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Bisphosphonates and implants in the jaw bone
Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Maxillofacial Unit.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. , 144 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1348
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-89669ISBN: 978-91-7519-724-1 (print)OAI: oai:DiVA.org:liu-89669DiVA: diva2:608749
Public defence
2013-03-22, Berzeliussalen, hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-03-01 Created: 2013-03-01 Last updated: 2016-09-07Bibliographically approved
List of papers
1. Bisphosphonate coating might improve fixation of dental implants in the maxilla: A pilot study
Open this publication in new window or tab >>Bisphosphonate coating might improve fixation of dental implants in the maxilla: A pilot study
2010 (English)In: International Journal of Oral and Maxillofacial Surgery, ISSN 0901-5027, E-ISSN 1399-0020, Vol. 39, no 7, 673-677 p.Article in journal (Refereed) Published
Abstract [en]

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 Branemark 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.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam, 2010
Keyword
bisphosphonate coating; dental implants; fixation
National Category
Orthopedics Other Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-58193 (URN)10.1016/j.ijom.2010.04.002 (DOI)000279972500007 ()
Available from: 2010-08-11 Created: 2010-08-09 Last updated: 2017-12-12
2. A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants
Open this publication in new window or tab >>A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants
2012 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no 5, 1148-1151 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Bone healing, Dental implant, Drug delivery, Mechanical test, Osseointegration bisphosphonates
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77527 (URN)10.1016/j.bone.2012.02.001 (DOI)000303274400018 ()
Note

Funding Agencies|Swedish Research Council|VR 2009-6725|

Available from: 2012-05-28 Created: 2012-05-22 Last updated: 2017-12-07
3. Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. No primary necrosis in unexposed bone
Open this publication in new window or tab >>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 (English)In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 41, no 6, 494-499 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley and Sons, 2012
Keyword
bisphosphonates; bisphosphonate associated osteonecrosis of the jaw; osteonecrosis; rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79679 (URN)10.1111/j.1600-0714.2011.01125.x (DOI)000305961100010 ()
Available from: 2012-08-14 Created: 2012-08-13 Last updated: 2017-12-07
4. Effect of Local vs. Systemic Bisphosphonate Delivery on Dental Implant Fixation in a Model of Osteonecrosis of the Jaw
Open this publication in new window or tab >>Effect of Local vs. Systemic Bisphosphonate Delivery on Dental Implant Fixation in a Model of Osteonecrosis of the Jaw
2013 (English)In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 92, no 3, 279-283 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Sage Publications, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89667 (URN)10.1177/0022034512472335 (DOI)000314914100013 ()23264610 (PubMedID)
Available from: 2013-03-01 Created: 2013-03-01 Last updated: 2017-12-06Bibliographically approved
5. Prevention of osteonecrosis of the jaw by mucoperiosteal coverage in a rat model
Open this publication in new window or tab >>Prevention of osteonecrosis of the jaw by mucoperiosteal coverage in a rat model
2013 (English)In: International Journal of Oral and Maxillofacial Surgery, ISSN 0901-5027, E-ISSN 1399-0020, Vol. 42, no 5, 632-636 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
Bisphosphonates, osteonecrosis, jaw, rat, mucoperiosteal flap, antibiotics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-89668 (URN)10.1016/j.ijom.2013.02.007 (DOI)000318132600014 ()
Available from: 2013-03-01 Created: 2013-03-01 Last updated: 2017-12-06Bibliographically approved

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Abtahi, Jahan

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