Exploratory meta-analysis on dose-related efficacy and morbidity of bone morphogenetic protein in spinal arthrodesis surgery

Abstract

<jats:sec> <jats:title>OBJECT</jats:title> <jats:p>Bone morphogenetic protein (BMP) is frequently used for spinal arthrodesis procedures in an “off-label” fashion. Whereas complications related to BMP usage are well recognized, the role of dosage is less clear. The objective of this meta-analysis was to assess dose-dependent effectiveness (i.e., bone fusion) and morbidity of BMP used in common spinal arthrodesis procedures. A quantitative exploratory meta-analysis was conducted on studies reporting fusion and complication rates following anterior cervical discectomy and fusion (ACDF), posterior cervical fusion (PCF), anterior lumbar interbody fusion (ALIF), transforaminal lumbar interbody fusion (TLIF), posterior lumbar interbody fusion (PLIF), and posterolateral lumbar fusion (PLF) supplemented with BMP.</jats:p></jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>A literature search was performed to identify studies on BMP in spinal fusion procedures reporting fusion and/or complication rates. From the included studies, a database for each spinal fusion procedure, including patient demographic information, dose of BMP per level, and data regarding fusion rate and complication rates, was created. The incidence of fusion and complication rates was calculated and analyzed as a function of BMP dose. The methodological quality of all included studies was assessed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Data were analyzed using a random-effects model. Event rates are shown as percentages, with a 95% CI.</jats:p></jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>Forty-eight articles met the inclusion criteria: ACDF (n = 7), PCF (n = 6), ALIF (n = 9), TLIF/PLIF (n = 17), and PLF (n = 9), resulting in a total of 5890 patients. In ACDF, the lowest BMP concentration analyzed (0.2–0.6 mg/level) resulted in a fusion rate similar to the highest dose (1.1–2.1 mg/level), while permitting complication rates comparable to ACDF performed without BMP. The addition of BMP to multilevel constructs significantly (p &lt; 0.001) increased the fusion rate (98.4% [CI 95.4%–99.4%]) versus the control group fusion rate (85.8% [CI 77.4%–91.4%]). Studies on PCF were of poor quality and suggest that BMP doses of ≤ 2.1 mg/level resulted in similar fusion rates as higher doses. Use of BMP in ALIF increased fusion rates from 79.1% (CI 57.6%–91.3%) in the control cohort to 96.9% (CI 92.3%–98.8%) in the BMP-treated group (p &lt; 0.01). The rate of complications showed a positive correlation with the BMP dose used. Use of BMP in TLIF had only a minimal impact on fusion rates (95.0% [CI 92.8%–96.5%] vs 93.0% [CI 78.1%–98.0%] in control patients). In PLF, use of ≥ 8.5 mg BMP per level led to a significant increase of fusion rate (95.2%; CI 90.1%–97.8%) compared with the control group (75.3%; CI 64.1%–84.0%, p &lt; 0.001). BMP did not alter the rate of complications when used in PLF.</jats:p></jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p>The BMP doses used for various spinal arthrodesis procedures differed greatly between studies. This study provides BMP dosing recommendations for the most common spine procedures.</jats:p></jats:sec>

IL-6 potentiates BMP-2-induced osteogenesis and adipogenesis via two different BMPR1A-mediated pathways

“…While high doses of rhBMP-2 lead to a promising bone formation yield, these doses do not benefit clinical outcomes and cause a significant increase in complication rates 4 – 6 . Thus, increasing concerns regarding the efficacy and safety profile of high doses of rhBMP-2 in clinical practice remain a challenging clinical problem 7 – 9 .…”

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

“…Although clinical findings appertaining to the use of BMP-2 in spinal fusion are fairly impressive, the success of the procedure is often overshadowed by the manifestation of severe undesired side effects, which can seriously impair the health and the musculoskeletal functions of the treated patient (Faundez et al, 2016;James et al, 2016). These include ectopic bone formation, paralysis and neurological disturbances (Hofstetter et al, 2016;Vavken et al, 2015) [but not malignant pathologies (Cahill et al, 2015;Malham et al, 2015)]. …”

“…The recommended dosage is exceedingly high [e.g. 12 mg/ACS (absorbable collagen sponge), 7.5 cm × 10 cm × 0.4 cm, 0.322 g; this corresponds to 37.3 mg of BMP-2/g of ACS], and it is thus more than conceivable that therein lies the trigger for many of the untoward side effects (Benglis et al, 2008;Hofstetter et al, 2016). Many growth factors, including BMP-2, are known to act pleiomorphically.…”

BMP and Beyond: A 25-Year Historical Review of Translational Spine Research at Emory University

“…More recently, two separate metaanalyses assessing the dose-dependent fusion rate when rhBMP-2/ACS is used in two or more level anterior cervical discectomy with fusions (ACDFs), ALIFs, transforaminal lumbar interbody fusions (TLIFs), and posterolateral fusions were performed 30,31) . Both studies concluded that rhBMP-2 is indicated in ACDFs with two or more levels and in posterolateral fusions, but not in TLIFs.…”