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  • 1.
    Abtahi, Jahan
    et al.
    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.
    Tengvall, Pentti
    Gothenburg University.
    Aspenberg, Per
    Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics. Linköping University, Faculty of Health Sciences.
    A bisphosphonate-coating improves the fixation of metal implants in human bone. A randomized trial of dental implants2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no 5, p. 1148-1151Article in journal (Refereed)
    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.

  • 2.
    Aspenberg, Per
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Astrand, J
    Linkoping Univ Hosp, Dept Orthoped, SE-58185 Linkoping, Sweden.
    Bone allografts pretreated with a bisphosphonate do not resorb2002In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 30, no 3, p. B1-Conference paper (Other academic)
  • 3.
    Fahlgren, Anna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics. Linköping University, Faculty of Health Sciences.
    Yang, Xu
    Hospital for Special Surgery, New York, USA.
    Ciani, Cesare
    Hospital for Special Surgery, New York, USA.
    Ryan, James A.
    Hospital for Special Surgery, New York, USA.
    Kelly, Natalie
    Hospital for Special Surgery, New York, USA.
    Ko, Frank C.
    Cornell University, Ithaca, USA.
    van der Meulen, Marjolein C. H.
    Hospital for Special Surgery, New York, USA.
    Boström, Mathias P. G.
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, The Institute of Technology.
    The effects of PTH, loading and surgical insult on cancellous bone at the bone-implant interface in the rabbit2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 52, no 2, p. 718-724Article in journal (Refereed)
    Abstract [en]

    Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the pen-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on pen-implant bone volume fraction. In this model, PTH enhanced pen-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced pen-implant bone volume, and surgery and PTH treatment had a strong combined effect This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.

  • 4. Goldhahn, Jörg
    et al.
    Scheele, Wim H.
    Mitlak, Bruce H.
    Abadie, Eric
    Aspenberg, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Augat, Peter
    Brandi, Maria-Luisa
    Burlet, Nansa
    Chines, Arkadi
    Delmas, Pierre D.
    Dupin-Roger, Isabelle
    Ethgen, Dominique
    Hanson, Beate
    Hartl, Florian
    Kanis, John A.
    Kewalramani, Reshma
    Laslop, Andrea
    Marsh, David
    Ormarsdottir, Sif
    Rizzoli, René
    Santora, Art
    Schmidmaier, Gerhard
    Wagener, Michael
    Reginster, Jean-Yves
    Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis2008In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 43, no 2, p. 343-347Article in journal (Refereed)
    Abstract [en]

    Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care. © 2008 Elsevier Inc. All rights reserved.

  • 5.
    Gustafsson, Anna
    et al.
    Lund University, Sweden.
    Schilcher, Jörg
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Grassi, Lorenzo
    Lund University, Sweden.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Isaksson, Hanna
    Lund University, Sweden.
    Strains caused by daily loading might be responsible for delayed healing of an incomplete atypical femoral fracture2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 88, p. 125-130Article in journal (Refereed)
    Abstract [en]

    Atypical femoral fractures are insufficiency fractures in the lateral femoral diaphysis or subtrochanteric region that mainly affect older patients on bisphosphonate therapy. Delayed healing is often seen in patients with incomplete fractures (cracks), and histology of bone biopsies shows mainly necrotic material inside the crack. We hypothesized that the magnitude of the strains produced in the soft tissue inside the crack during normal walk exceeds the limit for new bone formation, and thereby inhibit healink. A patient specific finite element model was developed, based on clinical CT images and high resolution CT images of a biopsy from the crack site. Strain distributions in the femur and inside the crack were calculated for load cases representing normal walk. The models predicted large strains inside the crack, with strain levels above 10% in more than three quarters of the crack volume. According to two different tissue differentiation theories, bone would only form in less than 1-5% cif the crack volume. This can explain the impaired healing generally seen in incomplete atypical fractures. Furthermore, the microgeometry of the crack highly influenced the strain distributions. Hence, a realistic microgeometry needs to be considered when modeling the crack. Histology of the biopsy showed signs of remodeling in the bone tissue adjacent to the fracture line, while the crack itself contained mainly necrotic material and signs of healing only in portions that seemed to have been widened by resorption. In conclusion, the poor healing capacity of incomplete atypical femoral fractures can be explained by biomechanical factors, and daily low impact activities are enough to cause strain magnitudes that prohibit bone formation. (C) 2016 Elsevier Inc. All rights reserved.

  • 6.
    Hilding, MB
    et al.
    Cent Hosp Vasteras, Dept Orthopaed, S-72189 Vasteras, Sweden Linkoping Univ Hosp, Dept Orthopaed, Linkoping, Sweden.
    Ryd, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine .
    Aspenberg, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Clodronate inhibits prosthetic migration - A randomized double-blind placebo controlled radiostereometric (RSA) study of 50 total knee patients2002In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 30, no 3, p. B48-Conference paper (Other academic)
  • 7.
    Kälvesten, Johan
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra AB, Linkoping, Sweden.
    Lui, Li-Yung
    Calif Pacific Medical Centre, CA USA.
    Brismar, Torkel
    Karolinska Institute, Sweden.
    Cummings, Steven
    Calif Pacific Medical Centre, CA USA.
    Digital X-ray radiogrammetry in the study of osteoporotic fractures: Comparison to dual energy X-ray absorptiometry and FRAX2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 86, p. 30-35Article in journal (Refereed)
    Abstract [en]

    Osteoporosis is often underdiagnosed and undertreated. Screening of post -menopausal women for clinical risk factors and/or low bone mineral density (BMD) has been proposed to overcome this. Digital X-ray radiogrammetry (DXR) estimates hand BMD from standard hand X-ray images and have shown to predict fractures and osteoporosis. Recently, digital radiology and the internet have opened up the possibility of conducting automated opportunistic screening with DXR in post -fracture care or in combination with mammography. This study compared the performance of DXR with FRAX (R) and DXA in discriminating major osteoporotic fracture (MOF) (hip, clinical spine, forearm or shoulder), hip fracture and femoral neck osteoporosis. This prospective cohort study was conducted on 5278 women 65 years and older in the Study of Osteoporotic Fractures (SOF) cohort Baseline hand X-ray images were analyzed and fractures were ascertained during 10 years of follow up. Age -adjusted area under receiver operating characteristic curve (AUC) for MOF and hip fracture and for femoral neck osteoporosis (DXA FN BMD T -score <= -2.5) was used to compare the methods. Sensitivity to femoral neck osteoporosis at equal selection rates was tabulated for FRAX and DXR. DXR-BMD, FRAX (no BMD) and lumbar spine DXA BMD were all similar in fracture discriminative performance with an AUC around 0.65 for MOF and 0.70 for hip fractures for all three methods. As expected femoral neck DXA provided fracture discrimination superior both to other BMD measurements and to FRAX. AUC for selection of patients with femoral neck osteoporosis was higher with DXR-BMD, 0.76 (0.74-0.77), than with FRAX, 0.69 (0.67-0.71), (p < 0.0001). In conclusion, DXR-BMD discriminates incident fractures to a similar degree as FRAX and predicts femoral neck osteoporosis to a larger degree than FRAX. DXR shows promise as a method to automatically flag individuals who might benefit from an osteoporosis assessment (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

  • 8.
    Linder, Cecilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Englund, Ulrika
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Narisawa, Sonoko
    Sanford Burnham Medical Research Institute, CA USA .
    Luis Millan, Jose
    Sanford Burnham Medical Research Institute, CA USA .
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Isozyme profile and tissue-origin of alkaline phosphatases in mouse serum2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 53, no 2, p. 399-408Article in journal (Refereed)
    Abstract [en]

    Mouse serum alkaline phosphatase (ALP) is frequently measured and interpreted in mammalian bone research. However, little is known about the circulating ALPs in mice and their relation to human ALP isozymes and isoforms. Mouse ALP was extracted from liver, kidney, intestine, and bone from vertebra, femur and calvaria tissues. Serum from mixed strains of wild-type (WT) mice and from individual ALP knockout strains were investigated, i.e., Alpl(-/-) (a.k.a. Akp2 encoding tissue-nonspecific ALP or TNALP), Akp3(-/-) (encoding duodenum-specific intestinal ALP or dIALP), and Alpi(-/-) (a.k.a. Akp6 encoding global intestinal ALP or gIALP). The ALP isozymes and isoforms were identified by various techniques and quantified by high-performance liquid chromatography. Results from the WT and knockout mouse models revealed identical bone-specific ALP isoforms (B/I. B1, and B2) as found in human serum, but in addition mouse serum contains the B1x isoform only detected earlier in patients with chronic kidney disease and in human bone tissue. The two murine intestinal isozymes, dIALP and gIALP, were also identified in mouse serum. All four bone-specific ALP isoforms (B/I, B1x, B1, and B2) were identified in mouse bones, in good correspondence with those found in human bones. All mouse tissues, except liver and colon, contained significant ALP activities. This is a notable difference as human liver contains vast amounts of ALP. Histochemical staining, Northern and Western blot analyses confirmed undetectable ALP expression in liver tissue. ALP activity staining showed some positive staining in the bile canaliculi for BALB/c and FVB/N WT mice, but not in C57BI/6 and ICR mice. Taken together, while the main source of ALP in human serum originates from bone and liver, and a small fraction from intestine (andlt;5%), mouse serum consists mostly of bone ALP, including all four isoforms, B/I, B1x, B1, and B2, and two intestinal ALP isozymes dIALP and gIALR We suggest that the genetic nomenclature for the Alpl gene in mice (i.e., ALP liver) should be reconsidered since murine liver has undetectable amounts of ALP activity. These findings should pave the way for the development of user-friendly assays measuring circulating bone-specific ALP in mouse models used in bone and mineral research.

  • 9.
    Linderbäck, Paula
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Agholme, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Wermelin, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Närhi, Timo
    Turku Clinical Biomaterial Centre, The University of Turku, FI-20520 Turku, Finland.
    Tengvall, Pentti
    University of Gothenburg.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Weak effect of strontium on early implant fixation in rat tibia2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no 1, p. 350-356Article in journal (Refereed)
    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.

  • 10.
    Löfman, Owe
    et al.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Larsson, Lasse
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Ross, I.
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Toss, Göran
    Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Berglund, K.
    Department for Community Medicine and Public Health, County Council, Jönköping, Sweden.
    Bone mineral density in normal Swedish women1997In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 20, no 2, p. 167-174Article in journal (Refereed)
    Abstract [en]

    We examined 429 women, aged 20–80 years, randomly selected from the population register to establish normal values for bone mineral density (BMD) in Swedish women. BMD of the spine and hip was measured by dual-energy X-ray absorptiometry (DEXA; Hologic QDR 1000) and in the forearm by single photon absorptiometry (SPA; Molsgaard ND-1100). The recalled age of menarche was negatively correlated to BMD at all ages. There was no significant change in BMD from 20–49 years at any site except a slight decline at Ward's triangle. Bone loss was rapid at all sites during the first decade after menopause. Thereafter, BMD declined slowly in the trochanter and total hip but more rapidly in the forearm, femoral neck, and Ward's triangle. BMD in the spine even increased in the eighth decade probably due to osteoarthritis. The average change in forearm BMD during the 15 perimenopausal years comprising mean age for menopause ± 2 SD (43–57 years) was −0.4% per year in premenopausal females and −1.6% per year in postmenopausal females. The corresponding annual percental change was, for the spine, +0.2 and −1.7; neck, −0.7 and −1.7; trochanter, +0.5 and −1.5; and Ward's triangle, −0.1% and −2.2%, respectively. Our normal values for lumbar spine BMD prior to menopause did not differ from published values or the manufacturer's normal values; however, our spine BMD values for the first decade after menopause were significantly lower (≈10%) than in other studies. Our femoral neck BMD values for younger women were, like those of several other groups, significantly lower than the manufacturer's normal values, but our sample of young women in this study was small. The prevalence of osteoporosis, if defined as t score < −2.5 is highly dependent on the sampling of the reference population of young adult women, and also on the choice of skeletal site. Further studies on bone mineral density in healthy young adult women are needed.

  • 11.
    Macias, Brandon R.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Agholme, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Paradoxical Sost gene expression response to mechanical unloading in metaphyseal bone2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 53, no 2, p. 515-519Article in journal (Refereed)
    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.

  • 12.
    Sandberg, Olof
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Macias, Brandon R
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. University of California, San Diego, USA.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed2014In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 63, p. 15-19Article in journal (Refereed)
    Abstract [en]

    Stimulation of bone formation by PTH is related to mechanosensitivity. The response to PTH treatment in intact bone could therefore be blunted by unloading. We studied the effects of mechanical loading on the response to PTH treatment in bone healing. Most fractures occur in the metaphyses, therefor we used a model for metaphyseal bone injury. One hind leg of 20 male SD rats was unloaded via intramuscular botulinum toxin injections. Two weeks later, the proximal unloaded tibia had lost 78% of its trabecular contents. At this time-point, the rats received bilateral proximal tibiae screw implants. Ten of the 20 rats were given daily injections of 5 μg/kg PTH (1-34). After two weeks of healing, screw fixation was measured by pull-out, and microCT of the distal femur cancellous compartment was performed. Pull-out force provided an estimate for cancellous bone formation after trauma. PTH more than doubled the pull-out force in the unloaded limbs (from 14 to 30 N), but increased it by less than half in the loaded ones (from 30 to 44 N). In relative terms, PTH had a stronger effect on pull-out force in unloaded bone than in loaded bone (p=0.03). The results suggest that PTH treatment for stimulation of bone healing does not require simultaneous mechanical stimulation.

  • 13.
    Sandberg, Olof
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Tätting, Love
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Bernhardsson, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Temporal role of macrophages in cancellous bone healing2017In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 101, p. 129-133Article in journal (Refereed)
    Abstract [en]

    Macrophages are important phagocytosing and cytokine producing cells with effects on fracture healing. We used clodronate-containing liposomes to reduce the number of macrophages, in order to study their role in the early phases of cancellous bone healing. Holes were drilled bilaterally into the cancellous bone of the proximal metaphysis of the tibia of 60 mice. A screw was inserted in the hole in the right tibia. The day of surgery was day 0. Clodronate-containing liposomes were injected intraperitoneally as a single injection either day 4 or 1 (before surgery) or day 1 or 3 (after surgery). A control group underwent surgery as above, but received no clodronate. The mice were killed day 7. The mechanical quality of the new formed cancellous bone holding the screw was evaluated by a pull-out test. The contents of the drill hole in the left tibia was analyzed by microCT. Another set of 20 mice received a drill hole in the metaphysis of the right tibia, and were given either clodronate or saline injections days 3 and 2. The animals were killed day 1 and 3. Flow cytometry was used to analyze the composition of macrophage subpopulations in the regenerating tissue. Flow cytometry showed that clodronate injections day 3 and 2 led to a decrease in mature monocytes day 1 together with an increase in immature monocytes. On day 3 this effect had mostly disappeared, suggesting that the effect of the injections lasted 3 to 5 days. Mechanical testing revealed that the injections prior to surgery decreased the strength of the new formed bone, holding the screw, by about half. Bone density in the drill hole was similarly reduced. In contrast, the injections given day I and 3 had smaller and statistically insignificant effects. Since their depletion at later time points failed to produce a significant effect, it seems that the role of macrophages in cancellous bone is most crucial during the first two days after trauma. (C) 2017 Elsevier Inc. All rights reserved.

  • 14.
    Schilcher, Jörg
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Koeppen, Veronika
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ranstam, Jonas
    Lund University, Sweden .
    Skripitz, Ralf
    University Hospital Rostock, Germany .
    Michaelsson, Karl
    Uppsala University, Sweden .
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls2013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 52, no 1, p. 389-392Article in journal (Refereed)
    Abstract [en]

    Background: Estimations of the risk of bisphosphonate associated atypical femoral fractures vary between different population-based studies, from considerable to neglectable. A possible explanation for these discrepancies could be different definitions of atypical fractures. We aimed to identify specific radiographic fracture characteristics associated with bisphosphonate use. less thanbrgreater than less thanbrgreater thanMethods: In a previous nationwide study, 59 atypical and 218 ordinary fractures were diagnosed. The atypical fractures were defined by their stress-type fracture pattern. All fractures were now re-assessed by a physician in training, without information about bisphosphonate use. The fracture angle (0-180 degrees) was measured. Presence of local lateral cortical thickening (a callus reaction), more than 2 fragments, or a medial spike was noted. The reader then made a judgment whether the fracture appeared as an atypical fracture based on the ASBMR criteria. less thanbrgreater than less thanbrgreater thanResults: Frequency distribution analysis of the fracture angle showed a distinct subgroup, comprising 25% of all 277 fractures, with a mean of 89 and SD of 10 degrees. Forty-two of 57 patients in this subgroup used bisphosphonates, whereas only 27 of 213 others did (specificity 0.93; 95% CI 0.88-0.96). Presence of a callus reaction had also a high specificity for bisphosphonate use (0.96; 95% CI 0.92-0.98). The ASBMR criteria had a lower specificity, increasing the number of atypical fractures without bisphosphonate use from 13 to 31. This led to a decrease in age-adjusted relative risk associated with bisphosphonate use from 47 (95% CI 26-87) to 19 (95% CI 12-29). less thanbrgreater than less thanbrgreater thanInterpretation: Stress fractures of the femoral shaft are a specific entity, which is easily diagnosed on radiographs and strongly related to bisphosphonate use. Differences in diagnostic criteria may partially explain the large differences in relative risk between different population-based studies.

  • 15.
    Sharp, Christopher
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Increased bone alkaline phosphatase levels do not necessarily cause hypermineralization per se2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 89, p. 83-84Article in journal (Other academic)
    Abstract [en]

    Diminished bone health and increased risk of fracture is increasingly recognised as a complication of diabetes mellitus and even as a consequence of its management. We read with interest the recently published review by Starup-Linde and Vestergaard [1] about bone turnover markers (BTMs) in patients with types 1 and 2 diabetes mellitus and their value in assessing bone health in diabetic patients. In brief, 611 eligible studies were identified of which 47 were included: 1 meta-analysis, 29 cross-sectional, 13 randomized controlled trials and 4 longitudinal studies.

  • 16.
    Swolin-Eide, Diana
    et al.
    Univ Gothenburg, Sweden.
    Andersson, Bjorn
    Univ Gothenburg, Sweden.
    Hellgren, Gunnel
    Univ Gothenburg, Sweden.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Albertsson-Wikland, Kerstin
    Univ Gothenburg, Sweden.
    Variation of bone acquisition during growth hormone treatment in children can be explained by proteomic biomarkers, bone formation markers, body composition and nutritional factors2018In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 116, p. 144-153Article in journal (Refereed)
    Abstract [en]

    Objective: Growth hormone (GH) regulates both longitudinal growth and bone acquisition in children, and has profound metabolic effects. The aim was to investigate the association between proteomic biomarkers, body fat, nutrition and bone formation markers, and longitudinal growth in response to GH during the first year of treatment. The degree to which changes in these factors could explain variations in GH-dependent longitudinal growth and bone mineralization was also assessed. Methods: The individualized GH dose trial included 128 short prepubertal children with either normal (non-GHdeficient) or reduced levels of GH secretion (GH-deficient) (mean age +/- SD, 8.6 +/- 2.6 years; 90 boys), i.e., with a broad range of GH-secretion and GH-responsiveness, receiving GH treatment (mean 43 mu g/kg/day). Blood samples were taken and dual-energy X-ray absorptiometry (DXA) measured at baseline and 1 year of treatment. Step-wise multiple regression models were constructed including three steps with different independent variables added at each step to explain the variance in outcome variables (height(SDS), bone mineral content (BMC) and bone mineral density (BMD). Independent variables included in Step I were previously identified proteomic markers related to GH treatment response, bone formation markers (intact PINP, bone -specific alkaline phosphatase and osteocalcin), variables at treatment start (GH dose mU/kg/clay, GH maximum secretion, and difference between childs current and mid-parental height(SDS)). Step II explored the added influence of body composition data (body mass index or DXA). Step HI explored the added influence of serum nutritional markers and hormones. Results: Step I variables explained 71% of the variation in first year heightsDs gain, median (minimum-maximum) 0.8 (0.24-1.67); and the proportion explained rose to 73% following inclusion of step H variables and 75% following step III. Corresponding values for total body BMC were 58%, 78%, and 80%, respectively. Proportions fell by approximately 20% when BMC was adjusted for height; 33%, 57%, and 57% for steps I, II, and III, respectively. Corresponding values for total body BMD were 29%, 39%, and 45%, respectively. Conclusion: For total BMC, as much as 80% of the variation during the first year of GH treatment could be explained by proteomic biomarkers, body fat, nutrition and bone formation markers, whereas for height -adjusted BMC 57% could be explained. The inclusion of information about either body composition (fat/lean mass) or nutritional markers contributed with approximately 20%. The variation in heightsps gain could be explained to 75%. Hence, information of fat or nutrition markers was needed for explaining the variation in bone acquisition to the same magnitude as explaining the variation in height response.

  • 17.
    Tubic, Bojan
    et al.
    University of Gothenburg, Sweden.
    Magnusson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Marild, Staffan
    University of Gothenburg, Sweden.
    Leu, Monica
    University of Gothenburg, Sweden.
    Schwetz, Verena
    Medical University of Graz, Austria.
    Sioen, Isabelle
    University of Ghent, Belgium; Flanders, Belgium.
    Herrmann, Diana
    BIPS, Germany.
    Obermayer-Pietsch, Barbara
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, A-8036, Graz, Austria.
    Lissner, Lauren
    University of Gothenburg, Sweden.
    Swolin-Eide, Diana
    University of Gothenburg, Sweden.
    Different osteocalcin forms, markers of metabolic syndrome and anthropometric measures in children within the IDEFICS cohort2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 84, p. 230-236Article in journal (Refereed)
    Abstract [en]

    Objective: Osteocalcin (OC), an aboundant non-collagenous bone protein, is inversely associated with parameters of glucose metabolism. Interactions between bone tissue and energy metabolism have not been thoroughly investigated during childhood. This study investigated OC, metabolic parameters and anthropometric characteristics in normal weight and overweight/obese children. Methods: This study comprised 108 (46 normal weight/62 overweight/obese) Swedish 2-9 year old children. Anthropometric data, insulin, glucose, glycosylated haemoglobin (HbA1c), HOMA index, vitamin D, adiponectin, total OC, carboxylated OC (cOC) and undercarboxylated OC (ucOC) were analysed. Results: No difference was found for total OC between the normal and overweight/obese groups, with a mean (+/- SD) value of 82.6 ( +/- 2.8) ng/mL and 77.0 ( +/- 2.4) ng/mL, (P = 0.11), respectively. Overweight children had lower cOC levels, mean 69.1 ( +/- 2.2) ng/mL, vs. normal weight children, mean 75.6 ( +/- 2.5) ng/mL (P = 0.03). The mean ucOC levels of 7.9 ( +/- 0.4) ng/mL in overweight children did not differ vs. normal weight children, mean level 7.0 (+/- 0.4) ng/mL, (P = 0.067). None of the three OC forms correlated with any of the measured parameters. Conclusions: The cOC levels were lower in overweight children. There was no correlation between the three OC forms and any of the measured anthropometric or metabolic parameters. OC has been suggested to have a possible metabolic role, but in general the current study in prepubertal children does not support the hypothesis of an association between OC and a positive metabolic profile. (C) 2016 Elsevier Inc. All rights reserved.

  • 18.
    Wermelin, Karin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences.
    Suska, F.
    Department of Biomaterials, Inst. of Surgical Sciences, Sahlgrenska Academy at Göteborg University, Box 412, SE-405 30 Göteborg, Sweden.
    Tengvall, Pentti
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics . Linköping University, The Institute of Technology.
    Thomsen, P.
    Department of Biomaterials, Inst. of Surgical Sciences, Sahlgrenska Academy at Göteborg University, Box 412, SE-405 30 Göteborg, Sweden.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Stainless steel screws coated with bisphosphonates gave stronger fixation and more surrounding bone. Histomorphometry in rats2008In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 42, no 2, p. 365-371Article in journal (Refereed)
    Abstract [en]

    Coating of stainless steel screws with bisphosphonate in a fibrinogen matrix leads to an enhancement of the pullout strength 2 weeks after insertion in rat tibiae. This effect then increases over time until at least 8 weeks. The pullout force reflects the mechanical properties of the bone within the threads, which acts as a screw nut. The aim of the present study was to find descriptive and morphometric histological correlates to the increased pullout strength. Because the bisphosphonates are applied via the implant surface, we also measured bone to implant contact and how far away from the surface any effects could be seen.

    Stainless steel screws underwent one of three treatments: uncoated control, controls coated with a layer of cross-linked fibrinogen, or screws further modified with bisphosphonates covalently linked and physically adsorbed to the fibrinogen layer. At 1 (n = 33) and 8 (n = 27) weeks, bone to implant contact and bone area density in the threads were measured, as well as bone area density at 250 and 500 μm from the outer edge of the threads. Additionally, removal torque for each screw treatment was measured at 2 weeks (n = 28).

    At 8 weeks, the part of the bisphosphonate screw that was located in the marrow cavity had become surrounded with bone, whereas there was almost no bone surrounding the controls. The bone area density in the threads along the entire bisphosphonate screw was increased by 40% compared with uncoated controls, and at 250 μm distance it was more than doubled. At 1 week, coated screws had less implant–bone contact, but at 8 weeks there was no difference between uncoated and bisphosphonate-coated screws. The bisphosphonate screws had 50% increased removal torque at 2 weeks compared to uncoated screws. Howship's lacunae and osteoclasts were found near the screws with bisphosphonates at 8 weeks, suggesting that some bone remodeling took place near the implant, in spite of the presence of bisphosphonates.

  • 19.
    Wilczek, M
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Kälvesten, Johan
    Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences.
    Algulin, J
    Sectra Imtec AB, Sweden .
    Beiki, O
    Karolinska Institute, Stockholm, Sweden Kermanshah University of Medical Science, Iran .
    Brismar, T
    Karolinska Institute, Stockholm, Sweden .
    Predicting hip fracture risk with hand or wrist radiographs using digital X-ray Radiogrammetry2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S65-S65Article in journal (Refereed)
    Abstract [en]

    Abstract: Background: More than 50% of patients diagnosed with osteoporosis after a fracture have had at least one previous fracture. Despite an established relationship between bone mineral density (BMD) and fracture risk, as well as proven effective pharmacological treatment, there is still no routine for screening for osteoporosis. Digital X-ray Radiogrammetry (DXR) analysis provides a simple way to obtain a BMD measurement. However, there is a need for larger studies evaluating the relationship between BMD obtained through DXR and future fracture risk. If such a relationship is strong enough, it should be possible to find osteoporotic patients already at the time of the first fracture by analyzing hand X-ray images with DXR. Aim: To evaluate if conventional radiographs can be used to estimate future hip fracture risk with DXR analysis. Method and materials: After receiving approval from the local ethical committee, all radiographs depicting the left hand were collected from three emergency hospitals in Stockholm, Sweden (n = 45,538). Radiographs with insufficiently depicted metacarpal bone, foreign material such as fixation pins, unacceptable positioning of the metacarpals or fractures in the measurement regions, were manually excluded. 18,824 radiographs from 15,072 unique patients were considered suitable for DXR analysis. These patients were matched with the death and inpatient registers found at the Swedish National Board of Health and Welfare. Exclusion criteria were age < 40 years (n = 6,611) and prior hip fracture (n = 199). ICD-10 codes were used to identify hip fractures, including only patients coded for both diagnosis and adequate intervention. Results: 5420 women and 2842 men met the inclusion criteria. Average observation time was 3 years and 3 months, resulting in a total observation time of 27,072 person years. In total 122 patients had a hip fracture after their radiograph of the hand or wrist. Patients who suffered from a hip fracture had a significantly lower BMD than that of non-fractured patients when adjusted for age (0.53 g/cm2, SD 0.08 versus 0.42 g/cm2, SD 0.05 in females and 0.63 g/cm2, SD 0.07 versus 0.54 g/cm2, SD 0.09 in males; p < 0.0001, both). The age-adjusted RR/SD for hip fracture was 2.52 in females and 2.08 in males. The AUC was 0.89 in female and 0.84 in male. Conclusion: DXR analysis of wrist and hand radiographs obtained at emergency hospitals in Sweden predicts hip fracture risk in women and men.

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