Giant cell arteritis associated with intravenous zoledronic acid administration.

Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report 2 patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals.

The Eucalcemic Patient With Elevated Parathyroid Hormone Levels.

Primary hyperparathyroidism (PHPT) is classically characterized by hypercalcemia with elevated or inappropriately normal parathyroid hormone (PTH) levels. Elevated PTH levels in the presence of normal calcium levels are not infrequently found during the evaluation of metabolic bone disorders or kidney stone disease. This can be caused by secondary hyperparathyroidism (SHPT) or normocalcemic primary hyperparathyroidism (NPHPT). NPHPT is due to autonomous parathyroid function whereas SHPT is caused by a physiologic stimulation to PTH secretion. Many medical conditions and medications can contribute to SHPT, and differentiation between SHPT and NPHPT may be difficult. Cases are presented to illustrate examples. In this paper, we review the distinction between SHPT and NPHPT as well as end organ effects of NPHPT and outcomes of surgery in NPHPT. We suggest that the diagnosis of NPHPT be made only after careful exclusion of causes of SHPT and consideration of medications that can increase PTH secretion. Further, we advise a conservative approach to surgery in NPHPT.

C11 choline PET/CT succeeds when conventional imaging for primary hyperparathyroidism fails.

BACKGROUND: Focused parathyroidectomy in primary hyperparathyroidism is possible with accurate preoperative localization. A growing body of data exists regarding the role of radio-labeled C11 choline positron emission tomography/computed tomography. In cases of nonlocalized disease, it may be a useful adjunct to ultrasound, (123)I/(99)Tc-sestamibi (I-123 sestamibi), or 4-dimensional computed tomography imaging. METHODS: Patients who received a neck and chest limited coverage C11 choline positron emission tomography/computed tomography for evaluation of primary hyperparathyroidism from 2017 to 2021 at a single institution were retrospectively reviewed. We assessed the sensitivity, positive predictive value, and false negative rate. We also compared these rates to the standard modalities of ultrasound, I-123 sestamibi, 4-dimensional computed tomography, and examined concordance rates. RESULTS: We identified 43 patients, of whom 33 had a positive C11 choline positron emission tomography/computed tomography finding. This cohort of patients had failed to localize on multiple standard imaging modalities. Twenty-five patients proceeded to surgery, 72% of whom were reoperative cases. Twenty (80%) achieved an intraoperative cure. Analysis showed that C11 choline positron emission tomography/computed tomography achieved a sensitivity of 64% (95% confidence interval 47%-82%) and positive predictive value of 72% (95% confidence interval 54%-90%). There were 5/25 (20%) false positive positron emission tomography C11 choline results found to be lymph nodes, normal parathyroid, and 1 recurrent laryngeal nerve neuroma. CONCLUSION: C11 choline positron emission tomography/computed tomography is a useful adjunct for parathyroid localization in a complex population of patients who have failed standard localization techniques including ultrasound, I-123 sestamibi, or 4-dimensional computed tomography and/or prior operations. Although routine inclusion of C11 choline positron emission tomography/computed tomography imaging may not be necessary, it may aid in preoperative localization in the reoperative setting.

Persistence and Recurrence of Hypercalcemia After Parathyroidectomy Over 5 Decades (1965-2010) in a Community-based Cohort.

BACKGROUND: There is limited long-term follow-up of patients undergoing parathyroidectomy. Recurrence is described as 4% to 10%. This study evaluated persistence and recurrence of hypercalcemia in primary hyperparathyroidism after parathyroidectomy. METHODS: Single-institution retrospective (1965-2010) population-based cohort from Olmsted County (MN) of patients undergoing surgery for primary hyperparathyroidism. Patients' demographic data, preoperative and postoperative laboratory values, clinical characteristics, surgical treatment, and follow-up were noted. RESULTS: A total of 345 patients were identified, 75.7% female, and median age 58.4 years [interquartile range (IQR): 17.6]. In all, 68% of patients were asymptomatic and the most common symptoms were musculoskeletal complaints (28.4%) and nephrolithiasis (25.6%). Preoperative median serum calcium was 11 mg/dL (IQR: 10.8-11.4 mg/dL), and median parathyroid hormone was 90 pg/mL (IQR: 61-169 pg/dL). Bilateral cervical exploration was performed in 38% and single gland resection in 79% of cases. Median postoperative serum calcium was 9.2 mg/dL (IQR: 5.5-11.3). Nine percent of patients presented persistence of hypercalcemia, and recurrence was found in 14% of patients. Highest postoperative median serum calcium was 10 mg/dL (IQR: 6-12.4), and median number of postoperative calcium measurements was 10 (IQR: 0-102). Postoperative hypercalcemia was identified in 37% of patient. Fifty-three percent were attributed to secondary causes, most commonly medications, 22%. Three percent of patients required treatment for postoperative hypercalcemia. Median time to recurrence and death were 12.2 and 16.7 years, respectively. CONCLUSION: Recurrent hypercalcemia after successful parathyroidectomy is higher than previously reported. Most cases are transient and often associated to other factors with only the minority requiring treatment. Long-term follow-up of serum calcium should be considered in patients after successful parathyroidectomy.

Survival in primary hyperparathyroidism over five decades (1965-2010) a population-based retrospective study.

CONTEXT: Survival in patients with primary hyperparathyroidism (PHPT) remains uncertain. OBJECTIVE: To update survival in patients with PHPT in a United States community population. DESIGN: Retrospective cohort study. SETTING: Community population in Rochester, Minnesota. PARTICIPANTS: Residents who met criteria for PHPT from 1965 to 2010. INTERVENTIONS: Survival was estimated using the Kaplan Meier product-limit method. The Cox proportional hazards model was used to determine associations, as relative hazards (RR) with 95% confidence intervals (CI), of various risk factors with time to death. MAIN OUTCOME MEASURE: The overall age and gender-adjusted survival compared to white Minnesota residents. RESULTS: We identified 1139 PHPT individuals, 76% female, with a median age of 58 years. Most were observed without parathyroidectomy (69%). The relative risk of death among the entire cohort was 0.996 (95% CI: 0.91-1.09, P = 0.935) which was not different compared to Minnesota residents. Those with maximum serum calcium level ≥ 10.8 mg/dL (0.7 mg/dL above the reference range) had an increase in mortality (RR 1.32, 95% CI: 1.10-1.58, P = 0.002). Survival among all PHPT individuals after parathyroidectomy was no different from expected (RR = 1.06, 95% CI 0.89-1.28; P = 0.508). Mortality was significantly decreased after parathyroidectomy in those with serum calcium levels ≥10.8 mg/dL (HR 0.47, 95% CI: 0.36-0.61, P < 0.001). CONCLUSIONS: Mortality in the entire cohort was not different from expected. PHPT patients with a maximum serum calcium level ≥ 10.8 mg/dL had increased mortality. Survival was improved after parathyroidectomy in those with this degree of hypercalcemia.

Hypoparathyroidism: An Uncommon Complication Associated With Immune Checkpoint Inhibitor Therapy.

As immune checkpoint inhibitor drugs are being used in the treatment of some cancers, unusual adverse events are being reported, labeled as immune-related adverse events. Various endocrinopathies related to immune-related adverse events have been described, among which hypoparathyroidism is exceedingly rare. We report a case of hypoparathyroidism induced by immune checkpoint drugs, highlighting the need for awareness of this emerging complication.

Oral cinacalcet responsiveness in non-parathyroid hormone mediated hypercalcemia of malignancy.

Hypercalcemia of malignancy develops in approximately 20-30% of patients with advanced cancer and is an ominous sign. This condition is subdivided into three categories: i) humoral hypercalcemia of malignancy (80% of cases), mediated by systemic parathyroid hormone-related protein; ii) osteolytic metastases (20% of cases), mediated by inflammatory cytokines locally released by tumor cells and/or peri-tumor macrophages; and iii) ectopic production of 1,25-dihydroxyvitamin D (<1% of cases), leading to intestinal hyperabsorption of calcium and increased osteoclastic bone resorption. Humoral hypercalcemia of malignancy is seen in a variety of solid tumors, while osteolytic metastases are most common in breast cancer and multiple myeloma. Hypercalcemia of malignancy mediated by 1,25-dihydroxyvitamin D is primarily seen in lymphomas, having only rarely been reported in solid tumors. Pharmacologic management of humoral hypercalcemia of malignancy and osteolytic metastases mainly involves inhibition of bone resorption with intravenous bisphosphonates, subcutaneous denosumab, and subcutaneous calcitonin. Glucocorticoid therapy is the mainstay for management of increased 1,25-dihydroxyvitamin D. Unfortunately, management of hypercalcemia of malignancy often requires inpatient admission in the acute setting, and loss of effectiveness of antiresorptive therapy is common. We propose oral cinacalcet may be an efficacious therapy for hypercalcemia of malignancy related to elevated 1,25-dihydroxyvitamin D, and we present supporting data from two cases involving solid tumors. Furthermore, we hypothesize that this effect is primarily mediated by cinacalcet's interaction with the calcium-sensing receptor in the intestine with lesser effects at bone and kidney. Lastly, the role of 1,25-dihydroxyvitamin D in hypercalcemia malignancy may be underappreciated in solid tumors.

Parathyroidectomy improves hypercalciuria in patients with primary hyperparathyroidism.

BACKGROUND: Hypercalciuria is an important manifestation of primary hyperparathyroidism and may contribute to the risk of nephrolithiasis. This study examined the impact of parathyroidectomy on 24-hour urinary calcium (24-hour UCa) levels and rates of resolution of hypercalciuria after surgery. METHODS: A retrospective cohort study was performed of patients who underwent curative parathyroidectomy for primary hyperparathyroidism from 2007 to 2017. Baseline and postoperative urine and serum biochemistry levels were analyzed. The relationship between preoperative 24-hour UCa levels and the absolute decrease in postoperative UCa excretion was assessed using Spearman's rank correlation coefficient. RESULTS: Of 110 patients, 84 (76.4%) experienced a ≥20% decrease in 24-hour UCa level postoperatively. These patients had a higher baseline median 24-hour UCa level (293.5 vs 220.5 mg/24-hour; P = .001), higher baseline mean serum parathyroid hormone (106.5 vs 83; P = .05) and were more likely to have single gland disease (85.7% vs 65.4%, P = .04) compared with patients in whom 24-hour UCa excretion did not improve. Of the 28 patients (25%) who were hypercalciuric (24-hour UCa >400 mg/day) at baseline, 22 (79%) became normocalciuric postoperatively. A linear correlation was observed between preoperative 24-hour UCa levels and the decline in 24-hour UCa excretion after surgery (R2 = 0.59, P < .0001) such that the degree of improvement could be predicted using the following equation: absolute decrease in postoperative 24-hour UCa = 0.68 × preoperative 24-hour UCa-68. CONCLUSION: Parathyroidectomy reduces 24-hour UCa excretion in the majority of patients with PHPT and restores normocalciuria in 79% of patients with hypercalciuria at baseline.

Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations.

Inactivating mutations of the ENPP1 gene are associated with generalized arterial calcification of infancy (GACI) and less often autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). We aimed to investigate the spectrum of phenotypes in a family with monoallelic and biallelic mutations of ENPP1 after identification through whole exome sequencing of a 54-year-old female with biallelic mutation of ENPP1, c.323G > T; p.Cys108Phe and c.1441C > T; p.Arg481Trp. Including the proband, 2 subjects had biallelic mutations, 5 had monoallelic mutations, and 2 had no mutation of ENPP1. The maternal mutation, a known pathogenic variant associated with GACI, was found in 3 subjects with monoallelic mutations, while the paternal mutation, which was not previously reported, was present in 2 subjects with monoallelic mutations. Both subjects with biallelic mutations had bowing of bilateral femurs, periarticular mineral deposition, normocalcemic primary hyperparathyroidism with multigland parathyroidectomy, increased carotid intima-media thickness, and enthesopathy was also noted in one subject. Intact FGF23 was elevated in both subjects with biallelic mutations, while C-terminal FGF23 was only elevated in one and PPi was reduced in one. Subjects with monoallelic mutations did not have periarticular calcifications or bone deformities. To conclude, patients with biallelic GACI causing mutations can survive well into adulthood, and despite the same biallelic ENPP1 pathogenic variants, clinical and biochemical manifestations can significantly differ, and include enthesopathy and primary hyperparathyroidism, which have not been previously described. Although carriers of monoallelic ENPP1 variants appear unaffected by classic disease manifestations, there may be subtle biochemical and clinical findings that warrant further investigation. © 2019 American Society for Bone and Mineral Research.

Clinical characteristics and depression score response after parathyroidectomy in primary hyperparathyroidism.

OBJECTIVE: Several studies indicate that patients with primary hyperparathyroidism (PHPT) undergoing parathyroid surgery have improvement in mood and neuropsychological functioning. The current analysis aims to examine the relationship between biochemical and clinical variables and the improvement in depression scores and in specific symptoms, after parathyroidectomy. DESIGN: A prospective observational case-control study at a referral centre. PATIENTS: Patients with PHPT undergoing parathyroidectomy (n = 88) or thyroid surgery (n = 85). MEASUREMENTS: The Patient Health Questionnaire-9 (PHQ-9) was utilized to obtain depression scores at enrolment and 12 months after surgery. The changes in PHQ-9 were analysed and correlated with baseline clinical and biochemical parameters. RESULTS: At enrolment, there was no difference between the groups in the number with a depression diagnosis (PHPT 34.1%, thyroid surgery, 35.5%, P = 0.86). However, baseline PHQ-9 scores were significantly higher in PHPT (median 7.5, range 0-27) than thyroid surgery patients (median 3.0, range 0-18, P < 0.0001). Following surgery, all PHQ-9 scores, total and symptom group (cognitive, somatic) improved and were no longer different between PHPT (total PHQ-9 median 2, range 0-16) and thyroid (median 1, range 0-14, P = 0.31) groups. Baseline parathyroid hormone level, but not calcium, had a weak relationship with change in PHQ-9 score after parathyroid surgery (P = 0.003). Baseline PHQ-9 score was correlated with change in PHQ-9 score at 12 months after parathyroid surgery (P < 0.001). CONCLUSIONS: Depression scores improve in both somatic and cognitive domains after parathyroidectomy for PHPT and baseline severity of depression predicts the response.

TRANSIENT OSTEOPOROSIS: CLINICAL SPECTRUM IN ADULTS AND ASSOCIATED RISK FACTORS.

Objective: We aimed to describe the natural history of the rare clinical syndrome of transient osteoporosis (TO) and ascertain potential risk factors. Methods: Retrospective cohort study of adults with TO at Mayo Clinic, Rochester, Minnesota, over 15 years. Adults with acute-onset joint pain worsened by weight bearing and bone marrow edema on magnetic resonance imaging were included; exclusion criteria were trauma, tumors, rheumatic diseases, avascular necrosis, infection, and hyperesthesia. Results: Thirty-three patients with TO were identified: 20 males, median age at diagnosis 47 years, and median body mass index 28 kg/m2. Median time to diagnosis was 2 months, and time to symptom resolution was 4 months. All cases involved the lower extremity, with the majority affecting the hip. Most patients (79%) had at least one possible identified risk factor. The most frequent risk factor was low bone mineral density (BMD) in 13 patients (39% of cohort). Of the 16 patients with BMD measure, 8 had low BMD at a site other than TO. The next most frequent risk factors were sudden limb overuse and more than one episode of TO, observed in 30%, followed by a disorder of bone and mineral metabolism in 27%. Conclusion: TO affects middle-age men more than women, primarily involves weight-bearing joints, and usually resolves with conservative management. Its etiology remains unclear; however, the common presence of risk factors, abnormalities in bone and mineral laboratories, and decrease in BMD suggest that systemic factors may be important in its development. Abbreviations: AVN = avascular necrosis; BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; MRI = magnetic resonance imaging; TO = transient osteoporosis.

Relationship of Number of Missing Teeth to Hip Fracture in Elderly Patients: A Cohort Pilot Study.

PURPOSE: To determine the relationship between the number of missing natural teeth or remaining natural teeth and osteoporotic hip fracture in elderly patients and to determine the relationship between the number of missing teeth or remaining teeth and osteoporotic fracture risk assessment (FRAX) probability. MATERIALS AND METHODS: Number of missing teeth was determined by clinical oral exam on a total of 100 subjects, 50 with hip fractures and 50 without. Ten-year fracture risk and hip fracture risk probabilities were calculated using the FRAX tool. Statistical analyses were performed to determine strength of associations between number of missing natural teeth and likelihood of experiencing a fracture. Degree of correlation between number of missing natural teeth and FRAX probabilities were calculated. RESULTS: There appears to be an association between the number of missing natural teeth and hip fractures. For every 5-tooth increase in the number of missing teeth, the likelihood of being a subject in the hip fracture group increased by 26%. Number of missing natural teeth was positively correlated with FRAX overall fracture and hip fracture probability. CONCLUSIONS: Number of missing natural teeth may be a valuable tool to assist members of medical and dental teams in identifying patients with higher FRAX scores and higher likelihood of experiencing a hip fracture. Additional research is necessary to validate these findings.

Implementation of Bar-Code Medication Administration to Reduce Patient Harm.

OBJECTIVE: To assess the impact of implementing bar-code medication administration (BCMA) technology on the rate of medication administration errors in the inpatient setting, specifically those that affect the patient and result in harm. PATIENTS AND METHODS: Implementation of the new technology began in September 2008 in a staged rollout of 4 or 5 units at a time in 11 separate waves. All corresponding medication administrations and voluntarily reported medication-related adverse events from March 1, 2007, through September 30, 2013, were included for analyses. Adherence to the use of BCMA technology and the number of adverse events were tracked and compared across the preimplementation period through follow-up. Actual errors, not potential errors, were included in the analysis. RESULTS: After the BCMA technology was introduced, reported medication administration errors decreased by 43.5%. More importantly, the rate of harmful medication errors decreased from 0.65 per 100,000 medications preintervention to 0.29 per 100,000 medications postintervention. This resulted in a 55.4% decrease in actual patient harm events. None of the errors at category E or higher was caused by BCMA factors. CONCLUSION: Consistent use of BCMA technology improves patient safety by decreasing the number of patients harmed by medication administration errors.

Surgery for Primary Hyperparathyroidism with Normal Non-suppressed Parathyroid Hormone can be Both Challenging and Successful.

BACKGROUND: Criteria for diagnosing primary hyperparathyroidism (PHPT) include hypercalcemia in the presence of parathyroid hormone (PTH) levels that are either elevated (classic PHPT) or normal but non-suppressed. However, there is no standard definition of what constitutes normal non-suppressed levels, and data are lacking regarding the potential for surgical cure in these patients. METHODS: A retrospective review of patients undergoing parathyroidectomy for sporadic PHPT between 2012 and 2014 was performed. Patients with normal PTH were compared to classic PHPT patients to assess demographics, imaging, operative findings, and outcomes. RESULTS: In total, 332 patients met study criteria, and 60 (18%) had normal PTH levels. Negative sestamibi scans were seen more often with normal PTH levels (18.3 vs. 4.8%, p < 0.001). Patients with normal PTH were more likely to have ≥2 glands removed (26.7 vs. 14.3%, p = 0.02), and the specimens were more likely to be classified as only mildly hypercellular or normocellular (20 vs. 2.9%, p < 0.001). Average follow-up was 24 months (range 6-55). Cure rate was 88% in the normal PTH group, compared to 96% in classic PHPT (p = 0.02). Among patients with normal PTH, those with PTH ≤ 55 pg/mL had an 83% cure rate, whereas those with PTH 56-65 had a 96% cure rate (p = 0.12). CONCLUSIONS: Parathyroidectomy can have a high cure rate in the context of normal PTH levels despite an increased likelihood of negative imaging and multigland resection. Operative success is equivalent to classic PHPT when PTH levels are > 55 pg/mL.

Hypocalcemia After Bariatric Surgery: Prevalence and Associated Risk Factors.

BACKGROUND: The reported prevalence of hypocalcemia after bariatric surgery ranges from 1% after Roux-en-Y gastric bypass (RYGB) to 25% after bilio-pancreatic diversion-duodenal switch (BPD-DS). OBJECTIVE: We aimed to define the prevalence of post-operative hypocalcemia and identify clinical predisposing factors. SETTING: The study was conducted in an Academic Medical Center, USA. METHODS: Retrospective analysis of all patients undergoing bariatric surgery from May 2008 to December 2014 at Mayo Clinic Rochester, Minnesota was performed. Patients with revision surgeries were excluded. Hypocalcemia was defined as the lowest recorded serum calcium occurring at least 2 weeks post-operatively. RESULTS: Nine hundred ninety-nine patients fulfilled the criteria above. After correction for serum albumin concentration, 36 patients had serum calcium ≤8.9 mg/dl. Mean serum calcium was 8.1 ± 0.6 mg/dl. The prevalence was 1.9% in the RYGB group, 9.3% in the sleeve gastrectomy (SG) group, and 10% in the BPD-DS group. In all three surgical types, patients with hypocalcemia had significantly lower serum albumin and serum 25 (OH) vitamin D concentrations when compared to their normocalcemic counterparts (P < 0.01). The presence of renal insufficiency and vitamin D deficiency was associated with the highest risk of developing hypocalcemia after surgery [OR 16.8 (6.45-47.7) and 7.1(2.9-17.3), respectively]. Pre-operative renal insufficiency increased the odds of developing hypocalcemia by 20-fold. CONCLUSIONS: In our series, hypocalcemia was identified in 3.6% of patients undergoing all bariatric surgery. Patients who are predisposed to developing post-operative hypocalcemia, such as those with pre-operative renal impairment, or post-operative vitamin D deficiency and renal insufficiency, may benefit from increased surveillance and prevention strategies.

Selective Parathyroid Hormone Venous Sampling in Patients with Persistent or Recurrent Primary Hyperparathyroidism and Negative, Equivocal or Discordant Noninvasive Imaging.

BACKGROUND: In patients with persistent (P-PHPT) or recurrent (R-PHPT) primary hyperparathyroidism, preoperative localization is important. Selective parathyroid hormone venous sampling (sPVS) is an invasive technique that can be used to regionalize and/or lateralize the source of PHPT when noninvasive imaging studies are nonlocalizing. The aim of the present study was to assess the role of sPVS in the preoperative evaluation of patients with P-PHPT or R-PHPT and negative, equivocal, or discordant noninvasive imaging localization. METHODS: After IRB-approval a retrospective review of all patients with P-PHPT or R-PHPT and nonlocalizing noninvasive imaging that underwent sPVS from 2000 to 2014 was performed. The location of the source of PHPT at sPVS was predicted by a parathyroid hormone (PTH) gradient and compared to the surgical, pathology, and biochemical follow-up data as the gold standard. Sensitivity and positive predictive value (PPV) were calculated. RESULTS: Of 30 patients who underwent sPVS, 12 patients did not undergo surgical exploration due to negative or non-localizing PTH gradient (n = 8) or opted for medical management (n = 4). Of the 18 patients who underwent surgical exploration, 17 (94 %) had a positive PTH gradient and pathologic parathyroid tissue identified at surgery. Sensitivity and PPV of sPVS were 93 and 77 %, respectively, for all surgical cases, 86 and 60.0 % for cervical cases (n = 11), and 100 and 100 % for mediastinal cases (n = 7). Sixteen patients (89 %) were surgically cured. CONCLUSIONS: In patients with P-PHPT or R-PHPT and nonlocalizing imaging studies, sPVS is a sensitive test for localizing the source of PHPT when a positive PTH gradient is present.

Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades.

CONTEXT: Thiazide diuretics, the antihypertensive agent prescribed most frequently worldwide, are commonly associated with hypercalcemia. However, the epidemiology and clinical features are poorly understood. OBJECTIVE: To update the incidence of thiazide-associated hypercalcemia and clarify its clinical features. PATIENTS AND METHODS: In a population-based descriptive study, Olmsted County, Minnesota, residents with thiazide-associated hypercalcemia were identified through the Rochester Epidemiology Project and the Mayo Clinic Laboratory Information System from 2002-2010 and were added to the historical cohort beginning in 1992. MAIN OUTCOME: Incidence rates were adjusted to the 2010 United States white population. RESULTS: Overall, 221 Olmsted County residents were identified with thiazide-associated hypercalcemia an average of 5.2 years after initiation of treatment. Subjects were older (mean age, 67 years) and primarily women (86.4%). The incidence of thiazide-associated hypercalcemia increased after 1997 and peaked in 2006 with an annual incidence of 20 per 100,000, compared to an overall rate of 12 per 100,000 in 1992-2010. Severe hypercalcemia was not observed in the cohort despite continuation of thiazide treatment in 62.4%. Of patients discontinuing thiazides, 71% continued to have hypercalcemia. Primary hyperparathyroidism was diagnosed in 53 patients (24%), including five patients who underwent parathyroidectomy without thiazide discontinuation. CONCLUSIONS: Many patients with thiazide-associated hypercalcemia have underlying primary hyperparathyroidism. Additionally, a sharp rise in thiazide-associated hypercalcemia incidence began in 1998, paralleling the increase observed in primary hyperparathyroidism in this community. Case ascertainment bias from targeted osteoporosis screening is the most likely explanation.