Bone Profile Interpretation

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Introduction

A bone profile is a commonly ordered blood test and includes:

  • Serum calcium
  • Serum phosphate
  • Serum albumin
  • Alkaline phosphatase (ALP)

This guide gives an overview of the tests included in a bone profileΒ and aΒ structured approach to bone profile interpretation.


Why request a bone profile?

A bone profile can be requested for many reasons:

  • To diagnose and monitor disorders of the bone (e.g. osteomalacia, Paget’s disease, bony metastases)
  • To diagnose and monitor cases of hypocalcaemia or hypercalcaemia
  • To investigate otherwise unexplained symptoms, such as fatigue or pain
You might also be interested in our collection of 800+ OSCE Stations that cover clinical examination, procedures, communication skills and data interpretation.

Reference ranges

Table 1. Bone profile reference ranges

Test Reference range
Calcium (total / corrected) 2.2 – 2.6 mmol/L
Phosphate 0.8 – 1.5 mmol/L
Albumin 35-50 g/L
Alkaline phosphatase (ALP) 30-130 IU/L
Corrected calcium

Around 40% of calcium is bound to albumin in the bloodstream, and in this form, it is physiologically inactive.1 The remaining 60% is known as ionised or β€˜free’ calcium, which is physiologicallyΒ active.

In severe hypoalbuminaemia, the total calcium level may appear normal, yet ionised (β€˜free’) calcium levels (which are physiologically active) can be markedly increased due to decreased albumin binding. Conversely, if serum albumin levels are raised, the total calcium level may be high, but the serum ionised calcium level may be normal due to increased albumin binding.

Therefore, most laboratories report a β€˜corrected calcium’ alongside total calcium, in which the serum calcium level is adjusted for the serum albumin level.


Calcium

Ionised calcium (Ca2+) plays a crucial role in many bodily functions, including:

  • Bone formation and turnover
  • Muscle contraction (including myocardial function)
  • Blood coagulation

Disruptions in calcium homeostasis can thus cause extensive physiological disturbance.

Calcium homeostasis

Three main processes determine serum calcium level: intestinal absorption, renal excretion and bone turnover.Β 

Intestinal absorption

Calcium is absorbed from the small intestine in a process predominantly regulated by vitamin D. Vitamin D deficiency leads to decreased calcium absorption from the gut.

Renal excretion

The kidneys regulate the amount of calcium excreted in the urine by altering calcium reabsorption in the distal tubules. This process is regulated by parathyroid hormone (PTH). Increased PTH levels lead to decreased levels of renal calcium excretion.

Bone turnover

Bone is constantly being remodelled, with old bone broken down and new bone formed. Calcium is released from old bone and taken up by new bone. Once again, this process is regulated by parathyroid hormone (PTH). Increased PTH levels lead to increased calcium resorption from the bone into the bloodstream.

Parathyroid hormone (PTH)

Reference range: 1.6 – 6.9 pmol/L

Parathyroid hormone plays a key role in calcium homeostasis. The parathyroid glands are found just posterior to the thyroid and act to secrete PTH in response to hypocalcaemia (or low vitamin D).

PTH then directly increases serum calcium levels by decreasing renal excretion of calcium and increasing calcium resorptionΒ from bone. PTH also indirectly increases calcium levels by increasing Vitamin D activation in the kidney, thus increasing calcium absorption from the small intestine.Β 

Secretion of PTH will lead to increased serum calcium levels. When serum calcium levels rise, a negative feedback mechanism exists to decrease PTH release from the parathyroid glands, keeping serum calcium regulated.

Hypercalcemia

Hypercalcemia is defined as a serum calcium level >2.6 mmol/L.

Aetiology

Causes of hypercalcaemia include:

  • Excessive PTH: primary hyperparathyroidism, tertiary hyperparathyroidism, ectopic PTH secretion (rare)
  • Malignancy: myeloma, bony metastases, paraneoplastic syndromes
  • Excess vitamin D: exogenous excess / granulomatous disease (e.g. sarcoidosis)
  • Excess calcium intake: β€˜milk-alkali’ syndrome
  • Renal disease: severe acute kidney injury
  • Drugs: thiazide diuretics / lithium
  • Hereditary: familial hypocalciuric hypercalcaemia

Hint: Over 90% of cases of hypercalcemia are due to either primary hyperparathyroidism or malignancy. The next step is always to request a PTH. PTH levels will be raised in primary hyperparathyroidism but suppressed in malignancy (due to the negative feedback mechanism described above).

Clinical features

Hypercalcemia may be asymptomatic. However, if symptoms develop, they are commonly remembered as β€˜bones, renal stones, abdominal groans and psychic moans’:

  • Bones: bone pain, pathological fractures
  • Renal stones: presenting with renal colic
  • Abdominal groans: abdominal pain, vomiting, constipation, pancreatitis
  • Psychic moans: confusion, hallucination, lethargy, depression

The ECG will classically show a shortened QT interval, and this can progress to cause complete AV nodal block and cardiac arrest.

Management

The management of hypercalcemia initially involves reducing serum calcium levels with aggressive IV fluid rehydration (normal saline) whilst investigating and managing the underlying cause. Hypercalcemia refractory to rehydration may require bisphosphonates.

Hypocalcaemia

Hypocalcaemia is defined as serum calcium <2.2 mmol/L.

Aetiology2

Causes of hypocalcaemia include:

  • PTH deficiency: primary hypoparathyroidism (autoimmune); parathyroid damage (post thyroid/parathyroid surgery or post neck irradiation); severe hypomagnesemia (impairs PTH secretion)
  • Vitamin D deficiency
  • Acute pancreatitis
  • Drugs: bisphosphonates, calcitonin

Hint: Requesting a PTH level is also the essential β€˜next step’ test to investigate hypocalcaemia. Without PTH deficiency, PTH should be raised as the body attempts to restore homeostasis.

Clinical features

Β Hypocalcaemia may be asymptomatic or present with non-specific symptoms:Β 

  • Muscle weakness/cramps
  • Muscle tetany/spasm
  • Perioral paraesthesia
  • Psychological disturbance
  • Seizures

There are pathognomonic clinical signs of hypocalcaemia related to muscle tetany:

  • Trosseau’s sign: occlusion of the brachial artery (e.g. with a blood pressure cuff) leads to involuntary contraction of the hand/wrist
  • Chvostek’s sign: tapping over the facial nerve causes contraction of facial nerves

The ECG may show QT prolongation, which can progress to torsades de pointes and cardiac arrest.

Management

The management of hypocalcaemia involves replacing calciumΒ whilst investigating and managing the underlying cause. For mild or moderate symptoms, oral calcium replacement is often sufficient (e.g. calcium carbonate). If symptoms are severe or ECG changes are present, urgent IV calcium gluconate is indicated.


Phosphate

Phosphate [PO4]is an inorganic molecule comprising a central phosphorous atom and four oxygen atoms. Phosphate is a major component of boneΒ and plays a key role in cellular energy production (ATP) and function.

Serum phosphate level requires less tight homeostatic control than serum calcium. In normal conditions, serum phosphate level is mainly determined by the kidney’s ability to excrete phosphate.3 Β Parathyroid hormone (PTH) is also involved in phosphate homeostasis and acts to increase renal excretion of phosphate.

Hyperphosphataemia

Hyperphosphataemia can have various pathological consequences, including cardiovascular disease (secondary to vascular calcification) and decreased bone mineral density. It is associated with increased mortality in those with chronic kidney disease.

Most patients will be asymptomatic. Severe hyperphosphatemia can present with altered mental status, muscle weakness, muscle pain, and even seizures.Β 

Aetiology

Β Causes of hyperphosphataemia include:

  • Renal impairment: chronic kidney disease is the most common cause of hyperphosphatemia, with phosphate excretion markedly impaired as the eGFR falls below 25
  • Acute phosphate load: tumour lysis syndrome, rhabdomyolysis, exogenous phosphate-containing laxatives
  • Excessive phosphate resorption: hypoparathyroidism, drugs (e.g. bisphosphonates)

Management

Acute hyperphosphatemia will generally self-resolve within 6-12 hours if renal function is normal and may need no specific treatment. Intravenous saline can be used to help accelerate phosphate excretion. Severe cases are often associated with significant hypocalcaemia; these patients may need urgent renal replacement therapy.

In chronic hyperphosphatemia (e.g. due to CKD), treatment is focused on decreasing phosphate intake (dietary modification) and absorption (phosphate-binding medications).

Hypophosphatemia

Hypophosphatemia is most commonly an incidental finding. Severe hypophosphatemia may present with CNS features such as delirium, seizures and coma.

Aetiology4

Causes of hypophosphataemia include:

  • Decreased absorption: inadequate intake, medications (e.g. antacids or phosphate binders), chronic diarrhoea
  • Increased urinary excretion: hyperparathyroidism, vitamin D deficiency
  • Internal redistribution: refeeding syndrome (phosphate shifts intracellularly), hungry-bone syndrome (increased calcium and phosphate deposition in bone post parathyroidectomy)
  • Renal replacement therapy

Management

Most cases of hypophosphataemia are mild and can safely be managed with oral phosphate replacement. IV replacement is indicated if the deficiency is severe (<0.3 mmol/L) or the patient is symptomatic whilst investigating and treating the underlying cause.


Albumin

Albumin is the most abundant circulating protein in the bloodstream, making up around half of the total protein content.5 Albumin is synthesised by the liver. Its functions include maintaining plasma oncotic pressure and transporting various substances in the bloodstream, such as cations, fatty acids and exogenous drugs.

Hint: Albumin is mainly reported in the bone profile due to its binding effects with calcium described above. It is also reported as part of liver function tests as it is a marker of the synthetic function of the liver.

Hypoalbuminemia

Low albumin levels in the blood generally arise from either decreased albumin production or increased albumin loss.

Albumin levels can fall due to:

Hypoalbuminemia can lead to widespread oedema, as loss of oncotic pressure in the blood leads to fluid accumulation in the interstitium.

The management generally involves identifying and treating the underlying cause, with human albumin solution (HAS) replacement reserved for specific circumstances (e.g. drainage of ascites).

Hyperalbuminemia

Raised albumin levels in the blood are relatively rare and may be seen in cases of severe dehydration or excessive protein intake.


Alkaline phosphatase (ALP)

Serum alkaline phosphatase (ALP) is derived from biliary epithelial cells (cells lining the biliary tract) and bone turnover. 6 Raised ALP levels can therefore be suggestive of cholestasis or bone disease.

Hint: Cholestasis describes an interruption in bile flow from hepatocytes to the gut. For more information, see the Geeky Medics guide to liver function test interpretation.

To differentiate between cholestasis and bone disease, gamma-glutamyltransferase (GGT) can be used. GGT is part of the liver function tests and is found in hepatocytes and biliary epithelial cells. It is a non-specific but highly sensitive marker of liver damage and cholestasis:

  • An ALP rise withΒ normal GGTΒ suggests increased bone turnover
  • An ALP rise withΒ associated GGT riseΒ is more suggestive of cholestasis

Causes of an isolated ALP rise (normal GGT)

This is most likely due to bone pathology and may include:

  • Paget’s disease of the bone
  • Bony metastases
  • Osteomalacia (Vitamin D deficiency)
  • Healing fractures

Serum ALP will also be physiologically raised in children and adolescents as well as in the third trimester of pregnancy.


Summary table

The bone profile with PTH can indicate the likely underlying disease process affecting the bones.

Table 1. Diagnosis of common bone disorders.

Β  Calcium Phosphate ALP PTH
Primary hyperparathyroidism

↑

↓

↑

↑

Bony metastases

↑

N

↑

↓

Paget’s disease

N

N

↑

N

Osteoporosis

N

N

N

N

Osteomalacia

N / ↓

N / ↓

↑

N / ↑


Editor

Dr Chris Jefferies


References

  1. UpToDate. Diagnostic approach to hypercalcemia. November 2022. Available at [LINK].
  2. UpToDate. Etiology of hypocalcemia in adults. August 2022. Available at [LINK].
  3. UpToDate. Overview of the causes and treatment of hyperphosphatemia. April 2023. Available at [LINK].
  4. StatPearls. Hypophosphatemia. December 2022. Available at [LINK].
  5. StatPearls. Physiology, Albumin. January 2023. Available at [LINK].
  6. UpToDate. Approach to the patient with abnormal liver biochemical and function tests. April 2022. Available at [LINK].

 

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