Scientific publications for cranial & spinal technologies
| Article title | The Use of Bone Morphogenetic Protein in the Intervertebral Disk Space in Minimally Invasive Transforaminal Lumbar Interbody Fusion: 10-year Experience in 688 Patients |
| Authors | White IK, Tuohy M, Archer J, Schroeder GD, Vaccaro AR, Mobasser JP. |
| Journal | Clinical Spine Surgery |
| Published date | July 2019 |
| Medtronic summary | This publication describes an IRB approved, retrospective, single surgeon cohort of consecutive patients undergoing minimally invasive transforaminal lumbar interbody fusion (MISTLIF) in which recombinant human bone morphogenetic protein-2 (rhBMP-2) was placed in the intervertebral disc space. This application of Infuse™ Bone Graft (multi-level fusion, graft placed anterior to cage, with a posterior approach) constitutes use outside of approved labeling in the United States and safety and effectiveness for this unapproved use has not been established. The study covered procedures from 2004–2014 and sought to (1) describe fusion and complication outcomes and (2) explore whether rhBMP-2 dose per level was associated with those outcomes. Computed tomography (CT) at 9–12 months was used to assess fusion, with ≥18 months of clinical follow up. Prespecified safety reviews captured reoperations for symptomatic pseudoarthrosis and for foraminal hyperostosis; records were also reviewed for seroma and osteolysis requiring reoperation. Dose groups were 8.4 mg/level (“medium kit,” used earlier) versus 4.2 mg/level (“small kit,” used later). Notably, in 2006 the surgeon adopted fully navigated instrumentation; fusion technique otherwise remained constant (time/technique change may confound dose comparisons). A total of 688 patients (single‑level = 462; two‑level = 226) underwent MIS‑TLIF, encompassing 914 levels. rhBMP‑2 dose by period was medium in 97 patients and small in 591 patients. The overall CT‑confirmed fusion rate was 97.9%; fusion did not differ by dose (96/97 medium vs 577/591 small; P = 0.40). There were 5 reoperations for symptomatic pseudoarthrosis; 10 additional radiographic pseudoarthrosis did not require reoperation. Foraminal hyperostosis requiring reoperation occurred in 4/97 (4.12%) medium‑dose patients and 0/591 (0%) small‑dose patients (P = 0.0004); while not observed in the small‑dose cohort, a zero count implies an approximate 95% upper confidence bound ≈ 0.5% (rule‑of‑three). No reoperations for seroma or osteolysis were observed in either dose group. Analyses were primarily unadjusted between‑group comparisons (t‑tests). Conclusion: In this single surgeon MIS TLIF series, disc space rhBMP-2 was associated with high CT confirmed fusion and low reoperation for nonunion. A cohort specific association between higher rhBMP-2 dose and foraminal hyperostosis was observed, whereas fusion rates were similar across doses. These findings are observational, not causal, and interpretation should consider key limitations. Additional Considerations: This unadjusted, retrospective, single surgeon/single center analysis coincided with a 2006 shift in both rhBMP-2 dose (8.4 mg → 4.2 mg per level) and technique (fluoroscopy → navigation), so any difference in hyperostosis rates cannot be attributed to dose alone and the findings should be interpreted as observational rather than causal. Although no reoperations for hyperostosis were observed among 591 small dose cases, the 95% upper confidence bound is ≈0.5% (rule of three), so risk should not be considered “eliminated”; follow up (~18 months) may miss late events, outcomes emphasized radiographic fusion rather than prespecified patient reported endpoints, multivariable adjustment was not performed, and rhBMP-2 use in TLIF is off label. Contact: CST Office of Medical Affairs |
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Disclosure:
This publication involves a use of Medtronic’s Infuse™ Bone Graft that is not approved by the U.S. Food and Drug Administration (FDA) and safety and effectiveness of Medtronic’s Infuse™ Bone Graft for the unapproved use has not been established.
Off label context. The publication evaluates rhBMP2 (Infuse™ Bone Graft) at 1- or 2-levels, placed in the intervertebral disc space (anterior to cage) during minimally invasive TLIF, which is a posterior approach; this application (multi-level, graft placed anterior to cage, with a posterior approach (TLIF)) constitutes use outside the approved labeling.
Current FDA‑approved indications & routes. Per the current IFU, Infuse™ Bone Graft is approved only as part of the Infuse™ Bone Graft/Medtronic Interbody Fusion Device for single‑level treatment of DDD from L2–S1 in skeletally mature patients after ≥6 months of non‑operative care, and only when implanted through anterior (open or laparoscopic ALIF) or oblique‑lateral (OLIF) approaches with specified Medtronic interbody devices (LT‑Cage™, Inter Fix™/Inter Fix™ RP, and certain sizes of Perimeter™, Clydesdale™, Divergence‑L™, Pivox™, and Anteralign™ LS/TL). The Instructions for Use specify that the complete device is implanted through an anterior approach (ALIF/OLIF).
Preparation & dosing guardrails. Infuse™ Bone Graft is prepared at 1.5 mg/mL rhBMP‑2 on the provided ACS; labeled dose/volume is determined by the internal volume of the indicated cages, and the IFU cautions against over‑filling or compressing the implant, which may alter concentration and lead to complications. No dose is established for TLIF, and safety and effectiveness of Infuse™ Bone Graft for this unapproved use has not been established.
Limitations of use outside labeled techniques. The IFU states that the safety and effectiveness have not been established when Infuse™ Bone Graft is used with other implants, at locations other than the lower lumbar spine, or with surgical techniques other than anterior (open/laparoscopic) or oblique‑lateral approaches—which includes posterior approaches such as TLIF/PLIF.
Risk information relevant to posterior use. The IFU notes posterior bone formation outside of the disc space has been observed when DDD is treated by a posterior lumbar interbody fusion procedure and that such ectopic/exuberant bone may compress nerves and require re‑operation; the IFU also warns that heterotopic or undesirable exuberant bone formation is a potential risk.
Anatomic limitation. Cervical use is not established; Infuse™ Bone Graft is approved only for the lumbar spine as indicated.
Infuse™ Bone Graft
Indications and risks
- In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable of crossing the placenta. Reduced ossification of the frontal and parietal bones of the skull was noted infrequently (<3%) in fetuses of rabbit dams immunized to rhBMP-2; however, there was no effect noted in limb bud development. There are no adequate and well controlled studies in human pregnant women. Women of child-bearing potential should be warned by their surgeon of potential risk to a fetus and informed of other possible orthopedic treatments.
- Women of child-bearing potential should be advised that antibody formation to rhBMP-2 or its influence on fetal development has not been completely assessed. In the clinical trial supporting the safety and effectiveness of the Infuse™ bone graft/LT-Cage™ lumbar tapered fusion device, 2/277 (0.7%) patients treated with Infuse™ bone graft component and 1/127 (0.8%) patients treated with autograft bone developed antibodies to rhBMP-2. The effect of maternal antibodies to rhBMP-2, as might be present for several months following device implantation, on the unborn fetus is unknown. Additionally, it is unknown whether fetal expression of BMP-2 could re-expose mothers who were previously antibody positive. Theoretically, re-exposure may elicit a more powerful immune response to BMP-2 with possible adverse consequences for the fetus. However, pregnancy did not lead to an increase in antibodies in the rabbit study. Studies in genetically altered mice indicate that BMP-2 is critical to fetal development and that a lack of BMP-2 activity may cause neonatal death or birth defects. It is not known if anti-BMP-2 antibodies may affect fetal development or the extent to which these antibodies may reduce BMP-2 activity.
- Infuse™ bone graft should not be used immediately prior to or during pregnancy. Women of childbearing potential should be advised not to become pregnant for one year following treatment with the Infuse™ bone graft/Medtronic interbody fusion device.
- The safety and effectiveness of the Infuse™ bone graft/Medtronic interbody fusion device in nursing mothers has not been established. It is not known if BMP-2 is excreted in human milk.
Note: the Primeter™, Clydesdale™, Divergence-L™, Pivox™, and Anteralign™ TL devices must be used with any supplemental fixation cleared for use in the lumbar spine.
Contraindications for Medtronic’s Infuse™ Bone Graft include:
- The Infuse™ Bone Graft/Medtronic Interbody Fusion Device is contraindicated for patients with a known hypersensitivity to recombinant human Bone Morphogenetic Protein-2, bovine Type I collagen, or to other components of the formulation.
- The Infuse™ Bone Graft/Medtronic Interbody Fusion Device should not be used in the vicinity of a resected or extant tumor, in patients with any active malignancy, or patients undergoing treatment for a malignancy.
- Infuse™ Bone Graft/Medtronic Interbody Fusion Device should not be used in patients who are skeletally immature (<18 years of age or no radiographic evidence of epiphyseal closure).
- The Infuse™ Bone Graft/Medtronic Interbody Fusion Device should not be used in pregnant women. The potential effects of rhBMP-2 on the human fetus have not been evaluated.
- The Infuse™ Bone Graft/Medtronic Interbody Fusion Device should not be implanted in patients with an active infection at the operative site or with an allergy to titanium, titanium alloy, or polyetheretherketone.
- Medtronic does not market its products for off-label uses and makes no representations regarding safety, effectiveness, and performance without the required market authorizations for use.
View the FDA-required labeling.
Financial Disclosures: Dr. Shroeder reported travel funds from Medtronic. Drs. Vaccaro and Mobasser reported consultant/independent contractors roles with and royalties from Medtronic.