Abundant heterotopic bone formation following use of rhBMP-2 in the treatment of acetabular bone defects during revision hip arthroplasty

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Abstract

Revision hip arthroplasty in the setting of periacetabular bone loss presents a significant challenge, as options for restoring bone loss are limited. Recombinant human bone morphogenetic protein-2 may offer a solution by promoting bone growth to restore bone stock before implant reimplantation. Here we present a case of a patient with a periprosthetic acetabulum fracture, resulting in pelvic discontinuity as the result of significant periacetabular bone loss. Using a staged approach, periacetabular bone stock was nearly entirely reconstituted using recombinant BMPs and allograft, which resulted in stable fixation, but with abundant heterotopic bone formation. Recombinant BMP-2 offers a useful tool for restoring bone stock in complex hip arthroplasty revision cases with periacetabular bone loss; however, caution must be used as overabundant bone growth as heterotopic ossification may result.

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

Eugene J Carragee, Eric L Hurwitz, Bradley K Weiner (2011)

Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases. Systematic review. Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses. There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2-associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy. Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications. Copyright © 2011 Elsevier Inc. All rights reserved.

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Novel regulators of bone formation: molecular clones and activities.

J Wozney, R Kriz, R Hewick … (1988)

Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.

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Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing.

Tae-Joon Cho, Louis C Gerstenfeld, Thomas A Einhorn (2002)

Fracture healing is a unique postnatal repair process in which the events of endochondral and intramembranous bone formation follow a definable temporal sequence. The temporal patterns of messenger RNA (mRNA) expression for members of the transforming growth factor beta (TGF-beta) superfamily were examined over a 28-day period of fracture healing in mouse tibias. Bone morphogenetic protein 2 (BMP-2) and growth and differentiation factor 8 (GDF8) showed maximal expression on day 1 after fracture, suggesting their roles as early response genes in the cascade of healing events. Restricted expression of GDF8 to day 1, in light of its known actions as a negative regulator of skeletal muscle growth, suggests that it may similarly regulate cell differentiation early in the fracture healing process. GDF5, TGF-beta2, and TGF-beta3 showed maximal expression on day 7, when type II collagen expression peaked during cartilage formation. In contrast, BMP-3, BMP-4, BMP-7, and BMP-8 showed a restricted period of expression from day 14 through day 21, when the resorption of calcified cartilage and osteoblastic recruitment were most active. TGF-beta1, BMP-5 and BMP-6, and GDF10 were constitutively expressed from day 3 to day 21. However, during the same time period, GDF3, GDF6, and GDF9 could not be detected, and GDF1 was expressed at extremely low levels. These findings suggest that several members of the TGF-beta superfamily are actively involved in fracture healing and although they are closely related both structurally and functionally, each has a distinct temporal expression pattern and potentially unique role in fracture healing.

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Author and article information

Contributors

Alexander Arzeno

Journal

Journal ID (nlm-ta): Arthroplast Today

Journal ID (iso-abbrev): Arthroplast Today

Title: Arthroplasty Today

Publisher: Elsevier

ISSN (Electronic): 2352-3441

Publication date PMC-release: 12 January 2018

Publication date Collection: June 2018

Publication date (Electronic): 12 January 2018

Volume: 4

Issue: 2

Pages: 162-168

Affiliations

[1]Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, CA, USA

Author notes

[∗ ]Corresponding author. 300 Pasteur Drive Rm HC 435, Stanford, CA 94305, USA. Tel.: +1 650 723 5948. aarzeno@ 123456stanford.edu

Article

Publisher ID: S2352-3441(17)30180-2

DOI: 10.1016/j.artd.2017.12.004

PMC ID: 5994604

PubMed ID: 29896546

SO-VID: 126d70d0-dd6d-4712-855d-920bb30853c9

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 26 August 2017

Date revision received : 12 December 2017

Date accepted : 13 December 2017

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Abundant heterotopic bone formation following use of rhBMP-2 in the treatment of acetabular bone defects during revision hip arthroplasty

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Karger: Ophthalmology

Most cited references 69

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

Novel regulators of bone formation: molecular clones and activities.

Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing.

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