Efficacy of a sclerostin antibody compared to a low dose of PTH on metaphyseal bone healing

ABSTRACT We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone healing. Screws of steel or poly methyl methacrylate (PMMA) were inserted bilaterally into the proximal tibia of young male rats. During 4 w...

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Published in	Journal of orthopaedic research Vol. 32; no. 3; pp. 471 - 476
Main Authors	Agholme, Fredrik, Macias, Brandon, Hamang, Matt, Lucchesi, Jonathan, Adrian, Mary D., Kuhstoss, Stuart, Harvey, Anita, Sato, Masahiko, Aspenberg, Per
Format	Journal Article
Language	English
Published	United States Blackwell Publishing Ltd 01.03.2014
Subjects	Animals Antibodies - therapeutic use Bone Density Conservation Agents - pharmacology Bone Density Conservation Agents - therapeutic use bone formation bone healing Bone Morphogenetic Proteins - antagonists & inhibitors Bone Morphogenetic Proteins - immunology Bone Screws Drug Evaluation, Preclinical Fracture Healing - drug effects Fractures, Bone - drug therapy Genetic Markers - immunology implant fixation Male mechanical testing MEDICIN MEDICINE Random Allocation Rats Rats, Sprague-Dawley Teriparatide - pharmacology Teriparatide - therapeutic use Wnt-signaling implant fixation bone formation Wnt-signaling mechanical testing bone healing
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Abstract	ABSTRACT We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone healing. Screws of steel or poly methyl methacrylate (PMMA) were inserted bilaterally into the proximal tibia of young male rats. During 4 weeks the animals then received injections of either phosphate buffered saline (control), sclerostin antibody (25 mg/kg, twice weekly) or PTH (5 µg/kg, daily). The healing response around the screws was then assessed by mechanical testing and X‐ray microtomography (µCT). 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. µCT 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. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:471–476, 2014.
AbstractList	ABSTRACT We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone healing. Screws of steel or poly methyl methacrylate (PMMA) were inserted bilaterally into the proximal tibia of young male rats. During 4 weeks the animals then received injections of either phosphate buffered saline (control), sclerostin antibody (25 mg/kg, twice weekly) or PTH (5 µg/kg, daily). The healing response around the screws was then assessed by mechanical testing and X‐ray microtomography (µCT). 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. µCT 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. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:471–476, 2014. 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. 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 (25 mg/kg, twice weekly) or PTH (5 µg/kg, daily). The healing response around the screws was then assessed by mechanical testing and X-ray microtomography (µCT). 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. µCT 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.
Author	Agholme, Fredrik Adrian, Mary D. Aspenberg, Per Kuhstoss, Stuart Harvey, Anita Macias, Brandon Sato, Masahiko Lucchesi, Jonathan Hamang, Matt
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References_xml	– volume: 88 start-page: 569 year: 2009 end-page: 574 article-title: Sclerostin in mineralized matrices and van Buchem disease publication-title: J Dent Res – volume: 63 start-page: 192 year: 2003 end-page: 197 article-title: The natural history of sclerosteosis publication-title: Clin Genet – volume: 17 start-page: 2038 year: 2002 end-page: 2047 article-title: Mechanisms for the enhancement of fracture healing in rats treated with intermittent low‐dose human parathyroid hormone (1‐34) publication-title: J Bone Miner Res – volume: 25 start-page: 2412 year: 2010 end-page: 2418 article-title: Sclerostin antibody treatment enhances metaphyseal bone healing in rats publication-title: J Bone Miner Res – volume: 26 start-page: 2804 year: 2011 end-page: 2811 article-title: Patients with sclerosteosis and disease carriers: human models of the effect of sclerostin on bone turnover publication-title: J Bone Miner Res – volume: 71 start-page: 619 year: 2000 end-page: 624 article-title: Strong effect of PTH (1‐34) on regenerating bone: a time sequence study in rats publication-title: Acta Orthop Scand – volume: 93 start-page: 1583 year: 2011 end-page: 1587 article-title: Parathyroid hormone 1‐84 accelerates fracture‐healing in pubic bones of elderly osteoporotic women publication-title: J Bone Joint Surg Am – volume: 90 start-page: 31 year: 2008 end-page: 35 article-title: Osteocyte‐derived sclerostin inhibits bone formation: its role in bone morphogenetic protein and Wnt signaling publication-title: J Bone Joint Surg Am – volume: 81 start-page: 234 year: 2010 end-page: 236 article-title: Teriparatide improves early callus formation in distal radial fractures publication-title: Acta Orthop – volume: 138 start-page: 4330 year: 1997 end-page: 4337 article-title: Biosynthetic human parathyroid hormone (1‐34) effects on bone quality in aged ovariectomized rats publication-title: Endocrinology – volume: 4 start-page: e249 year: 2007 article-title: Beta‐catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing publication-title: PLoS Med – volume: 22 start-page: 6267 year: 2003 end-page: 6276 article-title: Osteocyte control of bone formation via sclerostin, a novel BMP antagonist publication-title: Embo J – volume: 25 start-page: 404 year: 2010 end-page: 414 article-title: Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double‐blind study of 102 postmenopausal women with distal radial fractures publication-title: J Bone Miner Res – volume: 25 start-page: 178 year: 2010 end-page: 189 article-title: Parathyroid hormone (PTH)‐induced bone gain is blunted in SOST overexpressing and deficient mice publication-title: J Bone Miner Res – volume: 14 start-page: 960 year: 1999 end-page: 968 article-title: Intermittent parathyroid hormone (1‐34) treatment increases callus formation and mechanical strength of healing rat fractures publication-title: J Bone Miner Res – volume: 49 start-page: 591 year: 2011 end-page: 599 article-title: Small animal bone healing models: standards, tips, and pitfalls results of a consensus meeting publication-title: Bone – volume: 109 start-page: E725 year: 2012 end-page: E733 article-title: Silencing of parathyroid hormone (PTH) receptor 1 in T cells blunts the bone anabolic activity of PTH publication-title: Proc Natl Acad Sci USA – volume: 42 start-page: 365 year: 2008 end-page: 371 article-title: Stainless steel screws coated with bisphosphonates gave stronger fixation and more surrounding bone. Histomorphometry in rats publication-title: Bone – volume: 16 start-page: 319 year: 2005 end-page: 327 article-title: SOST/sclerostin, an osteocyte‐derived negative regulator of bone formation publication-title: Cytokine Growth Factor Rev – volume: 280 start-page: 26770 year: 2005 end-page: 26775 article-title: SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor publication-title: J Biol Chem – volume: 68 start-page: 577 year: 2001 end-page: 589 article-title: Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot‐containing protein publication-title: Am J Hum Genet – volume: 286 start-page: 19489 year: 2011 end-page: 19500 article-title: Bone overgrowth‐associated mutations in the LRP4 gene impair sclerostin facilitator function publication-title: J Biol Chem – volume: 83 start-page: 437 year: 2001 end-page: 440 article-title: Implant fixation enhanced by intermittent treatment with parathyroid hormone publication-title: J Bone Joint Surg Br – volume: 90 start-page: 6392 year: 2005 end-page: 6395 article-title: Bone mineral density in sclerosteosis; affected individuals and gene carriers publication-title: J Clin Endocrinol Metab – volume: 17 start-page: 1151 year: 2002 end-page: 1161 article-title: Commentary on clinical safety of recombinant human parathyroid hormone 1‐34 in the treatment of osteoporosis in men and postmenopausal women publication-title: J Bone Miner Res – volume: 26 start-page: 1012 year: 2011 end-page: 1021 article-title: Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of non‐fractured bones publication-title: J Bone Miner Res – volume: 78 start-page: 385 year: 2007 end-page: 392 article-title: Surface‐bound bisphosphonates enhance screw fixation in rats–increasing effect up to 8 weeks after insertion publication-title: Acta Orthop – volume: 39 start-page: 91 year: 2002 end-page: 97 article-title: Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease publication-title: J Med Genet – volume: 392 start-page: 427 year: 2001 end-page: 432 article-title: Early effect of parathyroid hormone (1‐34) on implant fixation publication-title: Clin Orthop Relat Res – volume: 84 start-page: 393 year: 1976 end-page: 397 article-title: The clinical features of sclerosteosis. A review of the manifestations in twenty‐five affected individuals publication-title: Ann Intern Med – volume: 11 start-page: 161 year: 2010 end-page: 171 article-title: Suppression of Wnt signaling by Dkk1 attenuates PTH‐mediated stromal cell response and new bone formation publication-title: Cell Metab – volume: 48 start-page: 988 year: 2011 end-page: 996 article-title: The effects of Dickkopf‐1 antibody on metaphyseal bone and implant fixation under different loading conditions publication-title: Bone
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Snippet	ABSTRACT We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone... 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....
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SubjectTerms	Animals Antibodies - therapeutic use Bone Density Conservation Agents - pharmacology Bone Density Conservation Agents - therapeutic use bone formation bone healing Bone Morphogenetic Proteins - antagonists & inhibitors Bone Morphogenetic Proteins - immunology Bone Screws Drug Evaluation, Preclinical Fracture Healing - drug effects Fractures, Bone - drug therapy Genetic Markers - immunology implant fixation Male mechanical testing MEDICIN MEDICINE Random Allocation Rats Rats, Sprague-Dawley Teriparatide - pharmacology Teriparatide - therapeutic use Wnt-signaling
Title	Efficacy of a sclerostin antibody compared to a low dose of PTH on metaphyseal bone healing
URI	https://api.istex.fr/ark:/67375/WNG-030411JZ-H/fulltext.pdf https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fjor.22525 https://www.ncbi.nlm.nih.gov/pubmed/24243768 https://search.proquest.com/docview/1490775128 https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-103861
Volume	32
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