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Sandberg, Olof
Publikasjoner (10 av 18) Visa alla publikasjoner
Sandberg, O., Bernhardsson, M. & Aspenberg, P. (2017). Earlier effect of alendronate in mouse metaphyseal versus diaphyseal bone healing. Journal of Orthopaedic Research, 35(4), 793-799
Åpne denne publikasjonen i ny fane eller vindu >>Earlier effect of alendronate in mouse metaphyseal versus diaphyseal bone healing
2017 (engelsk)Inngår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 35, nr 4, s. 793-799Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Healing of injured cancellous bone is characterized by a transient stage of rapid bone formation throughout the traumatized bone volume, often followed by similarly rapid resorption. This is different from the slower diaphyseal healing via an external callus. We, therefore, hypothesized that antiresorptive treatment might have an earlier positive effect in cancellous bone healing than in diaphyseal fractures. One hundred and twenty-three male C57bl6 mice received either an internally stabilized diaphyseal osteotomy of the femur or a screw inserted into the tibial metaphysis. The mice were randomized to daily alendronate injections (200 μg/kg/day), or control injections, and killed for mechanical testing after 14, 21, or 28 days. The hypothesis was tested by a three-way Anova (time, site, and drug). The ultimate force was increased by bisphosphonate treatment in both models. There was a significant interaction between time, site, and drug (p < 0.001) so that the full positive effect of alendronate was evident in the metaphysis at 14 days, but first after 28 days in the diaphysis. While the early effect in the metaphysis might be translated into earlier healing, the late effect in the diaphysis was due to delayed remodeling of the callus, which might have less clinical importance. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2017
Emneord
fracture, bisphosphonate, metaphysis, cancellous bone, trabecular bone, alendronate
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-130921 (URN)10.1002/jor.23316 (DOI)000399728400008 ()27233101 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilLinköpings universitetÖstergötland County CouncilEU, FP7, Seventh Framework Programme
Merknad

Funding agencies: Swedish Research Council [VR 02031-47-5]; Linkoping University; Ostergotland County Council; European Communitys Seventh Framework Programme [FP7/2007-2013]

Tilgjengelig fra: 2016-08-31 Laget: 2016-08-31 Sist oppdatert: 2018-05-03bibliografisk kontrollert
Sandberg, O. (2016). Metaphyseal Fracture Healing. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Åpne denne publikasjonen i ny fane eller vindu >>Metaphyseal Fracture Healing
2016 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Most of what is known about fracture healing comes from studies of shaft fractures in long bones. In contrast, patients more often have fractures closer to the ends (metaphyses). Here most bone tissue has a spongy, cancellous structure different from the compact bone of the shaft. There is an increasing awareness that metaphyseal fractures heal differently. However, the more easily studied shaft healing has usually been considered as good enough representative for fracture healing in general.

My work shows that the biology of metaphyseal healing is more different from shaft healing than was previously known and that this has implications on the effect of various commonly prescribed drugs.

First we studied biopsies of healing cancellous bone collected from human donors. We found that the most abundant new bone formation occurred freely in the marrow rather than on the surface of old trabeculae, as described in most literature. There was little cartilage, indicating that the dominant bone formation process is mostly membranous in nature. This is a contrast to the ample cartilage formation commonly found in the well-characterized shaft fracture models.

Next we characterized a model that allows for mechanical quantification of regenerating cancellous bone. By contrasting this cancellous healing model with the standard shaft healing model we could demonstrate that the NSAID indomethacin, the glucocorticoid dexamethasone, and the bisphosphonate alendronate all had different effects on the mechanical quality of bone regeneration in shaft and metaphysis; while anti-inflammatory drugs strongly impaired shaft healing, metaphyseal healing was not similarly affected. Alendronate had a positive effect on both models, though the effect was strongest in the metaphyseal model. Taken together these differences shed some light as to the differences in healing biology.

The last step (within the boundaries of this thesis) was a characterization of how healing in cortical and cancellous bone differs in terms of immune cell involvement. We could find little difference between the two bone types day 3. However, day 5 an increase in the number of granulocytes could be noted in the cancellous bone while the cortical bone had a higher number of lymphocytes.

To conclude, this work furthers our understanding of how metaphyseal healing differs from shaft healing. It has clinical implications as it motivates an increased attention to the site of fracture while contemplating treatment. I hope this thesis can be read as an argument for increased interest in metaphyseal fracture healing.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2016. s. 22
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1502
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-126148 (URN)10.3384/diss.diva-126148 (DOI)978-91-7685-865-3 (ISBN)
Disputas
2016-04-26, Nils Holger salen, ing 71 pl 8, Campus US, Linköping, 14:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2016-03-15 Laget: 2016-03-15 Sist oppdatert: 2018-01-10bibliografisk kontrollert
Bernhardsson, M., Sandberg, O. & Aspenberg, P. (2015). Anti-RANKL treatment improves screw fixation in cancellous bone in rats. Injury, 46(6), 990-995
Åpne denne publikasjonen i ny fane eller vindu >>Anti-RANKL treatment improves screw fixation in cancellous bone in rats
2015 (engelsk)Inngår i: Injury, ISSN 0020-1383, E-ISSN 1879-0267, Vol. 46, nr 6, s. 990-995Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Bisphosphonates improve implant fixation in randomised clinical trials of knee prostheses, hip prostheses and dental implants. However, a limited amount of bone resorption is required for bisphosphonates to exert an effect. Anti-RANKL treatment does not have this limitation, and we therefore tested whether if they might be more effective for improvement of implant fixation. This is of interest, as anti-RANKL treatment with denosumab is now in common clinical use. Male SD rats received a stain-less steel screw in the right proximal tibia and a drill hole in the left (n = 42). They were randomised to subcutaneous injections of either alendronate (20 mu g/kg/day), alendronate (200 mu g/kg/day), osteoprotegerin with an Fc tag (OPG-Fc; 8 mg/kg, twice weekly), or saline control. After 4 weeks, the fixation of the steel screw was measured by pull-out test. The tibia with the drill hole was evaluated with mu CT. OPG-Fc increased the pull-out force compared to saline controls by 153% (p less than 0.001). There was no significant difference between OPG-Fc and the alendronate groups. OPG-Fc increased the bone density (BV/TV) in the previous drill hole compared to controls 7-fold (p less than 0.001). This increase was higher than with any alendronate dose (p less than 0.001). OPG-Fc increased the bone density of the L5 vertebral body, but there was no significant difference between OPG-Fc and alendronate. Our results suggest that screw fixation in cancellous bone can be dramatically improved by an antiRANKL agent. The effect was comparable to very high bisphosphonate doses. Screw insertion in cancellous bone elicits a metaphyseal fracture healing response, and our findings might be relevant not only for implant fixation, but also for fracture healing in cancellous bone.

sted, utgiver, år, opplag, sider
Elsevier, 2015
Emneord
Antiresorptives; Denosumab; Bisphosphonates; Rat model; Implant fixation; Fracture healing
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-119239 (URN)10.1016/j.injury.2015.02.011 (DOI)000355018800009 ()25744169 (PubMedID)
Merknad

Funding Agencies|Swedish Research Council [2031-47-5]; AFA Insurance company; European Union 7th framework programme (FP7) [279239]; Linkoping University

Tilgjengelig fra: 2015-06-15 Laget: 2015-06-12 Sist oppdatert: 2017-12-04
Sandberg, O. & Aspenberg, P. (2015). Different effects of indomethacin on healing of shaft and metaphyseal fractures. Acta Orthopaedica, 86(2), 243-247
Åpne denne publikasjonen i ny fane eller vindu >>Different effects of indomethacin on healing of shaft and metaphyseal fractures
2015 (engelsk)Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 86, nr 2, s. 243-247Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background and purpose - NSAIDs are commonly used in the clinic, and there is a general perception that this does not influence healing in common types of human fractures. Still, NSAIDs impair fracture healing dramatically in animal models. These models mainly pertain to fractures of cortical bone in shafts, whereas patients more often have corticocancellous fractures in metaphyses. We therefore tested the hypothesis that the effect of an NSAID is different in shaft healing and metaphyseal healing. Methods - 26 mice were given an osteotomy of their left femur with an intramedullary nail. 13 received injections of indomethacin, 1 mg/kg twice daily. After 17 days of healing, the femurs were analyzed with 3-point bending and microCT. 24 other mice had holes drilled in both proximal tibias, to mimic a stable metaphyseal injury. A screw was inserted in the right tibial hole only. After 7 days of indomethacin injections or control injections, screw fixation was measured with mechanical pull-out testing and the side without a screw was analyzed with microCT. Results - In the shaft model, indomethacin led to a 35% decrease in force at failure (95% CI: 14-54). Callus size was reduced to a similar degree, as seen by microCT. Metaphyseal healing was less affected by indomethacin, as no effect on pull-out force could be seen (95% CI: - 27 to 17) and there was only a small drop in new bone volume inside the drill hole. The difference in the relative effect of indomethacin between the 2 models was statistically significant (p = 0.006). Interpretation - Indomethacin had a minimal effect on stable metaphyseal fractures, but greatly impaired healing of unstable shaft fractures. This could explain some of the differences found between animal models and clinical experience.

sted, utgiver, år, opplag, sider
Informa Healthcare, 2015
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-117204 (URN)10.3109/17453674.2014.973328 (DOI)000351740100017 ()25323801 (PubMedID)
Merknad

Funding Agencies|Swedish Research Council; Linkoping University; Ostergotland County Council; King Gustaf V and Queen Victoria Freemason Foundation

Tilgjengelig fra: 2015-04-22 Laget: 2015-04-21 Sist oppdatert: 2017-12-04
Bernhardsson, M., Sandberg, O. & Aspenberg, P. (2015). Experimental models for cancellous bone healing in the rat Comparison of drill holes and implanted screws. Acta Orthopaedica, 86(6), 745-750
Åpne denne publikasjonen i ny fane eller vindu >>Experimental models for cancellous bone healing in the rat Comparison of drill holes and implanted screws
2015 (engelsk)Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 86, nr 6, s. 745-750Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background and purpose - Cancellous bone appears to heal by mechanisms different from shaft fracture healing. There is a paucity of animal models for fractures in cancellous bone, especially with mechanical evaluation. One proposed model consists of a screw in the proximal tibia of rodents, evaluated by pull-out testing. We evaluated this model in rats by comparing it to the healing of empty drill holes, in order to explain its relevance for fracture healing in cancellous bone. To determine the sensitivity to external influences, we also compared the response to drugs that influence bone healing. Methods - Mechanical fixation of the screws was measured by pull-out test and related to the density of the new bone formed around similar, but radiolucent, PMMA screws. The pull-out force was also related to the bone density in drill holes at various time points, as measured by microCT. Results - The initial bone formation was similar in drill holes and around the screw, and appeared to be reflected by the pull-out force. Both models responded similarly to alendronate or teriparatide (PTH). Later, the models became different as the bone that initially filled the drill hole was resorbed to restore the bone marrow cavity, whereas on the implant surface a thin layer of bone remained, making it change gradually from a trauma-related model to an implant fixation model. Interpretation - The similar initial bone formation in the different models suggests that pull-out testing in the screw model is relevant for assessment of metaphyseal bone healing. The subsequent remodeling would not be of clinical relevance in either model.

sted, utgiver, år, opplag, sider
TAYLOR & FRANCIS LTD, 2015
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-123812 (URN)000365484500019 ()26200395 (PubMedID)
Merknad

Funding Agencies|Swedish Research Council [2031-47-5]; AFA insurance company; EU [279239]; Linkoping University; Eli Lilly and Company

DOI does not work: 10.3109/17453674.2015.1075705

Tilgjengelig fra: 2016-01-11 Laget: 2016-01-11 Sist oppdatert: 2018-10-29
Sandberg, O. & Aspenberg, P. (2015). Glucocorticoids inhibit shaft fracture healing but not metaphyseal bone regeneration under stable mechanical conditions. BONE and JOINT RESEARCH, 4(10), 170-175
Åpne denne publikasjonen i ny fane eller vindu >>Glucocorticoids inhibit shaft fracture healing but not metaphyseal bone regeneration under stable mechanical conditions
2015 (engelsk)Inngår i: BONE and JOINT RESEARCH, ISSN 2046-3758, Vol. 4, nr 10, s. 170-175Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Objectives Healing in cancellous metaphyseal bone might be different from midshaft fracture healing due to different access to mesenchymal stem cells, and because metaphyseal bone often heals without a cartilaginous phase. Inflammation plays an important role in the healing of a shaft fracture, but if metaphyseal injury is different, it is important to clarify if the role of inflammation is also different. The biology of fracture healing is also influenced by the degree of mechanical stability. It is unclear if inflammation interacts with stability-related factors.

Methods We investigated the role of inflammation in three different models: a metaphyseal screw pull-out, a shaft fracture with unstable nailing (IM-nail) and a stable external fixation (ExFix) model. For each, half of the animals received dexamethasone to reduce inflammation, and half received control injections. Mechanical and morphometric evaluation was used.

Results As expected, dexamethasone had a strong inhibitory effect on the healing of unstable, but also stable, shaft fractures. In contrast, dexamethasone tended to increase the mechanical strength of metaphyseal bone regenerated under stable conditions.

Conclusions It seems that dexamethasone has different effects on metaphyseal and diaphyseal bone healing. This could be explained by the different role of inflammation at different sites of injury.

sted, utgiver, år, opplag, sider
BRITISH EDITORIAL SOC BONE JOINT SURGERY, 2015
Emneord
Bone; healing; fracture
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-123157 (URN)10.1302/2046-3758.410.2000414 (DOI)000364596200002 ()
Merknad

Funding Agencies|Swedish Research Council [VR 2009-6725]; Linkoping University; Ostergotland County Council; King Gustav V and Queen Victoria Mason Foundation; European Community [279239]

Tilgjengelig fra: 2015-12-07 Laget: 2015-12-04 Sist oppdatert: 2016-03-15
Sandberg, O., Dånmark, I., Eliasson, P. & Aspenberg, P. (2015). Influence of a lower leg brace on traction force in healthy and ruptured Achilles tendons. MLTJ Muscles, Ligaments and Tendons Journal, 5(2), 63-67
Åpne denne publikasjonen i ny fane eller vindu >>Influence of a lower leg brace on traction force in healthy and ruptured Achilles tendons
2015 (engelsk)Inngår i: MLTJ Muscles, Ligaments and Tendons Journal, ISSN 2240-4554, Vol. 5, nr 2, s. 63-67Artikkel i tidsskrift (Annet vitenskapelig) Published
Abstract [en]

Background: we investigated how ruptured Achilles tendons are loaded in a brace. There is an ongoing discussion whether patients should be recommended to bear weight on the injuredlimb. However, little is known about the effects of bracing on tensional loading of the healing Achilles tendon: it is uncertain if load-bearing actually stresses the Achilles tendon inside a brace.

Methods: we measured plantar flexion moment inside the brace, in order to estimate tensional loading of the tendon, by use of an insole with pressure transducers.

Results: after wearing the brace for 1 hour, young healthy individuals reduced their maximum flexion moment during gait by half. Patients with Achilles tendon rupture showed no measurable flexion moment during gait with the brace, 4 or 7 weeks after injury. Only when specifically instructed, they could produce a considerable plantar flexion moment. We noted that gait speed with the brace at 4 weeks correlated with a heel-raise functional test at 1 year: the higher the spontaneous gait speed, the less the functional difference between the injured and the uninjured leg (r2=0.68; p=0.002).

Conclusion: the correlation with gait speed suggests that the patients’ general physical aptness has an impact on the end result.

sted, utgiver, år, opplag, sider
Rome, Italy: C I C Edizioni Internazionali, 2015
Emneord
Achilles tendon rupture; bracing; immobilization; loading; flexion moment
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-125335 (URN)10.11138/mltj/2015.5.2.063 (DOI)26261783 (PubMedID)
Tilgjengelig fra: 2016-02-19 Laget: 2016-02-19 Sist oppdatert: 2018-01-10bibliografisk kontrollert
Schilcher, J., Sandberg, O., Isaksson, H. & Aspenberg, P. (2014). Histology of 8 atypical femoral fractures. Acta Orthopaedica, 85(3), 280-286
Åpne denne publikasjonen i ny fane eller vindu >>Histology of 8 atypical femoral fractures
2014 (engelsk)Inngår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 85, nr 3, s. 280-286Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

BACKGROUND AND PURPOSE:

The pathophysiology behind bisphosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself may provide clues.

PATIENTS AND METHODS:

Between 2008 and 2013, we collected bone biopsies including the fracture line from 4 complete and 4 incomplete atypical femoral fractures. 7 female patients reported continuous bisphosphonate use for 10 years on average. 1 patient was a man who was not using bisphosphonates. Dual-energy X-ray absorptiometry of the hip and spine showed no osteoporosis in 6 cases. The bone biopsies were evaluated by micro-computed tomography, infrared spectroscopy, and qualitative histology.

RESULTS:

Incomplete fractures involved the whole cortical thickness and showed a continuous gap with a mean width of 180 µm. The gap contained amorphous material and was devoid of living cells. In contrast, the adjacent bone contained living cells, including active osteoclasts. The fracture surfaces sometimes consisted of woven bone, which may have formed in localized defects caused by surface fragmentation or resorption.

INTERPRETATION:

Atypical femoral fractures show signs of attempted healing at the fracture site. The narrow width of the fracture gap and its necrotic contents are compatible with the idea that micromotion prevents healing because it leads to strains within the fracture gap that preclude cell survival.

sted, utgiver, år, opplag, sider
Informa Healthcare, 2014
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-109188 (URN)10.3109/17453674.2014.916488 (DOI)000337845000013 ()24786905 (PubMedID)
Tilgjengelig fra: 2014-08-12 Laget: 2014-08-11 Sist oppdatert: 2019-05-27bibliografisk kontrollert
Sandberg, O., Macias, B. R. & Aspenberg, P. (2014). Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed. Bone, 63, 15-19
Åpne denne publikasjonen i ny fane eller vindu >>Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed
2014 (engelsk)Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 63, s. 15-19Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Stimulation of bone formation by PTH is related to mechanosensitivity. The response to PTH treatment in intact bone could therefore be blunted by unloading. We studied the effects of mechanical loading on the response to PTH treatment in bone healing. Most fractures occur in the metaphyses, therefor we used a model for metaphyseal bone injury. One hind leg of 20 male SD rats was unloaded via intramuscular botulinum toxin injections. Two weeks later, the proximal unloaded tibia had lost 78% of its trabecular contents. At this time-point, the rats received bilateral proximal tibiae screw implants. Ten of the 20 rats were given daily injections of 5 μg/kg PTH (1-34). After two weeks of healing, screw fixation was measured by pull-out, and microCT of the distal femur cancellous compartment was performed. Pull-out force provided an estimate for cancellous bone formation after trauma. PTH more than doubled the pull-out force in the unloaded limbs (from 14 to 30 N), but increased it by less than half in the loaded ones (from 30 to 44 N). In relative terms, PTH had a stronger effect on pull-out force in unloaded bone than in loaded bone (p=0.03). The results suggest that PTH treatment for stimulation of bone healing does not require simultaneous mechanical stimulation.

sted, utgiver, år, opplag, sider
Elsevier, 2014
Emneord
Botulinum toxin; Fracture healing; Mechanical loading; Metaphyseal fracture; Parathyroid hormone
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-111393 (URN)10.1016/j.bone.2014.02.008 (DOI)000335094200003 ()24582802 (PubMedID)2-s2.0-84896034433 (Scopus ID)
Tilgjengelig fra: 2014-10-16 Laget: 2014-10-16 Sist oppdatert: 2018-01-11bibliografisk kontrollert
Movérare-Skrtic, S., Henning, P., Liu, X., Nagano, K., Saito, H., Börjesson, A. E., . . . Ohlsson, C. (2014). Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Nature Medicine, 20(11), 1279-1288
Åpne denne publikasjonen i ny fane eller vindu >>Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures
Vise andre…
2014 (engelsk)Inngår i: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 20, nr 11, s. 1279-1288Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.

sted, utgiver, år, opplag, sider
Nature Publishing Group, 2014
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-111388 (URN)10.1038/nm.3654 (DOI)000344724300017 ()25306233 (PubMedID)
Tilgjengelig fra: 2014-10-16 Laget: 2014-10-16 Sist oppdatert: 2018-01-11bibliografisk kontrollert
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