| 1. |
- Aspenberg, Per, et al.
(author)
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Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening
- 2011
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In: BONE. - : Elsevier Science B.V., Amsterdam.. - 8756-3282. ; 48:2, s. 225-230
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Journal article (peer-reviewed)abstract
- Orthopedic joint prostheses may loosen because of localized bone resorption. Despite initial optimism, there are no reports showing that bisphosphonates can stop the progression of prosthetic loosening once it has begun. This might be due to the strong resorptive stimulus, which continuously recruits new osteoclasts. Therefore, we hypothesized that a treatment targeting osteoclast recruitment would be more efficacious than a treatment reducing osteoclast activity. We used a previously described rat model for instability-induced bone resorption, and compared OPG-Fc with alendronate at a clinically relevant or an extreme dose. A titanium plate was osseointegrated at the rat tibial surface. Instability was simulated by a piston, moving perpendicularly to the bone surface. Piston movement induced bone loss via hydrostatic pressure or fluid flow. Rats were randomized to 5 groups (total n = 56), of which 4 were subjected to instability and one was stable. The unstable groups were injected with either high-dose OPG-Fc (10 mg/kg, twice weekly), a high dose of alendronate (20 mu g /kg/day), an extreme dose of alendronate (200 mu g/kg/day) or saline. Significant protection against resorption could only be shown for OPG-Fc and the extreme alendronate dose. Both alendronate doses reduced serum levels of tartrate-resistant acid phosphatase isoform 5b to a similar extent, demonstrating that the lower dose was able to reduce resorption in the normally remodeling skeleton, although not in the osteolytic lesions caused by instability. Osteoclast numbers in the lesion were increased by the lower bisphosphonate dose and reduced by OPG-Fc. The results suggest the possibility of targeting osteoclast recruitment via the RANKL system in patients with impending prosthetic loosening.
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| 2. |
- Persson, Per-Erik, 1949-
(author)
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Heterotopic Ossification : Clinical and Experimental Studies on Risk Factors, Etiology and Inhibition by Non-steroidal Anti-inflammatory Drugs
- 2004
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Doctoral thesis (other academic/artistic)abstract
- In this thesis, occurrence of heterotopic ossification (HO) following total hip arthroplasty (THA) was studied. Preventive effects and complications with non-steroidal anti-inflammatory drugs (NSAIDs) were analyzed. Experimental investigations on bone formation were employed to gain insight to the mechanism of NSAIDs action on bone.(I). Fifty-six patients with bilateral THAs were analyzed. We found a strong correlation between HO on the two sides. Incidence and grade of HO were higher in men than in women.(II). Sixty-nine patients with bilateral THAs who had been treated with NSAIDs after one or both THAs were analyzed for HO. Widespread HO occurred in untreated THAs, but in none of the treated THAs.(III). A consecutive series of THAs were analyzed for HO. No widespread HO occurred in patients treated with NSAIDs for 21 days. In contrast, widespread HO occurred in 23% of patients not treated.(IV). A randomized, double-blind, prospective study on 144 patients was performed to determine the efficacy and minimum treatment time with Ibuprofen for prophylaxis of HO after THA. Treatment with Ibuprofen was effective for preventing HO and a treatment time of 8 days was sufficient.(V). A ten-year follow-up examination was performed on the patients from study IV. Thirteen patients had been revised. All but one belonged to groups treated with Ibuprofen. However, the prosthetic survival time was not statistically different for patients treated with NSAIDs compared to the control group. Eighty-four more patients underwent radiographic examination10 years after THA. Nine loose prostheses were found. These were equally distributed between NSAIDs-treated and non-treated THAs. When combining complications (revisions and radiographic loosening) no significant effects could be verified.(VI). Experimental induction of heterotopic new bone with demineralized allogeneic bone matrix (DABM) and with bone autografts, was used in rats to study effects of NSAIDs on new bone formation. Indomethacin inhibited net bone formation in DABMs and in orthotopic fractured bone. In contrast, a net mineral loss occurred in autografts, but neither mineral content nor 45Ca incorporation was affected by Indomethacin treatment. The amount of bone formed per mg implanted DABM was linearly correlated to implant size.
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| 3. |
- Abtahi, Jahan, et al.
(author)
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A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants
- 2012
-
In: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 50:5, s. 1148-1151
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Journal article (peer-reviewed)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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| 4. |
- Abtahi, Jahan, et al.
(author)
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Bisphosphonate coating might improve fixation of dental implants in the maxilla: A pilot study
- 2010
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In: International Journal of Oral and Maxillofacial Surgery. - : Elsevier Science B.V., Amsterdam. - 0901-5027 .- 1399-0020. ; 39:7, s. 673-677
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Journal article (peer-reviewed)abstract
- This pilot study evaluates the clinical stability of bisphosphonate-coated dental implants placed using a two-stage surgical procedure in five patients. Each patient received seven regular Brånemark implants, one of which was coated with bisphosphonate in a fibrinogen matrix. The coated implant was inserted where the bone was expected to have the least favourable quality. The level of the marginal bone around each implant was measured by intraoral periapical radiographs and implant stability was recorded using resonance frequency measurements. Frequency values (ISQ) were obtained peroperatively before flap closure and after 6 months at abutment connection. At abutment connection the bisphosphonate-coated implants were removed en bloc in two patients for histological examination. An animal experiment had previously confirmed that gamma-sterilization did not reduce bioactivity of the bisphosphonate coating. In each patient, the bisphosphonate-coated implant showed the largest improvement in ISQ level of all implants. Their values at the start tended to be lower, and the absolute value at 6 months did not differ. No complications occurred with the coated implants. Histology showed no abnormalities. Improvement in ISQ values was an expected effect of the bisphosphonate coating, but could be due to the choice of insertion site. This finding warrants a randomized, blinded study.
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| 5. |
- Abtahi, Jahan, et al.
(author)
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Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. No primary necrosis in unexposed bone
- 2012
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In: Journal of Oral Pathology & Medicine. - : John Wiley and Sons. - 0904-2512 .- 1600-0714. ; 41:6, s. 494-499
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Journal article (peer-reviewed)abstract
- J Oral Pathol Med (2012) 41: 494499 Background: Bisphosphonate-related osteonecrosis of the jaw was first described to start with sterile osteocyte death, similar to osteonecrosis in other parts of the skeleton. The typical chronic osteomyelitis was thought to develop when the dead bone was exposed to the oral cavity. An alternative explanation would be that the chronic osteomyelitis is a result of a bisphosphonate-related inability of infected bony lesions to heal. We tested the hypothesis that primary osteocyte death is not necessary for the development of jaw osteonecrosis. Material and methods: Forty rats were randomly allocated to four groups of 10. All animals underwent unilateral molar extraction and received the following drug treatments: Group I, controls with no drug treatment; Group II, 200 mu g/kg per day alendronate; Groups III and IV, 200 mu g/kg per day alendronate and 1 mg/kg of dexamethasone. All rats were euthanized after 14 days. Presence of osteonecrosis was determined by clinical and histological observations for groups IIII. For group IV, osteocyte viability at the contralateral uninjured site was examined using lactate dehydrogenase histochemistry (LDH). Results: All animals in the alendronate plus dexamethasone groups developed large ONJ-like lesions. Lactate dehydrogenase staining showed viable osteocytes in the contralateral jaw with no tooth extraction. No signs of osteonecosis were seen in the other groups. Conclusion: Bisphosphonates and dexamethasone caused no osteocyte death in uninjured bone, but large ONJ-like lesions after tooth extraction. Osteonecrosis of the jaw appears to arise first after the bone has been exposed. Possibly, bisphosphonates hamper the necessary resorption of bone that has become altered because of infection.
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| 6. |
- Abtahi, Jahan, 1965-
(author)
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Bisphosphonates and implants in the jaw bone
- 2013
-
Doctoral thesis (other academic/artistic)abstract
- Insertion of metal implants in bone is one of the commonest of all surgical procedures. The success of these operations is dependent on the fixation of the implants, which, in turn, depends on the strength of the bone that holds them. If the quality of the bone holding the implant could be improved locally, surgical procedures would become simpler and rehabilitation would become faster. Bisphosphonates are anti-resorptive drugs that act specifically on osteoclasts, thereby maintaining bone density and strength. Once released from the surface of a coated implant, bisphosphonates reduce osteoclast activity, thereby changing the balance of bone turnover in favor of bone formation, leading to a net gain in local bone density. During the last decades, the effects of bisphosphonate treatment on the stability of implants have been tested in several clinical and animal studies, but not in human jaws. This may be because it has been suggested that there is a link between the use of bisphosphonates (especially those given intravenously) and a condition called osteonecrosis of the jaw (ONJ). The pathophysiology and treatment of ONJ is controversial. The difficulty in treating ONJ has highlighted the importance of prevention.The overall aim of the present thesis was to evaluate the effect of local and systemic use of bisphosphonates on bone tissue. Could a thin, bisphosphonate-eluting fibrinogen coating improve the fixation of metal implants in the human jaw? Would it be possible to reproduce ONJ and prevent the development of this condition in an animal model?In two clinical studies, a total number of 96 implants were inserted in 21 patients. In a randomized trial with a paired design, one implant in each pair was coated with a thin fibrinogen layer containing two bisphosphonates (pamidronate and ibandronate). The bisphosphonate-coated implants showed better stability as measured by resonancefrequency analysis. Radiographic intraoral films also showed less bone loss. Three animal models were developed. In a study comparing local and systemic effects of bisphosphonates, zoledronate-coated screws inserted in rats showed better fixation in spite of a drug treatment that is known to induce ONJ-like lesions when given systemically. In another rat model, ONJ-like lesions were reproducibly induced at sites of tooth extraction whereas there were no signs of bone cell death in uninjured sites. Finally, rat experiments showed that the development of ONJ-like lesions after tooth extraction could be prevented by early mucoperiosteal coverage.In conclusion, a thin, bisphosphonate-eluting fibrinogen coating can improve the fixation of dental implants in human bone. This may lead to new possibilities in orthopaedic surgery and dentistry. The pathophysiology of ONJ is strongly linked to bone exposure in combination with drugs that reduce resorption.
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| 7. |
- Abtahi, Jahan, et al.
(author)
-
Effect of Local vs. Systemic Bisphosphonate Delivery on Dental Implant Fixation in a Model of Osteonecrosis of the Jaw
- 2013
-
In: Journal of Dental Research. - : Sage Publications. - 0022-0345 .- 1544-0591. ; 92:3, s. 279-283
-
Journal article (peer-reviewed)abstract
- Locally applied bisphosphonates may improve the fixation of metal implants in bone. However, systemic bisphosphonate treatment is associated with a risk of osteonecrosis of the jaw (ONJ). We hypothesized that local delivery of bisphosphonate from the implant surface improves the fixation of dental implants without complications in a setting where systemic treatment induces ONJ. Forty rats were randomly allocated to 4 groups of 10. All groups received a titanium implant inserted in an extraction socket. Group I received the implants only. Group II received dexamethasone (0.5 mg/kg). Group III received dexamethasone as above plus alendronate (200 µg/kg). Group IV received zoledronate-coated implants and dexamethasone as above. The animals were sacrificed 2 weeks after tooth extraction. All 10 animals with systemic alendronate treatment developed large ONJ-like changes, while all with local treatment were completely healed. Implant removal torque was higher for the bisphosphonate-coated implants compared with the other groups (p < 0.03 for each comparison). Micro-computed tomography of the maxilla showed more bone loss in the systemic alendronate group compared with groups receiving local treatment (p = 0.001). Local bisphosphonate treatment appears to improve implant fixation in a setting where systemic treatment caused ONJ.
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| 8. |
- Abtahi, Jahan, 1965-, et al.
(author)
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Impact of a zoledronate coating on early post-surgical implant stability and marginal bone resorption in the maxilla-A split-mouth randomized clinical trial.
- 2019
-
In: Clinical Oral Implants Research. - : John Wiley & Sons. - 0905-7161 .- 1600-0501. ; 30:1, s. 49-58
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: The objective of this clinical study was to evaluate the effect of a bisphosphonate coating on a titanium implant on the implant stability quotient (ISQ) and the radiographic marginal bone levels at implants during early healing (2-8 weeks).MATERIALS AND METHODS: In a randomized double-blind trial with internal controls, 16 patients received a dental implant coated with zoledronate and one uncoated implant as a control. The coated and uncoated implants which were visually indistinguishable were bone level titanium implants with a moderately rough surface and a microthreaded neck. ISQ values were obtained at insertion and at 2, 4, 6, and 8 weeks. Radiographs were obtained at insertion and at 8 weeks. The primary outcome was the difference in ISQ values between the coated implants and the control implants at 4 and 6 weeks, corrected for insertion values. The secondary outcome was loss of marginal bone level from insertion to 8 weeks.RESULTS: Implant stability quotient values remained largely constant over the 8 weeks, and there was no significant difference between coated and uncoated implants at any time point. There was 0.12 (SD 0.10) mm marginal bone loss at the control implants and 0.04 (SD 0.08) mm at the coated implants. The difference was 0.17 mm; SD 0.14; p < 0.006). On blind qualitative scoring, 13 of the 15 control implants and two of 15 coated implants showed small marginal bone defects (p = 0.003).CONCLUSIONS: There were no statistically significant differences observed in ISQ values between the coated and uncoated implants during the early healing. There was less marginal bone loss at the coated implants.
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| 9. |
- Abtahi, Jahan, et al.
(author)
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Prevention of osteonecrosis of the jaw by mucoperiosteal coverage in a rat model
- 2013
-
In: International Journal of Oral and Maxillofacial Surgery. - : Elsevier BV. - 0901-5027 .- 1399-0020. ; 42:5, s. 632-636
-
Journal article (peer-reviewed)abstract
- There is evidence for a link between the use of systemic bisphosphonates and osteonecrosis of the jaw (ONJ). This condition has the appearance of chronic osteomyelitis, and antibiotics prevent the development of ONJ in animal models. Clinically, ONJ can sometimes be successfully treated by mucoperiosteal coverage. If ONJ is indeed primarily caused by bacterial infection, immediate coverage of the extraction alveolus might reduce the risk of ONJ development in risk patients. Therefore, we studied whether immediate mucoperiosteal coverage after tooth extraction could prevent ONJ development in a rat model. Thirty rats were randomly allocated to three groups of 10. Group I (controls): extraction, no drug treatment; Group II (non-coverage): extraction, dexamethasone plus alendronate; Group III (coverage): dexamethasone plus alendronate, plus coverage by a mucoperiosteal flap. Rats were examined for macroscopic ONJ-like wounds after 2 weeks. All animals in the non-coverage group developed large ONJ-like changes. The coverage and control groups showed an intact overlying mucosa in all rats. Findings were confirmed with histology. Bisphosphonates and dexamethasone caused ONJ-like lesions after tooth extraction in a rat model. This was prevented by immediate mucoperiosteal coverage. The risk of ONJ in patients using bisphosphonates might be reduced by mucoperiosteal coverage after tooth extraction.
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| 10. |
- Abtahi, Jahan, et al.
(author)
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Randomised trial of bisphosphonate-coated dental implants: Radiographic follow-up after five years of loading
- 2016
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In: International Journal of Oral and Maxillofacial Surgery. - : CHURCHILL LIVINGSTONE. - 0901-5027 .- 1399-0020. ; 45:12, s. 1564-1569
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Journal article (peer-reviewed)abstract
- The results of a randomised trial with bisphosphonate-coated dental implants have been reported previously. Each patient received one coated and one uncoated implant in a double-blind split-mouth design study. After 6 months of osseointegration, resonance frequency analysis indicated better fixation of the coated implants. Reduced marginal bone resorption was also shown. However, it was not known whether the advantage of the bisphosphonate coating would persist over time. The radiographic results at 5 years after implant installation are reported herein. A blinded investigator measured marginal resorption on fresh radiographs obtained for 14 of the 16 patients (two had died) and compared these with the post-implantation images. Non-parametric statistics were used. All implants functioned well. The median marginal bone loss for control implants was found to be 0.70 mm, which is less than usually reported in the literature. The bisphosphonate-coated implants showed even less resorption (median 0.20 mm). The median difference within each pair of implants after 5 years of use was 0.34 mm (95% confidence interval 0.00-0.75 mm; P = 0.04). The present data suggest that bisphosphonate-coated implants enable prolonged preservation of the marginal bone.
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| 11. |
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| 12. |
- Agholme, Fredrik, et al.
(author)
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Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats
- 2011
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In: Acta Orthopaedica. - : Taylor and Francis. - 1745-3674 .- 1745-3682. ; 82:5, s. 628-632
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Journal article (peer-reviewed)abstract
- Background and purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.Interpretation: Scl-Ab increases bone formation and screwfixation to a similar degree in loaded and unloaded bone.
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| 13. |
- Agholme, Fredrik, et al.
(author)
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Efficacy of a Sclerostin Antibody Compared to a Low Dose of PTH on Metaphyseal Bone Healing
- 2014
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In: Journal of Orthopaedic Research. - : Wiley-Blackwell. - 0736-0266 .- 1554-527X. ; 32:3, s. 471-476
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Journal article (peer-reviewed)abstract
- We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone healing. Screws of steel or poly methyl methacrylate (PMMA) were inserted bilaterally into the proximal tibia of young male rats. During 4 weeks the animals then received injections of either phosphate buffered saline (control), sclerostin antibody (25mg/kg, twice weekly) or PTH (5 mu g/kg, daily). The healing response around the screws was then assessed by mechanical testing and X-ray microtomography (mu CT). To distinguish between effects on healing and general effects on the skeleton, other untraumatized bone sites and serum biomarkers were also assessed. After 4 weeks of treatment, PTH yielded a 48% increase in screw pull-out force compared to control (p=0.03), while the antibody had no significant effect. In contrast, the antibody increased femoral cortical and vertebral strength where PTH had no significant effect. mu CT showed only slight changes that were statistically significant for the antibody mainly at cortical sites. The results suggest that a relatively low dose of PTH stimulates metaphyseal repair (screw fixation) specifically, whereas the sclerostin antibody has wide-spread effects, mainly on cortical bone, with less influence on metaphyseal healing.
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| 14. |
- Agholme, Fredrik, et al.
(author)
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Experimental results of combining bisphosphonates with allograft in a rat model
- 2009
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In: Journal of Bone and Joint Surgery - Series B. - 0301-620X. ; 91:5, s. 670-675
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Journal article (peer-reviewed)abstract
- Soaking bone grafts in a bisphosphonate solution before implantation can prevent their resorption and increase the local bone density in rats and humans. However, recent studies suggest that pre-treatment of allografts with bisphosphonate can prevent bone ingrowth into impaction grafts. We tested the hypothesis that excessive amounts of bisphosphonate would also cause a negative response in less dense grafts. We used a model where nonimpacted metaphyseal bone grafts were randomised into three groups with either no bisphosphonate, alendronate followed by rinsing, and alendronate without subsequent rinsing, and inserted into bone chambers in rats. The specimens were evaluated histologically at one week, and by histomorphometry and radiology at four weeks. At four weeks, both bisphosphonate groups showed an increase in the total bone content, increased newly formed bone, and higher radiodensity than the controls. In spite of being implanted in a chamber with a limited opportunity to diffuse, even an excessive amount of bisphosphonate improved the outcome. We suggest that the negative results seen by others could be due to the combination of densely compacted bone and a bisphosphonate. We suggest that bisphosphonates are likely to have a negative influence where resorption is a prerequisite to create space for new bone ingrowth.
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| 15. |
- Agholme, Fredrik, et al.
(author)
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Local bisphosphonate release versus hydroxyapatite coating for stainless steel screw fixation in rat tibiae
- 2012
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In: Journal of materials science. Materials in medicine. - : Springer Verlag (Germany). - 0957-4530 .- 1573-4838. ; 23:3, s. 743-752
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Journal article (peer-reviewed)abstract
- Implant fixation in bone can be improved by a coating that delivers bisphosphonates locally, or by a hydroxyapatite (HA) coating. In this study, we compared these different types of coatings. For mechanical testing, 30 rats were assigned into three groups, and similar screws were implanted bilaterally in the proximal tibiae. The rats received screws that were either uncoated, coated with nano-crystalline hydroxyapatite or coated with a bisphosphonate releasing protein matrix. After 4 weeks, one screw was subjected to pull-out testing, and the contra-lateral one to torsion testing. For morphology, 30 rats were assigned to similar treatment groups, but received only one screw each. Bisphosphonates enhanced the pull-out force by 41% (P = 0.02) compared to controls, HA increased the pull-out force although not significantly. Conversely, HA increased the maximal torque by 64% (P = 0.02). Morphometry showed higher bone volume around bisphosphonate screws in comparison to HA-coated screws (P andlt; 0.001) and controls (P andlt; 0.001). The results suggest that bisphosphonates improve fixation by increasing the amount of surrounding bone, whereas HA mainly improves bone to implant attachment.
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| 16. |
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| 17. |
- Agholme, Fredrik, et al.
(author)
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Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats
- 2010
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In: JOURNAL OF BONE AND MINERAL RESEARCH. - : American Society for Bone and Mineral Research. - 0884-0431. ; 25:11, s. 2412-2418
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Journal article (peer-reviewed)abstract
- Sclerostin is the product of the SOST gene Loss of-function mutations in the SOST gene result in a high bone-mass phenotype demonstrating that sclerostin is a negative regulator of bone mass Primarily expressed by osteocytes in bone sclerostin is reported to bind the LRP5/6 receptor thereby antagonizing canonical Wnt signaling and negatively regulating bone formation We therefore investigated whether systemic administration of a sclerostin neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks In four groups, the screws were tested for pull out strength At the time of euthanasia a similar screw also was inserted in the contralateral tibia and pull-out tested immediately Sclerostin antibody significantly increased the pull out force by almost 50% compared with controls after 2 and 4 weeks Also the screws inserted at the time of euthanasia showed increased pull out force Micro-computed tomography (mu CT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw There also was a general increase in trabecular thickness in cancellous bone Thus as measured by the amount of bone and its mechanical resistance the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone
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| 18. |
- Agholme, Fredrik, et al.
(author)
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The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions
- 2011
-
In: BONE. - : Elsevier Science B.V., Amsterdam.. - 8756-3282. ; 48:5, s. 988-996
-
Journal article (peer-reviewed)abstract
- The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, mu CT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.
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| 19. |
- Agholme, Fredrik, et al.
(author)
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Wnt gene expression during metaphyseal bone healing under different load conditions
-
Other publication (other academic/artistic)abstract
- Bone Wnt signalling has been presented as one of the key pathways through which bone responds to mechanical load. This pathway is also active during the healing process after bone trauma. Bone healing can be improved by pharmacological modulation of Wnt signalling. We investigated how the expression of several Wntrelated genes changed due to trauma and unloading in metaphyseal bone. 20 male rats had one hind limb unloaded by intramuscular Botox injections. In half of the animals a hole was drilled bilaterally in the proximal tibia. After 7 days, a cylindrical biopsy was taken from the bone surrounding the hole and at a corresponding site in animals without trauma. The biopsies were analyzed for the mRNA expression of Wnt1, Wnt3a, Wnt4, Wnt5a, Wnt5b, Sost, Dkk1, Dkk2, Sfrp1, Sfrp4, Lrp5, Lrp6, Wisp1, Wif1 and Wnt10b. Trauma led to upregulation of most of the studied genes. This effect was most evident in unloaded bone, where 8 genes were upregulated, among them Wnt receptors, ligands and inhibitors. Unloading increased the expression of Sost in untraumatized bone, but did not significantly influence the other genes.
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| 20. |
- Agholme, Fredrik
(author)
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Wnt signaling and metaphyseal bone healing
- 2011
-
Doctoral thesis (other academic/artistic)abstract
- This thesis relates to some new aspects on the regulation of bone healing. In the last few years, Wnt-signaling has been shown to play a central role in bone biology. As well as being involved in bone maintenance and repair, Wnt-signaling has been presented as one of the key pathways through which bone responds to mechanical load. Two secreted extracellular inhibitors of Wnt-signaling, sclerostin and dickkopf-1 are potent negative regulators of bone formation.Using a rat fracture model we investigated how metaphyseal bone healing is influenced by changes in Wnt-signaling.Antibodies were used to suppress levels of sclerostin and dickkopf-1, and thereby increase Wnt-signaling. Primarily, we investigated if those antibody treatments lead to improved bone healing. Also, we investigated if the response was coupled to the loading conditions of the bone.Our findings suggest that suppression of either sclerostin or dickkopf-1 leads to increased bone formation and improved bone healing. Apart from just having an effect on healing, the treatment also improved bone formation in other parts of the skeleton. Depending on the loading conditions, the effects were different. Dickkopf-1 appeared to have a stronger effect on bone volume density in unloaded bone, implying a role mainly in mechano-transduction, while sclerostin had similar effect in both loaded and unloaded bone. To confirm these findings, we studied how the expression of several Wnt-related genes changed due to trauma and unloading in metaphyseal bone. We found that trauma led to upregulation of most of the genes with the largest effect seen in the unloaded bone. In untraumatized bone, there was mainly an effect on the sclerostin gene.In conclusion, antibodies against sclerostin and dickkopf-1 appear to be able to improve metaphyseal bone healing. There appear to be some differences in how the effect of the two antibodies manifests itself, especially if the loading conditions of the bone are altered. These findings suggest a potential for clinical use to shorten fracture healing time.
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| 21. |
- Agholme, Fredrik, et al.
(author)
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Wnt signaling and orthopedics, an overview
- 2011
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In: ACTA ORTHOPAEDICA. - : Informa Healthcare. - 1745-3674 .- 1745-3682. ; 82:2, s. 125-130
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Journal article (peer-reviewed)abstract
- Wnt signaling is a ubiquitous system for intercellular communication, with multiple functions during development and in homeostasis of the body. It comprises several ligands, receptors, and inhibitors. Some molecules, such as sclerostin, appear to have bone-specific functions, and can be targeted by potential drugs. Now, ongoing clinical trials are testing these drugs as treatments for osteoporosis. Animal studies have also suggested that these drugs can accelerate fracture healing and implant fixation. This brief overview focuses on currently available information on the effects of manipulations of Wnt signaling on bone healing.
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| 22. |
- Amirhosseini, Mehdi, et al.
(author)
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Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening
- 2017
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In: Bone Reports. - : Elsevier. - 2352-1872. ; 7, s. 17-25
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Journal article (peer-reviewed)abstract
- Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change = ± 1.5 and adjusted p-value = 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1ß, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.
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| 23. |
- Andersson, Per, et al.
(author)
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The Configuration Of Actors In Market Practice
- 2009
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In: Marketing Theory. - : SAGE Publications (UK and US). - 1741-301X .- 1470-5931. ; 8:1, s. 67-90
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Journal article (peer-reviewed)abstract
- This paper addresses three conceptual challenges concerning actors and agency that arise when taking interest in market practice: i) how agency is awarded in practical situations, ii) how actors are preconfigured, and iii) how actors are represented. These issues are explored in three empirical scenes taken from a case study of the introduction of an e-procurement system at an international transport and logistics company. First, we suggest that practical interaction can be fruitfully regarded as a process of interdefinition involving prescriptions and subscriptions between acting entities, or actants . Second, we employ the term inscription to address efforts to affect in advance the configuration of such actants. Third, we suggest that actors are entities to which actions are ascribed, ex post . Through this secondary process a number of actants may be subsumed under a common actor label, thus offering a way of accounting for agency as part of a practice perspective. We conclude by discussing implications of the proposed vocabulary for multiplicity, reflexivity and market agency.
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| 24. |
- Andersson, Therese, et al.
(author)
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Achilles tendon healing in rats is improved by intermittent mechanical loading during the inflammatory phase
- 2012
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In: Journal of Orthopaedic Research. - : Wiley Online Library. - 0736-0266 .- 1554-527X. ; 30:2, s. 274-279
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Journal article (peer-reviewed)abstract
- Tendons adapt to changes in mechanical loading, and numerous animal studiesshow that immobilization of a healing tendon is detrimental to the healingprocess. The present study addresses whether the effects of a few episodes ofmechanical loading are different during different phases of healing. Fifty femalerats underwent Achilles tendon transection, and their hind limbs were unloadedby tail suspension on the day after surgery. One group of 10 rats was taken downfrom suspension to walk on a treadmill for 30 minutes per day, on days 2-5 aftertransection. They were euthanized on day 8. Another group underwent similartreadmill running on days 8-11 and was euthanized on day 14. Completelyunloaded groups were euthanized on day 8 and 14. Tendon specimens were thenevaluated mechanically. The results showed that just 4 loading episodesincreased the strength of the healing tendon. This was evident irrespective of thetime-point when loading was applied (early or late). The positive effect on earlyhealing was unexpected, considering that the mechanical stimulation was appliedduring the inflammatory phase, when the calluses were small and fragile. Ahistological study of additional groups with early loading also showed someincreased bleeding in the loaded calluses. Our results indicate that a smallamount of early loading may improve the outcome of tendon healing. This couldbe of interest to clinical practice.
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| 25. |
- Andersson, Therese, et al.
(author)
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Growth hormone does not stimulate early healing in rat tendons
- 2012
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In: International Journal of Sports Medicine. - Stuttgart : Georg Thieme Verlag KG. - 0172-4622 .- 1439-3964. ; 33:3, s. 240-243
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Journal article (peer-reviewed)abstract
- Growth Hormone stimulates bone growth and fracture repair. It acts mainly by increasing the systemic levels of IGF-1. Local treatment with IGF-1 appears to stimulate tendon healing. We therefore hypothesized that systemic treatment with Growth Hormone would also stimulate tendon healing. Rat Achilles tendons were transected and left to heal. 4 groups were studied. Intramuscular injections of botulinum toxin A (Botox) were used to reduce loading in 2 groups. The animals were randomized to twice daily injections of Growth Hormone (n=2×10) or saline (n=2×10), and killed after 10 days. Healing was assessed by mechanical testing. Muscle paralysis induced by Botox reduced the strength of the healing tendon by two thirds. Growth Hormone increased femoral and tibial length in the unloaded, and femoral and tibial weight in the loaded group. Body weight and muscle weight were increased in both. In contrast, there was no increase in the strength of the healing tendons, regardless of mechanical loading status. An increase in peak force of the loaded healing tendons by more than 5% could be excluded with 95% confidence. In spite of its stimulatory effects on other tissues, Growth Hormone did not appear to stimulate tendon or tendon repair.
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