A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2

Abstract

Bone morphogenetic protein-2 (BMP-2) is currently the only Food and Drug Administration (FDA)-approved osteoinductive growth factor used as a bone graft substitute. However, with increasing clinical use of BMP-2, a growing and well-documented side effect profile has emerged. This includes postoperative inflammation and associated adverse effects, ectopic bone formation, osteoclast-mediated bone resorption, and inappropriate adipogenesis. Several large-scale studies have confirmed the relative frequency of adverse events associated with the clinical use of BMP-2, including life-threatening cervical spine swelling. In fact, the FDA has issued a warning of the potential life-threatening complications of BMP-2. This review summarizes the known adverse effects of BMP-2, including controversial areas such as tumorigenesis. Next, select animal models that replicate BMP-2's adverse clinical effects are discussed. Finally, potential molecules to mitigate the adverse effects of BMP-2 are reviewed. In summary, BMP-2 is a potent osteoinductive cytokine that has indeed revolutionized the bone graft substitute market; however, it simultaneously has accrued a worrisome side effect profile. Better understanding of these adverse effects among both translational scientists and clinicians will help determine the most appropriate and safe use of BMP-2 in the clinical setting.

Domains with highest heparan sulfate–binding affinity reside at opposite ends in BMP2/4 versus BMP5/6/7: Implications for function

“…Given their pro-skeletogenic properties, recombinant human BMP2 and BMP7 are currently used clinically to stimulate fracture repair and spine fusion (68,69). However, because the proteins are very potent and are used in large excess over endogenous levels in these clinical conditions, they exert broad and unrestrained action and can elicit side effects, at times severe (68,69).…”

Dose reduction of bone morphogenetic protein-2 for bone regeneration using a delivery system based on lyophilization with trehalose

“…[8][9][10]34 Therefore, an appropriate delivery system for reducing the dose of BMP-2 for bone regeneration is required. Recent studies have mainly focused on organic, inorganic, and synthetic carrier scaffolds.…”

“…6,7 However, high dosages of BMP-2 increase the cost of treatment and also cause unexpected serious complications, including ectopic new bone formation, osteolysis, excessive immune responses, postoperative neurological impairment, and compromised airways. [8][9][10] Therefore, novel methods for reducing the dose of BMP-2 are needed to prevent the occurrence or reduce the severity of these adverse effects.…”

Biodegradable mesoporous delivery system for biomineralization precursors

“…6 Although bone morphogenetic protein-2 is critical for osteogenesis and bone regeneration, 7 there have been recent concerns regarding the clinical side effects associated with the use of large doses of this recombinant growth factor supplement. 8 Thus, it is desirable to develop a multifunctional scaffold supplement that is osteoinductive, biodegradable, and performs other significant bone regenerative roles apart from stimulation of osteogenic differentiation.…”