Overview of Treatment for Ossification of the Longitudinal Ligament and the Ligamentum Flavum

Dorn Spinal Therapy

Spine Healing Therapy

Get Instant Access

Motoki Iwasaki

Introduction

The Investigation Committee on Ossification of the Spinal Ligaments, subsidized by the Japanese Ministry of Health, Labor, and Welfare, has conducted various studies of the ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) since 1975. In 2002, the Committee established a subcommittee on clinical practice guidelines, which set out to systematically review articles on OPLL. This review, presented in this chapter, is based on knowledge obtained by that subcommittee.

For cervical myelopathy secondary to OPLL, modalities that have been applied for myelopathy due to spondylosis and disc herniation have been adopted for the most part. When strictly classifying modalities for OPLL, the treatment is either conservative or surgical; the former includes (1) a cervical orthosis and halter or skull traction that aims to avoid the effects of dynamic factors; (2) corticosteroids for spinal cord edema; (3) nonsteroidal antiinflammatory drugs (NSAIDs) for pain control; (4) bisphosphonates to prevent progression of the ossification; and (5) alternative medicine for pain control. The latter consists of spinal cord decompression by an anterior or posterior procedure and spinal stabilization.

Conservative Treatment

Studies have suggested that dynamic factors play an important role in the development of cervical myelopa-thy and radiculopathy in OPLL [1-3]. Cervical myelop-athy is recognized in all patients in whom more than 60% of the spinal canal is compromised by OPLL. On the other hand, in patients with less than 60% spinal canal stenosis, the range of motion of the cervical spine is significantly greater in patients with myelopathy

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan than those without myelopathy [2,3]. In a study of the natural history of OPLL in 207 patients, clinical symptoms did not change in 66% of patients, whereas preexisting myelopathy was aggravated in 7% [1]. In addition, a long-term follow-up cohort study of patients with OPLL reported a 71% myelopathy-free survival rate after 30 years in patients who did not have myelopathy at their first presentation [3]. These studies of the natural history of the disease indicate that dynamic factors as well as static factors play an important role in the development of myelopathy, especially with mixed- or segmental-type OPLL [1-3]. Therefore, conservative treatment of cervical OPLL is indicated to eliminate dynamic factors for patients whose predominant complaint is neck/shoulder/arm pain (local pain, radicular pain, or both) without any symptoms of myelopathy or patients with mild ossification in whom myelopathy is subclinical and not predominant. On the other hand, conservative treatment for thoracic OPLL or OLF is less effective because the thoracic spine is less mobile and has a narrower spinal canal than the cervical spine.

Conservative treatment of cervical OPLL aimed at eliminating exposure to dynamic factors includes methods such as cervical orthosis, halter traction, and skull traction using a halo ring. Although no scientific evidence supports the effectiveness of such conservative treatments, they are thought to have short-term benefits at most, and it remains unclear which conservative approach is preferable. Therefore, patients with obvious myelopathy cannot be treated adequately by nonoperative conservative treatment.

A positive head compression test is a good selection criterion for applying cervical traction [4]. When traction is indicated for patients with cervical OPLL, it is important to keep patients comfortable with the cervical spine in slight flexion. If cervical traction increases the pain, the direction of the traction should be changed or the traction stopped entirely. Cervical traction in the neck-extended position should be avoided as it risks precipitating or promoting myelopathy. Alternative medical treatments such as acupuncture, massage, and spinal manipulation are considered effective for patients whose complaints consist solely of neck/shoulder/arm pain or stiffness (or both) without any symptoms of myelopathy [5]; however, there is no scientific evidence of benefit. Physicians should also be aware that the literature contains several reports on neurological risks during spinal manipulation in patients with OPLL and spinal canal stenosis [6-8]. Therefore, patients with moderate or severe myelopathy should not be treated with spinal manipulation.

With regard to medication, NSAIDs and muscle relaxants are considered effective for local pain and stiffness. However, the only medication available for OPLL and OLF is bisphosphonate [9], which is believed to prevent OPLL progression after surgery. In practice, when symptoms and signs of myelopathy are absent or are slight and do not limit activities of daily life, conservative treatment is indicated. In particular, when patients with cervical OPLL complain mainly of neck pain, radicular pain, or both, physicians should select conservative treatment. It is important to advise patients with OPLL not to hyperextend the neck and to be vigilant regarding trauma and falls due to sports activities or excessive alcohol intake.

When disturbed circulation in and around the spinal cord is assumed to be an etiological factor for myelopa-thy, remedies that improve the circulatory condition may be applied, such as corticosteroids, recently pros-taglandin Ej (PGj), and so on. However, no evidence has been established regarding the efficacy of these drugs.

Surgical Treatment

Surgical decompression is indicated for patients who have long tract signs such as spastic gait disturbance and clumsiness of the hands. Surgical treatment is not generally recommended when the sole symptom is pain. Even among patients with myelopathy, surgical treatment is not always effective in patients whose predominant complaint is pain.

Surgical decompression of the spinal cord is necessary for patients with obvious myelopathy because long-term compression of the spinal cord may cause irreversible degeneration. For patients with symptoms and signs of moderate or severe myelopathy, early surgical decompression is recommended, particularly for relatively young patients with a narrow spinal canal, because reports indicate that better neurological recovery is associated with younger age at operation and mild myelopathy [10]. Even if the myelopathy is mild, surgery may be indicated for patients with severe spinal stenosis (SAC: space available for the spinal cord <6 mm or an occupying ratio >60%) [2,11]. During the natural course of OPLL, all patients with a SAC of <6 mm suffered myelopathy [2]. However, there is no evidence indicating the effectiveness of prophylactic surgical decompression for patients who have no or slight symptoms or signs of myelopathy [11]. Because myelopathy is often exacerbated by minor trauma and hyperextension of the neck, physicians should meticulously weigh the surgical indications, taking into consideration the occupying ratio of ossification, space available for the spinal cord, and dynamic factors [3,11].

Some controversy exists over the appropriate method of surgery for myelopathy caused by cervical OPLL. There are two surgical options: (1) an anterior procedure with extirpation or floating of the ossified lesion or (2) a posterior procedure that includes various types of expansive laminoplasty. Regarding the anterior procedure, extirpation of the ossified lesion is not always necessary, and anterior floating with thinning of the ossified lesion can work well [12,13]. Although these two procedures do not differ significantly in terms of surgical outcome [10,13], the anterior procedure is usually selected when OPLL involves fewer than three intervertebral levels, whereas the posterior procedure is usually selected when more than three levels are affected. In addition, when preoperative alignment of the cervical spine is kyphotic or the preoperative occupying ratio of ossification is relatively high, the anterior procedure with extirpation or floating of the ossified lesion can yield outcomes superior to those achieved with posterior decompression [14]. For both procedures, a poorer prognosis is associated with older age at surgery, severe preoperative symptoms of myelopathy, and a history of trauma causing onset or progression of myelopathy [10,15]. Intramedullary hyperintensity on MR imaging (T2-weighted images) reflects myelomalacia and neurological severity, although this finding does not indicate a poor outcome after decompression surgery [16].

The only surgical treatment currently available for OLF of the thoracic spine is posterior decompression. However, the surgical outcome of this procedure for myelopathy caused by thoracic OPLL has generally been poor and inferior to that of myelopathy caused by cervical OPLL. The treatment of choice for thoracic OPLL depends on the spinal level of the ossification, coexistence of OLF, and the degree of thoracic kypho-sis. The relative importance of these factors remains controversial among surgeons. For patients with OLF and thoracic OPLL, the most common choices of treatment are anterior decompression via a posterior approach, extensive cervicothoracic laminoplastic decompression, wide laminectomy with posterior instrumentation, lateral rachotomy, and combined anterior and posterior decompression [17-21].

Surgical Complications

Complications associated with the anterior procedure include graft-related complications and adjacent segment involvement after spinal fusion. On the other hand, complications associated with posterior decompression include postoperative neck/shoulder/arm pain, nerve root palsy (commonly C5), and progression of ossification, although the causes of these complications related to posterior decompression remain unclear. Regarding progression of the ossified lesion, OPLL generally continues to progress after surgery. The incidence of OPLL progression after posterior decompression is approximately 50%-60% at 2 years and 70% at 10 years or more. Younger patients (<59 years of age) and patients with mixed- or continuous-type OPLL are at higher risk for progression [10,22].

With regard to surgical complications of thoracic myelopathy due to thoracic OPLL, postoperative paraplegia is unfortunately still sometimes associated with each procedure because of technical difficulties and the vulnerability of the thoracic spinal cord. Surgical treatment of thoracic OPLL remains one of the most challenging problems for spinal surgeons.

References

1. Matsunaga S, Sakou T, Taketomi E, Yamaguchi M, Okano T (1994) The natural course of myelopathy caused by ossification of the posterior longitudinal ligament in the cervical spine. Clin Orthop Relat Res 305: 168-177

2. Matsunaga S, Kukita M, Hayashi K, Shinkura R, Koriyama C, Sakou T, Komiya S (2002) Pathogenesis of myelopathy in patients with ossification of the posterior longitudinal ligament. J Neurosurg (Spine 2) 96:168-172

3. Matsunaga S, Sakou T, Taketomi E, Komiya S (2004) Clinical course of patients with ossification of the posterior longitudinal ligament: a minimum 10-year cohort study. J Neurosurg (Spine 3) 100:245-248

4. Ohwada T, Ohkouchi T, Yamamoto T, Ono K (1998) Traction (with a cervical halter or skull tongs) and epidural steroid injection for radicular pain secondary to cervical disc hernia and spondylosis. In: Ono K, Dvorak J, Dunn E (eds) Cervical spondylosis and similar disorders. World Scientific, Singapore, pp 349-356

5. Birch S, Jamison RN (1998) Controlled trial of Japanese acupuncture for chronic myofascial neck pain: assessment of specific and nonspecific effects of treatment. Clin J Pain 14:248-255

6. Chung OM (2002) MRI confirmed cervical cord injury caused by spinal manipulation in a Chinese patient. Spinal Cord 40:196-199

7. Padua L, Padua R, LoMonaco M, Tonali PA (1996) Radic-ulomedullary complications of cervical spinal manipulation. Spinal Cord 34:488-492

8. Stevinson C, Honan W, Cooke B, Ernst E (2001) Neurological complications of cervical spine manipulation. J R Soc Med 94:107-110

9. Ono K, Yonenobu K, Sakou T, Kawai S, Nagata K (1998) Prevention of progression of ossification of the posterior longitudinal ligament (OPLL) by the administration of etidronate disodium (EHDP) after posterior decompression (in Japanese). Nippon Sekitsui Geka Gakkai Zasshi 9:432-442

10. Iwasaki M, Kawaguchi Y, Kimura T, Yonenobu K (2002) Long-term results of expansive laminoplasty for ossification of the posterior longitudinal ligament of the cervical spine: more than 10 years' follow-up. J Neurosurg (Spine 2) 96:180-189

11. Matsunaga S, Sakou T, Hayashi K, Ishidou Y, Hirotsu M, Komiya S (2002) Trauma-induced myelopathy in patients with ossification of the posterior longitudinal ligament. J Neurosurg (Spine 2) 97:172-175

12. Yamaura I, Kurosa Y, Matuoka T, Shindo S (1999) Anterior floating method for cervical myelopathy caused by ossification of the posterior longitudinal ligament. Clin Orthop Relat Res 359:27-34

13. Matsuoka T, Yamaura I, Kurosa Y, Nakai O, Shindo S, Shinomiya K (2001) Long-term results of the anterior floating method for cervical myelopathy caused by ossification of the posterior longitudinal ligament. Spine 26:241 -248

14. Iwasaki M, Okuda S, Miyauchi A, Sakaura H, Mukai Y, Yonenobu K, Yoshikawa H (2006) Surgical strategy for cervical OPLL—limitations of laminoplasty and advantages of anterior decompression and fusion. Nippon Sekitsui Sekitzui Byo Gakkai Zasshi 17:43-44

15. Iwasaki M, Yonenobu K (in press) Ossification of the posterior longitudinal ligament. In: Herkowitz HN (ed) Rothman-Simone. The Spine (5th edition) Elsevier, Philadelphia

16. Koyanagi I, Iwasaki Y, Hida K Imamura H, Abe H (1998) Magnetic resonance imaging findings in ossification of the posterior longitudinal ligament of the cervical spine. J Neurosurg 88:247-254

17. Ohtsuka K, Terayama K, Tsuchiya T (1983) A surgical procedure of the anterior decompression of the thoracic spinal cord through the posterior approach (in Japanese). Seikei Saigaigeka 26:1083-1090

18. Tomita K, Kawahara N, Baba H, Kikuchi Y, Nishimura H (1990) Circumspinal decompression for thoracic mye-lopathy due to combined ossification of the posterior longitudinal ligament and ligamentum flavum. Spine 15: 1114-1120

19. Tsuzuki N, Wadano Y, Kikuchi S (1997) Extensive cervi-cothoracic laminoplastic decompression of the spinal cord: a new method of posterior decompression for thoracic myelopathy caused by ossification of the posterior longitudinal ligament. In: Yonenobu K, Sakou T, Ono K (eds) OPLL: ossification of the posterior longitudinal ligament. Springer-Verlag, Tokyo, pp 185-192

20. Yonenobu K, Ebara S, Fujiwara K, Yamashita K, Ono K, Yamamoto T, Harada N, Ogino H, Ojima S (1987) Thoracic myelopathy secondary to ossification of the spinal ligament. J Neurosurg 66:511-518

21. Yonenobu K, Korkusuz F, Hosono N, Ebara S, Ono K (1990) Lateral rhachotomy for thoracic spinal lesions. Spine 15:1121-1125

22. Chiba K, Yamamoto I, Hirabayashi H, Iwasaki M, Goto H, Yonenobu K, Toyama Y (2005) Multicenter study investigating the postoperative progression of ossification of the posterior longitudinal ligament in the cervical spine: a new computer-assisted measurement. J Neurosurg Spine 3:17-23

Pharmacotherapy for Ossification of the Spinal Ligaments: Clinical Trial of Disodium (1-Hydroxyethylidene) Diphosphonate to Inhibit Progression of Ossification of the Posterior Longitudinal Ligament in the Cervical Spine after Posterior Decompression Surgery

Kazuo Yonenobu1, Kensei Nagata2, Kuniyoshi Abumi3, Yoshiaki Toyama4, and Sinya Kawai5

Introduction

With advances in surgical techniques for ossification of the posterior longitudinal ligament (OPLL), the surgical results of both anterior and posterior procedures have been improved. However, the regression of neurological symptoms due to progression of OPLL during the follow-up period has been reported, and preventing progression of OPLL after surgery is an issue to be solved urgently from the viewpoint of stable long-term surgical results. Fortunately, the incidence of neurological symptom appearance is relatively low, but the incidence of postoperative progression of OPLL during the follow-up period is reported to be high after both anterior and posterior decompression. After anterior procedures, the reported incidence varies from 31% to 36% [1,2]. After posterior procedures, including laminectomy [3] and laminoplasty [4-7], the incidence is reported to be high (40%-100%).

Etidronate disodium—chemical name: disodium (1-hydroxyethylidene) diphosphonate, or EHDP—has the ability to adsorb onto hydroxyapatite and its noncrys-talline precursors chemically and to inhibit aggregation, growth, and calcification of these crystals [8]. It is

'Department of Orthopaedic Surgery, Osaka University Medical School, National Hospital Organization, OsakaMinami Medical Center, 2-1 Kidohigashi, Kawachinagano, Osaka 586-8521, Japan

2Department of Orthopaedic Surgery, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan

3Health Administration Center, Hokkaido University, N8 W5, Kita-ku, Sapporo 060-0808, Japan

4Department of Orthopedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

5Department of Orthopedic Surgery, Yamaguchi University School of Medicine, Yamaguchi, Japan therefore widely used to treat heterotopic ossification in clinical practice. Considering that OPLL is a form of heterotopic ossification, we hypothesized that EHDP has the therapeutic potential to inhibit the progress of OPLL because of its calcification-inhibitory effect.

The preventive effect of EHDP on postoperative ossification was evaluated by other investigators in 66 patients with OPLL of the cervical spine who underwent posterior decompression and were treated with a cyclic regimen of oral EHDP at 200-1000 mg daily for 3 months followed by treatment withdrawal for 3 months; this regimen was repeated for 2 years [9]. At study termination, significant suppression of ossification was observed with EHDP 1000 mg/day compared with control treatment; moreover, at the 1-year follow-up there was no progression of ossification. These clinical findings led us to conduct the present study: a randomized dose-ranging, double-blind, placebo-controlled, parallel-group, multicenter study (study 1). Simultaneous with study 1, a retrospective study (study 2) was conducted, as the target disease is rare and the size of the patient population in study 1 was considered to be small and likely to limit the power to detect significant group differences. The efficacy of EHDP in inhibiting progression of OPLL after posterior decompression was evaluated based on the combined data from studies 1 and 2. We also conducted a pilot study of EHDP to reconfirm the results of the previous clinical trial.

Patients and Methods Study 1

Study subjects were patients with OPLL who underwent posterior decompression including laminectomy and laminoplasty and had ossified lesions of the posterior longitudinal ligament between the second (C2) and seventh (C7) cervical vertebra on lateral plain cervical spine radiographs. The patients also had clinical symptoms or signs thought to have a strong causal relation with OPLL, including numbness in the extremities and trunk, pain, sensory and motor disturbances, bladder and bowel dysfunction, limited spinal movement, abnormal tendon reflex, and pathological reflex, as defined in the patient selection criteria for studies of treatment of spinal ligaments (ossification of the posterior longitudinal and yellow ligaments) proposed by the Committee on Ossification of Spinal Ligaments, revised 1992 version [10].

The present study was a randomized dose-ranging, double-blind, placebo-controlled, parallel-group, multicenter study of EHDP (study period: February 1999 to January 2004) conducted with the objectives of determining the dose-related inhibitory effect of the drug on postoperative ossification progression and demonstrating a significantly superior effect of the drug at 1000 mg/ day to placebo in OPLL patients. A total of 21 medical institutions participated in this study. The efficacy of EHDP was evaluated in patients with OPLL after decompression surgery using postoperative ossification progression as the primary endpoint. There were four treatment groups: EHDP 200, 600, and 1000 mg/day dosage groups and a placebo group.

Patients were placed on a cyclic regimen for four cycles (96 weeks, or approximately 22 months), where EHDP was administered at 5 tablets once daily between meals for 12 weeks, followed by withdrawal for 12 weeks in each cycle. We employed periodic intermittent administration selected on the basis of the following clinical information and considerations: EHDP is known to be effective in patients with heterotopic ossification after spinal cord injury or hip arthroplasty, which is an approved indication, at a regimen of 8001000 mg daily for 3 months. Bone turnover is commonly believed to require 3-4 months. There is a risk of osteomalacia with long-term use of EHDP at high doses. The pilot study of EHDP showed that four cycles (2 years) of intermittent treatment (3 months on the drug/3 months off) at 1000 mg/day significantly inhibited postoperative progression of ossification (16.7% in treated patients vs. 57.1% in untreated patients; P = 0.033 with Fisher's exact probability test) [9].

Study 2

Study 2 was a retrospective study that followed up the ossification progression at 1, 2, and 5 years after surgery in patients who underwent posterior decompression during or after 1985 but were not medicated with EHDP. Patients who met the inclusion criteria (see below) were randomly selected for the study. Altogether, 13 medical institutions participated in study 2. The method for measuring the size of ossified lesions, the criteria for determining ossification progression, the personnel who measured the lesions or determined the progression, and the time of determination were the same as in study 1.

For random patient selection, each participating institution listed patients who underwent posterior decompression in 1985 or later, and investigators of this study selected study subjects using a random numbers table. Informed consent was obtained from all patients whose X-ray films were selected for use in this study. Additional patients were selected to replace those who failed to meet the inclusion criteria or who met the exclusion criteria (n = 131).

Method for Evaluating Ossification Progression

The effect of EHDP on inhibiting ossification progression was evaluated using the Evaluation System for Cervical Myelopathy proposed by the Japanese Orthopaedic Association (JOA score) [11] and plain radiographic findings of ossification. However, as the JOA score tends largely to reflect the influence of surgical treatment, only the radiographic measurement is summarized here.

Ossified lesions often involve multiple vertebral bodies. In the preceding pilot study, a radiographic measurement method was developed to measure the entire size of the lesion using the corner of the vertebral body as the fixed point for observation [9]. A computerassisted method was newly developed for the present study to minimize variations among examiners and medical institutions and to increase measurement reliability.

Baseline lateral plain cervical spine radiographs were obtained using a laser film digitizer (model 2905; Array Corporation, Tokyo, Japan) during the period from 2 weeks to 120 days after operation and within 30 days prior to EHDP administration in study 1. The radiographs obtained within 4 months after the operation were used as the baseline in study 2. To determine ossification progression, 12-bit grayscale images were used from the radiographs obtained at the end of the treatment-free period in cycle 4 (or cycle 3) or at the time of withdrawal in study 1 and the radiographs at 1, 2, and 5 years after operation in study 2. Digital data on the upper and lower levels and the width of the ossified lesion (where data were available) at each level from C2 to C7 were fed into a computer using OPLL Image Measurement Software (Array Corporation). Film reduction ratios and distance between the X-ray tube focal spot and the film (focus-film distance) were also entered into the software for automatically adjusted ossification values. The automatically calculated difference in the ossification value between two (baseline and postoperative) time points was used to evaluate postoperative progression of ossification. Progression of ossification was judged to have occurred if at least one of the following criteria was met.

This evaluation system, which was validated for its reliability prior to conducting study 1, has proved to be able to detect lesions 2.0 mm in size in terms of standard deviations for the extent of ossification progression [12]. Based on this validation result and the conventional standard criteria of regarding a lesion increase of 2.0 mm or more as progression of ossification, the following criteria of progression were established for this study.

1. An increase of >2.0 mm in one or more existing lesions

2. Appearance of a new ossified lesion >2.0 mm in size

3. Bridging between separate segmental or mixed-type lesions to form a continuous-type lesion (including lesions <2.0 mm in size)

When multiple measurable lesions were identified in a single patient, the lesion showing the most progression was employed for statistical analysis.

The Ossification Evaluation Committee, comprised of the committee chairperson and three committee members, was established to undertake measurement of ossified lesions. As a rule, the same committee member measured the lesion in the same patient, judged ossification within 1 day, and prepared a judgment report. The committee chairperson reevaluated the lesion, reviewed the judgment report, and made the final judgment.

In study 1, the dose-response effect of EHDP for preventing ossification progression was determined based on the incidence of progression in the final judgment for each dosage group. The distribution of the incidence was statistically analyzed by a Cochran-Armitage trend test and a max i-test There were no data on patients treated with EHDP in study 2. Therefore, the retrospective data were combined with data from the placebo group in study 1 for statistical comparison with the data from patients on EHDP therapy. Because the data from the EHDP therapy group employed in the integrated data analysis were identical to those in study 1, and the incidence of progression in the combined data from studies 1 and 2 was presumed to decrease in the order placebo (or control) > EHDP 200 mg/day > EHDP 600 mg/day > EHDP 1000 mg/day, data were evaluated by sequential analysis using a one-sided test based on a closed testing procedure with a significance level of P = 2.5%.

The superiority of clinical efficacy of EHDP was tested with the Fisher two-sided exact probability test at a significance level of P < 5% by comparing ossification data from the EHDP 1000 mg/day dosage group versus the placebo group. Two significance levels remained unadjusted for the two aims of analysis: testing dose responsiveness and proving the superiority of EHDP treatment over placebo.

The greatest progression of ossification was analyzed using the Wilcoxon two-sided rank-sum test with a significance level of P < 5%.

Results Study 1

Patient Numbers

Altogether, 43, 45, 43, and 37 patients were enrolled in the placebo group and the EHDP 200,600, and 1000 mg/ day groups, respectively. There were 9, 11, 8, and 12 dropouts in the four groups, respectively, leaving 34, 34, 35, and 25 patients available for evaluation of EHDP's inhibitory effect on the progression of ossification.

Patient's Demographics

The following baseline demographic characteristics were compared across the groups including the placebo group to confirm that these factors were similarly distributed among groups: sex, age, height, weight, operative procedure (laminectomy, laminoplasty), type of OPLL, duration of disease, systemic complications, and past history. There was a slight deviation in age, with a larger proportion of young patients in the 1000 mg/day group; P = 0.149, by the Kruskal-Wallis test (H-test). No other factors showed apparent deviations.

Inhibitory Effect on Ossification Progression

Proportions of Patients with Ossification Progression The proportions of patients who showed postoperative progression were 52.9%, 40.0%, and 44.0% at EHDP doses of 200, 600, and 1000 mg/day, respectively, and 47.1% for placebo. No statistically significant differences were found between groups. Sex-specific analysis was conducted. Analysis of the 95 male patients indicated that the proportions of patients with postoperative progression were 58.3%, 37.9%, and 33.3% in the 200, 600, and 1000 mg/day groups, respectively, and 54.2% in the placebo group. Again, no statistically significant differences were noted between groups. However, the analysis by max i-test showed a tendency toward significance (P = 0.06) between the 200 mg/day and placebo groups and between the 600 and 1000 mg/ day groups, suggesting a positive dose-response for the efficacy of EHDP (Fig. 1). Analysis of the 33 female patients indicated that the proportions of the patients with postoperative progression were 40.0% (n = 10), 50.0% (n = 6), and 71.4% (n = 7) in the 200, 600, and 1000 mg/day groups, respectively, versus 30.0% (n = 10) in the placebo group. None of the group differences was statistically significant.

Extent of Greatest Ossification Progression The degree of progression could be measured in 127 of 128 patients included in the evaluation of ossification progression. The greatest degree of ossification progression in these patients is shown in Table 1. There were no significant group differences. Factorial analysis by sex did not reveal significant group differences in either sex.

Study 2

Patient Demographics

The baseline demographic characteristics in study 2— sex, age, operative procedure, type of OPLL—were compared with those in study 1. No significant differences were observed between the two studies for any of the factors.

Progression of Ossification

Proportions of Patients with Ossification Progression The proportions of patients who showed postoperative progression of ossification in study 2 were 38.9% (49/126), 56.5% (74/131), and 71.0% (44 patients evaluated, but estimation made by Kaplan-Meier method) at 1,2, and 5 years after operation, respectively. Analysis by sex indicated that the proportions of male patients with postoperative progression were 40.0% (38/95), 58.6% (58/99), and 73.7% (estimated by the Kaplan-Meier method) at 1, 2, and 5 years after operation, respectively. The proportions of female patients with postoperative progression were 35.5% (11/31), 50.0% (16/32), and 62.5% (estimated by the Kaplan-Meier method) at 1,2, and 5 years after operation, respectively. Generally, the ratios were similar between sexes; however, proportions for the female patients were lower than those for the male patients.

Extent of Greatest Ossification Progression The change in the greatest degree of ossification progression indicates that ossification progressed with time in both male and female patients (Table 2). The measured greatest degree of progression was slightly lower in the female patients than in the male patients. The average extent of ossification at 2 years was less than that at 5 years. The reversal of the trend was caused by a case of extremely severe progression of ossification at 2 years.

Analysis of Integrated Data from Studies 1 and 2

The incidence of postoperative progression at 2 years after operation in study 2 were combined with the corresponding data for the placebo group in study 1 to reorganize the control data for integrated data analysis. These control data were then statistically compared with those of the EHDP 200, 600, and 1000 mg/day groups for sex-specific and sex-nonspecific analysis of ossification progression.

Opll Operation

Ratio of the patients with ossification progress of OPLL (%)

Fig. 1. Effect of disodium (1-hydroxyethylidene) diphosphonate (EHDP) on the proportion of patients with progressive ossification of the posterior longitudinal ligament (OPLL) in male patients in study 1

Ratio of the patients with ossification progress of OPLL (%)

Fig. 1. Effect of disodium (1-hydroxyethylidene) diphosphonate (EHDP) on the proportion of patients with progressive ossification of the posterior longitudinal ligament (OPLL) in male patients in study 1

Table 1. Parameters of ossification progress of OPLL in Study 1

Placebo

200 mg

600 mg

1000 m

All patients

Number of patients

34

34

35

24

Median (mm)

1.65

1 .90

1.70

1 .75

25% percentile (mm)

1.00

1 .30

1 .20

0.60

75% percentile (mm)

3.10

4.10

3.60

3.10

Average (mm)

2.4

4.1

2.4

2.2

Male patients

Number of patients

24

24

29

18

Median (mm)

1 .65

2.15

1 . 60

1 .10

25% percentile (mm)

1 .05

1 .60

1 .20

0.60

75% percentile (mm)

3.10

5.35

3.00

3.10

Average (mm)

2.6

4.8

2.3

2.0

Female patients

Number of patients

10

10

6

6

Median (mm)

1 .75

1.35

2.85

2.65

25% percentile (mm)

1 .00

1 .00

1 .90

2.40

75% percentile (mm)

2.90

1 .90

4.10

4.10

Average (mm)

2.0

2.4

3.2

3.0

Table 2. Parameters of ossification progress of OPLL after posterior decompression in Study 2

1 year 2 years 5 years

All patients

Table 2. Parameters of ossification progress of OPLL after posterior decompression in Study 2

1 year 2 years 5 years

All patients

Number of patients

101

102

31

Median (mm)

1.80

2.20

3.10

25% percentile (mm)

1.00

1.30

1.80

75% percentile (mm)

3.40

4.80

6.00

Average (mm)

2.6

4.2

4.4

Male patients

Number of patients

81

78

25

Median (mm)

1.90

2.50

3.50

25% percentile (mm)

1.00

1.40

2.20

75% percentile (mm)

3.60

5.30

6.00

Average (mm)

2.8

4.7

4.1

Female patients

Number of patients

20

24

6

Median (mm)

1.55

1.80

2.35

25% percentile (mm)

1.00

1.30

1 .20

75% percentile (mm)

2.40

4.05

6.80

Average (mm)

1.6

2.9

5.8

Proportions of Patients with Ossification Progression In the sex-nonspecific analysis, the proportions of patients who showed postoperative progression were 52.9%, 40.0%, and 44.0% in the EHDP 200, 600, and 1000 mg/ day groups, respectively, compared with 54.5% (90/165) in the control group. The Cochran-Armitage trend test and max i-test did not indicate a significant dose-response relation among the active treatment groups (P = 0.068 and P = 0.097, respectively), and superiority of EHDP at 1000 mg dose/day over placebo was not proven (Fisher's exact probability test, P = 0.441).

In the sex-specific analysis, the proportions of men who showed progression of ossification were 58.3%,

37.9%, and 33.3% in the EHDP 200, 600, and 1000 mg/ day groups, respectively, compared with 57.7% (71/123) in the control group. The Cochran-Armitage trend test and max i-test demonstrated a significant dose-response relation for the efficacy of EHDP (P = 0.009 and P = 0.012, respectively). However, the superiority of EHDP treatment over placebo was not proven in a comparison of the EHDP 600 and 1000 mg/day groups with the control group (Fisher's exact probability test, P = 0.086 and 0.091, respectively) (Fig. 2).

Extent of Greatest Ossification Progression The greatest ossification progression was analyzed in a similar manner to that for the proportion of patients with postoperative progression (Table 3). As a result, the analysis in all patients did not show any significant group differences (e.g., P = 0.088 for a comparison between the EHDP 1000 mg/day group and the placebo group by the Wilcoxon rank-sum test). The greatest progression measured in male patients in the EHDP 1000 mg/day group was significantly less than that for the control male patients (Fig. 3). Analysis of female patients did not reveal a statistically significant difference between the EHDP-treated groups and the control group.

Discussion

OPLL has attracted much attention because it tends to lead to severe quadriplegia due to compression of the spinal cord by ossified lesions. Various therapies, based mainly on a surgical approach, have been developed. However, recent research has identified patients with OPLL who show progression of ligament ossification

Cochran Armitage trend test: P = 0.009

Cochran Armitage trend test: P = 0.009

t value for Placebo vs t value for Placebo vs t value for ( Placebo + 2GG mg ) vs ( 6GG mg + 1GGG mg ) : 2.5SS

(vs Placebo, Fisher's exact probability test )

t value for ( Placebo + 2GG mg + 6GGmg ) vs 1GGG mg : 1.717

(vs Placebo, Fisher's exact probability test )

Ratio of the patients with ossification progress of OPLL (%)

Fig. 2. Effect of EHDP on the proportion of patients with progressive OPLL in male patients based on the analysis of integrated data from studies 1 and 2

Table 3. Parameters of ossification progress of OPLL in analysis of integrated data from Studies 1 and 2

Control

200 mg

600 mg

1000 mg

All patients

Number of patients 136 34 35 24

Number of patients 102 24 29 18

Number of patients 34 10 6 6

*P = 0.020 vs Control, Wilcoxon two-sided rank-sum test ranging from the cervical vertebrae to the posterior longitudinal or yellow ligament of the thoracic vertebra, further causing ossification of the posterior longitudinal ligament of the lumbar vertebra and occasionally resulting in spinal cord compression and then paraplegia. It has also been reported that the ossification of ligaments can progress not only to the posterior longitudinal and yellow ligaments but also to the anterior longitudinal and other spinal ligaments, subsequently limiting movement of the spine and causing various nonneurological disorders. Naturally, these conditions and clinical symptoms are not curable with surgical treatment, and critical questions about OPLL remain unresolved. Furthermore, ossification of ligaments has been found to progress even after operative treatment. Postoperative progression of ossification is associated with the recurrence or onset of neurological symptoms due to ossification of the posterior longitudinal or yellow ligaments in the thoracic or lumbar spine; hence the desired outcome of therapy has not been attained in long-term studies of OPLL [3,4]. The successful development of new drugs effective in preventing the progression of ossification is greatly desired.

The pathophysiology of OPLL, which is described in detail elsewhere, may be interpreted as a type of heterotopic ossification. There are no drugs, except EHDP,

62.9

36.3

Control

200 mg

600 mg

62.9

36.3

( Wilcoxon two-sided rank-sum test )

i

X

P = 0.126

P = 0.020

*

X

X i*

M

X

x

C

51

T

X

!|r

L. s

h

1

1

i

V

200 mg

600 mg

1000 mg

1000 mg

percentile Average Median 25%

percentile Min.

Fig. 3. Effect of EHDP on the most ossification progression in male patients with OPLL based on the analysis of integrated data from studies 1 and 2

indicated for the treatment of heterotopic ossification because of EHDP's direct pharmacologic actions on ossification. EHDP was approved by the U.S. Food and Drug Administration (FDA) for treating Paget's disease in 1977 and for heterotopic ossification in 1979. The drug was also approved by the French health authority for use in the treatment of hypercalcemia in 1987 and osteoporosis via periodic intermittent administration in 1990. The EHDP treatment of heterotopic ossification is accessible in more than 15 countries including the United States, United Kingdom, Germany, Israel, and Japan. Because EHDP has long been used in clinical practice and because no serious adverse reactions have been reported, we decided to examine the efficacy of EHDP in the treatment of OPLL.

In this study, EHDP failed to demonstrate efficacy in preventing the progression of ossification after posterior decompression at the predetermined level of statistical significance. However, in male patients, the drug demonstrated a tendency toward significance (P = 0.063) in the results of the max i-test compared with the placebo control in study 1. The difference between the EHDP-treated male patients and the control male patients was found to be significant when the sample size of the control group was increased by adding the control patients from study 2 to those in study 1. No similar tendency was noted in female patients, so the efficacy of EHDP was considered to have a sex difference.

Epidemiologic and pathologic investigations suggest that there is a marked sex difference in the prevalence of OPLL. Although it varies among surveys, the male/ female ratio of OPLL cases is approximately 2 : 1 in most surveys. Patients with OPLL are known to have higher serum estrogen levels than do healthy people, and patients with mixed or continuous ossification, which may be associated with more severe ossification progression, are also known to have higher serum estrogen levels than those with segmental-type ossification. Interestingly, high-affinity estrogen receptors have been identified in isolated spinal ligament cells from OPLL patients, and accelerated proliferation and increased production of bone-forming cytokines have been observed following estrogen stimulation [13]. Thus, sex effects are evident at the onset and during the progression of ossification; and possibly they have an effect on the efficacy of EHDP in OPLL.

The results of the present study did not provide convincing evidence of the therapeutic efficacy of EHDP in the treatment of OPLL. However, in male patients, the drug seems to have a potential to prevent the progression of ossification, and further studies are necessary to verify the efficacy of the drug in men. On the other hand, OPLL has not yet been etiologically or patho-physiologically defined. Because progression is mild in most cases, it is not always easy to assess the progress of ossification accurately. OPLL is a rare disease, and it is difficult to recruit a sufficient number of patients to evaluate minor alterations in such a rare disease. These situations highlight the need to develop new methods of assessment, improve techniques to detect minute alterations in ossification, and identify the alterations by metabolic approaches. OPLL is not localized in the cervical vertebrae and so should be viewed as a systemic disorder. Both myelopathy and dysfunction of spinal movement are major symptoms of this disorder that require treatment. Pharmacological agents comprise an essential therapeutic tool for controlling the progress of ossification, and successful development of OPLL-preventive drug is greatly needed.

Acknowledgments. The authors express sincere thanks to the members of The Ossification Evaluation Committee, Dr. Itsuo Yamamoto (chairperson), Director of Yamamoto Clinic (Kyoto), Dr. Hisashi Hirabayashi (Department of Orthopaedic Surgery, Keio University), Dr. Motoki Iwasaki (Department of Orthopaedic Surgery, Osaka University Medical School), and Dr. Hiroshi Goto, Director of Kurume Orthopedic Clinic (Kita-Kyushu). Without their tenacious efforts for measuring, these studies could not be completed.

References

1. Matsuoka T, Yamaura I, Kurosa Y, Nakai O, Shindo S, Shinomiya K (2001) Long-term results of the anterior floating method for cervical myelopathy caused by ossification of the posterior longitudinal ligament. Spine 26:241-248

2. Tomita T, Harata S, Ueyama K, Itou J, Nitobe T (1999) Radiological follow-up evaluation of the progression of ossification of the posterior longitudinal ligament: the operative influence on the progression of ossification. Rinsho Seikei Geka 34:167-172 (in Japanese)

3. Kato Y, Iwasaki M, Fuji T, Yonenobu K, Ochi T (1998) Long-term follow-up results of laminectomy for cervical myelopathy caused by ossification of the posterior longitudinal ligament. J Neurosurg 89:217-223

4. Iwasaki M, Kawaguchi Y, Kimura T, Yonenobu K (2002) Long-term results of expansive laminoplasty for ossification of the posterior longitudinal ligament of the cervical spine: more than 10 years follow up. J Neurosurg 96(Suppl 2):180-189

5. Chiba K, Yamamoto I, Hirabayashi H, Iwasaki M, Goto I, Yonenobu K, Toyama Y (2005) Multicenter study to investigate postoperative progression of the posterior longitudinal ligament in the cervical spine using a new computer-assisted measurement. J Neurosurg Spine 3:1723

6. Kawaguchi Y, Kanamori M, Ishihara H, Nakamura H, Sugimori K, Tsuji H, Kimura (2001) Progression of ossification of the posterior longitudinal ligament following en bloc cervical laminoplasty. J Bone Joint Surg Am 83:1798-1802

7. Hirabayashi K, Toyama Y, Chiba K (1999) Expansive laminoplasty for myelopathy in ossification of the longitudinal ligament. Clin Orthop 359:35-48

8. Russell RGG, Fleish H (1975) Pyrophosphate and diphosphonates in skeletal metabolism, physiological, clinical and therapeutic aspect. Clin Orthop 108:241263

9. Ono K, Yonenobu K, Sakou T, Kawai S, Nagata K (1998) Prevention of progression of ossification of the posterior longitudinal ligament (OPLL) by the administration of etidronate disodium (EHDP) after posterior decompression. J Jpn Spine Res Soc 9:432-442

10. Sakou T, Hirabayashi K (1994) Patient selection criteria for study on treatment of OPLL: revised version (proposal). 1994 annual report, Committee on Ossification of Spinal Ligament (Ministry of Health and Welfare), pp 6-7

11. Yonenobu K, Abumi K, Nagata K, Taketomi E, Ueyama K (2001) Inter- and intra-observer reliability of the Japanese Orthopaedic Association scoring system for evaluation of cervical compression myelopathy. Spine 26: 1890-1894

12. Chiba K, Kato Y, Tsuzuki N, Nagata K, Toyama Y, Iwasaki M, Susaki H, Yonenobu K (2005) Computer-assisted measurement of the size of ossification in patients with ossification of the posterior longitudinal ligament in the cervical spine: validation and reliability. J Orthop Sci 10:451-456

13. Motegi M (1998) Influence of sex hormones on the posterior longitudinal ligament of the cervical spine. J Jpn Spine Res Soc 9:407-417

Was this article helpful?

0 0
Acupuncture For Cynics

Acupuncture For Cynics

Have You Always Been Curious About Acupuncture, But Were Never Quite Sure Where To Stick The Needles? If you associate acupuncture with needles, pain and weird alternative medicine then you are horribly misinformed about the benefits of the world's oldest form of medicinal treatment.

Get My Free Ebook


Responses

  • geremia
    What is conservative treatment for opll?
    8 months ago

Post a comment