A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned

Carragee, Eugene J.; Hurwitz, Eric L.; Weiner, Bradley K.

doi:10.1016/j.spinee.2011.04.023

Cited by 1,235 publications

(977 citation statements)

References 72 publications

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“…[ 12 ] Previously BMP-2 has been applied in supraphysiological doses for adequate bone regeneration. [ 13 ] An implanted scaffold can act as a foreign material and the protein interactions at their surface are crucial for the nature of the host response toward it. [ 14 ] An implanted scaffold initiates a series of events similar to a foreign body reaction, starting with an acute infl ammatory response and leading in some cases to a chronic infl ammatory response and/or granulation tissue development, a foreign body reaction and fi brous capsule development.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Host Response and Degradation of Copolymer Scaffolds Functionalized with Nanodiamonds and Bone Morphogenetic Protein 2

Suliman

Sun

Pedersen

et al. 2016

Adv Healthcare Materials

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The aim is to evaluate the effect of modifying poly[( L -lactide)-co-(ε-caprolactone)] scaffolds (PLCL) with nanodiamonds (nDP) or with nDP+physisorbed BMP-2 (nDP+BMP-2) on in vivo host tissue response and degradation. The scaffolds are implanted subcutaneously in Balb/c mice and retrieved after 1, 8, and 27 weeks. Molecular weight analysis shows that modifi ed scaffolds degrade faster than the unmodifi ed. Gene analysis at week 1 shows highest expression of proinfl ammatory markers around nDP scaffolds; although the presence of infl ammatory cells and foreign body giant cells is more prominent around the PLCL. Tissue regeneration markers are highly expressed in the nDP+BMP-2 scaffolds at week 8. A fi brous capsule is detectable by week 8, thinnest around nDP scaffolds and at week 27 thickest around PLCL scaffolds. mRNA levels of ALP, COL1α2, and ANGPT1 are signifi cantly upregulating in the nDP+BMP-2 scaffolds at week 1 with ectopic bone seen at week 8. Even when almost 90% of the scaffold is degraded at week 27, nDP are observable at implantation areas without adverse effects. In conclusion, modifying PLCL scaffolds with nDP does not aggravate the host response and physisorbed BMP-2 delivery attenuates infl ammation while lowering the dose of BMP-2 to a relatively safe and economical level.

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Section: Introductionmentioning

confidence: 99%

In Vivo Host Response and Degradation of Copolymer Scaffolds Functionalized with Nanodiamonds and Bone Morphogenetic Protein 2

Suliman

Sun

Pedersen

et al. 2016

Adv Healthcare Materials

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“…Recent studies have also raised safety concerns with protein therapies, (9)(10)(11) including osteolysis, ectopic bone growth, wound complications, and urogenital events. (10) The full extent and frequency of complications associated with rhBMPs is still under investigation. The reasons for this are currently unclear but may be associated with the exceedingly high protein concentrations required to maintain a therapeutic response.…”

Section: J Jbmrmentioning

confidence: 99%

Realizing the potential of gene-based molecular therapies in bone repair

Rose

Uludağ

2013

Journal of Bone and Mineral Research

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A better understanding of osteogenesis at genetic and biochemical levels is yielding new molecular entities that can modulate bone regeneration and potentially act as novel therapies in a clinical setting. These new entities are motivating alternative approaches for bone repair by utilizing DNA-derived expression systems, as well as RNA-based regulatory molecules controlling the fate of cells involved in osteogenesis. These sophisticated mediators of osteogenesis, however, pose unique delivery challenges that are not obvious in deployment of conventional therapeutic agents. Viral and nonviral delivery systems are actively pursued in preclinical animal models to realize the potential of the gene-based medicines. This article will summarize promising bone-inducing molecular agents on the horizon as well as provide a critical review of delivery systems employed for their administration. Special attention was paid to synthetic (nonviral) delivery systems because they are more likely to be adopted for clinical testing because of safety considerations. We present a comparative analysis of dose-response relationships, as well as pharmacokinetic and pharmacodynamic features of various approaches, with the purpose of clearly defining the current frontier in the field. We conclude with the authors' perspective on the future of genebased therapy of bone defects, articulating promising research avenues to advance the field of clinical bone repair. © 2013 American Society for Bone and Mineral Research. KEY WORDS: OSTEOGENESIS; BIOENGINEERING; MOLECULAR PATHWAYS; GENE-BASED THERAPYClinical Need for New Bone-Regeneration Strategies N early 2.2 million bone grafts are performed worldwide annually (1) and up to 20% of fractures are hampered by impaired healing. (2) The economic impact of nonunions is enormous, with the cost of spinal fusions alone reaching $20 billion annually. (3) The gold standard for repair of large segmental defects remains autologous grafts, where bone harvested from a non-weight-bearing site, usually the iliac crest, is used to repair defects. Bone grafts, however, are limited in several aspects, including potency of the grafts and the physiological detriment resulting from harvest surgery. Allografts are alternatively employed, where donor tissue is used to repair the defect, but the risk of disease transmission is always a concern. Allografts are extensively processed to reduce this risk, but osteopotency of the graft could be decreased in this way. (4) Demineralized bone matrix derived from decalcified bone can similarly act as a substitute; its potency, however, is variable and depends on the processing conditions. Synthetic scaffolds have been used to provide a hospitable environment for new bone formation. Scaffolds have been constructed from the organic (collagen) and inorganic (hydroxyapatite [HA]) components of bone, but such scaffolds are incapable of inducing osteogenesis on their own and they are more suitable for smaller defects.Osteogenic proteins are frequently employed to render ost...

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“…More recently, there has been significant controversy regarding the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) augmenting spinal fusion, leading to hostile interchanges between protagonists and antagonists both in the scientific literature [11][12][13][14] and in the lay media.…”

Section: The Hypementioning

confidence: 99%

Antibiotics a cure for back pain, a false dawn or a new era?

O’Dowd

Casey

2013

Eur Spine J

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The recent publication in this journal of papers by Albert and colleagues [1,2] from Denmark suggesting that low grade anaerobic bacterial infection may be the underlying cause of significant persistent chronic back pain in a welldefined group of patients has precipitated an unprecedented response in the medical and lay media. In the midst of claim and counterclaim, these studies represent a significant and substantial change in our understanding of the pathophysiology of back pain in some patient groups, and the importance of this should not be lost amidst the negative, unstructured and unscientific response to this study. The factsThe story starts in 2001 with the publication of a research letter in the Lancet by a group from Birmingham [3] demonstrating that 31 % of patients with sciatica tested positive to a newly developed serological test, which diagnosed deep-seated infections caused by virulent Grampositive microorganisms. In addition, intervertebral disc material excised during microdiscectomy in a different group of patients, which was cultured in a specialist anaerobic environment, had positive cultures after longterm incubation in 53 % of patients and of this group 84 % grew Propionibacterium acnes.Following the ISSLS 2006 meeting, a collaboration developed between the Birmingham group and the group from Southern Denmark. This led to publication of a pilot study in 2008 [4] where 32 chronic low back pain patients with Modic type 1 endplate changes and a previous lumbar herniated disc were treated with amoxicillin and clavulanate for 90 days. In this uncontrolled trial, there was a clinically important and statistically significant difference in outcome at 10-month follow-up following antibiotic treatment.In the meantime, the evidence was accumulating about the significant correlation between Modic endplate changes and back pain. Albert and Manniche [5] identified a strong association between Modic changes and non-specific low back pain, a stronger association with Modic type 1 than type 2, and that a lumbar disc herniation is a strong risk factor for developing Modic changes, especially type 1, during the following year and that these changes are strongly associated with low back pain.A systematic review from Southern Denmark in 2008 [6] identified the prevalence of vertebral endplate signal changes as 43 % in patients with non-specific low back pain and/or sciatica, and 6 % in a non-clinical population, demonstrating that endplate changes are associated with pain. A further systematic review in the same year from Shanghai [7] identified two possible pathophysiological mechanisms for Modic changes-one biomechanical and one biochemical. A biomechanical pathway for development of Modic changes was supported by a large population MRI scan study in 2011 [8].Against this background two key papers were then published in this journal in 2013. In one study [2] Albert and colleagues established a strong relationship between

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A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned

Cited by 1,235 publications

References 72 publications

In Vivo Host Response and Degradation of Copolymer Scaffolds Functionalized with Nanodiamonds and Bone Morphogenetic Protein 2

In Vivo Host Response and Degradation of Copolymer Scaffolds Functionalized with Nanodiamonds and Bone Morphogenetic Protein 2

Realizing the potential of gene-based molecular therapies in bone repair

Antibiotics a cure for back pain, a false dawn or a new era?

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