A 60-year-old woman on long-term phenytoin therapy develops osteomalacia. Serum calcium and phosphate are low-normal; alkaline phosphatase is elevated. Serum 25-OH vitamin D is markedly low, but 1,25-(OH)2 vitamin D is also low. Which of the following BEST explains the mechanism?
- A Phenytoin inhibits intestinal calcium absorption by directly blocking TRPV6 calcium channels, independent of vitamin D status
- B Phenytoin induces hepatic CYP2C9/CYP3A4 enzymes, accelerating catabolism of 25-OH vitamin D to inactive metabolites, reducing substrate for renal 1α-hydroxylase and depleting both forms of vitamin D ✓
- C Phenytoin reduces PTH secretion by stabilizing parathyroid cell membranes, reducing 1α-hydroxylase upregulation in the kidney
- D Phenytoin chelates calcium in the gastrointestinal lumen, forming insoluble phenytoin-calcium complexes that are excreted
Explanation
Phenytoin (and other CYP-inducing anticonvulsants: carbamazepine, phenobarbital, rifampicin) upregulate hepatic cytochrome P450 enzymes (CYP2C9, CYP3A4, CYP24A1) that hydroxylate and deactivate vitamin D metabolites. Accelerated catabolism of 25-hydroxyvitamin D3 (calcidiol) depletes circulating levels, reducing substrate availability for renal 1α-hydroxylase, which subsequently also reduces 1,25-(OH)2D3 (calcitriol). The result is impaired intestinal calcium absorption, secondary hyperparathyroidism, and eventually osteomalacia. This explains why both 25-OH D and 1,25-(OH)2D are low. Options B, C, and D describe mechanisms that are either not established for phenytoin or are pharmacologically implausible as primary causes of osteomalacia.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
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