The Journal of Bone & Joint Surgery

The Journal of Bone & Joint Surgery, Volume 91, Issue 5

Scientific Articles | May 01, 2009

Six-Year Outcomes of Anterior Lumbar Interbody Arthrodesis with Use of Interbody Fusion Cages and Recombinant Human Bone Morphogenetic Protein-2

J. Kenneth Burkus, MD¹; Matthew F. Gornet, MD²; Thomas C. Schuler, MD³; Thomas J. Kleeman, MD⁴; Thomas A. Zdeblick, MD⁵

¹ The Hughston Clinic, 6262 Veterans Parkway, Columbus, GA 31908. E-mail address: JKB66@knology.net
² Spine Research Center, 14825 North Outer Forty Road, Suite 320, St. Louis, MO 63017
³ Virginia Spine Institute, 1831 Wiehle Avenue, Reston, VA 20190
⁴ New Hampshire NeuroSpine Institute, 4 Hawthorne Drive, Bedford, NH 03110
⁵ Department of Orthopedics and Rehabilitation, University of Wisconsin, 600 Highland Avenue, Suite K3705, Madison, WI 53792

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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from Medtronic Sofamor Danek. In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 or a commitment or agreement to provide such benefits from a commercial entity (Medtronic Sofamor Danek). No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Investigation performed at the Hughston Clinic, Columbus, Georgia; the Spine Research Center, St. Louis, Missouri; the Virginia Spine Institute, Reston, Virginia; the New Hampshire NeuroSpine Institute, Bedford, New Hampshire; and the Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, Wisconsin

The Journal of Bone and Joint Surgery, Inc.

J Bone Joint Surg Am, 2009 May 01;91(5):1181-1189. doi: 10.2106/JBJS.G.01485

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Abstract

Background: Twenty-four-month outcomes have been reported for patients with degenerative lumbar disc disease who were treated with stand-alone anterior lumbar interbody arthrodesis with use of dual tapered interbody fusion cages and recombinant human bone morphogenetic protein-2. This report represents an update of the clinical and radiographic results of this treatment at six years.

Methods: Two hundred and seventy-seven patients with single-level degenerative disc disease with up to grade-I spondylolisthesis were enrolled in two prospective, multicenter, U.S. Food and Drug Administration-approved investigational device exemption studies and were treated with an open or a laparoscopic surgical procedure. The patients received recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge with lumbar fusion cage implants. One hundred and forty-six patients completed the six-year clinical follow-up evaluations, and 130 patients had complete radiographic follow-up at six years. Outcomes were determined with use of well-established clinical outcome measurements (Oswestry Disability Index, Short Form-36, and back and leg pain scores) and radiographic assessments.

Results: At six years, 128 (98%) of the 130 patients treated with recombinant human bone morphogenetic protein-2 and stand-alone fusion cages had a fusion. The second surgery rate was 6.7% (eighteen patients) prior to two years and 3.7% (seven patients) from two to six years. A worst-case scenario analysis, which includes all second surgical procedures due to pseudarthrosis, resulted in a fusion rate at seventy-two months of 91% (128 of 141). Significant improvements in the Oswestry Disability Index scores, Short Form-36 health survey physical component summary scores, and back and leg pain scores were achieved by six weeks in both the open and laparoscopic groups and were sustained at six years (p < 0.001). The percentage of patients who were working at six months (63%) was higher than the percentage who had been working preoperatively (52%), and this improvement was sustained at six years (68%).

Conclusions: The use of dual tapered threaded fusion cages and recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge obtained and maintained intervertebral spinal fusion, improved clinical outcomes, and reduced pain after anterior lumbar interbody arthrodesis in patients with degenerative lumbar disc disease.

Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Figures in this Article

Introduction

Introduction | Materials and Methods | Results | Discussion | References

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is an osteoinductive growth factor that stimulates pluripotential cells to form bone. In animal and human studies, rhBMP-2 on an absorbable collagen sponge (rhBMP-2/ACS) has been shown to be capable of inducing new bone formation^1,2. At twenty-four months of follow-up in randomized clinical trials, the use of rhBMP-2 as an iliac crest bone graft replacement has been shown to increase fusion rates in patients undergoing anterior lumbar interbody arthrodesis, and its use has been associated with decreased pain and improved clinical outcomes^3-5. When used in combination with a lumbar tapered fusion device, rhBMP-2/ACS resulted in significantly higher fusion rates than iliac crest bone graft (94.4% compared with 89.4%; p = 0.022)⁶. Additional studies of rhBMP-2 on an absorbable collagen sponge in patients undergoing lumbar interbody arthrodesis have shown similar rates of successful fusion^3-5,7-14.

The current study was undertaken to determine the long-term safety and efficacy of the use of stand-alone interbody fusion cages and rhBMP-2/ACS as an iliac crest bone graft replacement. The fusion rates and clinical outcomes of the patients in the present study were determined at six years and were compared with the outcomes at two years^4-6,15.

Materials and Methods

Introduction | Materials and Methods | Results | Discussion | References

Two prospective, multicenter U.S. Food and Drug Administration (FDA)-approved investigational device exemption studies of patients undergoing treatment for single-level lumbar degenerative disc disease were conducted, with use of a similar arthrodesis technique through two different surgical approaches^4,15. All patients were entered into these studies inclusively from 1997 to 1999 and were treated with INFUSE Bone Graft and the LT-CAGE Device (Medtronic Sofamor Danek, Memphis, Tennessee). These studies used identical inclusion and exclusion criteria; however, the laparoscopic cohort was a nonrandomized, single-arm study, whereas the patients in the open study were randomized to receive either rhBMP-2/ACS or iliac crest bone graft. At the time of surgery, the patients ranged in age from nineteen to seventy years. They had symptomatic degenerative disc disease at the L4-L5 or L5-S1 levels and low-back pain that was recalcitrant to nonoperative treatment modalities, such as physical therapy, bed rest, and anti-inflammatory medications, for at least six months before surgery. Patients were included in the study if the plain radiographic findings documented single-level disc disease, and they had undergone at least one additional confirmatory neuroradiographic study, such as magnetic resonance imaging, computed tomography-enhanced myelography, or discography. All patients were considered candidates for a single-level anterior lumbar interbody arthrodesis. Patients were excluded from the study if they had a spinal condition other than single-level symptomatic degenerative disc disease or greater than grade-I (<25%) spondylolisthesis. Other exclusion criteria were symptomatic disc disease at a level other than L4-L5 or L5-S1, obesity (>40% above ideal body weight), or a medical condition that required medication, such as corticosteroids or nonsteroidal anti-inflammatory medications, that could interfere with fusion.

The two studies were conducted to evaluate the efficacy of rhBMP-2/ACS as a replacement for iliac crest bone graft and were not designed to compare the open and laparoscopic surgical approaches directly. In this prospective study, patients were followed for six years to determine their long-term radiographic and clinical outcomes. Institutional review board approval was obtained, and all patients enrolled in the follow-up studies provided informed consent.

Patient Follow-up

A total of 277 patients were enrolled at thirty-one sites in the initial FDA investigational device exemption studies: 143 were in the open surgery arm and 134 were in the laparoscopic surgery arm. As a condition of market approval, the FDA requested that a postapproval study be conducted to obtain six years of postoperative data from a statistically justified number of patients. All investigational sites received protocols and were invited, but not required, to participate in the six-year follow-up postapproval study. Of the thirty-one initial sites, twenty-three elected to participate in the long-term follow-up. Seven sites declined participation, and one site was not eligible for inclusion in the postapproval study. Additionally, patients who were classified as having a second surgery failure (secondary lumbar surgical procedures performed subsequent to the index operation that involved the index level regardless of the radiographic findings) prior to two years were not followed for six years and were excluded from this study.

As a result of second surgery failures prior to two years and nonparticipating sites, fifty-five patients were excluded from this study, leaving 222 patients who were eligible for the FDA investigational device exemption postapproval follow-up assessments (112 in the open surgery arm and 110 in the laparoscopic surgery arm). One hundred and forty-six patients completed the seventy-two-month follow-up assessments. The numbers of patients at the two and six-year follow-up intervals are shown in Table I. This subgroup of patients was examined to determine the clinical outcome measures and fusion status at each time point and to evaluate clinical and radiographic outcomes from two to six years.

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TABLE I Patients Available for Follow-up at Two and Six Years

	Open	Laparoscopic
Total no. of patients treated	143	134
Patients seen at follow-up at =2 yr
No. who died	0	0
No. who had second surgery failures	9	9
No. seen at nonparticipating sites	22	15
Total no. available at 2 yr	112	110
Patients seen at follow-up of >2 yr
No. who died	2	0
No. who had second surgery failures	7	0
Total no. available at 6 yr	103	110
No. not evaluated	25	42
Total no. evaluated at 6 yr	78	68

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TABLE I Patients Available for Follow-up at Two and Six Years

	Open	Laparoscopic
Total no. of patients treated	143	134
Patients seen at follow-up at =2 yr
No. who died	0	0
No. who had second surgery failures	9	9
No. seen at nonparticipating sites	22	15
Total no. available at 2 yr	112	110
Patients seen at follow-up of >2 yr
No. who died	2	0
No. who had second surgery failures	7	0
Total no. available at 6 yr	103	110
No. not evaluated	25	42
Total no. evaluated at 6 yr	78	68

Surgical Procedures

Patients underwent an anterior lumbar interbody arthrodesis with use of either an open⁴ or a laparoscopic approach¹⁵, and had two LT-CAGE devices implanted at either the L4-L5 or L5-S1 lumbar interspace.

RhBMP-2/ACS was used exclusively as an iliac crest bone graft replacement^4,15. The rhBMP-2 was reconstituted to a concentration of 1.5 mg/mL and was bound to the absorbable collagen sponge for a minimum of fifteen minutes, which resulted in 95% of the protein being bound to the sponge¹⁶. The total dose of rhBMP-2 ranged from 4.2 to 8 mg and was determined by matching the volume of the prepared collagen sponge to the internal volume of the fusion cage.

The results from the studies with use of the two surgical approaches were pooled and analyzed independently to better define the effects of the surgical approach on the surgical parameters, hospital stay, and the long-term clinical and radiographic outcomes.

Clinical Outcome Measures

Clinical outcome measures, including the Oswestry Disability Index¹⁷, the Medical Outcomes Study 36-item Short-Form health survey (SF-36) questionnaire^18,19, as well as back and leg pain and return-to-work status questionnaires, were self-administered preoperatively and at six weeks and three, six, twelve, twenty-four, forty-eight, and seventy-two months postoperatively. Back and leg pain scores were determined with use of a 20-point scale (10 points for frequency and 10 points for intensity). The scale was designed such that a reduction in the pain score by half corresponds to a patient reporting that he or she had half as much pain.

Radiographic Assessment

Plain radiographs (lateral, anteroposterior, and flexion-extension views) and thin-cut computed tomography scans with sagittal and coronal reconstructions were used to assess the status of the fusion^4,5. Two independent blinded radiologists interpreted the radiographs and computed tomography scans, with a third radiologist available for adjudication. Fusion was defined as bridging bone connecting the adjacent vertebral bodies either through the implants or around the implants, <5° of angular motion, =3 mm of translation, and an absence of radiolucent lines around >50% of either implant. Secondary lumbar surgical procedures performed subsequent to the index operation because of a suspected nonunion, regardless of the radiographic findings, were classified as second surgery failures and fusion failures⁴. Second surgeries performed for reasons other than pseudarthrosis were defined as second surgery failures only because these reasons were independent of bone formation and fusion. Fusion was assessed at six, twelve, twenty-four, forty-eight, and seventy-two months and was considered successful only if all criteria were achieved.

Additional Surgical Procedures

Revisions, removals, supplemental fixations, or reoperations performed subsequent to the index operation were classified as second surgical procedures. Second surgeries that occurred as a result of adjacent-level disease but involved the index level were also classified as second surgical procedures. A survivorship analysis was used to determine the percentage of patients who were classified as having a second surgical procedure, taking into account all available patients at each follow-up time point.

Adverse Events

Adverse events were classified as to their severity and relationship with the implants and with surgical procedures.

Statistical Analysis

For assessing the significance of postoperative improvement in outcome scores from preoperative values within each treatment group, a paired t test was used. For statistical comparisons of differences between the open and laparoscopic treatment groups, analysis of variance was used for continuous variables and the Fisher exact test was used for categorical data.

Source of Funding

Medtronic Sofamor Danek sponsored this FDA-approved investigational device exemption clinical trial. The authors are consultants and clinical investigators for the company distributing the device studied.

Results

Introduction | Materials and Methods | Results | Discussion | References

Patient Follow-up

One hundred and forty-six patients (sixty-eight in the laparoscopic group and seventy-eight in the open group) were available for six-year follow-up and had radiographic or clinical outcome data, or both. The overall follow-up rate was 52.7% (146 of 277 patients), and the follow-up rate at six years was 65.8% (146 of 222 patients). The subset of patients who were available for follow-up at six years had similar demographic data and twenty-four-month outcomes compared with those previously reported for the entire group of patients (see Clinical Outcomes section below)^4,5.

Demographic data were compiled for the patients included in the analysis (Table II). The open and laparoscopic surgical groups were enrolled in separate FDA investigational device exemption studies at different study sites and were not randomized relative to each other; however, the demographic characteristics and prognostic factors in these two groups were similar except with regard to the sex of the patients and alcohol use.

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TABLE II Demographic Data on the Patients

Variable	Open	Laparoscopic	Combined
No. of patients	78	68	146
Mean age (yr)	43.1	43.3	43.2
Mean weight (kg)	82.1	78.3	80.4
Male patients*(%)	56.4	38.2	47.9
Patients who used tobacco (%)	26.9	27.9	27.4
Patients receiving Workers' Compensation (%)	30.8	25.0	28.1
Patients with pending litigation (%)	10.3	10.3	10.3
Patients who used alcohol†(%)	21.8	54.4	37.0

A significant difference was detected between the groups (p < 0.05).A significant difference was detected between the groups (p < 0.001).

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TABLE II Demographic Data on the Patients

Variable	Open	Laparoscopic	Combined
No. of patients	78	68	146
Mean age (yr)	43.1	43.3	43.2
Mean weight (kg)	82.1	78.3	80.4
Male patients*(%)	56.4	38.2	47.9
Patients who used tobacco (%)	26.9	27.9	27.4
Patients receiving Workers' Compensation (%)	30.8	25.0	28.1
Patients with pending litigation (%)	10.3	10.3	10.3
Patients who used alcohol†(%)	21.8	54.4	37.0

A significant difference was detected between the groups (p < 0.05).A significant difference was detected between the groups (p < 0.001).

Surgical Data

The laparoscopic group spent an average of eighteen minutes longer under anesthesia, lost an average of 7.3 mL more blood, and left the hospital an average of 1.7 days earlier than the open group.

Clinical Outcomes

Oswestry Disability Index

By six weeks, the Oswestry Disability Index scores had improved significantly from the preoperative scores in both groups individually and in combination, and these improvements were maintained at six years (p < 0.001) (Table III and Fig. 1). For the open group, the Oswestry Disability Index scores improved an average of 32.8 points and 27.7 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 53.8 points. For the laparoscopic group, the Oswestry Disability Index scores improved an average of 34.4 points and 34.3 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 49.8 points. These improvements were similar to those seen at twenty-four months (31.0 points for the open group and 32.6 points for the laparoscopic group).

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Fig. 1: Comparison of the open and laparoscopic (Lap) groups with regard to the Oswestry Disability Index scores, which improved from the preoperative scores in both groups individually and with the data combined. These improvements were maintained at six years.

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TABLE III Clinical Outcomes Scores

	Preoperative			1 Yr			2 Yr			4 Yr	6 Yr
	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients
Oswestry Disability Index*
Open	53.8 (13.5)	78	22.7 (16.9)	75	22.8 (18.7)	77	20.6 (19.2)	48	25.8 (19.3)	70
Laparoscopic	49.8 (10.4)	68	17.0 (17.7)	66	17.6 (20.1)	61	14.3 (18.2)	55	15.5 (18.9)	68
Combined	52.0 (12.3)	146	20.1 (17.5)	141	20.5 (19.4)	138	17.2 (18.9)	103	20.7 (19.7)	138
Back Pain*
Open	15.3 (3.9)	78	7.0 (5.7)	74	6.6 (6.0)	77	7.4 (6.5)	47	8.4 (6.3)	69
Laparoscopic	15.6 (3.6)	68	5.8 (5.8)	66	5.6 (6.1)	61	4.9 (5.6)	55	5.4 (5.9)	68
Combined	15.4 (3.7)	146	6.4 (5.8)	140	6.1 (6.1)	138	6.0 (6.1)	102	6.9 (6.3)	137
Leg Pain*
Open	13.4 (5.0)	78	5.9 (6.2)	74	6.1 (6.2)	77	6.1 (6.3)	47	6.6 (6.4)	69
Laparoscopic	9.6 (6.5)	68	4.2 (5.5)	66	4.4 (5.7)	61	3.5 (5.6)	55	3.1 (4.6)	67
Combined	11.6 (6.0)	146	5.1 (5.9)	140	5.3 (6.0)	138	4.7 (6.0)	102	4.8 (5.9)	136
SF-36 physical component score*
Open	27.1 (5.7)	77	42.6 (11.0)	76	43.5 (11.9)	77	41.9 (12.8)	48	39.7 (12.6)	70
Laparoscopic	28.7 (6.1)	68	45.5 (11.4)	66	45.4 (12.3)	60	47.5 (11.9)	55	46.5 (11.6)	68
Combined	27.9 (5.9)	145	44.0 (11.3)	142	44.4 (12.1)	137	44.9 (12.6)	103	43.1 (12.6)	138

Clinical outcomes measures improved significantly from preoperative values by six weeks, and these improvements were maintained at each time point out to six years (p < 0.001). Outcomes at forty-eight and seventy-two months were not significantly different from the outcomes at twenty-four months.

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TABLE III Clinical Outcomes Scores

	Preoperative			1 Yr			2 Yr			4 Yr	6 Yr
	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients	Mean Score (Standard Deviation)	No. of Patients
Oswestry Disability Index*
Open	53.8 (13.5)	78	22.7 (16.9)	75	22.8 (18.7)	77	20.6 (19.2)	48	25.8 (19.3)	70
Laparoscopic	49.8 (10.4)	68	17.0 (17.7)	66	17.6 (20.1)	61	14.3 (18.2)	55	15.5 (18.9)	68
Combined	52.0 (12.3)	146	20.1 (17.5)	141	20.5 (19.4)	138	17.2 (18.9)	103	20.7 (19.7)	138
Back Pain*
Open	15.3 (3.9)	78	7.0 (5.7)	74	6.6 (6.0)	77	7.4 (6.5)	47	8.4 (6.3)	69
Laparoscopic	15.6 (3.6)	68	5.8 (5.8)	66	5.6 (6.1)	61	4.9 (5.6)	55	5.4 (5.9)	68
Combined	15.4 (3.7)	146	6.4 (5.8)	140	6.1 (6.1)	138	6.0 (6.1)	102	6.9 (6.3)	137
Leg Pain*
Open	13.4 (5.0)	78	5.9 (6.2)	74	6.1 (6.2)	77	6.1 (6.3)	47	6.6 (6.4)	69
Laparoscopic	9.6 (6.5)	68	4.2 (5.5)	66	4.4 (5.7)	61	3.5 (5.6)	55	3.1 (4.6)	67
Combined	11.6 (6.0)	146	5.1 (5.9)	140	5.3 (6.0)	138	4.7 (6.0)	102	4.8 (5.9)	136
SF-36 physical component score*
Open	27.1 (5.7)	77	42.6 (11.0)	76	43.5 (11.9)	77	41.9 (12.8)	48	39.7 (12.6)	70
Laparoscopic	28.7 (6.1)	68	45.5 (11.4)	66	45.4 (12.3)	60	47.5 (11.9)	55	46.5 (11.6)	68
Combined	27.9 (5.9)	145	44.0 (11.3)	142	44.4 (12.1)	137	44.9 (12.6)	103	43.1 (12.6)	138

Back Pain

By six weeks, the back pain scores had improved significantly from the preoperative values in both groups individually and in combination, and these improvements were maintained at six years (p < 0.001, Table III). For the open group, back pain scores improved an average of 7.7 points and 6.9 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 15.3 points. For the laparoscopic group, the back pain scores improved an average of 10.6 points and 10.2 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 15.6 points. These improvements were similar to those seen at twenty-four months (8.7 points for the open group and 10.1 points for the laparoscopic group).

Leg Pain

By six weeks, the leg pain scores had improved significantly from the preoperative values in both groups individually and in combination, and these improvements were maintained at six years (p < 0.001) (Table III). For the open group, the leg pain scores improved an average of 7.0 points and 6.8 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 13.4 points. For the laparoscopic group, the leg pain scores improved an average of 5.8 points and 6.6 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 9.6 points. These improvements were similar to those seen at twenty-four months (7.3 points for the open group and 5.2 points for the laparoscopic group).

Short Form-36 (SF-36)

By six weeks, the SF-36 physical component summary scores had improved significantly from the preoperative scores in both groups, and these improvements were maintained at six years (p < 0.001) (Table III). For the open group, the SF-36 physical component summary score improved an average of 15.3 points and 12.4 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 27.1 points. For the laparoscopic group, the SF-36 physical component summary scores improved an average of 19.1 points and 17.8 points at forty-eight and seventy-two months, respectively, from an average preoperative score of 28.7 points. These improvements were similar to those seen at twenty-four months (16.3 points for the open group and 17.5 points for the laparoscopic group). Additional SF-36 outcomes are presented in Table IV.

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TABLE IV Change in SF-36 Scores from the Preoperative Evaluation to the Seventy-two-Month Follow-up

	Open*	Laparoscopic*	Combined*
Physical component score	12.4 (12.6)†	17.8 (10.2)	15.1 (11.7)†
Mental component score	4.9 (13.2)	7.3 (10.2)	6.1 (11.8)
Physical function	31.5 (30.4)†	42.8 (26.8)	37.0 (29.1)†
Role-physical	50.7 (46.2)	64.3 (43.0)	57.4 (45.0)
Pain index	34.8 (27.6)†	43.9 (25.8)	39.3 (27.0)
General health perception	-8.3 (27.0)†‡	5.0 (17.3)	-1.7 (23.6)†‡
Social function	29.8 (31.7)†	41.2 (27.7)	35.4 (30.2)
Mental health	15.8 (23.5)	16.4 (20.1)	16.1 (21.8)
Role-emotional	10.1 (52.5)†‡	26.0 (40.7)	18.0 (47.5)
Vitality	18.8 (24.6)†	27.1 (23.0)	22.9 (24.1)

The values are given as the mean with the standard deviation in parentheses.The changes in SF-36 scores from twenty-four months to seventy-two months were significant (p < 0.05).All scores, except for general health perception and role-emotional, improved significantly (p = 0.019) from the preoperative evaluation to the seventy-two month evaluation.

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TABLE IV Change in SF-36 Scores from the Preoperative Evaluation to the Seventy-two-Month Follow-up

	Open*	Laparoscopic*	Combined*
Physical component score	12.4 (12.6)†	17.8 (10.2)	15.1 (11.7)†
Mental component score	4.9 (13.2)	7.3 (10.2)	6.1 (11.8)
Physical function	31.5 (30.4)†	42.8 (26.8)	37.0 (29.1)†
Role-physical	50.7 (46.2)	64.3 (43.0)	57.4 (45.0)
Pain index	34.8 (27.6)†	43.9 (25.8)	39.3 (27.0)
General health perception	-8.3 (27.0)†‡	5.0 (17.3)	-1.7 (23.6)†‡
Social function	29.8 (31.7)†	41.2 (27.7)	35.4 (30.2)
Mental health	15.8 (23.5)	16.4 (20.1)	16.1 (21.8)
Role-emotional	10.1 (52.5)†‡	26.0 (40.7)	18.0 (47.5)
Vitality	18.8 (24.6)†	27.1 (23.0)	22.9 (24.1)

Radiographic Outcomes

At seventy-two months, a complete radiographic examination had been done for 130 (89%) of 146 patients who were available for follow-up and for 130 (46.9%) of all 277 patients enrolled in both the open and laparoscopic groups (Figs. 2-A through 2-D). At forty-eight and seventy-two months, 98% (ninety-two) of ninety-four patients and 98% (128) of 130 patients included in this analysis had radiographic evidence of fusion (Fig. 3). The high rates of fusion seen at these later time points were similar to the rates of fusion seen at six, twelve, and twenty-four months. The fusion rates were similar between the open and laparoscopic groups. The first and second radiologist reviewers agreed 94.3% to 100% of the time for the study groups at the follow-up intervals.

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Fig. 2-A Fig. 2-B: Figs. 2-A through 2-D Preoperative and postoperative images of a patient in the study. Fig. 2-A The preoperative lateral radiograph shows disc-space narrowing at L5-S1, posterior radial osteophyte formation, and retrolisthesis of L5 on S1. The L4-L5 disc has a normal height, physiologic segmental lordosis, and no radial osteophytes. Fig. 2-B A lateral radiograph, made six weeks after surgery, shows the dual tapered interbody fusion cages in the L5-S1 disc space. Physiologic disc-space height and normal sagittal contours have been restored at L5-S1.

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Fig. 2-C Fig. 2-D: Fig. 2-C A lateral radiograph, made seventy-two months postoperatively, shows new bone formation spanning the L5-S1 disc space anterior to the cages. There has been no subsidence of the cages. The disc-space height and sagittal contours have been maintained. The L4-L5 disc shows no radiographic evidence of adjacent segment degeneration. Fig. 2-D A sagittal computed tomography scan, made seventy-two months after surgery, shows continuous trabecular bone formation through the interbody fusion cage spanning the L5-S1 interspace.

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Fig. 3: Comparison of radiographic fusion success between the open and laparoscopic (Lap) groups. At seventy-two months, 128 (98%) of 130 patients with complete radiographic follow-up had evidence of fusion.

In an effort to determine a worst-case scenario for fusion success, all second surgery failures due to pseudarthrosis were carried forward for the entire 277 patients enrolled in the investigational device exemption studies. We believe this analysis introduces bias and results in artificially low fusion rates in this cohort because all of the failures, regardless of participation in the postapproval study, were carried forward. This report includes only the subset of patients with greater than two years of follow-up; thus, fusion successes from nonparticipating patients and sites were not counted in the calculations. With use of this analysis, fusion rates at forty-eight and seventy-two months would be 88% (ninety-two of 104 patients) and 91% (128 of 141 patients), respectively.

Second Surgical Procedures

To better determine the overall failure rate for the procedure, any second surgery that occurred during the six years of follow-up was reported. This included all 277 patients enrolled in the investigational device exemption studies as well as the 146 who were followed for six years. A total of twenty-five second surgical procedures were performed over the six-year follow-up period: sixteen were in the open group and nine were in the laparoscopic group. There were twenty-three supplemental fixations, one cage removal, and one revision. The reasons for second surgeries (implant positioning, migration or loosening, nonunion, suspected nonunion, subsidence, stenosis, radiculopathy, adjacent segment degeneration, and postlaminectomy syndrome) were reported by the enrolling surgeon. Cage removal was necessitated in one patient because of anterior placement of the implant at the time of the index surgical procedure. Second surgical procedures occurred from five days to sixty-two months after the index surgery.

Adjusting for the patients available at each follow-up interval by a time-to-event analysis, the overall second surgery rate was 10.4% (13.7% in the open group and 7.1% in the laparoscopic group) (Fig. 4). Eighteen of the twenty-five second surgeries occurred before two years, and the second surgery rate during this time period was 6.7% for the combined group (6.4% for the open group and 7.1% for the laparoscopic group)^4,5. The remaining seven second surgeries occurred from two to six years, and the rate of second surgery for the combined group during this time was 3.7% (7.3% for the open group and 0% for the laparoscopic group). All seven of the procedures were supplemental fixations, and investigators reported suspected nonunion (two patients), back pain (two patients), stenosis (two patients), and postlaminectomy syndrome (one patient) as the causes for reoperation. Three of the second surgeries involved only the index level, and the remaining four included both the index and an adjacent level.

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Fig. 4: Comparison of second surgical procedures between the open and laparoscopic groups. Over the six-year follow-up interval, the overall second surgery rate was 10.4% (13.7% in the open group and 7.1% in the laparoscopic [Lap] group).

Return-to-Work Status

At forty-eight and seventy-two months, more patients were working than had been working before surgery (69% [seventy-two] of 104 patients and 68% [ninety-four] of 138 patients at forty-eight and seventy-two months, respectively, compared with 52% [seventy-six] of 146 patients preoperatively). The percentage of patients working at the later time points was similar to that at twenty-four months (70%). By six months, 63% of the patients and approximately 90% of the patients who had been working preoperatively had returned to work, and this rate was maintained through the seventy-two-month time point.

Adverse Events

Relevant adverse events are shown in Table V, and all adverse events in these categories occurred prior to two years of follow-up. Technical difficulty occurred only in the laparoscopic surgical group during the laparoscopic exposure of the lumbosacral spine and involved an inability to adequately mobilize the great vessels anterior to the disc space and insert two appropriately sized interbody fusion cages. Seven of the nine events resulted in a conversion to an open anterior (five patients) or instrumented posterolateral (two patients) arthrodesis procedure. If only one cage was inserted in the disc space, a posterior stabilization was carried out. Subsidence occurred in seven patients, with all events occurring within the first six months. Of the twenty-five patients listed in Table V, seven patients had a second surgical procedure.

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TABLE V Patients Who Had Adverse Events Occurring Before Two Years and Between Two and Six Years

	Events at =2 Yr*			Events at >2 Yr and <6 Yr
Adverse Event	Open (N = 143)	Laparoscopic (N = 134)	Open (N = 78)	Laparoscopic (N = 68)
Anatomical and/or technical difficulty	0	9	0	0
Malpositioned implant	1	4 (2)	0	0
Implant displacement and/or loosening	2 (1)	2	0	0
Subsidence	6 (4)	1	0	0

The numbers in parentheses represent the number of patients within the adverse event category who had a second surgical procedure.

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TABLE V Patients Who Had Adverse Events Occurring Before Two Years and Between Two and Six Years

	Events at =2 Yr*			Events at >2 Yr and <6 Yr
Adverse Event	Open (N = 143)	Laparoscopic (N = 134)	Open (N = 78)	Laparoscopic (N = 68)
Anatomical and/or technical difficulty	0	9	0	0
Malpositioned implant	1	4 (2)	0	0
Implant displacement and/or loosening	2 (1)	2	0	0
Subsidence	6 (4)	1	0	0

The numbers in parentheses represent the number of patients within the adverse event category who had a second surgical procedure.

Discussion

Introduction | Materials and Methods | Results | Discussion | References

This study represents what we believe is the longest follow-up to date of patients undergoing spinal fusion with INFUSE Bone Graft (recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge)^4-15. In the patients with six years of follow-up, the observed radiographic fusion rates were high, the rates of second surgery were low, and improvements in clinical outcomes were maintained. In our study, 79% (109) of 138 patients treated with INFUSE Bone Graft had an improvement in the Oswestry Disability Index score of >15 points at six years. Radiographic fusion success at six years was 98% (128) for the 130 patients included in this analysis and 91% (128) of 141 patients in a worst-case analysis. Over the six-year follow-up period, the second surgery rate for the procedure was 10.4% (twenty-five patients). These outcomes compare favorably with those previously reported in the literature for patients undergoing lumbar arthrodesis^20-25.

An observation in our study was that patients treated by the laparoscopic surgical technique tended to have shortened hospital stays (p = 0.128), fewer reoperations (p = 0.194), and greater improvement in the Oswestry Disability Index scores (p = 0.102), SF-36 physical component summary scores (p = 0.085), and low-back pain scores (p = 0.598) at six years compared with the open surgical group. This study was not designed to compare the open and laparoscopic surgical approaches, however, and there are likely a number of confounding factors that may have contributed to this observation. Whether the trends in these outcomes are of clinical importance is a point of debate, as the minimally important clinical differences reported in the literature are variable¹⁷.

The improvement we found in functional outcomes is maintained at six years after treatment with rhBMP-2 and is also reflected in the high rates of employment in both the open and laparoscopic groups. In particular, the high rate of segmental fusion may serve to provide long-term maintenance of these significant improvements in clinical outcomes²⁶.

Weaknesses of this study include an overall follow-up rate of 52.7%, which has the potential to introduce bias and impact the long-term results. Additionally, the study did not follow patients who received iliac crest bone graft; therefore, comparison with a control could not be performed.

In conclusion, the use of rhBMP-2 on an absorbable collagen sponge is an effective method of obtaining anterior intervertebral spinal fusion with use of a stand-alone interbody fusion device. In this long-term study, treatment with INFUSE Bone Graft and threaded titanium cages was shown to lead to high rates of fusion that were maintained at six years after urgery, and significant improvements in clinical outcome measures were maintained. Image Not Available

References

Introduction | Materials and Methods | Results | Discussion | References

Boden SD, Martin GJ Jr, Horton WC, Truss TL, Sandhu HS. Laparoscopic anterior spinal arthrodesis with rhBMP-2 in a titanium interbody threaded cage. J Spinal Disord.1998;11:95-101.1195 1998 [PubMed]

Hecht BP, Fischgrund JS, Herkowitz HN, Penman L, Toth JM, Shirkhoda A. The use of recombinant human bone morphogenetic protein 2 (rhBMP-2) to promote spinal fusion in a nonhuman primate anterior interbody fusion model. Spine.1999;24:629-36.24629 1999 [CrossRef]

Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine.2000;25:376-81.25376 2000 [CrossRef]

Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech.2002;15:337-49.15337 2002 [CrossRef]

Burkus JK, Sandhu HS, Gornet MF, Longley MC. Use of rhBMP-2 in combination with structural cortical allografts: clinical and radiographic outcomes in anterior lumbar spinal surgery. J Bone Joint Surg Am.2005;87:1205-12.871205 2005 [CrossRef]

Burkus JK, Heim SE, Gornet MF, Zdeblick TA. Is INFUSE bone graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device. J Spinal Disord Tech.2003;16:113-22.16113 2003 [CrossRef]

Anand N, Hamilton JF, Perri B, Miraliakbar H, Goldstein T. Cantilever TLIF with structural allograft and RhBMP2 for correction and maintenance of segmental sagittal lordosis: long-term clinical, radiographic, and functional outcome. Spine.2006;31:E748-53.31E748 2006 [CrossRef]

Kuklo TR, Rosner MK, Polly DW Jr. Computerized tomography evaluation of a resorbable implant after transforaminal lumbar interbody fusion. Neurosurg Focus.2004;16:E10.16E10 2004

Lanman TH, Hopkins TJ. Lumbar interbody fusion after treatment with recombinant human bone morphogenetic protein-2 added to poly(L-lactide-co-D,L-lactide) bioresorbable implants. Neurosurg Focus.2004;16:E9.16E9 2004

Mummaneni PV, Pan J, Haid RW, Rodts GE. Contribution of recombinant human bone morphogenetic protein-2 to the rapid creation of interbody fusion when used in transforaminal lumbar interbody fusion: a preliminary report. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2004. J Neurosurg Spine.2004;1:19-23.119 2004 [CrossRef]

Potter BK, Freedman BA, Verwiebe EG, Hall JM, Polly DW Jr, Kuklo TR. Transforaminal lumbar interbody fusion: clinical and radiographic results and complications in 100 consecutive patients. J Spinal Disord Tech.2005;18:337-46.18337 2005 [CrossRef]

Schwender JD, Holly LT, Rouben DP, Foley KT. Minimally invasive transforaminal lumbar interbody fusion (TLIF): technical feasibility and initial results. J Spinal Disord Tech.2005;18 Suppl:S1-6.18S1 2005 [CrossRef]

Slosar PJ, Josey R, Reynolds J. Accelerating lumbar fusions by combining rhBMP-2 with allograft bone: a prospective analysis of interbody fusion rates and clinical outcomes. Spine J.2007;7:301-7.7301 2007 [CrossRef]

Villavicencio AT, Burneikiene S, Nelson EL, Bulsara KR, Favors M, Thramann J. Safety of transforaminal lumbar interbody fusion and intervertebral recombinant human bone morphogenetic protein-2. J Neurosurg Spine.2005;3:436-43.3436 2005 [CrossRef]

Kleeman TJ, Ahn UM, Talbot-Kleeman A. Laparoscopic anterior lumbar interbody fusion with rhBMP-2: a prospective study of clinical and radiographic outcomes. Spine.2001;26:2751-6.262751 2001 [CrossRef]

Hsu HP, Zanella JM, Peckham SM, Spector M. Comparing ectopic bone growth induced by rhBMP-2 on an absorbable collagen sponge in rat and rabbit models. J Orthop Res.2006;24:1660-9.241660 2006 [CrossRef]

Fairbank JC, Couper J, Davies JB, O'Brien JP. The Oswestry low back pain disability questionnaire. Physiotherapy.1980;66:271-3.66271 1980

McHorney CA, Ware JE Jr, Lu JF, Sherbourne CD. The MOS 36-item Short-Form Health Survey (SF-36): III. Tests of data quality, scaling assumptions, and reliability across diverse patient groups. Med Care.1994;32:40-66.3240 1994 [CrossRef]

Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care.1992;30:473-83.30473 1992 [CrossRef]

Bagby G. The Bagby and Kuslich (BAK) method of lumbar interbody fusion. Spine.1999;24:1857.241857 1999 [CrossRef]

Brantigan JW, Neidre A, Toohey JS. The Lumbar I/F Cage for posterior lumbar interbody fusion with the variable screw placement system: 10-year results of a Food and Drug Administration clinical trial. Spine J.2004;4:681-8.4681 2004 [CrossRef]

Button G, Gupta M, Barrett C, Cammack P, Benson D. Three- to six-year follow-up of stand-alone BAK cages implanted by a single surgeon. Spine J.2005;5:155-60.5155 2005 [CrossRef]

Kuslich SD, Danielson G, Dowdle JD, Sherman J, Fredrickson B, Yuan H, Griffith SL. Four-year follow-up results of lumbar spine arthrodesis using the Bagby and Kuslich lumbar fusion cage. Spine.2000;25:2656-62.252656 2000 [CrossRef]

Kuslich SD, Ulstrom CL, Griffith SL, Ahern JW, Dowdle JD. The Bagby and Kuslich method of lumbar interbody fusion. History, techniques, and 2-year follow-up results of a United States prospective, multicenter trial. Spine.1998;23:1267-79.231267 1998 [CrossRef]

Martin BI, Mirza SK, Comstock BA, Gray DT, Kreuter W, Deyo RA. Are lumbar spine reoperation rates falling with greater use of fusion surgery and new surgical technology? Spine.2007;32:2119-26.322119 2007 [CrossRef]

Kornblum MB, Fischgrund JS, Herkowitz HN, Abraham DA, Berkower DL, Ditkoff JS. Degenerative lumbar spondylolisthesis with spinal stenosis: a prospective long-term study comparing fusion and pseudarthrosis. Spine.2004;29:726-34.29726 2004 [CrossRef]

Topics

back pain ; bone transplantation ; laparoscopy ; pain ; surgical sponges ; lower limb pain ; spinal cage ; oswestry disability index ; sf-36 ; adverse event

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J. Kenneth Burkus, MD

Posted on May 18, 2010

Dr. Burkus and colleagues respond to Dr. Smoljanovic and colleagues

The Hughston Clinic, Columbus, Georgia

Our paper (1) presented the long-term INFUSE/LT-CAGE outcomes data collected from 277 patients: data from 143 rhBMP-2 patients treated via an open approach who were enrolled in a randomized controlled trial (RCT) (2) and data from 134 rhBMP-2 patients treated via a laparoscopic approach who were enrolled in a concurrent, non-randomized, single-arm, prospective trial. In total, as reported to the FDA labeling (3), there were 288 rhBMP - 2 patients and 139 control iliac crest bone graft (ICBG) patients enrolled in these 2 trials plus an additional 11 rhBMP-2-treated patients and 3 ICBG patients from a pilot study (4). In the FDA labeling cohort of patients, 11 retrograde ejaculation (RE) events were listed in the rhBMP-2 group, and 1 RE event was in the ICBG control group. Four important points must be made:

1. There is no relationship between the use of rhBMP-2 in stand-alone interbody fusion cages and the postoperative development of retrograde ejaculation (RE).

In the prospective RCT comparing the use of rhBMP-2 with autograft, the RE rates were 6.4% (5/78) and 1.5% (1/68) in male patients, respectively. These are not significantly different on the basis of treatment (Fisherâ€™s exact test, p = 0.216). Previous reports in the literature and experience have established that the laparoscopic (transperitoneal) technique increases the risk of RE (5-10). It is, therefore, not surprising that the rates of RE would be increased when a non-randomized group of 134 patients treated laproscopically was included.

In a more recent RCT (11), rhBMP-2 with the LT-CAGE device was used as the control group and compared with an investigational artificial lumbar disc. All surgeries were performed through an open approach. RE was observed in 2.3% (2/86) of male patients who received the rhBMP-2 treatment compared with 2.0% (4/205) of male patients, who received the lumbar disc treatment. The rates were similar (p = 1.000), which further confirms that there is no relationship between the application of the rhBMP-2 treatment and RE occurrence.

2. There is no relationship between the use of rhBMP-2 and the late development of RE.

There were no new RE events reported during the follow-up assessments between 12 months and 72 months. In a 2003 publication (5), the use of transperitoneal approach to the lumbosacral spine was established as a predisposing factor in the development of RE, not the use of rhBMP-2. This conclusion is also widely supported in the literature (6-10). In the Sasso publication (5), RE symptoms resolved in 2 of the 6 patients. Overall, the RE events were resolved in 5 of the 11 patients, while still ongoing in the 6 other patients when they were last seen at 48 months (2 patients) or 72 months (4 patients).

3. Late RE is not associated with anterior lumbar bone formation.

Local, exuberant bone formation posterior to the disc space may cause neurologic compression. The spinal canal is a closed area bounded by the pedicles, facet joints, lamina and soft tissues. In contrast, the retroperitoneal space anterior to the disc is not a closed area. Radial osteophytes commonly occur in degenerative lumbar spondylosis. Posterior neurologic compromise from the development of radial osteophytes commonly results in neurogenic claudication and lumbar radiculopathies. Retrograde ejaculation has never been reported following the development of anterior osteophytes.

4. There is no clinical evidence of significant anterior bone formation in this series.

Dr. Smoljanovicâ€™s comment refers to a figure from a 2000 pilot study (4), which shows that the cages are placed flush with the anterior cortex of the vertebral bodies. The cages are not recessed within the disc space. There is a thin, shallow rim of bone covering the cages and not extending into the soft tissues of the retroperitoneal space. New bone formation commonly occurs within 1 -2 mm of cages filled with rhBMP-2. This is not ectopic bone formation.

Radiographic reviewers did not assess anterior bone formation in the studies. Treating physicians identified no symptoms related to anterior bone formation. There were no reoperations or reported complications from anterior bone formation. The senior author reviewed the radiographs and CT scans for all 11 patients with RE complaints. Two patients had both cages recessed more than 3 mm inside the disc space; 2 patients had cages prominently placed anterior to disc space; and 7 patients had cages placed flush with anterior cortical margins of the disc space. Five of the 11 patients had a thin shell of new formation covering the cages. None showed any bone extending into the soft tissues.

References

1. Burkus JK, Gornet MF, Schuler TC, Kleeman TJ, Zdeblick TA. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am. 2009;91:1181-9.

2. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002;15:337-49.

3. United States Food and Drug Administration, Department of Health and Human Services, Center for Devices and Radiological Health. InFUSEâ„¢ Bone Graft/LT-CAGEâ„¢ Lumbar Tapered Fusion Devices - P000058. July 2, 2002. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=P000058. Accessed 2010 May 21.

4. Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976). 2000;25:376-81.

5. Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976). 2003;28:1023-6.

6. Birch N, Shaw M. Retrograde ejaculation after anterior lumbar interbody fusion. Spine (Phila Pa 1976). 2004;29:106-7.

7. Lu S, Xu YQ, Chang S, Zhang YZ, Shi JH, Ding ZH, Li ZH, Zhong SZ. Clinical anatomy study of autonomic nerve with respective to the anterior approach lumbar surgery. Surg Radiol Anat. 2009;31:425-30.

8. Escobar E, Transfeldt E, Garvey T, Ogilvie J, Graber J, Schultz L. Video-assisted versus open anterior lumbar spine fusion surgery: a comparison of four techniques and complications in 135 patients. Spine (Phila Pa 1976). 2003;28:729-32.

9. Inamasu J, Guiot BH. Laparoscopic anterior lumbar interbody fusion: a review of outcome studies. Minim Invasive Neurosurg. 2005;48:340-7.

10. Kaiser MG, Haid RW Jr, Subach BR, Miller JS, Smith CD, Rodts GE Jr. Comparison of the mini-open versus laparoscopic approach for anterior lumbar interbody fusion: a retrospective review. Neurosurgery. 2002;51:97-105.

11. Gornet MF, Burkus JK, Mathews HH, Dryer RF, Peloza J. Maverickâ„¢ total disc replacement versus anterior lumbar interbody fusion with the INFUSEÂ® Bone Graft /LT-CAGEÂ® Device: a prospective, randomized, controlled, multicenter IDE trial [abstract]. Spine J. 2007;7:1S.

Tomislav Smoljanovic, MD, PhD

Posted on April 10, 2010

Retrograde Ejaculation and Ectopic Bone Formation Following Labeled Use of rhBMP-2

Clinical Hospital Center Zagreb, School of Medicine, Zagreb University, Zagreb, Croatia

To the Editor:

As a condition for market approval of InFUSE ^TM Bone Graft/LT-CAGE ^TM Lumbar Tapered Fusion Device (Medtronic Sofamor Danek, Inc., Memphis, TN, U.S.) (1), the U.S. Food and Drug Administration (FDA) required that a postapproval study be conducted to obtain six years postoperative data from patients enrolled in the initial FDA investigational device exemption (IDE) studies (2,3). Long-term safety and efficacy data in this population, all of whom underwent single level anterior lumbar interbody fusion (ALIF) assisted with stand-alone interbody fusion cages and recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge (rhBMP-2/ACS), was published by Burkus et al. in 2009 (4). A total of 277 InFUSE ^TM patients were enrolled at 31 sites: 143 were in the open surgery arm and 134 were in the laparoscopic surgery arm. The Burkus et al. 2009 report provides 72-month follow-up data on 146 (70 males) of the 277 patient enrolled in the study.

Data posted at the FDAâ€™s web site indicates that retrograde ejaculation developed postoperatively in 11 patients (7.9% of 140 male patients) from the rhBMP-2/ACS IDE group, but in only one patient (1.4% of 70 male patients) from the autologous iliac crest bone graft group (AICBG) (1).

In 2003 Sasso, Burkus et al., without providing the incidence data reported by the FDA, attributed the onset of retrograde ejaculations in the IDE population to surgical technique (5). However, in addition to demonstrating 7.9% (rhBMP-2) to 1.4% (AICBG) disparity in the incidence of retrograde ejaculation, the FDAâ€™s reporting of IDE data shows that retrograde ejaculation in some IDE patients was first reported from 9 up to 19 months postoperatively (1). Wong et al. have shown that an adherence of the neural structures to an ectopic bone has caused neurologic compromise up to 12 months after posterior interbody fusions assisted with rhBMP/ACS (6). Furthermore, Chen et al. have recently presented cases of delayed neural compression following rhBMP-2 use for TLIF (23 to 51 months after rhBMP-2 application) (7).

As the superior hypogastric plexus (which provides innervation to the internal vesical sphincter) resides in the retroperitoneal space overlying the lumbosacral junction, it is possible that rhBMP-2 related ectopic bone formation could eventually compromise that plexus, prompting delayed onset retrograde ejaculation. We understand that Burkus et al. reported that although progressive ossification was observed anterior to the implants (2,3), no ectopic bone formation outside the annular confines of the disc space was observed (2). However, a close look at Figure 1 in the article which reported the rhBMP-2 FDA sanctioned pilot study reveals that there was bone formation anterior to the instrumented disc space (8).

Although the IDE data at FDAâ€™s website reports that 11 rhBMP-2 patients (7.9% of 140 male patients) developed retrograde ejaculation, Burkus et al.â€™s 6 year follow-up does not mention a single patient with permanent retrograde ejaculation, nor does the follow up study mention ectopic bone formation anterior to the instrumented disc spaces (4).

We are interested in the authorsâ€™ experiences with respect to several issues. What happened to the 11 rhBMP-2 IDE patients who developed retrograde ejaculation, per the FDA data base? Were any of them included in Burkus et al.â€™s follow up? How many patients had ectopic bone formation anterior to the instrumented disc space? How many rhBMP-2 IDE patients had late onset retrograde ejaculation?

The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

References

1. United States Food and Drug Administration, Department of Health and Human Services, Center for Devices and Radiological Health. InFUSEâ„¢ Bone Graft/LT-CAGEâ„¢ Lumbar Tapered Fusion Devices - P000058. 2002 Jul 2. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cftopic/pma/pma.cfm?num=P000058. Accessed 2010 Jan 31.

2. Burkus JK, Gornet MF, Dickman CA, Zdeblick TA. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. J Spinal Disord Tech. 2002;15:337-49.

3. Kleeman TJ, Ahn UM, Talbot-Kleeman A. Laparoscopic anterior lumbar interbody fusion with rhBMP-2: a prospective study of clinical and radiographic outcomes. Spine (Phila Pa 1976). 2001;26:2751-6.

4. Burkus JK, Gornet MF, Schuler TC, Kleeman TJ, Zdeblick TA. Six-year outcomes of anterior lumbar interbody arthrodesis with use of interbody fusion cages and recombinant human bone morphogenetic protein-2. J Bone Joint Surg Am. 2009;91:1181-9.

5. Sasso RC, Burkus JK, LeHuec JC. Retrograde ejaculation after anterior lumbar interbody fusion: transperitoneal versus retroperitoneal exposure. Spine (Phila Pa 1976). 2003;28:1023-6.

6. Wong DA, Kumar A, Jatana S, Ghiselli G, Wong K. Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J. 2008;8:1011-8.

7. Chen NF, Smith ZA, Stiner E, Armin S, Sheikh H, Khoo LT. Symptomatic ectopic bone formation after off-label use of recombinant human bone morphogenetic protein-2 in transforaminal lumbar interbody fusion. J Neurosurg Spine. 2010;12:40-6.

8. Boden SD, Zdeblick TA, Sandhu HS, Heim SE. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976). 2000;25:376-81.

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J. Kenneth Burkus, Matthew F. Gornet, Thomas C. Schuler, Thomas J. Kleeman, Thomas A. Zdeblick; Six-Year Outcomes of Anterior Lumbar Interbody Arthrodesis with Use of Interbody Fusion Cages and Recombinant Human Bone Morphogenetic Protein-2. The Journal of Bone & Joint Surgery. 2009 May;91(5):1181-1189.

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