The Tactics of Modern-Day Regulatory Trials

Dent-Acosta, Ricardo E; Storm, Neal E.; Steiner, Randall S; Martín, Javier San

doi:10.2106/jbjs.l.00194

Cited by 13 publications

(10 citation statements)

References 10 publications

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“…After 9 months, similar and high percentages of patients in each group exhibited healing based on radiographic assessments and fracture site pain. BMP‐7 was FDA‐approved in 2001 under a humanitarian device exemption as an alternative to autograft …”

Section: Agents and Biological Pathways That Promote Fracture Healingmentioning

confidence: 99%

“…BMP-7 was FDA-approved in 2001 under a humanitarian device exemption as an alternative to autograft. 29 BMP-2 was approved for fracture healing in the form of BMP-2 mixed with an absorbable collagen sponge (ACS) delivered locally to open fractures. This combination product "device," known as INFUSE 1 Bone Graft, was FDA-approved in 2004 for use in acute tibial fractures treated with an intramedullary nail within 14 days of injury, 54 based on data from a randomized controlled trial of 450 patients with open tibial fracture.…”

Section: Therapies For Delayed/non-union Fracturesmentioning

confidence: 99%

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Fracture healing physiology and the quest for therapies for delayed healing and nonunion

Kostenuik

Mirza

2016

Journal Orthopaedic Research

148

121

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Delayed healing and nonunion of fractures represent enormous burdens to patients and healthcare systems. There are currently no approved pharmacological agents for the treatment of established nonunions, or for the acceleration of fracture healing, and no pharmacological agents are approved for promoting the healing of closed fractures. Yet several pharmacologic agents have the potential to enhance some aspects of fracture healing. In preclinical studies, various agents working across a broad spectrum of molecular pathways can produce larger, denser and stronger fracture calluses. However, untreated control animals in most of these studies also demonstrate robust structural and biomechanical healing, leaving unclear how these interventions might alter the healing of recalcitrant fractures in humans. This review describes the physiology of fracture healing, with a focus on aspects of natural repair that may be pharmacologically augmented to prevent or treat delayed or nonunion fractures (collectively referred to as DNFs). The agents covered in this review include recombinant BMPs, PTH/PTHrP receptor agonists, activators of Wnt/β‐catenin signaling, and recombinant FGF‐2. Agents from these therapeutic classes have undergone extensive preclinical testing and progressed to clinical fracture healing trials. Each can promote bone formation, which is important for the stability of bridged calluses, and some but not all can also promote cartilage formation, which may be critical for the initial bridging and subsequent stabilization of fractures. Appropriately timed stimulation of chondrogenesis and osteogenesis in the fracture callus may be a more effective approach for preventing or treating DNFs compared with stimulation of osteogenesis alone. © 2016 The Authors. Journal of Orthopaedic Research published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 35:213–223, 2017.

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Section: Agents and Biological Pathways That Promote Fracture Healingmentioning

confidence: 99%

Section: Therapies For Delayed/non-union Fracturesmentioning

confidence: 99%

Fracture healing physiology and the quest for therapies for delayed healing and nonunion

Kostenuik

Mirza

2016

Journal Orthopaedic Research

148

121

View full text Add to dashboard Cite

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“…Among patients with open long bone fractures, as many as 25% may develop delayed union or nonunion, which can cause major loss of productivity, decreased quality of life, and extensive health care utilization . Despite clear unmet clinical needs, no pharmacological agents are currently approved for the acceleration of fracture healing or for the treatment of delayed or nonunion fractures . Recombinant human bone morphogenetic protein‐2 (rhBMP‐2) mixed with an absorbable collagen sponge (ACS) is indicated for the acute treatment of tibial shaft fractures, but this combination “device” product is associated with several safety issues and is only indicated for the treatment of tibial fractures that have accessible fracture lines .…”

mentioning

confidence: 99%

“…[12][13][14] Despite clear unmet clinical needs, no pharmacological agents are currently approved for the acceleration of fracture healing or for the treatment of delayed or nonunion fractures. 3,15 Recombinant human bone morphogenetic protein-2 (rhBMP-2) mixed with an absorbable collagen sponge (ACS) is indicated for the acute treatment of tibial shaft fractures, 16 but this combination "device" product is associated with several safety issues and is only indicated for the treatment of tibial fractures that have accessible fracture lines. 17 There remains an unmet need for agents that can enhance the healing of open and closed fractures, and systemically-administered bone anabolic agents have the potential to fulfill some of these needs.…”

mentioning

confidence: 99%

Abaloparatide, a PTH receptor agonist with homology to PTHrP, enhances callus bridging and biomechanical properties in rats with femoral fracture

Lanske

Chandler

Pierce

et al. 2019

Journal Orthopaedic Research

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Fractures typically heal via endochondral and intramembranous bone formation, which together form a callus that achieves union and biomechanical recovery. PTHrP, a PTH receptor agonist, plays an important physiological role in fracture healing as an endogenous stimulator of endochondral and intramembranous bone formation. Abaloparatide, a novel systemically‐administered osteoanabolic PTH receptor agonist that reduces fracture risk in women with postmenopausal osteoporosis, has 76% homology to PTHrP, suggesting it may have potential to improve fracture healing. To test this hypothesis, ninety‐six 12‐week‐old male rats underwent unilateral internally‐stabilized closed mid‐diaphyseal femoral fractures and were treated starting the next day with daily s.c. saline (Vehicle) or abaloparatide at 5 or 20 µg/kg/d for 4 or 6 weeks (16 rats/group/time point). Histomorphometry and histology analyses indicated that fracture calluses from the abaloparatide groups exhibited significantly greater total area, higher fluorescence scores indicating more newly‐formed bone, and higher fracture bridging scores versus Vehicle controls. Callus bridging score best correlated with callus cartilage score (r = 0.64) and fluorescence score (r = 0.67) at week 4, and callus area correlated with cartilage score (r = 0.60) and fluorescence score (r = 0.89) at Week 6. By micro‐CT, calluses from one or both abaloparatide groups had greater bone volume, bone volume fraction, bone mineral content, bone mineral density, and cross‐sectional area at both time points versus Vehicle controls. Destructive bending tests indicated greater callus maximum load and stiffness in one or both abaloparatide groups at both time points versus Vehicle controls. These results provide preliminary preclinical evidence for improved fracture healing with systemically‐administered abaloparatide. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res

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“…The initial results demonstrated a statistically significant shorter time to the radiologic consolidation of the fractures but not differences in terms of the range of motion, grip strength and VAS or DASH scores [ 107 ]. Furthermore, the trial failed to show any statistically significant difference in the time of removal of the immobilization device, which was the primary end point of the study [ 108 ].…”

Section: Resultsmentioning

confidence: 99%

The role of peptides in bone healing and regeneration: a systematic review

Pountos

Panteli

Lampropoulos

et al. 2016

BMC Med

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BackgroundBone tissue engineering and the research surrounding peptides has expanded significantly over the last few decades. Several peptides have been shown to support and stimulate the bone healing response and have been proposed as therapeutic vehicles for clinical use. The aim of this comprehensive review is to present the clinical and experimental studies analysing the potential role of peptides for bone healing and bone regeneration.MethodsA systematic review according to PRISMA guidelines was conducted. Articles presenting peptides capable of exerting an upregulatory effect on osteoprogenitor cells and bone healing were included in the study.ResultsBased on the available literature, a significant amount of experimental in vitro and in vivo evidence exists. Several peptides were found to upregulate the bone healing response in experimental models and could act as potential candidates for future clinical applications. However, from the available peptides that reached the level of clinical trials, the presented results are limited.ConclusionFurther research is desirable to shed more light into the processes governing the osteoprogenitor cellular responses. With further advances in the field of biomimetic materials and scaffolds, new treatment modalities for bone repair will emerge.

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The Tactics of Modern-Day Regulatory Trials

Cited by 13 publications

References 10 publications

Fracture healing physiology and the quest for therapies for delayed healing and nonunion

Fracture healing physiology and the quest for therapies for delayed healing and nonunion

Abaloparatide, a PTH receptor agonist with homology to PTHrP, enhances callus bridging and biomechanical properties in rats with femoral fracture

The role of peptides in bone healing and regeneration: a systematic review

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