Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.

The parathyroid glands are the only known source of circulating parathyroid hormone (PTH), which initiates an endocrine cascade that regulates serum calcium concentration. Glial cells missing2 (Gcm2), a mouse homologue of Drosophila Gcm, is the only transcription factor whose expression is restricted to the parathyroid glands. Here we show that Gcm2-deficient mice lack parathyroid glands and exhibit a biological hypoparathyroidism, identifying Gcm2 as a master regulatory gene of parathyroid gland development. Unlike PTH receptor-deficient mice, however, Gcm2-deficient mice are viable and fertile, and have only a mildly abnormal bone phenotype. Despite their lack of parathyroid glands, Gcm2-deficient mice have PTH serum levels identical to those of wild-type mice, as do parathyroidectomized wild-type animals. Expression and ablation studies identified the thymus, where Gcm1, another Gcm homologue, is expressed, as the additional, downregulatable source of PTH. Thus, Gcm2 deletion uncovers an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands. We propose that this backup mechanism may be a general feature of endocrine regulation.

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Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.

ABSTRACT:We recently described an unexpected high bone mass phenotype in mice lacking the Calca gene that encodes CT and ␣CGRP. Here we show that mice specifically lacking ␣CGRP expression display an osteopenia caused by a decreased bone formation. These results show that ␣CGRP is a physiological activator of bone formation and that the high bone mass phenotype of the Calca-deficient mice is caused by the absence of CT.Introduction: Calcitonin (CT) and ␣-calcitonin gene-related peptide (␣CGRP) are two polypeptides without completely defined physiologic functions that are both derived from the Calca gene by alternative splicing. We have recently described an unexpected high bone mass phenotype in mice carrying a targeted deletion of the Calca gene. To uncover whether this phenotype is caused by the absence of CT or by the absence of ␣CGRP, we analyzed a mouse model, where the production of ␣CGRP is selectively abolished. Materials and Methods: Bones from CalcaϪ/Ϫ mice, ␣CGRP Ϫ/Ϫ mice, and their corresponding wildtype controls were analyzed using radiography, CT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring the urinary collagen degradation products. CT expression was determined using radioimmunoassay and RT-PCR. Immunohistochemistry was performed using an anti-CGRP antibody on decalcified bone sections. Results: Unlike the Calca-deficient mice, the ␣CGRP-deficient mice do not display a high bone mass phenotype. In contrast, they develop an osteopenia that is caused by a reduced bone formation rate. Serum levels and thyroid expression of CT are not elevated in ␣CGRP-deficient mice. While CGRP expression is detectable in neuronal cell close to trabecular bone structures, the components of the CGRP receptor are expressed in differentiated osteoblast cultures. Conclusion:The discrepancy between the bone phenotypes of Calca Ϫ/Ϫ mice and ␣CGRP Ϫ/Ϫ mice show that the high bone mass phenotype of the Calca Ϫ/Ϫ mice is caused by the absence of CT. The osteopenia observed in the ␣CGRP Ϫ/Ϫ mice that have normal levels of CT further show that ␣CGRP is a physiologic activator of bone formation.

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The InterTan device appears to be a reliable implant for the treatment of intertrochanteric femoral fractures. Its design provides for stability against rotation and minimizes neck malunions (shortening) through linear intraoperative compression of the head/neck segment to the shaft. As a result of the negligible complication rate and improved clinical outcomes, this implant is now the standard treatment for all intertrochanteric fractures at our institution.

IntroductionExact knowledge of femoral neck inclination and torsion angles is important in recognizing, understanding and treating pathologic conditions in the hip joint. However, published results vary widely between different studies, which indicates that there are persistent difficulties in carrying out exact measurements.MethodsA three dimensional modeling and analytical technology was used for the analysis of 1070 CT datasets of skeletally mature femurs. Individual femoral neck angles and torsion angles were precisely computed, in order to establish whether gender, age, body mass index and ethnicity influence femoral neck angles and torsion angles.ResultsThe median femoral neck angle was 122.2° (range 100.1–146.2°, IQR 117.9–125.6°). There are significant gender (female 123.0° vs. male 121.5°; p = 0.007) and ethnic (Asian 123.2° vs. Caucasian 121.9°; p = 0.0009) differences. The median femoral torsion angle was 14.2° (-23.6–48.7°, IQR 7.4–20.4°). There are significant gender differences (female 16.4° vs. male 12.1°; p = 0.0001). Femoral retroversion was found in 7.8% of the subjects.ConclusionPrecise femoral neck and torsion angles were obtained in over one thousand cases. Systematic deviations in measurement due to human error were eliminated by using automated high accuracy morphometric analysis. Small but significant gender and ethnic differences were found in femoral neck and torsion angles.