Ten patients with systemic mastocytosis (SM) were evaluated for their metabolic bone disease (4 men and 6 women; mean +/- SD, 59 +/- 13 yr). All patients presented with generalized osteopenia and/or atraumatic vertebral compression fractures. Three patients had long-standing urticaria pigmentosa; in these, the diagnosis of cutaneous mastocytosis had been established by skin biopsy. One of the 3 and 2 of the other 7 individuals had symptoms suggestive of SM. Although six patients had previously undergone decalcified bone marrow trephine core biopsy (DBMB), findings were consistent with SM in only 2 of them. X-Ray survey revealed generalized osteopenia in all 10 patients and vertebral compression fractures in 9. No patient had sclerotic bone lesions. Histological findings of undecalcified transiliac crest biopsy (UTBB) specimens from 9 patients (5 patients underwent both DBMB and UTBB, 4 underwent only UTBB, and 1 had only DBMB) disclosed bone marrow that contained nodules characteristic of mast cell granulomas and numerous scattered oval- and spindle-shaped mast cells. The trabecular bone contained abundant newly synthesized bone matrix and a significant increase in osteoblastic, osteoclastic, and resorptive surfaces. Dynamic histomorphometric parameters revealed a significantly increased mineral apposition rate. Our study suggests that SM may be a more frequent cause of osteoporosis than previously recognized. Generalized osteopenia with compression fractures may be the only presentation of SM. Undecalcified bone biopsy is useful in the diagnosis of SM. Accelerated bone remodeling is a characteristic histomorphometric feature of SM with diffuse osteopenia.