| 1. |
- Abtahi, Jahan, et al.
(författare)
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A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants
- 2012
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 50:5, s. 1148-1151
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Tidskriftsartikel (refereegranskat)abstract
- Many surgical procedures use metal implants in bone. The clinical results depend on the strength of the bone holding these implants. Our objective was to show that a drug released from the implant surface can improve parameters reflecting the quality or amount of this bone. Sixteen patients received paired dental titanium implants in the maxilla, in a randomized, double-blinded fashion. One implant in each pair was coated with a thin fibrinogen layer containing 2 bisphosphonates. The other implant was untreated. Fixation was evaluated by measurement of resonance frequency (implant stability quotient; ISQ) serving as a proxy for stiffness of the implant-bone construct. Increase in ISQ at 6 months of follow-up was the primary variable. None of the patients had any complications. The resonance frequency increased 6.9 ISQ units more for the coated implants (p = 0.0001; Cohens d = 1.3). The average difference in increase in ISQ and the effect size, suggested a clinically relevant improvement. X-ray showed less bone resorption at the margin of the implant both at 2 months (p = 0.012) and at 6 months (p = 0.012). In conclusion, a thin, bisphosphonate-eluting fibrinogen coating might improve the fixation of metal implants in human bone. This might lead to new possibilities for orthopedic surgery in osteoporotic bone and for dental implants.
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| 2. |
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| 3. |
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| 4. |
- Bronckers, Antonius L. J. J., et al.
(författare)
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Murine ameloblasts are immunonegative for Tcirg1, the v-H-ATPase subunit essential for the osteoclast plasma proton pump
- 2012
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 50:4, s. 901-908
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Tidskriftsartikel (refereegranskat)abstract
- Maturation stage ameloblasts of rodents express vacuolar type-H-ATPase in the ruffled border of their plasma membrane in contact with forming dental enamel, similar to osteoclasts that resorb bone. It has been proposed that in ameloblasts this v-H-ATPase acts as proton pump to acidify the enamel space, required to complete enamel mineralization. To examine whether this v-H-ATPase in mouse ameloblasts is a proton pump, we determined whether these cells express the lysosomal, T-cell, immune regulator I (Tcirg1, v-H-Atp6v(0)a(3)), which is an essential part of the plasma membrane proton pump that is present in osteoclasts. Mutation of this subunit in Tcirg1 null (or oc/oc) mice leads to severe osteopetrosis. No immunohistochemically detectable Tcirg1 was seen in mouse maturation stage ameloblasts. Strong positive staining in secretory and maturation stage ameloblasts however was found for another subunit of v-H-ATPase, subunit b, brain isoform (v-H-Atp6v(1)b(2)). Mouse osteoclasts and renal tubular epithelium stained strongly for both Tcirg1 and v-H-Atp6v(1)b(2). In Tcirg1 null mice osteoclasts and renal epithelium were negative for Tcirg1 but remained positive for v-H-Atp6v(1)b(2). The bone in these mutant mice was osteopetrotic, tooth eruption was inhibited or delayed, and teeth were often morphologically disfigured. However, enamel formation in these mutant mice was normal, ameloblasts structurally unaffected and the mineral content of enamel similar to that of wild type mice. We concluded that Tcirg1, which is essential for osteoclasts to pump protons into the bone, is not appreciably expressed in maturation stage mouse ameloblasts. Our data suggest that the reported v-H-ATPase in maturation stage ameloblasts is not the typical osteoclast-type plasma membrane associated proton pump which acidifies the extracellular space, but rather a v-H-ATPase potentially involved in intracellular acidification. (C) 2012 Elsevier Inc. All rights reserved.
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| 5. |
- Coelho, Paulo G., et al.
(författare)
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Nanometer-scale features on micrometer-scale surface texturing : A bone histological, gene expression, and nanomechanical study
- 2014
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 65, s. 25-32
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Tidskriftsartikel (refereegranskat)abstract
- Micro- and nanoscale surface modifications have been the focus of multiple studies in the pursuit of accelerating bone apposition or osseointegration at the implant surface. Here, we evaluated histological and nanomechanical properties, and gene expression, for a microblasted surface presenting nanometer-scale texture within a micrometer-scale texture (MB) (Ossean (TM) Surface, Intra-Lock International, Boca Raton, FL) versus a dual-acid etched surface presenting texture at the micrometer-scale only (AA), in a rodent femur model for 1, 2, 4, and 8 weeks in vivo. Following animal sacrifice, samples were evaluated in terms of histomorphometry, biomechanical properties through nanoindentation, and gene expression by real-time quantitative reverse transcription polymerase chain reaction analysis. Although the histomorphometric, and gene expression analysis results were not significantly different between MB and AA at 4 and 8 weeks, significant differences were seen at 1 and 2 weeks. The expression of the genes encoding collagen type I (COL-1), and osteopontin (OPN) was significantly higher for MB than for AA at 1 week, indicating up-regulated osteoprogenitor and osteoblast differentiation. At 2 weeks, significantly up-regulated expression of the genes for COL-1, runt-related transcription factor 2 (RUNX-2), osterix, and osteocalcin (OCN) indicated progressive mineralization in newly formed bone. The nanomechanical properties tested by the nanoindentation presented significantly higher-rank hardness and elastic modulus for the MB compared to AA at all time points tested. In conclusion, the nanotopographical featured surfaces presented an overall higher host-to-implant response compared to the microtextured only surfaces. The statistical differences observed in some of the osteogenic gene expression between the two groups may shed some insight into the role of surface texture and its extent in the observed bone healing mechanisms. (C) 2014 Elsevier Inc. All rights reserved.
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| 6. |
- Cosman, Felicia, et al.
(författare)
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Determinants of stress fracture risk in United States Military Academy cadets
- 2013
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 55:2, s. 359-366
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Tidskriftsartikel (refereegranskat)abstract
- Background: Prior studies have identified some risk factors for stress fracture in athletes and military recruits. Objective: To determine whether historical factors, physical measures, biochemical variables of skeletal metabolism, genetic factors, bone density (BMD) and bone size could predict risk of stress fracture over 4 years in physically fit cadets at the US Military Academy (USMA). Methods: Baseline surveys, assessments of height, weight, scores on the Army Physical Fitness Test, and peripheral BMD were obtained in all cadets (755 men, 136 women), and central BMD in a subset. Blood samples were analyzed for variables of calcium homeostasis, bone turnover, and selected hormones and genetic factors. Stress fractures were adjudicated by review of orthopedic notes and imaging reports. Results: 5.7% of male and 19.1% of female cadets had at least 1 stress fracture (58% metatarsal and 29% tibial), most within 3 months of entry to USMA. In males, risk of stress fracture was higher in those who exercised <7 h per week during the prior year (RR 2.31; CI 1.29,4.12), and in those with smaller tibial cortical area (RR 1.12; CI 1.03,1.23), lower tibial bone mineral content (RR 1.11; CI 1.03,1.20) and smaller femoral neck diameter (RR 1.35, CI 1.01, 1.81). In women, higher stress fracture risk was seen in those with shorter time since menarche (RR 1.44 per year; Cl 1.19, 1.73) and smaller femoral neck diameter (RR 1.16; Cl 1.01, 1.33.). Conclusion: Although prior physical training in men, length of prior estrogen exposure in women and leg bone dimensions in both genders played a role, the maximum variance explained by all of these factors was below 10%. We conclude these factors play a minor role in the development of stress fractures in physically fit USMA cadets. (C) 2013 Elsevier Inc. All rights reserved.
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| 7. |
- Díez-Pérez, Adolfo, et al.
(författare)
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Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW)
- 2011
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 49:3, s. 493-498
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Tidskriftsartikel (refereegranskat)abstract
- PurposeTo determine if important geographic differences exist in treatment rates for osteoporosis and whether this variation can be explained by regional variation in risk factors.MethodsThe Global Longitudinal Study of Osteoporosis in Women is an observational study of women ≥ 55 years sampled from primary care practices in 10 countries. Self-administered questionnaires were used to collect data on patient characteristics, risk factors for fracture, previous fractures, anti-osteoporosis medication, and health status.ResultsAmong 58,009 women, current anti-osteoporosis medication use was lowest in Northern Europe (16%) and highest in USA and Australia (32%). Between 48% (USA, Southern Europe) and 68% (Northern Europe) of women aged ≥ 65 years with a history of spine or hip fracture since age 45 were untreated. Among women with osteoporosis, the percentage of treated cases was lowest in Europe (45–52% versus 62–65% elsewhere). Women with osteopenia and no other risk factors were treated with anti-osteoporosis medication most frequently in USA (31%) and Canada (31%), and least frequently in Southern Europe (12%), Northern Europe (13%), and Australia (16%). After adjusting for risk factors, US women were threefold as likely to be treated with anti-osteoporosis medication as Northern European women (odds ratio 2.8; 95% confidence interval 2.5–3.1) and 1.5 times as likely to be treated as Southern European women (1.5, 1.4–1.6). Up to half of women reporting previous hip or spine fracture did not receive treatment.ConclusionsThe likelihood of being treated for osteoporosis differed between regions, and cannot be explained by variation in risk factors. Many women at risk of fracture do not receive prophylaxis.
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| 8. |
- Engstrom, Annette, et al.
(författare)
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Associations between dietary cadmium exposure and bone mineral density and risk of osteoporosis and fractures among women
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:6, s. 1372-1378
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis and its main health outcome, fragility fractures, are large and escalating public health problems. Cadmium, a widespread food contaminant, is a proposed risk factor; still the association between estimated dietary cadmium exposure and bone mineral density (BMD) has never been assessed. Within a sub-cohort of the Swedish Mammography Cohort, we assessed dietary cadmium exposure based on a food frequency questionnaire (1997) and urinary cadmium (2004-2008) in relation to total-body BMD and risk of osteoporosis and fractures (1997-2009) among 2676 women (aged 56-69 years). In multivariable-adjusted linear regression, dietary cadmium was inversely associated with BMD at the total body and lumbar spine. After further adjustment for dietary factors important for bone health and cadmium bioavailability-calcium, magnesium, iron and fiber, the associations became more pronounced. A 32% increased risk of osteoporosis (95% Cl: 2-71%) and 31% increased risk for any first incident fracture (95% Cl; 2-69%) were observed comparing high dietary cadmium exposure (>= 13 mu g/day, median) with lower exposures (<13 mu g/day). By combining high dietary with high urinary cadmium (>= 0.50 mu g/g creatinine), odds ratios among never-smokers were 2.65 (95% Cl: 1.43-4.91) for osteoporosis and 3.05 (95% Cl; 1.66-5.59) for fractures. In conclusion, even low-level cadmium exposure from food is associated with low BMD and an increased risk of osteoporosis and fractures. The partial masking of the associations by essential nutrients indicates important interplay between dietary factors and contaminants present in food. In separate analyses, dietary and urinary cadmium underestimated the association with bone effects.
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| 9. |
- Fahlgren, Anna, et al.
(författare)
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The effects of PTH, loading and surgical insult on cancellous bone at the bone-implant interface in the rabbit
- 2013
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 52:2, s. 718-724
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Tidskriftsartikel (refereegranskat)abstract
- Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the pen-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on pen-implant bone volume fraction. In this model, PTH enhanced pen-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced pen-implant bone volume, and surgery and PTH treatment had a strong combined effect This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.
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| 10. |
- Granholm, Susanne, et al.
(författare)
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Osteoclast progenitor cells present in significant amounts in mouse calvarial osteoblast isolations and osteoclastogenesis increased by BMP-2
- 2013
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 52:1, s. 83-92
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Tidskriftsartikel (refereegranskat)abstract
- Enzymatically released cells from neonatal mouse calvarial bones are frequently used as primary mouse osteoblasts for in vitro studies. We, here, report that although these cells lack mRNA expression of the osteoclastic genes Calcr, Acp5 and Mmp-9 at early time points after their isolation, these transcripts are gradually upregulated when the calvarial osteoblast cultures are differentiated to more mature osteoblasts in long term cultures. Similarly, Calcr, Acp5, Mmp-9, as well as Rank and Nfatc1 mRNA expressions are robustly increased when the osteoblast cultures were induced to differentiate by treatment with bone morphogenetic protein (BMP-2). The increased Calcr mRNA resulted in functionally active calcitonin receptors. Enhanced osteoblastic differentiation was associated with increased Rankl mRNA expression and decreased Opg and Cfs1 mRNA expression. Treatment of the osteoblastic cells with BMP-2 or RANKL, either on plastic dishes or bone slices, resulted in the formation of multinucleated tartrate-resistant acid phosphatase positive cells, which were able to excavate resorption pits and release CTX from the bones. In contrast, increased osteoblastic differentiation induced by BMP-2 in the mouse calvarial osteoblastic cell line MC3T3-E1 was not associated with increased mRNA expression of Calcr, Acp5, Rank, c-Fms or Oscar. Interestingly, Ctsk mRNA was increased during osteoblastic differentiation in both mouse calvarial osteoblast cultures and in MC3T3-E1 cultures. Also osteoblasts isolated from mouse long bones by outgrowth from explant cultures were contaminated with osteoclast progenitors able to differentiate into bone resorbing osteoclasts. These data indicate that mouse calvarial osteoblast cultures contain osteoclast progenitor cells, which will be differentiated along the osteoclastic lineage during osteoblastic differentiation. Moreover, the data show that BMP-2 not only stimulates osteoblastic differentiation but can also induce osteoclastogenesis through increased RANKL.
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| 11. |
- Halldin, Anders, et al.
(författare)
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The effect of static bone strain on implant stability of bone remodelling
- 2011
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 49:4, s. 783-789
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Tidskriftsartikel (refereegranskat)abstract
- Bone remodeling is a process involving both dynamic and static bone strain. Although there exist numerous studies on the effect of dynamic strain on implant stability and bone remodeling, the effect of static strain has yet to be clarified. Hence, for this purpose, the effect of static bone strain on implant stability and bone remodeling was investigated in rabbits. Based on Finite Element (FE) simulation two different test implants, with a diametrical increase of 0.15 mm (group A) and 0.05 mm (group B) creating static strains in the bone of 0.045 and 0.015 respectively, were inserted in the femur (group A) and the proximal tibia metaphysis (groups A and B respectively) of 14 rabbits to observe the biological response. Both groups were compared to control implants, with no diametrical increase (group C), which were placed in the opposite leg. At the time of surgery, the insertion torque (ITQ) was measured to represent the initial stability. The rabbits were euthanized after 24 days and the removal torque (RTQ) was measured to analyze the effect on implant stability and bone remodeling. The mean ITQ value was significantly higher for both groups A and B compared to group C regardless of the bone type. The RTQ value was significantly higher in tibia for groups A and B compared to group C while group A placed in femur presented no significant difference compared to group C. The results suggest that increased static strain in the bone not only creates higher implant stability at the time of insertion, but also generates increased implant stability throughout the observation period.
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| 12. |
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| 13. |
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| 14. |
- Harding, Anna Kajsa, et al.
(författare)
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A single dose zoledronic acid enhances pin fixation in high tibial osteotomy using the hemicallotasis technique. A double-blind placebo controlled randomized study in 46 patients.
- 2010
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 46:3, s. 649-654
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Bisphosphonates have been shown to reduce osteoclastic activity and enhance pin fixation in both experimental and clinical studies. In this prospective, randomized study of high tibial osteotomy using the hemicallotasis (HCO) technique, we evaluate whether treatment by one single infusion of zoledronic acid can enhance the pin fixation. MATERIALS AND METHODS: 46 consecutive patients (35-65 years) were operated on for knee osteoarthritis by the HCO technique. After the osteotomy, two hydroxyapatite-coated pins were inserted in the metaphyseal bone and two non-coated pins in the diaphyseal bone. The insertion torque was measured by a torque force screw driver. Four weeks postoperatively, the patients were randomized to either one infusion of zoledronic acid or sodium chloride intravenously. At time for removal of the pins, the extraction torque forces of the pins were measured. RESULTS: All osteotomies healed and no difference was found in time to healing. The mean extraction torque force in the non-coated pins in the diaphyseal bone was doubled in the zoledronic treated group (4.5 Nm, SD 2.1) compared to the placebo group (2.4 (SD 1.0, p<0.0001). The mean extraction torque forces of the hydroxyapatite-coated pins in the metaphyseal bone were similar in the zoledronic acid group (4.7 Nm, SD 1.3) and in the placebo group (4.0 Nm, SD 1.3). DISCUSSION: A single infusion of zoledronic acid improved twofold the fixation of non-coated pins in diaphyseal bone. Bisphosphonates might be an alternative to hydroxyapatite-coated pins in nonosteoporotic bone.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Johannesdottir, Fjola, et al.
(författare)
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Distribution of cortical bone in the femoral neck and hip fracture: A prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study
- 2011
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 48:6, s. 1268-1276
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Tidskriftsartikel (refereegranskat)abstract
- In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm(2), DXA-like), (p = 0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n = 143) from controls (n = 298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture. (C) 2011 Elsevier Inc. All rights reserved.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Keyak, J. H., et al.
(författare)
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Effect of finite element model loading condition on fracture risk assessment in men and women: The AGES-Reykjavik study
- 2013
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 57:1, s. 18-29
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Tidskriftsartikel (refereegranskat)abstract
- Proximal femoral (hip) strength computed by subject-specific CT scan-based finite element (FE) models has been explored as an improved measure for identifying subjects at risk of hip fracture. However, to our knowledge, no published study has reported the effect of loading condition on the association between incident hip fracture and hip strength. In the present study, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort Baseline (pre-fracture) quantitative CT (QCT) scans of 5500 older male and female subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as controls from a pool of age- and sex-matched subjects. From the QCT data, FE models employing nonlinear material properties computed FE-strength of the left hip of each subject in loading from a fall onto the posterolateral (F-PL), posterior (F-P) and lateral (F-L) aspects of the greater trochanter (patent pending). For comparison, FE strength in stance loading (F-Stance) and total femur areal bone mineral density (aBMD) were also computed. For all loading conditions, the reductions in strength associated with fracture in men were more than twice those in women (p <= 0.01). For fall loading specifically, posterolateral loading in men and posterior loading in women were most strongly associated with incident hip fracture. After adjusting for aBMD, the association between F-P and fracture in women fell short of statistical significance (p = 0.08), indicating that FE strength provides little advantage over aBMD for identifying female hip fracture subjects. However, in men, after controlling for aBMD, F-PL was 424 N (11%) less in subjects with fractures than in controls (p = 0.003). Thus, in men, FE models of posterolateral loading include information about incident hip fracture beyond that in aBMD. (c) 2013 Elsevier Inc. All rights reserved.
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| 24. |
- Keyak, J. H., et al.
(författare)
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Male-female differences in the association between incident hip fracture and proximal femoral strength: A finite element analysis study
- 2011
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 48:6, s. 1239-1245
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Tidskriftsartikel (refereegranskat)abstract
- Hip fracture risk is usually evaluated using dual energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) which provide surrogate measures for proximal femoral strength. However, proximal femoral strength can best be estimated explicitly by combining QCT with finite element (FE) analysis. To evaluate this technique for predicting hip fracture in older men and women, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) QCT scans of 5500 subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as age- and sex-matched controls. FE-strength of the left hip of each subject for stance (F-Stance) and posterolateral fall (F-Fall) loading, and total femur areal bone mineral density (aBMD) were computed from the QCT data. F-Stance and F-Fall in incident hip fracture subjects were 13%-25% less than in control subjects (p <= 0.006) after controlling for demographic parameters. The difference between FE strengths of fracture and control subjects was disproportionately greater ill men (stance, 22%; fall, 25%) than in women (stance, 13%; fall, 18%) (p <= 0.033), considering that Fstar,ce and FFall in fracture subjects were greater in men than in women ( p < 0.001). For men, F-Stance was associated with hip fracture after accounting for aBMD (p = 0.013). These data indicate that F-Stance provides information about fracture risk that is beyond that provided by aBMD (p = 0.013). These findings support further exploration of possible sex differences in the predictors of hip fracture and of sex-specific strategies for using FE analysis to manage osteoporosis. (C) 2011 Elsevier Inc. All rights reserved.
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| 25. |
- Kos, O., et al.
(författare)
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Elevated serum soluble CD200 and CD200R as surrogate markers of bone loss under bed rest conditions
- 2014
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 60, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- CD200 is a transmembrane protein that belongs to the immunoglobulin family of proteins and is ubiquitously expressed on a variety of cell types. Upon interaction with its receptors (CD200Rs) expressed on myeloid-derived cells and T lymphocytes, an immunoregulatory signal is delivered to receptor-expressing cells. Previous studies have implicated a role for CD200:CD200R in the regulation of the expression of mRNA markers of osteoclastogenesis/osteoblastogenesis, following interaction of CD200 (on osteoblast precursors) with CD200R1 (on osteoclast precursors). Signaling of CD200R1 is hypothesized to attenuate osteoclastogenesis. We have investigated whether levels of soluble forms of CD200 and/or CD200R1 (sCD200, sCD200R1) are altered in volunteers undergoing 6° head down tilt bed rest to mimic conditions of microgravity known to be associated with preferential osteoclastogenesis and whether countermeasures, reported to be beneficial in attenuation of bone loss under microgravity conditions, would lead to altered sCD200 and sCD200R1 levels. Our data suggest that, as predicted, sCD200 levels fall under bed rest conditions while sCD200R1 levels rise. In subjects undergoing 30-minute per day continuous centrifugation protocols, as a countermeasure to attenuate changes which may lead to bone loss, these alterations in sCD200 and sCD200R1 levels seen under conditions of bed rest were abolished or attenuated. Our results suggest that measurement of sCD200 and/or sCD200R1 may prove a useful and rapid means of monitoring subjects at risk of bone loss and/or accessing the efficacy of treatment regimes designed to counter bone loss.
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| 26. |
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| 27. |
- Kumar, Jitender, et al.
(författare)
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LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways.
- 2011
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 49, s. 343-348
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporosis is a common complex disorder in postmenopausal women leading to changes in the micro-architecture of bone and increased risk of fracture. Members of the low-density lipoprotein receptor-related protein (LRP) gene family regulates the development and physiology of bone through the Wnt/β-catenin (Wnt) pathway that in turn cross-talks with the bone morphogenetic protein (BMP) pathway. In two cohorts of Swedish women: OPRA (n=1002; age 75years) and PEAK-25 (n=1005; age 25years), eleven single nucleotide polymorphisms (SNPs) from Wnt pathway genes (LRP4; LRP5; G protein-coupled receptor 177, GPR177) were analyzed for association with Bone Mineral Density (BMD), rate of bone loss, hip geometry, quantitative ultrasound and fracture. Additionally, interaction of LRP4 with LRP5, GPR177 and BMP2 were analyzed. LRP4 (rs6485702) was associated with higher total body (TB) and lumbar spine (LS) BMD in the PEAK-25 cohort (p=0.006 and 0.005 respectively), and interaction was observed with LRP5 (p=0.007) and BMP2 (p=0.004) for TB BMD. LRP4 also showed significant interaction with LRP5 for femoral neck (FN) and LS BMD in this cohort. In the OPRA cohort, LRP4 polymorphisms were associated with significantly lower fracture incidence overall (p=0.008-0.001) and fewer hip fractures (rs3816614, p=0.006). Significant interaction in the OPRA cohort was observed for LRP4 with BMP2 and GPR177 for FN BMD as well as for rate of bone loss at TB and FN (p=0.007-0.0001). In conclusion, LRP4 and interaction between LRP4 and genes in the Wnt and BMP signaling pathways modulate bone phenotypes including peak bone mass and fracture, the clinical endpoint of osteoporosis.
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| 28. |
- Lagerholm, Sofia, et al.
(författare)
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Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat.
- 2010
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 47, s. 1039-1047
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Tidskriftsartikel (refereegranskat)abstract
- The F344 rat carries alleles contributing to bone fragility while the GK rat spontaneously develops type-2 diabetes. These characteristics make F344xGK crosses well suited for the identification of genes related to bone size and allow for future investigation on the association with type-2 diabetes. The aim of this study was to identify quantitative trait loci (QTLs) for bone size phenotypes measured by a new application of three-dimensional computed tomography (3DCT) and to investigate the effects of sex- and reciprocal cross. Tibia from male and female GK and F344 rats, representing the parental, F1 and F2 generations, were examined with 3DCT and analyzed for: total and cortical volumetric BMD, straight and curved length, peri- and endosteal area at mid-shaft. F2 progeny (108 male and 98 female) were genotyped with 192 genome-wide microsatellite markers (average distance 10cM). Sex- and reciprocal cross-separated QTL analyses were performed for the identification of QTLs linked to 3DCT phenotypes and true interactions were confirmed by likelihood ratio analysis in all F2 animals. Several genome-wide significant QTLs were found in the sex- and reciprocal cross-separated progeny on chromosomes (chr) 1, 3, 4, 9, 10, 14, and 17. Overlapping QTLs for both males and females in the (GKxF344)F2 progeny were located on chr 1 (39-67cM). This region confirms previously reported pQCT QTLs and overlaps loci for fasting glucose. Sex separated linkage analysis confirmed a male specific QTL on chr 9 (67-82cM) for endosteal area at the fibula site. Analyses separating the F2 population both by sex and reciprocal cross identified cross specific QTLs on chr 14 (males) and chr 3 and 4 (females). Two loci, chr 4 and 6, are unique to 3DCT and separate from pQCT generated loci. The 3DCT method was highly reproducible and provided high precision measurements of bone size in the rat enabling identification of new sex- and cross-specific loci. The QTLs on chr 1 indicate potential genetic association between bone-related phenotypes and traits affecting type-2 diabetes. The results illustrate the complexity of the genetic architecture of bone size phenotypes and demonstrate the importance of complementary methods for bone analysis.
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| 29. |
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| 30. |
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| 31. |
- Lang, T. F., et al.
(författare)
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Age-related loss of proximal femoral strength in elderly men and women: The Age Gene/Environment Susceptibility Study - Reykjavik
- 2012
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 50:3, s. 743-748
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Tidskriftsartikel (refereegranskat)abstract
- The risk of hip fracture rises rapidly with age, and is particularly high in women. This increase in fracture risk reflects both the age-related change in the risk of falling and decrements in the strength of the proximal femur. To better understand the extent to which proximal femoral density, structure and strength change with age as a function of gender, we have carried out a longitudinal analysis of proximal femoral volumetric quantitative computed tomographic (vQCT) images in men and women, analyzing changes in trabecular and cortical bone properties, and using subject-specific finite element modeling (FEM) to estimate changes in bone strength. In the AGES-Reykjavik Study vQCT scans of the hip were performed at a baseline visit in 2002-2006 and at a second visit 5.05 +/- 0.25 years later. From these, 223 subjects (111 men, 112 women, aged 68-87 years) were randomly selected. The subjects were evaluated for longitudinal changes in three bone variables assessed in a region similar to the total femur region quantified by DXA: areal bone mineral density (aBMD), trabecular volumetric bone mineral density (tBMD) and the ratio of cortical to total tissue volume (cvol/ivol). They were also evaluated for changes in bone strength using FEM models of the left proximal femur. Models were analyzed under single-limb stance loading (F-Stance), which approximates normal physiologic loading of the hip, as well as a load approximating a fall onto the posterolateral aspect of the greater trochanter (F-Fall). We computed five-year absolute and percentage changes in aBmD, tBMD, cvol/ivol, F-Fall and F-Stance. The Mann-Whitney Test was employed to compare changes in bone variables between genders and the Wilcoxon Signed Rank Test was used to compare changes in bone strength between loading conditions. Multiple (linear) regression was employed to determine the association of changes in F-Fall and F-Stance with baseline age and five-year weight loss. Both men and women showed declines in indices of proximal femoral density and structure (aBMD: men -3.9 +/- 6.0%, women -6.1 +/- 6.2%; tBMD: men -14.8 +/- 20.3%, women -23.9 +/- 26.8%; cvol/ivol: men -2.6 +/- 4.6%, women -4.7 +/- 4.8%, gender difference: p<0.001). Both men and women lost bone strength in each loading condition (F-Stance: men -4.2 +/- 9.9%, women -8.3 +/- 8.5%; F-Fall: men -7.0 +/- 15.7%, women -12.8 +/- 13.2%; all changes from baseline p<0.0001). The gender difference in bone strength loss was statistically significant in both loading conditions (p<0.001 for F-Stance and P<0.01 for F-Fall) and F-Fall, was lost at a higher rate than F-Stance in men (p<0.01) and women (p<0.0001). The gender difference in strength loss was statistically significant after adjustment for baseline age and weight loss in both loading conditions (p<0.01). In these multi-linear models, men showed increasing rates of bone loss with increasing age (F-Fall: p=0.002; F-Stance; p=0.03), and women showed increasing bone strength loss with higher degrees of weight loss (F-Stance: p=0.003). The higher loss of F-Fall compared to F-Stance supports previous findings in animal and human studies that the sub-volumes of bone stressed under normal physiologic loading are relatively better protected in aging. The gender difference in hip bone strength loss is consistent with the higher incidence of hip fractureamong elderly women. (C) 2011 Elsevier Inc. All rights reserved.
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| 32. |
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| 33. |
- Lind, Thomas, et al.
(författare)
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High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats
- 2011
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 48:3, s. 496-506
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin A (retinol) is the only molecule known to induce spontaneous fractures in laboratory animals and we have identified retinol as a risk factor for fracture in humans. Since subsequent observational studies in humans and old animal data both show that high retinol intake appears to only have small effects on bone mineral density (BMD) we undertook a mechanistic study of how excess retinol reduces bone diameter while leaving BMD essentially unaffected. We fed growing rats high doses of retinol for only 1week. Bone analysis involved antibody-based methods, histology, pQCT, biomechanics and bone compartment-specific PCR together with Fourier Transform Infrared Spectroscopy of bone mineral. Excess dietary retinol induced weakening of bones with little apparent effect on BMD. Periosteal osteoclasts increased but unexpectedly endosteal osteoclasts disappeared and there was a reduction of osteoclastic serum markers. There was also a lack of capillary erythrocytes, endothelial cells and serum retinol transport protein in the endosteal/marrow compartment. A further indication of reduced endosteal/marrow blood flow was the increased expression of hypoxia-associated genes. Also, in contrast to the inhibitory effects in vitro, the marrow of retinol-treated rats showed increased expression of osteogenic genes. Finally, we show that hypervitaminotic bones have a higher degree of mineralization, which is in line with biomechanical data of preserved stiffness in spite of thinner bones. Together these novel findings suggest that a rapid primary effect of excess retinol on bone tissue is the impairment of endosteal/marrow blood flow leading to hypoxia and pathological endosteal mineralization.
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| 34. |
- Lindahl, Katarina, et al.
(författare)
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Genotype-phenotype correlations and pharmacogenetic studies in 140 Swedish families with osteogenesis imperfecta
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50, s. S109-S109
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Osteogenesis imperfecta (OI) is a rare heterogeneous disease of connective tissue leading to varying degrees of bone fragility. The worst form (type II) is peri-natally lethal whereas the mildest form (type I) is compatible with a normal life span. Over 1000 mutations causing OI have been described in the genes encoding collagen type I. As COL1A1 and COL1A2 are large genes, there are still many codon positions where no mutations have been reported and only a fraction of theoretically possible glycine substitutions have been described. In this study the spectrum of mutations causing OI in Sweden will be investigated and genotype–phenotype correlations as well as pharmacogenetics will be studied. Method: All patients with OI cared for at the Uppsala Osteoporosis Unit (Uppsala University Hospital) or Astrid Lindgren's Paediatric Hospital (Karolinska Institutet, Stockholm) were offered to enter the study. Patients from 140 unrelated families with OI accepted participation; 77 type I, 34 type IV, 20 type III, 5 without previous diagnosis and 4 with unclear OI type. Extensive clinical data is currently being collected on enrolled patients. Exons and flanking intron sequences of COL1A1 and COL1A2 are being sequenced in these families. Results: So far 133/140 families have been completely analyzed and in 27 no mutation was found. A total of 120 mutations have been detected, of which 104 are of a typical OI-type. In COL1A1 73 mutations were found and in COL1A2 31 mutations were noted. In 7 families 2 mutations were present, but only one of these was a typical OI-causing mutation. To date 16 amino acid changing mutations that were not of a typical OI-causing type have been noted and the majority of these have an unclear significance. Calculations of delta BMD Z-score response to bisphosphonate treatment did not show a difference in treatment response between groups with different types of OI or between patients with OI type I due to a qualitative vs. a quantitative collagen type I defect. Conclusion: The spectrum of mutations causing OI described in this Swedish cohort is of the expected type, with the exception of the amino acid changing mutations. It is notable that in seven families two separate mutations were identified. Calculations do not support a mutation dependent response to bisphosphonate treatment.
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| 35. |
- Linder, Cecilia, et al.
(författare)
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Isozyme profile and tissue-origin of alkaline phosphatases in mouse serum
- 2013
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 53:2, s. 399-408
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Tidskriftsartikel (refereegranskat)abstract
- Mouse serum alkaline phosphatase (ALP) is frequently measured and interpreted in mammalian bone research. However, little is known about the circulating ALPs in mice and their relation to human ALP isozymes and isoforms. Mouse ALP was extracted from liver, kidney, intestine, and bone from vertebra, femur and calvaria tissues. Serum from mixed strains of wild-type (WT) mice and from individual ALP knockout strains were investigated, i.e., Alpl(-/-) (a.k.a. Akp2 encoding tissue-nonspecific ALP or TNALP), Akp3(-/-) (encoding duodenum-specific intestinal ALP or dIALP), and Alpi(-/-) (a.k.a. Akp6 encoding global intestinal ALP or gIALP). The ALP isozymes and isoforms were identified by various techniques and quantified by high-performance liquid chromatography. Results from the WT and knockout mouse models revealed identical bone-specific ALP isoforms (B/I. B1, and B2) as found in human serum, but in addition mouse serum contains the B1x isoform only detected earlier in patients with chronic kidney disease and in human bone tissue. The two murine intestinal isozymes, dIALP and gIALP, were also identified in mouse serum. All four bone-specific ALP isoforms (B/I, B1x, B1, and B2) were identified in mouse bones, in good correspondence with those found in human bones. All mouse tissues, except liver and colon, contained significant ALP activities. This is a notable difference as human liver contains vast amounts of ALP. Histochemical staining, Northern and Western blot analyses confirmed undetectable ALP expression in liver tissue. ALP activity staining showed some positive staining in the bile canaliculi for BALB/c and FVB/N WT mice, but not in C57BI/6 and ICR mice. Taken together, while the main source of ALP in human serum originates from bone and liver, and a small fraction from intestine (andlt;5%), mouse serum consists mostly of bone ALP, including all four isoforms, B/I, B1x, B1, and B2, and two intestinal ALP isozymes dIALP and gIALR We suggest that the genetic nomenclature for the Alpl gene in mice (i.e., ALP liver) should be reconsidered since murine liver has undetectable amounts of ALP activity. These findings should pave the way for the development of user-friendly assays measuring circulating bone-specific ALP in mouse models used in bone and mineral research.
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| 36. |
- Linderbäck, Paula, et al.
(författare)
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Weak effect of strontium on early implant fixation in rat tibia.
- 2012
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 50:1, s. 350-356
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Tidskriftsartikel (refereegranskat)abstract
- Strontium ranelate increases bone mass and is used in the treatment of osteoporosis. Its effects in metaphyseal bone repair are largely unknown. We inserted a stainless steel and a PMMA screw into each tibia of male Sprague-Dawley rats. The animals were fed with ordinary feed (n = 20) or with addition of strontium ranelate (800 mg/kg/day; n = 10). As a positive control, half of the animals on control feed received alendronate subcutaneously. The pullout force of the stainless steel screws was measured after 4 or 8 weeks, and µCT was used to assess bone formation around the PMMA screws. No significant effects of strontium treatment on pullout force were observed, but animals treated with bisphosphonate showed a doubled pullout force. Strontium improved the micro architecture of the cancellous bone below the primary spongiosa at the growth plate, but no significant effects were found around the implants. Strontium is known to improve bone density, but it appears that this effect is weak in conjunction with metaphyseal bone repair and early implant fixation.
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| 37. |
- Ljunggren, Östen
(författare)
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Anabolic treatment
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50, s. S15-S15
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Osteoporosis is caused by an imbalance in the remodelling cycle with subsequent bone loss due to either enhanced osteoclastic resorption, or to a decrease in osteoblastic activity. Over time this loss of bone results in thinning and disappearance of trabeculi and to enhanced cortical porosity. With the knowledge of the pathogenetic mechanisms underlying the development of osteoporosis it is evident that there are two main strategies to develop pharmacological treatment for this condition. Either the goal is to inhibit bone resorption with e.g. bisphosphonates or RANKL interference, or alternatively to stimulate osteoblastic bone formation with anabolic treatment and thereby create new bone. Today it is well documented that intermittent injections with PTH1-34, or with full length PTH, cause a direct stimulatory effect on the osteoblastic bone formation. The treatment length is currently between 18 and 24 months and it is not known whether there is an optimal duration, called anabolic window, for this sort of treatment. The antifracture efficacy is well proven in randomised phase III trials, and real life efficacy and safety are well documented in large post marketing observational studies. When compared to antiresorptive treatment with bisphosphonates there are data that at least PTH 1–34 might be superior in some instances such as in glucocorticoid induced osteoporosis. Future development with new anabolic agents focusing on the LRP5/Wnt signalling system is under development and might bring to the clinic even more potent drugs that eventually might enable us to treat to a bone density target, and thereby in theory cure osteoporosis.
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| 38. |
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| 39. |
- Macias, Brandon R., et al.
(författare)
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Paradoxical Sost gene expression response to mechanical unloading in metaphyseal bone
- 2013
-
Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 53:2, s. 515-519
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Tidskriftsartikel (refereegranskat)abstract
- The Sost gene encodes Sclerostin, an inhibitor of Wnt-signaling, generally considered a main response gene to mechanical loading in bone. Several papers describe that unloading leads to upregulation of Sost, which in turn may lead to loss of bone. These studies were based on whole bone homogenates or cortical bone. By serendipity, we noted an opposite response to unloading in the proximal rat tibia. Therefore, we hypothesized that Sost-expression in response to changes in mechanical load is bone site specific. less thanbrgreater than less thanbrgreater thanOne hind limb of male, 3 month old rats was unloaded by paralyzing the extensors with Botulinium toxin A (Botox) injections. A series of experiments compared the expression of Sost mRNA in the unloaded and contralateral, loaded limbs, after 3 or 10 days, in metaphyseal cancellous bone, metaphyseal cortical bone, and diaphyseal cortical bone. We also conducted mu CT to confirm changes in bone volume density related to unloading. Sost mRNA expression in the cancellous metaphyseal bone was downregulated almost 2-fold, both 3 days and 10 days after unloading (Pandlt;0.05). A similar tendency was seen in the metaphyseal cortical bone, in which Sost was 1.5-fold downregulated (Pandlt;0.05) after 10 days, but not significantly changed after 3 days. In contrast, diaphyseal cortical Sost expression was instead upregulated 1.4-fold (Pandlt;0.05) following 3-day unloading, while there was no significant change after 10 days. Cancellous bone volume density was 58% lower (Pandlt;0.001, compared to cage controls) in the unloaded limb but not significantly affected in the loaded limb. less thanbrgreater than less thanbrgreater thanThe results suggest that Sost mRNA expression in metaphyseal bone responds to mechanical unloading in an opposite direction to that observed in diaphyseal cortical bone. This proposes a more complex expression pattern for Sost in response to unloading. Therapeutics that target Sclerostin during altered loading conditions may result in local bone mass changes that are difficult to predict.
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| 40. |
- Malo, M K H, et al.
(författare)
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Ultrasound Backscatter Measurements of Intact Human Proximal Femurs - Relationships of ultrasound parameters with tissue structure and mineral density.
- 2014
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 64:Online April 24, 2014, s. 240-245
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Tidskriftsartikel (refereegranskat)abstract
- Ultrasound reflection and backscatter parameters are related to mechanical and structural properties of bone in vitro. However, the potential of ultrasound reflection and backscatter measurements has not been tested with intact human proximal femurs ex vivo. We hypothesize that ultrasound backscatter can be measured from intact femurs and that the measured backscattered signal is associated with cadaver age, bone mineral density (BMD) and trabecular bone microstructure. In this study, human femoral bones of 16 male cadavers (47.0±16.1years, range: 21-77 years) were investigated using pulse-echo ultrasound measurements at the femoral neck in the antero-posterior direction and at the trochanter major in the antero-posterior and latero-medial directions. Recently introduced ultrasound backscatter parameters, independent of cortical thickness, e.g., time slope of apparent integrated backscatter (TSAB) and mean of the backscatter difference technique (MBD) were obtained and compared with the structural properties of trabecular bone samples, extracted from the locations of ultrasound measurements. Moreover, more conventional backscatter parameters, e.g., apparent integrated backscatter (AIB) and frequency slope of apparent integrated backscatter (FSAB) were analysed. Bone mineral density of the intact femurs was evaluated using dual energy X-ray absorptiometry (DXA). AIB and MDB measured from the femoral neck correlated significantly (p<0.01) with the neck BMD (R(2)=0.44 and 0.45), cadaver age (R(2)=0.61 and 0.41) and several structural parameters, e.g., bone volume fraction (R(2)=0.33 and 0.39, p<0.05 and p<0.01), respectively. To conclude, ultrasound backscatter parameters, measured from intact proximal femurs, are significantly related (p<0.05) to trabecular bone structural properties and mineral density.
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| 41. |
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| 42. |
- Marsell, Richard, et al.
(författare)
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GSK-3 inhibition by an orally active small molecule increases bone mass in rats
- 2012
-
Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:3, s. 619-627
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Tidskriftsartikel (refereegranskat)abstract
- Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01). Furthermore, histomorphometry showed a dramatic increase in bone formation indices, and serum markers of both bone formation (Osteocalcin, 146% of control; p<0.001) and resorption (CTX, 189% of control; p<0.001) were elevated. Our conclusion is that a GSK-3 inhibitor drug may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass, since AZD2858 has extensive bone building effects at predominantly trabecular sites.
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| 43. |
- Mathavan, Neashan, et al.
(författare)
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Investigating the synergistic efficacy of BMP-7 and zoledronate on bone allografts using an open rat osteotomy model.
- 2013
-
Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 56:2, s. 440-448
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Tidskriftsartikel (refereegranskat)abstract
- Bone grafts are well-established in the treatment of fracture non-unions but union is still not always achieved. Harvesting autograft is associated with donor site morbidity and the available amount of bone is limited. Allograft is more easily obtained and available in greater quantities but lacks the osteoinductive characteristics of autograft. We have previously shown a synergistic effect of bone morphogenetic protein (BMP-7), systemic bisphosphonates and autograft. In the present study we hypothesized that the combination of allograft+BMP-7+systemic ZA is more effective than autograft alone, which is currently the most frequently used aid in augmenting fracture and non-union healing. Femoral osteotomies were performed on 82 male Sprague Dawley rats and fixed with intramedullary K-wires. The rats were randomized into 7 groups: i. saline, ii. autograft, iii. allograft, iv. allograft+BMP-7, v. autograft+zoledronate (ZA), vi. allograft+ZA and vii. allograft+BMP-7+ZA. Autografts were harvested from the contralateral tibia. Allografts were obtained from donor rats and frozen. BMP-7 was administered locally in the form of a putty placed circumferentially around the osteotomy. At 2weeks, the rats were injected with a single dose of either saline or ZA. The rats were sacrificed at 6weeks and the femurs were evaluated using radiography, histology, μCT and three-point bending tests. Complete radiological healing was seen in all rats in the BMP-7 groups. The callus volume was larger and the calluses were denser with allograft+BMP-7+ZA than in all other groups (μCT, p<0.001). Mechanical testing yielded a substantially higher peak force with the allograft+BMP-7+ZA combination than all other groups (p<0.01, p<0.001). This was further reinforced in the 59% increase in the peak force observed in the osteotomized femurs of the allograft+BMP-7+ZA group compared to the control femurs (p<0.01), whereas significant decreases of 22-27% were observed in the saline or bone-graft alone groups (p<0.01, p<0.05). Thus our results suggest that allograft combined with the anabolic effect of BMP-7 and the anti-catabolic effect of zoledronate is more efficient than autograft alone.
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| 44. |
- Moscatelli, Ilana, et al.
(författare)
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Lentiviral gene transfer of TCIRG1 into peripheral blood CD34(+) cells restores osteoclast function in infantile malignant osteopetrosis.
- 2013
-
Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 57:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Infantile malignant osteopetrosis (IMO) is a rare, lethal, autosomal recessive disorder characterized by non-functional osteoclasts. More than 50% of the patients have mutations in the TCIRG1 gene, encoding for a subunit of the osteoclast proton pump. The aim of this study was to restore the resorptive function of IMO osteoclasts by lentiviral mediated gene transfer of the TCIRG1 cDNA. CD34(+) cells from peripheral blood of five IMO patients and from normal cord blood were transduced with lentiviral vectors expressing TCIRG1 and GFP under a SFFV promoter, expanded in culture and differentiated on bone slices to mature osteoclasts. qPCR analysis and western blot revealed increased mRNA and protein levels of TCIRG1, comparable to controls. Vector corrected IMO osteoclasts generated increased release of Ca(2+) and bone degradation product CTX-I into the media as well as increased formation of resorption pits in the bone slices, while non-corrected IMO osteoclasts failed to resorb bone. Resorption was approximately 70-80% of that of osteoclasts generated from cord blood. Furthermore, transduced CD34(+) cells successfully engrafted in NSG-mice. In conclusion we provide the first evidence of lentiviral-mediated correction of a human genetic disease affecting the osteoclastic lineage.
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| 45. |
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| 46. |
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| 47. |
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| 48. |
- Oei, L., et al.
(författare)
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Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus
- 2014
-
Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 59, s. 20-27
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Tidskriftsartikel (refereegranskat)abstract
- Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.
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| 49. |
- Olkku, Anu, et al.
(författare)
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Ultrasound-induced activation of Wnt signaling in human MG-63 osteoblastic cells.
- 2010
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 47:2, s. 320-330
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Tidskriftsartikel (refereegranskat)abstract
- The benefit from an ultrasound (US) exposure for fracture healing has been clearly shown. However, the molecular mechanisms behind this effect are not fully known. Recently, the canonical Wnt signaling pathway has been recognized as one of the essential regulators of osteoblastogenesis and bone mass, and thereby considered crucial for bone health. Mechanical loading and fluid shear stress have been reported to activate the canonical Wnt signaling pathway in bone cells, but previous reports on the effects of therapeutic US on Wnt signaling in general or in bone, in particular, have not been published yet. Therefore, activation of Wnt signaling pathway was assayed in human osteoblastic cells, and indeed, this pathway was found to be activated in MG-63 cells through the phosphoinositol 3-kinase/Akt (PI3K/Akt) and mTOR cascades following a single 10 min US exposure (2 W, 1.035 MHz). In addition to the reporter assay results, the Wnt pathway activation was also observed as nuclear localization of beta-catenin. Wnt activation showed also temperature dependence at elevated temperatures, and the expression of canonical Wnt ligands was induced under the thermal exposures. However, existence of a specific, non-thermal US component was evident as well, perhaps evidence of a potential dual action of therapeutic US on bone. Neither US nor heat exposures affected cell viability in our experiments. In summary, this is the first study to report that Wnt signaling cascade, important for osteoblast function and bone health, is one of the pathways activated by therapeutic US as well as by hyperthermia in human osteoblastic cells. Our results provide evidence for the potential molecular mechanisms behind the beneficial effects of US on fracture healing. Combinations of US, heat, and possible pharmacological treatment could provide useful flexibility for clinical cases in treating various bone disorders.
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| 50. |
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