Osteopenia is a metabolic bone disease which affects a great deal of preterm infants. X-Ray evaluation is still the main step of the diagnostic and follow-up procedures. The Authors prospectively studied 77 newborn infants with birth weight less than 2500 grams, to identify specific clinical and biochemical features of the osteopenic infants. From the 2nd to the 12th week of life clinical, biochemical and radiological signs of osteopenia were looked for, every 2 weeks: the diagnosis of osteopenia was made on the basis of X-Ray. 26 osteopenic subjects with ga less than or equal to 32 weeks and/or bw less than or equal to 1500 grams were compared with 20 controls with ga less than or equal to 32 weeks and/or bw less than or equal to 1500 grams and with 31 control infants with ga greater than 32 weeks and bw greater than 1500 grams. Wider anterior funtanels, their progressively increasing dimensions, and craniotabe (with the "ping pong ball" sign) were the most characteristic features, as well as the increasing pattern of alkaline phosphatase activity, of the osteopenic babies. The Authors suggest a specific clinical and biochemical score to make the correct diagnosis and a non invasive follow-up in the osteopenic subjects and to avoid dangerous X-Ray exposure to babies that are not osteopenic.