Accepted Manuscript

Management of Normocalcemic Primary Hyperparathyroidism

Natalie E. Cusano, MD, MS, Cristiana Cipriani, MD, PhD, John P. Bilezikian, MD,
PhD (hon)

PII: S1521-690X(18)30109-X
DOI: 10.1016/j.beem.2018.09.009
Reference: YBEEM 1243

To appear in: Best Practice & Research Clinical Endocrinology & Metabolism

Please cite this article as: Cusano NE, Cipriani C, Bilezikian JP, Management of Normocalcemic Primary
Hyperparathyroidism, Best Practice & Research Clinical Endocrinology & Metabolism (2018), doi: https://
doi.org/10.1016/j.beem.2018.09.009.

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 ACCEPTED MANUSCRIPT

Management of Normocalcemic Primary Hyperparathyroidism

Natalie E. Cusano1, MD, MS, Cristiana Cipriani2, MD, PhD,

John P. Bilezikian3, MD, PhD (hon)

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1
Divison of Endocrinology, Department of Medicine, Lenox Hill Hospital, 110 East 59th St, Suite
8B, New York, NY 10022, ncusano@northwell.edu, Phone: 212-434-4972, Fax: 212-434-4974
(Corresponding author)

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2
Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Viale
del Policlinico 155, 00161, Rome, Italy, cristiana.cipriani@gmail.com

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3
Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of
Physician and Surgeons, Columbia University, 630 West 168th St, New York, New York, 10032,
USA, jpb2@cumc.columbia.edu

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Abstract

Traditional hypercalcemic primary hyperparathyroidism is a common endocrine disease.

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Patients with a history of nephrolithiasis or a suspected metabolic bone disease are increasingly

being identified with elevated PTH concentrations in the setting of consistently normal serum
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and ionized calcium concentrations. In the absence of secondary causes of

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hyperparathyroidism, a diagnosis of normocalcemic primary hyperparathyroidism is reasonable.

As most cohorts described in the literature are from referral populations, involvement of the
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skeleton and the kidneys is common, two traditional target organs of primary

hyperparathyroidism. Data from small cohorts show patients with normocalcemic disease
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respond similarly to hypercalcemic primary hyperparathyroidism with regard to medical and

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surgical approaches. In normocalcemic patients, multiglandular disease may be more common.

In this article, we review the available literature on the epidemiology, diagnosis, clinical features,

medical and surgical management of this newer phenotype of primary hyperparathyroidism.

 ACCEPTED MANUSCRIPT

Introduction

Traditional hypercalcemic primary hyperparathyroidism is a common endocrine disease.

Patients with a history of nephrolithiasis or a suspected metabolic bone disease are increasingly

being identified with elevated PTH concentrations in the setting of consistently normal serum

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and ionized calcium concentrations. In the absence of secondary causes of

hyperparathyroidism, a diagnosis of normocalcemic primary hyperparathyroidism is reasonable.

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As most cohorts described in the literature are from referral populations, involvement of the

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skeleton and the kidneys is common, two traditional target organs of primary

hyperparathyroidism. Data from small cohorts show patients with normocalcemic disease

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respond similarly to hypercalcemic primary hyperparathyroidism with regard to medical and

surgical approaches. In normocalcemic patients, multiglandular disease may be more common.

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In this article, we review the available literature on the epidemiology, diagnosis, clinical features,

medical and surgical management of this newer phenotype of primary hyperparathyroidism.

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Pathophysiology
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Several hypothesis have been advanced regarding the pathophysiology of

normocalcemic primary hyperparathyroidism. One hypothesis is that the normocalcemic

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phenotype represents an early or milder form of traditional primary hyperparathyroidism without

frank hypercalcemia. This concept would argue that in a certain percentage of patients,
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hypercalcemia would become evident over time. Another concept relates to the very narrow
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normal range of the serum calcium in a given individual in relationship to the much wider normal

population normal range for an analyte like calcium, typically around 8.4-10.5 mg/dL (1). If a

given individual’s normal day-to-day variance of calcium is 8.9-9.3 mg/dL, an increase to 10.0

mg/dL could represent for that patient a hypercalcemic value while still within the population

normal range. Another hypothesis is that the hypersecretion of PTH is less in normocalcemic

versus hypercalcemic individuals, although there is considerable overlap in PTH levels between

Cusano et al., Management of Normocalcemic Primary Hyperparathyroidism 2

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these groups (2). Finally, Maruani and colleagues have advanced the concept of partial tissue

resistance to PTH (3). In a small cohort of patients with normocalcemic primary

hyperparathyroidism, evidence of renal and skeletal resistance to PTH was found. The

multiplicity of putative pathophysiological mechanisms underscores the need for more research

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in this area.

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Diagnosis

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Normocalcemic primary hyperparathyroidism can be diagnosed in the setting of elevated

PTH concentrations with consistently normal albumin-adjusted serum and ionized calcium

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levels. The expert panel from the Fourth International Workshop on the Management of

Asymptomatic Primary Hyperparathyroidism stated that PTH concentrations should be elevated

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on at least two occasions during a 3 to 6 month period to confirm persistence of the

hyperparathyroid state (4). The persistent elevation of the PTH level in association with
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persistently normal serum calcium levels is in contrast to the hypercalcemic form of the disease
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in several ways. Patients with traditional hypercalcemic primary hyperparathyroidism can

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occasionally have normal serum or ionized calcium as a part of their clinical course but much

more often than not the serum calcium is elevated. In addition, in hypercalcemic primary
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hyperparathyroidism, the parathyroid hormone level can be within the normal population range.

This is clearly not normal for someone with hypercalcemia but it differentiates this form of
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primary hyperparathyroidism from the normocalcemic variant in which the PTH is always
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elevated. (5, 6).

It is very important to consider and rule out secondary causes of an elevated PTH level if

the diagnosis of normocalcemic primary hyperparathyroidism is to be made.

1. Vitamin D deficiency. Vitamin D deficiency is a common cause of secondary

hyperparathyroidism. Experts recommend a 25-hydroxyvitamin D concentration of at least

20 ng/mL to exclude vitamin D deficiency as the cause of elevated PTH (4), but many

Cusano et al., Management of Normocalcemic Primary Hyperparathyroidism 3

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recommend a level of at least 30 ng/mL in order to be more secure in the diagnosis (7).

After attaining vitamin D sufficiency, PTH concentrations can remain elevated for some

period of time, usually up to a few months. In addition, some patients with traditional primary

hyperparathyroidism with severe vitamin D deficiency can become hypercalcemic once

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vitamin D replete (7A).

2. Stage 3-5 chronic kidney disease. PTH concentrations become elevated as estimated

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glomerular filtration rate (eGFR) declines. Martinez and colleagues (8, 9) demonstrated that

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PTH begins to rise when the eGFR falls below 60 mL/min. It is thus prudent to make a

diagnosis of normocalcemic primary hyperparathyroidism only in individuals in whom eGFR

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is greater than or equal to 60 mL/min.

3. Medications. Loop diuretics have been demonstrated to increase PTH and should be
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excluded as a secondary cause of hyperparathyroidism (10, 11). Thiazide diuretics may

have a confounding effect on calcium metabolism, although studies have not shown a clear
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association between hyperparathyroidism and hydrochlorothiazide-treated patients (12).

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Many patients who develop hypercalcemia on hydrochlorothiazide have underlying primary

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hyperparathyroidism (13). Lithium therapy can also raise PTH levels, although individuals

who become hypercalcemic on lithium are also often shown to have primary
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hyperparathyroidism (14, 15). If these medications can be temporarily discontinued safely,

and the elevated PTH level persists, the diagnosis of normocalcemic primary
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hyperparathyroidism can be made. Treatment with bisphosphonates or denosumab can also

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result in transient PTH elevations in healthy patients as a result of positive calcium signaling

to the parathyroid glands in the context of inhibited bone resorption. With bisphosphonate

therapy, PTH concentrations may rise within the first 24 hours-3 months of the initiation of

treatment, and typically normalize within one year (16-19). With denosumab, the signal to

increase PTH levels appears to be greater than bisphosphonates with levels of PTH

reaching twice baseline within 3 months of administering denosumab. With this degree of

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stimulation, PTH levels can occasionally rise out of the normal range after exposure to this

receptor activator of nuclear factor kappa-Β ligand inhibitor.

4. Hypercalciuria. The recommendation to exclude hypercalciuria is based on an early

understanding that idiopathic hypercalciuria may precipitate secondary hyperparathyroidism

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(20). More recent investigations have demonstrated that many individuals with idiopathic

hypercalciuria, despite net renal calcium losses, do not develop elevated PTH levels (21).

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However, recent data suggest that in primary hyperparathyroidism, hypercalciuria may

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persist after successful parathyroidectomy in association with parathyroid hyperplasia.

Therefore, it may be hypothesized that in patients with persistent hypercalciuria after

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successful parathyroid surgery, a preexisting chronic hypercalciuria may have exerted a

chronic stimulatory effect on the parathyroid glands leading to the development of

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parathyroid hyperplasia and eventually to hyperparathyroidism and hypercalcemia (21A).

5. Calcium deficiency or malabsorption. Insufficient calcium intake or gastrointestinal disorders

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resulting in calcium malabsorption should also be considered (22). Celiac disease should be
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a diagnostic consideration, especially in patients with concomitant vitamin D deficiency.

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Epidemiology
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There are few investigations into the epidemiology of normocalcemic primary

hyperparathyroidism, and the data are confounded by differing methods used to exclude
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secondary hyperparathyroidism. Most studies are not population-based but instead from a
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referral population undergoing evaluation for kidney stones or a suspected metabolic bone

disease. The studies are summarized in Table 1. The prevalence ranges from 0.4-8.9%

depending on the population studied and the criteria used for exclusion of secondary causes of

hyperparathyroidism (23-27). Of note, none of these studies examined ionized calcium levels.

The adoption of clear diagnostic criteria for further study of normocalcemic primary

hyperparathyroidism is of paramount importance for further research activities.

Cusano et al., Management of Normocalcemic Primary Hyperparathyroidism 5

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Clinical Features

Many patients or cohorts have been diagnosed when they are being evaluated for

nephrolithiasis or a suspected metabolic bone disease. In these cohorts, not surprisingly, there

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are high rates of osteoporosis, fracture, and nephrolithiasis, above the rates typically seen in

cohorts of patients with hypercalcemic primary hyperparathyroidism. In the case of patients with

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hypercalcemic disease, it is usually discovered incidentally while in the normocalcemic variant,

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the discovery is precipitated usually by a target organ abnormality. Thus, selection bias may

well account for clinical presentation of the normocalcemic form of the disease. Data regarding

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clinical features are summarized in Table 2 (2, 3, 26-32).

There are clinical data from a few population-based, unselected cohorts. Garcia-Martin
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(26) and colleagues evaluated 100 healthy postmenopausal women in Spain and found 6

patients with normocalcemic primary hyperparathyroidism (6% prevalence) after exclusion of

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vitamin D deficiency, renal failure, and malnutrition. Women identified with normocalcemic
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primary hyperparathyroidism were compared to women with secondary hyperparathyroidism.

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Clinical indices, bone turnover markers, and bone mass as measured by quantitative ultrasound

were similar between the two groups, with the exception that the women with secondary
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hyperparathyroidism had lower 25-hydroxyvitamin D levels.

While severe hypercalcemic primary hyperparathyroidism has been associated with

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adverse cardiovascular outcomes, there are limited data showing an effect in mild,
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asymptomatic hypercalcemic disease. The potential effects of normocalcemic primary

hyperparathyroidism on various metabolic outcomes have now been studied in a few small

cohorts. Three of four case control studies investigating glucose metabolism and lipid profiles

showed a small but significant increase in mean fasting glucose levels, although no difference in

hemoglobin A1c or in insulin sensitivity between individuals with normocalcemic primary

hyperparathyroidism and controls (30, 33-35). Only one study noted an adverse lipid profile in

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patients with normocalcemic primary hyperparathyroidism (33). In a retrospective investigation,

11 patients with normocalcemic primary hyperparathyroidism were compared to 296 controls

matched for cardiovascular risk factors and found to have higher systolic (141 ± 20 vs. 131 ± 17

mm Hg) and diastolic (85 ± 12 vs. 77 ± 10 mm Hg) blood pressures (36). A study of arterial

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stiffness and compliance, noninvasive measures of vascular function, found no differences

between patients with hypercalcemic or normocalcemic primary hyperparathyroidism and

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controls matched for cardiovascular risk factors (37). A recent study evaluating coronary

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calcium score found no differences between patients with normocalcemic primary

hyperparathyroidism versus controls (38).

Natural History
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There are limited data regarding the natural history of the disease. In the cohort of 32

patients described by Tordjman and colleagues (28), 12 patients with positive localization
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studies underwent parathyroid surgery. Pathology reports were available for 11 of these
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patients, nine of whom were noted to have a discrete adenoma and two with hyperplasia. Of the
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remaining 20 patients who were managed nonoperatively, none developed hypercalcemia over

an average follow-up period of 4.1 ± 3.1 years. In the cohort of six patients described by Garcia-
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Martin and colleagues (26), PTH levels remained elevated at one year after the initial diagnosis

but none had developed hypercalcemia, nephrolithiasis or fracture in this short follow-up period.
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In the symptomatic cohort described by Lowe and colleagues (2), 41% of patients
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developed worsening disease over an average follow-up period of 3.1 ± 0.3 years. Seven

patients (13%) became hypercalcemic. Three patients who developed hypercalcemia and four

patients with persistently normal serum calcium underwent parathyroid surgery. Two of the

hypercalcemic patients had a discrete adenoma while two hyperplastic glands were removed

from the remaining patient. In the normocalcemic patients, a single adenoma was removed in

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one, a single hyperplastic gland removed in two patients, and two hyperplastic glands removed

from one patient.

The most recent report comes from Šiprová and colleagues (32) who followed 187

patients with normocalcemic primary hyperparathyroidism up to seven years. In this cohort, 36

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patients (19%) became hypercalcemic; in a group of 111 patients followed for at least four

years, 30 patients (27%) became hypercalcemic. Among these patients, 67% became

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hypercalcemic within two years, 28% between years two to four, and 5% after four years. Of the

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36 patients who became hypercalcemic, nine underwent surgery. An adenoma was found and

removed in seven individuals, with one patient undergoing a successful re-operation and the

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second declining a second procedure. One year postoperatively, eight of these nine patients

had normal serum calcium and five had normal PTH concentrations.
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Management
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There are no data regarding the optimal treatment strategy for normocalcemic patients.
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Management guidelines are available from the Fourth International Workshop on the
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Management of Asymptomatic Primary Hyperparathyroidism based on expert recommendation

due to the lack of evidence-based data (39). Patients can be considered for parathyroid surgery
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if they have complications of the disease, including fractures or nephrolithiasis. In patients

without complications at the time of presentation, monitoring should include annual clinical
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assessment, measurement of biochemical parameters including total/ionized calcium and PTH

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annually, and bone density measurement every 1-2 years. If there is worsening of the disease,

surgery can be considered. Patients who develop hypercalcemia can be managed according to

the guidelines for mild, asymptomatic hypercalcemic disease.

Alendronate has been demonstrated to improve bone density in patients with

hypercalcemic primary hyperparathyroidism (40, 41). A small study has also shown a benefit in

patients with normocalcemic disease (42). Thirty postmenopausal women with normocalcemic

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primary hyperparathyroidism and osteoporosis were randomized to receive alendronate 70 mg

with vitamin D 2800 intl units weekly or vitamin D 2800 intl units alone weekly for one year. The

patients treated with alendronate experienced significant improvements in bone density at the

lumbar spine of +4.7% and at the total hip of +4.0%, whereas patients treated with vitamin D

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alone had ongoing declines in bone density. Serum and urine testing demonstrated no

significant changes, demonstrating safety. A pilot study of cinacalcet with the aim of reducing

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the number and size of kidney stones in 10 patients with primary hyperparathyroidism, including

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six with normocalcemic disease, demonstrated that cinacalcet at doses sufficient to normalize

PTH concentrations significantly reduced the number and diameter of kidney stones in both

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hypercalcemic and normocalcemic patients over 10 months of therapy (43).
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Surgery

An important element for successful parathyroid surgery is preoperative localization.

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While there are limited data for patients with normocalcemic primary hyperparathyroidism, it
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appears as if localization studies may be less likely to localize a parathyroid lesion than in
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patients with traditional hypercalcemic disease. In the cohort described by Šiprová and

colleagues (32), patients with initially normocalcemic disease underwent sestamibi imaging that
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was successful in localizing an adenoma in only 14% of patients during the normocalcemic

period. In patients who became hypercalcemic with repeat sestamibi imaging, imaging was
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successful in localizing an adenoma in 73% (p=0.001). A study by Cunha-Bezerra and

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colleagues (44) investigated three different imaging modalities in 18 patients subsequently

undergoing parathyroid surgery with positive pathology, 10 with hypercalcemic primary

hyperparathyroidism and 8 with normocalcemic primary hyperparathyroidism. The sensitivity of

all imaging procedures was lower for the normocalcemic individuals compared to the

hypercalcemic cohort, with 4-dimensional computed tomography performing best for

normocalcemic patients: ultrasound 22% vs. 58%, scintigraphy 11% vs. 75%, and 4-

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dimensional computed tomography 56% vs. 75%. Traini and colleagues (45), however, found

no overall statistically significant differences in the accuracy of preoperative sestamibi or

ultrasound imaging between normocalcemic and hypercalcemic patients. In the subgroup of

patients with multiglandular disease, sestamibi imaging had a sensitivity of 57% in the

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normocalcemic group and 72% in the hypercalcemic cohort.

A few series have reported a higher percentage of normocalcemic patients with

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multiglandular disease. Traini and colleagues (45) studied 731 consecutive patients with primary

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hyperparathyroidism managed surgically at their institution, including 154 with normocalcemic

disease. Multiglandular disease was higher in the normocalcemic group (13.0 vs 6.8%; p<0.05).

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In the cohort of Kiriakopoulos and colleagues (46) of 149 patients with primary

hyperparathyroidism, patients were subdivided into groups of patients with high serum calcium
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and high PTH (classic primary hyperparathyroidism, n=115), patients with high serum calcium

and inappropriately normal PTH (norhormonal, n=11), and patients with normocalcemic primary
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hyperparathyroidism (n=23). The normocalcemic subgroup had a higher percentage of

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multiglandular disease (21.7%) versus patients with high serum calcium/high PTH (16.5%) and
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high serum calcium/normal PTH (9.1%), although the differences did not achieve statistical

significance. Lim and colleagues (47) analyzed data from 573 patients who underwent
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parathyroidectomy at their institution, again subdivided into groups of patients with classic

primary hyperparathyroidism (n=405), norhormonal patients (n=96), and patients with

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normocalcemic primary hyperparathyroidism (n=72). Normocalcemic primary

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hyperparathyroidism was associated with multiglandular disease in 45% of patients, compared

to the normohormonal (10%) and classic (9%) subgroups. On logistic regression, the only

factors associated with multiglandular disease were normocalcemic primary

hyperparathyroidism and family history. Patients with normocalcemic primary

hyperparathyroidism were over eight times as likely to have multiglandular disease (odds ratio

8.17, 95% confidence interval 4.49-14.83).

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When patients with normocalcemic primary hyperparathyroidism have parathyroid

surgery, the limited data indicate that there is a similar improvement in bone density as for

patients with hypercalcemic disease. In the cohort described by Traini and colleagues above

(45), 96 patients with normocalcemic primary hyperparathyroidism were followed for an average

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of 72.9 ± 46.8 months postoperatively. In patients with evidence of skeletal disease

preoperatively, 42% had improvement in bone density postoperatively with 50% showing

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stability without further progression. In patients with nephrolithiasis, there was improvement in

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40% of patients and stability in 60%. In a longitudinal study by Koumakis and colleagues (48,

49) of 16 patients with normocalcemic primary hyperparathyroidism with normal total and

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ionized calcium levels, successful parathyroid surgery was associated with a +2.3% increase in

bone density at the lumbar spine and +1.9% at the femoral neck at one year, comparable to
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gains in patients with hypercalcemic disease. In this cohort, 44% of patients with normocalcemic

disease demonstrated improvement in bone density at one or more sites. In a multivariate

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analysis, while baseline serum total or ionized calcium or PTH levels were not found to be
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predictive of bone density gains after surgery, baseline alkaline phosphatase above the median
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value was positive associated with bone density postoperatively, especially in the

normocalcemic cohort.
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Summary
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The available data suggest that patients with normocalcemic primary

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hyperparathyroidism develop complications, including nephrolithiasis and osteoporosis, at

similar or higher rates to patients with traditional hypercalcemic disease, despite having normal

calcium levels. Most publications are from referral populations with selection bias and there is

limited information regarding a mild, asymptomatic form of the disease. Similar to the mild,

asymptomatic hypercalcemic form of primary hyperparathyroidism, the cardiovascular outcomes

of normocalcemic primary hyperparathyroidism remain unclear. Patients with normocalcemic

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primary hyperparathyroidism may have a higher incidence of multiglandular disease, but appear

to respond similarly to medical and surgical therapy. Future research into this normocalcemic

phenotype of the disease requires a standardized approach to the diagnostic criteria.

Practice Points:

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• The available data suggest that patients with normocalcemic primary

hyperparathyroidism develop complications, including nephrolithiasis and osteoporosis,

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at rates similar to or higher than rates for patients with traditional hypercalcemic disease,

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despite having normal calcium levels.

• Most publications are based on referral populations and, thus, may not be representative

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of the disease as it presents in the general population where one might consider a mild,
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asymptomatic form of normocalcemic primary hyperparathyroidism to be more common.

• Patients with normocalcemic primary hyperparathyroidism may have a higher incidence

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of multiglandular disease, but appear to respond similarly to hypercalcemic primary

hyperparathyroidism with regard to medical and surgical approaches.

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Research Agenda

• Future research requires a standardized set of diagnostic criteria for normocalcemic

primary hyperparathyroidism.

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• More data is needed regarding a more mild, asymptomatic form of the disease.

• Investigation is needed regarding the optimal treatment strategy for normocalcemic

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patients.

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Table 1. Epidemiology of normocalcemic primary hyperparathyroidism

Study Population Prevalence Diagnostic criteria
Cusano et al. (23) 2364 unselected community 0.4% Elevated PTH concentration and normal albumin-
dwelling men, age 65 years or adjusted total serum calcium; exclusion of renal failure

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older, investigated for fracture (GFR < 60 mL/min), vitamin D deficiency (25-
risk factors [The Osteoporotic hydroxyvitamin D < 20 ng/ml), medication effect
Fractures in Men Study (MrOS)

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cohort, United States]
Vignali et al. (24) 685 adult men and women living 0.4% Elevated PTH concentration and normal albumin-

SC
in a village in Southern Italy adjusted total serum calcium; exclusion of renal failure
(Italy) (GFR < 60 mL/min), vitamin D deficiency (25-
hydroxyvitamin D < 30 ng/ml), medication effect, overt

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gastrointestinal or metabolic bone diseases
Lundgren et al. (25) 5202 postmenopausal women 0.5% Elevated PTH concentration with normal albumin-

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age 55 to 75 years attending a adjusted total serum calcium and normal ionized
population-based mammography calcium on repeat measure; none had history of
screening (Sweden) malabsorption

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Cusano et al. (23) 3450 community dwelling men 3.1% (Baseline) Elevated PTH concentration and normal albumin-
and women, age 18 to 65 years, 0.6% (Follow-up) adjusted total serum calcium; exclusion of renal failure

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investigated for cardiovascular (eGFR < 60 mL/min), vitamin D deficiency (25-
disease (Dallas Heart Study hydroxyvitamin D < 20 ng/ml), medication effect

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cohort, United States)
Garcia-Martin et al. (26) 100 healthy, unselected 6% Elevated PTH concentration and normal albumin-
postmenopausal women (Spain) adjusted total serum calcium; exclusion of renal failure
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(creatinine clearance < 70 mL/min), vitamin D
deficiency (25-hydroxyvitamin D < 30 ng/ml)
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Marques et al. (27) 156 women referred for 8.9% Elevated PTH concentration and normal albumin-
osteoporosis screening (Brazil) adjusted total serum calcium; exclusion of renal failure
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(eGFR < 40 mL/min), vitamin D deficiency (25-

hydroxyvitamin D < 30 ng/ml), history of metabolic
bone disease, liver disease, malabsorption
syndromes, medication effect
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Table 2. Clinical summary of skeletal and renal complications in cohorts of patients with normocalcemic primary hyperparathyroidism
Study Cohort Age Female Osteoporosis Nephrolithiasis Comments
Size (years) (%)
Symptomatic cohorts

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Lowe et al. (2) 37 58 ± 2 95 57% 14% Ionized calcium not available for all
11% with fragility fracture
Maruani et al. (3) 34 53 ± 14 68 Radiographic bone 35%

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demineralization in 18%
(bone density not
performed)

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36%
Marques et al. (27) 14 61 ± 15 100** 21%
21% with fragility fracture
Tordjman et al. (28) 32 61 ± 11 84 36% 9%

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Amaral et al. (29) 33 64 ± 14 79 15%* 18% Ionized calcium not measured
*Only fracture history

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available
Cakir et al. (30) 18 50 ± 2 47 47% 11% Ionized calcium not measured
25% Surgical cohort
Wade et al. (31) 8 60 63 25%

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13% with fragility fracture
%
42 described as having
Šiprová et al. (32) 137 61 81 4%
“reduced bone density”

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Asymptomatic cohort

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Garcia-Martin et al. 6 56 ± 3 100** 0% 0% Ionized calcium not measured
(26) Population-based cohort
Mean ± SD
**Study design
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Cusano et al., Management of Normocalcemic Primary Hyperparathyroidism 18