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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intron 4 mutation in multiple endocrine neoplasia type 1. J Clin

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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

parafibromin, is mutated in hyperparathyroidismejaw tumor

syndrome. Nat Genet 2002; 32: 676e80.

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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.