), and URTIs (HR 1.46) were greater in subcohorts without those conditions prior to index. After matching for baseline characteristics, the elevated risk of renal complications, UTIs, and URTIs remained while there was no difference in the risk of CV events or death between individuals with postsurgical chronic HypoPT and controls.
Conclusion
The substantial clinical burden of postsurgical chronic HypoPT in Medicare patients highlights the treatment gaps associated with current therapy and the need for parathyroid hormone replacement therapies.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12325-025-03264-x.
Keywords: Long-term complications, Parathyroid hormone level control, Postsurgical chronic hypoparathyroidism
Key Summary Points
| Why carry out this study? |
| Postsurgical chronic hypoparathyroidism imposes a significant clinical burden, particularly due to its sequelae. Knowledge gaps, however, exist as to the risk of long-term complications associated with it. |
| We conducted the study to examine the risk of long-term complications among patients with postsurgical chronic hypoparathyroidism versus patients without hypoparathyroidism in the Medicare Fee-For-Service population in the US. |
| What was learned from the study? |
| In unmatched cohorts, individuals with postsurgical chronic hypoparathyroidism in Medicare had significantly higher mortality and incident risk of cardiovascular events, renal complications, urinary tract infections, and upper respiratory infections compared with individuals without hypoparathyroidism. |
| After matching, there was no difference in mortality or cardiovascular risk between the two patient groups, but the study period of 2.5 years may have been insufficient to adequately detect a difference. The incident higher risk of renal complications, urinary tract infections, and upper respiratory infections persisted for individuals with postsurgical chronic hypoparathyroidism who use Medicare. |
Introduction
Hypoparathyroidism (HypoPT) is a rare endocrine disease caused by insufficient levels of parathyroid hormone (PTH), which results in abnormally low serum calcium and elevated serum phosphate levels [1]. HypoPT is primarily caused by the removal of or injury to the parathyroid glands during anterior neck surgery, which accounts for approximately three-quarters of cases. It is estimated that 7.6% of neck surgeries conducted in the USA result in cases of hypoparathyroidism, approximately 25% of which are chronic [2, 3]. Other causes of HypoPT include genetic mutations and autoimmune diseases [4]. HypoPT is considered chronic if it persists more than 6 months following surgery as per the 2016 Endocrine Society Guidelines [5], 2019 Canadian and International Consensus Statement [6], and the 2022 European Society of Endocrinology Consensus Statement [7]. While acute hypocalcemia may occur as an early consequence of anterior neck surgery, it can be managed with immediate intravenous calcium to raise blood calcium levels [5]. The 2022 Guidelines from the Second International Workshop consider HypoPT as permanent if it persists more than 12 months following surgery and highlight that the most commonly used definition of permanent HypoPT is a continued requirement for conventional therapy (consisting of active vitamin D and calcium) [8]. Conventional therapy for HypoPT aims to alleviate hypocalcemia but does not address insufficient PTH [9, 10] and is associated with increased urinary calcium excretion and long-term renal complications, including nephrocalcinosis, nephrolithiasis, and chronic kidney disease (CKD) [10]. Guidelines classify the use of conventional therapy as first-line therapy and state to consider the use of PTH in individuals who are inadequately controlled with conventional therapy, which is considered to be any one of the following: symptomatic hypocalcemia, hyperphosphatemia, renal insufficiency, hypercalciuria, or poor quality of life [8].
Individuals aged over 65 years make up more than one-third of HypoPT cases in the US [2]. In the US, the estimated incidence of postsurgical HypoPT is 22 per 100,000 person-years, and the prevalence is 29 per 100,000 person-years [2, 11]. Hyperphosphatemia and hypocalcemia are characteristic of HypoPT and are associated with other adverse health outcomes, including elevated risk of mortality and infection for the former [12] and increased risk of CKD [13, 14] and cardiovascular (CV) disease [12] for the latter. A series of retrospective studies using a cohort from a managed care claims database in the US found that, in general, individuals with chronic HypoPT were at greater risk for infections [15], nephrocalcinosis and nephrolithiasis [16], CKD [17], and CV disease [18]. An observational study of individuals with chronic HypoPT (91% postsurgical) in Germany found a higher rate of impaired renal function compared with matched non-HypoPT members of the general public [19]. Several studies have also shown a significant reduction in health-related quality of life associated with chronic HypoPT [20, 21].
There is a considerable clinical burden associated with chronic HypoPT, particularly due to its sequelae. Significant knowledge gaps, however, exist as to the risk of long-term complications associated with HypoPT, especially in the Medicare population. Therefore, this observational, retrospective cohort study of Medicare Fee-For-Service claims data among individuals with postsurgical chronic HypoPT aimed to address those gaps in the literature.
The study objectives were to assess (i) the incident risk of CV events, infections, and renal complications (both in terms of composite domains and individual events of interest) and (ii) all-cause mortality in individuals with postsurgical chronic HypoPT vs. non-HypoPT controls. Comparisons were conducted with and without matching between the two groups.
Methods
Data Source
This retrospective database analysis was conducted using 100% Medicare Limited Data Set (LDS) administrative claims data from January 1, 2017, to March 31, 2021. The LDS standard analytical files include de-identified beneficiary-level data such as enrollment, age, sex, race, region, International Classification of Diseases, Tenth Revision (ICD-10-CM), diagnosis and procedural codes, claim dates, and dates of death. LDS contains information for both institutional and non-institutional providers; the data set is available to health services researchers to examine a variety of epidemiological and economic questions of interest [22–24]. The limited nature of LDS stems from the fact that it does not include prescription drugs, physician claims, or durable equipment claims in comparison with other Medicare data sets such as Research Identifiable Files.
Patient Selection and Study Design
Eligible patients identified for inclusion were Medicare beneficiaries aged 18 years or older, categorized as those with postsurgical chronic HypoPT and those without HypoPT (the non-HypoPT control group). Inclusion in the postsurgical chronic HypoPT group required at least two claims with a HypoPT diagnosis code (ICD-10-CM E200, E208, E209, or E892). The first diagnosis had to have occurred after thyroidectomy, parathyroidectomy, goiter removal, excision procedures on the parathyroid, or resection of the thyroid gland, which were identified by CPT or ICD-10 codes, as shown in the Supplementary Material (Table S1); the date of that claim served as the index date. The second claim had to have been made 6–12 months from the index date in the patient identification period (July 1, 2017–March 31, 2020) and served as a confirmatory diagnosis of chronic disease. At least one claim of a related surgical procedure in the 6-month baseline period prior to the index date (first HypoPT diagnosis) was required to confirm that the HypoPT was postsurgical. Patients were excluded if they had a previous diagnosis of HypoPT in the baseline period. A total of 1166 individuals with postsurgical chronic HypoPT were ultimately included in the study (Fig. 1).
Fig. 1.
Study sample selection. CV cardiovascular, HypoPT hypoparathyroidism, URTI upper respiratory tract infection, UTI urinary tract infection
Individuals included in the non-HypoPT control group (N = 11,258) could not have a HypoPT diagnosis in the study period but had to have at least one medical claim in the patient identification period. For this group, a synthetic index date was assigned on the basis of the distribution of time between their first medical claim of any kind and the index date as observed among individuals with postsurgical chronic HypoPT. Namely, the synthetic index date among individuals without postsurgical chronic HypoPT was calculated by adding the time difference described above, borrowed from their matched case with HypoPT, to the date of their own first medical encounter observed during the study period.
Continuous enrollment in Medicare for at least 6 months before and 12 months after the index date was required for inclusion. The observation period of all patients in the analysis was until death, the end of Medicare enrollment, or the end of the study period (March 31, 2021), whichever came first.
Ethical Approval
As a result of the de-identified nature of the retrospective data set, the study did not require ethics committee review. Permission for reuse of the Medicare 100% Limited Data Set was granted by its owner.
Patient and Baseline Characteristics
Variables considered in this study included baseline sociodemographic characteristics (age, gender, race, and Census region), and clinical characteristics (Charlson Comorbidity Index [CCI] score, CV complications, infections, renal complications, mental ill-health, fractures, cataracts, hypocalcemia, and neurological complications).
Study Outcomes
Study outcomes included four domains of complications: CV events (composite domain as well as individual risk of component acute myocardial infarction (ICD-10 code I21), congestive heart failure, cerebrovascular disease, arrhythmia, ischemic heart disease), renal complications (composite domain as well as individual risk of component nephrocalcinosis, nephrolithiasis, and stage 3–5 CKD), urinary tract infections (UTIs), and upper respiratory tract infections (URTIs). These complications were assessed via ICD-10 codes, as shown in the Supplementary Material (Table S2). All-cause mortality was also examined as an outcome.
Statistical Analysis
Analyses of all study objectives were conducted among unmatched and matched cohorts and compared with their respective control groups. An exact matching algorithm allowing for a variable ratio between the number of matched treated and control patients [25, 26] was used to balance individuals with postsurgical chronic HypoPT and controls on age, gender, race, region, CCI score (categorical), and index year. A matching ratio of 1:2 of cases to controls was chosen to optimize the retention of sample size while balancing baseline characteristics.
The overall unmatched and matched cohorts from each patient group were used to assess mortality. In contrast, to examine the incident risk of long-term complications, four subcohorts were assembled from the full patient groups for the assessment of the incident risk of CV events, renal complications, UTIs, and URTIs (Fig. 1). To achieve this, individuals who experienced the respective complication in the baseline period were excluded for each subcohort (i.e., for the examination of incident CV event risk, patients with CV event at baseline were first excluded). Within each subcohort, matching was also performed to create two comparable groups of individuals with postsurgical chronic HypoPT and non-HypoPT controls using the same matching method as described above.
Within the unmatched and matched cohorts, Kaplan–Meier analysis was used to describe the time to event for individuals with postsurgical chronic HypoPT and non-HypoPT controls; hazard ratios for the risk of complications and death were reported on the basis of Cox proportional hazards models.
Sensitivity Analysis
The time-to-event analysis described above was repeated with 3-month washout periods after the index date, where patients with an event during the specified washout period were censored at that point. This was done as a sensitivity analysis to examine the impact on the risk of complications as earlier events after index may be less likely to be due to a HypoPT diagnosis.
Results
Patient and Baseline Characteristics
The index HypoPT (first) diagnosis for patients with postsurgical chronic HypoPT occurred on average 58 days after neck surgery. Non-HypoPT control patients were those who had at least one claim during the study period and who met the continuous enrollment criteria for the study window. After matching, there were 607 patients in the postsurgical chronic HypoPT group and 1107 in the non-HypoPT control group.
The unmatched HypoPT cohort was older than the non-HypoPT control group (median age of 69 vs. 64 years) and had a greater proportion of female patients (76% vs. 57%) (Table 1). Compared with non-HypoPT controls at baseline, individuals with postsurgical chronic HypoPT had a higher CCI score on average (3.24 vs. 0.73) and a notably higher prevalence of long-term complications such as CKD (stage 3–4, 14.1% vs. 1.8%; stage 5, 12.4% vs. 1.8%), nephrocalcinosis (59.9% vs. 0.6%), nephrolithiasis (8.3% vs. 1.0%), UTIs (9.9% vs. 2.2%), and congestive heart failure (13.1% vs. 3.0%), among others.
Table 1.
Sample characteristics: unmatched and matched cohorts
| Variable | Statistic or category | Unmatched cohort | Matched cohort | ||||
|---|---|---|---|---|---|---|---|
| Patients with postsurgical chronic HypoPT (N = 1166) | Medicare control patients without HypoPT (N = 11,258) | P value | Patients with postsurgical chronic HypoPT (N = 607) | Medicare control patients without HypoPT (N = 1107) | P value | ||
| Follow-up period after index diagnosis (months) | Median (Q1–Q3) | 30.0 (22.0–37.0) | 30.0 (22.0–37.0) | 0.771 | 31.0 (22.0–37.0) | 31.0 (23.0–37.0) | 0.865 |
| Age at index diagnosis | Median (Q1–Q3) | 69.0 (64.0–74.0) | 64.0 (63.0–65.0) | < 0.001 | 66.0 (58.0–70.0) | 65.0 (64.0–68.0) | 0.686 |
| Age categorical, N (%) | 18–65 years | 361 (31.0%) | 9668 (85.9%) | < 0.001 | 301 (49.6%) | 560 (50.6%) | 0.648 |
| 66–75 years | 574 (49.2%) | 1470 (13.1%) | 275 (45.3%) | 501 (45.3%) | |||
| 76+ years | 231 (19.8%) | 120 (1.1%) | 31 (5.1%) | 46 (4.2%) | |||
| Gender, N (%) | Male | 278 (23.8%) | 4829 (42.9%) | < 0.001 | 158 (26.0%) | 279 (25.2%) | 0.707 |
| Female | 888 (76.2%) | 6429 (57.1%) | 449 (74.0%) | 828 (74.8%) | |||
| Charlson Comorbidity Index score (continuous) | Mean (SD) | 3.24 (3.23) | 0.73 (1.37) | < 0.001 | 2.11 (2.41) | 1.87 (2.20) | 0.12 |
| Race, N (%) | White | 917 (78.6%) | 8675 (77.1%) | 0.002 | 472 (77.8%) | 882 (79.7%) | 0.967 |
| Black | 160 (13.7%) | 1319 (11.7%) | 97 (16.0%) | 168 (15.2%) | |||
| Asian*** | 19 (1.6%) | 211 (1.9%) | < 11* | < 11* | |||
| Hispanic | 32 (2.7%) | 358 (3.2%) | 17 (2.8%) | 27 (2.4%) | |||
| North American Native | < 11* | 70 (0.6%) | < 11* | < 11* | |||
| Other** | < 11* | 202 (1.8%) | < 11* | < 11* | |||
| Unknown | 24 (2.1%) | 423 (3.8%) | 12 (2.0%) | 17 (1.5%) | |||
| Geographic region, N (%) | North Central | 410 (35.2%) | 3138 (27.9%) | < 0.001 | 195 (32.1%) | 365 (33.0%) | 0.986 |
| Northeast | 160 (13.7%) | 2114 (18.8%) | 84 (13.8%) | 150 (13.6%) | |||
| South | 409 (35.1%) | 3942 (35.0%) | 232 (38.2%) | 421 (38.0%) | |||
| West | 187 (16.0%) | 2038 (18.1%) | 96 (15.8%) | 171 (15.4%) | |||
| Year of index date, N (%) | 2017 | 243 (20.8%) | 2462 (21.9%) | 0.061 | 137 (22.6%) | 242 (21.9%) | 0.926 |
| 2018 | 544 (46.7%) | 4809 (42.7%) | 265 (43.7%) | 493 (44.5%) | |||
| 2019 | 314 (26.9%) | 3361 (29.9%) | 181 (29.8%) | 334 (30.2%) | |||
| 2020 | 65 (5.6%) | 626 (5.6%) | 24 (4.0%) | 38 (3.4%) | |||
| HypoPT-related complications | Myocardial infarction, N (%) | 22 (1.9%) | 47 (0.4%) | < 0.001 | < 11** | 12 (1.1%) | 0.444 |
| Congestive heart failure, N (%) | 153 (13.1%) | 339 (3.0%) | < 0.001 | 63 (10.4%) | 77 (7.0%) | 0.013 | |
| Stroke, N (%) | 18 (1.5%) | 77 (0.7%) | 0.001 | < 11* | 20 (1.8%) | 0.619 | |
| Arrhythmia, N (%) | 64 (5.5%) | 86 (0.8%) | < 0.001 | 22 (3.6%) | 14 (1.3%) | 0.001 | |
| Ischemic heart disease, N (%) | 220 (18.9%) | 675 (6.0%) | < 0.001 | 88 (14.5%) | 117 (10.6%) | 0.017 | |
| All infections, N (%) | 417 (35.8%) | 1,474 (13.1%) | < 0.001 | 192 (31.6%) | 187 (16.9%) | < 0.001 | |
| Hospitalization for all infections, N (%) | 139 (11.9%) | 283 (2.5%) | < 0.001 | 53 (8.7%) | 57 (5.1%) | 0.004 | |
| Upper respiratory tract infections, N (%) | 155 (13.3%) | 431 (3.8%) | < 0.001 | 63 (10.4%) | 52 (4.7%) | < 0.001 | |
| Urinary tract infections, N (%) | 115 (9.9%) | 244 (2.2%) | < 0.001 | 48 (7.9%) | 32 (2.9%) | < 0.001 | |
| Nephrocalcinosis, N (%) | 698 (59.9%) | 62 (0.6%) | < 0.001 | 362 (59.6%) | 11 (1.0%) | < 0.001 | |
| Nephrolithiasis, N (%) | 97 (8.3%) | 107 (1.0%) | < 0.001 | 60 (9.9%) | 13 (1.2%) | < 0.001 | |
| Cataracts, N (%) | 44 (3.8%) | 119 (1.1%) | < 0.001 | 17 (2.8%) | 16 (1.4%) | 0.051 | |
| Chronic kidney disease stage 3 or 4, N (%) | 164 (14.1%) | 201 (1.8%) | < 0.001 | 52 (8.6%) | 61 (5.5%) | 0.015 | |
| Chronic kidney disease stage 5, N (%) | 145 (12.4%) | 205 (1.8%) | < 0.001 | 96 (15.8%) | 50 (4.5%) | < 0.001 | |
| Delirium, N (%) | < 11* | 17 (0.2%) | < 0.001 | < 11* | < 11* | > 0.999 | |
| Depression, N (%) | 220 (18.9%) | 610 (5.4%) | < 0.001 | 117 (19.3%) | 70 (6.3%) | < 0.001 | |
| Fracture, N (%) | 40 (3.4%) | 156 (1.4%) | < 0.001 | 17 (2.8%) | 20 (1.8%) | 0.176 | |
| Hallucination/agitation, N (%) | < 11* | 25 (0.2%) | 0.057 | < 11* | < 11* | 0.194 | |
| Hypocalcemia, N (%) | 53 (4.5%) | 51 (0.5%) | < 0.001 | 30 (4.9%) | < 11* | < 0.001 | |
| Seizure, N (%) | < 11* | < 11* | > 0.999 | < 11* | < 11* | > 0.999 | |
HypoPT hypoparathyroidism
*As per the Centers for Medicare and Medicaid Services’ cell suppression policy, no cells with values < 11 can be directly reported
**The demographic terminology reported in this table reflects that reported by the SEER-Medicare race_code variable. No further specification of ethnicities can be provided
Within the matched cohort (Table 1), postsurgical chronic HypoPT and non-HypoPT groups were balanced on age, gender, race, region, CCI score, and index year, but some differences remained. Individuals with HypoPT had a higher prevalence of CKD (stage 3–4, 8.6% vs. 5.5%; stage 5, 15.8% vs. 4.5%), nephrocalcinosis (59.6% vs. 1.0%), nephrolithiasis (9.9% vs. 1.2%), UTIs (7.9% vs. 2.9%), and congestive heart failure (10.4% vs. 7.0%) compared with non-HypoPT controls. Matching on sociodemographics and CCI score did not eliminate the baseline prevalence difference in complications between the two cohorts.
Race, geographic region, and year of index date were similar across individuals with postsurgical chronic HypoPT and non-HypoPT controls in both the unmatched and matched cohorts. Approximately three-quarters of patients across both groups were white, about one-third were from the North Central region, and one-third from the South region; approximately half had an index date during 2018.
Risk of Complications and Overall Survival
Within the four unmatched subcohorts, individuals with postsurgical chronic HypoPT showed a statistically significant (P < 0.0001) elevated risk of composite CV events (myocardial infarction, congestive heart failure, cerebrovascular disease, ischemic heart disease, or arrhythmia) (HR 1.35), composite renal complications (nephrocalcinosis, nephrolithiasis, CKD stage 3–4 or 5) (HR 4.92), UTIs (HR 2.09), and URTIs (HR 1.46) compared with unmatched controls when patients with the respective complication at baseline were excluded (Fig. 2, Table 2). Within the four matched subcohorts, individuals with postsurgical chronic HypoPT also showed a statistically significant (P < 0.0001) elevated risk of composite renal complications (HR 4.11), UTIs (HR 1.60), and URTIs (HR 1.58) compared with matched controls. Unlike individuals in the unmatched subcohort, individuals with postsurgical chronic HypoPT from the matched subcohort showed no significant elevation in composite CV events (HR 0.90, P = 0.4123) (Fig. 3, Table 2).
Fig. 2.
Time to first hypoparathyroidism complication among unmatched subcohorts. HR hazard ratio
Table 2.
Association of postsurgical chronic hypoparathyroidism diagnosis with incident risk of complications compared with non-hypoparathyroidism controls
| Unmatched cohorts | Matched cohorts | |||||||
|---|---|---|---|---|---|---|---|---|
| No washout | 3-month washout | No washout | 3-month washout | |||||
| HR | P value | HR | P value | HR | P value | HR | P value | |
| Cardiovascular events | 1.35 | < 0.0001 | 1.46 | < 0.0001 | 0.90 | 0.4123 | 0.90 | 0.4619 |
| Acute myocardial infarction | 1.13 | 0.498 | 1.22 | 0.2989 | 1.08 | 0.8027 | 1.23 | 0.5275 |
| Congestive heart failure | 1.40 | 0.0079 | 1.56 | 0.001 | 0.86 | 0.5037 | 0.90 | 0.6637 |
| Cerebrovascular disease | 1.40 | 0.0096 | 1.47 | 0.006 | 0.99 | 0.9543 | 0.93 | 0.7417 |
| Ischemic heart disease | 1.25 | 0.0218 | 1.37 | 0.0024 | 0.93 | 0.6615 | 1.01 | 0.9733 |
| Arrhythmia | 1.83 | < 0.0001 | 1.93 | < 0.0001 | 0.81 | 0.4291 | 0.81 | 0.4717 |
| Renal complications | 4.92 | < 0.0001 | 4.00 | < 0.0001 | 4.11 | < 0.0001 | 3.28 | < 0.0001 |
| Nephrocalcinosis | 18.79 | < 0.0001 | 11.63 | < 0.0001 | 11.54 | < 0.0001 | 7.52 | < 0.0001 |
| Nephrolithiasis | 2.48 | < 0.0001 | 2.76 | < 0.0001 | 2.88 | 0.0042 | 3.33 | 0.0022 |
| Chronic kidney disease stage 3–4 | 2.23 | < 0.0001 | 2.65 | < 0.0001 | 1.76 | 0.111 | 1.75 | 0.1399 |
| Chronic kidney disease stage 5 | 2.56 | 0.0358 | 3.01 | 0.013 | 1.81 | 0.5483 | 1.81 | 0.5483 |
| Urinary tract infection | 2.09 | < 0.0001 | 2.19 | < 0.0001 | 1.60 | 0.0003 | 1.61 | 0.0008 |
| Upper respiratory tract infection | 1.46 | < 0.0001 | 1.46 | < 0.0001 | 1.58 | < 0.0001 | 1.47 | 0.0027 |
HR hazard ratio
Fig. 3.
Time to first hypoparathyroidism complication among matched subcohorts. HR hazard ratio
Individuals with postsurgical chronic HypoPT were significantly more likely to die during follow-up than unmatched non-HypoPT controls (HR 2.75). After matching, there was no difference in mortality risk between the two groups (HR 1.08, P = 0.7402) (Fig. 4).
Fig. 4.
Overall survival among matched and unmatched cohorts. CI confidence interval, HR hazard ratio
Risk of Individual Complications
Within the unmatched cohort, analyses showed a significantly greater incident risk of congestive heart failure (HR 1.40, P = 0.0079), cerebrovascular disease (HR 1.40, P = 0.0096), ischemic heart disease (HR 1.25, P = 0.0218), arrhythmia (HR 1.83, P < 0.0001), nephrocalcinosis (HR 18.79, P < 0.0001), nephrolithiasis (HR 2.48, P < 0.0001), and CKD stage 3–4 (HR 2.23, P < 0.0001) or stage 5 (HR 2.56, P = 0.0358) for individuals with postsurgical chronic HypoPT, but within the matched cohort only the incident risk of nephrocalcinosis (HR 11.54, P < 0.0001) and nephrolithiasis (HR 2.88, P = 0.0042) was elevated significantly (Table 2).
Sensitivity Analysis
The statistically significant (P < 0.0001) risk of composite CV events (HR 1.46), composite renal complications (HR 4.00), UTIs (HR 2.19), and URTIs (HR 1.46) persisted among the unmatched cohort with a 3-month washout period (Table 2; also Fig. S1 in the Supplementary Material). Similarly, among the matched cohort with a 3-month washout period, the risk of composite renal complications (HR 3.28), UTIs (HR 1.61), and URTIs (HR 1.47) was higher for postsurgical chronic HypoPT while the risk of composite CV events (HR 0.90) remained non-significant (Table 2; also Fig. S2 in the Supplementary Material).
Discussion
This study found that for individuals with postsurgical HypoPT, risk of cardiac events, renal disease, UTIs, and URTIs as well as risk of mortality were all elevated compared to non-HypoPT controls in the unmatched analysis. In the matched analysis, risk remained elevated for renal disease, UTIs, and URTIs, but the findings for the risk of cardiac events and mortality were non-significant. Additionally, to examine the temporal relationship between HypoPT and the risk of complications, sensitivity analyses were performed in which CV events, renal complications, UTIs, and URTIs within 3 months after diagnosis were censored. The results pertaining to the risk of complications are consistent with the findings of a 2021 meta-analysis of six European retrospective cohort studies with a combined sample size of 14,055 patients, which found that individuals with postsurgical HypoPT were at higher risk of cardiac events (OR 1.43), renal disease (OR 4.85), and infection (OR 1.51), but had no significant difference in risk of mortality (OR 1.19, P = 0.12) [27].
Four studies, two conducted by Chen et al. in 2019 and two by Gosmanova et al. in 2021, performed similar risk analyses in individuals with chronic HypoPT (not exclusively in postsurgical populations) from 2007 to 2017 and achieved results broadly similar to this research effort despite some differences in methodology. The first Chen et al. 2019 study focused on sepsis, respiratory infections, and kidney or other genitourinary (GU) infections [15], and the second one on nephrolithiasis and nephrocalcinosis [16]. The first paper by Gosmanova et al. focused on CKD [17], and the second one on CV conditions [18]. There are some key differences in methodology between those four studies and this study. The above studies were conducted using a commercial claims data set as opposed to the Medicare claims data set, resulting in a significantly younger population (mean ± SD ages were 58.6 ± 16.3 and 47.3 ± 18.0 years for the postsurgical chronic HypoPT and non-HypoPT control groups, respectively, compared with 67.2 ± 11.0 and 61.3 ± 9.0 for the current study [unmatched cohort]). These studies included all types of chronic HypoPT, while the current study focused specifically on postsurgical chronic HypoPT. The more recent data set used in the current study (2017–2020) was restricted to a 2.5-year follow-up period, while the four studies allowed for a 5-year follow-up period. Additionally, those studies used a random claim as the index date for non-HypoPT controls, while the current study assigned a synthetic index date based on the distribution of time between the first medical claim of any kind and the diagnosis date as observed among individuals with postsurgical chronic HypoPT. And finally, adjustment in the four studies was made for age, gender, race, region, index year, and some baseline comorbidities, while the current study matched on age, gender, race, region, index year, and CCI score and excluded patients with the corresponding condition at baseline for the risk of complication analysis performed among patient subcohorts.
The Chen et al. 2019 study that focused on sepsis, respiratory infections, and kidney or other GU infections [15] found a slightly lower risk of respiratory tract infection (HR 1.20) for individuals with chronic HypoPT compared with the risk identified in the current analysis (HR 1.58). Risks for kidney or other GU infections (HR 1.41) and sepsis (HR 1.64), the latter of which can result from UTIs, were similar to the risk of UTIs found here (HR 1.60) [15]. The Chen et al. 2019 study that focused on nephrolithiasis and nephrocalcinosis [16] found lower risks of nephrocalcinosis (HR 6.94) and nephrolithiasis (HR 1.97) for individuals with chronic HypoPT than the risk identified in the current analysis (HR 11.54 and 2.88, respectively) [16]. The Gosmanova et al. 2021 study that focused on CKD [17] found that risks for incident CKD (HR 2.91) were considerably higher than in the current study (HR 1.76 for CKD 3–4; HR 1.81 for CKD 5), but the risks found for CKD stage progression (HR 1.58) and CKD progression to end-stage kidney disease (HR 2.14) were closer to this study’s findings [17].
The Gosmanova et al. 2021 study that focused on CV conditions [18] found significantly higher risks of complications across the board (HR 1.18–1.72) for individuals with chronic HypoPT. In contrast, increased incident CV or mortality risks were not detected in matched subcohorts in this analysis. One explanation is that the older population in the current study may have been at higher risk of CV complications at baseline, resulting in a smaller apparent increase in risk due to HypoPT. Additionally, the study period of approximately 2.5 years may have been insufficient to adequately detect a difference in the risk of CV events or death. For example, as estimated by the American College of Cardiology/American Heart Association Pooled Cohort Equation, the 10-year risk of congestive heart failure for an elderly population like that in the current study is under 10% and varies depending on baseline assumptions regarding lipid parameters, current smoking, and presence of diabetes, among others [28].
The chief strength of this study is that it utilized Medicare claims data, making it representative of a larger proportion of the US population than can typically be achieved through chart reviews or clinical trials. The findings of the study, consistent with those of a companion paper in which we examined the economic burden of postsurgical chronic HypoPT [29], highlight the gaps associated with current treatment options and the need to address insufficient PTH levels in individuals with postsurgical chronic HypoPT. The use of conventional therapy as first-line therapy for individuals with postsurgical chronic HypoPT is categorized by the 2022 Guidelines from the Second International Workshop as a weak recommendation based on low-quality evidence [8]. In individuals who are inadequately controlled with conventional therapy (which is considered to be any one of the following: symptomatic hypocalcemia, hyperphosphatemia, renal insufficiency, hypercalciuria, or poor quality of life), the guidelines suggest the use of PTH [8]. These recommendations are supported by meta-analyses demonstrating that, in addition to maintaining serum calcium in the normal range and reducing serum phosphate, PTH therapy may result in improvement in physical health-related quality of life and reduction in pill burden, compared with conventional therapy [8].
Our study is not without limitations. Prescription drugs, physician claims, and durable equipment claims are not included in the LDS, so study findings may not have captured all diagnostic codes appearing on medical claims. Additionally, misclassification bias may occur when sourcing diagnoses from billing data, so misdiagnosis or miscoding may affect the precision of these results. Additionally, while matching was used to balance baseline characteristics, there may still be residual confounding due to unmeasured factors such as income level, education, and social determinants of health. These characteristics, which are not captured in claims data, could influence both healthcare access and outcomes, and may contribute to differences observed between the study groups.
Conclusion
To our knowledge, this is the first study to weigh the clinical burden of postsurgical chronic HypoPT against a non-HypoPT control group in the Medicare population in the USA. The substantial clinical burden of postsurgical chronic HypoPT in individuals highlights the outcome gaps associated with current conventional therapy and further demonstrates the need for PTH replacement therapies to address those gaps.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
Medical Writing, Editorial, and Other Assistance
The authors thank Sushmita Inguva for analytic support and Christina DuVernay for copyediting support, both from OPEN Health. The study sponsor, Ascendis Pharma, funded this support.
Author Contributions
Wahidullah Noori: Made substantial contributions to study conception and design; reviewed the manuscript critically for important intellectual content; approved the final version for publication; agreed to be accountable for all aspects of the work. Christopher T. Sibley: Made substantial contributions to study conception and design; reviewed the manuscript critically for important intellectual content; approved the final version for publication; agreed to be accountable for all aspects of the work. Viktor V. Chirikov: Made substantial contributions to study conception and design; performed materials preparation, data collection, and data analysis; reviewed the manuscript critically for important intellectual content; approved the final version for publication; agreed to be accountable for all aspects of the work. Kyle Roney: Made substantial contributions to study conception and design; performed materials preparation, data collection, and data analysis; drafted the manuscript; reviewed the manuscript critically for important intellectual content; approved the final version for publication; agreed to be accountable for all aspects of the work. Alden R. Smith: Made substantial contributions to study conception and design; reviewed the manuscript critically for important intellectual content; approved the final version for publication; agreed to be accountable for all aspects of the work.
Funding
Ascendis Pharma Bone Diseases A/S funded this study and participated in the study design, research, analysis, data collection, interpretation of the data, and the review and approval of the manuscript. All authors had access to relevant data and participated in the drafting, review, and approval of this study. Ascendis Pharma also funded the journal’s Rapid Service and Open Access fees. No honoraria or payments were made for authorship. The financial arrangements of the authors with companies whose products may be related to this manuscript are listed as declared by the authors.
Data Availability
The data sets generated during and/or analyzed during the current study are not publicly available due to the data use agreement stipulations covering the Medicare Limited Data Set Files, as per the Centers for Medicare and Medicaid Services. The authors thank the individuals who contributed data to the Medicare Limited Data Set used in this study.
Declarations
Conflict of Interest
Wahidullah Noori is an employee of Ascendis Pharma, which funded the study. Christopher T. Sibley is an employee of Ascendis Pharma, which funded the study. Viktor V. Chirikov is an employee of OPEN Health, which received consulting fees from Ascendis Pharma to conduct this study. Kyle Roney is an employee of OPEN Health, which received consulting fees from Ascendis Pharma to conduct this study. Alden R. Smith is an employee of Ascendis Pharma, which funded the study.
Ethical Approval
As a result of the de-identified nature of the retrospective data set, the study did not require ethics committee review. Permission for reuse of the Medicare 100% Limited Data Set was granted by its owner.
Footnotes
Prior Presentation: Aspects of the current study were presented at ENDO 2023, then published in the abstract: Noori W, Inguva S, Sibley CT, Chirikov V, Smith AR. SAT233 Clinical and Economic Burden of Postsurgical Chronic Hypoparathyroidism: A US Medicare Retrospective Analysis. J Endocr Soc. 2023;7(Suppl_1):bvad114-529; 10.1210/jendso/bvad114.529. Also delivered as an encore presentation at AMCP Nexus 2023.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Change history
8/24/2025
The article was updated due to correction in references
References
- 1.Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab. 2016;101(6):2300–12. [DOI] [PubMed] [Google Scholar]
- 2.Powers J, Joy K, Ruscio A, Lagast H. Prevalence and incidence of hypoparathyroidism in the United States using a large claims database. J Bone Miner Res. 2013;28(12):2570–6. [DOI] [PubMed] [Google Scholar]
- 3.Lorente-Poch L, Sancho J, Ruiz S, Sitges-Serra A. Importance of in situ preservation of parathyroid glands during total thyroidectomy. J Br Surg. 2015;102(4):359–67. [DOI] [PubMed] [Google Scholar]
- 4.Bilezikian JP, Khan A, Potts JT Jr, et al. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res. 2011;26(10):2317–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab. 2016;101(6):2273–83. [DOI] [PubMed] [Google Scholar]
- 6.Khan AA, Koch CA, Van Uum S, et al. Standards of care for hypoparathyroidism in adults: a Canadian and International Consensus. Eur J Endocrinol. 2019;180(3):P1–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Bollerslev J, Rejnmark L, Zahn A, et al. European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders (PARAT 2021). Eur J Endocrinol. 2022;186(2):R33–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Khan AA, Bilezikian JP, Brandi ML, et al. Evaluation and management of hypoparathyroidism summary statement and guidelines from the second international workshop. J Bone Miner Res. 2022;37(12):2568–85. [DOI] [PubMed] [Google Scholar]
- 9.Shoback D. Hypoparathyroidism. N Engl J Med. 2008;359(4):391–403. [DOI] [PubMed] [Google Scholar]
- 10.Mannstadt M, Bilezikian JP, Thakker RV, et al. Hypoparathyroidism. Nat Rev Dis Primers. 2017;3(1):1–21. [DOI] [PubMed] [Google Scholar]
- 11.Clarke BL, Brown EM, Collins MT, et al. Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab. 2016;101(6):2284–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Underbjerg L, Sikjaer T, Rejnmark L. Long-term complications in patients with hypoparathyroidism evaluated by biochemical findings: a case-control study. J Bone Miner Res. 2018;33(5):822–31. [DOI] [PubMed] [Google Scholar]
- 13.Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab. 2012;97(12):4507–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gosmanova EO, Ayodele O, Chen K, et al. Association of calcium and phosphate levels with incident chronic kidney disease in patients with hypoparathyroidism: a retrospective case-control study. Int J Endocrinol. 2022;2022:6078881. [DOI] [PMC free article] [PubMed]
- 15.Chen K, Curhan G, Gosmanova E, et al., editors. Risk of sepsis, respiratory infections, and kidney or other genitourinary (GU) infections in patients with chronic hypoparathyroidism (HypoPT): a retrospective cohort study. In: Endocrine Abstracts; 2019: Bioscientifica.
- 16.Chen K, Curhan G, Gosmanova EO, et al., editors. Risk of nephrolithiasis and nephrocalcinosis in patients with chronic hypoparathyroidism (HypoPT): a retrospective cohort study. In: Endocrine Abstracts; 2019: Bioscientifica. [DOI] [PMC free article] [PubMed]
- 17.Gosmanova EO, Chen K, Rejnmark L, et al. Risk of chronic kidney disease and estimated glomerular filtration rate decline in patients with chronic hypoparathyroidism: a retrospective cohort study. Adv Ther. 2021;38(4):1876–88. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Gosmanova EO, Chen K, Ketteler M, et al. Risk of cardiovascular conditions in patients with chronic hypoparathyroidism: a retrospective cohort study. Adv Ther. 2021;38(8):4246–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Gronemeyer K, Fuss CT, Hermes F, et al. Renal complications in chronic hypoparathyroidism—a systematic cross-sectional assessment. Front Endocrinol. 2023;14:1244647. [DOI] [PMC free article] [PubMed]
- 20.Jørgensen CU, Homøe P, Dahl M, Hitz MF. Postoperative chronic hypoparathyroidism and quality of life after total thyroidectomy. J Bone Mineral Res Plus. 2021;5(4): e10479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Astor MC, Løvås K, Debowska A, et al. Epidemiology and health-related quality of life in hypoparathyroidism in Norway. J Clin Endocrinol Metab. 2016;101(8):3045–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Sacks NC, Cyr PL, Louie AC, et al. Burden of acute myeloid leukemia among older, newly diagnosed patients: retrospective analysis of data from the 2010–2012 Medicare limited data set. Clin Therap. 2018;40(5):692-703.e2. [DOI] [PubMed] [Google Scholar]
- 23.Kimball CC, Nichols CI, Nunley RM, Vose JG, Stambough JB. Skilled nursing facility star rating, patient outcomes, and readmission risk after total joint arthroplasty. J Arthroplasty. 2018;33(10):3130–7. [DOI] [PubMed] [Google Scholar]
- 24.Haidar S, Vazquez R, Medic G. Impact of surgical complications on hospital costs and revenues: retrospective database study of Medicare claims. J Comp Effect Res. 2023;12(7):e230080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Faries D, Zhang X, Kadziola Z, et al. Real world health care data analysis: causal methods and implementation using SAS. Cary: SAS Institute; 2020. [Google Scholar]
- 26.Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci Rev J Inst Math Stat. 2010;25(1):1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hadedeya D, Kay J, Attia A, et al. Effect of postsurgical chronic hypoparathyroidism on morbidity and mortality: a systematic review and meta-analysis. Gland Surg. 2021;10(10):3007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25_suppl_2):S49–73. [DOI] [PubMed] [Google Scholar]
- 29.Noori W, Sibley CT, Chirikov VV, Roney K, Smith AR. Economic burden of postsurgical chronic hypoparathyroidism: a US Medicare claims retrospective analysis. Adv Ther. 2025. 10.1007/s12325-025-03265-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data sets generated during and/or analyzed during the current study are not publicly available due to the data use agreement stipulations covering the Medicare Limited Data Set Files, as per the Centers for Medicare and Medicaid Services. The authors thank the individuals who contributed data to the Medicare Limited Data Set used in this study.