Manipulation of the Anabolic and Catabolic Responses With OP-1 and Zoledronic Acid in a Rat Critical Defect Model

Little, David; McDonald, Michelle M.; Bransford, Rick; Godfrey, Craig; Amanat, Negin

doi:10.1359/jbmr.050712

Cited by 127 publications

(126 citation statements)

References 19 publications

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“…However, for a majority of bone tissue engineering applications, the new bone is largely unloaded and this lack of mechanical stimulation can lead to premature or excessive resorption (Giannoudis et al, 2007a). There is an increasingly established paradigm that fracture repair outcomes represent a sum of both bone forming and bone resorbing responses (Little et al, 2007). This paradigm is now beginning to be applied to bone tissue engineering strategies with drugs such as bisphosphonates being shown to act synergistically with rhBMPs .…”

Section: A Sugar-based Phase-transitioning Delivery System For Bone Tmentioning

confidence: 99%

“…Under normal homeostatic conditions, bone exists in a state of dynamic equilibrium of anabolism and catabolism (Little et al, 2007). The addition of rhBMP-2 drives a strong anabolic response that induces bone production, but it is also accompanied by a catabolic increase in osteoclast numbers (Giannoudis et al, 2007b).…”

Section: Tl Cheng Et Al Saib For Bone Tissue-engineeringmentioning

confidence: 99%

“…However, rhBMP-2 was not directly added to the SAIB and the capacity for injection and subsequent phase transitioning was not employed. The investigator's main purpose in using SAIB was to slow rhBMP-2 release from the collagen-chondroitin sulphate discs, rather than to develop an injectable delivery system.Under normal homeostatic conditions, bone exists in a state of dynamic equilibrium of anabolism and catabolism (Little et al, 2007). The addition of rhBMP-2 drives a strong anabolic response that induces bone production, but it is also accompanied by a catabolic increase in osteoclast numbers (Giannoudis et al, 2007b).…”

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A sugar-based phase-transitioning delivery system for bone tissue engineering

Cheng

Valtchev²,

Murphy³

et al. 2013

eCM

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Bone tissue engineering approaches commonly involve the delivery of recombinant human bone morphogenetic proteins (rhBMPs). However, there are limitations associated with the currently used carriers, including the need for surgical implantation and the associated increase in infection risk. As an alternative to traditional porous collagen sponge, we have adopted a solution of the injectable sucrose acetate isobutyrate (SAIB) as a carrier for rhBMP-2. The ability to deliver rhBMP-2 and other agents by injection reduces the infection risk and lesion size whilst in surgery, with the potential to avoid open surgery altogether in some indications.The primary methodology used for this in vivo study was a C57BL6/J mouse ectopic bone formation model. Specimens were examined by x-ray, microCT, and histology at 3 weeks. SAIB was delivered non-invasively and produced up to 3-fold greater bone volume compared to collagen. To further refine and improve upon the formulation, SAIB containing rhBMP-2 was admixed with candidate compounds including ceramic microparticles, antiresorptives, and cell signalling inhibitors and further tested in vivo. The formulation combining SAIB/rhBMP-2, the bisphosphonate zoledronic acid (ZA), and hydroxyapatite (HA) microparticles yielded a 10-fold greater bone volume than SAIB/rhBMP-2 alone. To investigate the mechanism underlying the synergy between ZA and HA, we used in vitro binding assays and in vivo fluorescent biodistribution studies to demonstrate that ceramic particles could bind and sequester the bisphosphonate. These data show the utility of SAIB as a non-invasive rhBMP delivery system as well as describing an optimised formulation for bone tissue engineering. (Im and Tae, 2005). In another study, the risk of septic knee after retrograde intramedullary femoral nailing was four times greater in open fractures than closed fractures (Halvorson et al., 2012). In a trial comparing recombinant human bone morphogenetic protein-2 (rhBMP-2)/collagen sponge treatment with the standard of care treatment in open tibial fractures, the rhBMP-2 treated group showed a significant increase in infections (Aro et al., 2011). Thus the development of a system able to deliver rhBMPs percutaneously to an orthopaedic site could reduce lesion size and minimise infection risk. KeywordsAlthough various polymeric materials, such as degradable hydrogels, have been developed by many groups to serve as injectable scaffolds (Miyamoto and Takaoka, 1993;Han and Hubbell, 1996;Burdick and Anseth, 2002;Lutolf et al., 2003), progression towards clinical application has been limited. However, we have chosen a material called sucrose acetate isobutyrate (SAIB), a sugar-based ester that is currently used as a food additive (emulsifier E444), as well as in cosmetics and industrial processes. In the United States, SAIB is approved by the Food and Drug Administration as a food additive, and has an allowable daily intake of 20 mg/kg/ day (21 CFR 172.833; 64 Fed. Reg. 29949, 4 June 1999). It has been considered safe for u...

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Section: A Sugar-based Phase-transitioning Delivery System For Bone Tmentioning

confidence: 99%

Section: Tl Cheng Et Al Saib For Bone Tissue-engineeringmentioning

confidence: 99%

mentioning

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A sugar-based phase-transitioning delivery system for bone tissue engineering

Cheng

Valtchev²,

Murphy³

et al. 2013

eCM

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“…In another bone chamber study in rabbits allowing motion, the response to BMP-2 switched from net resorption to net formation when micromotion was added. 16 In a multicenter randomized study of 450 open tibial fractures, 13 the fractures treated with intramedullary nail fixation and an implant containing BMP-2 had reduced frequency of secondary interventions, accelerated fracture and wound healing, and reduced infection rate compared to those treated with intramedullary nail fixation and routine soft-tissue management. The rate of union, however, was similar to autograft.…”

Section: Manipulating Responses In Bone Graft Remodelingmentioning

confidence: 99%

“…12 The optimal time-point for administering a systemic bisphosphonate, to maintain the BMP-7-mediated callus, is 2 weeks as shown in a critical defect rat model. 13 The aim of our study was to examine if the combination of BMP-7 and a potent nitrogen-containing bisphosphonate given systemically, even as a single dose, will lead to both increased ingrowth distance into a bone graft and retained or increased total bone volume. …”

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Manipulating the anabolic and catabolic response in bone graft remodeling: Synergism by a combination of local BMP‐7 and a single systemic dosis of zoledronate

Harding

Aspenberg

Kataoka

et al. 2008

Journal Orthopaedic Research

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Remodeling of a bone graft can be influenced both by anabolic substances, such as a bone morphogenic protein (BMP) and by anticatabolic substances, such as the bisphosphonates. BMPs are potent bone anabolic substances, but also boost catabolism and cause resorption. Bisphosphonates inhibit osteoclast function and can be used to postpone resorption. In the present study a combination of both drugs was explored in a rat bone chamber model. Cancellous bone grafts were treated with either BMP-7 or saline and placed in a bone chamber implanted in the proximal tibia. After 2 weeks, an injection of either zoledronate 0.1 mg/kg or saline was given subcutaneously. The rats were killed after 6 weeks, and bone ingrowth distance into the graft and graft resorption were measured by histomorphometry. BMP-7 significantly (p ¼ 0.007) increased new bone ingrowth distance into the graft from 2.0 mm (SD ¼ 0.98 mm) in the controls to 3.1 mm (SD ¼ 0.93 mm). If bisphosphonate was not given, most of the newly formed and old graft bone was resorbed. A single injection of zoledronate significantly (p < 0.001) increased the trabecular volume/total volume to 40% (SD ¼ 9%) compared to 14% (SD ¼ 10%) in the nonbisphosphonate treated. In total, the net amount of bone increased by 400% when BMP-7 and zoledronate combined was compared to saline. A bone graft can be treated with BMP-7 to increase new bone formation and at the same time be protected against premature catabolism by a single dose of a bisphosphonate. This combination might be useful in various conditions in orthopedic reconstruction. Healing and normal physiological skeletal repair involve a complex set of regulated signaling pathways that control the formation of new bone matrix and the resorption of damaged bone at the disease or injury site. These pathways are mediated by a number of effector cells, primarily the catabolic bone-resorbing osteoclasts and the anabolic bone-forming osteoblasts, which produce new bone tissue to restore skeletal integrity. A balance between them is required for normal fracture repair and bone graft remodeling. Delayed healing or non-union can be a failure of the anabolic response, an increased or premature catabolic response, or sometimes both. 1 The anabolic and catabolic responses can be manipulated with pharmaceuticals, and in the bone conduction chamber, 2 we can study how drugs, separately or in combinations, influence bone formation and resorption.Bisphosphonates reduce osteoclastic catabolic activity in experimental studies. Circulating bisphosphonates bind to bone mineral, and, when the bone is resorbed by osteoclasts, bisphosphonates are internalized and interfere with cell metabolism leading to osteoclast apoptosis. 3 Systemic bisphosphonate treatment can postpone resorption of a bone graft. 4 In fractures, postponing the catabolic response and in consequence the resorption of the new-forming callus, leads to a stronger callus. 5 Bone morphogenic proteins (BMPs) bind to specific cell receptors, starting a signaling cascade that l...

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Chapter 12. Biomechanics of Fracture Healing

Morgan

Einhorn

2008

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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Manipulation of the Anabolic and Catabolic Responses With OP-1 and Zoledronic Acid in a Rat Critical Defect Model

Cited by 127 publications

References 19 publications

A sugar-based phase-transitioning delivery system for bone tissue engineering

A sugar-based phase-transitioning delivery system for bone tissue engineering

Manipulating the anabolic and catabolic response in bone graft remodeling: Synergism by a combination of local BMP‐7 and a single systemic dosis of zoledronate

Chapter 12. Biomechanics of Fracture Healing

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