Influence of drugs on vitamin D and calcium metabolism

Figures & data

Table 1. Drugs that activate the pregnane-X-receptor (PXR) (selection)

PXR-Ligands	Examples
Antiepileptics	Phenytoin, Carbamazepine
Antineoplastic drugs	Cyclophophamide, Taxol, Tamoxifen
Antibiotics	Clotrimazole, Rifampicin
Anti-inflammatory agents	Dexamethasone
Antihypertensives	Nifedipine, Spironolactone
Antiretroviral drugs	Ritononavir, Saquinavir
Endocrine drugs	Cyproterone acetate
Herbal medicines	Kava kava, St. John's wort (Hyperforin)

Figure 1. PXR-mediated drug-induced degradation of vitamin D (proposed model according to Pascussi, 2005 and Holick, 2006).

Table 2. Possible factors in the pathogenesis of AED-induced bone disease (selection), according to references 15 and 17

Probable mechanism	Antiepileptic agents (examples)
Increased vitamin D breakdown • Pregnane X receptor-mediated induction of microsomal enzymes in the liver; Results: decrease of 25(OH)D and 1,25(OH)2D, increase of parathyroid levels, increased bone turnover	Carbamazepine, phenobarbital, phenytoin, primidone
Changes in the calcium balance • Reduced intestinal calcium absorption • Renal-tubular dysfunction, leading to increased renal calcium and phosphate losses	Phenytoin, Valproic acid
Change in the parathyroid hormone balance • Hyperparathyroidism • Reduced cellular sensitivity to parathyroid hormone	Various antiepileptic agents Phenobarbital*, phenytoin*
Change in the calcitonin balance • Inhibition of calcitonin secretion	Phenytoin
Direct effect on osteoblasts or osteoclasts • Inhibition of osteoblasts • Stimulation of osteoclasts • Inhibition of osteocalcin secretion in osteoblasts	Carbamazepine, phenytoin Valproic acid, carbamazepine Phenytoin
Increased bone turnover (irrespective of vitamin D and parathyroid hormone levels)	Valproic acid, phenytoin, carbamazepine
Vitamin K deficiency due to increased vitamin K metabolism (with influence on the vitamin K-dependent modification of matrix proteins)	Phenytoin*
Change in the sex hormone balance • Change in the synthesis or metabolism of sex hormones, increased levels of the sex hormone-binding proteins, modulation of aromatase activity	Various antiepileptic agents

* in animal studies.

Table 3. Effect of glucocorticoids and vitamin D hormone on bone metabolism (selection)

Effect on	Glucocorticoids	Vitamin D hormone
Osteoblasts	Differentiation ↓ Osteoblastogenesis ↓	Differentiation ↑ Osteoblastogenesis ↑
Calcium homeostasis	Intestinal absorption ↓ Renal excretion ↑	Intestinal Absorption ↑ Renal excretion ↓
Sex hormones	Production ↓	Production ↑
Bones	Absorption ↑	New formation ↑

Figure 2. Vitamin D-deficiency and development of hypertension and insulin resistance (possible mechanisms).

Valsamis HA, Arora SK, Labban B, McFarlane SI. Antiepileptic drugs and bone metabolism. Nutr Metab (Lond) 2006; 3:36; http://dx.doi.org/10.1186/1743-7075-3-36; PMID: 16956398

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Gröber U, Arzneimittel und Mikronährstoffe. Medikationsorientierte Supplementierung. 2. Auflage. Stuttgart: Wissenschaftliche Verlagsgesellschaft, 2012.

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