Bone effects of raloxifene in a man with estradiol deficiency

We present the first case of a 25-year-old man with low estradiol levels (studied for aromatase activity), who was treated with raloxifene 60 mg/day for one year. Previously, we described the favorable response to estradiol treatment of two men with aromatase deficiency, a genetic defect characterized in men by high stature, persistent linear growth, eunuchoid skeleton, unfused epiphyses, genu valgum and osteoporosis (Carani, N Engl J Med 1997; Maffei, J Clin Endocrinol Metab 2004). Clinical character- istics of the patient here presented were bone pain, tall height and persistent linear growth due to incomplete closure of growth cartilages (bone age 15.3 years), low BMD and eunuchoid proportions of the skeleton. We show the effects of raloxifene administration (60 mg/day) after 6 and 12 months of treatment [supplemented with calcium citrate 3000 mg/day (630 mg Ca+) + vitamin D 400 UI/day]. Ultrasound forearm bone mineral density (BMD) mostly improved after the first 6 months of treatment altogether with a progressive decrease of the markers of bone resorption and increase in those of formation, with no effect on bone age. In aromatase deficient men estrogen therapy results in the induction of bone maturation, closure of growth cartilages, normalization of serum markers of bone remodeling and an increase in BMD observed during. Conversely in this patient raloxifene led only to an improvement of bone remodeling markers and to an increase of BMD. Bone biopsy before treatment showed an increased trabecular remodeling with wide bone resorption and formation surfaces, and increased osteoblastic activity; after an year of treatment bone remodeling appeared greatly reduced with a normalization of all histomorphometric parameters. These data prove that in men mechanisms of estrogen action are different in relation to the tissue involved (cartilage or bone) and the biological effects (growth or mineralization), suggesting that pathways recruited for estrogen action may be heterogeneous with respect to the activation of different receptors or post-receptorial transductive way as well as the characteristics of the estrogen compound used for treatment.