Accepted Manuscript

Primary Hyperparathyroidism

Barbara C. Silva, MD, PhD, Natalie E. Cusano, MD, MS., John P. Bilezikian, MD,
PhD(hon)

PII: S1521-690X(18)30104-0
DOI: 10.1016/j.beem.2018.09.004
Reference: YBEEM 1238

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

Please cite this article as: Silva BC, Cusano NE, Bilezikian JP, Primary Hyperparathyroidism, Best
Practice & Research Clinical Endocrinology & Metabolism (2018), doi: https://doi.org/10.1016/
j.beem.2018.09.004.

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 ACCEPTED MANUSCRIPT
Silva et al., Primary Hyperparathyroidism 1

Primary Hyperparathyroidism

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Barbara C. Silva1 MD, PhD, Natalie E. Cusano2, MD, MS. and

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John P. Bilezikian, MD, PhD(hon)3,

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1
Division of Endocrinology, Felicio Rocho and Santa Casa Hospital, Belo Horizonte, Brazil
2
Division of Endocrinology, Lenox Hill Hospital, New York, NY, USA
3
Division of Endocrinology, College of Physicians and Surgeons, Columbia University, New
York, NY, USA

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Correspondence:
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John P. Bilezikian, MD
Department of Medicine
College of Physicians and Surgeons
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630 W. 168th Street

New York, NY 10032
Phone: 212.305.6257
Fax: 212.305.6486
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e-mail: jpb2@columbia.edu
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Silva et al., Primary Hyperparathyroidism 2

Abstract

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often

identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels

that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT

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includes three phenotypes: target organ involvement of the renal and skeletal systems; mild

asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently

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normal albumin-corrected and ionized serum calcium values. The factors that determine which

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of these three clinical presentations is more likely to predominate in a given country include the

extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and

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whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation

of low bone density or frank osteoporosis. When biochemical screening is common,

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asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries

where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health
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care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally,
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when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is
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seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three

clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also
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be an appropriate option if there are no medical contraindications to surgery. In settings where

either the serum calcium or bone mineral density is of concern, and surgery is not an option,
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pharmacological approaches are available and effective. Referencing in this article the most
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current published articles, we review the different presentations of PHPT, with particular

emphasis on recent advances in our understanding of target organ involvement and

management.

Keywords: primary hyperparathyroidism; normocalcemic primary hyperparathyroidism;

parathyroidectomy; vitamin D; bisphosphonates, calcimimetics.

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Silva et al., Primary Hyperparathyroidism 3

1- Introduction

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is

most often identified in postmenopausal women with hypercalcemia and parathyroid hormone

(PTH) levels that are either frankly elevated or inappropriately normal. It is caused by excessive

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synthesis and secretion of PTH by one or more of the four parathyroid glands [1, 2].

When PHPT was first described almost a century ago, in the 1930’s, the disease was

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associated with severe hypercalcemia and serious skeletal and renal complications. The

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indelible association of PHPT with signs (kidney stones and fractures) and symptoms (due to

hypercalcemia) persisted until the 1970’s when biochemical screening tests became routinely

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employed, first in the United States and then elsewhere. The clinical phenotype of PHPT

changed from overt bone and renal involvement to asymptomatic hypercalcemia. These
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patients were discovered essentially in the context of biochemical screening and not for any

signs or symptoms that would have prompted the health care provider to measure the serum
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calcium. Four more decades passed when yet another phenotype of PHPT emerged, namely a
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normocalcemic variant in which albumin-corrected and ionized serum calcium concentrations

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were persistently normal but the PTH level was persistently elevated. Of course, all known

secondary causes for a high PTH have to be ruled out [3]. Not the subject of this discussion, but
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it is noteworthy that patients have recently been recognized with PHPT but only by pathological

examination of parathyroid tissue. The calcium and PTH levels are normal [4, 5].
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These different clinical phenotypes of PHPT have raised many issues with regard to
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parathyroid surgery, the definitive management of the disease. In the hands of expert

parathyroid surgeons, parathyroidectomy (PTX) offers very high cure rates [6], but in patients

who are completely asymptomatic, a surgical option is not necessarily the obvious one. The

normocalcemic variant of PHPT presents yet another challenge in the decision to recommend

parathyroid surgery or not. To this end, the Fourth International Workshop on Asymptomatic
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Silva et al., Primary Hyperparathyroidism 4

PHPT [7], recently revisited by others [8-10], offers reasonable evidence-based guidance as to

who is best advised to have parathyroid surgery.

In this article, we review these different profiles of PHPT with particular emphasis on

recent publications.

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2- Epidemiology

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The peak incidence of PHPT is in the early postmenopausal years, coincident with the

loss of estrogen [11]. Many more women than men develop this disease with a ratio of

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approximately 4:1. In the United States, the prevalence is 0.86% [12]. Racial predilection favors

African Americans [13]. While there is wide variability in prevalence estimates for the classic

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hypercalcemic form of PHPT, there are even more widely variant prevalence estimates of
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normocalcemic PHPT (0.4 to 11%). To a certain extent, the wide variability in the prevalence of

the normocalcemic form of PHPT is due to limited published experience as well as to how
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vitamin D deficiency is defined. Since vitamin D deficiency can be a cause of a high PTH when
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the serum calcium is normal, cut-off values for normal 25-hydroxyvitamin D (25OHD) can
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influence prevalence estimates of normocalcemic PHPT [14-16]. Irrespective of the actual

prevalence estimates, it is clear that in the USA, Europe, and China, the incidence and
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prevalence of the disease have increased in the past several decades. While it is not clear why

PHPT is being seen more often now, greater recognition and diagnostic pursuit of mild
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hypercalcemia, when present, along with the likelihood that biochemical screening is even more
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widespread than it used to be could account for this world-wide observation [16-20]. Clearly, in

countries where serum calcium becomes part of a biochemical screening panel, the incidence of

PHPT will increase [1].

As shown in numerous studies from the USA, Canada, and Europe, PHPT is discovered

through the biochemical screening and, when discovered, appears to be an asymptomatic

disorder characterized primarily by hypercalcemia [8, 18, 21, 22]. Standard radiological
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Silva et al., Primary Hyperparathyroidism 5

abnormalities (salt and pepper degranulation of the skull, distal clavicular tapering,

subperiosteal bone resorption, bone cysts and brown tumors) and classical neuromuscular

symptoms with proximal muscle weakness are virtually absent. In these patients, a history of a

clinically event consistent with a kidney stone is seen in approximately 20% of patients. This

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minority of cohorts in developed countries with a history of kidney stones contrasts with

developing countries in which PHPT continues to present with higher serum calcium levels,

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kidney stones, and fractures [23, 24].

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Another concept related to the different forms of PHPT is that as countries introduce

multichannel screening, the relative incidence of symptomatic disease falls. A good example is

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China where there has been a shift towards more asymptomatic disease [20, 25]. In Latin

America, similarly, there is a greater prevalence of asymptomatic disease, but some reports
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continue to report nephrolithiasis as a common feature of PHPT’s presentation [26-28].

Selection bias is also an aspect of this discussion. In premenopausal women and men,
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in whom screening tests are less likely to be utilized than in postmenopausal women,
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symptomatic PHPT is more common [29].

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3- Etiology and risk factors

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The vast majority of patients with PHPT harbor a single, benign, parathyroid adenoma. It

accounts for approximately 80% of cases of PHPT. Multiglandular disease, in which 4-gland
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parathyroid hyperplasia is the predominant form, is seen in 15-20% of cases. Multiglandular

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disease can also be manifest as two and, very rarely, three adenomas. Parathyroid carcinoma

accounts for well under 1% of all cases of PHPT [2]. Parathyroid cancer presents in a very

different manner than its benign counterpart. Patients with parathyroid cancer typically have

much higher serum calcium and PTH levels along with evidence for target organ involvement.

They also tend to be younger by about a decade. For reasons not at all clear, parathyroid

cancer appears to be on the increase in the USA and in China [20, 30].
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Silva et al., Primary Hyperparathyroidism 6

In the vast majority of patients, PHPT is a sporadic disease, with no family history and no other

endocrine gland involvement. The incidence of heredity forms of PHPT is no more than 10% of

the PHPT population. The genetic form of PHPT can be isolated to the parathyroid glands, or it

can be part of a multi-gland endocrine syndrome [31]. The germline mutations that have been

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associated with hereditary forms of PHPT are shown in Table 1 along with at least 6 somatic

mutations that have been described [31-33].

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While in no way implying causation, certain environmental and modifiable risk factors have been

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implicated as contributing to the development of PHPT. In the Nurses’ Health Study, a large

cohort of over 50,000 women followed for over 2 decades, PHPT was more likely in those

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whose calcium intake and physical activity were lower, and whose waist circumference and

body weight were higher [34-36]. Hypertension and the use of the loop diuretic, furosemide, also
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seemed to be associated with greater risk of developing PHPT [37]. Confirming previous

reports, external radiation to the neck region [38, 39], and lithium therapy [40] were identified as
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risk factors. With specific reference to thiazide diuretics, it used to be thought that it was just as
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likely for those who became hypercalcemic on the drug would become normocalcemic when it
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was stopped. It is much clearer now with more recent data that when hypercalcemia surfaces in

the setting of thiazide use, it is more likely to persist and PHPT is present [41]. Thus, thiazides
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are less likely to be a modifiable risk factor but rather a provocation to unmasking the underlying

disease.
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4- Clinical Presentation

When hypercalcemia is high enough, generally over 12 mg/dL, or if it rises rapidly, over

several days, signs and symptoms of PHPT may be due to the hypercalcemia itself. Symptoms

include polyuria, polydipsia, constipation, anorexia, vomiting, dehydration, arrhythmias, and

altered mental status.

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Silva et al., Primary Hyperparathyroidism 7

The clinical presentation of PHPT can also include the key target organs, kidney and

bone. With regard to the kidney, any combination of hypercalciuria, nephrolithiasis,

nephrocalcinosis and reduced renal function is possible [42]. The incidence of overt renal

involvement has declined over the years, as the incidence of asymptomatic disease has risen.

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However, without a careful and systematic evaluation of the kidneys among these asymptomatic

patients, one could have missed a greater proportion of subjects with nephrocalcinosis or

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nephrolithiasis. To address this possibility, Cipriani et al. have recently demonstrated, for

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example, that if a systematic approach to renal involvement is taken, stones and/or calcinosis

can be seen in a majority of patients with asymptomatic PHPT [43].

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With regard to the skeleton, any combination of fragility fractures, skeletal deformities,

and bone pain is possible. When the disease is advanced and prolonged, the classical
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radiological depictions are known as osteitis fibrosa cystica, as noted above [44, 45]. They are

clearly seen by routine skeletal X-rays. One of the major advances in our appreciation of the
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potential of PHPT to involve the skeleton, even among those with asymptomatic PHPT, is the
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use of bone mineral density (BMD) imaging. By DXA (dual energy X-ray absorptiometry) the
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distal 1/3 radius, a site of cortical bone, will typically be low [46]. Skeletal sites in which

trabecular bone is more enriched, namely the hip and lumbar spine (LS) regions, will show
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lesser degrees of involvement. While this pattern is typically seen, and emphasizes the need to

measure the distal forearm in all patients with PHPT, the opposite pattern can also be seen in
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which the LS is preferentially reduced [47]. The unusual reduction in BMD at the LS, seen most
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often in postmenopausal women, could reflect the early effects of estrogen deficiency prior to

the onset of the parathyroid disease. It should also be noted that patients with PHPT can

present with universally low BMD and, at times, values that are within normal limits at all sites.

The 1/3 radius is comprised primarily of cortical bone, and early studies documented

preferential involvement at that site. These data were consistent with the concept that the

effects of excessive PTH in a disease that is classically catabolic to the skeletal would be first
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Silva et al., Primary Hyperparathyroidism 8

and most evidently manifested at the 1/3 radius with relative sparing of the trabecular-rich

lumbar spine. However, this observation was not consistent with reports of Khosla et al. [48] and

Vignali et al. [49] in which vertebral fractures were significantly higher than control populations.

It required more sophisticated imaging technology to address this apparent paradox, namely

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that there is an increase in fracture incidence at a site that by DXA should signal fracture

protection. Indeed, by High Resolution peripheral Quantitative Computed Tomography

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(HRpQCT; Figure 1A) and Trabecular Bone Score (TBS; Figure 1B), trabecular bone is clearly

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affected in PHPT, even among those with the common presentation of asymptomatic disease

[50-53].

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There are other organ systems that are on the list of potential target organs. When

PHPT is symptomatic, neuromuscular manifestations, with proximal muscle weakness, gait

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disturbance, muscle atrophy, and hyperreflexia are common. However, such manifestations are

virtually never seen when the disease presents in its asymptomatic form [54].
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The so-called neurocognitive features of PHPT have been a vexing issue because
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complaints of fatigue, anxiety, poor concentration, cognitive decline, and reduced quality of life
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have all been reported. The problem has been and continues to be that these manifestations

are commonly seen in many chronic disease and do not bear any distinctive features that can
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be attributed with specificity to PHPT. Moreover, attempts to document an etiological

association by demonstrating reversibility after successful parathyroid surgery have been met
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with mixed and inconclusive results [55-59].

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Similarly, cardiovascular abnormalities, which used to be seen regularly when PHPT

was more often seen as a symptomatic disease, are not often clinically apparent. However, by

careful physiological studies, endothelial dysfunction, valvular calcification, and left ventricular

hypertrophy can be demonstrated, but these findings may not be reversible after successful

PTX [2, 42].

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Silva et al., Primary Hyperparathyroidism 9

The potential protean manifestations of PHPT include peptic ulcer disease, acute

pancreatitis, chondrocalcinosis (pseudogout), and gout. In asymptomatic PHPT, such

manifestations are rarely seen [60].

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4.1- Normocalcemic PHPT

Normocalcemic PHPT (NPHPT) was discovered in centers where PTH levels are routinely

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measured in patients being evaluated for low bone mass or frank osteoporosis [22]. When

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NPHPT is identified at such referral centers, the incidence of low BMD and kidney stones is

similar to hypercalcemic PHPT [22, 61-67]. Metabolic abnormalities such as dyslipidemia,

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hyperglycemia, and increased body mass index, have also been described in NPHPT, but the

findings are not consistently reported [65]. One of the interesting oddities of this form of PHPT is
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that the initial cohorts were highly symptomatic, while the more recent cohorts of the

hypercalcemic form of the disease, discovered incidentally by biochemical screening, were not
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symptomatic. Not surprisingly, however, in large epidemiological cohorts in which selection bias
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is obviated, an asymptomatic form of normocalcemic PHPT could be identified [68]. Thus,

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NPHPT can be asymptomatic or symptomatic [65].

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5. A World View of How PHPT Can Present

These three different presentations of PHPT were described chronologically with the
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symptomatic variant described first, following by the discovery of asymptomatic PHPT via the
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use of biochemical screening, and most recently by the normocalcemic variant in which the

routine measurement of PTH among those with normal serum calcium levels was prompted

initially by the proactive approach to the evaluation of low bone density. However, these three

forms of PHPT exist concurrently in the world today. The preponderance of one over another

will depend upon country-specific factors. For example, in countries where biochemical

screening is not routinely part of the health care system, symptomatic PHPT is the likely form to
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Silva et al., Primary Hyperparathyroidism 10

present itself and it will be considered to be an uncommon disease. In countries where

biochemical screening is routine, then asymptomatic PHPT is likely and the incidence will be

much greater. Parenthetically, the use of the term asymptomatic probably needs some

adjustment, even if only semantically, because with greater imaging tools applied to this

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population, it is apparent that such patients can often be shown to have involvement of the

skeleton and/or kidneys. Finally, in centers where PTH measurements are routinely measured

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even among those whose serum calcium is normal, the normocalcemic variant of PHPT

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becomes more evident. Rather than considering these three presentations of PHPT from a

historical and chronological view point, therefore, it is also useful to consider the coexistence of

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all three forms with an incidence that is defined by country- and practice-specific variables.
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6- Diagnosis and evaluation

Classical PHPT is diagnosed readily by hypercalcemia in association with a frankly

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elevated PTH or inappropriately ‘normal’ PTH. A PTH level within the normal range is clearly not
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a normal value physiologically when someone is hypercalcemic. The question then arises, how
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low can the PTH be when hypercalcemia is present and have it still be compatible with the

diagnosis of PHPT? A level of 20-25 pg/mL or higher in the setting of hypercalcemia is

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considered to be compatible with the diagnosis of PHPT [69]. Careful note should be made of

patients who are on biotin supplementation, because in some assays, PTH levels can read
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falsely low [70]. These patients should stop taking biotin and several weeks later have the PTH
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measurement repeated.

The diagnosis of NPHPT depends upon an elevated PTH level with persistently normal

concentrations of albumin-adjusted total calcium and ionized calcium [3]. In contrast to the

hypercalcemic form of PHPT, in which the serum calcium can occasionally be normal, the

serum calcium level in these patients is consistently normal. To confirm the diagnosis, it is very

important to exclude secondary causes of increased PTH, the most important one of which is
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Silva et al., Primary Hyperparathyroidism 11

vitamin D deficiency. While the Institute of Medicine defines vitamin D deficiency [71] as a

25OHD level < 20 ng/mL (50nmol/l), for this discussion, most experts feel that the threshold

value should be > 30 ng/mL (75 nmol/l). The reason for this cautionary note is that on an

individual basis, some patients can show an increase in PTH when the level of 25OHD falls

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below 30 ng/mL [72]. Renal insufficiency (eGFR <60 cc/min), primary hypercalciuria,

malabsorption syndromes, and the use of certain medications, such as diuretics, lithium,

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bisphosphonates and denosumab should all be ruled out, since they can all be associated with

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an increase in PTH against a backdrop of normal serum calcium concentrations.

There are other etiologies of PTH-dependent hypercalcemia. If possible, diuretics and/or

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lithium should be discontinued. Familial Hypocalciuric Hypercalcemia (FHH), a rare disorder of

the calcium-sensing receptor gene (CASR), can enter into the differential diagnosis. In FHH, 24-
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hour urinary calcium excretion is very low (<100mg) and the calcium clearance/creatinine

clearance ratio (CCCR) is < 0.01. It is important to ensure that the patient is not unduly
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restricting dietary calcium. While FHH is an important disorder to rule out, the postmenopausal
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state of most patients with PHPT essentially eliminates FHH, because the high penetrance of
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this genetic disorder virtually ensures that FHH patients will have become hypercalcemic before

the age of 30. A low urinary calcium excretion in a postmenopausal woman with PHPT is more
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likely to be due to dietary calcium restriction along with the calcium conserving actions of PTH at

the renal tubule.

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The recommended evaluation of a patient with PHPT is shown in Table 2 [7]. This is one
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disorder of bone and mineral metabolism in which 3-site DXA should routinely be obtained

(lumbar spine, hip, and 1/3 radius) [73]. With recent evidence that many patients with

asymptomatic PHPT have vertebral involvement, some form of vertebral imaging should be

obtained (X-rays, Vertebral Fracture Assessment, or TBS). Also, because of the recent

appreciation that renal stones and/or nephrocalcinosis are seen rather commonly in
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Silva et al., Primary Hyperparathyroidism 12

asymptomatic PHPT, some form of abdominal imaging (abdominal X-ray, ultrasound, or CT)

should be performed [43, 74].

7- Treatment of PHPT

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7.1- Surgical management:

The definitive cure of PHPT is surgical removal of hyperfunctioning parathyroid tissue.

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Successful PTX leads to normalization of all biochemical indices and eventually to higher BMD,

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reduced fracture risk and reduced risk of kidney stones [21, 55-57, 75, 76]. Even in NPHPT,

PTX has been associated with beneficial outcomes [77, 78]. In patients who are symptomatic of

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hypercalcemia or who have sustained target organ issues (e.g., fractures, stones), surgery is

clearly indicated with the only exception being medical or other contraindications [7]. The more
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vexing issue of surgery relates to those who are asymptomatic and who, when they present, do

not have any clear cut evidence for target organ involvement. However, in the course of the
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evaluation, these individuals can show evidence that the disease has already begun to affect
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organ systems. The question of surgical guidelines for such patients has been addressed in all
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four International Workshops on the Management of Asymptomatic PHPT. The most recent,

revised guidelines for surgery in these patients are summarized in Table 3. It is important to
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note that even in patients who do not meet guidelines for surgery, PTX is not inappropriate as

long as there are no medical contraindications. The Workshop also proposed guidelines for
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surgical management of NPHPT. For these normocalcemic patients, PTX is recommended if

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they have or develop evidence for target organ involvement (e.g., reduced bone density with T-

scores < -2.5, fracture, kidney stone) much in the same way that hypercalcemic patients with

PHPT are considered [7].

7.2 Parathyroid localization. While the dictum that the most important aspect of parathyroid

localization is locating the expert parathyroid surgeon, even such experts are aided by
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Silva et al., Primary Hyperparathyroidism 13

successful localization of the parathyroid tissue. The precise modality to be used will vary from
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center to center. Some combination of ultrasound, Technetium-labeled sestamibi, and CT is

commonly used [8]. In centers where parathyroid surgery is done in high volume, parathyroid

localization and successful parathyroid surgery tend to go hand in hand with success rates of

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over 95%.

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7.3- Nonsurgical management:

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Patients who do not undergo surgery should be monitored as recommended by The

Fourth International Workshop and summarized in Table 3 [7]. If any surgical guideline is met

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during ongoing monitoring, patients should be considered for surgery.

Nutritional guidelines. Many patients with PHPT are advised by their physician to restrict
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their intake of calcium. While there is an intrinsic logic to this advice, it is not in the patient’s best

interest to do so, because dietary calcium restriction can lead to further increases in PTH levels
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[79]. The Institute of Medicine’s recommendations for adequacy of calcium intake should be
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followed by patients with PHPT. The other important nutrient to address in PHPT is vitamin D
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because reduced levels can fuel further increases in PTH and associated bone turnover

markers [25, 79-81]. More recent studies have shown that vitamin D deficiency is not as
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commonly seen in PHPT as it used to be, undoubtedly due to the widespread use of vitamin D

supplements in the general population [82]. Seasonal variability in biochemical indices of PHPT
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may also be a function of seasonal variability in 25OHD levels [83]. Such relationships between
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low vitamin D and biochemical indices did not influence structural skeletal indices as measured

by TBS [84, 85], QCT [85], or HRpQCT [86]. The general advice is when patients are vitamin D

deficient, as defined for the purpose of this disease as levels of 25OHD <30 ng/mL, repletion is

in order. Modest of amounts of vitamin D2 or D3 should be employed, starting with 1,000 IU per

day [7]. To justify this approach, a daily dose of 2,800 IU of vitamin D for 6 months in a

randomized clinical trial led to an increase in 25OHD from 20 ng/mL to 38 ng/mL which in turn
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Silva et al., Primary Hyperparathyroidism 14

was associated with lower serum C-telopeptide and PTH levels, and improved LS BMD. These

salutary effects occurred without changes in serum or urinary calcium [87].

Pharmacological guidelines. In most cases, the decision to use a pharmacological

approach is made because hypercalcemia greater than 1 mg/dL above the upper limits of

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normal needs to be controlled and/or BMD is low. In either case, such a patient would meet at

least 1 criterion for surgery. The assumption, therefore, is that the patient is not going to have

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surgery, despite meeting a guideline. In subjects whose BMD is low, alendronate has been

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shown to be beneficial, particularly at the lumbar spine. The serum calcium does not change

[88-92]. It has also been demonstrated that alendronate increases BMD in NPHPT [93]. There is

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a paucity of data for other bisphosphonates in PHPT [94] and, to date, none for denosumab.

Paradoxically, an increase in fracture risk was reported from a large retrospective cohort study
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utilizing an insurance database in patients treated with bisphosphonate in comparison to PTX or

no intervention [76]. A serious selection bias may have been at hand here in that the
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bisphosphonate group was older, had worse osteoporosis and higher comorbidities. Such
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differences may not have been sufficiently well adjusted statistically, raising doubt as to the
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conclusions of the study.

Cinacalcet is a calcimimetic agent that binds to the calcium-sensing receptor,

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mimicking the calcium ion. The net intracellular effect is to reduce PTH synthesis and secretion.

The main indication for cinacalcet is to reduce the serum calcium in those for whom PTX is not
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an option. Cinacalcet will reduce the serum calcium to normal in over 70% of patients as shown
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in the registration trial [95]. PTH levels fall but only modestly. The long-term, 5-year experience

with cinacalcet in PHPT documents the ability of the drug to control calcium levels, even among

those with severe disease [79, 96-98]. Even though biochemical control is achieved with

cinacalcet, bone density does not improve. This observation has led to the idea that the

combination of alendronate and cinacalcet might effectively reduce the serum calcium and

increase BMD. Early studies are promising in this regard [99, 100].
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Silva et al., Primary Hyperparathyroidism 15

8- Natural history of PHPT with and without surgery

Based upon a number of studies, comparing PTX with non-operative management [21, 55-57,

75, 76], BMD significantly improves after PTX while it remains stable or declines in those

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without surgical intervention. The longest observational study to date followed patients with or

without PTX for 15 years. In the non-surgical group [21], biochemical indices remained stable

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for 15 years, the only exception being the serum calcium that trended upwards between years

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13 and 15. After stable BMD for the first 8 years, the femoral neck and distal radius began to

decline. Between years 10 and 15, rather dramatic changes in femoral neck and distal radius

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BMD were observed (Figure 2). A more recent clinical trial evaluated 145 patients with

asymptomatic PHPT randomized to PTX or observation [75]. After 5 years, PTX led to
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significant decreases in BTMs and improvements in BMD at all sites, except for the 1/3 radius.

Patients who did not undergo PTX experienced declines in BMD at the hip and radius, but not
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the LS, over the 5-year period. There was also a lower fracture rate in those who underwent
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PTX [55, 76, 101].

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Recent observations have also been made with regard to changes in TBS, bone

microarchitecture and estimated strength by HRpQCT following PTX [102-104]. With a relatively
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short follow up period of 2 years, TBS did not change following PTX [102]. Microstructure as

measured by HRpQCT through 2 years post-PTX did show improved volumetric BMD, bone
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microarchitecture and strength at the distal radius and tibia [103]. Finite element analysis of
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these findings documented increased stiffness and failure load. These results corroborated

those of Hansen et al. through 1 year post-PTX [104].

With regard to the renal system, long-term non-operative monitoring, for up to 15 years, showed

stable serum creatinine and urinary calcium values. In those with a history of kidney stones,

however, recurrence was common [21]. After PTX, urinary calcium excretion and the incidence

of kidney stones decline [105].

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Silva et al., Primary Hyperparathyroidism 16

Attempts to demonstrate improvement in neurocognitive and cardiovascular features

have been met with inconsistencies after PTX [42]. A recent meta-analysis of both randomized

clinical trials and observational ones in asymptomatic patients with PHPT concluded that PTX

has no substantial effects on quality of life, neuropsychiatric symptoms, cardiovascular events,

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fractures or kidney stones, the latter in part due to lack of events [106]. These uncertain results

are the basis for caution in recognizing cardiovascular or neurocognitive features as an

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indication for PTX.

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9- Summary

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The three clinical forms of PHPT present in frequency as a function of several factors: the

presence of routine biochemical screening; endogenous vitamin D deficiency; the use of PTH in
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the evaluation of reduced bone mass even if the serum calcium is normal. Even among those

whose PHPT is discovered incidentally, signs of skeletal and renal involvement can often be
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demonstrated. Successful PTX cures the disease. It is recommended in those with symptomatic
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disease and for those who are asymptomatic but who meet surgical guidelines. NPHPT is an
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acknowledged clinical variant. Successful PTX reverses biochemical abnormalities, increases

BMD, and reduces the risk of fracture and kidney stones. Pharmacological treatment is an
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option to improve BMD or reduce serum calcium in individuals who cannot undergo PTX.
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Practice Points:
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• A proactive assessment of renal and skeletal involvement should be performed in

patients with asymptomatic PHPT.

• Successful parathyroidectomy improves skeletal and renal abnormalities.

• In patients with normocalcemic PHPT, surgery is indicated for those with target organ

involvement or evidence of disease progression.

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Silva et al., Primary Hyperparathyroidism 17

• Pharmacological treatment is an option to improve BMD or reduce serum calcium in

individuals managed nonoperatively.

Research Agenda:

- Prospective, randomized studies that evaluate neurocognitive and vascular function

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before and after parathyroidectomy.

- To investigate the effects of alendronate, other bisphosphonates and denosumab on

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fracture risk in individuals with low BMD followed conservatively.

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- To evaluate the ability of TBS and HRpQCT measures to predict fracture risk in PHPT.

- Studies that further characterize features that predict progression of the disease in those

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who do no meet surgical criteria.

Acknowledgments
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This work was supported, in part, by NIH grant DK 32333.

Figure Legends:
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Figure 1A. Microarchitectural indices in Primary Hyperparathyroidism. Both cortical and

trabecular indices are abnormal. The red line indicates relative normality. The indices to the left
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or right of theline are abnormal as per the index measured. Adapted form ref. #53 (Stein E, Silva
BC et al. J Bone Miner Res, 2013)
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Figure 1B. TBS more often reflects trabecular bone (lumbar spine) abnormalities than does
DXA. More patients were shown to have ‘fully degraded’ microstructure by TBS (36%) than had
osteoporosis (14%) by T-score <-2.5 by DXA. More patients had osteoporosis by DXA (53%)
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than had normal TBS (27%). Adapted from ref #51 (Silva et al, J Clin Endo Metab, 2013)

Figure 2. Bone density in Primary Hyperparathyroidism: Natural History without intervention 15

years. For the first 10 years, there were no changes at any sites. At years 10-15, major
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reductions can be seen at the femoral neck and distal 1/3 radius sites. Adapted from ref #15
(Rubin et al. J Clin Endocrinol Metab, 2008)
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Silva et al., Primary Hyperparathyroidism 18

Table 1. Hereditary disorders associated with Primary Hyperparathyroidism:

Hereditary Disorder Inheritance Genes involved Phenotype

MEN1 Autosomal MEN1 PHPT (95%); pancreatic islet tumors

dominant (40%); anterior pituitary adenomas
(30%); additional features:

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adrenocorticoid or carcinoid tumors,
lipomas, cutaneous angiofibromas
and collagenomas

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MEN2a (or MEN2) Autosomal RET PHPT (20%); Medullary thyroid
dominant carcinomas (99%);

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pheochromocytomas (50%).

MEN4 Autosomal CDKN1B PHPT (~80%), anterior pituitary

dominant tumors (~40%), pancreatic

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neuroendocrine tumors; other
features: adrenal, thyroid, gonadal
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and renal tumors

HPT-JT Autosomal CDC73 PHPT with a high prevalence of

dominant parathyroid carcinomas (15%);
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ossifying fibromas of the mandible

and maxilla; renal and uterine
tumors.
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FIHP Autosomal MEN1, CDC73, Isolated PHPT

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dominant CASR, GCM2,

CDKN1B

NSHPT Autosomal CASR Severe neonatal PHPT

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recessive
or
dominant
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FHH Autosomal CASR, GNA11, Mild PTH-dependent hypercalcemia,

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dominant AP2S1 associated with low concentration of

urinary calcium

PHPT: primary hyperparathyroidism; MEN 1/MEN 2a /MEN 4: multiple endocrine neoplasia

types 1, 2a, and 4; HPT-JT: hyperparathyroid jaw-tumor syndrome; FIHP: familial isolated
hyperparathyroidism; NSHPT: neonatal severe primary hyperparathyroidism; FHH: familial
hypocalciuric hypercalcemia.
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Silva et al., Primary Hyperparathyroidism 19

Table 2. Evaluation of patients with primary hyperparathyroidism (adapted from [7]):

Recommended Optional

• Serum PTH, calcium, phosphate, alkaline • HRpQCT

phosphatase activity, renal function tests, 25- • TBS by DXA
hydroxyvitamin D • Bone turnover markers
• 24-hour urine for calcium and creatinine • DNA testing if genetic basis for

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• 3-site DXA (lumbar spine, hip, distal 1/3 radius) PHPT is suspected
• Vertebral spine assessment (radiography, CT or
VFA by DXA)
• Stone risk profile (if urinary calcium > 400 mg/day)

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• Abdominal imaging by radiography,
ultrasonography, or CT scan
PTH: parathyroid hormone; BMD, bone mineral density; DXA: Dual energy X-ray

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absorptiometry; CT: computed tomography; HRpQCT: high-resolution peripheral quantitative
computed tomography; TBS: trabecular bone score; VFA: vertebral fracture assessment.

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Table 3. Indications for surgery in asymptomatic PHPT and guideline for medical monitoring in
patients managed conservatively (adapted from [7]).
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Parameters Criteria for parathyroidectomy Frequency of re-evaluation in
patients with asymptomatic PHPT
managed conservatively
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Age < 50 years old NA

Serum calcium > 1 mg/dL above the upper limit of Annually

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normal
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Skeletal • Reduced bone mineral density by • 3-site DXA every 1–2 years
manifestations DXA to a T-score of < -2.5 at any • Imaging of spine to access
site (lumbar spine, hip, or distal vertebral fracture if clinically
1/3 radius). suspected (eg, height loss,
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• Vertebral fracture by X-ray, CT, back pain)

MR or vertebral fracture
assessment.
Renal • Creatinine clearance < 60 • Serum creatinine and eGFR
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manifestations mL/min. annually

• Kidney stone or nephrocalcinosis • If renal stones are clinically
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by abdominal imaging suspected: 24-hour

• Hypercalciuria (> 400 mg/d) biochemical stone profile,
accompanied by a biochemical abdominal imaging by x-ray,
stone risk profile that places the ultrasound, or CT
patient at risk for kidney stones
PHPT: primary hyperparathyroidism; DXA: Dual energy X-ray absorptiometry; eGFR: estimated
glomerular filtration rate; CT: computed tomography; MR: magnetic resonance.
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Silva et al., Primary Hyperparathyroidism 20

References:
[1] Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet. 2018;391:168-78.
[2] Bilezikian JP, Cusano NE, Khan AA, Liu JM, Marcocci C, Bandeira F. Primary
hyperparathyroidism. Nat Rev Dis Primers. 2016;2:16033.
[3] Eastell R, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic
primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol
Metab. 2014;99:3570-9.

PT
[4] Lavryk OA, Siperstein AE. Use of Calcium and Parathyroid Hormone Nomogram to Distinguish
Between Atypical Primary Hyperparathyroidism and Normal Patients. World J Surg. 2017;41:122-8.
[5] Rosario PW. Primary Hyperparathyroidism with Normal Calcium and PTH. World J Surg.
2017;41:1649-50.

RI
[6] Udelsman R, Akerstrom G, Biagini C, Duh QY, Miccoli P, Niederle B, et al. The surgical
management of asymptomatic primary hyperparathyroidism: proceedings of the Fourth
International Workshop. J Clin Endocrinol Metab. 2014;99:3595-606.

SC
[7] Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the
management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth
International Workshop. J Clin Endocrinol Metab. 2014;99:3561-9.
[8] Khan AA, Hanley DA, Rizzoli R, Bollerslev J, Young JE, Rejnmark L, et al. Primary

U
hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A
Canadian and international consensus. Osteoporos Int. 2017;28:1-19.
AN
[9] Stephen AE, Mannstadt M, Hodin RA. Indications for Surgical Management of
Hyperparathyroidism: A Review. JAMA Surg. 2017;152:878-82.
[10] Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, et al. The American Association of
Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA
M

Surg. 2016;151:959-68.
[11] Wermers R, Clarke B. Epidemiology of Primary Hyperparathyroidism. In: Bilezikian J, Marcus
R, Levine MA, Marcocci C, Silverberg SJ, Potts JT, Jr., editors. The Parathyroids. 3rd ed. UK and USA:
D

Elsevier; 2015. p. 297-308.

[12] Press DM, Siperstein AE, Berber E, Shin JJ, Metzger R, Monteiro R, et al. The prevalence of
undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from
TE

the electronic medical record. Surgery. 2013;154:1232-7; discussion 7-8.

[13] Yeh MW, Ituarte PH, Zhou HC, Nishimoto S, Liu IL, Harari A, et al. Incidence and prevalence of
primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab.
2013;98:1122-9.
EP

[14] Cusano NE, Maalouf NM, Wang PY, Zhang C, Cremers SC, Haney EM, et al. Normocalcemic
hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J
Clin Endocrinol Metab. 2013;98:2734-41.
C

[15] Vignali E, Cetani F, Chiavistelli S, Meola A, Saponaro F, Centoni R, et al. Normocalcemic primary
hyperparathyroidism: a survey in a small village of Southern Italy. Endocr Connect. 2015;4:172-8.
[16] Kontogeorgos G, Trimpou P, Laine CM, Oleröd G, Lindahl A, Landin-Wilhelmsen K.
AC

Normocalcaemic, vitamin D-sufficient hyperparathyroidism – high prevalence and low morbidity in

the general population: A long-term follow-up study, the WHO MONICA project, Gothenburg,
Sweden. Clinical Endocrinology. 2015;83:277-84.
[17] Abood A, Vestergaard P. Increasing incidence of primary hyperparathyroidism in Denmark.
Dan Med J. 2013;60:A4567.
[18] Adami S, Marcocci C, Gatti D. Epidemiology of primary hyperparathyroidism in Europe. J Bone
Miner Res. 2002;17 Suppl 2:N18-23.
[19] Collier A, Portelli M, Ghosh S, Nowell S, Clark D. Primary hyperparathyroidism: Increasing
prevalence, social deprivation, and surgery. Endocr Res. 2017;42:31-5.
 ACCEPTED MANUSCRIPT
Silva et al., Primary Hyperparathyroidism 21

[20] Sun B, Guo B, Wu B, Kang J, Deng X, Zhang Z, et al. Characteristics, management, and outcome of
primary hyperparathyroidism at a single clinical center from 2005 to 2016. Osteoporos Int. 2017.
[21] Rubin MR, Bilezikian JP, McMahon DJ, Jacobs T, Shane E, Siris E, et al. The natural history of
primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol
Metab. 2008;93:3462-70.
[22] Lowe H, McMahon DJ, Rubin MR, Bilezikian JP, Silverberg SJ. Normocalcemic primary
hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab.

PT
2007;92:3001-5.
[23] Pradeep PV, Jayashree B, Mishra A, Mishra SK. Systematic review of primary
hyperparathyroidism in India: the past, present, and the future trends. Int J Endocrinol.
2011;2011:921814.

RI
[24] Prasarttong-Osoth P, Wathanaoran P, Imruetaicharoenchoke W, Rojananin S. Primary
hyperparathyroidism: 11-year experience in a single institute in Thailand. Int J Endocrinol.
2012;2012:952426.

SC
[25] Liu JM, Cusano NE, Silva BC, Zhao L, He XY, Tao B, et al. Primary Hyperparathyroidism: A Tale
of Two Cities Revisited - New York and Shanghai. Bone Res. 2013;1:162-9.
[26] Bandeira F, Griz L, Caldas G, Bandeira C, Freese E. From mild to severe primary
hyperparathyroidism: The Brazilian experience. Arq Bras Endocrinol Metabol. 2006;50:657-63.

U
[27] Eufrazino C, Veras A, Bandeira F. Epidemiology of Primary Hyperparathyroidism and its Non-
classical Manifestations in the City of Recife, Brazil. Clin Med Insights Endocrinol Diabetes.
AN
2013;6:69-74.
[28] Spivacow FR, Martinez C, Polonsky A. [Primary hyperparathyroidism: postoperative long-term
evolution]. Medicina (B Aires). 2010;70:408-14.
[29] Castellano E, Attanasio R, Boriano A, Pellegrino M, Garino F, Gianotti L, et al. Sex Difference in
M

the Clinical Presentation of Primary Hyperparathyroidism: Influence of Menopausal Status. J Clin

Endocrinol Metab. 2017;102:4148-52.
[30] Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends in the incidence and treatment of
D

parathyroid cancer in the United States. Cancer. 2007;109:1736-41.

[31] Thakker RV. Genetics of parathyroid tumours. J Intern Med. 2016;280:574-83.
[32] Pardi E, Borsari S, Saponaro F, Bogazzi F, Urbani C, Mariotti S, et al. Mutational and large
TE

deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and

correlation with clinical features. PLoS One. 2017;12:e0186485.
[33] Stokes VJ, Nielsen MF, Hannan FM, Thakker RV. Hypercalcemic Disorders in Children. J Bone
Miner Res. 2017;32:2157-70.
EP

[34] Paik JM, Curhan GC, Taylor EN. Calcium intake and risk of primary hyperparathyroidism in
women: prospective cohort study. BMJ. 2012;345:e6390.
[35] Vaidya A, Curhan GC, Paik JM, Wang M, Taylor EN. Physical Activity and the Risk of Primary
C

Hyperparathyroidism. J Clin Endocrinol Metab. 2016;101:1590-7.

[36] Vaidya A, Curhan GC, Paik JM, Wang M, Taylor EN. Body Size and the Risk of Primary
AC

Hyperparathyroidism in Women: A Cohort Study. J Bone Miner Res. 2017;32:1900-6.

[37] Vaidya A, Curhan GC, Paik JM, Kronenberg H, Taylor EN. Hypertension, Antihypertensive
Medications, and Risk of Incident Primary Hyperparathyroidism. J Clin Endocrinol Metab.
2015;100:2396-404.
[38] Boehm BO, Rosinger S, Belyi D, Dietrich JW. The parathyroid as a target for radiation damage.
N Engl J Med. 2011;365:676-8.
[39] Cohen J, Gierlowski TC, Schneider AB. A prospective study of hyperparathyroidism in
individuals exposed to radiation in childhood. Jama. 1990;264:581-4.
[40] Szalat A, Mazeh H, Freund HR. Lithium-associated hyperparathyroidism: report of four cases
and review of the literature. Eur J Endocrinol. 2009;160:317-23.
 ACCEPTED MANUSCRIPT
Silva et al., Primary Hyperparathyroidism 22

[41] Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ, 3rd, et al. Thiazide-
associated Hypercalcemia: Incidence and Association with Primary Hyperparathyroidism over Two
Decades. J Clin Endocrinol Metab. 2016:jc20153964.
[42] Silverberg SJ, Clarke BL, Peacock M, Bandeira F, Boutroy S, Cusano NE, et al. Current issues in
the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth
International Workshop. J Clin Endocrinol Metab. 2014;99:3580-94.
[43] Cipriani C, Biamonte F, Costa AG, Zhang C, Biondi P, Diacinti D, et al. Prevalence of kidney

PT
stones and vertebral fractures in primary hyperparathyroidism using imaging technology. J Clin
Endocrinol Metab. 2015;100:1309-15.
[44] Bandeira F, Cusano NE, Silva BC, Cassibba S, Almeida CB, Machado VC, et al. Bone disease in
primary hyperparathyroidism. Arq Bras Endocrinol Metabol. 2014;58:553-61.

RI
[45] Misiorowski W, Czajka-Oraniec I, Kochman M, Zgliczynski W, Bilezikian JP. Osteitis fibrosa
cystica-a forgotten radiological feature of primary hyperparathyroidism. Endocrine. 2017;58:380-5.
[46] Silverberg SJ, Shane E, de la Cruz L, Dempster DW, Feldman F, Seldin D, et al. Skeletal disease in

SC
primary hyperparathyroidism. J Bone Miner Res. 1989;4:283-91.
[47] Bilezikian J, Silverberg S, Gartenberg F, Kim T, Jacobs T, Siris E, et al. Skeletal Disease in
Primary Hyperparathyroidism. In: Bilezikian J, Marcus R, Levine MA, editors. The Parathyroids. NY:
Paven Press; 1994. p. 457-70.

U
[48] Khosla S, Melton LJ, 3rd, Wermers RA, Crowson CS, O'Fallon W, Riggs B. Primary
hyperparathyroidism and the risk of fracture: a population-based study. J Bone Miner Res.
AN
1999;14:1700-7.
[49] Vignali E, Viccica G, Diacinti D, Cetani F, Cianferotti L, Ambrogini E, et al. Morphometric
vertebral fractures in postmenopausal women with primary hyperparathyroidism. J Clin
Endocrinol Metab. 2009;94:2306-12.
M

[50] Hansen S, Beck Jensen JE, Rasmussen L, Hauge EM, Brixen K. Effects on bone geometry, density,
and microarchitecture in the distal radius but not the tibia in women with primary
hyperparathyroidism: A case-control study using HR-pQCT. J Bone Miner Res. 2010;25:1941-7.
D

[51] Silva BC, Boutroy S, Zhang C, McMahon DJ, Zhou B, Wang J, et al. Trabecular bone score (TBS)--
a novel method to evaluate bone microarchitectural texture in patients with primary
hyperparathyroidism. J Clin Endocrinol Metab. 2013;98:1963-70.
TE

[52] Stein EM, Silva BC, Boutroy S, Zhou B, Wang J, Udesky J, et al. Primary hyperparathyroidism is
associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in
postmenopausal women. J Bone Miner Res. 2013;28:1029-40.
[53] Vu TD, Wang XF, Wang Q, Cusano NE, Irani D, Silva BC, et al. New insights into the effects of
EP

primary hyperparathyroidism on the cortical and trabecular compartments of bone. Bone.

2013;55:57-63.
[54] Turken SA, Cafferty M, Silverberg SJ, De La Cruz L, Cimino C, Lange DJ, et al. Neuromuscular
C

involvement in mild, asymptomatic primary hyperparathyroidism. Am J Med. 1989;87:553-7.

[55] Ambrogini E, Cetani F, Cianferotti L, Vignali E, Banti C, Viccica G, et al. Surgery or surveillance
AC

for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin
Endocrinol Metab. 2007;92:3114-21.
[56] Bollerslev J, Jansson S, Mollerup CL, Nordenstrom J, Lundgren E, Torring O, et al. Medical
observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a
prospective, randomized trial. J Clin Endocrinol Metab. 2007;92:1687-92.
[57] Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery
versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin
Endocrinol Metab. 2004;89:5415-22.
[58] Walker MD, McMahon DJ, Inabnet WB, Lazar RM, Brown I, Vardy S, et al. Neuropsychological
features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab.
2009;94:1951-8.
 ACCEPTED MANUSCRIPT
Silva et al., Primary Hyperparathyroidism 23

[59] Walker M, Silverberg S. Non-traditional manifestations of primary hyperparathyroidism. In:

Bilezikian J, Marcus R, Levine MA, Marcocci C, Silverberg SJ, Potts JT, Jr., editors. The Parathyroids.
3rd ed. UK and USA: Elsevier; 2015. p. 469-80.
[60] Bilezikian JP. Primary Hyperparathyroidism. In: De Groot LJ, Chrousos G, Dungan K, Feingold
KR, Grossman A, Hershman JM, et al., editors. Endotext. South Dartmouth (MA)2000.
[61] Amaral LM, Queiroz DC, Marques TF, Mendes M, Bandeira F. Normocalcemic versus
Hypercalcemic Primary Hyperparathyroidism: More Stone than Bone? J Osteoporos.

PT
2012;2012:128352.
[62] Garcia-Martin A, Reyes-Garcia R, Munoz-Torres M. Normocalcemic primary
hyperparathyroidism: one-year follow-up in one hundred postmenopausal women. Endocrine.
2012;42:764-6.

RI
[63] Marques TF, Vasconcelos R, Diniz E, Rego D, Griz L, Bandeira F. Normocalcemic primary
hyperparathyroidism in clinical practice: an indolent condition or a silent threat? Arq Bras
Endocrinol Metabol. 2011;55:314-7.

SC
[64] Maruani G, Hertig A, Paillard M, Houillier P. Normocalcemic primary hyperparathyroidism:
evidence for a generalized target-tissue resistance to parathyroid hormone. J Clin Endocrinol
Metab. 2003;88:4641-8.
[65] Pawlowska M, Cusano NE. An overview of normocalcemic primary hyperparathyroidism. Curr

U
Opin Endocrinol Diabetes Obes. 2015;22:413-21.
[66] Tordjman KM, Greenman Y, Osher E, Shenkerman G, Stern N. Characterization of
AN
normocalcemic primary hyperparathyroidism. Am J Med. 2004;117:861-3.
[67] Tuna MM, Caliskan M, Unal M, Demirci T, Dogan BA, Kucukler K, et al. Normocalcemic
hyperparathyroidism is associated with complications similar to those of hypercalcemic
hyperparathyroidism. J Bone Miner Metab. 2016;34:331-5.
M

[68] Cusano N, Silverberg SJ, Bilezikian J. Normocalcemic PHPT. In: bilezikian J, Marcus R, Levine
MA, Marcocci C, Silverberg SJ, Potts JT, Jr., editors. The Parathyroids. 3rd ed. USA: Elsevier; 2015.
[69] Yu N, Donnan PT, Murphy MJ, Leese GP. Epidemiology of primary hyperparathyroidism in
D

Tayside, Scotland, UK. Clin Endocrinol (Oxf). 2009;71:485-93.

[70] Piketty ML, Prie D, Sedel F, Bernard D, Hercend C, Chanson P, et al. High-dose biotin therapy
leading to false biochemical endocrine profiles: validation of a simple method to overcome biotin
TE

interference. Clin Chem Lab Med. 2017;55:817-25.

[71] Rosen CJ, Gallagher JC. The 2011 IOM report on vitamin D and calcium requirements for north
america: clinical implications for providers treating patients with low bone mineral density. J Clin
Densitom. 2011;14:79-84.
EP

[72] Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, et al.
Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338:777-83.
[73] Castellano E, Attanasio R, Gianotti L, Cesario F, Tassone F, Borretta G. Forearm DXA Increases
C

the Rate of Patients With Asymptomatic Primary Hyperparathyroidism Meeting Surgical Criteria. J
Clin Endocrinol Metab. 2016;101:2728-32.
AC

[74] Cassibba S, Pellegrino M, Gianotti L, Baffoni C, Baralis E, Attanasio R, et al. Silent renal stones in
primary hyperparathyroidism: prevalence and clinical features. Endocr Pract. 2014;20:1137-42.
[75] Lundstam K, Heck A, Godang K, Mollerup C, Baranowski M, Pernow Y, et al. Effect of Surgery
Versus Observation: Skeletal 5-Year Outcomes in a Randomized Trial of Patients With Primary HPT
(the SIPH Study). J Bone Miner Res. 2017;32:1907-14.
[76] Yeh MW, Zhou H, Adams AL, Ituarte PH, Li N, Liu IL, et al. The Relationship of
Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism: An
Observational Study. Ann Intern Med. 2016;164:715-23.
[77] Koumakis E, Souberbielle J-C, Payet J, Sarfati E, Borderie D, Kahan A, et al. Individual site-
specific bone mineral density gain in normocalcemic primary hyperparathyroidism. Osteoporosis
International. 2014;25:1963-8.
 ACCEPTED MANUSCRIPT
Silva et al., Primary Hyperparathyroidism 24

[78] Koumakis E, Souberbielle J-C, Sarfati E, Meunier M, Maury E, Gallimard E, et al. Bone mineral
density evolution after successful parathyroidectomy in patients with normocalcemic primary
hyperparathyroidism. The Journal of Clinical Endocrinology & Metabolism. 2013;98:3213-20.
[79] Marcocci C, Bollerslev J, Khan AA, Shoback DM. Medical management of primary
hyperparathyroidism: proceedings of the fourth International Workshop on the Management of
Asymptomatic Primary Hyperparathyroidism. J Clin Endocrinol Metab. 2014;99:3607-18.
[80] Walker MD, Bilezikian JP. Vitamin D and primary hyperparathyroidism: more insights into a

PT
complex relationship. Endocrine. 2017;55:3-5.
[81] Battista C, Guarnieri V, Carnevale V, Baorda F, Pileri M, Garrubba M, et al. Vitamin D status in
primary hyperparathyroidism: effect of genetic background. Endocrine. 2017;55:266-72.
[82] Walker MD, Cong E, Lee JA, Kepley A, Zhang C, McMahon DJ, et al. Low vitamin D levels have

RI
become less common in primary hyperparathyroidism. Osteoporos Int. 2015;26:2837-43.
[83] Nevo-Shor A, Kogan S, Joshua BZ, Bahat-Dinur A, Novack V, Fraenkel M. Seasonal changes in
serum calcium, PTH and vitamin D levels in patients with primary hyperparathyroidism. Bone.

SC
2016;89:59-63.
[84] Lee JH, Kim JH, Hong AR, Kim SW, Shin CS. Skeletal effects of vitamin D deficiency among
patients with primary hyperparathyroidism. Osteoporos Int. 2017;28:1667-74.
[85] Walker MD, Saeed I, Lee JA, Zhang C, Hans D, Lang T, et al. Effect of concomitant vitamin D

U
deficiency or insufficiency on lumbar spine volumetric bone mineral density and trabecular bone
score in primary hyperparathyroidism. Osteoporos Int. 2016;27:3063-71.
AN
[86] Walker MD, Nishiyama KK, Zhou B, Cong E, Wang J, Lee JA, et al. Effect of Low Vitamin D on
Volumetric Bone Mineral Density, Bone Microarchitecture, and Stiffness in Primary
Hyperparathyroidism. J Clin Endocrinol Metab. 2016;101:905-13.
[87] Rolighed L, Rejnmark L, Sikjaer T, Heickendorff L, Vestergaard P, Mosekilde L, et al. Vitamin D
M

treatment in primary hyperparathyroidism: a randomized placebo controlled trial. J Clin Endocrinol

Metab. 2014;99:1072-80.
[88] Chow CC, Chan WB, Li JK, Chan NN, Chan MH, Ko GT, et al. Oral alendronate increases bone
D

mineral density in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol

Metab. 2003;88:581-7.
[89] Khan AA, Bilezikian JP, Kung A, Dubois SJ, Standish TI, Syed ZA. Alendronate therapy in men
TE

with primary hyperparathyroidism. Endocr Pract. 2009;15:705-13.

[90] Khan AA, Bilezikian JP, Kung AW, Ahmed MM, Dubois SJ, Ho AY, et al. Alendronate in primary
hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol
Metab. 2004;89:3319-25.
EP

[91] Parker CR, Blackwell PJ, Fairbairn KJ, Hosking DJ. Alendronate in the treatment of primary
hyperparathyroid-related osteoporosis: a 2-year study. J Clin Endocrinol Metab. 2002;87:4482-9.
[92] Rossini M, Gatti D, Isaia G, Sartori L, Braga V, Adami S. Effects of oral alendronate in elderly
C

patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res. 2001;16:113-
9.
AC

[93] Cesareo R, Di Stasio E, Vescini F, Campagna G, Cianni R, Pasqualini V, et al. Effects of

alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism.
Osteoporos Int. 2015;26:1295-302.
[94] Tournis S, Fakidari E, Dontas I, Liakou C, Antoniou J, Galanos A, et al. Effect of
parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at
the tibia in postmenopausal women with primary hyperparathyroidism. J Bone Miner Metab.
2014;32:151-8.
[95] Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride
maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin
Endocrinol Metab. 2005;90:135-41.
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Silva et al., Primary Hyperparathyroidism 25

[96] Cetani F, Saponaro F, Banti C, Cianferotti L, Vignali E, Chiavistelli S, et al. Cinacalcet efficacy in
patients with moderately severe primary hyperparathyroidism according to the European Medicine
Agency prescription labeling. J Endocrinol Invest. 2012;35:655-60.
[97] Luque-Fernandez I, Garcia-Martin A, Luque-Pazos A. Experience with cinacalcet in primary
hyperparathyroidism: results after 1 year of treatment. Ther Adv Endocrinol Metab. 2013;4:77-81.
[98] Peacock M, Bolognese MA, Borofsky M, Scumpia S, Sterling LR, Cheng S, et al. Cinacalcet
treatment of primary hyperparathyroidism: biochemical and bone densitometric outcomes in a

PT
five-year study. J Clin Endocrinol Metab. 2009;94:4860-7.
[99] Faggiano A, Di Somma C, Ramundo V, Severino R, Vuolo L, Coppola A, et al. Cinacalcet
hydrochloride in combination with alendronate normalizes hypercalcemia and improves bone
mineral density in patients with primary hyperparathyroidism. Endocrine. 2011;39:283-7.

RI
[100] Keutgen XM, Buitrago D, Filicori F, Kundel A, Elemento O, Fahey TJ, 3rd, et al. Calcimimetics
versus parathyroidectomy for treatment of primary hyperparathyroidism: retrospective chart
analysis of a prospective database. Ann Surg. 2012;255:981-5.

SC
[101] Vestergaard P, Mosekilde L. Parathyroid surgery is associated with a decreased risk of hip
and upper arm fractures in primary hyperparathyroidism: a controlled cohort study. J Intern Med.
2004;255:108-14.
[102] Cipriani C, Abraham A, Silva BC, Cusano NE, Rubin MR, McMahon DJ, et al. Skeletal changes

U
after restoration of the euparathyroid state in patients with hypoparathyroidism and primary
hyperparathyroidism. Endocrine. 2017;55:591-8.
AN
[103] Cusano NE, Rubin MR, Silva BC, Tay YD, Williams JM, Agarwal S, et al. Skeletal Microstructure
and Estimated Bone Strength Improve Following Parathyroidectomy in Primary
Hyperparathyroidism. J Clin Endocrinol Metab. 2018;103:196-205.
[104] Hansen S, Hauge EM, Rasmussen L, Jensen JE, Brixen K. Parathyroidectomy improves bone
M

geometry and microarchitecture in female patients with primary hyperparathyroidism: a one-year

prospective controlled study using high-resolution peripheral quantitative computed tomography. J
Bone Miner Res. 2012;27:1150-8.
D

[105] Verdelli C, Corbetta S. MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients

with primary hyperparathyroidism: an update on clinical and molecular aspects. Eur J Endocrinol.
2017;176:R39-R52.
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[106] Singh Ospina N, Maraka S, Rodriguez-Gutierrez R, Espinosa de Ycaza AE, Jasim S, Gionfriddo
M, et al. Comparative efficacy of parathyroidectomy and active surveillance in patients with mild
primary hyperparathyroidism: a systematic review and meta-analysis. Osteoporos Int.
2016;27:3395-407.
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Primary Hyperparathyroidism 2018:

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John P. Bilezikian, MD, PhD(hon)

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Figures for Article

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Figure 1A. Microarchitectural indices in Primary Hyperparathyroidism. Both cortical

and trabecular indices are abnormal. The red line indicates relative normality. The
indices to the left or right of the line are abnormal as per the index measured.
Adapted from ref #53. (Stein E, Silva BC et al. J Bone Miner Res, 2013)
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L1-L4 T-score classification n (%) L1-L4 TBS classification n (%)

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Osteoporosis 3 (14) Degraded 8 (36)

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Osteopenia 7 (32) Partially degraded 8 (36)

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Normal 12 (53) Normal 6 (27)

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Microarchitecture by TBS
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<1.2= degraded
1.2 – 1.35= partially degraded
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>1.35= normal
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Figure 1B. TBS more often reflects trabecular bone (lumbar spine) abnormalities than
does DXA. More patients were shown to have ‘fully degraded’ microstructure by TBS
(36%) than had osteoporosis (14%) by T-score <-2.5 by DXA. More patients had
osteoporosis by DXA (53%) than had normal TBS (27%). Adapted from ref #51 (Silva et
al, J Clin Endo Metab, 2013)
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Figure 2. Bone density in Primary Hyperparathyroidism: Natural History without

intervention 15 years. For the first 10 years, there were no changes at any sites.
At years 10-15, major reductions can be seen at the femoral neck and distal 1/3
radius sites. Adapted from ref #15 (Rubin et al. J Clin Endocrinol Metab, 2008)