Bone and Mineral Profile

The bone and mineral profile combines total calcium (with an albumin corrected value), phosphate, magnesium and alkaline phosphatase (ALP). Parathyroid hormone and 25-hydroxyvitamin D complete the workup and are tested when the profile is abnormal.

Calcium and phosphate are measured by colorimetric methods (arsenazo or cresolphthalein for calcium, molybdate for phosphate), magnesium by xylidyl blue colorimetry and ALP by kinetic spectrophotometry. The panel detects disorders of calcium homeostasis, parathyroid and vitamin D disease, bone turnover, kidney mineral disease and magnesium deficiency.

Hypercalcaemia is found in about 1 in 100 to 1 in 200 adults screened, most often from primary hyperparathyroidism in outpatients and from malignancy in hospital patients. Hypocalcaemia is common in inpatients, mainly from low albumin.

Indications. Fatigue, bone pain, fractures, renal stones, polyuria, constipation, confusion, muscle cramps, paraesthesia, tetany, seizures, osteoporosis, chronic kidney disease, malignancy (especially breast, lung, myeloma), pancreatitis, thyroid or neck surgery, bariatric surgery, malabsorption, prolonged corticosteroid use, and drugs that disturb calcium (thiazides, lithium, denosumab, bisphosphonates, loop diuretics).

Specimen. Fasting serum, with minimal tourniquet time and no fist clenching. A prolonged tourniquet raises total calcium and phosphate by haemoconcentration. Avoid EDTA and citrate contamination, which gives low calcium and magnesium, high potassium and low ALP.

Adult reference ranges are given. Local ranges take precedence.

Total calcium. Sum of free (ionised, about 45 to 50%), albumin bound (about 40%) and complexed calcium. Range: 2.20 to 2.60 mmol/L (8.8 to 10.4 mg/dL).

Raised: primary hyperparathyroidism, malignancy (PTH-related peptide, bone metastases, myeloma, lymphoma with calcitriol production), vitamin D excess, sarcoidosis and other granulomatous disease, thiazides, lithium, milk alkali syndrome, thyrotoxicosis, immobilisation, adrenal insufficiency, familial hypocalciuric hypercalcaemia, dehydration and spurious rise from a prolonged tourniquet.

Lowered: low albumin (spurious), vitamin D deficiency, hypoparathyroidism (usually after neck surgery), chronic kidney disease, hypomagnesaemia, acute pancreatitis, rhabdomyolysis, tumour lysis, massive transfusion (citrate), osteoblastic metastases, hungry bone syndrome after parathyroidectomy, bisphosphonates and denosumab, sepsis, and pseudohypoparathyroidism.

Because about 40% of calcium is bound to albumin, a low albumin lowers total calcium without lowering the active fraction. Calcium and albumin are therefore read together.

Corrected calcium. Total calcium adjusted for albumin: measured calcium (mmol/L) plus 0.02 multiplied by (40 minus albumin in g/L). In mg/dL, add 0.8 multiplied by (4.0 minus albumin in g/dL). Range: 2.20 to 2.60 mmol/L (8.8 to 10.4 mg/dL).

The correction is a rough estimate and is unreliable in critical illness, chronic kidney disease, paraproteinaemia, acid base disturbance and pregnancy. Ionised calcium is measured when the result would change management. Hypercalcaemia is mild at a corrected value of 2.60 to 3.00 mmol/L, moderate at 3.01 to 3.50 and severe over 3.50 mmol/L (14 mg/dL). Symptoms of hypocalcaemia (paraesthesia, tetany, laryngospasm, seizures, prolonged QT interval) usually appear when the corrected calcium falls under 1.9 mmol/L, or sooner when it falls rapidly.

Phosphate. Mainly intracellular, with serum levels reflecting intake, renal excretion and shifts. Range: 0.80 to 1.50 mmol/L (2.5 to 4.5 mg/dL). Raised: chronic kidney disease, hypoparathyroidism, vitamin D excess, tumour lysis, rhabdomyolysis, acidosis, phosphate containing enemas and laxatives, haemolysis, and spuriously with paraproteins or hyperbilirubinaemia.

Lowered: refeeding, alcohol dependence, recovery from diabetic ketoacidosis, respiratory alkalosis, primary hyperparathyroidism, vitamin D deficiency, excess FGF23 (tumour induced osteomalacia, X-linked hypophosphataemia), renal tubular disorders (Fanconi syndrome), aluminium and magnesium antacids, malabsorption, burns and sepsis.

Severe hypophosphataemia (under 0.32 mmol/L, 1 mg/dL) causes weakness, respiratory failure, haemolysis, rhabdomyolysis, heart failure and encephalopathy. A phosphate over 1.8 mmol/L in chronic kidney disease, particularly with a high calcium phosphate product, carries a risk of vascular calcification.

Magnesium. Cofactor for over 300 enzymes and necessary for parathyroid hormone secretion and action. Range: 0.70 to 1.00 mmol/L (1.7 to 2.4 mg/dL). Raised: kidney failure with magnesium containing antacids or laxatives, magnesium sulphate therapy, lithium, adrenal insufficiency, hypothyroidism, tumour lysis. Lowered: loop and thiazide diuretics, proton pump inhibitors, alcohol dependence, diarrhoea and malabsorption, diabetes, cisplatin, calcineurin inhibitors, amphotericin, aminoglycosides, refeeding, and inherited tubular disorders.

A low magnesium causes refractory hypokalaemia and hypocalcaemia (parathyroid hormone resistance) that do not correct until magnesium is replaced. Serum magnesium reflects less than 1% of body stores, so a normal value does not exclude deficiency.

Alkaline phosphatase. Enzyme of bone, liver, bile duct, placenta and intestine. Range: 30 to 130 U/L in adults. Raised: rapid bone turnover (Paget disease, osteomalacia, rickets, healing fracture, bone metastases, hyperparathyroidism, hyperthyroidism), liver and biliary disease, pregnancy, growth in children and adolescents. Lowered: hypophosphatasia, zinc and magnesium deficiency, hypothyroidism, coeliac disease, and EDTA contamination.

In bone disease the ALP rises with normal GGT. A raised ALP with low calcium and phosphate suggests vitamin D deficiency with osteomalacia. A markedly raised ALP with normal calcium and phosphate in an older adult suggests Paget disease.

Critical values and findings needing immediate action. Triggers vary by laboratory.

• Corrected calcium over 3.50 mmol/L, or over 3.00 mmol/L with confusion, vomiting, dehydration, acute kidney injury or ECG shortening of the QT interval.
• Corrected calcium under 1.9 mmol/L, or any hypocalcaemia with tetany, seizures, stridor or prolonged QT interval.
• Phosphate under 0.32 mmol/L, particularly with refeeding or alcohol dependence.
• Magnesium under 0.4 mmol/L with arrhythmia, seizures or refractory hypokalaemia, or over 3.0 mmol/L with loss of reflexes or respiratory depression.
• Low calcium with high phosphate and rising potassium and creatinine in a patient with malignancy starting treatment.

Interferences and pitfalls.

• Prolonged tourniquet, fist clenching and delayed separation raise calcium and phosphate. Haemolysis raises phosphate and magnesium, and delayed separation raises phosphate.
• EDTA contamination lowers calcium, magnesium and ALP and raises potassium.
• The albumin correction is invalid in many acute and renal states, and ionised calcium is then needed.
• Paraproteins can cause a spuriously high or low calcium or phosphate with some methods.
• High dose biotin interferes with immunoassays for parathyroid hormone and vitamin D.
• Vitamin D and calcium supplements, thiazides and lithium need to be recorded with the request.
• A single mildly raised calcium is repeated on a fasting sample before workup.

Special groups.

• Neonates: calcium falls in the first 2 days, with early hypocalcaemia common in preterm infants and infants of diabetic mothers. Phosphate and ALP are higher, with phosphate up to about 2.5 mmol/L at birth.
• Children: phosphate (about 1.2 to 1.8 mmol/L) and ALP (up to several times the adult limit) are higher during growth.
• Pregnancy: albumin falls, so total calcium falls by about 0.1 to 0.2 mmol/L, ionised calcium is unchanged, and ALP rises 2 to 4 times from placental production by the third trimester.
• Older adults: mild hypercalcaemia is often primary hyperparathyroidism, and vitamin D deficiency with a raised ALP is common.
• Chronic kidney disease: the corrected calcium is less reliable, and target ranges for calcium and phosphate follow the stage of disease.
• Regions with high rates of rickets, malabsorption or low sun exposure: vitamin D deficiency is the leading cause of a low calcium with a raised ALP.

Follow up tests. Ionised calcium, parathyroid hormone, 25-hydroxyvitamin D, PTH-related peptide, calcitriol, 24-hour urine calcium or calcium to creatinine clearance ratio, urea and electrolytes with eGFR, liver function tests, thyroid function tests, serum protein electrophoresis and free light chains, bone specific ALP, ECG, bone densitometry, neck ultrasound and parathyroid scintigraphy, skeletal imaging.