Age-specific differences in parathyroidectomy after implementation of guidelines for primary hyperparathyroidism

Introduction

Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by hypercalcemia and elevated or inappropriately normal parathyroid hormone (PTH) levels. PHPT is frequently a progressive disease that can lead to significant skeletal and renal complications, among others (1,2). This condition affects all age groups, with increasing incidence and prevalence seen with advancing age (3).

Parathyroidectomy is the only definitive treatment for PHPT. The 2016 American Association of Endocrine Surgeons (AAES) Guidelines and the International Workshop Consensus—currently on its fifth iteration—have standardized evidence-based indications for parathyroidectomy, emphasizing timely surgical management in patients with specific biochemical and clinical features (4-6). Despite these efforts, real-world data suggest persistent disparities in the management of PHPT, particularly in older adults, who are less likely to undergo parathyroidectomy even when they meet accepted criteria for surgery (7-13). This practice pattern may negatively impact skeletal and renal outcomes in a group already at higher risk for these complications (14,15). The factors underlying this disparity remain uncertain, as existing data do not demonstrate increased perioperative risk associated with parathyroidectomy in elderly patients (10,16).

The aim of this study was to examine age-specific differences in the diagnosis of PHPT, completeness of preoperative evaluation, time from biochemical diagnosis to surgery, and indications for surgery in patients with PHPT who underwent parathyroidectomy at a tertiary academic center following implementation of management guidelines. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-410/rc).

Methods

This retrospective cohort study examined adult patients diagnosed with sporadic PHPT who underwent parathyroidectomy at the University of Florida between January 1^st, 2017 and December 31^st, 2022. Patients were identified using an electronic medical record (EMR) search of diagnosis and procedural codes. This study was approved by the University of Florida Institutional Review Board (No. 202202761), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The requirement for informed consent was waived due to the retrospective nature of the study, use of existing medical record data, and minimal risk to participants.

Patients were included in the study if they met the following criteria: (I) a confirmed diagnosis of either hypercalcemic or normocalcemic PHPT based on biochemical findings; (II) underwent parathyroidectomy within the specified study period; and (III) had preoperative biochemical and clinical data, regardless of completeness. A diagnosis of hypercalcemic PHPT was determined based on an albumin-adjusted serum calcium or ionized calcium above the upper limit of normal with an associated serum PTH that was either inappropriately in the normal range or above the upper limit of normal on two occasions at least 2 weeks apart. A diagnosis of nomocalcemic PHPT was determined based on the presence of a normal albumin-adjusted serum calcium or ionized calcium with an associated serum PTH level above the upper limit of normal on at least 2 occasions over 3–6 months after ruling out secondary causes of hyperparathyroidism, such as vitamin D deficiency, calcium deficiency, malabsorption issues, or chronic kidney disease (4,17). Patients were excluded if they had a previous operation for PHPT or if the indication for parathyroidectomy was secondary or tertiary hyperparathyroidism. Data was manually extracted from EMRs and included demographic data, referral pattern data, laboratory data, time-to-event data, comorbidities and associated conditions, and surgical extent data. Patient referral information was reviewed and referral patterns were characterized as: (I) institutional; (II) community-practice endocrinology; (III) community-practice primary care; and (IV) other. Laboratory data included serum calcium (corrected for albumin level), serum PTH, creatinine, estimated glomerular filtration rate (eGFR) and 25-hydroxy vitamin D. Corrected calcium and serum PTH levels were obtained at time of diagnosis and prior to surgery, both reported as a median. Symptomatic PHPT was defined as a biochemical diagnosis of PHPT in the setting of skeletal or renal complications, such as osteitis fibrosa cystica, fragility fractures, nephrolithiasis, or nephrocalcinosis (18). While proximal myopathy is also a component of symptomatic PHPT, this was not recorded in the majority of patients and thus excluded from the definition in this study. Time-to-event data included interval of time from biochemical diagnosis of PHPT to surgery (months) and interval of time from initial elevated calcium to first PTH testing (months). Preoperative cardiometabolic comorbidities were identified based on identification in the EMR problem list, as determined by a clinical provider. Comorbidities and associated conditions identified included skeletal disease (osteoporosis on DXA scan, fragility fractures, vertebral fractures) and renal disease (nephrolithiasis, nephrocalcinosis, 24-hour urine calcium >400 mg/24 h, eGFR <60 mL/min/1.73 m²). Nephrolithiasis was defined as the presence of calcium-based calculi on imaging, either X-ray, ultrasound, or cross-sectional, urinary studies, or by patient report. Nephrocalcinosis was defined as the presence of calcium deposits in the renal parenchyma on imaging (6,18). A complete preoperative evaluation was defined as the availability of all the following in a single patient: corrected serum calcium, PTH level, eGFR, 25-hydroxy vitamin D, DXA scan, and 24-hour urine calcium excretion.

The 2016 AAES Guidelines and the Fourth International Workshop Guidelines for definitive management of PHPT were used to identify evidence-based indications for surgery (4,17): (I) symptomatic PHPT and hypercalcemia; (II) serum calcium greater than 1 mg/dL above the upper limit of normal; (III) evidence of renal involvement, including silent nephrolithiasis, nephrocalcinosis, hypercalciuria (>400 mg/24 h), or impaired renal function (eGFR <60 mL/min/1.73 m²); (IV) evidence of skeletal involvement, including osteoporosis, fragility fractures, or vertebral compression fractures on spine imaging); and (V) age <50 years. Indications such as unwillingness to comply with observation protocols or neurocognitive and/or neuropsychiatric symptoms, both listed as potential indications in the 2016 AAES Guidelines, were not examined in this cohort due to subjectivity and lack of standardized measures for neurocognitive and/or neuropsychiatric symptoms.

The types of parathyroidectomy were performed at the discretion of the surgeon based on preoperative imaging studies and surgeon preference. Types of parathyroidectomy were as follows: (I) focused parathyroidectomy, defined as identification and resection of a single parathyroid gland; (II) unilateral parathyroid exploration, defined as identification of two parathyroid glands on the same side of the neck with or without resection of parathyroid glands; and (III) bilateral cervical exploration, defined as exploration of both sides of the neck for parathyroid tissue with or without resection of parathyroid glands. Patients were defined as having single gland disease at the index operation if they underwent resection of a single hypercellular parathyroid gland, confirmed as hypercellular on final pathology. Multigland disease at the index operation was defined as resection of more than one hypercellular parathyroid gland on final pathology. Biochemical cure after parathyroidectomy, as defined by the 2016 AAES Guidelines, was normal serum calcium level in patients with hypercalcemic PHPT and normal serum calcium and serum PTH levels in patients with normocalcemic PHPT at 6 months postoperatively (±2 months) (4).

Statistical analysis

Demographics and clinical characteristics were summarized using descriptive statistics. Continuous variables were presented as median with interquartile range (IQR) or mean with standard deviation (SD), as appropriate based on distribution. Categorical variables were reported as frequencies and percentages (%). Patients were stratified by age 65 years to evaluate the impact of age on parathyroidectomy indications, referral patterns, time to surgery, and clinical characteristics. Group comparisons were performed using the chi-square test for categorical variables and student’s t-test for continuous variables. Missing preoperative laboratory data was minimal due to the requirement of a biochemical diagnosis prior to surgery and were handled with complete-case analysis. All statistical tests were two-sided, and a P value <0.05 was considered statistically significant.

Results

We identified 266 patients who underwent parathyroidectomy for PHPT during the study period. Patients’ demographic and preoperative characteristics are included in Table 1. The median age of the patient population was 63.2 years (IQR, 53.2 to 70.6 years). For the entire cohort, the median albumin-adjusted serum calcium was 10.8 mg/dL (IQR, 10.5, 11.4 mg/dL) and median serum PTH level was 127 pg/mL (IQR, 98.3, 175 pg/mL). The majority (n=256, 96.2%) of patients were diagnosed with hypercalcemic PHPT while the remainder (n=10, 3.8%) were diagnosed with normocalcemic PHPT. Symptomatic PHPT was identified in 107 patients (40.2%), of whom 0 patients had osteitis fibrosa cystica, 18 patients (6.8%) had fragility fractures, 99 patients (37.2%) had nephrolithiasis, and 56 patients (21.0%) had nephrocalcinosis. The cohort had the following preoperative cardiometabolic comorbidities: history of myocardial infarction (MI) (4.5%, n=12), transient ischemic attack (TIA) or stroke (n=8, 3.0%), diabetes mellitus (n=65, 24.4%), arrhythmia (n=23, 8.6%), and congestive heart failure (n=18, 6.8%).

Most patients (n=138, 51.9%) were referred to surgery from within the institution. Of these patients, 98 (71.0%) were referred from Endocrinology, 19 (13.8%) were referred from Internal Medicine, 10 (7.2%) were referred from Nephrology, 5 (3.6%) were referred from Urology, and the remaining 6 (4.3%) were referred from other departments (Dermatology, Emergency Medicine, Surgical Oncology and OB/GYN). Seventy-three patients (27.4%) were referred from community-based endocrinologists, 44 (16.5%) were referred from community-based primary care providers, and 11 (4.1%) were referred by other means (i.e., hospital transfers or community-based surgeons). On average, it took 7.3 (IQR, 1.74, 27.3) months to obtain a biochemical diagnosis after an initial elevated serum calcium was detected. Of note, we were unable to identify the date of the initial serum calcium in 77 (53.1%) patients. Once a biochemical diagnosis was obtained, patients underwent surgery after approximately 9.0 (IQR, 4.2, 19.6) months. Of the entire cohort, only 100 patients (37.8%) had a complete preoperative evaluation prior to parathyroidectomy. Preoperative DXA scans were reviewed in 141 patients (53.0%) and 142 (53.4%) had 24-hr urine calcium collections obtained.

Table 2 outlines the indications for parathyroidectomy and operative techniques. Based on the 2016 AAES and Fourth International Working Group objective indications for surgery, we found that the majority of patients (n=135, 50.8%) underwent surgery based on albumin-adjusted serum calcium being >1 mg/dL above the upper limit of normal. Bone-specific indications for parathyroidectomy were identified in 67 (25.2%) patients of whom 52 (19.9%) had osteoporosis. Renal-specific indications for parathyroidectomy were identified in 161 (60.5%) patients, of whom 99 (37.2%) had nephrolithiasis and 72 (27.1%) had eGFR <60 mL/min/1.73 m². Twenty-eight patients (10.5%) did not meet strict guideline-concordant indications for surgery.

In the entire cohort, the majority of patients (n=116, 43.6%) underwent bilateral cervical exploration as shown in Table 2. While final pathology was suggestive of single gland disease in 214 patients (80.4%), multigland disease was found in 42 patients (15.8%), and pathology showed no hypercellular parathyroid tissue in 10 patients (3.8%). The interpretation of biochemical cure is limited by lack of 6-month follow-up in 81 patients (30.4%). Of the remaining 185 patients, cure was achieved in 155 patients (83.8%) while persistent disease was seen in 30 patients (16.2%).

Age-specific differences in parathyroidectomy

Patients who underwent parathyroidectomy were stratified into two groups by age 65 years. Patients’ demographic and preoperative characteristics stratified by age 65 years are included in Table 1. There was no statistically significant difference in female sex or preoperative serum calcium, albumin-adjusted serum calcium, or PTH levels. Patients ≥65 years had a lower median 25-hydroxy vitamin D level than patients <65 years [21.8 (IQR, 21.1, 40.9) vs. 33.0 (IQR, 23.1, 40.9) ng/mL, P<0.001]. Of the 10 patients with normocalcemic PHPT, 6 patients were <65 years and 4 patients were ≥65 years. There was no statistical difference in the number of symptomatic PHPT patients in either age group [65 patients (44.8%) <65 years vs. 42 patients (34.7%) ≥65 years, P=0.10]. Patients less than 65 years had the following preoperative cardiometabolic comorbidities: history of MI (n=5, 3.4%), TIA or stroke (n=3, 2.1%), diabetes mellitus (n=34, 23.4%), arrhythmia (n=6, 4.1%), and congestive heart failure (n=5, 3.4%). Patients 65 years and older had the following preoperative cardiometabolic comorbidities: history of MI (n=7, 5.8%), TIA or stroke (n=5, 4.1%), diabetes mellitus (n=31, 25.6%), arrhythmia (n=17, 14.1%), and congestive heart failure (n=13, 10.7%). Patients 65 years or older were more likely to have a history of arrhythmia and congestive heart failure than patients less than 65 years (P<0.05).

The referral patterns for patients <65 years were as follows: 84 patients (57.9%) referred from within the institution (70.2% from Endocrinology, 14.2% from Internal Medicine, 7.1% from Nephrology, 3.6% from Urology, 4.8% from other departments), 32 patients (22.0%) referred from community-based endocrinologists, 22 patients (15.2%) referred from community-based primary care providers, and 7 (4.8%) from other non-institutional providers. The referral patterns for patients ≥65 years were as follows: 54 patients (44.6%) referred from within the institution (72.2% from Endocrinology, 13.0% from Internal Medicine, 7.4% from Nephrology, 3.7% from urology, and 3.7% from other departments), 41 patients (33.9%) referred from community-based endocrinologists, 22 patients (18.2%) referred from community-based primary care providers, and 4 (3.3%) referred from other non-institutional providers. When comparing institutional versus non-institutional or community-based providers, patients ≥65 years were more likely to be referred from non-institutional or community-based providers (P=0.03). There was no statistical difference in time to biochemical diagnosis between the two cohorts (Figure 1A). However, patients ≥65 years had a longer interval from biochemical diagnosis to parathyroidectomy compared to patients <65 years [11.3 (IQR, 5.0, 20.7) vs. 7.5 (IQR, 3.8, 16.0) months, P=0.02, Figure 1B]. There was no statistically significant difference in the percentage of patients who underwent complete preoperative evaluation between the two age cohorts.

Figure 1 Dot plots show individual values with median and interquartile range for (A) time from initial serum calcium level to parathyroid hormone level detection and biochemical diagnosis and (B) time from biochemical diagnosis to parathyroidectomy for patients <65 and ≥65 years. P<0.05 is considered statistically significant and is denoted by an asterisk (*).

There was no statistically significant difference in the number of patients who had an albumin-adjusted serum calcium >1 mg/dL above the upper limit of normal between the two cohorts. Patients ≥65 years were more likely to have bone-specific indications for surgery compared to those <65 years [38 (31.4%) vs. 29 (20.0%), P=0.03]. Although older adults had a higher percentage of osteoporosis and fragility fractures than patients <65 years, this was not statistically significant (P=0.09). Patients ≥65 years were less likely to have renal-specific indications for surgery [56 (46.3%) vs. 105 (72.4%), P<0.001]. While older adults were less likely to have nephrolithiasis compared to those <65 years [36 (29.5%) vs. 63 (43.4%), P=0.02], they were more likely to have eGFR <60 mL/min/1.73 m² as an indication for surgery [53 (36.6%) vs. 19 (13.1%), P<0.001]. There were no statistically significant differences in the number of indications for surgery met per patient between the two cohorts.

There were no statistically significant differences in the operative technique employed between patients <65 years and patients ≥65 years. Of patients ≥65 years, 103 patients (85.1%) had single gland disease, 15 patients (12.4%) had multigland disease, and 3 patients (2.4%) had no hypercellular glands resected. Of patients <65 years, 111 patients (76.6%) had single gland disease, 27 patients (18.6%) had multigland disease, and 7 patients (4.8%) had no hypercellular glands resected. There was no statistically significant difference between age-specific cohorts regarding the presence of single gland disease (P=0.09). Again, the interpretation of biochemical cure is limited by lack of 6-month follow-up in 47 patients (32.4%) <65 years and 34 patients (28.1%) ≥65 years. Of the remaining 185 patients, cure was achieved in 79 patients <65 years (80.6%) compared to 76 patients ≥65 years (87.4%), which was not statistically significantly different (P=0.23).

Discussion

The results of this study demonstrate significant age-specific differences in the clinical presentation and surgical management of PHPT following the implementation of consensus guidelines (4,17). While biochemical severity and the number of surgical indications were largely similar between age groups, older patients (≥65 years) were more likely to present with bone-specific comorbidities, whereas younger patients (<65 years) were more likely to have renal manifestations, particularly overt nephrolithiasis. These findings are consistent with known age-related phenotypic variations in PHPT, where skeletal fragility and declining renal function often predominate in older individuals, while stone disease is a more common presenting feature among younger adults (11,12,14,15).

Our study shows that older patients experienced longer delays from biochemical diagnosis to surgery, which may reflect barriers in patient access to academic institutions, provider hesitancy, competing comorbidities, or perceived surgical risk. This pattern aligns with multiple reports showing a significant underutilization of parathyroidectomy in older adult patients with PHPT (7-10). Wu et al. (7) found that only 45% of patients aged 60–69 years and 24% of patients over 70 years underwent parathyroidectomy, and patients over 60 experienced significantly longer delays from diagnosis to surgery, which are in accordance with our findings. However, available evidence from high-volume surgical centers has failed to demonstrate an excess in perioperative morbidity in older compared to younger adult cohorts, and some data indicate even less perioperative morbidity in older adults (10,16). In addition to being safe, parathyroidectomy has been demonstrated to yield high cure rates and significant quality of life gains in this age group (16). Although data on the impact of parathyroidectomy and functional independence is limited, several reports found that older adults with PHPT who were previously considered “asymptomatic” demonstrated significant improvements in measures of functional capacity, such as 6-minute walk distance, after parathyroidectomy (19,20). Furthermore, parathyroidectomy was shown to reduce risk of any fracture and hip fracture and lower adverse cardiovascular outcomes in older adults, two outcomes which can adversely impact longevity, functional independence, and quality of life in this cohort of patients (14,21,22). In spite of the overwhelming evidence on the safety and positive impact of parathyroidectomy in older adults, this patient population continues to have delays to surgical intervention. We found that older adults were more likely to be referred from community-based practices compared to younger adults, which could account for delays in being seen by academic surgeons for parathyroidectomy. Unfortunately, barriers to referral to high-volume surgeons at academic centers, as well as provider hesitancy, are understudied and may contribute to delays in parathyroidectomy.

Despite differences in clinical presentation, the rate of complete preoperative evaluation remained suboptimal across all age groups, with only 37.8% of patients undergoing a comprehensive workup as defined by current guidelines. These gaps in adherence appear to be independent of patient age but may be driven in part by provider type, emphasizing the ongoing need for improved multidisciplinary coordination and standardized preoperative pathways (4,6,23). For example, Li et al. (24) performed a single-institution retrospective study and found that 24-hour urine calcium results altered surgical management in only 4% of their patients and led to genetic testing consideration in 1%. These findings highlight the limited impact of this test on surgical decision-making in PHPT patients referred for parathyroidectomy, while also potentially overlooking its role in the diagnosis, follow-up, and surveillance of non-surgical candidates. Furthermore, 53% of our patients had completion of DXA scans and 24-hour urine calcium levels during workup for PHPT. Similar rates of 24-hour urine calcium collection were reported by Fieber et al. (25), who also found that DXA scans were less likely to be performed in African American patients, underscoring racial differences in preoperative evaluation of patients with PHPT. Although several factors such as access to care, provider type, and clinical utility may impact the ability to obtain a complete preoperative workup, multidisciplinary input and coordination are essential to providing patients with comprehensive care and ultimately surgical referral for parathyroidectomy.

Notably, bone disease (i.e., osteoporosis and fragility fractures) was the predominant indication for parathyroidectomy in older adults. Nonetheless, about half of the patients in this group (53.0%) did not get a DXA scan during evaluation. Given the fact that fracture leads to significant morbidity in older adults and availability of improved bone-modulating agents, baseline DXA scan should be emphasized in these patients to identify those who may require further medical treatment after surgery to minimize fracture risk. Additionally, while eGFR <60 mL/min/1.73 m² was more commonly present in older adults, possibly leading to surgery in some cases, Seib et al. (26) showed that parathyroidectomy had no effect on long-term kidney function in older adults with PHPT. These data highlight the importance of creating evidence-based older adult-specific guidelines and considerations for parathyroidectomy to aid in shared decision-making in this particularly vulnerable population.

Of note, a small but important fraction of patients (10.5%) underwent parathyroidectomy without meeting strict guideline-concordant indications, suggesting either limitations in guideline applicability or variability in clinical decision-making. This was slightly higher among older adult patients, demonstrating the growing interest in expanding criteria to include osteopenia, neurocognitive symptoms or functional capacity in older adults with PHPT (19,27). Bartz-Kurycki et al. (27) reported that of the 13% of patients who underwent parathyroidectomy without meeting guideline-concordant criteria, the majority underwent surgery due to neurocognitive symptoms and osteopenia. Further, they found that expanding the age threshold to 70 years would increase parathyroidectomy by 10%, although the lasting benefit has yet to be studied. Given evolving evidence on the benefits of early surgical intervention even in asymptomatic or normocalcemic patients (often categorized as “mild” disease), further studies are warranted to understand how clinicians balance standardized criteria with individualized care (9,14,23).

This study has several strengths, including contemporary data demonstrating persistent underreferral and delayed surgical treatment of older adults with PHPT, and a study population whose demographic and clinical characteristics enhance the generalizability of the findings. However, several limitations should be acknowledged. The retrospective and observational nature of our study limits causal inference regarding factors contributing to surgical delay, including referral patterns, symptom burden, and preoperative comorbidities. Although we identified age-specific differences in referral source and cardiometabolic comorbidities, data on time from referral to surgery and the direct impact of these factors on surgical timing were not available. Symptom status was defined using objective skeletal and renal criteria; however, incomplete access to DXA testing and external renal imaging, often performed outside our health system and summarized in referral documentation, may have led to underestimation or misclassification of disease manifestations. Additionally, provider and patient preferences, which significantly influence decision-making around parathyroidectomy, were not systemically captured. Furthermore, while we utilized the Fourth International Workshop guidelines and AAES 2016 guidelines for consistency across the inclusion period, more recent recommendations from the Fifth International Workshop [2022] include revised thresholds for hypercalciuria, which may influence future classifications of surgical eligibility (6). These limitations constrain definitive conclusions regarding the drivers of age-related differences in surgical timing and disease presentation.

Conclusions

Our findings highlight meaningful age-related differences in the manifestations of PHPT and call attention to persistent gaps in preoperative evaluation and delays in surgical management, particularly in older adults. Future efforts should aim to improve adherence to guideline-recommended assessments, consider age-specific guideline recommendations, promote timely referral to experienced surgical specialists, and better align care delivery with patient-specific risks across the age spectrum.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-410/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-410/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-410/prf

Funding: This work was supported by the University of Florida Claude D. Pepper Older American Independence Center (No. P30AG028740 to A.S.S.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-410/coif). A.S.S. serves as an unpaid editorial board member of Gland Surgery from March 2025 to February 2027. A.S.S. also reports receiving funding from the University of Florida Claude D. Pepper Older American Independence Center (No. P30AG028740). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the University of Florida Institutional Review Board (No. 202202761). The requirement for informed consent was waived due to the retrospective nature of the study, use of existing medical record data, and minimal risk to participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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