RESUMEN
Osteopenia and osteoporosis have increasingly become a recognized morbidity in those persons with hemophilia (PwH) receiving inadequate prophylactic clotting factor replacement. Animal models can control or eliminate genetic and environmental factors and allow for invasive testing not clinically permissible. Here, we describe the skeletal phenotype of juvenile and adult male mice with a genetically engineered deficiency in coagulation factor IX (FIX KO). Although the somatic growth of FIX KO mice matched that of their wild-type (WT) littermates at 10 and 20 weeks of age, the FIX KO mice displayed reduced bone mineral density (BMD), reduced cortical and cancellous bone mass, and diminished whole bone fracture resistance. These findings coupled with parallel observations in a murine model of hemophilia A (FVIII deficiency) point to an effector downstream of the coagulation cascade that is necessary for normal skeletal development. Further study of potential mechanisms underlying the bone disease observed in rare clotting factor deficiency syndromes may lead to new diagnostic and therapeutic insights for metabolic bone diseases in general.
Asunto(s)
Hemofilia A , Hemofilia B , Animales , Densidad Ósea , Modelos Animales de Enfermedad , Factor IX/genética , Hemofilia A/genética , Hemofilia B/genética , Masculino , RatonesRESUMEN
Worldwide, one in five men aged over 50 years will experience osteoporosis or a clinical bone fracture, with a greater fracture-related mortality rate than women. However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI-adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD (N = 98) and highest adjusted BMD (N = 110) were chosen for exome sequencing. Controls (N = 82) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher's exact test was performed to compare low- or high-BMD subjects with controls for single-gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single-gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low-BMD subjects compared with controls (p = 0.009). Additionally, genes associated with EDS had a twofold increased frequency in low-BMD subjects compared with controls (p = 0.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene-panel approach to screen for multivariant associations in larger cohorts. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
RESUMEN
Peak bone mass, one of the most important predictors for fracture risk later in life, is attained during puberty and adolescence and influenced by neonatal and pubertal sex-specific gonadal hormones and GH-IGF-I secretion patterns. This study examined the effects of brief neonatal estrogen (NE) exposure on growth and skeletal development in C57BL/6J mice. A single injection of 100-µg estradiol or vehicle was administered on the first day of life. Growth parameters were monitored and skeletal phenotyping performed at 16 weeks in female mice and at 4 and 16 weeks in male mice. NE exposure negatively impacted adult femoral length in both sexes, but adult body weight, areal bone density, and bone strength in female mice were unaffected. In contrast, somatic growth was attenuated in estrogen-exposed male mice throughout the study period. At the prepubertal time point, the estrogen-exposed males exhibited higher bone mineral density, cortical volume, and cortical thickness compared with controls. However, by the time of peak bone mass acquisition, the early skeletal findings had reversed; estrogen-exposed mice had lower bone density with reduced cross-sectional area, cortical volume, and cortical thickness, resulting in cortical bones that were less resistant to fracture. NE exposure also resulted in reduced testicular volume and lower circulating IGF-I. Male mice exposed to estrogen on the first day of life experience age-dependent changes in skeletal development. Prepubertal animals experience greater endocortical bone acquisition as a result of estrogen exposure. However, by adulthood, continued developmental changes result in overall reduced skeletal integrity.
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Densidad Ósea/efectos de los fármacos , Desarrollo Óseo/efectos de los fármacos , Estradiol/análogos & derivados , Animales , Animales Recién Nacidos , Fenómenos Biomecánicos , Anticonceptivos/administración & dosificación , Anticonceptivos/farmacología , Estradiol/administración & dosificación , Estradiol/farmacología , Femenino , Hormona del Crecimiento/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factores SexualesRESUMEN
Skeletal integrity is dependent on the coordinated actions of bone-forming osteoblasts and bone-resorbing osteoclasts, which recognize and respond to multiple environmental inputs. Here we have studied the roles in bone development and growth of Akt1 and Akt2, two closely related signaling proteins, by evaluating mice lacking either of these enzymes. Global deficiency of Akt1 but not Akt2 caused a reduction in whole body and femoral bone mineral density, in femoral cortical thickness and volume, and in trabecular thickness in both males and females when measured at 20-weeks of age, which was reflected in diminished femoral resistance to fracture. Haplo-deficiency of Akt1 in male mice also decreased femoral cortical and trabecular skeletal parameters, and reduced bone strength. Cell-based studies showed that genetic Akt1 deficiency diminished the rate of proliferation of osteoblast progenitors and impaired osteoclast differentiation in primary culture but that loss of Akt2 did not. Our results demonstrate differential effects of Akt1 and Akt2 on skeletal maturation and architecture through actions on both osteoblast and osteoclast precursors.
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Densidad Ósea/fisiología , Fémur/enzimología , Osteoblastos/enzimología , Osteogénesis/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Células Madre/enzimología , Animales , Diferenciación Celular/fisiología , Femenino , Fémur/citología , Masculino , Ratones , Ratones Mutantes , Osteoblastos/citología , Proteínas Proto-Oncogénicas c-akt/genética , Células Madre/citologíaRESUMEN
Signaling via the type 4-melanocortin receptor (MC4R) is an important determinant of body weight in mice and humans, where loss of function mutations lead to significant obesity. Humans with mutations in the MC4R experience an increase in lean mass. However, the simultaneous accrual of fat mass in such individuals may contribute to this effect via mechanical loading. We therefore examined the relationship of fat mass and lean mass in mice lacking the type-4 melanocortin receptor (MC4RKO). We demonstrate that MC4RKO mice display increased lean body mass. Further, this is not dependent on changes in adipose mass, as MC4RKO mice possess more lean body mass than diet-induced obese (DIO) wild type mice with equivalent fat mass. To examine potential sources of the increased lean mass in MC4RKO mice, bone mass and strength were examined in MC4RKO mice. Both parameters increase with age in MC4RKO mice, which likely contributes to increases in lean body mass. We functionally characterized the increased lean mass in MC4RKO mice by examining their capacity for treadmill running. MC4R deficiency results in a decrease in exercise performance. No changes in the ratio of oxidative to glycolytic fibers were seen, however MC4RKO mice demonstrate a significantly reduced heart rate, which may underlie their impaired exercise performance. The reduced exercise capacity we report in the MC4RKO mouse has potential clinical ramifications, as efforts to control body weight in humans with melanocortin deficiency may be ineffective due to poor tolerance for physical activity.
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Tejido Adiposo/metabolismo , Densidad Ósea , Tolerancia al Ejercicio , Melanocortinas/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Envejecimiento/metabolismo , Envejecimiento/fisiología , Animales , Dieta/efectos adversos , Femenino , Técnicas de Inactivación de Genes , Fuerza de la Mano/fisiología , Frecuencia Cardíaca , Ratones , Fibras Musculares Esqueléticas/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Receptor de Melanocortina Tipo 4/deficiencia , Receptor de Melanocortina Tipo 4/genéticaRESUMEN
The melanocortin-3 receptor-deficient (MC3-R(-/-)) mouse exhibits mild obesity without hyperphagia or hypometabolism. MC3-R deletion is reported to increase adiposity, reduce lean mass and white adipose tissue inflammation, and increase sensitivity to salt-induced hypertension. We show here that the MC3-R(-/-) mouse exhibits defective fasting-induced white adipose tissue lipolysis, fasting-induced liver triglyceride accumulation, fasting-induced refeeding, and fasting-induced regulation of the adipostatic and hypothalamic-adrenal-pituitary axes. Close examination of the hypothalamic-pituitary-adrenal axis showed that MC3-R(-/-) mice exhibit elevated nadir corticosterone as well as a blunted fasting-induced activation of the axis. The previously described phenotypes of this animal and the reduced bone density reported here parallel those of Cushing syndrome. Thus, MC3-R is required for communicating nutritional status to both central and peripheral tissues involved in nutrient partitioning, and this defect explains much of the metabolic phenotype in the model.
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Metabolismo Energético/fisiología , Ayuno/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Receptor de Melanocortina Tipo 3/fisiología , Absorciometría de Fotón , Tejido Adiposo Blanco/metabolismo , Adiposidad/genética , Glándulas Suprarrenales/citología , Análisis de Varianza , Animales , Fenómenos Biomecánicos , Western Blotting , Composición Corporal/fisiología , Corticosterona/metabolismo , Inmunohistoquímica , Hibridación in Situ , Lipólisis/fisiología , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Melanocortina Tipo 3/deficiencia , Triglicéridos/metabolismoAsunto(s)
Modelos Animales de Enfermedad , Hemofilia A/patología , Animales , Densidad Ósea , Humanos , Masculino , Ratones , Ratones NoqueadosRESUMEN
Osteoporosis, the most common skeletal disorder, is characterized by low bone mineral density (BMD) and an increased risk of fragility fractures. BMD is the best clinical predictor of future osteoporotic fracture risk, but is a complex trait controlled by multiple environmental and genetic determinants with individually modest effects. Quantitative trait locus (QTL) mapping is a powerful method for identifying chromosomal regions encompassing genes involved in shaping complex phenotypes, such as BMD. Here we have applied QTL analysis to male and female genetically-heterogeneous F(2) mice derived from a cross between C57BL/6 and DBA/2 strains, and have identified 11 loci contributing to femoral BMD. Further analysis of a QTL on mouse chromosome 7 following the generation of reciprocal congenic strains has allowed us to determine that the high BMD trait, which tracks with the DBA/2 chromosome and exerts equivalent effects on male and female mice, is manifested by enhanced osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and by increased growth of metatarsal bones in short-term primary culture. An insertion/deletion DNA polymorphism in Ltbp4 exon 12 that causes the in-frame removal of 12 codons in the DBA/2-derived gene maps within 0.6 Mb of the marker most tightly linked to the QTL. LTBP4, one of four paralogous mouse proteins that modify the bioavailability of the transforming growth factor ß (TGF-ß) family of growth factors, is expressed in differentiating MSC-derived osteoblasts and in long bones, and reduced responsiveness to TGF-ß1 is observed in MSCs of mice homozygous for the DBA/2 chromosome 7. Taken together, our results identify a potential genetic and biochemical relationship between decreased TGF-ß1-mediated signaling and enhanced femoral BMD that may be regulated by a variant LTBP4 molecule.
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Huesos/metabolismo , Sitios de Carácter Cuantitativo/genética , Transducción de Señal/genética , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Densidad Ósea/efectos de los fármacos , Densidad Ósea/genética , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Proteína Morfogenética Ósea 2/farmacología , Huesos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Cruzamientos Genéticos , Femenino , Fémur/anatomía & histología , Fémur/metabolismo , Estudios de Asociación Genética , Laboratorios , Escala de Lod , Masculino , Huesos Metatarsianos/efectos de los fármacos , Huesos Metatarsianos/crecimiento & desarrollo , Ratones , Ratones Congénicos , Osteogénesis/efectos de los fármacos , Osteogénesis/genética , Fenotipo , Carácter Cuantitativo Heredable , Ratas , Transducción de Señal/efectos de los fármacos , Células del Estroma/citología , Células del Estroma/efectos de los fármacos , Células del Estroma/metabolismo , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Alkaline phosphatase (ALP) plays an essential role in the regulation of tissue mineralization, and its activity is highly heritable. Guided by genetic associations discovered in a murine model, we hypothesized a role for rare coding variants in determining serum ALP level and bone mineral density (BMD) in humans. We sequenced the coding regions of the ALP gene (ALPL) in men with low and normal serum ALP activity levels. Single-nucleotide ALPL variants, including 19 rare nonsynonymous variants (minor allele frequency <1%), were much more frequent among the low ALP group (33.8%) than the normal group (1.4%, p = 1 × 10(-11)). Within the low ALP group, men with a rare, nonsynonymous variant had 11.2% lower mean serum ALP (p = 3.9 × 10(-4)), 6.7% lower BMD (p = 0.03), and 11.1% higher serum phosphate (p = 0.002) than those without. In contrast, common nonsynonymous variants had no association with serum ALP, phosphate, or BMD. Multiple rare ALPL coding variants are present in the general population, and nonsynonymous coding variants may be responsible for heritable differences in mineralization and thus BMD.
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Fosfatasa Alcalina/sangre , Fosfatasa Alcalina/genética , Densidad Ósea/genética , Sistemas de Lectura Abierta/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Fosfatasa Alcalina/química , Secuencia de Aminoácidos , Animales , Huesos/metabolismo , Exones/genética , Haplotipos/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Fracturas Osteoporóticas/genética , Análisis de Secuencia de ADNRESUMEN
Disorders of water balance are among the most common and morbid of the electrolyte disturbances, and are reflected clinically as abnormalities in the serum sodium concentration. The transient receptor potential vanilloid 4 (TRPV4) channel is postulated to comprise an element of the central tonicity-sensing mechanism in the mammalian hypothalamus, and is activated by hypotonic stress in vitro. A nonsynonymous polymorphism in the TRPV4 gene gives rise to a Pro-to-Ser substitution at residue 19. We show that this polymorphism is significantly associated with serum sodium concentration and with hyponatremia (serum sodium concentration < or =135 mEq/L) in 2 non-Hispanic Caucasian male populations; in addition, mean serum sodium concentration is lower among subjects with the TRPV4(P19S) allele relative to the wild-type allele. Subjects with the minor allele were 2.4-6.4 times as likely to exhibit hyponatremia as subjects without the minor allele (after inclusion of key covariates). Consistent with these observations, a human TRPV4 channel mutated to incorporate the TRPV4(P19S) polymorphism showed diminished response to hypotonic stress (relative to the wild-type channel) and to the osmotransducing lipid epoxyeicosatrienoic acid in heterologous expression studies. These data suggest that this polymorphism affects TRPV4 function in vivo and likely influences systemic water balance on a population-wide basis.
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Hiponatremia/genética , Polimorfismo Genético , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/fisiología , Anciano , Alelos , Animales , Estudios de Cohortes , Humanos , Hiponatremia/diagnóstico , Masculino , Ratones , Mutación , Osteoporosis/genética , Prolina/química , Serina/química , Factores SexualesRESUMEN
PURPOSE OF REVIEW: With an aging population, osteoporosis has become a public health concern and an area of increased awareness among both patients and medical practitioners. Timely screening and pharmacologic treatment of low bone mass effectively reduces fracture risk. Nonpharmacologic interventions, however, deserve equal emphasis both in the prevention and treatment of osteoporosis. RECENT FINDINGS: Recent advances in bone biology have established that exercise in the form of short, repetitive mechanical loading leads to the greatest gains in bone strength. As demonstrated by both observational and randomized exercise intervention trials, these gains are best achieved in childhood but can be maintained in adulthood with continued regular weight-bearing exercise. In the later years, evidence supports the implementation of balance training to decrease fall risk, especially in elderly patients with low bone mass. Following an osteoporotic fracture, a multidisciplinary rehabilitation program with an emphasis on early mobilization, fall prevention, use of orthoses, and noninvasive surgical procedures is emerging as a promising approach. SUMMARY: Clinically, these findings should imply greater emphasis on high impact exercise during skeletal growth and on maintenance of weight bearing and balance training in the later years. Future research should examine the effect of these interventions on fracture prevention.
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Terapia por Ejercicio/métodos , Ejercicio Físico , Osteoporosis/rehabilitación , Accidentes por Caídas/prevención & control , Densidad Ósea/fisiología , Fracturas de Cadera/prevención & control , Fracturas de Cadera/rehabilitación , Humanos , Osteoporosis/terapiaRESUMEN
OBJECTIVE: Perioperative hypocalcemia from temporary parathyroid gland dysfunction is common after thyroid surgery. No reliable cutoff values for parathyroid hormone (PTH) and the subsequent possibility of developing hypocalcemia exist. The purpose of this study is to determine a criterion for predicting hypocalcemia based on different PTH levels as cutoff values. STUDY DESIGN: Retrospective chart review. METHODS: A centralized database of intraoperative PTH levels was analyzed. PTH values approximately 10 minutes after excision of the thyroid gland and in the recovery room were obtained; serial ionized calcium levels were also analyzed. PTH values were then compared using chi-square analysis with significance defined as P < .05. A receiver operator characteristic (ROC) curve was also constructed to define sensitivities and specificities of different PTH levels as potential cutoff values. RESULTS: Eighty patients were identified meeting the study criteria between January 1999 and February 2005. Fourteen of the 80 (17.5%) patients became hypocalcemic during the hospital stay; none experienced permanent hypocalcemia. Patients who became hypocalcemic during their hospitalization were more likely to have a PTH level below 15 pg/mL (P < .01). Patients with a PTH level less than 15 pg/mL were more likely to develop hypocalcemia (P < .01). Finally, an ROC curve was constructed, allowing the surgeon to determine acceptable sensitivities and specificities and various PTH cutoff values. CONCLUSION: Low perioperative PTH levels significantly correlate with the presence of postoperative hypocalcemia but cannot be used to predict it. Using the ROC curve allows different chosen cutoff values to predict hypocalcemia with varying sensitivity and specificity.
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Hormona Paratiroidea/sangre , Enfermedades de la Tiroides/cirugía , Tiroidectomía , Biomarcadores/sangre , Calcio/sangre , Femenino , Humanos , Hipocalcemia/sangre , Hipocalcemia/diagnóstico , Hipocalcemia/etiología , Masculino , Atención Perioperativa , Pronóstico , Curva ROC , Estudios Retrospectivos , Enfermedades de la Tiroides/sangre , Enfermedades de la Tiroides/complicacionesRESUMEN
UNLABELLED: The Alox15 gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12 may contribute to normal variation in BMD. INTRODUCTION: Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15-lipoxygenase (Alox15) gene was identified as a negative regulator of peak BMD in mice. MATERIALS AND METHODS: To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population- and family-based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18-61 years of age and 1291 premenopausal women 20-50 years of age. RESULTS: Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052-0.050). Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081). CONCLUSIONS: Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.
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Araquidonato 12-Lipooxigenasa/genética , Densidad Ósea/genética , Población Blanca/genética , Adolescente , Adulto , Araquidonato 15-Lipooxigenasa/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , HermanosRESUMEN
The development of osteoporosis involves the interaction of multiple environmental and genetic factors. Through combined genetic and genomic approaches, we identified the lipoxygenase gene Alox15 as a negative regulator of peak bone mineral density in mice. Crossbreeding experiments with Alox15 knockout mice confirmed that 12/15-lipoxygenase plays a role in skeletal development. Pharmacologic inhibitors of this enzyme improved bone density and strength in two rodent models of osteoporosis. These results suggest that drugs targeting the 12/15-lipoxygenase pathway merit investigation as a therapy for osteoporosis.
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Araquidonato 12-Lipooxigenasa/genética , Araquidonato 12-Lipooxigenasa/metabolismo , Araquidonato 15-Lipooxigenasa/genética , Araquidonato 15-Lipooxigenasa/metabolismo , Densidad Ósea/genética , Animales , Densidad Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Diferenciación Celular , Células Cultivadas , Cruzamientos Genéticos , Inhibidores Enzimáticos/farmacología , Femenino , Fluorenos/farmacología , Perfilación de la Expresión Génica , Ligamiento Genético , Riñón/metabolismo , Inhibidores de la Lipooxigenasa , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoblastos/citología , Osteoblastos/metabolismo , Osteoblastos/fisiología , Osteogénesis , Osteoporosis/enzimología , Polimorfismo Genético , Sitios de Carácter Cuantitativo , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Células del Estroma/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Size and shape are critical determinants of the mechanical properties of skeletal elements and can be anticipated to be highly heritable. Moreover, the genes responsible may be independent of those that regulate bone mineral density (BMD). To begin to identify the heritable determinants of skeletal geometry, we have examined femoral cross-sectional area (FCSA) in male and female mice from two inbred strains of mice with divergent FCSA (C57BL/6 [B6] and DBA/2 [D2]), a large genetically heterogeneous population (n = 964) of B6D2F2 mice and 18 BXD recombinant inbred (RI) strains derived from their F2 cross. Femora were harvested from 16-week-old mice and FCSA (bone and marrow space enclosed within the periosteum) was measured at the midshaft by digital image analysis. In all mouse populations examined, FCSA was positively correlated with body weight and weight-corrected FCSA (WC-FCSA) values were normally distributed in the BXD-RI and F2 populations, suggesting polygenic control of this trait. Genome-wide quantitative trait locus (QTL) analysis of the B6D2F2 population revealed regions on four different chromosomes that were very strongly linked to WC-FCSA (chromosomes 6, 8, 10, and X) in both genders. Evidence of gender-specific genetic influences on femoral geometry was also identified at three other chromosomal sites (chromosomes 2, 7, and 12). Supporting evidence for the WC-FCSA QTLs on chromosomes 2, 7, 8, 10, and 12 also was present in the RI strains. Interestingly, none of these WC-FCSA QTLs were identified in our previous QTL analysis of whole body BMD in the same B6D2F2 population. Thus, the genetic determinants of bone size appear to be largely, if not entirely, distinct from those that regulate BMD attainment. The identification of the genes responsible for geometric differences in bone development should reveal fundamentally important processes in the control of skeletal integrity.