Bone profile: calcium, phosphate, ALP, PTH and vitamin D

• A bone profile is read as a set, not as single numbers: calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH) and 25-hydroxyvitamin D (25-OHD) together describe bone turnover, parathyroid drive and vitamin D status.
• Always start with the calcium, adjusted for albumin, and with the laboratory's own reference range. Then look at whether PTH is appropriate for that calcium. ^[2]
• Ionised calcium is the biologically active form; most labs report total calcium, which has to be corrected when albumin is low.
• The most common patterns are primary hyperparathyroidism (high calcium, high or inappropriately normal PTH, low phosphate), vitamin D deficiency (low or normal calcium, high PTH, low 25-OHD) and the malignant pattern (high calcium, suppressed PTH).
• CKD mineral and bone disease, Paget disease and osteomalacia have their own recognisable shapes, usually involving ALP.
• Sample sheets and algorithms below are illustrative; they are not real patient data and the local laboratory interval always wins.

By the end of this page you should be able to:

1. Choose between total, albumin-adjusted and ionised calcium, and correct total calcium for albumin.
2. Explain how PTH, phosphate, ALP and 25-hydroxyvitamin D move together in the common disorders.
3. Read a result sheet and state a one-line conclusion with the next step.
4. State the vitamin D sufficiency cut-offs you are using and their source.
5. List the NICE and KDIGO actions that depend on the level of albumin-adjusted calcium.

The bone profile is a small panel with a large amount of physiology behind it. Calcium is the signal, PTH is the messenger, phosphate is calcium's partner in bone and blood, ALP is a marker of bone formation, and 25-hydroxyvitamin D (25-OHD) is the storage form of vitamin D. Reading them together is more reliable than reading any of them alone, because each value changes the meaning of the others. A high calcium with a suppressed PTH points to non-parathyroid causes of hypercalcaemia, while the same calcium with a raised PTH points to the parathyroid gland. A raised ALP with low phosphate and high calcium behaves differently from a raised ALP with low 25-OHD.

This page treats the panel as an investigation, so it is organised around what the tests measure, the ranges used, the causes of high and low values, the patterns they form, and short sample result sheets to interpret. It is written for a reader meeting the panel for the first time; it assumes no prior knowledge of mineral metabolism.

Calcium. Most laboratories report total (serum) calcium. About 45 per cent of circulating calcium is bound to albumin, about 45 per cent is ionised and biologically active, and about 10 per cent is bound to small anions such as phosphate and citrate. ^{[1] [2]} The ionised (free) fraction is what the body actually senses, and it is what the parathyroid glands, bones and kidneys respond to. Total calcium is convenient and cheap but is an estimate of the ionised fraction, and it is unreliable whenever albumin or pH changes. ^[2]

Albumin-adjusted (corrected) calcium. Because so much calcium is albumin-bound, a low albumin makes total calcium look low even when the patient is normocalcaemic. The standard correction is:

corrected calcium (mg/dL) = measured total calcium + 0.8 x (4.0 - albumin in g/dL)

where albumin is in g/dL and total calcium in mg/dL. In SI terms total calcium falls by about 0.25 mmol/L for each 10 g/L fall in albumin below 40 g/L. ^[1] NICE calls this "albumin-adjusted serum calcium" and bases its thresholds (2.6 mmol/L or above, 2.85 mmol/L or above, 3.0 mmol/L or above) on it. ^[6] The correction is an approximation and is least reliable in critical illness, severe hypoalbuminaemia or abnormal pH; when in doubt measure ionised calcium directly. ^[2]

Ionised calcium. The direct measurement of the active fraction. It is necessary in critical care, after massive transfusion, in severe acid-base disturbance and in situations where albumin is unreliable. ^[1] It requires an anaerobic sample handled carefully. NICE states that ionised calcium should not be measured when testing for primary hyperparathyroidism; use albumin-adjusted serum calcium instead. ^[6]

Phosphate. Phosphate is calcium's partner in bone mineral (hydroxyapatite) and a key intracellular anion. Renal excretion is the main regulator, with PTH, vitamin D and calcitonin acting on it alongside calcium. ^{[6] [8]} Because PTH inhibits renal phosphate reabsorption, phosphate falls as PTH rises.

Alkaline phosphatase (ALP). ALP is a membrane-bound enzyme. More than 80 per cent of serum ALP comes from liver and bone, with smaller contributions from intestine, placenta, kidney and (in pregnancy) placenta. ^[7] An isolated rise therefore needs a hepatic source to be excluded (for example with GGT) before it is attributed to bone. ^[1] In children, adolescents and pregnancy, ALP is physiologically higher because of bone growth or the placental isoenzyme. ^[12]

Parathyroid hormone (PTH). PTH is secreted by the parathyroid glands in response to a low ionised calcium, detected by the calcium-sensing receptor. It raises serum calcium by stimulating osteoclastic bone resorption, renal calcium reabsorption and calcitriol synthesis (which in turn increases intestinal calcium absorption), and it lowers serum phosphate by inhibiting renal phosphate reabsorption. ^{[3] [9]} PTH is the messenger whose appropriateness you judge against the calcium.

25-hydroxyvitamin D (25-OHD). This is the storage (circulating) form, the best marker of vitamin D status. It is hydroxylated in the liver and then converted in the kidney to the active form, calcitriol (1,25-dihydroxyvitamin D), under the control of PTH and FGF23. ^{[4] [9]} Assays differ, which is why guideline thresholds come from defined methods and should not be over-interpreted.

Ranges are assay-, age-, sex- and population-specific, and for several analytes they change with posture, time of day, fasting and pregnancy. The local laboratory interval printed on the result is authoritative. Where laboratory and textbook disagree, the laboratory wins. ^{[1] [2]}

A correction of total calcium for albumin is only an estimate. Ionised calcium is required in acidosis, alkalosis, massive transfusion, severe hypoalbuminaemia and critical illness. ^[2] The CaSR set point means that a "normal" calcium value is itself variable between people, which contributes to the overlap between health and disease. ^[3]

Causes are listed by the analyte most affected, but remember that a change in one value almost always changes another. PAUSE: high calcium with a normal or high PTH is not normal, because PTH should be suppressed by calcium. ^{[3] [6]}

The single most useful question in this panel is: is the PTH appropriate for the calcium? In primary hyperparathyroidism calcium is high and PTH is elevated or inappropriately normal (not suppressed). In hypercalcaemia of malignancy, granulomatous disease, milk-alkali and thyrotoxicosis, calcium is high and PTH is suppressed. ^{[3] [9]}

The named combinations (the "patterns" that exam questions test):

• Primary hyperparathyroidism = high albumin-adjusted calcium, high or inappropriately normal PTH, low or low-normal phosphate, often a raised ALP and low or low-normal 25-OHD. ^{[3] [9]} The most common cause is a single benign parathyroid adenoma. ^[3]
• Hypercalcaemia of malignancy = high calcium, suppressed (low) PTH, commoner in inpatients, often more severe than PHPT hypercalcaemia. ^[9]
• Familial hypocalciuric hypercalcaemia (FHH) = lifelong mild hypercalcaemia (around 2.5-2.7 mmol/L) with an inappropriately normal PTH and a low urine calcium to creatinine clearance ratio (under 0.01), not 0.02 or more as in PHPT. ^{[9] [6]}
• Vitamin D deficiency = 25-OHD under 12 ng/mL (30 nmol/L) on the 2019 Endocrine Society thresholds quoted in StatPearls; calcium low or normal, phosphate low or low-normal, ALP raised (osteomalacia), PTH raised (secondary hyperparathyroidism). ^[4]
• CKD mineral and bone disease = low or falling calcium in late disease, high phosphate (reduced GFR), high PTH (secondary hyperparathyroidism), often raised ALP and low 25-OHD. ^[8]
• Paget disease of bone = normal calcium and phosphate, markedly raised bone ALP, PTH normal; the high ALP is the clue, and GGT is normal if liver is the source. ^{[7] [12]}
• Osteomalacia = low or normal calcium, low phosphate, high ALP, high PTH, low 25-OHD. ^{[4] [5]}
• Hypoparathyroidism = low calcium, high phosphate, low or inappropriately normal PTH (the mirror image of PHPT). ^{[1] [6]}
• Milk-alkali syndrome / supplements = high calcium, low or normal PTH, normal phosphate, alkalosis. ^[2]
• Hypomagnesaemia = functional hypoparathyroidism: low calcium, high phosphate, low PTH that corrects when magnesium is replaced. ^[1]

Kidney and skeletal complications move the decision, not the biochemical numbers alone. NICE refers people with confirmed PHPT to surgery when they have symptoms of hypercalcaemia (thirst, polyuria, constipation), end-organ disease (renal stones, fragility fractures or osteoporosis) or an albumin-adjusted calcium of 2.85 mmol/L or above. ^[6]

Every value below is original and invented for teaching; these are not real patient results. The ranges, thresholds and rules in the interpretation are claims from the cited sources.

Sheet 1: normal adult, no disease

Interpretation:

1. Adjusted calcium is 2.42 mmol/L, which lies within the 2.12-2.62 mmol/L interval and is not 2.6 or above, so there is no hypercalcaemia. ^{[1] [6]}
2. PTH is 3.4 pmol/L and stated as normal for the method.
3. A normal calcium with a normal PTH and a normal 25-OHD (over 30 ng/mL / 50 nmol/L on the 2019 Endocrine Society thresholds quoted by StatPearls) excludes the common parathyroid and vitamin D problems. ^[4]
4. Conclusion: no biochemical abnormality of mineral metabolism; nothing further is required beyond routine care.

Sheet 2: primary hyperparathyroidism

Interpretation:

1. Adjusted calcium 2.91 mmol/L is 2.6 or above and therefore hypercalcaemia, and 2.85 or above, which meets the NICE surgical-referral calcium threshold when combined with the clinical assessment. ^[6]
2. PTH 9.6 pmol/L is not suppressed; it is elevated, so in the presence of a high calcium this is an inappropriate PTH. ^{[3] [6]}
3. Phosphate is low, the expected phosphaturic effect of PTH. ^{[3] [9]}
4. 25-OHD 34 nmol/L is under 50 nmol/L, so vitamin D repletion is advised before any surgical decision. NICE recommends measuring vitamin D in probable PHPT and offering supplementation. ^[6]
5. Conclusion: primary hyperparathyroidism is the most likely diagnosis; repeat adjusted calcium and PTH on at least two occasions 2 weeks apart, check urine calcium to exclude FHH, measure 25-OHD, renal tract ultrasound and DXA, and decide referral. ^{[6] [9]}

Sheet 3: malignant hypercalcaemia

Interpretation:

1. Adjusted calcium 3.24 mmol/L is severe hypercalcaemia. Phosphate is normal rather than low. ^{[2] [3]}
2. PTH 0.8 pmol/L is suppressed, below the midpoint of the reference range, so the parathyroid glands are not the driver; this is non-parathyroid hypercalcaemia. ^{[6] [9]}
3. The high ALP with normal phosphate and suppressed PTH fits malignant or osteolytic disease, although the pattern needs radiology and a cancer history; ALP alone cannot localise its source without GGT or isoenzymes. ^[7]
4. Conclusion: the pattern is of malignancy-related or other non-PTH hypercalcaemia; investigate for cancer and granulomatous disease, treat the calcium urgently, and do not refer for parathyroid surgery.

1. Low albumin. A total calcium at the lower end of the range may simply be hypoalbuminaemia. Correct it, or measure ionised calcium. ^{[1] [2]}
2. Acid-base. Acidosis increases ionised calcium at the expense of protein-bound calcium; alkalosis does the reverse. A normal total calcium in severe alkalosis can hide a symptomatic low ionised calcium. ^[2]
3. Ionised calcium in PHPT. NICE says do not measure ionised calcium when testing for primary hyperparathyroidism; use albumin-adjusted serum calcium. ^[6]
4. ALP source. An ALP rise is not "bone" until a hepatic cause is excluded (for example with GGT or an isoenzyme); liver and bone together account for over 80 per cent of serum ALP. ^[7]
5. Normal calcium does not exclude PHPT. Normocalcaemic PHPT exists and is a diagnosis of exclusion after secondary hyperparathyroidism (vitamin D deficiency, CKD, malabsorption) has been ruled out. ^[9]
6. Vitamin D thresholds. The 12, 30 and (using the Endocrine Society values quoted by StatPearls) 30 ng/mL numbers here are the 2019 Endocrine Society cut-offs; the 2024 Endocrine Society guideline did not support routine 25-OHD testing in asymptomatic adults and did not define an optimal disease-prevention target. ^{[4] [11] [9]}
7. ** assay-specific intervals.** Only cholesterol, creatinine and HbA1c are internationally harmonised; PTH, vitamin D and ALP in particular are method-specific. ^[2]
8. Pregnancy. ALP rises because of the placental isoenzyme and 25-OHD interpretation changes; use pregnancy-adjusted intervals. ^[12]