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Metaphyseal Fracture Healing
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 22 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1502
National Category
Other Clinical Medicine Orthopedics Nursing
Identifiers
URN: urn:nbn:se:liu:diva-126148DOI: 10.3384/diss.diva-126148ISBN: 978-91-7685-865-3 (print)OAI: oai:DiVA.org:liu-126148DiVA: diva2:911990
Public defence
2016-04-26, Nils Holger salen, ing 71 pl 8, Campus US, Linköping, 14:00 (English)
Opponent
Supervisors
Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2016-08-31Bibliographically approved
List of papers
1. Distal radial fractures heal by direct woven bone formation
Open this publication in new window or tab >>Distal radial fractures heal by direct woven bone formation
2013 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 84, no 3, 297-300 p.Article in journal (Refereed) Published
Abstract [en]

Background Descriptions of fracture healing almost exclusively deal with shaft fractures and they often emphasize endochondral bone formation. In reality, most fractures occur in metaphyseal cancellous bone. Apart from a study of vertebral fractures, we have not found any histological description of cancellous bone healing in humans.

Patients and methods We studied histological biopsies from the central part of 12 distal radial fractures obtained during surgery 6–28 days after the injury, using routine hematoxylin and eosin staining.

Results New bone formation was seen in 6 cases. It was always in the form of fetal-like, disorganized woven bone. It seldom had contact with old trabeculae and appeared to have formed directly in the marrow. Cartilage was scarce or absent. The samples without bone formation showed only necrosis, scar, or old cancellous bone.

Interpretation The histology suggests that cells in the midst of the marrow respond to the trauma by direct formation of bone, independently of trabecular surfaces.

Place, publisher, year, edition, pages
Informa Healthcare, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96485 (URN)10.3109/17453674.2013.792769 (DOI)000319749900012 ()
Available from: 2013-08-23 Created: 2013-08-20 Last updated: 2017-12-06
2. Experimental models for cancellous bone healing in the rat Comparison of drill holes and implanted screws
Open this publication in new window or tab >>Experimental models for cancellous bone healing in the rat Comparison of drill holes and implanted screws
2015 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 86, no 6, 745-750 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-123812 (URN)10.3109/17453674.2015.1075705 (DOI)000365484500019 ()26200395 (PubMedID)
Note

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

Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2017-11-30
3. Earlier effect of alendronate in mouse metaphyseal versus diaphyseal bone healing
Open this publication in new window or tab >>Earlier effect of alendronate in mouse metaphyseal versus diaphyseal bone healing
2017 (English)In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 35, no 4, 793-799 p.Article in journal (Refereed) 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

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keyword
fracture, bisphosphonate, metaphysis, cancellous bone, trabecular bone, alendronate
National Category
Clinical Medicine Orthopedics Nursing
Identifiers
urn:nbn:se:liu:diva-130921 (URN)10.1002/jor.23316 (DOI)000399728400008 ()27233101 (PubMedID)
Funder
Swedish Research CouncilLinköpings universitetÖstergötland County CouncilEU, FP7, Seventh Framework Programme
Note

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

Available from: 2016-08-31 Created: 2016-08-31 Last updated: 2017-06-15Bibliographically approved
4. Different effects of indomethacin on healing of shaft and metaphyseal fractures
Open this publication in new window or tab >>Different effects of indomethacin on healing of shaft and metaphyseal fractures
2015 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 86, no 2, 243-247 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Informa Healthcare, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117204 (URN)10.3109/17453674.2014.973328 (DOI)000351740100017 ()25323801 (PubMedID)
Note

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

Available from: 2015-04-22 Created: 2015-04-21 Last updated: 2017-12-04
5. Glucocorticoids inhibit shaft fracture healing but not metaphyseal bone regeneration under stable mechanical conditions
Open this publication in new window or tab >>Glucocorticoids inhibit shaft fracture healing but not metaphyseal bone regeneration under stable mechanical conditions
2015 (English)In: BONE and JOINT RESEARCH, ISSN 2046-3758, Vol. 4, no 10, 170-175 p.Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
BRITISH EDITORIAL SOC BONE JOINT SURGERY, 2015
Keyword
Bone; healing; fracture
National Category
Biomaterials Science
Identifiers
urn:nbn:se:liu:diva-123157 (URN)10.1302/2046-3758.410.2000414 (DOI)000364596200002 ()
Note

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

Available from: 2015-12-07 Created: 2015-12-04 Last updated: 2016-03-15

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