Osteoporosis, is a serious disease both in women and men, with a high risk of fractures. However, its pathogenesis differs markedly, with the secondary form being more common in men. The aim of this case study is to demonstrate the complex pathogenesis of a severe osteoporosis in a 23-year-old heavy smoker with histiocytosis X, diabetes insipidus (DI), subclinical hypogonadism and low serum levels of IGF-I. Later, after normalization of sex hormones and IGF-I levels, vasopressin substitution, cessation of smoking and after long-term antiresorption therapy, adequate increase in bone density at the hip was documented, but insufficient and very slow increase at the lumbar spine was observed. Severe osteoporosis at the spine is most probably the consequence of the interaction of smoking with multiple hormone insufficiency during development of peak bone mass. The effect of additional, unidentified factor(s) (gene or hormone) is also likely. On the other hand, a direct causal association between histiocytosis X and osteoporosis was not confirmed histomorphometrically in this patient.