High-dose recombinant human bone morphogenetic protein-2 impacts histological and biomechanical properties of a cervical spine fusion segment: results from a sheep model

Abstract

The 'off-label' use of high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) in lumbar and cervical fusion leads to heterotopic bone formation and vertebral osteolysis. These radiographically assessed side-effects in patients were frequently associated with an over-dosage of BMP-2. However, little is so far known about the histological, functional or biomechanical tissue consequences of over-dosage of rhBMP-2 in these specific clinical situations. We hypothesized that a high dose of rhBMP-2 in cervical spinal fusion could induce substantial alterations in bone, leading to mechanical impairment. An anterior cervical spinal fusion (C3-C4 ACDF) model in 16 sheep (aged > 2.5 years; n = 8/group) was used to quantify the consequences of a high rhBMP-2 dose (6 mg rhBMP-2) on fusion tissue compared to the 'gold standard' of autologous, cancellous bone graft. The fusion site was assessed by radiography after 0, 8 and 12 weeks. Biomechanical non-destructive testing and (immuno)histological and histomorphometrical analyses were performed 12 weeks postoperatively. Although high-dose rhBMP-2 treatment led to an advanced radiological fusion result compared to autograft treatment, heterotopic bone formation and vertebral bone resorption were induced simultaneously. Histological evaluation unveiled highly active bone-forming processes ventral to the fusion segment after 12 weeks, while radiolucent areas showed still a partial loss of regular trabecular structure, with rare signs of remodelling and restoration. Despite qualitative alteration of the trabecular bone structure within the fusion site, the massive anterior heterotopic bone formation led to a substantial increase in mechanical stiffness compared to the autograft group. Copyright © 2015 John Wiley & Sons, Ltd.

The combined mechanism of bone morphogenetic protein- and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells

“…The active receptor complex resides on one of the type1 receptors: Activin Receptorlike Kinase (ALK)1, ALK2, ALK3 or ALK6 and one of the type2 receptors: BMP-receptor type 2 (BMPR2), Activin type 2 receptor (ACVR2)a or ACVR2b (Shimasaki et al, 2004). BMP ligands bind to their receptors with different affinities depending on cell type, cellular state and environment, whereas the oligomerisation mechanism determines downstream signalling activation (Gilboa et al, 2000;Hartung et al, 2006;Nohe et al, 2002). Even though research progressively unravels the complex intracellular system of BMP-signalling, limited information is available regarding the biological performance of the different BMPs on clinically relevant progenitor cells such as hPDCs.…”

“…In the clinical setting, BMP-2 and BMP-7 have been approved, but due to the design of these medicinal products, supra-physiological levels of BMPs are required, leading to side effects (Glassman et al, 2007;Graham et al, 2014;Pobloth et al, 2015;Tiedemann et al, 2001;Varga and Wrana, 2005;White et al, 2007;Wu and Hill, 2009). When…”

Optimisation of BMP-2 dosage for the osseointegration of porous titanium implants in an ovine model

“…To account for this observation, we need to look no further than at the healing of a fractured or a lesioned bone in nature. This process involves a sequence of temporally defined events, which begins with the osteolysis of fragments of pre-existing bone (analogous to the osteoclast-mediated degradation of the coating during the first 3 postoperative weeks) (LissenbergThunnissen et al,2011;Noda et al, 2009;Schell et al, 2006). Later (after 3 weeks), bone-formative activity outweighs osteolytic activity (analogous to the slower rate of osteoclast-mediated coating degradation between the 3rd and the 6th postoperative weeks).…”

“…When BMP-2 is available in a free form, which is the case if it is adsorbed onto the surface of a titanium implant, then it is liberated rapidly in a single high-dose burst, which promotes osteolysis (Nakamura et al, 2009;Nakamura et al, 2003). In clinical practice, this mode of BMP-2 delivery was hitherto (McClellan et al, 2006;Saigal et al, 2012;Singh et al, 2013), and still is, the norm (Faundez et al, 2016). A coating of calcium phosphate is in itself osteoconductive (Liu et al, 2007;Wong et al, 1995), but not osteoinductive (Liu et al, 2007).…”

“…The induced response can, however, be readily reversed by a secondary adjustment of the dosage. BMP-2 acts osteoinductively at low (ng-to-µg) concentrations (Herberg et al, 2014), and osteolytically at high ones in the mg range (Pobloth et al, 2015). Moreover, not only the concentration, but also the mode of application and the manner in which the agent is presented to the targeted population of progenitor cells can influence their response (anabolic or catabolic), as well as their differentiation pathway.…”