Download Diagnosis and Management of Primary Hyperparathyroidism

Case-based review
Diagnosis and Management of Primary
Hyperparathyroidism
Case Study and Commentary, Natalie E. Cusano, MD, and John P. Bilezikian, MD
Abstract
• Objective: To review new developments in the diagnosis and management of primary hyperparathyroidism.
• Methods: Review of the literature.
• Results: Primary hyperparathyroidism is one of the
most common endocrine disorders, especially among
postmenopausal women. Patients with hypercalcemia
can be diagnosed with primary hyperparathyroidism
in the setting of elevated or inappropriately normal
parathyroid hormone (PTH) levels. A newer presentation of primary hyperparathyroidism has been
described, normocalcemic primary hyperparathyroidism, in which patients have normal total and ionized serum calcium concentrations and consistently
elevated PTH levels, excluding secondary etiologies of hyperparathyroidism. Most patients with primary hyperparathyroidism present asymptomatically,
although decreased bone density at the distal 1/3
radius site is usually noted at the time of diagnosis.
• Conclusion: Patients with symptomatic primary hyperparathyroidism and those with asymptomatic disease
who meet criteria for surgery should be advised to have
surgical removal of the abnormal parathyroid gland(s).
Those who do not meet criteria for surgery can be managed nonoperatively with surveillance by biochemical
and densitometric measurements. Pharmacologic
options are available for those who meet surgical
criteria but either refuse surgery or are not deemed
suitable for surgery.
O
ver the past 40 years, the clinical presentation
of primary hyperparathyroidism has changed
from a disorder with overt symptomatology to
one that presents most commonly asymptomatically. It
is discovered most often in the context of a biochemical
screening test in which the discovery of hypercalcemia is a
surprise. Investigation of this more modern phenotype of
primary hyperparathyroidism has revealed new insights
into the diagnosis, management, and natural history of
www.jcomjournal.com
primary hyperparathyroidism. This review will cover the
new developments in the field.
CASE STUDY
Initial Presentation
A 72-year-old Hispanic woman with a history of
hypertension and morbid obesity was referred to
an endocrinologist for hypercalcemia noted on routine
laboratory evaluation.
History
Her past medical and surgical history was otherwise significant for hyperlipidemia, hypothyroidism, depression,
gastroesophageal reflux disease, and chronic headache.
She denied a history of fracture or nephrolithiasis. Review of systems was significant only for chronic constipation. Her medications included amlodipine, telmisartan,
ezetimibe-simvastatin, levothyroxine, citalopram, and
lansoprazole. The patient was born and raised in the
Dominican Republic; social history was otherwise unremarkable. Family history was significant for leukemia
and breast cancer but negative for parathyroid disease or
other endocrine disorders.
Physical Examination, Laboratory, and
Radiographic Evaluation
Examination was significant for a body mass index
of 47.5 kg/m2, absence of thyromegaly or nodules,
absence of neck masses, absence of kyphosis or vertebral tenderness. Her most recent laboratory testing
prior to evaluation was significant for a serum calcium level of 10.8 mg/dL (reference range [rr], 8.6–
10.2), ionized calcium of 1.53 mM/L (rr, 1.12–1.32),
parathyroid hormone (PTH) 104 pg/mL (rr, 10–65),
From the Department of Medicine, Division of Endocrinology,
College of Physicians and Surgeons, Columbia University,
New York, NY.
Vol. 20, No. 4 April 2013 JCOM 181
Primary hyperparathyroidism
25-hydroxyvitamin D 28 ng/mL (rr, 30–100), albumin
4.0 g/dL (rr, 3.5–5.5), creatinine 0.8 mg/dL (rr, 0.50–
0.90), phosphorus 2.9 mg/dL (rr, 2.5–4.3), and total
alkaline phosphatase 102 U/L (rr, 33–96). A bone mineral
density was obtained and demonstrated T-scores of –0.3 at
the lumbar spine, –0.3 at the femoral neck, +1.2 at the total
hip, and –1.5 at the distal 1/3 radius. 24-hour urine calcium excretion was obtained and was noted to be 240 mg
(rr, 50–250).
• What is the epidemiology of primary hyperparathyroidism? What are the biochemical and
clinical features?
Maintenance of sufficient levels of calcium is required
for many physiologic processes, among them normal
neuromuscular function and bone mineralization. PTH
produced by the parathyroid glands is an important regulator of serum calcium through its effects on bone, the
kidney, and intestines. In primary hyperparathyroidism,
one or more of the parathyroid glands become enlarged
and overactive. Primary hyperparathyroidism is, thus,
a disorder characterized by elevated levels of PTH and
traditionally by hypercalcemia. Primary hyperparathyroidism is one of the most common endocrine disorders, with an estimated prevalence in the United States
between 1 and 2 per 1000. Most patients present after the
age of 45 years; women are affected more often than men
by 3:1. Prior to the advent of the multichannel autoanalyzer in the 1970s, classical primary hyperparathyroidism
presented usually as a symptomatic disorder [1–3]. The
original description more than 70 years ago as a disease
of “bones, stones and groans” was apt. Overt skeletal
disease was readily recognized by radiographic features
of osteitis fibrosa cystica: “salt and pepper” degranulation
of the skull, subperiosteal bone resorption of the distal
phalanges, brown tumors, loss of distal clavicular appearance and bone cysts [4]. With serum calcium values now
routinely available as a biochemical screening test result,
the clinical profile of primary hyperparathyroidism has
evolved into a disorder that presents most commonly in
an asymptomatic fashion. In these patients, the discovery
of hypercalcemia is made incidentally [5].
The typical biochemical features of primary hyperparathyroidism are shown in Table 1 [6,7]. Serum calcium is usually within 1.0 mg/dL (0.25 mmol/L) above
182 JCOM April 2013 Vol. 20, No. 4
the upper limit of normal. Serum phosphorus is usually in
the low normal range, although 25% of patients will have
levels that are frankly low. The average vitamin D level, as
measured by 25-hydroxyvitamin D, is low, averaging 20
ng/mL. Vitamin D deficiency is due in part to the effects
of PTH to facilitate the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D [8]. Up to 25% of
patients will have frankly elevated 1,25-dihydroxyvitamin
D levels. Total alkaline phosphatase activity and more
specific markers of bone turnover such as osteocalcin and
serum and urine N- and C-telopeptide levels, are all usually in the high normal range. 24-hour urinary calcium
excretion is typically in the upper range of normal, with
a 40% incidence of frank hypercalciuria [9]. While the
incidence of hypercalciuria has not changed over the past
60 years, the incidence of renal stone disease has fallen
markedly. This speaks to an interesting point, namely
that in primary hyperparathyroidism, hypercalciuria is
not a risk factor for kidney stones [7].
Despite the fact that most patients are discovered
incidentally, and x-rays rarely show classical findings of
primary hyperparathyroidism, bone mass is typically
reduced when it is measured by dual energy x-ray absorptiometry (DXA). Primary hyperparathyroidism tends
to preferentially affect cortical (also known as compact)
bone, the bone that forms the outer shell, or envelope, of
bones. The densitometric profile of primary hyperparathyroidism shows reductions at the distal 1/3 forearm,
a site composed primarily of cortical bone [5,6]. Highresolution imaging of the radius [10] and histomorphometric analysis of bone biopsies [11] have confirmed this
finding. In contrast, the lumbar spine, a site composed
primarily of trabecular bone (also known as spongy
bone), tends to be preserved [12]. In estrogen-deficient,
postmenopausal women without primary hyperparathyroidism, the lumbar spine site is at greatest risk for bone
loss, making the observation that trabecular bone is preserved in these individuals even more noteworthy. This
observation, namely preservation of trabecular bone in
primary hyperparathyroidism, offered clues to the osteoanabolic potential of PTH [13]. The administration of
low-dose, intermittent PTH revealed this osteoanabolic
property and led to the development of PTH as a treatment for osteoporosis [14–16]. Information about fracture risk in primary hyperparathyroidism is inconsistent
due to lack of rigorous prospective data and the inclusion
of populations with varying disease severity [17–20].
In a study by Vignali et al [21] stratifying by disease
www.jcomjournal.com
Case-based review
Table 1. Biochemical Indices in 57 Patients with Asymptomatic Primary Hyperparathyroidism
Baseline Values*
Normal Range
Serum calcium, mg/dL
10.5 ± 0.1
8.4–10.2
Serum parathyroid hormone, pg/mL
116 ± 7
10–65
Urinary calcium, mg/dL
Index
236 ± 17
< 300
Alkaline phosphatase, U/L
98 ± 6
Serum 25-hydroxyvitamin D, ng/mL
21 ± 1
< 100
> 30†
Serum 1,25-dihyroxyvitamin D, pg/mL
57 ± 2
15–60
Reprinted from reference 6.
*Values are mean ± SEM.
†Many experts consider 25-hydroxyvitamin D levels > 30 ng/mL to indicate sufficiency.
severity, both symptomatic and asymptomatic patients
with primary hyperparathyroidism had an increased risk
of vertebral fracture. However, those asymptomatic individuals who did not meet surgical criteria did not show
an increased risk in comparison to a control population.
While nephrolithiasis is still the most common complication of primary hyperparathyroidism, the incidence
has fallen to 15% to 20%, much lower than estimates of
about 60% in the era prior to the autoanalyzer [5,22].
Other renal manifestations of primary hyperparathyroidism include hypercalciuria and nephrocalcinosis. The frequency of nephrocalcinosis is unknown. An unexplained
reduction in the creatinine clearance is also believed to
be a potential renal manifestation of primary hyperparathyroidism. Walker et al [23] showed that a creatinine
clearance < 60 cc/min is associated with worse indices of
skeletal disease as determined by bone biopsy in comparison to subjects with primary hyperparathyroidism whose
renal function is normal.
Nontraditional manifestations of primary hyperparathyroidism, primarily potential effects on the cardiovascular system and neurocognitive function, are areas of
active research. In mild primary hyperparathyroidism,
subtle evidence for cardiovascular dysfunction, including
altered endovascular function [24] and increased vascular stiffness, has been reported [25,26], but the clinical
relevance of these findings are not clear. Nonspecific
neurocognitive features, such as weakness, easy fatigability, depression, cognitive impairment, anxiety, and sleep
disturbance, have been difficult to identify as direct
manifestations of primary hyperparathyroidism. Associated improvement in quality of life and psychological
functioning following successful parathyroidectomy has
www.jcomjournal.com
not been a consistent finding among the 4 groups that
have studied this problem recently [27–30].
•What are other presentations of primary
hyperparathyroidism?
Normocalcemic Primary Hyperparathyroidism
A newer clinical presentation of primary hyperparathyroidism has been described over the past decade, characterized by normal total and ionized serum calcium
concentrations and consistently elevated PTH levels
[31–34]. Patients with normocalcemic primary hyperparathyroidism have no obvious causes for secondary
elevations of PTH, such as renal disease or vitamin D
deficiency. Identification of this new phenotype of primary hyperparathyroidism is consistent with a biphasic
time course of the clinical development of primary hyperparathyroidism [33]. During the first phase, PTH
levels are elevated but the serum calcium is normal.
Until recently, this phase would not be recognized
clinically because PTH levels were not drawn in the
context of a normal serum calcium concentration. The
second phase, when overt hypercalcemia becomes apparent, is the stage of the disease that has characterized
most cohorts of primary hyperparathyroidism until
recently. The discovery of this putative first phase of
primary hyperparathyroidism, when the serum calcium
is normal, would appear to be due to the fact that many
osteoporosis and metabolic bone disease units now
measure PTH routinely in the evaluation of bone loss.
Reports of normocalcemic primary hyperparathyroid-
Vol. 20, No. 4 April 2013 JCOM 183
Primary hyperparathyroidism
Table 2. Genetic Hyperparathyroid Syndromes
Syndrome
Main Gene
Associated Features
Parathyroid pathology
Therapy
Familial hypocalciuric hypercalcemia
CASR
Hypocalciuria, rare pancreatitis
None (normal)
No parathyroidectomy
Neonatal severe hyperparathyroidism
CASR
Life-threatening hypercalcemia
Early, 4 large glands
Urgent total parathyroidectomy
Multiple endocrine neoplasia type 1
MEN1
Pituitary and pancreas tumors
Multiglandular
Subtotal parathyroidectomy
based on severity
Multiple endocrine neoplasia type 2A
RET
Pheochromocytoma and medullary thyroid cancer
Multiglandular
Subtotal parathyroidectomy
based on severity
HRPT2
Fibromas in the mandible or the maxilla, parathyroid cancer
Parathyroid carcinoma (20%)
Surgical resection of cancer if it develops
Unknown
None
Multiglandular
Parathyroidectomy based on severity
Hyperparathyroidism-jaw tumor syndrome
Familial isolated hyperparathyroidism
Note: All entries represent typical features of a broad spectrum of disease
ism have largely come, therefore, from referral centers
in which subjects were under evaluation for bone loss.
For example, of the 37 individuals who were described
with normocalcemic primary hyperparathyroidism at
Columbia University Medical Center [35], 57% had
osteoporosis by BMD, 11% had documented fragility fractures, and 14% had nephrolithiasis. The observation that subjects with this putative “early” phase of
primary hyperparathyroidism have evidence for skeletal involvement, not different from hypercalcemic
cohorts, raises the possibility that there is another
population of normocalcemic subjects with primary
hyperparathyroidism who would not have evidence
for skeletal involvement if they were identified from
a general population. Studies are in progress to
identify the other form of normocalcemic primary
hyperparathyroidism [36,37].
Primary Hyperparathyroidism in the
Developing World
Interestingly, while primary hyperparathyroidism in the
developed world has become a disorder of mild, asymptomatic hypercalcemia, the clinical picture of primary hyperparathyroidism in the developing world, in which vitamin
D deficiency is more common and biochemical screening
tests are not routinely performed, remains a disease with
classic signs and symptoms, including osteitis fibrosa cystica
as well as other skeletal and renal complications. Primary
hyperparathyroidism in the setting of vitamin D deficiency
is associated with a more severe phenotype [7], with larger
184 JCOM April 2013 Vol. 20, No. 4
adenomas, higher serum calcium, parathyroid hormone,
and alkaline phosphatase levels, lower bone mineral density,
and higher fracture rates [38–42].
• What is the etiology of primary hyperthyroidism?
In primary hyperparathyroidism, clones of abnormal
parathyroid cells alter the “set-point” sensitivity of the
parathyroid gland to calcium and increase the mass of
parathyroid tissue. PTH is higher for any given extracellular concentration of calcium [43]. A single gland adenoma is the most common cause of primary hyperparathyroidism, accounting for approximately 80% of cases.
Multiple adenomas are reported in 2% to 4% of patients,
and 4-gland hyperplasia in 10% to 15%. Very rarely,
primary hyperparathyroidism can present as a malignant
carcinoma, but the incidence is less than 0.5% among
the hyperparathyroid population [39,40]. There are no
clinical features that distinguish patients with single versus multiglandular disease. However, younger patients
(< 40 years), particularly those with a personal or family
history of a multiple endocrine neoplasia (MEN) syndrome, are more likely to have multiglandular disease.
Occasionally, parathyroid adenomas will be found in unexpected anatomic locations due to embryonal migration
patterns of parathyroid tissue. The most common sites
for ectopic adenomas are within the thyroid gland, the
superior mediastinum, and within the thymus [2].
www.jcomjournal.com
Case-based review
Although most patients have sporadic disease, hereditary syndromes in which primary hyperparathyroidism is
prominent include MEN types 1 and 2A, hyperparathyroidism-jaw tumor syndrome, neonatal severe primary
hyperparathyroidism, and familial isolated hyperparathyroidism (Table 2) [3,44,45].
Ionizing radiation to the head and neck has been
associated with the development of primary hyperparathyroidism many decades after exposure [46–48]. This
usual etiology is dependent, in part, on dose and time
from exposure. The absolute risk with therapeutic doses
of radiation remains quite low, < 1% at 35 years and only
about 5% after 50 years of follow-up [49]. There are case
reports and case series suggesting an association with radioactive iodine therapy for the treatment of benign and
malignant thyroid conditions [50–52], although a prospective cohort study failed to demonstrate an increased
incidence of parathyroid disease after radioactive iodine
treatment, with a mean follow-up time of 21 years [53].
• How is the diagnosis made?
The 2 principal causes of hypercalcemia are primary
hyperparathyroidism and malignancy. In the outpatient
setting, primary hyperparathyroidism is much more
common. Patients with hypercalcemia due to malignancy
usually have clinically established advanced cancer. The
clinical setting distinguishing between these 2 most
common etiologies of hypercalcemia is supported further
by measurement of the PTH level. It is frankly elevated
in about 75% to 80% of patients with primary hyperparathyroidism, and inappropriately normal in the remaining
subjects. In contrast, PTH is typically undetectable in
patients with malignancy-associated hypercalcemia. An
undetectable PTH level in a hypercalcemic individual,
however, does not indicate a malignancy because most of
the other causes of hypercalcemia, a long list indeed, are
associated with suppressed levels of PTH [3].
If the PTH is elevated, the disorders that could be
mistaken for primary hyperparathyroidism are small in
number. They include familial hypocalciuric hypercalcemia [54] and medications, specifically thiazide diuretics
[55] and lithium [56]. Very rarely a malignant tumor has
been reported to secrete ectopic PTH, as opposed to the
more commonly reported PTH-related peptide (PTHrP)
[57–59].
www.jcomjournal.com
Familial hypocalciuric hypercalcemia (FHH) is a rare,
benign disorder caused by loss of function mutations in
the calcium sensing receptor (CASR) gene. A diagnosis
of FHH can be suspected by a family history of FHH
or a 24-hour urine calcium collection showing very low
values for calcium excretion on a normal calcium diet.
In FHH, the 24-hour urinary calcium is well under 100
mg/day and calcium to creatinine clearance ratio is less
than 0.01 mmol/L [60]. If the calcium-to-creatinine
clearance ratio is greater than 0.02, FHH becomes very
unlikely. CASR gene analysis for a single point mutation
identified in FHH can be considered in a patient with
a calcium to creatinine clearance ratio < 0.02 [61]. It is
important to distinguish FHH from primary hyperparathyroidism because the parathyroid glands are normal in
FHH and surgery is never indicated. It is also important
to remember that FHH is a rare disorder while primary
hyperparathyroidism is a common one. Moreover, since
PTH is a calcium-conserving hormone, by facilitating
renal tubular calcium reabsorption, a low calcium-tocreatinine clearance ratio does not establish the diagnosis
of FHH.
Thiazide diuretics can be associated with hypercalcemia due to a number a factors such as thiazide-associated
reduced urinary calcium excretion, a metabolic alkalosis
resulting in a pH-dependent increase in protein-bound
calcium, and increased calcium absorption from the intestines [62,63]. Discontinuation or substitution of the
thiazide can be considered if there are no contraindications, with subsequent retesting of calcium and PTH in
3 to 6 months. Most hypercalcemic patients taking thiazide diuretics will ultimately be diagnosed with primary
hyperparathyroidism [64]. Lithium decreases sensitivity
to calcium within the parathyroid gland and may also
reduce urinary calcium excretion [56,65]. Short-term
use of lithium might be associated with reversible hypercalcemia but, like thiazide diuretic use, most patients on
lithium will have been on lithium for many years when
hypercalcemia is discovered [59]. It is not easy to discontinue lithium, as one can often stop or substitute for a
thiazide diuretic. The diagnosis of primary hyperparathyroidism in these individuals is usually clear. If they meet
criteria for surgery and there are no contraindications to
surgery, most experts will proceed to obtain preoperatively localization of the putative parathyroid adenoma.
Hypercalcemia, the classical biochemical hallmark
of primary hyperparathyroidism, is not always present
in traditional primary hyperparathyroidism. Although
Vol. 20, No. 4 April 2013 JCOM 185
Primary hyperparathyroidism
patients are hypercalcemic most of the time, the serum
calcium level can be normal during the course of monitoring. The “normal” serum calcium in these traditionally hypercalcemic individuals is usually in the upper
normal range. These individuals do not have “normocalcemic primary hyperparathyroidism” in which the serum
calcium is always normal (see above). The diagnostic
criteria for normocalcemic primary hyperparathyroidism
include consistently normal albumin-adjusted total serum
calcium and normal ionized calcium. Additionally, secondary causes of an elevated PTH level must be excluded:
• Vitamin D deficiency: There is controversy surrounding the precise threshold value for 25-hydroxyvitamin that leads to an increase in PTH. The Institute
of Medicine report [66] concluded that there was
insufficient evidence that levels of 25-hydroxyvitamin D
≥ 20 ng/mL are regularly associated with increases in
PTH levels in population sampling. However, these
studies are confounded by the lack of any prospective
data tracking PTH on an individual level as the 25hydroxyvitamin D level is increased. The diagnosis of
normocalcemic primary hyperparathyroidism can be
made with greater certainty when the 25-hydroxyvitamin D level is greater than 30 ng/mL. In addition,
normocalcemic patients with hyperparathyroidism will
occasionally become hypercalcemic when 25-hydroxyvitamin D levels are raised to over 30 ng/mL. Ensuring
vitamin D sufficiency, therefore, may unmask the latent
hypercalcemic state of primary hyperparathyroidism.
• Reduced creatinine clearance. Martinez et al [67–69]
demonstrated that PTH begins to rise with a glomerular filtration rate < 60 cc/min.
• Use of thiazide diuretics and lithium
• Hypercalciuria
• Gastrointestinal malabsorption
• What is the natural history of primary hyperparathyroidism?
Natural History Without Surgery
Two large, prospective cohorts have helped to define the
natural history of the disease and the criteria that are used
to determine which patients with asymptomatic primary
hyperparathyroidism are candidates for curative surgery.
Rao et al [33] followed 80 asymptomatic patients for up
to 11 years, during which time there was no worsening
186 JCOM April 2013 Vol. 20, No. 4
of biochemical or densitometric indices. Silverberg et al
[5] followed a cohort of 101 asymptomatic patients up
to 10 years, showing that while most patients did well,
approximately 25% of these patients did progress, with
age as the only predictor of disease progression. Patients
younger than 50 years of age were approximately 3 times
as likely to have disease progression. Rubin et al [6]
reported the 15-year follow-up study of these patients,
finding that disease progression over that longer time
period increased to 37% of the cohort. Particularly noteworthy was accelerated bone loss at the distal 1/3 radius
and femoral neck between years 10 and 15.
The natural history of normocalcemic primary hyperparathyroidism is less well defined. In the cohort
from Columbia University Medical Center [35], 40%
developed further signs of primary hyperparathyroidism
during a mean follow-up period of 3.1 ± 0.3 years. Hypercalcemia developed in 19% of these individuals. The
subjects who became hypercalcemic tended to be older,
have higher baseline serum calcium levels, and higher
baseline urinary calcium excretion.
Natural History With Surgery
In the cohort studied by the group at Columbia University
Medical Center, 59 patients who underwent successful
parathyroid surgery experienced densitometric gains at
5, 10, and 15 years, respectively, of 9%, 6%, and 12% at
the lumbar spine; 1%, 7% and 10% at the femoral neck;
and 4%, 8%, and 7% at the distal radius. Randomized
controlled trials of surgery versus observation [27,28,30]
have also shown increased bone density at the hip and/
or lumbar spine. These studies failed to show a change at
the distal 1/3 radius site, which is understandable given
the short-term follow-up. Using high-resolution peripheral
quantitative computed tomography (HRpQCT), subjects
1 year after parathyroidectomy [70] showed increases in
cortical and trabecular volumetric bone density in both
the radius and tibia along with improvements in bone
microarchitecture and estimated strength in the radius.
• How is primary hyperparathyroidism managed?
Surgical Management
Parathyroidectomy is the only curative option for patients with primary hyperparathyroidism. Patients with
www.jcomjournal.com
Case-based review
Table 3. Guidelines for the Treatment of Patients with Asymptomatic Primary Hyperparathyroidism
Measurement
Surgical Criteria*
Medical Surveillance
Serum calcium
1.0 mg/dL (0.25 mmol/L) > upper limit of normal
Annually
Reduced to < 60 cc/min (calculated)
T-score < –2.5 at any site‡ and/or Every 1–2 years (3 sites)
Creatinine clearance
Bone mineral density†
Annually
previous fragility fracture
Age
< 50 years
N/A
Reprinted from reference 80.
*Surgery is also indicated in patients for whom medical surveillance is neither desired nor possible.
†Consistent with the position established by the International Society for Clinical Densitometry, the use of Z-scores instead of T-scores is
recommended in evaluating bone mineral density in premenopausal women and men younger than 50 years.
‡Lumbar spine, total hip, femoral neck or 1/3 radius.
symptomatic primary hyperparathyroidism, manifested
by kidney stones, fracture or marked hypercalcemia,
should be managed surgically with removal of the abnormal parathyroid gland(s). Even with refinements to
the surgical procedure over the last decade, it remains
exceedingly important that highly experienced surgeons
with interest in, and aptitude for, parathyroid surgery
perform the procedure [71]. The standard operation for
parathyroidectomy used to be a full neck exploration
with identification of all 4 parathyroid glands, with the
rationale being that 15% to 20% of patients with sporadic
primary hyperparathyroidism will have 4-gland hyperplasia. Recent advances in preoperative imaging modalities
and in intraoperative monitoring of PTH levels have
led to the minimally invasive parathyroidectomy, which
can be performed under local anesthesia [72,73]. The
minimally invasive operation consists of identification
and removal of the abnormal tissue without visualization of the other glands by the surgeon. Before and after
the adenoma is removed, an intraoperative PTH level is
obtained to confirm that the resected gland was the only
source of excess PTH [74]. The abnormal tissue removed
is considered to be the entirety of abnormal parathyroid
tissue if the intraoperative PTH level falls by greater than
50% to a level into the normal range within 10 minutes
after removal of the adenoma. If these criteria are not
met, the operation is extended to an exploration of other
sites where abnormal parathyroid tissue may be found.
Success rates for parathyroid surgery with the minimally
invasive procedure are over 90%, similar to the rates obtained with the classical 4-gland exploration [72]. The
advantages of the minimally invasive procedure include
www.jcomjournal.com
its shorter length of time and much more rapid recovery
in comparison to general anesthesia. In many centers, the
operation is performed on an ambulatory basis without
need for overnight observation.
In the case of parathyroid hyperplasia, options include
subtotal parathyroidectomy (removal of 3.5 glands) or
total parathyroidectomy with immediate autotransplantation of parathyroid tissue into the forearm. Should
hyperparathyroidism recur, the forearm site provides
easy access to the transplanted tissue. Cryopreservation
facilities are necessary for autotransplantation in case the
initial graft does not take. This approach is often used in
cases of familial hyperparathyroidism in which 4-gland
disease is most common [75,76].
Preoperative localization studies are necessary in
preparation for any parathyroid surgery. The most
common localization studies include neck ultrasound,
computed tomography (CT) and radionuclide imaging
(ie, sestamibi). The sensitivity and specificity of each
modality vary among institutions. Ultrasound has the
advantages of low cost and ability to identify co-existing
thyroid pathology. The sensitivity ranges from 42% to
82% depending on the operator, although the specificity
is approximately 90% [77]. Sestamibi can be useful in
the identification of ectopic parathyroid tissue and has
a sensitivity approaching 90% for single adenomas, with
decreased sensitivity for multiple lesions [78]. If the patient is not taking thyroid hormone, double-labeling with
123I and 99T sestamibi is preferred because the thyroid
image generated by the 123I can be compute-subtracted
from the image obtained by 99T sestamibi. Fourdimensional CT has also proven to be very successful in
Vol. 20, No. 4 April 2013 JCOM 187
Primary hyperparathyroidism
identifying abnormal parathyroid tissue. Other localization approaches include magnetic resonance imaging
and positron emission tomography. Arteriography and
selective venous sampling may be needed in patients with
persistent or recurrent disease in whom the noninvasive
studies were unable to localize the lesion [79].
The Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism
in 2008 [80] defined guidelines for the management of
asymptomatic primary hyperparathyroidism (Table 3).
Surgical management in asymptomatic patients should be
considered in those with end-organ effects (osteoporosis
at any site, creatinine clearance < 60 cc/min) or a higher
likelihood of disease progression (age < 50 years, serum
calcium > 1.0 mg/dL above the upper limit of normal).
Marked hypercalciuria, a surgical indication in previous
consensus conferences, was removed from the most current guidelines because urinary calcium has not been
shown in primary hyperparathyroidism to be a risk factor
for kidney stones [7].
Medical Management
Patients who do not meet surgical criteria can be observed with annual serum calcium, calculated creatinine
clearance, and either annual or biannual bone densitometry (Table 3) [80]. Patients should be referred for
parathyroid resection if they develop an indication for
surgery during the follow-up period. While not part of
guidelines, renal imaging with abdominal x-ray, ultrasonography, or CT can be considered in order to rule out
renal involvement in subjects with no known history of
kidney stones. Whether this approach to detecting renal
calcifications should be part of conservative monitoring
is a matter of clinical judgment. Patients found to have or
to develop renal calcifications (nephrolithiasis or nephrocalcinosis) would become surgical candidates.
Patients with primary hyperparathyroidism and
vitamin D deficiency present a particularly challenging
dilemma due to the potential risk of worsening hypercalcemia with vitamin D supplementation. Moreover,
patients with vitamin D deficiency may be at greater
risk for developing hypocalcemia due to “hungry bone”
syndrome following parathyroidectomy. A few published
studies have focused upon the use of relatively high
doses of vitamin D [81–84]. These studies show that
vitamin D supplementation in primary hyperparathyroidism seems to be well tolerated and does not lead, in
general, to worsening hypercalcemia or hypercalciuria.
188 JCOM April 2013 Vol. 20, No. 4
The reports, however, also demonstrate the importance
of careful monitoring. The optimal management of vitamin D deficiency is unknown, although most experts
would recommend supplementation of 400 to 1000 IU
daily and close monitoring of serum and urine calcium.
More aggressive repletion of vitamin D deficiency can be
considered post-parathyroidectomy to prevent “hungry
bone” syndrome. Clinical trials are ongoing to determine
optimal management of vitamin D deficiency in primary
hyperparathyroidism (NCT00674154, NCT01306656,
NCT01329666).
Patients who are not surgical candidates, refuse
parathyroidectomy, or those with refractory primary hyperparathyroidism following surgery can be considered
for medical therapy. Cinacalcet, a calcimimetic, is the
only approved medical therapy for primary hyperparathyroidism in the United States, indicated for the treatment of severe hypercalcemia. Cinacalcet is an allosteric
modulator of the calcium-sensing receptor that increases
its sensitivity to extracellular calcium ions [85]. In a
double-blind, randomized, 52-week placebo-controlled
trial of 78 patients [86], cinacalcet was shown to significantly lower or normalize serum calcium and PTH levels
in subjects with primary hyperparathyroidism. Serum
phosphate was increased. Bone mineral density was unchanged. Cinacalcet was well tolerated, with the most
common adverse effects being nausea and headache. The
open-label 4.5-year extension of this trial [87] continued
to show efficacy of cinacalcet. In primary hyperparathyroidism, most patients can be well controlled on a daily
dose of 30 mg, although the official recommendation
is to start with a twice daily dosing regimen. It is very
uncommon for patients with primary hyperparathyroidism to require more than a twice daily dosing regimen.
Conversely, in parathyroid cancer, much larger doses may
be required, up to a maximum of 90 mg 4 times daily.
Such high doses are poorly tolerated.
Antiresorptive therapeutic approaches have also been
used in patients with primary hyperparathyroidism. In
small studies, hormone replacement therapy [88–92],
raloxifene [93,94], and bisphosphonates, with alendronate being the most studied [95–98], have all been
shown to reduce bone turnover. Estrogen and raloxifene
reduce the serum calcium concentration. Alendronate
increases bone mineral density. However, there are no
data on fracture efficacy with any of these therapies.
An ongoing trial is investigating use of denosumab,
a monoclonal antibody against receptor activator of
www.jcomjournal.com
Case-based review
nuclear factor kappa B ligand (RANKL), in postmenopausal women with primary hyperparathyroidism
(NCT01558115).
• What are considerations for the approach to
normocalcemic primary hyperparathyroidism?
At the time of the National Institutes of Health Consensus
Conference in 2008, the expert panel concluded that the
guidelines for the hypercalcemic form of primary hyperparathyroidism could not be applied to normocalcemic
primary hyperparathyroidism since so little was known
about this variant. Our approach is to monitor patients with
normocalcemic primary hyperparathyroidism similarly to
the way we monitor patients with asymptomatic hypercalcemic primary hyperparathyroidism, with annual serum
calcium, PTH, and bone mineral density. If the disease
evolves into the hypercalcemic form, the guidelines from
the Third International Workshop can then be followed
[80]. Progression of the disease in other respects, such as
worsening bone density, a fracture, or a kidney stone, would
signal a more proactive surgical approach to the disease,
even if patients continue to remain normocalcemic.
Case Follow-up
The patient was monitored for 5 years with stable annual serum calcium and PTH values and
biannual bone mineral density evaluation. Serum calcium
subsequently began to rise and was measured consistently
in the 11.2–11.6 mg/dL range. Due to the rise in serum
calcium to greater than 1 mg/dL above the normal
range, parathyroidectomy was discussed with the patient.
Parathyroid sestamibi demonstrated increased radiotracer
uptake in the region of the inferior pole of the right thyroid gland, most consistent with a parathyroid adenoma.
The patient was referred to an endocrine surgeon for
minimally invasive parathyroidectomy. A 0.47-g right
lower parathyroid was removed, with intraoperative PTH
declining from 244 to 25 pg/mL within 10 minutes.
Pathology was consistent with a parathyroid adenoma.
She has now been followed 1 year postoperatively with
normal serum calcium and PTH values. Conclusion
Prior to the advent of the multichannel autoanalyzer in
the 1970s, classical primary hyperparathyroidism comwww.jcomjournal.com
monly presented with marked hypercalcemia and symptomatic bone or stone disease. This presentation shifted
40 years ago to a disorder characterized by mild hypercalcemia without classical symptomatic features. We appear
to have entered a third era in the history of this disease in
which patients are now being discovered with normocalcemic primary hyperparathyroidism, defined by normal
total and ionized serum calcium concentrations but with
PTH levels that are consistently elevated. Our knowledge
of normocalcemic primary hyperparathyroidism remains
incomplete and further studies are required to further
define the disorder. Patients with symptomatic disease
or those who meet surgical criteria should be managed
with parathyroid resection. Patients with asymptomatic
primary hyperparathyroidism who do not meet criteria
for surgery can be managed with annual surveillance of
biochemical and densitometric indices.
Corresponding author: Natalie E. Cusano, MD, Columbia
University College of Physicians and Surgeons, Division of
Medicine, 630 West 168th St., PH 8W-864, New York, NY
10032, [email protected].
Funding/support: This work was supported in part by National Institutes of Health grants DK32333 and DK095944.
Financial disclosures: Dr. Bilezikian is a consultant for Eli
Lilly, NPS Pharmaceuticals, Merck, Warner-Chilcott, GSK,
and Amgen, and receives research support from NPS Pharmaceuticals and Amgen.
References
1. Bilezikian JP, Silverberg SJ. Primary hyperparathyroidism.
In: Rosen C, editor. Primer on metabolic bone diseases
and disorders of mineral metabolism. 7th ed. Washington,
DC:American Society for Bone and Mineral Research; 2009.
2. Bilezikian JP, Marcus R, Levine MA. The parathyroids: basic
and clinical concepts. 2nd ed. San Diego: Academic Press;
2001.
3. Bilezikian JP. Primary hyperparathyroidism. Endotextorg.
4. Cope O. The study of hyperparathyroidism at the Massachusetts General Hospital. N Engl J Med 1966;274:1174–82.
5. Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without
parathyroid surgery. N Engl J Med 1999;341:1249–55.
6. Rubin MR, Bilezikian JP, McMahon DJ, et al. The natural
history of primary hyperparathyroidism with or without
parathyroid surgery after 15 years. J Clin Endocrinol Metab
2008;93:3462–70.
7. Silverberg SJ, Lewiecki EM, Mosekilde L, et al. Presentation
of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol
Metab 2009;94:351–65.
Vol. 20, No. 4 April 2013 JCOM 189
Primary hyperparathyroidism
8. Fraser DR, Kodicek E. Regulation of 25-hydroxycholecalciferol-1-hydroxylase activity in kidney by parathyroid
hormone. Nature: New biology 1973;241:163–6.
9. Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism.
In: DeGroot LJ, Jameson JL, Potts JT, editors. Endocrinology. 6th ed. Philadelphia: Saunders-Elsevier; 2010:
1176–97.
10. Hansen S, Beck Jensen JE, Rasmussen L, et al. 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.
11. Christiansen P, Steiniche T, Brockstedt H, et al. Primary
hyperparathyroidism: iliac crest cortical thickness, structure, and remodeling evaluated by histomorphometric
methods. Bone 1993;14:755–62.
12. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res
1989;4:283–91.
13. Dempster DW, Muller R, Zhou H, et al. Preserved threedimensional cancellous bone structure in mild primary
hyperparathyroidism. Bone 2007;41:19–24.
14. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral
density in postmenopausal women with osteoporosis. N
Engl J Med 2001;344:1434–41.
15. Rosen CJ, Bilezikian JP. Clinical review 123: Anabolic therapy for osteoporosis. J Clin Endocrinol Metab
2001;86:957–64.
16. Rubin MR, Cosman F, Lindsay R, Bilezikian JP. The
anabolic effects of parathyroid hormone. Osteoporosis Int
2002;13:267–77.
17. Khosla S, Melton LJ 3rd, Wermers RA, et al. Primary
hyperparathyroidism and the risk of fracture: a populationbased study. J Bone Miner Res 1999;14:1700–7.
18. Wilson RJ, Rao S, Ellis B, et al. Mild asymptomatic primary
hyperparathyroidism is not a risk factor for vertebral fractures. Ann Intern Med 1988;109:959–62.
19. Melton LJ 3rd, Atkinson EJ, O’Fallon WM, Heath H 3rd.
Risk of age-related fractures in patients with primary hyperparathyroidism. Arch Intern Med 1992;152:2269–73.
20. Mosekilde L. Primary hyperparathyroidism and the skeleton. Clin Endocrinol 2008;69:1–19.
21. Vignali E, Viccica G, Diacinti D, et al. Morphometric vertebral fractures in postmenopausal women with
primary hyperparathyroidism. J Clin Endocrinol Metab
2009;94:2306–12.
22. Rejnmark L, Vestergaard P, Mosekilde L. Nephrolithiasis
and renal calcifications in primary hyperparathyroidism. J
Clin Endocrinol Metab 2011;96:2377–85.
23. Walker MD, Dempster DW, McMahon DJ, et al. Effect of
renal function on skeletal health in primary hyperparathyroidism. J Clin Endocrinol Metab 2012;97:1501–7.
24. Carrelli A, Walker M, DiTullio MR, et al. Endothelial function in mild primary hyperparathyroidism. Clin Endocrinol
2013;78:204–9.
25. Rubin MR, Maurer MS, McMahon DJ, et al. Arterial stiff-
190 JCOM April 2013 Vol. 20, No. 4
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
ness in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2005;90:3326–30.
Smith JC, Page MD, John R, et al. Augmentation of central
arterial pressure in mild primary hyperparathyroidism. J
Clin Endocrinol Metab 2000;85:3515–9.
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.
Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or
surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin
Endocrinol Metab 2007;92:3114–21.
Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab 2009;94:1951–8.
Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized
trial. J Clin Endocrinol Metab 2007;92:1687–92.
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.
Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: a “forme fruste” of an old disease. J Clin
Endocrinol Metab 2003;88:5348–52.
Rao DS, Wilson RJ, Kleerekoper M, Parfitt AM. Lack of
biochemical progression or continuation of accelerated
bone loss in mild asymptomatic primary hyperparathyroidism: evidence for biphasic disease course. J Clin Endocrinol
Metab 1988;67:1294–8.
Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism. Arq Bras Endocrinol Metabol
2010;54:106–9.
Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism: further characterization
of a new clinical phenotype. J Clin Endocrinol Metab
2007;92:3001–5.
Cusano NE, Wang PY, Cremers SC, et al. Asymptomatic
normocalcemic primary hyperparathyroidism: characterization of a new phenotype. Program of the 33rd annual meeting of the American Society of Bone and Mineral Research.
San Diego, CA: Abstract SU0167; 2011.
Cusano NE, Maalouf NM, Dworakowski E, et al. Epidemiology and natural history of normocalcemic primary
hyperparathyroidism and normocalcemic hypoparathyroidism. Program of the 34th annual meeting of the American
Society of Bone and Mineral Research. Minneapolis, MN:
Abstract MO0134; 2012.
Rao DS, Honasoge M, Divine GW, et al. Effect of vitamin
D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications. J Clin Endocrinol Metab
2000;85:1054–8.
Moosgaard B, Christensen SE, Vestergaard P, et al. Vitamin
D metabolites and skeletal consequences in primary hyperparathyroidism. Clin Endocrinol 2008;68:707–15.
www.jcomjournal.com
Case-based review
40. Inoue Y, Kaji H, Hisa I, et al. Vitamin D status affects
osteopenia in postmenopausal patients with primary hyperparathyroidism. Endocrine J 2008;55:57–65.
41. Nordenstrom E, Westerdahl J, Lindergard B, et al. Multifactorial risk profile for bone fractures in primary hyperparathyroidism. World J Surgery 2002;26:1463–7.
42. Rao DS, Agarwal G, Talpos GB, et al. Role of vitamin D
and calcium nutrition in disease expression and parathyroid
tumor growth in primary hyperparathyroidism: a global
perspective. J Bone Miner Res 2002;17 Suppl 2:N75–80.
43. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983;56:572–81.
44. Marx SJ. Hyperparathyroid genes: sequences reveal answers
and questions. Endocrine Pract 2011;17 Suppl 3:18–27.
45. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice
guidelines for multiple endocrine neoplasia type 1 (MEN1).
J Clin Endocrinol Metab 2012.
46. Beard CM, Heath H 3rd, O’Fallon WM, et al. Therapeutic
radiation and hyperparathyroidism. A case-control study in
Rochester, Minn. Arch Intern Med 1989;149:1887–90.
47. Tisell LE, Carlsson S, Fjalling M, et al. Hyperparathyroidism subsequent to neck irradiation. Risk factors. Cancer
1985;56:1529–33.
48. Boehm BO, Rosinger S, Belyi D, Dietrich JW. The parathyroid as a target for radiation damage. N Engl J Med
2011;365:676–8.
49. Schneider AB, Gierlowski TC, Shore-Freedman E, et al.
Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995;80:254–7.
50. Bondeson AG, Bondeson L, Thompson NW. Hyperparathyroidism after treatment with radioactive iodine: not only
a coincidence? Surgery 1989;106:1025–7.
51. Acar T, Gomceli I, Aydin R. Primary hyperparathyroidism
due to giant adenoma after treatment with radioactive iodine. N Z Med J 2003;116:U441.
52. Colaco SM, Si M, Reiff E, Clark OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surgery
2007;194:323–7.
53. Fjalling M, Dackenberg A, Hedman I, Tisell LE. An evaluation of the risk of developing hyperparathyroidism after
131I treatment for thyrotoxicosis. Act Chir Scandinav
1983;149:681–6.
54. Fuleihan Gel H. Familial benign hypocalciuric hypercalcemia. J Bone Miner Res 2002;17 Suppl 2:N51–6.
55. Paloyan E, Farland M, Pickleman JR. Hyperparathyroidism coexisting with hypertension and prolonged thiazide
administration. JAMA 1969;210:1243–5.
56. Mallette LE, Khouri K, Zengotita H, et al. Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume. J Clin Endocrinol Metab
1989;68:654–60.
57. Yoshimoto K, Yamasaki R, Sakai H, et al. Ectopic production of parathyroid hormone by small cell lung cancer in
a patient with hypercalcemia. J Clin Endocrinol Metab
1989;68:976–81.
www.jcomjournal.com
58. Iguchi H, Miyagi C, Tomita K, et al. Hypercalcemia caused
by ectopic production of parathyroid hormone in a patient
with papillary adenocarcinoma of the thyroid gland. J Clin
Endocrinol Metab 1998;83:2653–7.
59. Kandil E, Noureldine S, Khalek MA, et al. Ectopic secretion of parathyroid hormone in a neuroendocrine tumor: a
case report and review of the literature. Int J Clin Exp Med
2011;4:234–40.
60. El-Hajj Fuleihan G, Health HI. Familial benign hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
In: Bilezikian JP, Marcus R, Levine MA, editors. The parathyroids: basic and clinical concepts. San Diego: Academic
Press; 2001: 607.
61. Christensen SE, Nissen PH, Vestergaard P, et al. Discriminative power of three indices of renal calcium excretion for
the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on
methods. Clin Endocrinol 2008;69:713–20.
62. Middler S, Pak CY, Murad F, Bartter FC. Thiazide diuretics
and calcium metabolism. Metabolism: clinical and experimental 1973;22:139–46.
63. Bazzini C, Vezzoli V, Sironi C, et al. Thiazide-sensitive
NaCl-cotransporter in the intestine: possible role of hydrochlorothiazide in the intestinal Ca2+ uptake. J Biol Chem
2005;280:19902–10.
64. Wermers RA, Kearns AE, Jenkins GD, Melton LJ 3rd.
Incidence and clinical spectrum of thiazide-associated hypercalcemia. Am J Med 2007;120:911 e9–15.
65. Mallette LE, Eichhorn E. Effects of lithium carbonate on human calcium metabolism. Arch Intern Med
1986;146:770–6.
66. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary
reference intakes for calcium and vitamin d. dietary reference intakes. Washington, DC: The National Academies
Press; 2011.
67. Martinez I, Saracho R, Montenegro J, Llach F. The importance of dietary calcium and phosphorous in the secondary
hyperparathyroidism of patients with early renal failure. Am
J Kidney Dis 1997;29:496–502.
68. K/DOQI clinical practice guidelines for bone metabolism
and disease in chronic kidney disease. Am J Kidney Dis
2003;42:S1–201.
69. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney diseasemineral and bone disorder (CKD-MBD). Kidney Intl Suppl
2009:S1–130.
70. Hansen S, Hauge EM, Rasmussen L, et al. Parathyroidectomy improves bone geometry and microarchitecture in
female patients with primary hyperparathyroidism: a oneyear prospective controlled study using high-resolution peripheral quantitative computed tomography. J Bone Miner
Res 2012;27:1150–8.
71. Udelsman R, Pasieka JL, Sturgeon C, et al. Surgery for
asymptomatic primary hyperparathyroidism: proceedings of
the third international workshop. J Clin Endocrinol Metab
2009;94:366–72.
72. Udelsman R, Lin Z, Donovan P. The superiority of mini-
Vol. 20, No. 4 April 2013 JCOM 191
Primary hyperparathyroidism
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
mally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surgery 2011;253:585–91.
Kunstman JW, Udelsman R. Superiority of minimally invasive parathyroidectomy. Adv Surgery 2012;46:171–89.
Chen H, Pruhs Z, Starling JR, Mack E. Intraoperative
parathyroid hormone testing improves cure rates in patients
undergoing minimally invasive parathyroidectomy. Surgery
2005;138:583–97.
Wells SA Jr, Farndon JR, Dale JK, et al. Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surgery 1980;192:451–8.
Cohen MS, Dilley WG, Wells SA Jr, et al. Long-term functionality of cryopreserved parathyroid autografts: a 13-year
prospective analysis. Surgery 2005;138:1033–40.
Van Husen R, Kim LT. Accuracy of surgeon-performed
ultrasound in parathyroid localization. World J Surgery
2004;28:1122–6.
Civelek AC, Ozalp E, Donovan P, Udelsman R. Prospective
evaluation of delayed technetium-99m sestamibi SPECT
scintigraphy for preoperative localization of primary hyperparathyroidism. Surgery 2002;131:149–57.
Udelsman R, Donovan PI. Remedial parathyroid surgery:
changing trends in 130 consecutive cases. Ann Surgery
2006;244:471–9.
Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the
management of asymptomatic primary hyperparathyroidism: summary statement from the Third International
Workshop. J Clin Endocrinol Metab 2009;94:335–9.
Grey A, Lucas J, Horne A, et al. Vitamin D repletion in
patients with primary hyperparathyroidism and coexistent vitamin D insufficiency. J Clin Endocrinol Metab
2005;90:2122–6.
Tucci JR. Vitamin D therapy in patients with primary hyperparathyroidism and hypovitaminosis D. Eur J Endocrinol 2009;161:189–93.
Grubbs EG, Rafeeq S, Jimenez C, et al. Preoperative vitamin D replacement therapy in primary hyperparathyroidism: safe and beneficial? Surgery 2008;144:852-8.
Isidro ML, Ruano B. Biochemical effects of calcifediol
supplementation in mild, asymptomatic, hyperparathyroidism with concomitant vitamin D deficiency. Endocrine
2009;36:305–10.
Nemeth EF, Steffey ME, Hammerland LG, et al. Calcimimetics with potent and selective activity on the parathyroid
calcium receptor. Proceedings of the National Academy of
Sciences of the United States of America 1998;95:4040–5.
Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet
hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol
Metab 2005;90:135–41.
87. Peacock M, Bolognese MA, Borofsky M, et al. Cinacalcet
treatment of primary hyperparathyroidism: biochemical and
bone densitometric outcomes in a five-year study. J Clin
Endocrinol Metab 2009;94:4860–7.
88. Marcus R, Madvig P, Crim M, et al. Conjugated estrogens
in the treatment of postmenopausal women with hyperparathyroidism. Ann Intern Med 1984;100:633–40.
89. Selby PL, Peacock M. Ethinyl estradiol and norethindrone
in the treatment of primary hyperparathyroidism in postmenopausal women. N Engl J Med 1986;314:1481–5.
90. Grey AB, Stapleton JP, Evans MC, et al. Effect of hormone replacement therapy on bone mineral density in
postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. Ann Intern Med
1996;125:360–8.
91. Diamond T, Ng AT, Levy S, et al. Estrogen replacement
may be an alternative to parathyroid surgery for the treatment of osteoporosis in elderly postmenopausal women
presenting with primary hyperparathyroidism: a preliminary
report. Osteopor Intl 1996;6:329–33.
92. Guo CY, Thomas WE, al-Dehaimi AW, et al. Longitudinal
changes in bone mineral density and bone turnover in
postmenopausal women with primary hyperparathyroidism.
J Clin Endocrinol Metab 1996;81:3487–91.
93. Zanchetta JR, Bogado CE. Raloxifene reverses bone loss in
postmenopausal women with mild asymptomatic primary
hyperparathyroidism. J Bone Miner Res 2001;16:189–90.
94. Rubin MR, Lee KH, McMahon DJ, Silverberg SJ. Raloxifene lowers serum calcium and markers of bone turnover in
postmenopausal women with primary hyperparathyroidism.
J Clin Endocrinol Metab 2003;88:1174–8.
95. Khan AA, Bilezikian JP, Kung AW, et al. Alendronate in
primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab
2004;89:3319–25.
96. Rossini M, Gatti D, Isaia G, et al. Effects of oral alendronate in elderly patients with osteoporosis and mild primary
hyperparathyroidism. J Bone Miner Res 2001;16:113–9.
97. Chow CC, Chan WB, Li JK, et al. Oral alendronate increases bone mineral density in postmenopausal women
with primary hyperparathyroidism. J Clin Endocrinol
Metab 2003;88:581–7.
98. 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.
99. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency:
an Endocrine Society clinical practice guideline. J Clin
Endocrinol Metab 2011;96:1911–30.
Copyright 2013 by Turner White Communications Inc., Wayne, PA. All rights reserved.
192 JCOM April 2013 Vol. 20, No. 4
www.jcomjournal.com