Targeted disruption of the histidine decarboxylase gene (HDC ؊/؊ ), the only histamine-synthesizing enzyme, led to a histamine-deficient mice characterized by undetectable tissue histamine levels, impaired gastric acid secretion, impaired passive cutaneous anaphylaxis, and decreased mast cell degranulation. We used this model to study the role of histamine in bone physiology. Compared with WT mice, HDC ؊/؊ mice receiving a histamine-free diet had increased bone mineral density, increased cortical bone thickness, higher rate of bone formation, and a marked decrease in osteoclasts. After ovariectomy, cortical and trabecular bone loss was reduced by 50% in HDC ؊/؊ mice compared with WT. Histamine deficiency protected the skeleton from osteoporosis directly, by inhibiting osteoclastogenesis, and indirectly, by increasing calcitriol synthesis. Quantitative RT-PCR showed elevated 25-hydroxyvitamin D-1␣-hydroxylase and markedly decreased 25-hydroxyvitamin D-24-hydroxylase mRNA levels. Serum parameters confirming this indirect effect included elevated calcitriol, phosphorus, alkaline phosphatase, and receptor activator of NF-B ligand concentrations, and suppressed parathyroid hormone concentrations in HDC ؊/؊ mice compared with WT mice. After ovariectomy, histamine-deficient mice were protected from bone loss by the combination of increased bone formation and reduced bone resorption.

Osteopathia has been reported in Wilson disease (WD), but bone density has not been measured; therefore, we performed bone mineral density (BMD), bone mineral content (BMC), and quantitative bone ultrasound (QUS) assessments, as well as measured the serum levels of osteocalcin (OCN), ␤-cross-laps (␤-CTx's), and the recently discovered osteoprotegerin (OPG) and its ligand RANKL to investigate the underlying mechanism of osseous disorders. Serum OCN, ␤-CTx, OPG, and RANKL levels were measured by ELISA in 21 WD patients and in 20 age-and gender-matched healthy subjects. BMD, BMC, and QUS parameters were also determined. Osteoporosis was present in 9/21 (43%) WD patients. Abnormal QUS parameters were found in 7 (33%) of the patients. Although serum OCN levels were similar in patients and controls (