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xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article discussez current understanding of the potential role for pharmacologic agents in bone healing, particularly those used for osteoporosis treatment, of which parathyroid hormone shows the most clinical promise.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EBone Density \u0026amp; Structure Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EMetabolic Bone Disease Metabolic Bone Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EOrthopaedics \u0026amp; Sports Medicine\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EAurelia Nattiv, MD, University of California, Los Angeles, Los Angeles, California, USA, discussed current understanding of the potential role for pharmacologic agents in bone healing, particularly those used for osteoporosis treatment, of which parathyroid hormone (PTH) shows the most clinical promise.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ENew technologies to accelerate fracture healing have been investigated in animal studies for years, and there is growing clinical evidence to support the use of systemic agents to enhance fracture repair. Systemic agents for osteoporosis that improve bone mass and prevent fractures have received the most attention; most are US Food and Drug Administration (FDA)-approved for osteoporosis treatment but are off label for fracture healing, while others remain under investigation.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EFDA-APPROVED OSTEOPOROSIS AGENTS AND FRACTURE HEALING Estrogen\u003C\/h2\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EDespite a lack of clinical data, animal studies have shown that estrogen therapy enhances fracture healing (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Kolios L et al. \u003Cem\u003ECalcif Tissue Int\u003C\/em\u003E 2010], resulting in a callus with improved biomechanical competence and increased chondrocyte area and mineralization [Beil FT et al. \u003Cem\u003EJ Trauma\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/23\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Bone Healing in a Rat Metaphyseal Fracture Model\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1126507378\u0022 data-figure-caption=\u0022Bone Healing in a Rat Metaphyseal Fracture Model\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/23\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/23\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/23\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14881\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003EBone Healing in a Rat Metaphyseal Fracture Model\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003ECompared with physiologic healing in the sham group, callus formation in the osteoporotic (OP) control (C) group was enhanced but unstructured and less dense. Estrogen (E) administration induced less callus formation, but the callus present was very compact and dense, with increased amounts of trabecular structure. The alendronate (ALN) group displayed fewer and unconstrained calluses and trabeculas.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from Springer New York LLC from Kolios L, Hoerster AK, Sehmisch S, et al. Do estrogen and alendronate improve metaphyseal fracture healing when applied as osteoporosis prophylaxis? \u003Cem\u003ECalcif Tissue Int.\u003C\/em\u003E 2010;86:23\u201332.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cdiv id=\u0022sec-2\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003ERaloxifene\u003C\/h3\u003E\n            \u003Cp id=\u0022p-6\u0022\u003EIn a rat metaphyseal tibial fracture-healing model, raloxifene markedly induced total callus formation and improved the biomechanical properties of bone healing [Stuermer EK et al. \u003Cem\u003ELangenbecks Arch Surg\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003C\/div\u003E\n         \u003Cdiv id=\u0022sec-3\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003EBisphosphonates\u003C\/h3\u003E\n            \u003Cp id=\u0022p-7\u0022\u003EAlthough bisphosphonates (BPs) potently inhibit osteoclast-mediated bone resorption, there is mixed evidence for their effect on fracture healing. In a rat closed femur fracture model, bolus dosing with zoledronic acid increased callus size and strength without delaying endochondral ossification, although hard callus remodeling was slightly slower than in control animals [McDonald MM et al. \u003Cem\u003EBone\u003C\/em\u003E 2008].\u003C\/p\u003E\n            \u003Cp id=\u0022p-8\u0022\u003ESome of the best clinical data exist in compromised patients. In children with osteogenesis imperfecta, older age (odds ratio [OR] per year of age, 1.25; 95% CI, 1.06 to 1.47) and tibial osteotomy (OR, 3.51; 95% CI, 1.57 to 7.82) independently predicted delayed healing of lower limb fractures during pamidronate treatment. However, the treatment effect was not significant when age differences were taken into account (OR, 1.76; 95% CI, .61 to 5.10) [Munns CFJ et al. \u003Cem\u003EJ Bone Miner Res\u003C\/em\u003E 2004]. In a study in 19,731 older adults with humerus fractures, use of BP approximately doubled the risk for nonunion (OR, 2.37; 95% CI, 1.13 to 4.96) [Solomon DH et al. \u003Cem\u003EOsteoporos Int\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003C\/div\u003E\n         \u003Cdiv id=\u0022sec-4\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003EDenosumab\u003C\/h3\u003E\n            \u003Cp id=\u0022p-9\u0022\u003EAlthough no clinical data exist for the effect of the osteoclast inhibitor denosumab on fracture healing, it increased callus volume and bone mineral density (BMD) in a mouse femur fracture model [Gerstenfeld LC et al. \u003Cem\u003EJ Bone Miner Res\u003C\/em\u003E 2009]. Despite delayed callus remodeling, there was no compromise in its mechanical integrity.\u003C\/p\u003E\n         \u003C\/div\u003E\n         \u003Cdiv id=\u0022sec-5\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003EPTH\u003C\/h3\u003E\n            \u003Cp id=\u0022p-10\u0022\u003EPTH is the only FDA-approved anabolic therapy for osteoporosis and currently shows the most benefit for fracture healing in patients with nonunion or delayed healing. In a rat model, PTH enhanced callus formation, BMD, bone mineral content, and cartilage formation and increased mechanical strength at the tibial fracture site [Andreassen TT et al. \u003Cem\u003ECalcif Tissue Int\u003C\/em\u003E 2004].\u003C\/p\u003E\n            \u003Cp id=\u0022p-11\u0022\u003EIn a placebo-controlled, double-blinded, randomized, multicenter, multinational clinical study, 102 post-menopausal women with Colles\u0027 fracture who were treated conservatively without surgical intervention were randomly assigned to placebo (n = 34) or teriparatide, a recombinant form of PTH, at 20 \u03bcg (n = 34) or 40 \u03bcg (n = 34) within 10 days of fracture [Aspenberg P et al. \u003Cem\u003EJ Bone Miner Res\u003C\/em\u003E 2010]. Accelerated healing was seen in the teriparatide 20 \u03bcg group compared with placebo (p = .006).\u003C\/p\u003E\n            \u003Cp id=\u0022p-12\u0022\u003EIn a recent prospective study in BP-associated atypical femoral fractures, 5 of 14 patients treated with 20 \u03bcg teriparatide experienced a 2- to 3-fold increase in bone remodeling markers (p = .01) and fracture healing, while 9 of 14 control patients experienced poor healing and ongoing pain [Chiang CY et al. \u003Cem\u003EBone\u003C\/em\u003E 2013].\u003C\/p\u003E\n         \u003C\/div\u003E\n         \u003Cdiv id=\u0022sec-6\u0022 class=\u0022subsection\u0022\u003E\n            \u003Ch3\u003EEmerging Agents\u003C\/h3\u003E\n            \u003Cp id=\u0022p-13\u0022\u003EThe Wnt signaling pathway has emerged as one of the most essential signaling cascades in osteogenic disorders. Targeting this pathway can modulate fracture healing and represents an attractive therapeutic approach for the development of potential therapeutic avenues.\u003C\/p\u003E\n            \u003Cp id=\u0022p-14\u0022\u003ERomosozumab exemplifies this translation of emerging agents into clinical application. The humanized monoclonal antibody increases bone formation by binding to the osteoblast inhibitor sclerostin and was associated with increased BMD and bone formation, and decreased bone resorption, in a recent Phase 2 study in 419 post-menopausal women with low bone mass [McClung MR et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2014].\u003C\/p\u003E\n            \u003Cp id=\u0022p-15\u0022\u003EOther agents that target the Wnt signaling pathway, such as anti-Dkk-1 antibody, remain under investigation and may soon become available for clinical use [Kim JH et al. \u003Cem\u003ETher Adv Musculoskelet Dis\u003C\/em\u003E 2013].\u003C\/p\u003E\n            \u003Cp id=\u0022p-16\u0022\u003EFuture randomized controlled trials of clinical fracture healing are needed to improve the characterization of clinical end points such as decrease in pain, improved function, radiographic evidence of union, and decrease in reoperation rate.\u003C\/p\u003E\n         \u003C\/div\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/23\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzowod\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzowod\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}