Mary Bouxsein

Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States

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Publications (30)147.89 Total impact

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    ABSTRACT: Osteocytes secrete paracrine factors that regulate the balance between bone formation and destruction. Among these molecules, sclerostin (encoded by the gene SOST) inhibits osteoblastic bone formation, and is an osteoporosis drug target. The molecular mechanisms underlying SOST expression remain largely unexplored. Here we report that histone deacetylase 5 (HDAC5) negatively regulates sclerostin levels in osteocytes in vitro and in vivo. HDAC5 shRNA increases, whereas HDAC5 overexpression decreases SOST expression in the novel murine Ocy454 osteocytic cell line. HDAC5 knockout mice show increased levels of SOST mRNA, more sclerostin-positive osteocytes, decreased Wnt activity, low trabecular bone density, and reduced bone formation by osteoblasts. In osteocytes, HDAC5 binds and inhibits the function of MEF2C, a crucial transcription factor for SOST expression. Using chromatin immunoprecipitation, we have mapped endogenous MEF2C binding in the SOST gene to a distal intergenic enhancer 45 kB downstream from the transcription start site. HDAC5 deficiency increases SOST enhancer MEF2C chromatin association and H3K27 acetylation and decreases recruitment of co-repressors NCoR and HDAC3. HDAC5 associates with and regulates the transcriptional activity of this enhancer, suggesting direct regulation of SOST gene expression by HDAC5 in osteocytes. Finally, increased sclerostin production achieved by HDAC5 shRNA is abrogated by simultaneous knockdown of MEF2C, indicating that MEF2C is a major target of HDAC5 in osteocytes. © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2014; · 6.04 Impact Factor
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    ABSTRACT: Fragility fractures commonly involve metaphyses. The distal radius is assembled with a thin cortex formed by fusion (‘corticalization’) of trabeculae arising from the periphery of the growth plate. Centrally positioned trabeculae reinforce the thin cortex and transfer loads from the joint to the proximal thicker cortical bone. We hypothesized that growth-and age-related deficits in trabecular bone disrupt this frugally assembled microarchitecture producing bone fragility.The microarchitecture of the distal radius was measured using high-resolution peripheral quantitative computed tomography in 135 females with distal radial fractures, including 32 girls (7-18 years), 35 premenopausal women (18-44 years), and 68 post-menopausal women (50-76 years). We also studied 240 fracture free controls of comparable age and 47 healthy fracture-free premenopausal mother-daughter pairs (30-55 and 7-20 years, respectively).In fracture free girls, pre- and postmenopausal women, fewer or thinner trabeculae were associated with a smaller and more porous cortical area (r = 0.25 to 0.71 after age, height and weight adjustment, all p<0.05). Fewer and thinner trabeculae in daughters were associated with higher cortical porosity in their mothers (r = 0.30 to 0.47, all p<0.05). Girls, pre- and postmenopausal women with forearm fractures had 0.3 to 0.7 standard deviations (SD) fewer or thinner trabeculae and higher cortical porosity than controls in one or more compartment; one SD trait difference conferred odds ratio (95% CI) for fracture ranging from 1.56 (1.01-2.44) to 4.76 (2.86-7.69).Impaired trabecular corticalization during growth, and cortical and trabecular fragmentation during aging, may contribute to the fragility of the distal radius. © 2014 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 10/2014; · 6.04 Impact Factor
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    ABSTRACT: Abstract There is evidence that space flight condition-induced biological damage is associated with increased oxidative stress and extracellular matrix (ECM) remodeling. To explore possible mechanisms, changes in gene expression profiles implicated in oxidative stress and in ECM remodeling in mouse skin were examined after space flight. The metabolic effects of space flight in skin tissues were also characterized. STS-135 was launched at the Kennedy Space Center (KSC) on a 13 day mission. Female C57BL/6 mice were flown in the Space Shuttle Atlantis (STS-135) using animal enclosure modules (AEMs). Within 3-5 hours after landing, the mice were euthanized and skin samples were harvested for gene array analysis and metabolic biochemical assays. Many genes responsible for regulating production and metabolism of reactive oxygen species (ROS) were significantly (p<0.05) altered in the flight group, with fold changes >1.5 compared to AEM control. For ECM profile, several genes encoding matrix and metalloproteinases involved in ECM remodeling were significantly up-/down-regulated following space flight. To characterize the metabolic effects of space flight, global biochemical profiles were evaluated. Of 332 named biochemicals, 19 differed significantly (p<0.05) between space flight skin samples and AEM ground controls, with 12 up-regulated and 7 down-regulated including altered amino acid, carbohydrate metabolism, cell signaling and transmethylation pathways. Collectively, the data demonstrated that space flight condition leads to a shift in biological and metabolic homeostasis as the consequence of increased regulation in cellular antioxidants, ROS production, and tissue remodeling. This indicates that astronauts may be at increased risk for pathophysiologic damage or carcinogenesis in cutaneous tissue.
    Free Radical Research 05/2014; · 3.28 Impact Factor
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    ABSTRACT: Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. Cancer Res; 74(6); 1-13. ©2014 AACR.
    Cancer Research 03/2014; · 9.28 Impact Factor
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    ABSTRACT: Bisphosphonates are effective for preventing and treating skeletal disorders associated with hyperresorption. Their safety and efficacy has been studied in adults where the growth plate is fused, there is no longitudinal bone growth and little appositional growth. While bisphosphonate use in the pediatric population was pioneered for compassionate use in the treatment of osteogenesis imperfecta, they are being increasingly used for the treatment and prevention of bone loss in children at risk of hyperresorptive bone loss. However, the effect of these agents on the growing skeleton in disorders other than osteogenesis imperfecta has not been systematically compared. Studies were, therefore, undertaken to examine the consequences of bisphosphonate administration on the growth plate and skeletal microarchitecture during a period of rapid growth. C57Bl6/J male mice were treated from 18 to 38 days of age with vehicle, alendronate, pamidronate, zoledronate or clodronate at doses selected to replicate those used in humans. Treatment with alendronate, pamidronate and zoledronate, but not clodronate led to a decrease in the number of chondrocytes per column in the hypertrophic chondrocyte layer. This was not associated with altered hypertrophic chondrocyte apoptosis or vascular invasion at the growth plate. The effects of pamidronate on trabecular microarchitecture were less beneficial than those of alendronate and zoledronate. Pamidronate did not increase cortical thickness or cortical area/total area relative to control mice. These studies suggest that bisphosphonate administration does not adversely affect skeletal growth. Longterm investigations are required to determine if the differences observed among the agents examined, impact biomechanical integrity of the growing skeleton.
    Endocrinology 01/2014; · 4.72 Impact Factor
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    ABSTRACT: Objective: To assess the potential of electrical impedance myography (EIM) to serve as a marker of muscle fiber atrophy and secondarily as an indicator of bone deterioration by assessing the effects of spaceflight or hind limb unloading. Methods: In the first experiment, 6 mice were flown aboard the space shuttle (STS-135) for 13 days and 8 earthbound mice served as controls. In the second experiment, 14 mice underwent hind limb unloading (HLU) for 13 days; 13 additional mice served as controls. EIM measurements were made on ex vivo gastrocnemius muscle. Quantitative microscopy and areal bone mineral density (aBMD) measurements of the hindlimb were also performed. Results: Reductions in the multifrequency phase-slope parameter were observed for both the space flight and HLU cohorts compared to their respective controls. For ground control and spaceflight groups, the values were 24.7±1.3°/MHz and 14.1±1.6°/MHz, respectively (p=0.0013); for control and HLU groups, the values were 23.9±1.6°/MHz and 19.0±1.0°/MHz, respectively (p=0.014). This parameter also correlated with muscle fiber size (ρ=0.65, p=0.011) for spaceflight and hind limb aBMD (ρ=0.65, p=0.0063) for both groups. Conclusions: These data support the concept that EIM may serve as a useful tool for assessment of muscle disuse secondary to immobilization or microgravity.
    Journal of musculoskeletal & neuronal interactions 12/2013; 13(4):405-11. · 2.40 Impact Factor
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    ABSTRACT: Bone receives mechanical stimulation from two primary sources, muscle contractions and external gravitational loading; but the relative contribution of each source to skeletal health is not fully understood. Understanding the most effective loading for maintaining bone health has important clinical implications for prescribing physical activity for the treatment or prevention of osteoporosis. Therefore, we investigated the relative effects of muscle paralysis and reduced gravitational loading on changes in muscle mass, bone mineral density, and microarchitecture. Adult female C57Bl/6J mice (n = 10/group) underwent one of the following: unilateral botulinum toxin (BTX) injection of the hind limb, hind limb unloading (HLU), both unilateral BTX injection and HLU, or no intervention. BTX and HLU each led to significant muscle and bone loss. The effect of BTX was diminished when combined with HLU, though generally the leg that received the combined intervention (HLU+BTX) had the most detrimental changes in bone and muscle. We found an indirect effect of BTX affecting the uninjected (contralateral) leg that led to significant decreases in bone mineral density and deficits in muscle mass and bone architecture relative to the untreated controls; the magnitude of this indirect BTX effect was comparable to the direct effect of BTX treatment and HLU. Thus, while it was difficult to definitively conclude whether muscle force or external gravitational loading contributes more to bone maintenance, it appears that BTX-induced muscle paralysis is more detrimental to muscle and bone than HLU.
    Calcified Tissue International 11/2013; · 2.75 Impact Factor
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    ABSTRACT: A recent report shows that more than 30% of the astronauts returning from Space Shuttle missions or the International Space Station (ISS) were diagnosed with eye problems that can cause reduced visual acuity. We investigate here whether spaceflight environment-associated retinal damage might be related to oxidative stress-induced mitochondrial apoptosis. Female C57BL/6 mice were flown in the space shuttle Atlantis (STS-135), and within 3-5 h of landing, the spaceflight and ground-control mice, similarly housed in animal enclosure modules (AEMs) were euthanized and their eyes were removed for analysis. Changes in expression of genes involved in oxidative stress, mitochondrial and endothelial cell biology were examined. Apoptosis in the retina was analyzed by caspase-3 immunocytochemical analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Levels of 4-hydroxynonenal (4-HNE) protein, an oxidative specific marker for lipid peroxidation were also measured. Evaluation of spaceflight mice and AEM ground-control mice showed that expression of several genes playing central roles in regulating the mitochondria-associated apoptotic pathway were significantly altered in mouse ocular tissue after spaceflight compared to AEM ground-controls mice. In addition, the mRNA levels of several genes, which are responsible for regulating the production of reactive oxygen species were also significantly up-regulated in spaceflight samples compared to AEM ground-control mice. Further more, the level of HNE protein was significantly elevated in the retina after spaceflight compared to controls. Our results also revealed that spaceflight conditions induced significant apoptosis in the retina especially inner nuclear layer (INL) and ganglion cell layer (GCL) compared to AEM ground controls. The data provided the first evidence that spaceflight conditions induce oxidative damage that results in mitochondrial apoptosis in the retina. This data suggest that astronauts may be at increased risk for late retinal degeneration.
    Radiation Research 09/2013; · 2.70 Impact Factor
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    ABSTRACT: Microbialites, which are organosedimentary structures formed by microbial communities through binding and trapping and/or in situ precipitation, have a wide array of distinctive morphologies and long geologic record. The origin of morphological variability is hotly debated; elucidating the cause or causes of microfabric differences could provide insights into ecosystem functioning and biogeochemistry during much of Earth's history. Although rare today, morphologically distinct, co-occurring extant microbialites provide the opportunity to examine and compare microbial communities that may be responsible for establishing and modifying microbialite microfabrics. Highborne Cay, Bahamas, has extant laminated (i.e., stromatolites) and clotted (i.e., thrombolites) marine microbialites in close proximity, allowing focused questions about how community composition relates to physical attributes. Considerable knowledge exists about prokaryotic composition of microbialite mats (i.e., stromatolitic and thrombolitic mats), but little is known about their eukaryotic communities, especially regarding heterotrophic taxa. Thus, the heterotrophic eukaryotic communities of Highborne stromatolites and thrombolites were studied. Here, we show that diverse foraminiferal communities inhabit microbialite mat surfaces and subsurfaces; thecate foraminifera are relatively abundant in all microbialite types, especially thrombolitic mats; foraminifera stabilize grains in mats; and thecate reticulopod activities can impact stromatolitic mat lamination. Accordingly, and in light of foraminiferal impacts on modern microbialites, our results indicate that the microbialite fossil record may reflect the impact of the radiation of these protists.
    Proceedings of the National Academy of Sciences 05/2013; · 9.81 Impact Factor
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    ABSTRACT: Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis.
    Journal of Endocrinology 03/2013; 217(1):69-81. · 3.59 Impact Factor
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    ABSTRACT: Iliac crest bone biopsies are used to assess the mechanism of action of drug treatments, yet there are little data comparing this site to sites prone to fracture. The purpose of this study was to compare the delay and the amplitude of responses to treatment in two different bone sites. The short-term effects of zoledronic acid and teriparatide on microarchitecture, collagen crosslinks and bone remodeling were evaluated in iliac crest and lumbar vertebrae. Aged ewes (n=8/gr) received either vehicle (CTRL) or a single injection of zoledronic acid (ZOL, 10mg) or daily injections of teriparatide (TPTD, 20 μg/d) for 3 months. Blood samples were collected monthly for assessing bone turnover markers. At the end of the study, a transiliac bone biopsy (IC) and L1 lumbar vertebrae (LV1) were collected to assess bone microarchitecture; pyridinoline (PYD), deoxypyridinoline (DPD), pentosidine (PEN) content, static and dynamic parameters of bone remodeling. In CTRL, Tb-BV/TV was significantly higher in LV1 than IC (p<0.0001). This was associated with a trend of higher Tb.N, Tb.Th, DA, an inferior Conn.D and a lower bone turnover as shown by the decreases of osteoid parameters, MS/BS, Ac.f in LV1 when compared to IC. In addition, the ratio PYD/DPD was 4 times higher in LV1 than IC. After 3 months, significant decreases of sALP (p<0.001) and sCTX (p<0.001) were observed in the ZOL-group whereas in TPTD-group, after transient increases, they returned to baseline values. When compared to their respective CTRL, ZOL induced significant increases in Tb.BV/TV, Conn.D, Tb.N and Tb.Sp, in IC but not in LV1. Regardless of the site, ZOL markedly depressed the bone turnover: The static parameters of bone formation significantly decreased and the diminution of MS/BS, BFR/BS and Ac.f varied from -94 to -98% vs CTRL (p<0.01 to 0.001). It was associated with a diminution of the DPD content and the PYD/DPD ratio mainly in IC cortices. In contrast, after 3 months, TPTD did not modify the 3D structure and microarchitecture in IC and LV1, except a trend of higher Conn.D in IC, compared to IC-CTRL. TPTD treatment induced a significant increase in cortical porosity in LV1 (p<0.05) when compared to LV1-CTRL. Static parameters of bone formation and resorption were augmented in both sites, significantly only in LV1 (p<0.05) with a trend of increases in MS/BS and BFR/BS, compared to LV1-CTRL. In conclusion, in adult ewes, the bone mass, microarchitecture, remodeling and collagen crosslink content differ according to the bone site (iliac crest and vertebra). Furthermore, after 3 months, the responses to ZOL and TPTD were of different magnitude and delay between the two bone sites. The distinction of bone sites to study the early effects of anti-osteoporotic therapies appears meaningful in order to approach their site-specific anti-fracture efficacy.
    Bone 07/2012; 51(4):714-9. · 4.46 Impact Factor
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    M J Devlin, M L Bouxsein
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    ABSTRACT: Early life nutrition has substantial influences on postnatal health, with both under- and overnutrition linked with permanent metabolic changes that alter reproductive and immune function and significantly increase metabolic disease risk in offspring. Since perinatal nutrition depends in part on maternal metabolic condition, maternal diet during gestation and lactation is a risk factor for adult metabolic disease. Such developmental responses may be adaptive, but might also result from constraints on, or pathological changes to, normal physiology. The rising prevalence of both obesity and osteoporosis, and the identification of links among bone, fat, brain, and gut, suggest that obesity and osteoporosis may be related, and moreover that their roots may lie in early life. Here we focus on evidence for how maternal diet during gestation and lactation affects metabolism and skeletal acquisition in humans and in animal models. We consider the effects of overall caloric restriction, and macronutrient imbalances including high fat, high sucrose, and low protein, compared to normal diet. We then discuss potential mechanisms underlying the skeletal responses, including perinatal developmental programming via disruption of the perinatal leptin surge and/or epigenetic changes, to highlight unanswered questions and identify the most critical areas for future research.
    Bone 06/2011; 50(2):444-51. · 4.46 Impact Factor
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    ABSTRACT: This paper reviews the evidence for an association between atypical subtrochanteric fractures and long-term bisphosphonate use. Clinical case reports/reviews and case-control studies report this association, but retrospective phase III trial analyses show no increased risk. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is yet unproven. A Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the International Osteoporosis Foundation has reviewed the evidence for a causal association between subtrochanteric fractures and long-term treatment with bisphosphonates, with the aim of identifying areas for further research and providing recommendations for physicians. A PubMed search of literature from 1994 to May 2010 was performed using key search terms, and articles pertinent to subtrochanteric fractures following bisphosphonate use were analysed. Several clinical case reports and case reviews report a possible association between atypical fractures at the subtrochanteric region of the femur in bisphosphonate-treated patients. Common features of these 'atypical' fractures include prodromal pain, occurrence with minimal/no trauma, a thickened diaphyseal cortex and transverse fracture pattern. Some small case-control studies report the same association, but a large register-based study and retrospective analyses of phase III trials of bisphosphonates do not show an increased risk of subtrochanteric fractures with bisphosphonate use. The number of atypical subtrochanteric fractures in association with bisphosphonates is an estimated one per 1,000 per year. It is recommended that physicians remain vigilant in assessing their patients treated with bisphosphonates for the treatment or prevention of osteoporosis and advise patients of the potential risks. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further research. Were the case to be proven, the risk-benefit ratio still remains favourable for use of bisphosphonates to prevent fractures.
    Osteoporosis International 11/2010; 22(2):373-90. · 4.04 Impact Factor
  • Bone 03/2010; 46. · 4.46 Impact Factor
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    ABSTRACT: A recent study suggests that activin inhibits bone matrix mineralization, whereas treatment of mice with a soluble form of the activin type IIA receptor markedly increases bone mass and strength. To further extend these observations, we determined the skeletal effects of inhibiting activin signaling through the ActRIIA receptor in a large animal model with a hormonal profile and bone metabolism similar to humans. Ten female cynomolgus monkeys (Macaca fascicularis) were divided into two weight-matched groups and treated biweekly, for 3 months, with either a subcutaneous injection 10 mg/kg of a soluble form of the ActRIIA receptor fused with the Fc portion of human IgG(1) (ACE-011) or vehicle (VEH). Bone mineral density (BMD), micro-architecture, compressive mechanical properties, and ash fraction were assessed at the end of the treatment period. BMD was significantly higher in ACE-011 treated individuals compared to VEH: +13% (p=0.003) in the 5th lumbar vertebral body and +15% (p=0.05) in the distal femur. In addition, trabecular volumetric bone density at the distal femur was 72% (p=0.0004) higher than the VEH-treated group. Monkeys treated with ACE-011 also had a significantly higher L5 vertebral body trabecular bone volume (p=0.002) and compressive mechanical properties. Ash fraction of L4 trabecular bone cores did not differ between groups. These results demonstrate that treatment with a soluble form of ActRIIA (ACE-011) enhances bone mass and bone strength in cynomolgus monkeys, and provide strong rationale for exploring the use of ACE-011 to prevent and/or treat skeletal fragility.
    Bone 09/2009; 46(1):64-71. · 4.46 Impact Factor
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    ABSTRACT: Early after estrogen loss in postmenopausal women and ovariectomy (OVX) of animals, accelerated endosteal bone resorption leads to marrow expansion of long bone shafts that reduce mechanical integrity. Both growth hormone (GH) and insulin-like growth factor (IGF-1) are potent regulators of bone remodeling processes. To investigate the role of the GH/IGF-1 axis with estrogen deficiency, we used the liver IGF-1-deficient (LID) mouse. Contrary to deficits in controls, OVX of LID mice resulted in maintenance of cortical bone mechanical integrity primarily owing to an enhanced periosteal expansion affect on cross-sectional structure (total area and cortical width). The serum balance in LID that favors GH over IGF-1 diminished the effects of ablated ovarian function on numbers of osteoclast precursors in the marrow and viability of osteocytes within the cortical matrix and led to less endosteal resorption in addition to greater periosteal bone formation. Interactions between estrogen and the GH/IGF-1 system as related to bone remodeling provide a pathway to minimize degeneration of bone tissue structure and osteoporotic fracture.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 08/2009; 25(2):235-46. · 6.04 Impact Factor
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    ABSTRACT: Nonvertebral fractures account for 80% of all fractures and their accompanying morbidity and mortality. Despite this, the effect of drug therapy on cortical morphology has received limited attention, partly because cortical bone is believed to remodel less and decrease less with age than trabecular bone. However, the haversian canals traversing the cortex provide a surface for remodeling that produces bone loss, porosity, and cortical fragility. We developed a new method of 3D micro-computed tomography (microCT) to quantify intracortical porosity and the effects of treatment. Women with osteoporosis randomized to risedronate (5 mg/day, n = 28) or placebo (n = 21) had paired transiliac biopsies at baseline and 5 years imaged using 3D microCT. Pores determined from 8 to 12 slices were stratified by their minor axis length into those 25 to 100 microm (closing cone of haversian canals), 100 to 300 microm (cutting cone of haversian canals), and >300 microm (coalescent cavities). Porosity was analyzed as pore area (percent bone area) and pore density (pore number/mm(2)). Medians are reported. Risedronate reduced pore area in the 25 to 100, 100 to 300, and 300 to 500 microm ranges over 5 years (p = .0008, .04, NS, respectively) corresponding to an 18% to 25% reduction. In the placebo group, pore area was unchanged. At 5 years, pore area and pore number/mm(2) in the 25 to 100 microm range were each 17% lower in the risedronate group than in the placebo group (p = .02 and .04, respectively). Risedronate is likely to maintain bone strength and reduce nonvertebral fracture risk in part by reducing remodeling and therefore the number and size of intracortical cavities.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 08/2009; 25(1):41-7. · 6.04 Impact Factor
  • M. J. Devlin, D. A. Panus, M. L. Bouxsein
    Bone 05/2009; 44. · 4.46 Impact Factor
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    ABSTRACT: Strong correlations between serum IGF-1 levels and fracture risk indicate that IGF-1 plays a critical role in regulating bone strength. However, the mechanism by which serum IGF-1 regulates bone structure and fracture resistance remains obscure and cannot be determined using conventional approaches. Previous analysis of adult liver-specific IGF-1-deficient (LID) mice, which exhibit 75% reductions in serum IGF-1 levels, showed reductions in periosteal circumference, femoral cross-sectional area, cortical thickness, and total volumetric BMD. Understanding the developmental sequences and the resultant anatomical changes that led to this adult phenotype is the key for understanding the complex relationship between serum IGF-1 levels and fracture risk. Here, we identified a unique developmental pattern of morphological and compositional traits that contribute to bone strength. We show that reduced bone strength associated with low levels of IGF-1 in serum (LID mice) result in impaired subperiosteal expansion combined with impaired endosteal apposition and lack of compensatory changes in mineralization throughout growth and aging. We show that serum IGF-1 affects cellular activity differently depending on the cortical surface. Last, we show that chronic reductions in serum IGF-1 indirectly affect bone strength through its effect on the marrow myeloid progenitor cell population. We conclude that serum IGF-1 not only regulates bone size, shape, and composition during ontogeny, but it plays a more fundamental role-that of regulating an individual's ability to adapt its bone structure to mechanical loads during growth and development.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2009; 24(8):1481-92. · 6.04 Impact Factor
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    ABSTRACT: Compressive fatigue properties of whole vertebrae, which may be clinically relevant for osteoporotic vertebral fractures, were determined in untreated, intact rats and zoledronic-acid-treated, ovariectomized rats. Typical fatigue behavior was found and was similar to that seen in other species. Fatigue properties were comparable between both groups. Osteoporosis is often treated with bisphosphonates, which reduce fracture risk. Effects of bisphosphonates on fatigue strength, which may be clinically relevant for vertebral fractures, are unknown. We determined vertebral, compressive fatigue properties in normal and zoledronic acid (ZOL)-treated, OVX rats. Thirty-five-week old Wistar rats were divided into SHAM-OVX (n = 7) and OVX with ZOL treatment (n = 5; single injection, 20 microg/kg b.w. s.c.). After 16 weeks, vertebral trabecular microarchitecture and cortical thickness were determined using micro-CT. Vertebrae were cyclically compressed in load-control at 2 Hz starting at 0.75% apparent strain. A line parallel to the apparent strain curve was drawn at 0.5% higher offset, after which the intersection was defined as the time to failure and the apparent strain at failure. Data were compared using Student's t test. Morphology and fatigue properties were the same in both groups. Samples failed between 10 min and 15 h. Force-displacement curves displayed typical fatigue behavior. Displacement increased over time due to mostly creep and to decreasing secant stiffness. We established a technique to determine compressive fatigue properties in the rat vertebral body. Our initial results indicate that ZOL-treated OVX rats have similar vertebral fatigue properties as SHAM-OVX controls.
    Osteoporosis International 01/2009; 20(8):1377-84. · 4.04 Impact Factor

Publication Stats

683 Citations
147.89 Total Impact Points

Institutions

  • 2001–2014
    • Beth Israel Deaconess Medical Center
      Boston, Massachusetts, United States
  • 2007–2013
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2008–2009
    • Technische Universiteit Eindhoven
      • Department of Biomedical Engineering
      Eindhoven, North Brabant, Netherlands
  • 2005
    • University of Geneva
      • Department of Rehabilitation and Geriatrics
      Genève, GE, Switzerland