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Agholme, Fredrik
Publications (10 of 21) Show all publications
Agholme, F., Macias, B., Hamang, M., Lucchesi, J., Adrian, M. D., Kuhstoss, S., . . . Aspenberg, P. (2014). Efficacy of a Sclerostin Antibody Compared to a Low Dose of PTH on Metaphyseal Bone Healing. Journal of Orthopaedic Research, 32(3), 471-476
Open this publication in new window or tab >>Efficacy of a Sclerostin Antibody Compared to a Low Dose of PTH on Metaphyseal Bone Healing
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2014 (English)In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 32, no 3, p. 471-476Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
Keywords
implant fixation; bone healing; mechanical testing; bone formation; Wnt-signaling
National Category
Orthopaedics
Identifiers
urn:nbn:se:liu:diva-103861 (URN)10.1002/jor.22525 (DOI)000329421500015 ()
Available from: 2014-01-31 Created: 2014-01-30 Last updated: 2018-01-11
Abtahi, J., Agholme, F., Sandberg, O. & Aspenberg, P. (2013). Effect of Local vs. Systemic Bisphosphonate Delivery on Dental Implant Fixation in a Model of Osteonecrosis of the Jaw. Journal of Dental Research, 92(3), 279-283
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, p. 279-283Article 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
Macias, B. R., Aspenberg, P. & Agholme, F. (2013). Paradoxical Sost gene expression response to mechanical unloading in metaphyseal bone. Bone, 53(2), 515-519
Open this publication in new window or tab >>Paradoxical Sost gene expression response to mechanical unloading in metaphyseal bone
2013 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 53, no 2, p. 515-519Article in journal (Refereed) Published
Abstract [en]

The Sost gene encodes Sclerostin, an inhibitor of Wnt-signaling, generally considered a main response gene to mechanical loading in bone. Several papers describe that unloading leads to upregulation of Sost, which in turn may lead to loss of bone. These studies were based on whole bone homogenates or cortical bone. By serendipity, we noted an opposite response to unloading in the proximal rat tibia. Therefore, we hypothesized that Sost-expression in response to changes in mechanical load is bone site specific. less thanbrgreater than less thanbrgreater thanOne hind limb of male, 3 month old rats was unloaded by paralyzing the extensors with Botulinium toxin A (Botox) injections. A series of experiments compared the expression of Sost mRNA in the unloaded and contralateral, loaded limbs, after 3 or 10 days, in metaphyseal cancellous bone, metaphyseal cortical bone, and diaphyseal cortical bone. We also conducted mu CT to confirm changes in bone volume density related to unloading. Sost mRNA expression in the cancellous metaphyseal bone was downregulated almost 2-fold, both 3 days and 10 days after unloading (Pandlt;0.05). A similar tendency was seen in the metaphyseal cortical bone, in which Sost was 1.5-fold downregulated (Pandlt;0.05) after 10 days, but not significantly changed after 3 days. In contrast, diaphyseal cortical Sost expression was instead upregulated 1.4-fold (Pandlt;0.05) following 3-day unloading, while there was no significant change after 10 days. Cancellous bone volume density was 58% lower (Pandlt;0.001, compared to cage controls) in the unloaded limb but not significantly affected in the loaded limb. less thanbrgreater than less thanbrgreater thanThe results suggest that Sost mRNA expression in metaphyseal bone responds to mechanical unloading in an opposite direction to that observed in diaphyseal cortical bone. This proposes a more complex expression pattern for Sost in response to unloading. Therapeutics that target Sclerostin during altered loading conditions may result in local bone mass changes that are difficult to predict.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Disuse, Sclerostin, Rat, Cancellous bone, Cortical bone
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90749 (URN)10.1016/j.bone.2013.01.018 (DOI)000315763700023 ()
Note

Funding Agencies|King Gustaf V and Queen Victoria Free Mason Foundation||Swedish Research Council, Linkoping University, Ostergotland County Council|VR 2009-6725|National Science Foundation (NSF)||

Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06
Abtahi, J., Agholme, F. & Aspenberg, P. (2013). Prevention of osteonecrosis of the jaw by mucoperiosteal coverage in a rat model. International Journal of Oral and Maxillofacial Surgery, 42(5), 632-636
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, p. 632-636Article 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.

Keywords
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
Abtahi, J., Agholme, F., Sandberg, O. & Aspenberg, P. (2012). Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. No primary necrosis in unexposed bone. Journal of Oral Pathology & Medicine, 41(6), 494-499
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, p. 494-499Article 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
Keywords
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
Aspenberg, P., Abtahi, J., Agholme, F. & Sandberg, O. (2012). Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. no primary necrosis in unexposed bone in BONE, vol 50, issue , pp S173-S173. In: BONE: (pp. S173-S173). Elsevier, 50
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 in BONE, vol 50, issue , pp S173-S173
2012 (English)In: BONE, Elsevier , 2012, Vol. 50, p. S173-S173Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier, 2012
Series
BONE, ISSN 8756-3282
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79105 (URN)10.1016/j.bone.2012.02.545 (DOI)000304503500514 ()
Available from: 2012-06-29 Created: 2012-06-29 Last updated: 2016-09-07
Aspenberg, P., Abtahi, J., Agholme, F. & Sandberg, O. (2012). Dental implants in a rat model: Bisphosphonate coating improved fixation while systemic treatment caused osteonecrosis in BONE, vol 50, issue , pp S173-S174. In: BONE: (pp. S173-S174). Elsevier, 50
Open this publication in new window or tab >>Dental implants in a rat model: Bisphosphonate coating improved fixation while systemic treatment caused osteonecrosis in BONE, vol 50, issue , pp S173-S174
2012 (English)In: BONE, Elsevier , 2012, Vol. 50, p. S173-S174Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Elsevier, 2012
Series
BONE, ISSN 8756-3282
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79828 (URN)10.1016/j.bone.2012.02.546 (DOI)000304503500515 ()
Available from: 2012-08-14 Created: 2012-08-14 Last updated: 2016-09-07
Sandberg, O., Eliasson, P. T., Andersson, T., Agholme, F. & Aspenberg, P. (2012). Etanercept does not impair healing in rat models of tendon or metaphyseal bone injury. Acta Orthopaedica, 83(3), 305-310
Open this publication in new window or tab >>Etanercept does not impair healing in rat models of tendon or metaphyseal bone injury
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2012 (English)In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 83, no 3, p. 305-310Article in journal (Refereed) Published
Abstract [en]

Background and purpose Should blockade of TNF-alpha be avoided after orthopedic surgery? Healing of injuries in soft tissues and bone starts with a brief inflammatory phase. Modulation of inflammatory signaling might therefore interfere with healing. For example, Cox inhibitors impair healing in animal models of tendon, ligament, and bone injury, as well as in fracture patients. TNF-alpha is expressed locally at increased levels during early healing of these tissues. We therefore investigated whether blocking of TNF-alpha with etanercept influences the healing process in established rat models of injury of tendons and metaphyseal bone. less thanbrgreater than less thanbrgreater thanMethods Rats were injected with etanercept, 3.5 mg/kg 3 times a week. Healing of transected Achilles tendons and bone healing around screws implanted in the tibial metaphysis were estimated by mechanical testing. Tendons were allowed to heal either with or without mechanical loading. Ectopic bone induction following intramuscular BMP-2 implants has previously been shown to be stimulated by etanercept in rodents. This was now tested as a positive control. less thanbrgreater than less thanbrgreater thanResults Tendon peak force after 10 days was not significantly influenced by etanercept. Changes exceeding 29% could be excluded with 95% confidence. Likewise, screw pull-out force was not significantly influenced. More than 25% decrease or 18% increase could be excluded with 95% confidence. However, etanercept treatment increased the amount of bone induced by intramuscular BMP-2 implants, as estimated by blind histological scoring. less thanbrgreater than less thanbrgreater thanInterpretation Etanercept does not appear to impair tendon or metaphyseal bone healing to any substantial degree.

Place, publisher, year, edition, pages
Informa Healthcare, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79101 (URN)10.3109/17453674.2012.693018 (DOI)000304781000018 ()
Note

Funding Agencies|Swedish Research Council|2009-6725|Linkoping University, Ostergotland County Council, Swedish Centre for Research in Sports||King Gustaf V and Queen Victoria Free Mason Foundation||

Available from: 2012-06-29 Created: 2012-06-29 Last updated: 2017-12-07
Agholme, F., Andersson, T., Tengvall, P. & Aspenberg, P. (2012). Local bisphosphonate release versus hydroxyapatite coating for stainless steel screw fixation in rat tibiae. Journal of materials science. Materials in medicine, 23(3), 743-752
Open this publication in new window or tab >>Local bisphosphonate release versus hydroxyapatite coating for stainless steel screw fixation in rat tibiae
2012 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 23, no 3, p. 743-752Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76616 (URN)10.1007/s10856-011-4539-5 (DOI)000301639900014 ()
Note
Funding Agencies|Swedish Research council|2009-6725|BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy at Sahlgrenska Academy, University of Gothenburg||Available from: 2012-04-13 Created: 2012-04-13 Last updated: 2017-12-07
Linderbäck, P., Agholme, F., Wermelin, K., Närhi, T., Tengvall, P. & Aspenberg, P. (2012). Weak effect of strontium on early implant fixation in rat tibia. Bone, 50(1), 350-356
Open this publication in new window or tab >>Weak effect of strontium on early implant fixation in rat tibia
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2012 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no 1, p. 350-356Article in journal (Refereed) Published
Abstract [en]

Strontium ranelate increases bone mass and is used in the treatment of osteoporosis. Its effects in metaphyseal bone repair are largely unknown. We inserted a stainless steel and a PMMA screw into each tibia of male Sprague-Dawley rats. The animals were fed with ordinary feed (n =40) or with addition of strontium ranelate (800mg/kg/day; n = 20). As a positive control, half of the animals on control feed received alendronate subcutaneously. The pullout force of the stainless steel screws was measured after 4 and 8 weeks, and μCT was used to assess bone formation around the PMMA screws. No significant effects of strontium treatment on pullout force were observed, but animals treated with bisphosphonate showed a doubled pullout force. Strontium improved the microarchitecture of the cancellous bone below the primary spongiosa at the growth plate, but no significant effects were found around the implants. Strontium is known to improve bone density, but it appears that this effect is weak in conjunction with metaphyseal bone repair and early implant fixation.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Bisphosphonate; bone; implant; rat; screw; Strontium ranelate
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-71288 (URN)10.1016/j.bone.2011.10.034 (DOI)000299064200045 ()
Note
funding agencies|Swedish Research Council| VR-2009-6725 |local strategic research project Materials in Medicine||County Council of Ostergotland||Linkopings Universitet, Sweden||Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2017-12-08Bibliographically approved
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