Endocrinology: Disorders of Calcium Homeostasis

Physiology of calcium, PTH and vitamin D metabolism

Serum calcium is tightly regulated and is predominantly under the control of vitamin D and parathyroid hormone
(PTH). The normal range is 2.2–2.6 mmol/L. It is important to understand the physiology of calcium metabolism to interpret abnormalities of serum calcium, vitamin D, phosphate and PTH in disease.

Parathyroid hormone

PTH is a peptide hormone secreted by the four parathyroid glands, situated behind the thyroid. Because of their
embryological origin, the parathyroids may be in an ectopic position such as in the thymus within the chest. PTH increases calcium absorption from the gut and kidney, and increases renal phosphate loss (Figure 15.1). High PTH levels are associated with low phosphate, and vice versa. Calcium-sensing receptors (Ca-SR) are situated on parathyroid and renal cell membranes. Hypocalcaemia increases PTH secretion, while hypercalcaemia suppresses PTH secretion via stimulation and inhibition of the Ca-SR, respectively. PTH increases osteoclastic bone resorption and synthesis of vitamin D (Figure 15.1).

Vitamin D

Vitamin D is synthesised by the skin in response to sunlight. Its chemical structure is similar to that of a steroid hormone, acting on nuclear receptors. Cholecalciferol, the precursor to vitamin D, undergoes 1-hydroxylation in the liver, and 25-hydroxylation in the kidney to produce active 1-25 di-hydroxy-cholecalciferol (Figure 15.1). The native form of vitamin D is vitamin D3. Vitamin D2 is derived synthetically from fungi and is less potent than D3. The action of vitamin D is to increase absorption of calcium in the gut and kidney, both directly and in concert with PTH.

Vitamin D deficiency

Vitamin D deficiency is very common in clinical practice. Risk factors include lack of sunlight, pigmented skin, religious
covering of skin and dietary deficiency (Figure 15.2a). Elderly and housebound patients are particularly at risk, as are patients with chronic kidney disease or malabsorption. In the UK, there is only sufficient sunlight between May and September to produce adequate vitamin D. Dietary sources include oily fish, cod liver oil, margarine and egg yolk. Pregnancy is a major drain on vitamin D so it is important for young women in at risk groups to replenish vitamin D levels prior to conception. Vitamin D deficiency causes de-mineralisation of bone. Unlike osteoporosis, which refers to brittle bones that fracture easily (Chapter 18), vitamin D deficiency leads to soft malleable bone. The clinical manifestations depend on whether presentation is in childhood or adulthood (Figure 15.2b).

Childhood presentation

The earliest clinical manifestation of vitamin D deficiency is neonatal hypocalcaemia. This can develop with neonatal tetany and seizures, and is a paediatric emergency requiring immediate correction with intravenous calcium. When the child becomes a toddler and stands up, bowing of the tibia can occur, which is a classic sign of rickets.

Adult presentation

Increasingly, vitamin D insufficiency is detected during routine investigation of non-specific symptoms. Vitamin D deficiency causes lethargy, low mood and alopecia, but these symptoms are also common in the healthy population. Increasingly, vitamin D deficiency is detected as part of the investigation of a raised PTH level. Severe vitamin D deficiency leads to osteomalacia. De-mineralised bone can lead to pseudo-fractures on X-ray (Looser zones). Neuromuscular dysfunction is common in osteomalacia, particularly in the gluteal muscles, leading to a waddling gait.
Severe osteomalacia can cause hypocalcaemia (Chapter 16).

Investigation

Vitamin D is measured by immunoassay or mass spectrometry, which measure total vitamin D levels Figure 15.2. Vitamin D levels are classified as deficient (<30 nmol/L), insufficient (30– 50 nmol/L) or adequate (>50 nmol/L). Bone health is at risk in patients with persistently low levels. Severe vitamin D deficiency causes metabolic bone disease, characterised by elevated alkaline phosphatase, hypocalcaemia and low phosphate due to secondary hyperparathyroidism. Plain X-ray can reveal Looser zones, and a bone isotope scan can show hotspots in areas of
increased metabolic activity.

Treatment

Management includes reversal of risk factors, increased dietary intake, correction of hypocalcaemia and vitamin D replacement Figure 15.2. The treatment aim is to replenish vitamin D to >50 nmol/L and improve symptoms. The maintenance replacement dose is 1000–2000 IU/day cholecalciferol. In profound vitamin D deficiency, 20 000 IU/week may be given for 7 weeks as a loading dose. Vitamin D toxicity is rare and it is not necessary to repeat serum vitamin D levels. Calcium should be re-checked several months after starting treatment as replacement can unmask primary hyperparathyroidism. There is a key role for healthcare professionals in educating at risk groups to reverse the increasing prevalence of severe vitamin D deficiency.

Hypercalcaemia

Hypercalcaemia occurs when serum calcium rises above 2.6 mmol/L. The most common causes are primary hyperparathyroidism and malignancy. The hallmark of hypercalcaemia of malignancy is a low PTH level, while primary hyperparathyroidism is typically associated with a normal or high PTH (Figure 16.1).

Hypercalcaemia with suppressed PTH

Malignancy must be excluded in all cases of hypercalcaemia where PTH is suppressed. Malignant causes of hypercalcaemia are usually associated with squamous cell epithelial tumours resulting from the secretion of PTH-related peptide (Figure 16.1). Hypercalcaemia of malignancy occurs in large or advanced tumours, and bony metastases are not always present. Hypercalcaemia with a low PTH can also be seen in benign granulomatous disease such as TB or sarcoidosis (Figure 16.1).

Hypercalcaemia with non-suppressed PTH

When PTH is elevated or in the upper part of the normal range, malignancy is unlikely. The usual cause is primary
hyperparathyroidism (Figure 16.1) which is usually caused by a single parathyroid adenoma. Parathyroid hyperplasia in more than one gland suggests a genetic cause (e.g. MEN; Chapter 14). A very high serum calcium (>3.5 mmol/L) with a large parathyroid tumour indicates parathyroid cancer but this is exceptionally rare. Parathyroid cancer may occur rarely in association with jaw tumours (hyperparathyroidism–jaw tumour syndrome).

Clinical features

Primary hyperparathyroidism is often asymptomatic and discovered incidentally during routine blood tests. Nonspecific
symptoms include tiredness, and generalised aches and pains. Specific symptoms include polyuria and polydipisa,
due to nephrogenic diabetes insipidus. Other symptoms are abdominal pain and constipation. Frank psychiatric symptoms may be present in the elderly. Nephrocalcinosis and renal calculi occur in about 5% of patients. Long-standing disease can give rise to metabolic bone disease, which can have a classic cystic appearance on X-ray (brown tumours) due to osteoclastic activity, and should not be confused with primary bone neoplasms.

Investigation

The hallmark of primary hyperparathyroidism is hypercalcaemia in the presence of high or non-suppressed PTH.
PTH can be in the upper part of the normal range in mild disease. Low phosphate is usually present as a result of the
phosphaturic effect of PTH. High alkaline phosphatase (ALP) reflects increased bone turnover and is common in patients with coexisting vitamin D deficiency. PTH may be very high due to both primary and secondary hyperparathyroidism in such patients. Bone density may be reduced, especially at the distal radius. Renal ultrasound may show nephrocalcinosis. Sub-periosteal erosion of the phalanges can be present in severe disease (Figure 16.2b).

Familial hypocalciuric hypercalcaemia

The main differential diagnosis of hypercalcaemia with nonsuppressed PTH is familial hypocalciuric hypercalcaemia
(FHH). This rare condition is caused by a genetic defect in the calcium sensing receptor. It is distinguished from primary
hyperparathyroidism by demonstration of a low urine calcium : creatinine ratio. In FHH there is usually a family
history of mild hypercalcaemia. It is important to exclude FHH before sending a patient for an unnecessary neck exploration.

Localisation of parathyroid adenoma

If parathyroid surgery is planned, the adenoma should be localised. This can be difficult if the lesion if small. In experienced hands, parathyroid ultrasound will detect an adenoma in 70–90% of cases, although this technique is highly operator-dependent. Sestamibi isotope scanning is often used alongside ultrasound, while other techniques in use in some centres include singlephoton emission CT (SPECT), CT/MRI and 4-D CT.

Treatment of hyperparathyroidism

calcium level. Surgery should be considered if serum calcium is 2.85 mmol/L and/or if symptoms are debilitating. In elderly patients with primary hyperparathyroidism, hypercalcaemia often worsens during intercurrent illness and simple rehydration can improve levels. Long-term complications of primary hyperparathyroidism include osteoporosis and nephrocalcinosis, hence these may be indications for surgery. Young patients and those with severe acute hypercalcaemia are also usually recommended for surgery.

Parathyroid surgery

Parathyroidectomy should always be performed by an experienced surgeon. Minimally invasive approaches are used, and many centres now use intra-operative PTH assay to confirm successful removal of the parathyroid adenoma. The aim of surgery is to normalise serum calcium and reverse symptoms. Complications of parathyroid surgery include infection, bleeding and recurrent laryngeal nerve palsy, which is usually temporary. In patients with severe hypercalcaemia, postoperative hypocalcaemia can occur, termed ‘hungry bone syndrome’. In patients with ectopic
parathyroid adenoma, thoracotomy may be required. In four-gland hyperplasia (e.g. MEN-1), total parathyroidectomy may be necessary followed by lifelong vitamin D and calcium replacement.

Non-surgical approaches

Medical management or simple observation can be an alternative for those patients unable to undergo surgery. Prevention of dehydration and treatment of osteoporosis with bisphosphonates is a common approach. Calcimimetic drugs (e.g. cinacalcet) are effective in lowering calcium in primary hyperparathyroidism but do not have an effect on bone mineral density. They act on the calcium sensing receptor to reduce PTH.

Acute severe hypercalcaemia

This is a medical emergency. Patients present with profound dehydration and renal impairment, requiring urgent treatment and consideration of the cause (Chapter 40).

Hypocalcaemia

Hypocalcaemia is less common than hypercalcaemia. Symptomatic hypocalcaemia occurs when serum calcium is
<1.9 mmol/L, or at higher values if there is a rapid drop in calcium. The most common cause of hypocalcaemia is post-surgical hypoparathyroidism following thyroidectomy.

Causes

Post-surgical hypoparathyroidism

Post-thyroidectomy hypocalcaemia is often temporary, but can be permanent because of damage to or inadvertent removal of the parathyroid glands. Long-term follow-up is needed to assess recovery of parathyroid function.

Non-surgical hypoparathyroidism

A low serum calcium with low PTH presenting in adulthood suggests idiopathic or autoimmune hypoparathyroidism. This can accompany polyglandular autoimmune syndrome. In children, congenital hypoparathyroidism should be considered; for example, Di George’s syndrome is a rare condition associated with hypoparathyroidism, immunodeficiency and cardiac defects resulting from developmental failure of the third and fourth branchial arches.

Vitamin D deficiency

Severe vitamin D deficiency causes hypocalcaemia and should be considered in high-risk groups. In the neonate, severe
vitamin D deficiency can present with seizures and tetany caused by hypocalcaemia. Typically, phosphate is low in
vitamin D deficiency because of elevated PTH levels, unlike hypoparathyroidism where phosphate is high.

Hypomagnesaemia

Hypomagnesaemia causes functional hypoparathyroidism, with normal or low PTH levels. Common causes of low magnesium include gastrointestinal loss, alcohol and drugs, particularly proton pump inhibitors.

Hyperphosphataemia

High phosphate levels lead to hypocalcaemia by increased binding of free calcium. Causes include chronic kidney disease and phosphate administration.

Miscellaneous causes

Other causes of hypocalcaemia include cytotoxic drugs, pancreatitis, rhabdomyolysis and large volume drug transfusions (Figure 17.1).

Clinical features

Symptoms

Acute severe hypocalcaemia causes laryngospasm, prolonged QT interval and seizures, and is a medical emergency (Chapter 41). However, hypocalcaemia usually presents less acutely with muscle cramps, carpopedal spasm, peri-oral and peripheral paraesthesia, and neuropsychiatric symptoms.

Signs

Patients may have a positive Chvostek’s sign (facial spasm when the cheek is tapped gently with the finger) or
Trousseau’s sign (carpopedal spasm induced after inflation of a sphygmomanometer).

Investigation

Renal function, phosphate, vitamin D and PTH should be measured when the cause of hypocalcaemia is not clear
(Figure 17.1). Hypocalcaemia associated with high phosphate and low PTH suggests hypoparathyroidism. Hypocalcaemia associated with low phosphate and high PTH is in keeping with vitamin D deficiency and secondary hyperparathyroidism (Figure 17.1). Demonstration of low vitamin D levels confirms a suspected diagnosis of severe deficiency. Magnesium deficiency should be excluded in refractory or unexplained hypocalcaemia.
Parathyroid antibody levels should be checked in non-surgical hypoparathyroidism to exclude an autoimmune cause. In chronic hypoparathyroidism, brain imaging can reveal basal ganglia calcification, caused by high phosphate binding to calcium within tissues.

Treatment

Calcium replacement is the mainstay of therapy. It is important to consider and reverse the underlying cause. Acute hypocalcaemia can be life-threatening and requires urgent treatment with intravenous calcium.

Vitamin D deficiency

Patients with severe vitamin D deficiency should be given a loading dose of cholecalciferol. A dose of 20,000 IU/week is given for 7 weeks followed by a maintenance dose of 1000–2000 IU/week.

Hypoparathyroidism

Hypoparathyroidism is treated with alfa-hydroxylated derivates of vitamin D (e.g. 1-alfacalcidol or calcitriol). These have a shorter half-life than cholecalciferol and should not be used in simple vitamin D deficiency. The typical starting dose is 0.25 μg/ day 1-alfacalcidol, with dose titration according to clinical and biochemical responses. Oral calcium supplements (e.g. Sandocal and Adcal D3) are given in combination with alfacalcidol. The aim of treatment is to keep calcium levels at the lower end of the reference range to reduce the risk of nephrocalcinosis.

Magnesium deficiency

In the acute situation, precipitating drugs should be stopped and IV magnesium replacement started. This is usually given as MgSO4 24 mmol/24 hours. If chronic gastrointestinal loss or alcohol ingestion is the cause, appropriate specialist input is indicated to prevent recurrent symptoms.

Pseudo-hypoparathyroidism

This rare condition is caused by a mutation in the GS alpha subunit (GNAS1) which is coupled to the PTH receptor and
leads to PTH resistance. It is characterised by hypocalcaemia and a high phosphate level, which would normally suggest
hypoparathyroidism, but high PTH and normal vitamin D levels suggests PTH resistance rather than deficiency, hence the term pseudo-hypoparathyroidsm. Patients have a syndromic appearance with short stature, round face and short 4th and 5th metacarpals. Peripheral resistance to TSH and gonadotrophins can also be seen in this rare condition.

Osteoporosis

Osteoporosis is characterised by reduced bone mass and increased bone fragility. It is very common in postmenopausal
females. Up to one in three women over 80 years have an osteoporotic hip fracture. Fragility fractures also occur
in the spine and distal radius. Osteoporosis, defined according to T score, occurs when bone density is >2.5 standard deviations below normal peak bone mass (T ≤2.5). When the T score is between –1 and –2.5, patients are classified as osteopenic (or borderline osteoporosis).

Causes

Primary osteoporosis

This is multifactorial, usually resulting from a combination of oestrogen deficiency and ageing. Osteoporosis is commonly familial so genetic factors are important. Vitamin D deficiency, smoking and alcohol are significant.

Secondary osteoporosis

This suggests a potentially reversible cause of osteoporosis. It should be considered when osteoporosis occurs in non-‘at risk’ groups including men and pre-menopausal women. Endocrine causes of secondary osteoporosis include hyperthyroidism, hyperparathyroidism, Cushing’s syndrome, hypogonadism and hyperprolactinaemia. Exogenous steroids commonly cause osteoporosis (Figure 18.1b).

Clinical features

Osteoporosis only causes symptoms when a fracture occurs. Typically, osteoporotic fractures occur after minimal trauma, termed low fragility fractures (Figure 18.1b). Hip fractures usually occur following a fall, leading to severe pain and a shortened externally rotated leg on examination. The 6-month mortality following a hip fracture is up to 20% because of associated frailty and co-morbidities. Vertebral fractures occur spontaneously or following lifting, leading to sudden onset of severe back pain at the level of the fracture. Vertebral wedge fractures can cause loss of vertical height and kyphosis. Falling on the outstretched hand can cause fracture of the distal radius (Colles’ fracture).

Investigation

A basic screen for secondary osteoporosis includes full blood count (FBC), liver function tests (LFTs), calcium, phosphate,
ALP and thyroid function (Figure 18.1c). Bone densitometry, measured by dual energy X-ray absorptiometry (DXA) scan;
Figure 18.2, is the mainstay of diagnosis. However, many elderly inpatients have clear osteoporosis on plain X-ray, and do not require a DXA scan if they have had a low trauma fracture. Biochemical markers of bone resorption and formation are not useful in establishing the diagnosis.

Assessing fracture risk

Clinical risk prediction of fracture is a better guide to treatment than DXA scanning alone. Algorithms exist to calculate the 10-year fracture risk. An example is the FRAX score, which takes into account age, sex, weight, height, previous fracture, parent with fractured hip, smoking, treatment with glucocorticoids, the presence of rheumatoid arthritis, alcohol intake, the presence of secondary osteoporosis and bone density.

Treatment

Non-pharmacological treatment

Lifestyle measures include adequate calcium and vitamin D intake, exercise, smoking cessation, falls prevention and
avoidance of excessive alcohol intake (Figure 18.1d). Supplements of 500–1000 mg calcium/day and 800–1000 IU vitamin D are recommended. Weight-bearing exercise for at least 30 minutes three times per week reduces the risk of osteoporosis. Avoidance of drugs that cause osteoporosis is important, particularly corticosteroids.

Pharmacological treatment

Drug treatments for osteoporosis predominantly act by inhibiting osteoclastic bone resorption, termed anti-resorptive
agents. Some drugs increase osteoblastic bone formation, such as parathyroid hormone.

Bisphosphonates

These are used first line, and are given once a week or less often. The main side effects are gastrointestinal, typically oesophagitis. They should therefore be taken with fluid while sitting upright for 30–60 minutes. Intravenous bisphosphonates are options if gastrointestinal side effects are intolerable. Long-term use can cause long bone mid-shaft fractures and osteonecrosis of the jaw. Although the risk is small, a drug holiday is recommended after
several years.

Monoclonal antibodies

Denosumab is a monoclonal antibody that binds to RANK ligand, which is essential for osteoclastic bone resorption. This reduction in bone resorption improves bone density and treatment should be considered in patients with severe osteoporosis who cannot tolerate bisphosphonates.

Parathyroid hormone

PTH (teriparatide) stimulates bone formation and activates remodelling of bone. It is expensive and only used in patients with severe osteoporosis who are unable to tolerate, or who have contraindications to bisphosphonates, or who do not respond to other treatment.

Hormone replacement therapy

HRT in peri-menopausal women can prevent or delay osteoporosis. HRT is particularly useful when women have other significant vasomotor symptoms. The pros and cons of HRT should be discussed with the patient because of the small increased risk of thrombotic disease and oestrogen-sensitive tumours.

Other agents

Strontium ranelate has weak anti-resorptive activity and can be used as an alternative in elderly patients who cannot tolerate bisphosphonates. Calcitonin has a small effect in reducing fractures, but the evidence base is limited and it is not commonly used in clinical practice.