Maturitas 70 (2011) 246255

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Maturitas
j our nal homepage: www. el sevi er . com/ l ocat e/ mat ur i t as
Review
Primary hyperparathyroidism: Skeletal and non-skeletal effects, diagnosis and
management
Ronald Pyram
a,b
, Geeti Mahajan
a,b
, Agnieszka Gliwa
a,
a
Division of Endocrinology SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, United States
b
Division of Endocrinology Brooklyn VA Medical Center, Brooklyn, NY, United States
a r t i c l e i n f o
Article history:
Received 20 July 2011
Accepted 22 July 2011
Keywords:
Primary hyperparathyroidism PHTP
Osteoporosis
Hypercalcemia
Hypercalciuria
Cardiovascular diseases
Neuro-psychiatric symptoms
a b s t r a c t
Primary hyperparathyroidism (PHPT) is the third most common endocrinopathy seen today, and is most
frequently found in the 6th to 7th decade of life. PHPT can present with various degrees of symptoms,
and can affect many organ systems, including the skeletal, renal, central nervous system and cardiovas-
cular system. Despite this, the most common presentation of hyperparathyroidism is asymptomatic
with the diagnosis being made incidentally with the initial nding of hypercalcemia on routine labora-
tory studies, leading to further investigation. Surgical versus medical management is usually based on
factors such as age and complications related to hyperparathyroidism (i.e. the presence of renal stones,
renal insufciency and bone loss and signicant increases in serum calcium). Treatment options include
parathyroidectomy, bisphosphonates, calcitonin and calcimimetics.
In this review, we discuss primary hyperparathyroidism in detail with a focus on clinical manifes-
tations particularly in the elderly population. We highlight the indications for surgical versus medical
management and compare some of the uses of newer therapeutic agents relative to traditional ones.
2011 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
2. Denition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
3. Epidemiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
4. Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
5. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
6. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
7. Clinical manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
7.1. Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
7.2. Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
7.3. Effect of PTH on cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.3.1. Cardiac function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.3.2. Hypertension and vascular smooth muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.4. Neuropsychiatric system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.4.1. Quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.4.2. Cognitive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
7.4.3. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
7.5. Bone and mineral metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
8. Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
8.1. Surgical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
8.2. Medical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
8.2.1. The guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

Corresponding author. Tel.: +1 347 8346050.

E-mail address: agnes.gliwa@downstate.edu (A. Gliwa).
0378-5122/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2011.07.021
R. Pyramet al. / Maturitas 70 (2011) 246255 247
8.2.2. Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
8.2.3. Cinacalcet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
8.3. Vitamin D replacement in PHPT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Competing interests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
1. Introduction
Primary hyperparathyroidismis a common endocrine disorder
of the6thto7thdecadeof life. Recent researchreveals that parathy-
roid hormone (PTH), besides its well described effect on mineral
metabolism and bone, also affects different organs, including the
nervous and cardiovascular system. In this article, we will review
the current data on the clinical implication of asymptomatic
hyperparathyroidism, its presentation and management.
2. Denition
Primary hyperparathyroidismis due toincreasedintrinsic activ-
ity of the parathyroid gland, altering the secretion of parathyroid
hormone, in the absence of a known or recognized stimulus (affect-
ing calciumhomeostasis).
3. Epidemiology
Primary hyperparathyroidism (PHPT) is the 3rd most common
endocrine disorder after diabetes and thyroid disorders. It is the
most commoncauseof hypercalcemia intheoutpatient population,
and along with malignancy associated hypercalcemia accounts for
over 90% cases of hypercalcemia. This disorder affects 1 in 500
women and 1 in 2000 men >40 years of age, with a peak incidence
in post menopausal women (5060 years) [1].
The prevalence depends on populations studied and the
detection methods used. Biochemical screening established the
prevalence at 1 per 1000 (USA). An estimation of the true incidence
is difcult, but overall gures (UK, USA, and Sweden) are consistent
with 27 and 30 per 100,000 person-years [13]. The introduction of
the automated serumcalciummeasurement was associated with a
dramatic increase in early 1970s (19741982 annual rate was 82.5
per 100,000), with a progressive decline in the incidence thereafter
[1].
In sporadic cases, primary hyperparathyroidism results from
a single enlarged gland (adenoma) in 8085 percent cases, usu-
ally involving the lower pole of the gland and tends to consist of
chief cells. Multiple gland hyperplasia accounts for approximately
1015 percent, double adenomas for an additional 25 percent
and parathyroid carcinoma for about 1 percent of cases of pri-
mary hyperparathyroidism [4,5]. In heritable disorders, primary
hyperparathyroidism is more frequently associated with multi-
ple abnormal parathyroid glands and a higher risk of persistent or
recurrent disease [6].
4. Physiology
Calcium homeostasis relies in large part on the actions of
parathyroid hormone (PTH). PTH is an 84 amino acid polypeptide
that is secreted solely fromthe parathyroid gland. It acts primarily
onbone andkidneys via PTHreceptors. Serumcalcium, phosphorus
and Vitamin D metabolites help to regulate release of PTH [8] and
are summarized in Fig. 1. PTH release is almost immediate in the
setting of hypocalcemia, reaching peak levels within410min with
an apparent half-life of 3min [9]. Approximately 99% of total body
calciumis located in bone [9], and is the major reservoir for reple-
tion of serumcalciumdecits. Movement of calciumin and out of
the body is regulated by the intestines and kidneys while move-
ment of calciumbetween extracellular uid and bone is regulated
mainly by bone itself [7]. PTH that is secreted into the circulation
acts primarily on the PTH1R receptors (a G protein-coupled recep-
tor that responds to both PTH and PTHrP) located throughout the
kidneys and bone [11]. PTHrP is an important calcium regulating
hormone during fetal development. In the mid-1990s, it was dis-
covered that in bone, PTH stimulates PTH1 receptor activator of
nuclear factor kB ligand (RANKL) on the osteoblasts which in turn,
promotes osteoclast differentiation and increased osteoclast activ-
ity, promotingbone resorptionof calcium, further increasingserum
calciumlevels [10].
In the kidney, PTH acts on the PTH1R receptors located on the
renal tubules which acts to increase reabsorption of calcium from
urine, mostly inthe thick ascending loopof Henle anddistal tubules
[10,11].
Furthermore, PTH acts on the kidneys to stimulate the release
of alpha-hydroxylase, an enzyme that converts 25 hydroxyvita-
min D, to the more active form of 1,25 hydroxyvitamin D. 1,25
hydroxyvitamin D contributes to calciumhomeostasis by enhanc-
ing the absorption of calcium in the intestine from dietary intake
Fig. 1. Secretion of PTH is controlled mainly by serum calcium through negative
feedback. The G-protein coupled calciumsensing receptors located on parathyroid
cells are activatedwhenextracellular calciumis low. Whereas elevatedextracellular
calciumresults in activation of the Gq G-protein coupled cascade via phospholipase
C (PLC). This signaling inhibits the secretion of preformed PTH from storage gran-
ules in the parathyroid gland. PTH functions to raise calcium via bone resorption
and renal calciumreabsorption. In the kidney, it also stimulates the metabolismof
Vitamin D to its active hormonal form, 1,25(OH)Vitamin D which in turn enhances
calcium absorption from the gut. PTH also inhibits renal phosphate reabsorption
Excessive PTH (in hyperparathyroidism), breaks the feedback loops.
248 R. Pyramet al. / Maturitas 70 (2011) 246255
[10,11]. Also, 1,25 hydroxyvitamin D further increases serum cal-
ciumlevels by increasing the production of osteoclasts fromstem
cells [13].
In 1993, Brown et al. [7,119] discovered calciumsensing recep-
tors (CaSR), which are G protein-coupled receptor made up of
1078 amino acid residues [7,12] and are located on various tissues,
including parathyroid, thyroidal C cells, intestines, bone and kid-
neys. These receptors respond mostly to Ca++ stimulus but can also
respond to Type 1 agonists as di- or tri- valent cations (i.e. magne-
siumor gadolinium, or other positively charged organic molecules)
and Type 2 agonists (includes various l-amino acids; yet requires
some level of Ca++) as well. Activation of the CaSR located on the
parathyroid by ionized Ca++ inhibits PTH secretion [7,10] and this
principle underlies the targeted calcimimetic treatment to lower
serumPTH in hyperparathyroidism.
CaSRs are located throughout the nephron. In the proximal con-
voluted tubule, the CaSR are partially responsible for excretion of
inorganic phosphate, and according to some studies, may in part,
helptoregulatethesynthesis andactions of 1,25hydroxyvitaminD.
In the thick ascending loop on Henle and distal convoluted tubules,
CaSRs may help in regulating calciumabsorption and excretion in
hypercalcemic states as well [7].
In bone, recent evidence shows expression of CaSRs on osteo-
clast precursors and mature cells as well as in preosteoblasts and
osteoblasts. Especially in preosteoblasts, CaSR has mitogenic prop-
erties and upon stimulation may promote cellular differentiation
and enhance bone formation [7]. As a result, high calcium levels
promote formation of bone while inhibiting bone resorption in the
normal circumstance (Fig. 2).
5. Etiology
Abnormalities in key controlling genes, protooncogenes or
tumor suppressor genes are responsible for the development of
parathyroid tumors.
2040 percent of sporadic parathyroid adenomas over express
cyclinD1 [1417], resulting inparathyroid cell proliferation. Trans-
genic mice in which cyclin D1 was over expressed had parathy-
roid cell proliferation and abnormal control of PTH secretion
[1819].
The MEN1 gene is a tumor suppressor gene also associated with
sporadic nonfamilial parathyroid adenomas. Somatic inactivating
mutation in the MEN1 gene was found in 1213 percent subjects
with true sporadic tumors [2021].
Familial hyperparathyroidismis associatedwithgainof function
of RET mutations similar to those in MEN 2A or 2B.
HRPT2 gene inactivating mutations have been described
in familial hyperparathyroidism, the hyperparathyroidism-jaw
tumor syndrome and associated with an increased risk of parathy-
roid cancer [22].
Hereditary forms of hyperparathyroidism are rare. Primary
hyperparathyroidism is the earliest and most common manifes-
tation of MEN1 (80100 percent) with mutation in MEN-1 gene
(menin) present with hypercalcemia by 40 years of age.
In contrast, primary hyperparathyroidism is associated only in
20 percent with MEN 2A, generally less severe, with inherited
mutation of RET proto-oncogene.
Radiationexposure. Ina retrospective analysis of patients treated
with radiation for tuberculous adenitis, risk of developing an ade-
noma was almost zero at doses below 300rad, but exceeded 50
percent at doses above 1200rad [23].
Irradiation for acne could have accounted for a 23 fold increase
indisease anda 4-foldincrease was notedinatomic bombsurvivors
[24,25].
Table 1
Clinical manifestation of hypercalcemia.
Cardiovascular
Arrythmia
Hypertension
EKG abnormalities: prolongation of QT interval
Gastroenterological
Pancreatitis
Peptic ulcer disease
Abnormal peristalsis: constipation
Nausea, vomiting
Renal
Nephrolithiasis
Nephocalcinosis
Tubular injury: distal renal tubuar acidosis, polyuria, nephrogenic DI
Acute or chronic renal failure
Neuro-psychiatric
Confusion
Fatigue
Stupor, coma
Cognitive: decreased concentration and ability to learn
Depression
Anxiety
Muscle-skeletal
Osteoporosis and osteopenia
Muscle weakness
Body pain
Present doses of radioactive iodine for thyrotoxicosis do not
increase the incidence of primary hyperparathyroidism[26].
6. Diagnosis
Primary hyperparathyroidism is diagnosed with elevation of
parathyroid hormone (PTH) (or lack of suppression) in the context
of hypercalcemia. Single elevations of serumcalciumlevel, should
be conrmed by repeating the test and corrected for any factors
that may inuence serumcalciummeasurement (e.g. serumalbu-
min level, acid-base status)[27]. PTH in human is a peptide of 84
aminoacids (184 PTH). The standard measurement of parathyroid
hormone (PTH) is the intact PTH (iPTH) immunoassay, which is
very specic for 1-84 PTH. This assay can also interact with other
truncated fragments of non-184 PTH(e.g. 784 PTH) in 2060% of
cases. This is clinically relevant mostly in dialysis patients, when
attempting to establish the diagnosis of PHPT, in whom PTH may
thus be falsely elevated [28]. Also, Familial Hypocalciuric Hyper-
calcemia (also known as FHH) must be ruled out. In FHH there is a
loss-of-functional mutation of the calcium-sensing receptor on the
parathyroid cells. Reecting this physiological change, the urinary
fractional calciumexcretionis usually less than0.1inFHH, whereas
in PHPT, it is greater than 0.2 [120]. The clinical importance of dis-
tinguishing these entities is that PHPT is usually treated whereas
hypercalcemia is usually mild in FHH and requires no specic
treatment as it is not associated with complications. Furthermore,
parathyroidectomy does not alter this mild hypercalcemia.
To localize a parathyroid adenoma, Sestimibi scanning can be
used. Adenomas appear as an increased area of uptake following a
washout of 99mTc-sestamibi. False-negatives are not infrequent
and are more common with multigland hyperplasia. A negative
scan is not a reason to not seek a surgical referral.
7. Clinical manifestations
7.1. Clinical presentation
The most common presentation of PHPT today is asymptomatic
hypercalemia, found routinely on blood test. The symptoms can
range fromnonspecic calciumhomeostasis disturbances to acute
presentation of hypercalcemia crisis (Table 1). In the past renal
R. Pyramet al. / Maturitas 70 (2011) 246255 249
Fig. 2. Left-hand panel (Ref [108]). Upper panel: pre-dose serum Ca, PTH, and BMD (meanSE) over time during the 4 year on the trial. Fasting samples were taken
approximately 12h after the prior evening dose of placebo or cinacalcet. (A) Serum Ca. The shaded region represents the normal reference range. (B) Plasma PTH. Lower
panel: the shaded region represents the normal reference range. (C) Total femur. (D) Lumbar spine. (E) Distal one third radius. The number of subjects (N) during each year
of the study are shown for the failed parathyroidectomy groups (closed circles), indicated for parathyroidectomy groups (opencircles), and asymptomatic groups (open
squares). BL, baseline. *P<0.05; **P<0.01; ***P<0.0001 compared with baseline (Wilcoxon signed ranks). Right-hand panel Ref. [104]: upper panel: serumcalciumand PTH
level (meanSE) in postmenopausal women with PHP receiving alendronate or placebo over 48 weeks. Serumcalciumwas albumin adjusted. Change in serumcalciumwas
signicantly different (P=0.036), whereas change in PTHwas not signicantly different (P=0.110) at 48 weeks. Lower panel: mean (SE) changes in BMD frombaseline-line
values in postmenopausal women with PHP receiving alendronate or placebo over 48 weeks. Data are shown for BMD (measured by dual energy X-ray absorptiometry) at
the femoral neck, spine, and distal forearm. Treatment was withdrawn at week 48. *P<0.05 between two groups.
stones, osteoporosis, and diffuse symptoms of hypercalcemia such
as acute pancreatitis, peptic ulcer were the classic and com-
mon presentation [29,30], but with the use of more sensitive
serum calcium assays, and more routinely prescribed biochem-
istry screening, this is a very rare presentation today. Out of all
of these classical complications, nephrolithiasis is the most com-
mon today and seen in up 20% [3133] of hyperparathyroid cases.
This change in the clinical spectrum over the last several decades
have grown to include patients with minimal objective symptoms.
These patients have been referred to as asymptomatic. Despite
this, as manypatients may suffer fromminimal objectivesymptoms
such as fatigue, constipation, polyuria, hypertension and neuro-
psychiatric complications. If PHPT is untreated for long periods,
it leads to deterioration of the bone mineral density (BMD) and
increased risk of fracture [8790]. It is worth mentioning that clin-
ical presentations and the degree of hypercalcemia differ between
different geographic areas and may in part be explained by dif-
ferences in endemic vitamin D nutrition [3436]. The degree of
hypercalcemia may be less pronounced, but the combined effect
on mineral metabolism, bone mass and stone formation may be
more evident in combination of PHPT and vitamin D deciency
[35,36].
7.2. Survival
Symptomatic PHPT has been linked with increase mortality of
all causes [3740]. In recent years, however, more research has
focused on the effect of asymptomatic PHPT on other organs espe-
cially the cardiovascular system. It has been reported that patients
suffering from chronic hyperparathyroidism are more likely to
have higher all-cause mortality with a standardized mortality
ratio of 2.62 [41]. The leading cause of this increased mortality in
PHPT is cardiovascular followed by malignancy [41,42] as found in
large cohort European studies [39,41,42]. In contrast, this was not
reportedinNorthernAmericanpopulations [43]. EvenmildPTHhas
been reported to be associated with cardiovascular and metabolic
abnormalities including diabetes mellitus, hypertension, renal dis-
eases [41,42]. It is still unclear whether hypercalcemia, PTH or the
calcium/phosphate product contributes to the worse outcomes in
patients with PHPT. Elevated serum calcium itself correlated neg-
atively with survival in a 25 year case control followup study [40].
One large cohort study [37] revealed that PHPT itself (its duration
and severity) was a risk factor in increased mortality. The effect
is thought to be related to impaired renal function, which is not
always detected by the serumcreatinine level. In this study, other
250 R. Pyramet al. / Maturitas 70 (2011) 246255
independent risk factors contributing to mortality in PHPT were
age, sex, diabetes, underlying cardiovascular disease, and weight of
the diseased parathyroid removed at surgery [37]. During the Third
International Workshop on asymptomatic PHPT, it was indicated
that the PTH level may be a risk factor for death [34].
7.3. Effect of PTH on cardiovascular system
Cardiovascular (CVD) complications are associated with
increased mortality among PHPT patients. Reported abnormali-
ties include: hypertension, disturbances in the pressor hormones
system, cardiac arrhythmias, metabolic abnormalities as well as
structural and functional alterations in the cardiac and vascular
wall. These include diastolic dysfunction, LVH, changes in endothe-
lial function as well as increased vascular stiffness [4451].
7.3.1. Cardiac function
Abnormal cardiac function, both systolic and diastolic, have
been identied across the spectrum of disease severity in hyper-
parathyroidism, although its causality and reversibility in mild
disease is controversial [5256]. Therefore current guidelines do
not include CVD complications as an indication for parathyroid
surgery. It is difcult to draw rm conclusions since most data is
derived from cohort studies which did not exclude pre-existing
CVD risk factors. Studies which included healthy subjects with
PHPT without preexisting CVD risk factors, showed no improve-
ment of cardiac function after parathyroidectomy [55,57]. The
severity of the PHPT seems to play an important role in the inci-
dence of cardiac complications [56,57] and is consistent with
data on survival [41]. PTH and calcium both have direct positive
inotropic effects on the myocardium [57,58]. Patients with mild
PHPT without any other known cardiovascular risk factors have a
higher systolic myocardial performance at baseline, which seems
to be associated with the level of PTH and Ca
++
. Theoretically, such
a chronic inotropic effect might promote cardiac hypertrophy and
explain the apparent paradox of increase mortality in PHPT. Also
duration of the disease seems to inuence the CVD morbidity and
reversibility of the disease, suggesting early surgical intervention
might be curative in the mild or early stage of the disease, prior to
the occurrence of irreversible structural cardiac changes [59].
7.3.2. Hypertension and vascular smooth muscle
Hypertension (HTN) has long been associated with PHPT and is
more prevalent in patients with PHPT than in the general popula-
tion [60,61,72].
Large observational studies have linked elevated blood PTHlev-
els to elevations in blood pressure. [62]. The effect initially was
thought tobepurelytheresult of elevatedPTH, but recent data from
NHANES revealed independent associations between low vitamin
D, high PTH and hypertension [63].
The underlying mechanismof PHPT on HTN is not fully under-
stood. PTH binds to PTH/PTHrp endothelium receptor on vascular
smooth muscle cells, which activates the cAMP and reduces Ca
inux in vitro settings [6466]. This is believed to have vasodilat-
ing effect on vasculature in a physiological state. However, in the
hyperparathyroid state the response of the endothelium to PTH
may be altered explaining the paradox of elevated BP in PHPT.
Several studies showeddecreasedendothelium-dependent vasodi-
lation in patients with PHPT [67,68], which was reversed after
parathyroid surgery however, this was not conrmed by other
studies [69]. Of note, most of the studies did not exclude subjects
with preexisting CVD risk factors such as essential hypertension
and smoking, which may contribute to discordant results.
Another possible explanation for causal relation between PHPT
and HTN, could be its effect on regulating hormones. Although
the inverse association of vitamin D on the renin-angiotensin-
aldosterone system is well established, a few small studies have
reported only a weak effect of PTH on the renin-angiotensin-
aldosterone system, and the topic remains open for debate
[51,70,71].
Gennari showed elevated pressor hormones and vascular
responsetoepinephrineas well as freecytosolic calciuminplatelets
of hypertensive PHPT patients as compared to normotensive PHPT
and control patients [51]. The authors also found reversibility of
these changes seen with parathyroidectomy.
In aggregate, these studies suggest that the vascular response
to PHPT may depend on the underlying state of the vasculature.
Whether this is a result of longstanding HTNleading to irreversible
vascular changes is not known.
Thus, the question whether there is any causal relationship
between HTN and PHPT remains unanswered and controversial as
thereversibilityof HTNbyparathyroidectomycanbedemonstrated
in only 50% of patients [7274]. Therefore, current guidelines do
not recommend parathyroidectomy for treatment of HTN in PHPT
patients.
7.4. Neuropsychiatric system
Severe hypercalcemia may result in psychosis, confusion, coma
even death. In recent decades, however, research has focused on
emotional or cognitive aspect of asymptomatic PHPT. Neuro-
psychiatric symptoms are mostly vague and nonspecic, particular
inelderlypatients, suchas asthenia, anxiety, depression, irritability,
mood swings, amnestic and cognitive disturbances. The prevalence
of the symptoms may be as high as 12%[75], and is higher in elderly
patients. It is still controversial whether PHPT with mild hypercal-
cemia is a cause of such symptoms and whether neuropsychiatric
symptoms should be included into criteria for medical/surgical
intervention.
7.4.1. Quality of life
Several prospective case-controlled, including some random-
ized studies were conducted in PHPT patients who underwent
parathyroidectomy to assess quality of life changes. Most of this
workwas done by Pasieka et al. [76,77]. He developeda parathyroid
assessment of symptoms (PAS) questionnaireconsistingof 13items
which included physical, emotional and pain symptoms to assess
changes in PHPT patients. In his 2002 multi-center prospective
study, Pasieka [77] evaluated the impact of parathyroidectomy on
QOL in 203 patients and showed that parathyroidectomy improved
overall scores of QOL and reduced symptoms of PHPT. Another
structured questionnaire, the Medical Outcomes Short Form36 of
QOL (SF-36), consisting of 8 domains of health status and function
(general health, physical function, physical role limitation, mental
health, emotional role limitation, social function, bodily pain, and
energy/fatigue) demonstratedimprovement inmost or all domains
after parathyroidectomy, in both symptomatic and asymptomatic
patients independently of serum calcium level [7880]. Recently,
Mihai et al. [81] comparedthese2questionnairescores (PASandSF-
36) in 101 patients who underwent parathyroidectomy and found
that both correlated well with one another. Thus, the authors con-
cluded that the PAS (a simpler system) should be used as a tool to
assess changes in QOL and as a possible indicator for symptomatic
disease and a reason for parathyroidectomy.
7.4.2. Cognitive function
Improvement has also been shown for neurocognitive symp-
toms in post-parathyroidectomy patients in several studies some
of which revealed improvement of cognitive function in elderly
patients. Using structured psychological testing, the ability to
concentrate under stress and retentiveness, was studied in 20
patient who underwent parathyroidectomy at 6 and 12 months
R. Pyramet al. / Maturitas 70 (2011) 246255 251
after surgery [82]. Patients concentration and ability to memo-
rize numbers improved signicantly post-operatively. In another
prospective trial [83], 41 patients who underwent parathyroid
surgery showed improvement in their learning efciency.
7.4.3. Depression
Wilhelm et al. [83] concluded a 1-year cost-effectiveness of
parathyroidectomy in patients with depression. He retrospectively
analyzed 360 patients who underwent parathyroidectomy using
DSM-IV-R diagnostic criteria for depression. More than a half of
those with pre-op depression showed improvement in their QOL
and 54% reduced or discontinued their anti-depressive medica-
tions.
In conclusion, in recent decades, there is growing evidence that
PHPT is associated with neuro-psychiatric changes. Parathyroidec-
tomy showed modest improvement in these symptoms in small
studies. This raises the question whether neuro-psychiatric evalu-
ation should be implemented into the assessment of symptomatic
disease andtobe one of the indications for surgical or medical treat-
ment for thecondition. Larger prospectivestudies areneededinthis
area.
7.5. Bone and mineral metabolism
Bone and mineral metabolismsymptoms in PHPT have changed
over last decades in developed countries fromclassic symptoms of
osteitis brosa cystica and kidney stones to a disease with none
to few symptoms. As mentioned earlier, of all the classic presen-
tations, nephrolithiasis is the most common nowadays and may
complicate up to 20% of the PHPT cases [3133]. However, even in
asymptomatic disease the endogenous excess of PTH increases
bone turnover leading to an insidious reversible loss of cortical
(forearm and femur) and trabecular bone (axial skeleton, verte-
brae/pelvis) [83]. Quantitative histomorphometric studies from
illiac crest biopsies from PHPT patients after intravital double-
labelling with tetracycline have revealed a 50%60% increase in
bone turnover leading to increased extension of resorption [8688]
at the endosteal surface.
Most studies reported decreased bone mineral density (BMD)
in PHPT, in both symptomatic and asymptomatic patients [8994].
The initial studies indicated that bone loss occurred mostly in the
cortical bone while sparing the trabecular bone [92]. In contrast, a
very recent prospective study of 36 PHPT female patients, assessing
volumetric bone mineral density [95] with peripheral quantitative
computed tomography, revealed negative effect of excess PTH on
both bone types.
Parathyroidectomy has been shown to halt bone deterioration,
improve BMD and reduce risk of fracture in patients with PHPT
[9698].
In a well designed study by Rao et al. [97], 216 patients with
PHPT were observed (108 who underwent parathyroidectomy and
108whodidnot) for 52months and47months, respectively. Cessa-
tion of bone loss was demonstrated (using DEXA scanning) among
the patients who underwent surgery, with corresponding Z-scores
became signicantly less negative over the observational period. In
the longest follow-up study of bone density (15 years) DXA scan-
ning showed that in asymptomatic PHPT 37% of patients showed
progression at any point [99] Interestingly, having surgical crite-
ria at baseline was not predictive of progression of one loss. In
a 2006 retrospective study by VanderWalde et al. [96] of a large
population database, patients with PHPT who underwent parathy-
roidectomy compared with those who did not had reduced risk of
fracture regardless of age, calcium, or parathyroid hormone level.
A large cohort study [98], reported an increased risk of fracture in
both cortical (forearm HR: 4.0) and trabercular (vertebra HR: 3.5)
bone in 674 patients with PHPT (median age 61) followed at least
10 years prior to and 10 years after parathyroidectomy. The risk
of fracture returned to normal after surgery. Based on these and
other evidence, the most recent guidelines in 2009 recommended
parathyroidectomy for patients with T-score less (2.5) on BMD at
any location and/or previous fracture fragility [34].
8. Therapy
With the advent of automated screening for calcium and large
increase in asymptomatic, often older patients, the question of
what constitutes optimal treatment arises. Several long-term and
other studies informed an expert panel, The Third International
Workshop on the Management of Asymptomatic Primary Hyper-
thyroidism, which published revised guidelines for surgical and
medical treatment in 2009 [34].
8.1. Surgical management
Inpatients withPHPT who have any one of the following criteria
should undergo surgical management in order to prevent progres-
sion.

Serumcalcium>1.0mg/dl (0.25mmol/l).

A reduction in CrCl <60ml/min.

T-score <2.5 at any site on BMD and/or previous fracture

fragility.

Age <50 years.

- Surgery may also be indicated in patients whose medical surveil-
lance is neither desired nor possible.
- Some physicians still use the older indication of 24h calcium
excretion of >400mg as an indication for surgery; however, it has
lost favor because it is only one of many factors that play a role
in renal stone formation. In addition, although those with stones
do tend to have elevated calciumexcretion, patients with higher
urinary calciumwithout stones have not been shown to be asso-
ciated with stone formation. Lastly, other mitigating factors that
play a role in calciumexcretion include age, sex, race, diet, renal
functionandvitaminDlevel, hence, making the arbitrary number
of 400mg of little value [34,110].
8.2. Medical management
8.2.1. The guidelines
For patients who do not undergo surgery, in the absence of clear
and compelling empirical evidence, the most recent recommended
guidelines for follow-up of patients includes:

Annual serumcalcium.

Annual serumcreatinine.

Bone density every 12 years (three sites).

Of interest is a recent report that among the elderly with clear
criteria for surgical treatment, the likelihood of parathyroidectomy
decreased linearly with age [110].
Among the PHPT patients who are not candidates for surgery,
the onlyapprovedmedical therapyis calcimimetic drugs. The use of
252 R. Pyramet al. / Maturitas 70 (2011) 246255
Table 2
SerumCalcium SerumPhosph Bone turnover markers SerumPTH BMD Fracture Frequency
Medical therapy
Bisphosphonates
*Alendronate Not sig Not sig Not sig
*Pamidronate Acute transient
*Zolendronic acid
Calcitonin
Calcimimetic 20%
SERMS
Estrogen
Surgical therapy
Parathyroidectomy
bisphosphonates, estrogens and SERMS (Selective Estrogen Recep-
tor Modulators) arenot currentlyapprovedfor asymptomatic PHPT.
Bisphosphanates are frequently used and this practice is supported
by several clinical trials. As withmost acute hypercalcemia, bispho-
sphonates are also effective in PHPT. Table 2 shows the effect of
surgical and medical treatment on key clinical markers on calcium
and bone metabolism.
8.2.2. Bisphosphonates
Bisphosphonates are potent inhibitors of bone resorption and
may be useful in long-termcontrol of osteopenia in asymptomatic
PHPT. Since a high percentage of patients are post menopausal
women, treatment targeting improvement in bone mineral density
should be considered.
Intravenous (iv) pamidronatecauses anacutetransient decrease
in calcium, urine calcium and bone turnover indicators; however,
an increase in parathyroid hormone and 1,25-dihydroxyvitamin D
follows, which can restrict effectiveness [100]. An improved func-
tional independence measure was noted in elderly patients after iv
pamidronate [101].
Oral alendronate is promising as seen in four studies including
119 postmenopausal women and 24 men treated up to 2 years,
which reported signicant increase in lumbar spine and femoral
neck bone mineral density, with no substantial change in radial
bone mineral density [102105]. There was no signicant effect
on serum calcium and urinary calcium but signicant decrease in
parathyroid hormone and bone turnover markers.
In one study a fall in urine deoxypyridinoline was seen
within the rst month of treatment, while a fall in serum
alkaline phosphatase and osteocalcin became signicant only
after 3 months of treatment; thereafter all other bone turnover
markers remained consistently suppressed for duration of
treatment [102].
Also notedinanother study was lower serumbone specic alka-
line phosphatase activity, a decrease in osteocalcin and urinary
N-telopeptide. These markers of bone turnover increased 24 weeks
after treatment was withdrawn [104].
However, there has been no documentation of benet of bis-
phosphonate therapy as being sustained and accompanied by a
decrease in fracture incidence.
The effect of prior bisphosphonate therapy on post-surgical
bonemineral densityimprovement is unknown. Sinceboneremod-
eling is necessary, bisphosphonates which decrease bone turnover,
may prevent post-parathyroidectomy increase in bone mass as
noted in observational and randomized trials.
Hence, the widespread use of bisphosphonates in patients with
primary hyperparathyroidism may not be optimal in candidates
for surgery. However bisphophonates may be used in patients who
do not meet the criteria for surgery, are unwilling to have, or are
unsuitable for surgery.
8.2.3. Cinacalcet
One of the newest targeted medical treatment options, cinacal-
cet, was recently approved by the US FDA (2011) and the European
EMA (2008) for the treatment of primary hyperparathyroidism.
Cinacalcet is a calcimimetic, that acts onthe calcium-sensingrecep-
tors expressed on the parathyroid cells and sensitizes them to
extracellular calcium. This results in decreased serum PTH levels,
which consequently leads to a decrease in serum calcium levels
[106,107].
Calcimimetics can cause modest reductions in PTHlevels (about
20%), as well as stabilization of normocalcemia, it does not appear
to have a signicant impact on BMD [106109]. Thus, in patients
with normal BMD, cinacalcet can be a good medical therapy to
reduce PTH and calciumlevels, reducing the risk of other possible
complications associated with primary hyperparathyroidism.
8.3. Vitamin D replacement in PHPT
Vitamin D deciency is more common in PHPT than in general
population, especially in frail elderly patients [111,112]. Current
guidelines recommend measurement and replacement of vita-
min D if the pre-parathyroidectomy vitamin D level is less than
20ng/ml (50nmol/l) [34]. The major complication of low vitamin
D levels after parathyroidectomy is hypocalcemia due to hungry
bone syndrome[113]. Although most of the physicians supple-
ment vitamin D prior to parathyroidectomy surgery, the safety of
this practice is not known. Several small studies on patients with
mild hypercalcemia (less than 12mg/dl or 3.0mol/l) showed that
supplementation of vitamin D in PHPT patients is safe and did not
cause signicant worsening of hypercalcemia [114118], evenwith
use of high doses of vitamin D (50,000IU). Some studies showed
improvement in bone density in PHPT patients [114], however
other did not [115,116]. The potential risk of replacing vitamin D
includes hypercalciuria [115,117]. There are no prospective ran-
domized studies, conrming that supplementation of vitamin D
is safe and effective in patients with PHPT, especially elderly
patients.
9. Conclusions
There is ample evidence that excessive parathyroid secretion
has a negative effect on multiple tissues of the body in addition
to the traditional targets of bone and kidney [121]. Hyperparathy-
roidism is associated with higher mortality due to cardiovascular
and possibly oncologic and has neuropsychiatric complications.
The full extent of PHPTs effect on the cardiovascular systemis not
known. There seems to be strong evidence that PHPT has a neg-
ative effect on quality of life (QOL), especially in the elderly. QOL
questionnaires should be considered part of the clinical evaluation
on these patients. More studies on cardiovascular and neuropsy-
chiatric evaluation should be conducted.
R. Pyramet al. / Maturitas 70 (2011) 246255 253
The diagnosis of PHPT is fairly straightforward although it is
imperative to identify FHH in which surgery is not indicated. Due
to the increase in prevalence and mostly asymptomatic presenta-
tion especially in the elderly, evidence and expert opinion-based
national guidelines for surgical treatment have been developed.
Patients who are not surgical candidates can be treated medically
with targeted therapy such as calcimimetics and adequate hydra-
tion. Bisphosphonates, although used clinically in asymptomatic
PHPT and supported by clinical studies showing benet for bone
densityarenot approvedfor usebyregulatoryagencies or theInter-
national expert panels [34]. Vitamin D replacement in the context
of PHPT should be undertaken cautiously.
Contributors
All authors contributed equally to this manuscript.
Competing interests
No competing interests.
Provenance and peer review
Commissioned and externally peer reviewed.
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