FR0050 Intermittent PTH Treatment Increases Intracortical Osteocyte Density and Decreases Fat Mass in Ovariectomized Rats. Steven Tommasini* 1 , Andrea Trinward 2 , Alvin Acerbo 3 , Lisa Miller 4 , Stefan Judex 5 . 1 SUNY Stony Brook, USA, 2 State University of New York at Stony Brook, USA, 3 Brookhaven National Laboratody, USA, 4 Brookhaven National Laboratory, USA, 5 Stony Brook University, USA Some pharmaceutical treatments for osteoporosis have the potential to deteriorate mechanical properties of the skeleton by altering specific aspects of bone’s tissue quality. Here, we hypothesized that PTH and bisphosphonate treatments differ in their effect on intracortical porosity, which has been linked to the stiffness and strength of cortical bone. Further, it is possible that any potential changes in bone porosity are not modulated directly by the specific treatment, but indirectly by altered adiposity. Here, we examined the effects of treatment on intracortical porosity and adiposity in the OVX rat. Six-month old female Sprague-Dawley rats were assigned to either: baseline control, age-matched control, untreated OVX, OVX treated with either 15mg/kg/d hPTH(1-34) (H-PTH) or 0.3mg/kg/d (L-PTH), or OVX treated with either 100mg/kg/2xwk Alendronate (H-ALN) or 1mg/kg/2xwk (L-ALN). Treatments started at 6 mo of age and rats were sacrificed at 6, 8, and 12 mo of age (n=10/group/ age). There were no significant differences in femoral diaphysis geomtery or composition among groups as measured via mCT (36mm resolution). Synchrotron CT (0.75mm resolution) detected intracortical microporosities not detected by conventional mCT. Within ages, treatments did not differ in %porosity or avg pore size. However, %porosity decreased with age for all groups. Even though no differences in %porosity were detected, prolonged H-PTH treatment maintained a 54% greater number of osteocyte lacunae (avg vol=250mm 3 ) and 46% more vascular canals (.1000mm 3 ) compared to all other groups (p,0.05). Tissue mineral density was inversely related to avg pore size (r=-0.83). In vivo mCT revealed PTH-treated rats also had significantly lower abdominal fat volume/body weight compared to all other groups (p,0.01). The data suggest that the greater number of osteocyte lacunae may be related to changes in metabolic rate, which has been correlated with osteocyte density. The increase in microporosities also may be evidence of ostecytic osteolysis previously reported with continuous PTH treatment. The mechanical consequences of the changes in porosity are yet to be established, but do not necessarily have a negative impact on bone’s ability to resist load as very small pores have the potential to delay crack propagation by absorbing shear forces. Therefore, understanding how osteoporosis treatments modulate the interactions between adiposity and bone quality may be critical for reducing fracture risk. Disclosures: Steven Tommasini, None. FR0052 A Comparison of Resistance and Aerobic Exercise Training on Physical Ability, Bone Mineral Density and Osteoprotegerin in Older Women. Elisa Marques* 1 , Fla ´ via Wanderley 1 , Daniel Gonc ¸alves 1 , Margarida Coelho 1 , Joa ˜o Viana 2 , Pedro Moreira 1 , Jorge Mota 1 , Joana Carvalho 1 . 1 University of Porto, Portugal, 2 Loughborough University, United Kingdom Purpose: This study compared the effects of a moderate-impact resistance training protocol and a moderate-impact aerobic training protocol on bone mineral density (BMD), physical ability and serum osteoprotegerin (OPG). Methods: Seventy-one older women were randomly assigned to resistance exercise (RE), aerobic exercise (AE) or control group (CON). RE included 3 sets of 8 repetitions at 70 to 80% of 1 repetition maximum focused on exercises with attachments to the proximal femur and additional complementary upper body exercises. AE program included dynamic activities involving stepping, skipping, walking, jogging, dancing, aerobics and step choreographies at an intensity that gradually increased from 65% to 85% of the heart rate reserve. Both interventions were conducted 3 times per week for 8 months. Outcome measures included proximal femur BMD (by dual X-ray absorptiometry), muscle strength, dynamic balance, handgrip strength, walking performance, fat mass, anthropometric data, and serum OPG. Potential confounding variables included dietary intake, accelerometer-based physical activity and molecularly defined lactase nonpersistence. Results: After 8 months, the RE group exhibited increases in BMD at the trochanter (2.3%) and total proximal femur (1.9%), and a trend (although nonsignificant) to improve muscle strength. In addition, reduced body mass index was observed. RE and AE decreased the percentage of fat mass and increased walking performance. CON group showed increases in fat mass and maintained or slightly decreased muscle strength. No significant interactions were observed for waist circumference and handgrip strength. Moreover, no significant changes in BMD were observed for AE and CON groups, and no associations were found between lactase nonpersistence and BMD changes. No group differences were apparent in baseline values or change in dietary intakes. Although a significant increase in physical activity level was observed, the change was similar among the groups and did not correlate with any bone and functional adaptations. No significant changes were observed in OPG levels, yet RE group showed the slighter positive mean percent change (0.52%) compared to the negative percent change in AE (-2.7%) and CON (-7.8%) groups. Conclusion: Data suggest that 8 months of RE may be more effective than AE for inducing favorable changes in BMD, while both interventions demonstrate to protect against the functional weakness that is strongly related to fall-risk. Disclosures: Elisa Marques, None. FR0053 Downregulation of Sost/sclerostin Expression is Required for the Osteogenic Response to Mechanical Loading. Xiaolin Tu* 1 , Yumie Rhee 2 , Racheal Lee 3 , Jeffrey Benson 3 , Keith Condon 3 , Nicoletta Bivi 3 , Lilian Plotkin 1 , Charles Turner 4 , Alexander Robling 3 , Teresita Bellido 1 . 1 Indiana University School of Medicine, USA, 2 IUMS, Yonsei University, College of Medicine, South korea, 3 Indiana University, USA, 4 Indiana University, Purdue University Indianapolis, USA The expression of osteocyte-derived sclerostin is reduced by mechanical loading, raising the possibility that osteocytes coordinate the osteogenic response to mechanical force by locally unleashing Wnt signaling. We investigated herein whether Sost downregulation is a pre-requisite for loading-induced anabolism by examining the response of transgenic mice (TG) overexpressing human Sost in osteocytes (driven by the 8kb-DMP1 promoter) and wild type (WT) littermates at 4-month of age. Loads required to obtain equal strains inTG and WT mice were measured ex vivo in 6 mice/genotype using gauges on ulnar midshafts. Loading induced 14% higher strains in TG (1295.5me/ N) compared to WT (1114.8me/N) mice, indicating that TG bones are less resistant to mechanical force. Right ulnae were subjected to in vivo cyclic axial loading at low, medium, and high strains for 1min/d, 2Hz; left ulnae were unloaded controls. Endogenous (murine) Sost mRNA expression measured 24h after 1 loading bout at high strain was similarly decreased in WT and TG mice (44¡15% and 47¡8% respectively, compared to unloaded ulnae; n=3/group). In contrast, human Sost, only expressed in TG mice, was not affected by loading. Six-8 mice/group were loaded on 3 consecutive days and forelimbs were collected 16d after initiation of loading. Dynamic histomorphometric analysis revealed that basal periosteal bone formation rate (pBFR) was similar in WT and TG mice. Loading caused a strain-dependent increase in pBFR in WT mice (0.08¡0.05; 0.24¡0.16; and 0.50¡0.18 um3/um2/d; p,0.05 vs unloaded ulnae for low, medium and high strain, respectively), resulting from an increase in both mineralizing surface covered by osteoblasts (MS/BS) as well as activity of individual osteoblasts (MAR). In contrast, loading-induced pBFR was dramatically reduced in TG mice by 70-82% (0.02¡0.02, 0.07¡0.08, and 0.09¡0.05 um3/um2/day), with significant changes only induced by high strains. Reduced pBFR resulted mainly from a marked decrease in MAR, which was not different in loaded vs unloaded ulnae in TG mice at any strain magnitude tested. Loading-induced MS/BS was also reduced in TG mice, with significant increase only induced by high strains. Dose-response curves of pBFR vs strain revealed an overall reduced mechanosensitivity and increased osteogenic threshold in TG bones. Therefore, downregulation of Sost/sclerostin is an obligatory step in the mechanotransduction cascade that directs osteogenesis to where bone is needed. Disclosures: Xiaolin Tu, None. FR0055 Modulation of Gene Expression by Mechanical Loading in Mice with Conditional Ablation of the Connexin43 Gene (Gja1). Susan Grimston* 1 , Marcus Watkins 2 , Jin Norris 3 , Valerie Salazar 2 , Michael Brodt 3 , Matthew Silva 2 , Roberto Civitelli 2 . 1 Washington University School of Medicine, USA, 2 Washington University in St. Louis School of Medicine, USA, 3 Washington University in St. Louis, USA We have previously reported attenuated response to anabolic mechanical loading at the endocortical surface in mice with conditional ablation of Gja1 in osteoblasts. To achieve insights on the mechanisms of such attenuated response, we studied gene expression in cortical bone shortly after application of mechanical loading, using DM1-Cre;Gja1flox/– (cKO) mice. These mice, where Gja1 is selectively ablated in the osteo-chondroprogenitor lineage, have a distinctive cortical bone phenotype characterized by larger cross-sectional area but reduced cortical thickness and decreased bone strength. They also have increases in both endocortical bone resorption and periosteal bone formation. We applied axial compression to the tibia of 2-month-old male mice at 7 N peak force for 120 cycles, with 10 sec rest between cycles. The contralateral tibia was used as an internal control. Tibiae were collected 2 hours post load, and after careful removal of the bone marrow, the bone was pulverized for total RNA extraction and real time qPCR analysis. Gja1 mRNA was barely detectable in cKO bones, confirming effective Gja1 deletion. In wild type (WT) littermates, abundance of Cox2 mRNA, a gene known to be regulated by mechanical stimulation, increased 3-fold (p,0.01), as opposed to only 1-fold increase in cKO mice. Interestingly, Sost mRNA abundance was dramatically down-regulated (~90%; p=0.04) by mechanical loading in WT mice. In cKO mice Sost was already about 50% lower relative to WT, and mechanical load down-regulated Sost mRNA in cKO, though to a lesser extent (~70%, n.s.) than in WT mice. BMP-4 mRNA was also significantly down-regulated by mechanical loading in both genotypes, whereas b- catenin and NFATc1 mRNA, also reported to be involved in mechano-responsiveness, were only marginally increased after mechanical stimulation in both groups. Finally, RANKL mRNA decreased 50% (p,0.05) in loaded WT tibiae, but it did not change in cKO mice. Thus, mechanical skeletal loading rapidly regulates expression of genes involved in BMP-2/4 and Wnt signaling in cortical bone consistent with activation of bone formation, in addition to reduced RANKL expression consistent with suppression of bone resorption. Genetic ablation of Gja1 in osteogenic cells alters these responses, perhaps reflecting an increased bone turnover state with consequent decreased ability to further activate bone formation upon stimulation. Disclosures: Susan Grimston, None. S87 ASBMR 2010 Annual Meeting