MCQs – Metabolic 1

Modern Study Review (AI-Generated)

High-Yield Summary

This topic is a staple of the Royal College exam, focusing heavily on calcium/phosphate metabolism, bone turnover markers, and metabolic bone diseases such as rickets, osteomalacia, Paget’s disease, and hypophosphatasia. The single most important clinical trade-off is differentiating causes of hypocalcemia and hypercalcemia using biochemical markers—especially urine calcium and alkaline phosphatase levels. The examiner often forces a choice between vitamin D deficiency and primary hyperparathyroidism based on urine calcium excretion. While classic teaching emphasizes fluoride’s bone mass benefits, modern practice recognizes its detrimental effect on cortical bone quality and fracture risk.

High-Yield Decision Matrix

Active Recall Q&A

Calcium Abnormalities & Malignancy

Q: What type of calcium abnormality does medullary thyroid cancer cause?
A: Hypocalcemia due to calcitonin production.
Related Pearl: Calcitonin lowers serum calcium by inhibiting osteoclast-mediated bone resorption, contrasting with most malignancies that cause hypercalcemia via osteolysis or PTHrP secretion.

Q: Which malignancies commonly cause hypercalcemia?
A: Breast cancer, sarcoidosis, and thyrotoxicosis.
Related Pearl: Hypercalcemia in malignancy often results from PTHrP secretion or osteolytic metastases increasing bone resorption.

Paget’s Disease & Bone Markers

Q: Is hypercalcemia common in Paget’s disease?
A: No, hypercalcemia and hypercalciuria are possible but uncommon.
Related Pearl: Hypercalcemia in Paget’s usually occurs only during immobilization or extensive disease due to increased bone turnover.

Q: What do increased urinary hydroxylysine and hydroxyproline indicate?
A: Increased collagen breakdown and bone resorption, as seen in Paget’s disease.
Related Pearl: These markers correlate with disease extent and are useful for monitoring treatment response.

Drug-Induced Bone Disease

Q: How does dilantin (phenytoin) cause osteomalacia?
A: By inducing hepatic P-450 enzymes that convert vitamin D into inactive metabolites, reducing 25(OH) vitamin D levels.
Related Pearl: Chronic anticonvulsant use is a classic cause of vitamin D deficiency-related bone disease due to impaired vitamin D metabolism.

Urine Calcium in Differential Diagnosis

Q: How can vitamin D deficient rickets be distinguished from primary hyperparathyroidism using urine calcium?
A: Vitamin D deficient rickets shows decreased urine calcium; hyperparathyroidism shows increased urine calcium (hypercalciuria).
Related Pearl: Urine calcium helps differentiate causes of hypocalcemia and bone disease when serum calcium is equivocal.

Calcium & Phosphorus Physiology

Q: What percentage of total body calcium is stored in bone?
A: 99%.
Related Pearl: Bone acts as the major reservoir for calcium, critical for maintaining serum calcium homeostasis.

Q: How tightly is phosphorus regulated in the body?
A: Phosphorus is not tightly controlled; wide swings are generally well tolerated.
Related Pearl: Phosphorus homeostasis is less stringent than calcium, partly due to its predominant intracellular distribution.

Q: What is the effect of PTH on renal calcium handling?
A: PTH stimulates renal calcium reabsorption, increasing serum calcium.
Related Pearl: PTH acts on distal renal tubules to increase calcium reabsorption, a key mechanism in hypercalcemia.

Q: How does PTH affect phosphate handling in the kidney?
A: PTH lowers the renal phosphate reabsorption threshold, decreasing serum phosphate.
Related Pearl: Phosphaturia induced by PTH prevents calcium phosphate precipitation in soft tissues.

Radiographic & Supplementation Effects

Q: What are Looser’s lines and where are they found?
A: Ribbonlike linear radiolucent lines of unmineralized osteoid seen transversely on the concave side of long bones in rickets/osteomalacia.
Related Pearl: Looser’s zones represent stress fractures through weakened osteoid and are pathognomonic for osteomalacia.

Q: What is the effect of fluoride supplementation on bone?
A: Increases bone mass but decreases cortical bone mineral density, increasing nonvertebral fracture risk.
Related Pearl: Fluoride increases cancellous bone formation but compromises bone quality, limiting its clinical use.

Bone Resorption Markers & Hypophosphatasia

Q: What markers are increased in hyperparathyroidism related to bone resorption?
A: Urinary calcium, hydroxyproline, and hydroxylysine.
Related Pearl: Elevated bone resorption markers correlate with disease severity and fracture risk in hyperparathyroidism.

Q: What enzyme deficiency causes hypophosphatasia?
A: Low alkaline phosphatase levels.
Related Pearl: Alkaline phosphatase is essential for bone mineralization by generating inorganic phosphate.

Q: What are the biochemical features of hypophosphatasia?
A: Low serum alkaline phosphatase, high serum calcium, hypercalciuria, and increased urinary phosphoethanolamine.
Related Pearl: High serum calcium results from impaired bone mineralization and calcium deposition.

Q: Why does pyrophosphate accumulate in hypophosphatasia?
A: Due to low alkaline phosphatase, pyrophosphate is not cleaved to inorganic phosphate, inhibiting hydroxyapatite formation.
Related Pearl: Pyrophosphate acts as a natural inhibitor of bone mineralization, causing rickets/osteomalacia in hypophosphatasia.

Bone Metabolism Enzymes

Q: What reaction does carbonic anhydrase catalyze relevant to bone metabolism?
A: H2O + CO2 ? H+ + HCO3-.
Related Pearl: Carbonic anhydrase activity in osteoclasts facilitates acid secretion necessary for bone resorption.

Classic Clinical Notes

• Medullary thyroid cancer is a calcitonin producing tumour which produces hypocalcemia, not hypercalcemia. Most other malignancies are apt to cause hypercalcemia (esp. Breast), in addition to sarcoidosis and thyrotoxicosis.

• Paget’s disease: can see hypercalcemia and hypercalciuria but this is uncommon.

• Dilantin causes osteomalacia in the liver. It induces P-450 mixed function oxidases within hepatic cells that convert vitamin D to inactive polar metabolites, thereby reducing the hydroxylation of cholecalciferol to 25(OH)Vit D.

• Vitamin D deficient rickets and primary hyperPTH can be distinguished by the urine calcium – in hyperPTH, the urine calcium is increased (hypercalciuria) while in vit D deficient rickets urine calcium is decreased. The calcium levels may not be all that different, but hyperPTH is likely to cause hypercalcemia, while rickets is more likely to have low or normal calcium.

• 99% of calcium in the body is entrapped in bone.

• Phosphorus is not that tightly controlled, and wide swings are well tolerated.

• PTH Action: PTH stimulates kidney to reabsorb calcium (increases serum calcium) while lowering the renal reabsorption threshold for phosphate and thus decreasing the serum phosphate.

• Looser’s lines in rickets/osteomalacia are localized collections of OSTEOID that is unmineralized – they appear as ribbonlike linear radiolucent lines that run transversly to the long axis of the bone and are found preferentially on the concave side of long bones including the medial femoral neck, ischium, pubic rami, ribs, and scapula.

• Fluoride supplementation has been investigated before and found to increase bone mass but make it more brittle – shown to not cause any change in the incidence of vertebral compression fractures, but has been shown to increase the number of nonvertebral fractures (hip, wrist, etc). Fluoride increases cancellous bone, but decreases cortical bone mineral density and therefore increases skeletal fragility.

• Hydroxylysine and hydroxyproline: once released from collagen during breakdown of collagen fibers, these are excreted in the urine at a rate that reflects the rate of collagen degradation. The presence of increased urinary excretion of peptides containing hydroxyproline and hydroxylysine in Paget’s disease patients is a useful tool for study of collagen turnover and can be used to assess treatment. The excretion of hydroxyproline is greater than normal in almost all patient’s with Paget’s disease, even with monostotic involvement; in general, the amount excreted is directly correlated with the extent of disease, and treatment of Pagets with agents that effect bone results in decreased hydroxyproline excretion.

• The urinary excretion of calcium, hydroxyproline, and hydroxylysine is, generally speaking, a good marker of bone resorption; in hyperPTH, you would expect all three to be increased.

• Hypophosphatasia is an autosomal recessive disorder caused by low levels of alkaline phosphatase which is important in the formation of inorganic phosphate for bone production. This therefore causes a rickets/osteomalacia syndrome. Serum alk phosphate is low, while serum calcium is high because it is not deposited in bone. Treatment is by phosphate therapy. Increased urinary phosphoethanolamine is diagnostic; they also have hypercalciuria.

• In hypophosphatasia, the low levels of alkaline phosphatase in hypophosphatasia result in high levels of pyrophosphates. Pyrophosphates are naturally occurring inhibitors of bone mineralization; normally, pyrophosphate is cleaved by alkaline phosphatase to form the inorganic phosphate required for hydroxyapatite formation. Pyrophosphate by itself acts as an endogenous inhibitor of crystallization – leads to the rickets/osteomalacia of hypophosphatasia.

• Carbonic anhydrase facilitates the H2O + CO2 ? H+ + HCO3- reaction.

Last Updated on January 25, 2026 by Christian Veillette