CALCIUM AND BONE
Hypercalcaemia and primaryhyperparathyroidismJeremy Turner
AbstractHypercalcaemia is most commonly caused by primary hyperparathyroidism
(PHPT) or malignancy. PHPT is common, affects more females than males,
and is usually due to a solitary parathyroid adenoma. The usual presenta-
tion now is asymptomatic and incidentally picked up on blood testing. The
only curative treatment is parathyroidectomy. In 2009 the Third Interna-
tional Workshop on the Management of Asymptomatic Primary Hyperpara-
thyroidism updated their guidance on management of asymptomatic PHPT.
They recommend surgery in: all symptomatic patients; asymptomatic
patients with hypercalcaemia greater than 0.25 mmol/litre above the
upper limit of reference range, evidence of end-organ damage, including
impaired renal function, and reduced bone mineral density; and patients
under 50 years old in whom disease is more likely to progress. In other
patients, conservative management is an acceptable management strategy
so long as they can be monitored regularly. However, defining ‘asymptom-
atic’ is not always clear and there is growing awareness of the prevalence of
reduced quality-of-life scores among patients with asymptomatic PHPT.
Therefore, careful clinical decision-making is required in this group of
patients.Medicalmanagement of PHPTis generally unsatisfactory although
there is some evidence that alendronate may increase bone mineral density
in PHPT and there are preliminary data supporting a possible role for the
calcimimetic, cinacalcet.
Keywords cinacalcet; conservative management; hypercalcaemia;
primary hyperparathyroidism; parathyroidectomy
Of the numerous causes of hypercalcaemia, primary hyperpara-
thyroidism (PHPT) is the most common in outpatient settings
and malignancy is most common in inpatients. Other causes of
hypercalcaemia include:
� tertiary hyperparathyroidism
� thyrotoxicosis
� Addison’s disease
� milkealkali syndrome
� sarcoidosis
� rarely, Paget’s disease of bone.
PHPT is characterized by hypercalcaemia with elevated or
inappropriately normal levels of parathyroid hormone (PTH) and
elevated urinary calcium. The prevalence is 1e3/1000. It is more
common in females (3:1) and most commonly presents after the
age of 50 years. Hypercalcaemia due to other causes is
distinguished from PHPT by reduced PTH levels.
Jeremy Turner DPhil MRCP is Consultant Endocrinologist at the Norfolk
and Norwich University Hospitals, Norwich, UK. Competing interests:
none declared.
MEDICINE 37:9 46
Aetiology
PHPT is caused by a solitary adenoma in 80e85% of cases. The
remaining 15e20% arise as a result of multiple adenomas or
four-gland hyperplasia. Carcinoma of the parathyroid gland is
a very rare cause of PHPT (<0.5%). PHPT is usually sporadic,
but may be associated with inherited syndromes, most
commonly multiple endocrine neoplasia (MEN) type 1 and type
2a.1 In MEN1, 90e95% of patients develop PHPT by the age of 50
years, the condition being associated with pancreatic endocrine
tumours (30e80%) and pituitary adenomas (15e50%). In
MEN2a, 10e25% have mild parathyroid hyperplasia, associated
with medullary thyroid carcinoma (100%) and phaeochromo-
cytoma (50%). Other rare forms of PHPT include familial
isolated hyperparathyroidism2 and hyperparathyroidismejaw
tumour syndrome.3 The latter comprises fibro-osseous tumours
of the jaw associated with renal cysts or Wilms’ tumour. These
inherited forms tend to present at a younger age.
Clinical features
Presentation of PHPT has changed since the introduction of
multichannel autoanalysers. Most patients (75e80%) are now
asymptomatic at diagnosis, with serum calcium less than 0.25
mmol/litre above the reference range.
Symptomatic patients typically have plasma calcium levels of
3 mmol/litre or more, and may present with general features of
hypercalcaemia with or without features of end-organ damage.
Symptoms of hypercalcaemia include polyuria, polydipsia and
renal colic (if stones have formed). Other features traditionally
associated with PHPT include depression, peptic ulcer disease
and generalized aches and pains (‘moans, bones, stones and
groans’), but these are common in the general population and it
is unclear whether they are causally related to PHPT. Some
reports have linked asymptomatic PHPT to reduced quality-
of-life scores but this does not consistently improve after para-
thyroidectomy.4,5 There is also an association of PHPT with
hypertension. Features of end-organ damage include
What’s new?
C In 2009, the Third International Workshop on the Management
of Asymptomatic Primary Hyperparathryroidism updated
guidelines on which groups of patients with asymptomatic
PHPT should undergo parathyroidectomy
C In 2005, the American Association of Clinical Endocrinologists
and the American Association of Endocrine Surgeons published
a position statement on the diagnosis and management of
primary hyperparathyroidism which essentially supports the
‘Guidelines for the Management of Asymptomatic Primary
Hyperparathyroidism: Summary Statement from the Third
International Workshop Guidance’ but emphasizes the role for
clinical judgement when assessing the risks and benefits of
parathyroidectomy in the ‘no indication for surgery’ group.
C The calcimimetic, cinacalcet, has been licensed for use in
secondary hyperparathyroidism in chronic renal disease and in
parathyroid carcinoma.
1 � 2009 Elsevier Ltd. All rights reserved.
CALCIUM AND BONE
osteoporosis, osteitis fibrosa cystica, nephrolithiasis and neph-
rocalcinosis. Classical skeletal changes (Brown tumours, osteitis
fibrosa cystica) occur in fewer than 2% of patients, but osteo-
porosis is a common feature of hyperparathyroidism and
predominantly affects cortical bone (e.g. distal radius) more than
trabecular bone (e.g. vertebral bodies).
Diagnosis and investigations
Elevated or inappropriately ‘normal’ PTH with elevated serum
calcium (corrected for serum albumin concentration) is almost
diagnostic of PHPT (see Figure 1). The exception is the rare
condition, familial hypocalciuric hypercalcaemia (FHH), which
can mimic the serum biochemistry of PHPT and is distinguishable
only on urine biochemistry. FHH is an autosomal dominant
condition caused by inactivating mutations in the calcium-sensing
receptor gene. There is mild resistance of the parathyroid cells to
calcium, and reduced capacity of the kidneys to up-regulate renal
calcium excretion. This results in a modest increase in serum
calcium with an inappropriately normal PTH concentration (slight
elevation in 5e10% of patients).
The calcium:creatinine clearance ratio is used to distinguish
PHPT from FHH. This ratio is calculated from simultaneous
measurements of urine and serum calcium and creatinine
concentrations, using the following formula:
calcium clearance/creatinine clearance ¼ urine calcium �plasma creatinine/plasma calcium � urine creatinine
MEDICINE 37:9 4
The plasma concentration must be converted to the same
units as the other parameters (mmol/litre). The ratio is less than
0.01 in FHH and more than 0.01 in PHPT.
Elevated PTH with normal calcium, so-called normocalcaemic
hyperparathyroidism, is an increasingly common biochemical
finding which, after causes of secondary hyperparathyroidism
such as vitamin D deficiency and renal disease have been
excluded, may represent ‘early’ PHPT before calcium levels have
had time to rise. However, its natural history is thus far poorly
described and no authoritative guidelines on its management yet
exist. Clearly, regular monitoring of such patients is a sensible
approach.
Management
Surgery is the only curative treatment for PHPT, but is not
appropriate in all patients; the potential benefits must be
weighed against the risks in each case. This process has been
simplified by the publication of guidelines from the Third Inter-
national Workshop on the Management of Asymptomatic
Primary Hyperparathryroidism (Table 1). However, these
guidelines do not apply in the familial PHPT syndromes
described above.
Surgery
Surgery is indicated in all symptomatic patients and asymptom-
atic patients with evidence of end-organ damage, specifically:
Investigation of hypercalcaemia
PTH, parathyroid hormone
Malignancy (most common in hospital setting)
Multiple myeloma
Bony metastases
Humoral hypercalcaemia
Sarcoidosis (high levels of 1,25-dihydroxyvitamin D lead to increased
gastrointestinal calcium absorption) and other granulomatous disease
Vitamin D toxicity
Milk–alkali syndrome
Addison’s disease
High-turnover bone disease with immobilization
• Paget’s disease
• Thyrotoxicosis
Vitamin A toxicity
High calcium (on two occasions)
Ensure no drug causes (e.g. thiazides, lithium)
Normal renal function
Check PTH
Normal High
< 0.01 > 0.01
Familial
hypocalciuric
hypercalcaemia
Primary
hyperparathyroidism
Low
Measure calcium:creatinine clearance ratio
Figure 1 Suggested algorithm for investigation of hypercalcaemia.
62 � 2009 Elsevier Ltd. All rights reserved.
CALCIUM AND BONE
� impaired renal function
� age <50 years (in a prospective study of conservatively
managed patients with PHPT followed over 10 years, the
disease progressed in only 27% of those with asymptomatic
PHPT; most of those who progressed were <50 years of age,
and age was the only predictive index)
� reduced bone mineral density (BMD), T score <�2.5. Results
post-surgery show an increase in BMD. Whether this trans-
lates into reduced fracture risk has, until recently, not been
clear. However, one report showed that parathyroidectomy
was associated with 10-year fracture-free survival of 73% as
compared to 59% in those managed conservatively.6
Choice of surgery: the standard operation has been full neck
exploration, with identification of all four glands. However,
minimally invasive surgery is now performed in some centres, if
technetium sestamibi scanning (Figure 2) and ultrasonography
2009 Third International Workshop on the Managementof Asymptomatic Primary Hyperparathryroidism guide-lines
Indications for surgery in primary hyperparathyroidism
Symptomatic
Asymptomatic
C Serum calcium >0.25 mmol/litre above upper limit of normal
C Creatinine clearance reduced to <60 ml/min
C Bone mineral density T score <�2.5 at any site and/or previous
fragility fracture
C Age <50 years
C Patients in whom medical surveillance is not practical or desired
Follow-up of primary hyperparathyroidism managed conservativelyC Serum calcium: annually
C Serum creatinine: annually
C Bone mineral density: 1e2-yearly (hip, spine, forearm)
Table 1
Figure 2 Technetium sestamibi scan showing right lower parathyroid
adenoma. (By courtesy of Dr J Frank, Charing Cross Hospital, London, UK.)
MEDICINE 37:9 46
show an adenoma in the same location (i.e. are ‘concordant’).
The location can be marked on the skin and surgery performed
under local anaesthetic. Patients in whom imaging is non-
concordant, who have multi-gland disease or who have under-
gone surgery before are generally not candidates for minimally
invasive surgery.
Recurrent PHPT and cases complicated by ectopic parathyroid
adenoma (mediastinal, intrathyroid, lateral neck and retro-
oesophageal) require more extensive preoperative imaging that
may include magnetic resonance imaging, computed tomog-
raphy, angiography and selective venous sampling.
Patients with four-gland hyperplasia are treated with subtotal
or total parathyroidectomy, followed by medical treatment for
hypoparathyroidism. Total parathyroidectomy and surgical re-
implantation of parathyroid tissue in the forearm is an alternative
still practised in some centres.
Complications: postoperative transient hypoparathyroidism may
develop in up to 70% of patients, as a consequence of suppres-
sion of the remaining glands. This usually resolves within 1 week
and may require oral calcium supplements plus 1a-hydroxylated
vitamin D metabolites. More severe hypocalcaemia may arise
from ‘hungry bones’; it occurs in patients with pre-existing bone
disease and may require intravenous calcium to correct the
hypocalcaemia. Permanent hypoparathyroidism is rare (<2%).
These patients require life-long calcium supplements and
1a-hydroxylated vitamin D metabolites.
Medical management
In patients with hyperparathyroidism who have only moderately
elevated calcium, general advice includes ensuring adequate
fluid intake and normal dietary calcium (1000e1200 mg/day)
and vitamin D (400e800 IU/day) intake, and avoiding thiazide
diuretics. Regular monitoring with annual serum calcium,
annual creatinine and 1e2-yearly BMD measurements is rec-
ommended (Table 1). About 25% of PHPT patients managed
conservatively for 10 years develop an indication for surgery; the
rest remain well. However, fracture risk may be higher in this
group6 and operation appears to reduce this. Accordingly, in
recent years there has been a shift of emphasis in the literature
favouring parathyroidectomy in an increasing proportion of such
cases.
Patients with severe hyperparathyroidism with symptomatic
hypercalcaemia require large volumes of intravenous fluid (e.g.
0.9% normal saline, 3e6 litres over the first 24 hours) to stabilize
calcium levels. Once the patient is adequately hydrated, a loop
diuretic may be added to encourage calciuresis. Administration of
intravenous bisphosphonate (e.g. pamidronate, 30e90 mg) results
in a decline in plasma calcium over 3e5 days, but is not normally
necessary if the patient has been fully rehydrated and should be
avoided if surgery is imminent because bisphosphonates can lead
to profound postoperative hypocalcaemia.
Antiresorptive agents in PHPT managed conservatively:
studies of alendronate in PHPT show an increase in BMD at 2
years in the lumbar spine, with lesser gains at the hip and radius.
Studies of the selective oestrogen receptor modulator, raloxifene,
suggest a beneficial effect on BMD and reduced calcium and bone
turnover, with no effect on PTH.
3 � 2009 Elsevier Ltd. All rights reserved.
CALCIUM AND BONE
Calcimimetic agents in PHPT managed conservatively: cina-
calcet is a calcimimetic agent that increases the sensitivity of
calcium-sensing receptors to extracellular calcium, thereby
directly reducing PTH secretion. It is licensed for the manage-
ment of secondary hyperparathyroidism in renal disease and for
the management of hypercalcaemia in parathyroid carcinoma. A
study in PHPT showed reduced calcium and PTH, but no change
in BMD at 12 months.7 A
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2 Pannett AA, Kennedy AM, Turner JJ, et al. Multiple endocrine neoplasia
type 1 (MEN1) germline mutations in familial isolated primary hyper-
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3 Carpten JD, Robbins CM, Villablanca A, et al. HRPT2, encoding
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MEDICINE 37:9 46
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FURTHER READING
AACE/AAES Task Force on Primary Hyperparathyroidism. The American
Association of Clinical Endocrinologists and The American Associa-
tion of Endocrine Surgeons position statement on the diagnosis and
management of primary hyperparathyroidism. Endocr Pract 2005; 11:
49e54.
Bilezikian JP, Brandi ML, Rubin M, et al. Primary hyperparathyroidism: new
concepts in clinical, densitometric and biochemical features. J Intern
Med 2005; 257: 6e17.
Bilezikian JP, Khan AA, Potts JT, et al. Guidelines for the management of
asymptomatic primary hyperparathyroidism: summary statement
from the third international workshop. J Clin Endocrinol Metab
2009; 94: 335e9.
4 � 2009 Elsevier Ltd. All rights reserved.