Enzyme induction, sex hormone-binding globulin and accelerated bone loss during oxcarbazepine exposure without vitamin D deficiency: a sixteen-year bone density series

Background. Enzyme-inducing antiepileptic drugs are associated with reduced bone mineral density (BMD), an effect usually attributed to accelerated vitamin D catabolism. Oxcarbazepine has separately been reported to raise sex hormone-binding globulin (SHBG), which reduces the free fractions of estradiol and testosterone available to tissue. The induction profile of oxcarbazepine in human hepatocytes indicates activation of the constitutive androstane receptor, which raises SHBG transcription in human cells; the two findings have not been joined in patients. This second pathway is rarely measured and its skeletal consequences are not described in patient labelling. Case. A woman treated with oxcarbazepine from February 2019 to November 2022 for cramp fasciculation syndrome underwent eight dual-energy X-ray absorptiometry studies between 2010 and 2026, including two before drug exposure. Lumbar spine BMD fell at 1.14% per year over the 8.5 years preceding treatment, 2.68% per year over the interval containing drug initiation, and 5% per year over the subsequent year, with a fall in T-score from −0.90 to −2.60. Density subsequently recovered at 9.7% and 9.97% per year following transdermal estradiol and topical testosterone, with trabecular bone score rising from 1.313 to 1.358. Serum 25-hydroxyvitamin D never fell below 115 ng/mL during the period of accelerated loss and never below 99 ng/mL during recovery (reference interval 30–100 ng/mL; deficiency below 20 ng/mL), excluding vitamin D deficiency as an explanation. On oxcarbazepine, SHBG was 129–135 nmol/L (reference 14–73 nmol/L) across three draws, the first three months before bilateral oophorectomy with the ovaries in situ. After oxcarbazepine was stopped SHBG ranged from 93 to 145 nmol/L. Conclusion. Accelerated bone loss occurred during oxcarbazepine exposure in the absence of vitamin D deficiency, alongside SHBG elevation and reduced free hormone fractions. Two samples were obtained after oophorectomy with undetectable estradiol, one during exposure and one seventeen months after the drug was stopped; the two differed by 42 nmol/L. SHBG did not return to the reference interval after oxcarbazepine was withdrawn. Measurement of SHBG and the free hormone fractions may be warranted in perimenopausal, menopausal and postmenopausal women receiving enzyme-inducing antiepileptic drugs.