Heterotopic ossification as a side effect of the use of recombinant human bone morphogenetic proteins

Abstract

Introduction Heterotopic ossification (HO), also known as myositis ossification, paraosteoarthropathy, or heterotopic calcification, among others, is a common pathological condition that refers to ectopic bone formation in soft tissues. Although the molecular mechanism of HO is not fully understood, it is believed that signaling of bone morphogenetic proteins (BMPs) plays a key role in the overall process of HO. Today, recombinant human BMP-2 (rhBMP-2) and recombinant human BMP-7 (rhBMP-7) have been already actively used in clinical practice in the treatment of bone defects. However, despite the positive sides of using rhBMPs, there are a number of side effects, one of which is HO. Purpose In this study, we demonstrate cases of HO following the use of rhBMPs in both clinical and preclinical studies and make an attempt to explain the relationship between the signaling pathways of BMPs and the HO process, as well as the possibilities of preventing and treating the HO process. Materials and methods PubMed, Embase, the Cochrane Database, and Google Scholar were comprehensively searched for original articles, literature reviews, case reports, and meta-analyses demonstrating a causal relationship between therapeutic rhBMPs and HO as a complication. Results This review analyzes the potential for therapeutic use of rhBMPs in neurosurgery and traumatology and orthopedics, demonstrated by both clinical and preclinical studies. In particular, the studies confirm that ectopic bone formation is one of the side effects following administration of rhBMPs. Moreover, the molecular mechanisms of the HO process were highlighted, and the possibilities of modern methods of prevention and treatment of HO were discussed. Conclusion According to the FDA safety database for rhBMPs, the rates of adverse effects related to HO range from 1 % to 10 %. However, to date, the clinical use of rhBMPs is justified, especially when there are no alternative substitutes for bone grafting.

Functions of the bone morphogenetic protein signaling pathway through non-coding RNAs

“…BMPs stimulate the formation of new blood vessels and promote migration, proliferation, and differentiation of mesenchymal stem cells (MSCs) into chondroblasts and osteoblasts. BMP-2, -4, -6, -7 and -9 have the most pronounced osteogenic properties [ 1 , 2 ].…”

“…There are two types of BMPs receptors on the cell membrane. The activin type I receptors (Act-RI), including Act-RIA and Act-RIB, and activin type II receptors (Act-RII), including Act-RIIA and Act-RIIB [ 1 , 2 ]. Both types of receptors are indispensable for the formation of a functional complex that initiates subsequent signaling cascades.…”