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Trabecular Bone Loss (trabecular + bone_loss)
Selected AbstractsOsteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2007Amanda J Notini Abstract The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. Introduction: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. Materials and Methods: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative ,CT at 6, 12, and 32 weeks of age (n = 8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. Results: ,CT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p < 0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p < 0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p < 0.01) and an increase in trabecular separation (p < 0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. Conclusions: These findings show that inactivation of the DNA binding,dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding,dependent actions of the AR in mature osteoblasts. [source] Tibolone Exerts Its Protective Effect on Trabecular Bone Loss Through the Estrogen ReceptorJOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2001A. G. H. Ederveen Abstract Tibolone (Org OD14) has estrogenic, progestogenic, and/or androgenic activity depending on the tissue. In postmenopausal women, tibolone prevents bone loss without stimulating the endometrium. Tibolone is effective in preventing trabecular bone loss from the peripheral and axial skeleton of young and old ovariectomized (OVX) rats by reducing bone turnover, that is, bone resorption, like estrogens. We evaluated the contribution of the various hormonal activities to tibolone's bone-conserving effect. Three-month-old OVX rats received tibolone (125 ,g/rat or 500 ,g/rat, twice daily), alone or combined with an antiestrogen, antiandrogen, or antiprogestogen, and the effects on trabecular bone mass and bone turnover were evaluated. Sham-operated and control OVX groups were treated with vehicle. The remaining OVX groups received oral doses of tibolone twice daily, alone or with twice daily (a) antiestrogen ICI 164.384, (b) antiandrogen flutamide, or (c) antiprogestogen Org 31710. For comparison, the effects of 17,-estradiol and testosterone were examined also. After 4 weeks, trabecular bone mineral density (BMD) in the distal femur, plasma osteocalcin, and urinary deoxypyridinoline/creatinine ratio (Dpyr/Cr) were measured. Tibolone or 17,-estradiol significantly blocked ovariectomy-induced loss of trabecular BMD and inhibited bone resorption and bone turnover as judged by reduced Dpyr/Cr ratio and osteocalcin, respectively. These effects of both compounds were counteracted by the antiestrogen. This suggests a major involvement of the estrogen receptor in the action of tibolone on bone metabolism. However, the antiandrogen and the antiprogestogen did not counteract the effects of tibolone, excluding a major role of the androgenic and progestogenic activities of tibolone in its action against trabecular bone loss. The results indicate that tibolone acts on bone almost entirely through activation of the estrogen receptor. [source] Female Estrogen Receptor ,,/, Mice Are Partially Protected Against Age-Related Trabecular Bone LossJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2001Sara H. Windahl Abstract Recently, it has been shown that inactivation of estrogen receptor , (ER-,) by gene targeting results in increased cortical bone formation in adolescent female mice. To study the possible involvement of ER-, in the regulation of the mature skeleton, we have extended the analyses to include 1-year-old ER-, knockout mice (ER-,,/,). Male ER-,,/, mice did not express any significant bone phenotypic alterations at this developmental stage. However, the increase in cortical bone parameters seen already in the adolescent female ER-,,/, mice was maintained in the older females. The aged female ER-,,/, mice further exhibited a significantly higher trabecular bone mineral density (BMD) as well as increased bone volume/total volume (BV/TV) compared with wild-type (wt) mice. This was caused by a less pronounced loss of trabecular bone during adulthood in female ER-,,/, mice. The growth plate width was unaltered in the female ER-,,/, mice. Judged by the expression of the osteoclast marker tartrate-resistant acid phosphatase (TRAP) and cathepsin K (cat K; reverse-transcription-polymerase chain reaction [RT-PCR]) as well as the serum levels of C-terminal type I collagen cross-linked peptide, bone resorption appeared unaffected. However, an increase in the messenger RNA (mRNA) expression levels of the osteoblast marker core-binding factor ,1 (Cbfa1) suggested an anabolic effect in bones of old female ER-,,/, mice. In addition, the mRNA expression of ER-, was augmented, indicating a role for ER-, in the development of this phenotype. Taken together, the results show that ER-, is involved in the regulation of trabecular bone during adulthood in female mice and suggest that ER-, acts in a repressive manner, possibly by counteracting the stimulatory action of ER-, on bone formation. [source] Mice Lacking the Plasminogen Activator Inhibitor 1 Are Protected from Trabecular Bone Loss Induced by Estrogen DeficiencyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2000E. Daci Abstract Bone turnover requires the interaction of several proteases during the resorption phase. Indirect evidence suggests that the plasminogen activator/plasmin pathway is involved in bone resorption and turnover, and recently we have shown that this cascade plays a role in the degradation of nonmineralized bone matrix in vitro. To elucidate the role of the plasminogen activator inhibitor 1 (PAI-1) in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of PAI-1 gene (PAI-1,/,) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (Sham) and compared with wild-type (WT) mice. PAI-1 inactivation was without any effect on bone metabolism at baseline or in Sham mice. However, significant differences were observed in the response of WT and PAI-1,/, mice to ovariectomy. The OVX WT mice showed, as expected, decreased trabecular bone volume (BV/TV) and increased osteoid surface (OS/BS) and bone formation rate (BFR), as assessed by histomorphometric analysis of the proximal tibial metaphysis. In contrast, no significant change in any of the histomorphometric variables studied was detected in PAI-1,/, mice after ovariectomy. As a result, the OVX PAI-1,/, had a significantly higher BV/TV, lower OS/BS, lower mineral apposition rate (MAR) and BFR when compared with the OVX WT mice. However, a comparable decrease in the cortical thickness was observed in OVX PAI-1,/, and WT mice. In addition, the cortical mineral content and density assessed in the distal femoral metaphysis by peripheral quantitative computed tomography (pQCT), decreased significantly after ovariectomy, without difference between PAI-1,/, mice and WT mice. In conclusion, basal bone turnover and bone mass are only minimally affected by PAI-1 inactivation. In conditions of estrogen deficiency, PAI-1 inactivation protects against trabecular bone loss but does not affect cortical bone loss, suggesting a site-specific role for PAI-1 in bone turnover. [source] An Uncoupling Agent Containing Strontium Prevents Bone Loss by Depressing Bone Resorption and Maintaining Bone Formation in Estrogen-Deficient RatsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2005Pierre J. Marie Ph.D. Trabecular bone loss in estrogen deficiency is associated with enhanced bone resorption with a smaller increase in bone formation. We previously reported that low doses of strontium can increase trabecular bone volume in rodents by affecting bone resorption and formation. In this study we determined the effect of a new divalent strontium salt (S12911) on bone loss induced by E2 deficiency. Sprague-Dawley female rats (230 g, n = 15,25 per group) were sham operated or ovariectomized (OVX) and treated with 17,-estradiol (E2, 10 ,g/kg/day, sc) or S12911 by gavage at the dose of 77, 154, or 308 mg/kg/day or the vehicle. Treatment for 60 days with S12911 resulted in a dose-dependent increase in plasma, urine, and bone strontium concentrations without any deleterious effect on total or skeletal growth. OVX rats were osteopenic compared to sham rats as shown by decreased femoral dry bone weight and mineral content measured on bone ash and by DXA. Treatment of OVX rats with S12911 prevented bone loss as bone ash and bone mineral content were restored to the values in sham rats. Trabecular bone volume measured by histomorphometry on the tibial metaphysis was decreased by 46% in OVX rats and was corrected by E2. Treatment of OVX rats with S12911 increased the trabecular bone volume by 30,36%. Histomorphometric indices of bone resorption (osteoclast surface and number) were increased in OVX rats and were reduced by S12911 to the levels in sham rats. In contrast to this inhibitory effect on bone resorption, the osteoid surface, osteoblast surface, mineral apposition rate, and bone formation rate were as high in OVX rats treated with S12911 as in untreated OVX rats. In addition, plasma osteocalcin (OC) and alkaline phosphatase (ALP) levels remained elevated or were further increased in OVX rats treated with S12911. In contrast, treatment with E2 reduced both bone resorption and formation and plasma ALP and OC to the levels in sham rats. The data indicate that the divalent strontium salt S12911 is acting as an uncoupling agent that can prevent the femoral osteopenia and partially prevent the trabecular bone loss in E2-deficient rats by inhibiting bone resorption without reducing bone formation. [source] Hip Fractures and the Contribution of Cortical Versus Trabecular Bone to Femoral Neck Strength,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2009Gerold Holzer Abstract Osteoporotic fractures are caused by both cortical thinning and trabecular bone loss. Both are seen to be important for bone fragility. The relative contributions of cortical versus trabecular bone have not been established. The aim of this study was to test the contribution of cortical versus trabecular bone to femoral neck stability in bone strength. In one femur from each pair of 18 human cadaver femurs (5 female; 4 male), trabecular bone was completely removed from the femoral neck, providing one bone with intact and the other without any trabecular structure in the femoral neck. Geometrical, X-ray, and DXA measurements were carried out before biomechanical testing (forces to fracture). Femoral necks were osteotomized, slices were analyzed for cross-sectional area (CSA) and cross-sectional moment of inertia (CSMI), and results were compared with biomechanical testing data. Differences between forces needed to fracture excavated and intact femurs (,F/F mean) was 7.0% on the average (range, 4.6,17.3%). CSA of removed spongiosa did not correlate with difference of fracture load (,F/F mean), nor did BMD. The relative contribution of trabecular versus cortical bone in respect to bone strength in the femoral neck seems to be marginal and seems to explain the subordinate role of trabecular bone and its changes in fracture risk and the effects of treatment options in preventing fractures. [source] Osteoblast Deletion of Exon 3 of the Androgen Receptor Gene Results in Trabecular Bone Loss in Adult Male Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 3 2007Amanda J Notini Abstract The mechanism of androgen action on bone was studied in male mice with the AR deleted in mature osteoblasts. These mice had decreased trabecular bone volume associated with a decrease in trabecular number, suggesting that androgens may act directly on osteoblasts to maintain trabecular bone. Introduction: Androgens modulate bone cell activity and are important for the maintenance of bone mass. However, the mechanisms by which they exert these actions on bone remain poorly defined. The aim of this study was to investigate the role of androgens acting through the classical androgen receptor (AR) signaling pathways (i.e., DNA-binding dependent pathways) in osteoblasts using male mice in which exon 3 of the AR gene was deleted specifically in mature osteoblasts. Materials and Methods: Mice with a floxed exon 3 of the AR gene were bred with Col 2.3-cre transgenic mice, in which Cre recombinase is expressed in mineralizing osteoblasts. The skeletal phenotype of mutant mice was assessed by histomorphometry and quantitative ,CT at 6, 12, and 32 weeks of age (n = 8 per group). Wildtype, hemizygous exon 3 floxed and hemizygous Col 2.3-cre male littermates were used as controls. Data were analyzed by one-way ANOVA and Tukey's posthoc test. Results: ,CT analysis of the fifth lumbar vertebral body showed that these mice had reduced trabecular bone volume (p < 0.05) at 32 weeks of age compared with controls. This was associated with a decrease in trabecular number (p < 0.01) at 12 and 32 weeks of age, suggesting increased bone resorption. These effects were accompanied by a reduction in connectivity density (p < 0.01) and an increase in trabecular separation (p < 0.01). A similar pattern of trabecular bone loss was observed in the distal femoral metaphysis at 32 weeks of age. Conclusions: These findings show that inactivation of the DNA binding,dependent functions of the AR, specifically in mature osteoblasts in male mice, results in increased bone resorption and decreased structural integrity of the bone, leading to a reduction in trabecular bone volume at 32 weeks of age. These data provide evidence of a role for androgens in the maintenance of trabecular bone volume directly through DNA binding,dependent actions of the AR in mature osteoblasts. [source] Ovariectomy-Induced Bone Loss Varies Among Inbred Strains of Mice,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2005Mary L Bouxsein PhD Abstract There is a subset of women who experience particularly rapid bone loss during and after the menopause. However, the factors that lead to this enhanced bone loss remain obscure. We show that patterns of bone loss after ovariectomy vary among inbred strains of mice, providing evidence that there may be genetic regulation of bone loss induced by estrogen deficiency. Introduction: Both low BMD and increased rate of bone loss are risk factors for fracture. Bone loss during and after the menopause is influenced by multiple hormonal factors. However, specific determinants of the rate of bone loss are poorly understood, although it has been suggested that genetic factors may play a role. We tested whether genetic factors may modulate bone loss subsequent to estrogen deficiency by comparing the skeletal response to ovariectomy in inbred strains of mice. Materials and Methods: Four-month-old mice from five inbred mouse strains (C3H/HeJ, BALB/cByJ, CAST/EiJ, DBA2/J, and C57BL/6J) underwent ovariectomy (OVX) or sham-OVX surgery (n = 6-9/group). After 1 month, mice were killed, and ,CT was used to compare cortical and trabecular bone response to OVX. Results: The effect of OVX on trabecular bone varied with mouse strain and skeletal site. Vertebral trabecular bone volume (BV/TV) declined after OVX in all strains (,15 to ,24%), except for C3H/HeJ. In contrast, at the proximal tibia, C3H/HeJ mice had a greater decline in trabecular BV/TV (,39%) than C57BL/6J (,18%), DBA2/J (,23%), and CAST/EiJ mice (,21%). OVX induced declines in cortical bone properties, but in contrast to trabecular bone, the effect of OVX did not vary by mouse strain. The extent of trabecular bone loss was greatest in those mice with highest trabecular BV/TV at baseline, whereas cortical bone loss was lowest among those with high cortical bone parameters at baseline. Conclusions: We found that the skeletal response to OVX varies in a site- and compartment-specific fashion among inbred mouse strains, providing support for the hypothesis that bone loss during and after the menopause is partly genetically regulated. [source] An Uncoupling Agent Containing Strontium Prevents Bone Loss by Depressing Bone Resorption and Maintaining Bone Formation in Estrogen-Deficient RatsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2005Pierre J. Marie Ph.D. Trabecular bone loss in estrogen deficiency is associated with enhanced bone resorption with a smaller increase in bone formation. We previously reported that low doses of strontium can increase trabecular bone volume in rodents by affecting bone resorption and formation. In this study we determined the effect of a new divalent strontium salt (S12911) on bone loss induced by E2 deficiency. Sprague-Dawley female rats (230 g, n = 15,25 per group) were sham operated or ovariectomized (OVX) and treated with 17,-estradiol (E2, 10 ,g/kg/day, sc) or S12911 by gavage at the dose of 77, 154, or 308 mg/kg/day or the vehicle. Treatment for 60 days with S12911 resulted in a dose-dependent increase in plasma, urine, and bone strontium concentrations without any deleterious effect on total or skeletal growth. OVX rats were osteopenic compared to sham rats as shown by decreased femoral dry bone weight and mineral content measured on bone ash and by DXA. Treatment of OVX rats with S12911 prevented bone loss as bone ash and bone mineral content were restored to the values in sham rats. Trabecular bone volume measured by histomorphometry on the tibial metaphysis was decreased by 46% in OVX rats and was corrected by E2. Treatment of OVX rats with S12911 increased the trabecular bone volume by 30,36%. Histomorphometric indices of bone resorption (osteoclast surface and number) were increased in OVX rats and were reduced by S12911 to the levels in sham rats. In contrast to this inhibitory effect on bone resorption, the osteoid surface, osteoblast surface, mineral apposition rate, and bone formation rate were as high in OVX rats treated with S12911 as in untreated OVX rats. In addition, plasma osteocalcin (OC) and alkaline phosphatase (ALP) levels remained elevated or were further increased in OVX rats treated with S12911. In contrast, treatment with E2 reduced both bone resorption and formation and plasma ALP and OC to the levels in sham rats. The data indicate that the divalent strontium salt S12911 is acting as an uncoupling agent that can prevent the femoral osteopenia and partially prevent the trabecular bone loss in E2-deficient rats by inhibiting bone resorption without reducing bone formation. [source] Tower Climbing Exercise Started 3 Months After Ovariectomy Recovers Bone Strength of the Femur and Lumbar Vertebrae in Aged Osteopenic Rats,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2003Takuya Notomi Abstract To determine both the preventive and recovery effects of tower climbing exercise on mass, strength, and local turnover of bone in ovariectomized (OVX) rats, we carried out two experiments. In experiment I, 60 Sprague-Dawley rats, 12 months of age, were assigned to four groups: a Baseline Control, Sham-Operated Sedentary, OVX-Sedentary and OVX-Exercise rats. Rats voluntarily climbed a 200-cm tower to drink water from a bottle set at the top. At 3 months, OVX elevated both the femoral cortex and lumbar trabecular turnover, leading to a reduction in bone mass and strength. However, in OVX-Exercise rats, those values were maintained at the same level as in the Sham-Sedentary rats. Thus, the climbing exercise, started after 3 days of OVX, prevented OVX-induced cortical and trabecular bone loss by depressing turnover elevation. After confirming the preventive effect, we evaluated the recovery effect of exercise. In experiment II, 90 Sprague-Dawley rats, 12 months of age, were assigned to six groups: a Baseline control, two groups of Sham-Operated Sedentary and OVX-Sedentary, and OVX-Exercise rats. The exercise started 3 months after the OVX operation. At 3 months, OVX increased the trabecular bone formation rate and osteoclast surface, leading to a decrease in compressive strength. In the midfemur, the cross-sectional area, moment of inertia, and bending load values decreased. At 6 months, in the OVX-Exercise rats, the parameters of breaking load in both the lumbar and midfemur, lumbar bone mass, and the total cross-sectional area recovered to the same levels as those in the Sham-Sedentary rats. However, the cortical bone area did not recover. Periosteal bone formation increased, while endosteal bone formation decreased. These results showed that the climbing exercise had both a preventive and recovery effect on bone strength in OVX rats. In the mid-femur, effects on bone formation were site-specific, and the cross-sectional morphology was improved without an increase in cortical bone area, supporting cortical drift by mechanical stimulation. [source] Tibolone Exerts Its Protective Effect on Trabecular Bone Loss Through the Estrogen ReceptorJOURNAL OF BONE AND MINERAL RESEARCH, Issue 9 2001A. G. H. Ederveen Abstract Tibolone (Org OD14) has estrogenic, progestogenic, and/or androgenic activity depending on the tissue. In postmenopausal women, tibolone prevents bone loss without stimulating the endometrium. Tibolone is effective in preventing trabecular bone loss from the peripheral and axial skeleton of young and old ovariectomized (OVX) rats by reducing bone turnover, that is, bone resorption, like estrogens. We evaluated the contribution of the various hormonal activities to tibolone's bone-conserving effect. Three-month-old OVX rats received tibolone (125 ,g/rat or 500 ,g/rat, twice daily), alone or combined with an antiestrogen, antiandrogen, or antiprogestogen, and the effects on trabecular bone mass and bone turnover were evaluated. Sham-operated and control OVX groups were treated with vehicle. The remaining OVX groups received oral doses of tibolone twice daily, alone or with twice daily (a) antiestrogen ICI 164.384, (b) antiandrogen flutamide, or (c) antiprogestogen Org 31710. For comparison, the effects of 17,-estradiol and testosterone were examined also. After 4 weeks, trabecular bone mineral density (BMD) in the distal femur, plasma osteocalcin, and urinary deoxypyridinoline/creatinine ratio (Dpyr/Cr) were measured. Tibolone or 17,-estradiol significantly blocked ovariectomy-induced loss of trabecular BMD and inhibited bone resorption and bone turnover as judged by reduced Dpyr/Cr ratio and osteocalcin, respectively. These effects of both compounds were counteracted by the antiestrogen. This suggests a major involvement of the estrogen receptor in the action of tibolone on bone metabolism. However, the antiandrogen and the antiprogestogen did not counteract the effects of tibolone, excluding a major role of the androgenic and progestogenic activities of tibolone in its action against trabecular bone loss. The results indicate that tibolone acts on bone almost entirely through activation of the estrogen receptor. [source] Rutin Inhibits Ovariectomy-Induced Osteopenia in RatsJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2000Marie-Noëlle Horcajada-Molteni Abstract Several studies suggest that polyphenols might exert a protective effect against osteopenia. The present experiment was conducted to observe the effects of rutin (quercetin-3- O -glucose rhamnose) on bone metabolism in ovariectomized (OVX) rats. Thirty 3-month-old Wistar rats were used. Twenty were OVX while the 10 controls were sham-operated (SH). Among the 20 OVX, for 90 days after surgery 10 were fed the same synthetic diet as the SH or OVX ones, but 0. 25% rutin (OVX + R) was added. At necropsy, the decrease in uterine weight was not different in OVX and OVX + R rats. Ovariectomy also induced a significant decrease in both total and distal metaphyseal femoral mineral density, which was prevented by rutin consumption. Moreover, femoral failure load, which was not different in OVX and SH rats, was even higher in OVX + R rats than in OVX or SH rats. In the same way, on day 90, both urinary deoxypyridinoline (DPD) excretion (a marker for bone resorption) and calciuria were higher in OVX rats than in OVX + R or SH rats. Simultaneously, plasma osteocalcin (OC) concentration (a marker for osteoblastic activity) was higher in OVX + R rats than in SH rats. High-performance liquid chromatography (HPLC) profiles of plasma samples from OVX + R rats revealed that mean plasma concentration of active metabolites (quercetin and isorhamnetin) from rutin was 9.46 + 1 ,M, whereas it was undetectable in SH and OVX rats. These results indicate that rutin (and/or its metabolites), which appeared devoid of any uterotrophic activity, inhibits ovariectomy-induced trabecular bone loss in rats, both by slowing down resorption and increasing osteoblastic activity. [source] Mice Lacking the Plasminogen Activator Inhibitor 1 Are Protected from Trabecular Bone Loss Induced by Estrogen DeficiencyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2000E. Daci Abstract Bone turnover requires the interaction of several proteases during the resorption phase. Indirect evidence suggests that the plasminogen activator/plasmin pathway is involved in bone resorption and turnover, and recently we have shown that this cascade plays a role in the degradation of nonmineralized bone matrix in vitro. To elucidate the role of the plasminogen activator inhibitor 1 (PAI-1) in bone turnover in vivo, bone metabolism was analyzed in mice deficient in the expression of PAI-1 gene (PAI-1,/,) at baseline (8-week-old mice) and 4 weeks after ovariectomy (OVX) or sham operation (Sham) and compared with wild-type (WT) mice. PAI-1 inactivation was without any effect on bone metabolism at baseline or in Sham mice. However, significant differences were observed in the response of WT and PAI-1,/, mice to ovariectomy. The OVX WT mice showed, as expected, decreased trabecular bone volume (BV/TV) and increased osteoid surface (OS/BS) and bone formation rate (BFR), as assessed by histomorphometric analysis of the proximal tibial metaphysis. In contrast, no significant change in any of the histomorphometric variables studied was detected in PAI-1,/, mice after ovariectomy. As a result, the OVX PAI-1,/, had a significantly higher BV/TV, lower OS/BS, lower mineral apposition rate (MAR) and BFR when compared with the OVX WT mice. However, a comparable decrease in the cortical thickness was observed in OVX PAI-1,/, and WT mice. In addition, the cortical mineral content and density assessed in the distal femoral metaphysis by peripheral quantitative computed tomography (pQCT), decreased significantly after ovariectomy, without difference between PAI-1,/, mice and WT mice. In conclusion, basal bone turnover and bone mass are only minimally affected by PAI-1 inactivation. In conditions of estrogen deficiency, PAI-1 inactivation protects against trabecular bone loss but does not affect cortical bone loss, suggesting a site-specific role for PAI-1 in bone turnover. [source] Bone Mineral Density in Postmenopausal Breast Cancer SurvivorsJOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS, Issue 6 2001APRN, Janice J. Twiss PhD Purpose The overall purpose of this longitudinal 18-month study was to test the feasibility and effectiveness of a multicomponent intervention for prevention and treatment of osteoporosis. The purpose of this article is to describe the baseline bone mineral density (BMD) findings for 30 postmenopausal women and to compare these BMD findings to time since menopause, body mass index, and tamoxifen use. Data Sources Baseline data of BMD findings for 30 post-menopausal women, who have had a variety of treatments including surgery, adjuvant chemotherapy and or tamoxifen, and are enrolled in the 18-month longitudinal study. A demographic questionnaire and a three day dietary record were used to collect baseline data. Conclusions Eighty percent of the women with breast cancer history had abnormal BMDs at baseline (t-scores below -1.00 SD). Thinner women showed a greater risk for accelerated trabecular bone loss at the spine and hip. Implications for Practice These findings suggest the need for early BMD assessments and for aggressive health promotion intervention strategies that include a multifaceted protocol of drug therapy for bone remodeling, 1500 mg of daily calcium, 400 IU vitamin D and a strength weight training program that is implemented immediately following chemotherapy treatment and menopause in this high risk population of women. [source] Differentiation and functions of osteoclasts and odontoclasts in mineralized tissue resorptionMICROSCOPY RESEARCH AND TECHNIQUE, Issue 6 2003Takahisa Sasaki Abstract The differentiation and functions of osteoclasts (OC) are regulated by osteoblast-derived factors such as receptor activator of NFKB ligand (RANKL) that stimulates OC formation, and a novel secreted member of the TNF receptor superfamily, osteoprotegerin (OPG), that negatively regulates osteoclastogenesis. In examination of the preosteoclast (pOC) culture, pOCs formed without any additives expressed tartrate-resistant acid phosphatase (TRAP), but showed little resorptive activity. pOC treated with RANKL became TRAP-positive OC, which expressed intense vacuolar-type H+ -ATPase and exhibited prominent resorptive activity. Such effects of RANKL on pOC were completely inhibited by addition of OPG. OPG inhibited ruffled border formation in mature OC and reduced their resorptive activity, and also induced apoptosis of some OC. Although OPG administration significantly reduced trabecular bone loss in the femurs of ovariectomized (OVX) mice, the number of TRAP-positive OC in OPG-administered OVX mice was not significantly decreased. Rather, OPG administration caused the disappearance of ruffled borders and decreased H+ -ATPase expression in most OC. OPG deficiency causes severe osteoporosis. We also examined RANKL localization and OC induction in periodontal ligament (PDL) during experimental movement of incisors in OPG-deficient mice. Compared to wild-type OPG (+/+) littermates, after force application, TRAP-positive OC were markedly increased in the PDL and alveolar bone was severely destroyed in OPG-deficient mice. In both wild-type and OPG-deficient mice, RANKL expression in osteoblasts and fibroblasts became stronger by force application. These in vitro and in vivo studies suggest that RANKL and OPG are important regulators of not only the terminal differentiation of OC but also their resorptive function. To determine resorptive functions of OC, we further examined the effects of specific inhibitors of H+ -ATPase, bafilomycin A1, and lysosomal cysteine proteinases (cathepsins), E-64, on the ultrastructure, expression of these enzymes and resorptive functions of cultured OC. In bafilomycin A1-treated cultures, OC lacked ruffled borders, and H+ -ATPase expression and resorptive activity were significantly diminished. E-64 treatment did not affect the ultrastructure and the expression of enzyme molecules in OC, but significantly reduced resorption lacuna formation, by inhibition of cathepsin activity. Lastly, we examined the expression of H+ -ATPase, cathepsin K, and matrix metalloproteinase-9 in odontoclasts (OdC) during physiological root resorption in human deciduous teeth, and found that there were no differences in the expression of these molecules between OC and OdC. RANKL was also detected in stromal cells located on resorbing dentine surfaces. This suggests that there is a common mechanism in cellular resorption of mineralized tissues such as bone and teeth. Microsc. Res. Tech. 61:483,495, 2003. © 2003 Wiley-Liss, Inc. [source] In vivo microfocal computed tomography and micro,magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the ratARTHRITIS & RHEUMATISM, Issue 9 2010Michael D. Jones Objective To determine whether treatment with an antiresorptive drug in combination with an antiinflammatory drug reduces periarticular bone and soft tissue adaptations associated with the progression of posttraumatic secondary osteoarthritis (OA). Methods We used in vivo microfocal computed tomography (micro-CT) to map bony adaptations and in vivo micro,magnetic resonance imaging (micro-MRI) to examine joint inflammation in a rat model of surgically induced OA secondary to knee triad injury. We examined the arthroprotective effects of the bisphosphonates alendronate and risedronate and the nonsteroidal antiinflammatory drug (NSAID) meloxicam. Results Micro-CT revealed reduced levels of periarticular trabecular bone loss in animals with knee triad injury treated with the bisphosphonate drugs alendronate or risedronate, or the NSAID meloxicam, compared with untreated animals. Alendronate treatment reduced bony osteophyte development. While risedronate as a monotherapy did not positively impact osteophytogenesis, combination therapy with risedronate and meloxicam reduced osteophyte severity somewhat. Micro-MRI revealed an increased, diffuse water signal in the epiphyses of untreated rats with knee triad injury 8 weeks after surgery, suggestive of a bone marrow lesion,like stimulus. In contrast, meloxicam-treated rats showed a significant reduction in fluid signal compared with both bisphosphonate-treated groups 8 weeks after surgery. Histologic analysis qualitatively confirmed the chondroprotective effect of both bisphosphonate treatments, showing fewer degradative changes compared with untreated rats with knee triad injury. Conclusion Our findings indicate that select combinations of bisphosphonate and NSAID drug therapy in the early stages of secondary OA preserve trabecular bone mass and reduce the impact of osteophytic bony adaptations and bone marrow lesion,like stimulus. Bisphosphonate and NSAID therapy may be an effective disease-modifying drug regimen if administered early after the initial injury. [source] | ||||||||||