| 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
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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
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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)
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Effect of Local vs. Systemic Bisphosphonate Delivery on Dental Implant Fixation in a Model of Osteonecrosis of the Jaw
- 2013
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In: Journal of Dental Research. - : Sage Publications. - 0022-0345 .- 1544-0591. ; 92:3, s. 279-283
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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
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In: Clinical Oral Implants Research. - : John Wiley & Sons. - 0905-7161 .- 1600-0501. ; 30:1, s. 49-58
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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
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In: International Journal of Oral and Maxillofacial Surgery. - : Elsevier BV. - 0901-5027 .- 1399-0020. ; 42:5, s. 632-636
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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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