Cerebrotendinous xanthomatosis (CTX) is known to be associated with osteoporosis and a higher incidence of bone fractures. However, the underlying pathogenesis is still unknown, and the effects of long-term replacement therapy with chenodeoxycholic acid (CDCA) on bone mineral density (BMD) have not been fully investigated. We studied 11 CTX patients aged 13-43 years. We performed dual-energy X-ray absorptiometry and assessed serum cholestanol and 25-hydroxyvitamin D (25-OHD) concentrations both at the time of diagnosis and after long-term treatment with CDCA. At baseline, we found low BMD in nine patients, cholestanol elevation in all subjects, and 25-OHD decrease in nine. After a mean follow-up time of 30 months (range 24-36), no substantial clinical changes including bone fractures occurred; and we detected a significant increase of both planar and volumetric BMD as well as normalization of plasma cholestanol levels and increase of serum 25-OHD. Densitometric improvement following CDCA introduction was not correlated to changes of biochemical parameters. Our study confirms the presence of low bone mass in CTX and demonstrates that long-term CDCA treatment increases bone mineral content. In this respect, improvement of vitamin D intestinal absorption secondary to bile acid restoration could play an important role. Moreover, our data strongly suggest the utility of periodic bone density evaluation in CTX patients.