Smoking is associated with lower areal bone mineral density and higher fracture risk, although most evidence has been derived from studies in elderly subjects. This study [1] investigates smoking habits in relation to areal and volumetric bone parameters and fracture prevalence in young, healthy males at peak bone mass. Healthy male siblings (n=677) at the age of peak bone mass (25 to 45 years) were recruited in a cross-sectional population-based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mass was determined using dual energy X-ray absorptiometry (DXA). Sex steroids and bone markers were determined using immunoassays. Prevalent fractures and smoking habits were assessed using questionnaires.

Self-reported fractures were more prevalent in the current and early smokers than in the never smokers (P<.05), with a fracture prevalence odds ratio for early smokers of 1.96 after adjustment for age, weight, educational level, and alcohol use and exclusion of childhood fractures. Current smoking was associated with a significantly larger endosteal circumference and a decreased cortical thickness at the tibia.
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The B cell lymphoma 2 (Bcl-2) family member Bcl-xL has a well-characterized antiapoptotic function in lymphoid cells. However, its functions in other cells - including osteoclasts, which are of hematopoietic origin - and other cellular processes remain unknown. The authors of a recent study [1] report an unexpected function of Bcl-xL in attenuating the bone-resorbing activity of osteoclasts in mice. To investigate the role of Bcl-xL in osteoclasts, they generated mice with osteoclast-specific conditional deletion of Bcl-x.

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Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. In a recent study [1], the authors 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 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.
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RANK ligand (RANKL) is produced by osteoblasts and is an essential mediator for osteoclast development. No study has examined in detail the direct skeletal consequences of excess RANKL on bone turnover, mineralization, architecture, and vascular calcification. The authors of a recent study [1] administered soluble RANKL continuously to mature rats and created a bone-loss model. Six-month-old Sprague-Dawley rats were assigned to three groups (n=12) receiving continuous administration of saline (VEH) or human RANKL (35 μg/kg/day or 175 μg/kg/day) for 28 days. Blood was collected routinely during the study. At sacrifice, hind limbs and aorta were removed and samples were analyzed.

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Major depressive disorder is a common condition and a major cause of disability. Besides mood changes, depression is associated with increased morbidity and non–suicide-related mortality. In addition to poor medical compliance and lifestyle factors, endocrine, immune, and autonomic dysregulation may play a causative role in producing medical illnesses in patients with major depression. An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder, mostly women. Moreover, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) may affect bone density and fracture risk per se, depending on the age of patients. The association of major depression disorder and BMD was investigated in a prospective study of bone turnover in which immune, pituitary-adrenal, and sympathetic biomarkers were measured [1]. The authors sought to determine whether premenopausal women with major depression had a higher prevalence of osteopenia and osteoporosis and of lower BMD than did healthy women. Baseline BMD was measured in 89 premenopausal women with major depression and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women.

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X-linked hypophosphatemia (XLH) is the archetypal vitamin D–resistant disease in humans, and the most common form of inherited rickets, with an incidence of approximately 1 in 20 000 live births. The disease is characterized by renal phosphate (Pi) wasting with resulting hypophosphatemia, abnormal vitamin D metabolism, defective bone and cartilage mineralization, dentine defects, and stunted growth. Recently, the gene involved in the pathogenesis of XLH was identified and designated as PHEX (the phosphate-regulating gene with homologies to endopeptidases on the X chromosome). The murine homolog of the human disease, the hyp-mouse, has a phenotype identical to that evident in patients with XLH, and is due to a large deletion in the 3′ region of the Phex gene. These findings suggest that a mutation in the PHEX/Phex gene is responsible for the phenotypic changes in patients with XLH and the hyp-mouse. Although PHEX/Phex expression occurs primarily in osteoblast lineage cells, transgenic Phex expression in hyp-mouse osteoblasts fails to rescue the phenotype, suggesting that Phex expression at other sites underlies XLH.
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The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. In this study[1], the authors used a rodent model of vitamin D depletion to quantify the 25-hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10-wk-old male Sprague-Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D3 for 4 months to achieve stable mean serum 25D levels ranging between 10 and 115 nmol/L. At 7 months of age, animals were killed, and the histomorphometry of distal and proximal femora and L2 vertebra was analyzed. Total RNA was extracted from whole femora for real-time RT-PCR analyses.
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Osteopetrosis is caused by a failure of osteoclasts to resorb bone tissue, resulting in bone marrow cavities becoming occluded. Osteopetrosis is a monogenetic disease and, whenever it occurs, can be traced to a gene essential to osteoclast function. The most severe form of human osteopetrosis is the malignant, infantile, autosomal recessive variant (ARO). ARO occurs because of specific mutations in genes responsible for osteoclast function. Despite a decrease in resorption, osteoclast numbers are normal or increased. These ‘‘osteoclast-rich’’ cases suggest that the osteoclast defect does not affect osteoclast formation but rather lies in their mature functional capacity. Providing osteoclast precursors via bone marrow transplantation successfully treats these patients.

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Bone alters its morphology and density in response to external loads. Lack of mechanical stimulation has been linked to bone loss in osteoporosis. Models of bone tissue predict that during loading, fluid flows through the compartments (lacunae) that house osteocytes within mineralized bone and through the channels (canaliculae) that connect lacunae to each other and to bone-forming osteoblasts at the bone surface. Experiments in cultured bone cells have shown that dynamic fluid flow stimulates osteogenic, and inhibits bone resorptive, responses. Primary cilia are solitary, immotile, microtubule-based organelles that grow from the centrosome and project from the cell surface in many vertebrate tissues, including bone. Primary cilia also function as flow sensors in kidney tubule epithelial cells where they mediate calcium entry through polycystin 2, a stretch-activated calcium channel. Mutations of polycystins cause polycystic kidney disease.

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Calcineurin is a protein phosphatase that regulates several physiological processes and is the target for cyclosporine A. Pharmacological inhibition of calcineurin by low concentrations of cyclosporin A increases osteoblast differentiation in vitro and bone mass in vivo. To determine whether calcineurin exerts direct actions on osteoblasts, the authors of a recent study [1] generated mice lacking a calcineurin regulatory subunit selectively in osteoblasts.
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