End-organ Damage Associated with Primary Hyperparathyroidism: A Natural History Study

Abstract

Importance:

Primary hyperparathyroidism (PHPT) is common and contributes to skeletal and kidney end-organ damage. Although parathyroidectomy can mitigate these complications, many patients are managed with observation, and real-world data on the population-based frequency and timing of end-organ damage under usual care are limited.

Objective:

Evaluate the frequency and timing of end-organ damage associated with PHPT.

Design:

Longitudinal cohort study with follow-up through 2023.

Setting:

Population-based cohort identified from national Truveta electronic health record (EHR) and claims data (2010-2023).

Participants:

Adults with a new biochemical diagnosis of PHPT.

Exposure:

A new biochemical diagnosis of PHPT was defined as an elevated PTH (>65 pg/mL) within 1 month after a second elevated calcium level (serum calcium >10.2 mg/dL or ionized calcium >1.3 mmol/L or >5.3 mg/dL).

Main Outcomes:

PHPT-associated end-organ damage (osteoporosis, atraumatic fractures, kidney stones, stage 3 or worse chronic kidney disease) at or after PHPT diagnosis using EHR/claim codes and laboratory data, in addition to the frequency and timing of parathyroidectomy.

Results:

We identified 43,399 patients with PHPT (mean [SD] age, 67.9 [12.5] years; 78% female), of which 22,279 (51.3%) had end-organ damage at diagnosis. Among 21,120 patients without end-organ damage at diagnosis, 6,762 (32.0%) progressed to end-organ damage after a median of 516 days (IQR: 166, 1,125). Only 4,442 patients (19.9%) with end-organ damage at diagnosis were treated with parathyroidectomy. Among those who progressed to end-organ damage, 1,348 (19.9%) underwent subsequent parathyroidectomy, which occurred a median of 154 days (IQR: 41, 439) later.

Conclusions and Relevance:

In this national cohort of adults with a biochemical diagnosis of PHPT, 67% had PHPT-associated end-organ damage at diagnosis or on follow-up. Despite this, parathyroidectomy was uncommon. These findings may inform strategies to optimize utilization of parathyroidectomy and mitigate PHPT-associated morbidity.

Introduction

Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with skeletal and kidney end-organ damage, including osteoporosis, kidney stones, and chronic kidney disease (CKD).¹ Multidisciplinary guidelines recommend parathyroidectomy for patients with evidence of end-organ damage, as surgery remains the only definitive treatment for PHPT.² Despite this, most patients are managed nonoperatively, often with observation and selective treatment of complications.^3–5 This approach may reflect the longstanding perception that PHPT, particularly among patients who are seemingly asymptomatic or have mild biochemical disease, is a low-risk disorder. Improved understanding of the burden of PHPT-associated end-organ damage in patients receiving usual care is necessary to assess the appropriateness, potential harms, and opportunities for improvement in current management strategies.

Despite the increasing prevalence of PHPT and the morbidity incurred by its associated skeletal and kidney complications, there are limited data describing the prevalence and progression of PHPT-associated end-organ damage in large, representative cohorts with biochemically confirmed disease.¹ Recent studies have focused on selected manifestations, such as osteoporosis or kidney stones in geographically limited cohorts.⁶ Long-term prospective studies from single centers have primarily evaluated biochemical progression and changes in bone mineral density, rather than hard clinical endpoints.^7,8 A more complete understanding of the spectrum of PHPT-associated morbidity, including osteoporosis, fractures, kidney stones, and CKD, as well as the likelihood of disease progression without surgical intervention, is critical to informed treatment counseling by clinicians and decision-making by patients.

We examined the prevalence and longitudinal incidence of skeletal and kidney morbidity in a nationally-representative cohort of U.S. adults with a new biochemical diagnosis of PHPT. Specifically, we evaluated the proportion of patients with evidence of end-organ damage at the time of PHPT diagnosis, as well as the proportion that developed evidence of end-organ damage over time, prior to operative management with parathyroidectomy. Our objective was to characterize the modern natural history of PHPT and provide context for current PHPT clinical care.

Methods

We performed a longitudinal cohort study of adults with a new biochemical diagnosis of PHPT from 2010 to 2023 using Truveta electronic health record (EHR) and claims data. Truveta is a national data source containing linked clinical data (laboratory results, pharmacy records, notes, imaging reports) from over 120 million patients across 50 states, with linkage to commercial claims data.⁹ The Stanford University institutional review board approved the study and waived the need for informed consent because of minimal risk. This study was conducted in accordance with STROBE guidelines for observational research.¹⁰

Cohort Creation

A new biochemical diagnosis of PHPT was defined as an elevated parathyroid hormone level (>65 pg/mL) within 1 month after a second elevated calcium level (serum calcium >10.2 mg/dL or ionized calcium >1.3 mmol/L or >5.3 mg/dL).¹¹ Only adults ≥18 years were included. To exclude patients with secondary or tertiary hyperparathyroidism, we excluded those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² in the year prior to diagnosis or prior diagnosis codes for stage 4-5 CKD, end-stage kidney disease, kidney transplant, or dialysis (Supplemental eTable 1). We excluded patients without linked claims data to ensure more complete capture of diagnoses and interventions. We also excluded patients with less than 1 year of available data before PHPT diagnosis or less than 1 year of follow-up after diagnosis or those who underwent parathyroidectomy prior to meeting criteria for biochemical diagnosis.

Outcomes

The primary outcome assessed at cohort entry and during longitudinal follow-up was PHPT-associated end-organ damage, which included osteoporosis, atraumatic fracture, kidney stone, or incident CKD stage 3 or worse. The criteria for each type of end-organ damage were validated definitions chosen to maximize specificity and minimize false positive findings (Supplement eTable 2-4). Osteoporosis was identified based on two separate patient encounters with an International Classification of Diseases (ICD-9/10) diagnosis code for osteoporosis within 2 years.¹² An atraumatic fracture was identified based on ICD-9/10 diagnosis codes for a major osteopathic fracture (vertebral, hip, humerus, or forearm) without an ICD-9/10 trauma code within 7 days before or after.^13,14 A kidney stone event was defined as an inpatient stay or emergency department encounter with a kidney stone ICD-9/10 diagnosis code, a Current Procedural Terminology (CPT) procedure for kidney stone management in any setting, or two separate outpatient encounters with ICD-9/10 diagnosis codes for kidney stone(s).¹⁵ Stage 3 or worse CKD was defined based on KDIGO criteria: two measurements of eGFR <60 mL/min/1.73 m², occurring at least 90 days apart.¹⁶ Patients were considered to have end-organ damage at cohort entry if they met any of the above criteria in the year prior to biochemical PHPT diagnosis.

Secondary outcomes included parathyroidectomy after diagnosis, as well as meeting guideline criteria for surgery based on the time-relevant International Workshop on PHPT: osteoporosis, atraumatic fracture, kidney stone, CKD stage 3 or worse, or hypercalciuria.^2,17,18 Parathyroidectomy was evaluated based on CPT and ICD-9/10 procedure codes. Hypercalciuria was defined based on 24-hr urine calcium excretion ≥400mg/day for encounters prior to and including August 2022, and as >300mg/day for men and >250mg/day for women for encounters in and after September 2022, to reflect existing guidelines during those time periods.^2,17,19 Patients were followed until date of last follow-up or until parathyroidectomy. Patients were censored at the time of parathyroidectomy given our focus on PHPT disease progression prior to definitive surgical treatment.

Statistical Analysis

Descriptive analyses evaluated: 1) the number of patients with evidence of end-organ damage at the time of PHPT biochemical diagnosis; and 2) the number of patients who did not initially have evidence of end-organ damage but developed evidence of end-organ damage during longitudinal follow-up. A similar descriptive analysis evaluated the number of patients who met guideline criteria for parathyroidectomy at diagnosis, as well as the number of patients who later progressed to meeting criteria for surgery. The proportion of patients who underwent parathyroidectomy was also evaluated.

The probability of survival without progression to PHPT-associated end-organ damage was evaluated with Kaplan-Meier analysis. Stratified subgroup analyses evaluated whether progression to end-organ damage differed based on age or the severity of baseline hypercalcemia. Patient age was dichotomized as either <65 or ≥65 years. Calcium levels were dichotomized as mild hypercalcemia (10.3-11.2 mg/dL) or severe hypercalcemia (>11.2 mg/dL), based on guideline thresholds.^2,17,18 A Cox proportional hazards model was used to estimate the association between severe hypercalcemia and the development of end-organ damage during longitudinal follow-up. The effects of calcium severity, age, and sex were modeled as time-varying to account for changes in their associations over time. Hypertension, diabetes, race, and ethnicity were included as fixed baseline covariates. Race and ethnicity data were obtained from the electronic health record and reflected classifications recorded by participating health systems, which may have been self-reported or administratively assigned. Race and ethnicity were included because of known differences in PHPT presentation and management across demographic groups.

Sensitivity Analysis

As a sensitivity analysis to evaluate the robustness of CKD-related findings, CKD stage 3 or worse was excluded from the baseline definition of end-organ damage. In this analysis, patients with baseline eGFR ≥60 mL/min/1.73m² were followed as in the primary analysis and patients with CKD stage 3 (baseline eGFR <60 mL/min/1.73m²) were followed longitudinally for worsening kidney dysfunction, defined as ≥2 subsequent eGFR measurements at least 5 mL/min/1.73m² below baseline, or development of other end-organ damage (atraumatic fracture, kidney stones, or osteoporosis).

Results

We identified 43,399 patients with a new biochemical diagnosis of PHPT after applying exclusion criteria (Figure 1). The cohort was predominantly female (78.0%, n=33,854) and White (75.4%, n=32,719) with a mean (SD) age of 67.9 years (12.5). The mean (SD) serum calcium at diagnosis was 10.5 mg/dL (1.6), and the mean (SD) PTH level was 115.3 pg/mL (64.7). A total of 10,697 (24.6%) patients underwent parathyroidectomy a median of 215 days (IQR: 86, 566) after PHPT diagnosis. Cohort characteristics are described in Table 1.

Figure 1. Cohort Selection and End-organ Damage Status.

Flow diagram illustrating cohort selection and categorization of patients according to end-organ damage status at diagnosis and during follow-up. Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone.

Table 1.

Cohort characteristics, stratified by the presence of PHPT-associated end-organ damage at the time of diagnosis.

	Total (N=43,399)	End-organ damage at PHPT diagnosis (N=22,279)	No end-organ damage at PHPT diagnosis (N=21,120)	P Value
Sex
Male	9,545 (22.0%)	4,775 (21.4%)	4,770 (22.6%)	.004
Female	33,854 (78.0%)	17,504 (78.6%)	16,350 (77.4%)
Age, mean (SD), y	67.9 (12.5)	72.1 (11.3)	63.5 (12.2)	<.001
Race
White	32,719 (75.4%)	17,164 (77.0%)	15,555 (73.7%)	<.001
Black or African American	6,771 (15.6%)	3,327 (14.9%)	3,444 (16.3%)
Asian	822 (1.9%)	281 (1.3%)	541 (2.6%)
Other or unknown	2,849 (6.6%)	1,393 (6.3%)	1,456 (6.9%)
American Indian or Alaska Native or Native Hawaiian or Pacific Islander	238 (0.5%)	114 (0.5%)	124 (0.6%)
Ethnicity
Hispanic or Latino	1,790 (4.1%)	710 (3.2%)	1,080 (5.1%)	<.001
Not Hispanic or Latino	39,308 (90.6%)	20,378 (91.5%)	18,930 (89.6%)
Unknown	2,301 (5.3%)	1,191 (5.3%)	1,110 (5.3%)
Hypertension	27,533 (63.4%)	16,115 (72.3%)	11,418 (54.1%)	<.001
Diabetes	9,249 (21.3%)	5,479 (24.6%)	3,770 (17.9%)	<.001
Region
West	5,797 (13.4%)	2,569 (11.5%)	3,228 (15.3%)	<.001
Midwest	7,753 (17.9%)	3,812 (17.1%)	3,941 (18.7%)
Northeast	2,298 (5.3%)	1,061 (4.8%)	1,237 (5.9%)
South	10,302 (23.7%)	5,273 (23.7%)	5,029 (23.8%)
Unknown	17,249 (39.7%)	9,564 (42.9%)	7,685 (36.4%)
Serum calcium, mean (SD), mg/dL	10.5 (1.6)	10.5 (1.6)	10.5 (1.7)	.07
PTH, mean (SD), pg/mL	115.3 (64.7)	116.9 (65.1)	113.6 (64.3)	<.001
BMI category
Underweight/Healthy	7,239 (16.7%)	4,106 (18.4%)	3,133 (14.8%)	<.001
Overweight	10,180 (23.5%)	5,358 (24.0%)	4,822 (22.8%)
Class 1 Obesity	8,163 (18.8%)	4,282 (19.2%)	3,881 (18.4%)
Class 2 Obesity	4,484 (10.3%)	2,315 (10.3%)	2,169 (10.3%)
Class 3 Obesity	3,729 (8.6%)	1,890 (8.5%)	1,839 (8.7%)
Unknown	9,604 (22.1%)	4,328 (19.4%)	5,276 (25.0%)

Data are n (%) or mean (SD). PTH indicates parathyroid hormone; BMI, body-mass index.

At the time of PHPT diagnosis, 22,279 (51.3%) patients had evidence of PHPT-associated end-organ damage (Figure 2). Patients with end-organ damage were older (72.1 [11.3] vs 63.5 [12.2] years, P<.001), and had higher PTH levels (116.9 [65.1] vs 113.6 [64.3] pg/mL, P<.001) than those without, while serum calcium was not different between groups (10.5 [1.6] vs 10.5 [1.6] mg/dL, P=.07). The most common type of end-organ damage at diagnosis was CKD stage 3 worse (72.8%, n=16,209), followed by kidney stones (21.2%, n=4,724), osteoporosis (21.1%, n=4,704), and atraumatic fractures (12.4%, n=2,759). Among these patients, 5,582 (23.7%) had more than one type of end-organ damage. Of those with end-organ damage at diagnosis, 4,442 (19.9%) underwent parathyroidectomy during follow-up, a median of 208 days (IQR: 81, 519) after diagnosis.

Figure 2. Development of End-organ Damage and Use of Parathyroidectomy in Primary Hyperparathyroidism.

Sankey diagram illustrating end-organ damage status at diagnosis, development of end-organ damage during follow-up, and subsequent parathyroidectomy among patients with primary hyperparathyroidism. End-organ damage included osteoporosis, atraumatic fracture, kidney stones, and chronic kidney disease stage 3 or worse.

Among 21,120 patients without end-organ damage at the time of PHPT diagnosis, 6,762 (32.0%) had newly documented evidence of end-organ damage during longitudinal follow-up, at a median of 516 days (IQR: 166, 1,125) after diagnosis. The most common incident end-organ damage after PHPT diagnosis was osteoporosis (n=3,990, 18.9%), followed by incident CKD stage 3 worse (n=2,224, 10.5%), kidney stones (n=1,461, 6.9%), and atraumatic fractures (n=1,179, 5.6%). Among these patients, 1,348 (19.9%) underwent parathyroidectomy a median of 154 days (IQR: 41, 439) after end-organ damage detection. A total of 14,358 patients (33.1% of the cohort) had no evidence of PHPT-associated end-organ damage during a median follow-up of 1,269 days (IQR: 780, 2,033), among whom 4,907 (34.2%) underwent parathyroidectomy a median of 181 days (IQR: 76, 448) after PHPT diagnosis.

In the Kaplan-Meier analysis among patients without end-organ damage at diagnosis, the probability of progression to any end-organ damage at 5 years was 43.5% (Figure 3). Estimated 5-year cumulative incidence was 24.7% for osteoporosis, 14.1% for CKD stage 3 or worse, 9.5% for kidney stones, and 7.5% for an atraumatic fracture. Patients ≥65 years had a higher estimated risk of end-organ damage at 5 years compared with patients <65 years (55% vs 31.1%) (Supplemental eFigure 1a). There was no difference in the estimated 5-year risk of end-organ damage between patients with mild versus severe hypercalcemia (43.4% vs 44.2%) (Supplemental eFigure 1b).

Figure 3. Kaplan-Meier Estimates of End-organ Damage-free Survival After Primary Hyperparathyroidism Diagnosis.

Kaplan-Meier estimates of survival without PHPT-associated end-organ damage among patients without end-organ damage at the time of diagnosis. Curves are shown for any end-organ damage, osteoporosis, kidney stones, chronic kidney disease (CKD) stage 3 or worse, and atraumatic fracture. Numbers at risk are shown below the figure. Abbreviations: CKD, chronic kidney disease; PHPT, primary hyperparathyroidism.

There were 22,977 (52.9%) patients who met criteria for surgery at PHPT diagnosis, and an additional 8,608 (19.8%) who developed at least one criterion after diagnosis, representing 72.8% of the cohort (n=31,585) (Supplemental eFigure 2). Of patients who met criteria for surgery, 6,999 (22.2%) underwent parathyroidectomy during follow-up, a median of 244 days (IQR: 98, 630) after PHPT diagnosis.

In Cox regression analysis with time-varying effects, severe hypercalcemia was associated with a 45% higher hazard of end-organ damage (HR 1.45; 95% CI, 1.32-1.60). However, this association attenuated over time, with the relative hazard decreasing by approximately 7% per year of follow-up (HR 0.93; 95% CI, 0.89-0.96) (Table 2).

Table 2:

Multivariable Cox analysis with time-varying effects evaluating the association of severe hypercalcemia with end-organ damage

	Hazard Ratio (95% CI)
Calcium severity (reference: Mild)
Severe hypercalcemia	1.45 (1.32-1.60)
Calcium severity with time interaction	0.93 (0.89-0.96)
Age (reference: <65 y)
≥65 y	1.93 (1.80-2.08)
Age with time interaction	1.03 (1.00-1.05)
Sex (reference: Male)
Female	0.70 (0.65-0.77)
Sex with time interaction	0.97 (0.94-1.00)
Hypertension (reference: No)	1.06 (1.01-1.11)
Diabetes (reference: No)	1.03 (0.96-1.10)
Race (reference: White)
Asian	0.98 (0.84-1.14)
Black or African American	0.72 (0.67-0.77)
Other or unknown	0.91 (0.82-1.01)
Ethnicity (Reference: Not Hispanic or Latino)
Hispanic or Latino	1.00 (0.89-1.13)
Unknown	0.93 (0.83-1.05)

In a sensitivity analysis excluding CKD from the baseline definition of end-organ damage and defining worsening kidney function as end-organ damage in patients with baseline eGFR <60 mL/min/1.73m², 10,623 patients (24.5%) met criteria for end-organ damage at diagnosis. During follow-up, 6,762 patients (15.6%) without baseline end-organ damage and without CKD stage 3 developed new end-organ damage. Among 11,656 patients with CKD stage 3 (eGFR <60 mL/min/1.73m²) at diagnosis, 8,132 (69.8%) developed additional end-organ damage or met criteria for worsening kidney dysfunction during follow-up. Overall, even after excluding CKD from the baseline definition of end-organ damage, 25,517 patients (58.8%) had end-organ damage at diagnosis or developed end-organ damage or worsening kidney dysfunction (Supplemental eFigure 3).

Discussion

In this large, nationally-representative cohort of patients with incident biochemical PHPT, we found that skeletal and kidney end-organ damage was common, with 51% of patients having documented morbidity at diagnosis and 32% of those without baseline end-organ damage developing morbidity during follow-up. Severe hypercalcemia at diagnosis was associated with an increased risk of end-organ damage during the first year, but this association decreased thereafter. Despite the high burden of morbidity and frequent fulfillment of guideline criteria for surgery, parathyroidectomy was uncommon. Together, these findings suggest that PHPT-associated end-organ damage is more prevalent in routine clinical practice than previously described and that definitive surgical treatment remains underutilized.

This study represents the first assessment of associated end-organ damage in a national cohort of patients with PHPT based on biochemical criteria. These results build on previous natural history studies in PHPT, including prospective single-center studies of Silverberg et al. and Rubin et al., which found that 27% to 37% of asymptomatic PHPT patients progressed to meeting parathyroidectomy criteria through the development of severe hypercalcemia, hypercalciuria, or low cortical bone density over 10 to 15 years.^7,8 Assadipour et al. evaluated PHPT progression to osteoporosis, kidney stones, and hypercalciuria in a Southern California Kaiser cohort and found that 35% of patients had end-organ damage at diagnosis (excluding CKD) and 29% without baseline end-organ damage developed osteoporosis, nephrolithiasis, decreased kidney function, or hypercalciuria after a median follow-up of 3.7 years.⁶

Our study expands on these prior publications by incorporating a comprehensive definition of end-organ damage, considering a broader range of skeletal and kidney morbidity associated with PHPT, and evaluating the burden of PHPT in a nationwide cohort.² In this updated evaluation, we report a higher prevalence of end-organ damage at PHPT diagnosis (51%), and a higher rate of progression to end-organ damage among patients without preexisting PHPT-associated sequelae (32%) over approximately 5 years of follow-up, resulting in 67% of the cohort demonstrating evidence of end-organ damage. Findings were overall similar in a sensitivity analysis excluding CKD from the baseline definition of end-organ damage, supporting the robustness of these observations. These results offer a national overview of disease progression across diverse care settings, leveraging data beyond a single center, payor, or geographic region, and including patients who may be underrepresented in other datasets. Additionally, use of laboratory data from a large EHR database allowed identification of PHPT based on biochemical criteria, increasing confidence in the diagnosis while enabling assessment of disease progression without reliance solely on diagnosis codes.

Among patients without end-organ damage at the time of PHPT diagnosis, we found no difference in Kaplan-Meier estimated risk of progression to end-organ damage at 5 years based on the severity of hypercalcemia. However, in the first year after PHPT diagnosis, severe hypercalcemia (>11.2 mg/dL) was associated with an increased hazard of end-organ damage in our multivariable analysis, which then decreased over time. One potential explanation for this time-limited difference is an unrecognized diagnosis of PHPT among patients with mild biochemical profiles (leading to less testing for associated end-organ damage) or more thorough evaluation of patients with severe hypercalcemia. Additionally, it has previously been shown that patients with severe hypercalcemia are more likely to undergo surgery, which censored them from further follow-up in this analysis.^6,20,21 If higher-risk individuals in the severe hypercalcemia group were preferentially treated surgically, this could reduce observed differences between groups over time. Nonetheless, these findings demonstrate that mild hypercalcemia does not preclude development of end-organ damage and should not reassure against future disease progression.

The high prevalence of PHPT-associated morbidity found in this national population calls for increased attention to the evaluation and management of these patients. Despite 67% of patients having PHPT-associated morbidity and 72% meeting multidisciplinary guidelines for surgical management, fewer than 25% of patients underwent parathyroidectomy. These low rates of surgery are consistent with prior publications.^3,22 In our study, one-third of patients without evidence of PHPT-associated end-organ damage at the time of diagnosis later developed end-organ damage, some of whom may have avoided this morbidity with timely surgical intervention.^23,24 These findings underscore that PHPT warrants greater clinical attention. Despite longstanding guidelines for PHPT management, a gap remains between disease burden and treatment delivery, representing an opportunity to improve evaluation and care of patients with PHPT.^2,17,18 Definitive treatment with parathyroidectomy is likely underutilized; however, rather than call for a uniform increase of surgical intervention, future efforts should prioritize care pathways that improve identification, risk-stratification, referral, and treatment of patients most likely to benefit from surgery, while accounting for patient-level heterogeneity in risks, preferences, and comorbidities. Developing systems of care that emphasize appropriate surgical candidacy is essential to improving outcomes in PHPT and delivering high-value care.

This study is not without limitations. First, we are unable to draw conclusions regarding causality between PHPT and skeletal or kidney end-organ damage in this observational cohort. However, these complications are well-established sequelae of PHPT in population-based studies comparing patients with and without PHPT, remain indications for parathyroidectomy, and are increasingly supported by comparative effectiveness data demonstrating organ-specific benefits of surgery.^{2,6,11,25–27} Although CKD is included in guideline-defined end-organ involvement in PHPT, the extent to which mild hypercalcemia may contribute to decline in kidney function is less understood. As such, inclusion of CKD as an outcome may overestimate PHPT-associated kidney morbidity, particularly among patients with less severe biochemical disease. However, findings from the sensitivity analysis excluding CKD from baseline assessments of end-organ damage were similar to the primary analysis, suggesting that this limitation did not meaningfully alter the overall conclusions. Additionally, because outcome ascertainment and timing depend on clinician evaluation, the recorded occurrence of end-organ damage likely represents detection, rather than true disease onset. As a result, some patients who may have had undiagnosed end-organ damage at baseline may have been misclassified as new incident morbidity on follow-up. Although this may overestimate newly identified events, reliance on clinically detected outcomes likely results in overall underestimation of the true burden of PHPT-associated end-organ damage. Finally, although we utilized a large database of linked electronic health records with available claims data, some patients may have received care outside contributing health systems or may have changed insurance during follow-up. However, our requirement for linked claims data and 1 year of follow-up before and after diagnosis minimized the impact of this limitation.

In summary, 67% of patients with PHPT had or developed end-organ damage over time, yet fewer than 20% underwent parathyroidectomy. This contemporary evaluation of end-organ complications among a national PHPT cohort highlights the skeletal and kidney morbidity associated with the condition and can inform clinician counseling and patient decision-making regarding disease management, supporting a shift from observation for disease progression toward prevention of associated morbidity. At a national level, these findings suggest a gap between guideline recommendations and clinical practice and highlight an opportunity to improve identification and referral of patients most likely to benefit from parathyroidectomy.

Key Points.

Question:

What is the frequency and timing of skeletal and kidney end-organ damage among adults with primary hyperparathyroidism (PHPT) under usual care?

Findings:

In this longitudinal cohort study of 43,399 patients with a biochemical diagnosis of PHPT, 51% had end-organ damage at the time of diagnosis and an additional 16% developed evidence of end-organ damage during follow-up. Less than 20% of patients with end-organ damage underwent parathyroidectomy.

Meaning:

PHPT-associated end-organ damage is more prevalent than previously described, yet definitive surgical treatment remains underutilized, highlighting an opportunity to improve the management of PHPT patients.