Inhibit Progression of Ossification of the Posterior Longitudinal Ligament in the Cervical Spine

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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 Yonenobu

¹

, Kensei Nagata

²

, Kuniyoshi Abumi

³

, Yoshiaki Toyama

⁴

, and Sinya Kawai

⁵

Introduction

With advances in surgical techniques for ossiﬁ cation of the posterior longitudinal ligament (OPLL), the surgical results of both anterior and posterior procedures have been improved. However, the regression of neurologi- cal 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 neuro- logical 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 lami- nectomy [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 aggrega- tion, growth, and calciﬁ cation of these crystals [8]. It is

therefore widely used to treat heterotopic ossifi cation in clinical practice. Considering that OPLL is a form of heterotopic ossifi cation, we hypothesized that EHDP has the therapeutic potential to inhibit the progress of OPLL because of its calcifi cation-inhibitory effect.

The preventive effect of EHDP on postoperative ossiﬁ cation 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, signifi cant suppression of ossifi cation was observed with EHDP 1000 mg/day compared with control treatment; moreover, at the 1-year follow-up there was no progression of ossifi cation. These clinical fi ndings led us to conduct the present study: a random- ized dose-ranging, double-blind, placebo-controlled, parallel-group, multicenter study (study 1). Simultane- ous 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 signifi cant group differences. The effi cacy 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 reconfi rm 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 ossiﬁ ed lesions of the posterior

1Department of Orthopaedic Surgery, Osaka University Medical School, National Hospital Organization, Osaka- Minami 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

169

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longitudinal ligament between the second (C2) and seventh (C7) cervical vertebra on lateral plain cervical spine radiographs. The patients also had clinical symp- toms 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 refl ex, and pathological refl ex, as defi ned in the patient selection criteria for studies of treatment of spinal ligaments (ossifi cation of the poste- rior longitudinal and yellow ligaments) proposed by the Committee on Ossifi cation of Spinal Ligaments, revised 1992 version [10].

The present study was a randomized dose-ranging, double-blind, placebo-controlled, parallel-group, mul- ticenter study of EHDP (study period: February 1999 to January 2004) conducted with the objectives of deter- mining the dose-related inhibitory effect of the drug on postoperative ossiﬁ cation progression and demonstrat- ing a signiﬁ cantly 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 efﬁ cacy of EHDP was evaluated in patients with OPLL after decom- pression surgery using postoperative ossiﬁ cation pro- gression 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 ossi- ﬁ cation after spinal cord injury or hip arthroplasty, which is an approved indication, at a regimen of 800–

1000 mg daily for 3 months. Bone turnover is commonly believed to require 3–4 months. There is a risk of osteo- malacia 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 signiﬁ cantly inhibited post- operative progression of ossiﬁ cation (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 ossiﬁ cation 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 ossiﬁ ed lesions, the criteria for determining ossiﬁ cation progression, the personnel who measured the lesions or determined the progres- sion, 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 ﬁ lms 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 ossifi cation progres- sion was evaluated using the Evaluation System for Cer- vical Myelopathy proposed by the Japanese Orthopaedic Association (JOA score) [11] and plain radiographic fi ndings of ossifi cation. However, as the JOA score tends largely to refl ect the infl uence of surgical treat- ment, only the radiographic measurement is summa- rized here.

Ossiﬁ ed 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 ﬁ xed point for observation [9]. A computer- assisted 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 ﬁ lm 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 radio-

graphs obtained within 4 months after the operation

were used as the baseline in study 2. To determine ossi-

ﬁ cation progression, 12-bit grayscale images were used

from the radiographs obtained at the end of the treat-

ment-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 ossiﬁ ed

lesion (where data were available) at each level from C2

to C7 were fed into a computer using OPLL Image Mea-

surement Software (Array Corporation). Film reduc-

tion ratios and distance between the X-ray tube focal

spot and the ﬁ lm (focus–ﬁ lm distance) were also entered

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into the software for automatically adjusted ossifi cation values. The automatically calculated difference in the ossifi cation value between two (baseline and postopera- tive) time points was used to evaluate postoperative progression of ossifi cation. Progression of ossifi cation was judged to have occurred if at least one of the fol- lowing 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 ossiﬁ cation pro- gression [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 ossiﬁ ca- tion, the following criteria of progression were estab- lished for this study.

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

2 . Appearance of a new ossiﬁ ed 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 identiﬁ ed in a single patient, the lesion showing the most progression was employed for statistical analysis.

The Ossifi cation Evaluation Committee, comprised of the committee chairperson and three committee members, was established to undertake measurement of ossifi ed lesions. As a rule, the same committee member measured the lesion in the same patient, judged ossifi cation within 1 day, and prepared a judgment report. The committee chairperson reevaluated the lesion, reviewed the judgment report, and made the fi nal judgment.

In study 1, the dose-response effect of EHDP for pre- venting ossifi cation progression was determined based on the incidence of progression in the fi nal judgment for each dosage group. The distribution of the incidence was statistically analyzed by a Cochran-Armitage trend test and a max t-test. There were no data on patients treated with EHDP in study 2. Therefore, the retrospec- tive 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 signifi cance level of

P

= 2.5%.

The superiority of clinical effi cacy of EHDP was tested with the Fisher two-sided exact probability test at a signifi cance level of P ≤ 5% by comparing ossifi ca- tion data from the EHDP 1000 mg/day dosage group versus the placebo group. Two signifi cance 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 ossiﬁ cation was analyzed using the Wilcoxon two-sided rank-sum test with a sig- niﬁ cance 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 ossiﬁ cation.

Patient’s Demographics

The following baseline demographic characteristics were compared across the groups including the placebo group to conﬁ rm that these factors were similarly dis- tributed among groups: sex, age, height, weight, opera- tive 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 signifi cant differ- ences were found between groups. Sex-specifi c analysis was conducted. Analysis of the 95 male patients indi- cated that the proportions of patients with postopera- tive 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 signifi cant differences were noted between groups.

However, the analysis by max t-test showed a tendency toward signiﬁ cance (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

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efﬁ cacy 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 signiﬁ cant.

Extent of Greatest Ossification Progression The degree of

progression could be measured in 127 of 128 patients included in the evaluation of ossiﬁ cation progression.

The greatest degree of ossifi cation progression in these patients is shown in Table 1. There were no signifi cant group differences. Factorial analysis by sex did not reveal signifi cant 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 signiﬁ cant differ- ences 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 pro- gression of ossiﬁ cation 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, respec- tively. The proportions of female patients with postop- erative 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, propor- tions for the female patients were lower than those for the male patients.

Extent of Greatest Ossification Progression The change

in the greatest degree of ossifi cation progression indi- cates that ossifi cation 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 ossifi cation 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 ossifi cation 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 cor- responding 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-specifi c and sex-nonspecifi c analysis of ossifi cation progression.

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

0 20 40 60 80 100

Placebo (n = 24)

200 mg (n = 24)

1000 mg (n = 18) 600 mg

(n = 29)

t value for Placebo vs ( 200 mg + 600 mg + 1000 mg ) : 0.892

t value for ( Placebo + 200 mg ) vs ( 600 mg + 1000 mg ) : 1.962

t value for ( Placebo + 200 mg + 600 mg ) vs 1000 mg : 1.227 ( max t method )

(vs Placebo, continuity adjusted Chi-square test ) 33.3%

37.9%

58.3%

54.2%

P = 0.063

χ

²

= 1.059, P = 0.303

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

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Proportions of Patients with Ossification Progression In

the sex-nonspeciﬁ c 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 t-test did not indicate a signiﬁ cant 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-speciﬁ c analysis, the proportions of men who showed progression of ossiﬁ cation 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 t-test demonstrated a signiﬁ cant dose-response relation for the efﬁ cacy 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

ossifi cation progression was analyzed in a similar manner to that for the proportion of patients with post- operative progression (Table 3). As a result, the analysis in all patients did not show any signifi cant group dif- ferences (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 signifi cantly less than that for the control male patients (Fig. 3). Analysis of female patients did not reveal a statistically signifi cant 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 ossiﬁ ed lesions. Various therapies, based mainly on a surgical approach, have been developed.

However, recent research has identiﬁ ed patients with OPLL who show progression of ligament ossiﬁ cation

Table 1. Parameters of ossiﬁ cation progress of OPLL in Study 1

Placebo 200 mg 600 mg 1000 mg

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

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

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 ossiﬁ cation 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

Median (mm) 1.90 2.50 3.50

Average (mm) 2.8 4.7 4.1

Female patients

Median (mm) 1.55 1.80 2.35

Average (mm) 1.6 2.9 5.8

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ranging from the cervical vertebrae to the posterior lon- gitudinal or yellow ligament of the thoracic vertebra, further causing ossiﬁ cation of the posterior longitudi- nal ligament of the lumbar vertebra and occasionally resulting in spinal cord compression and then paraple- gia. It has also been reported that the ossiﬁ cation of ligaments can progress not only to the posterior longi- tudinal 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, ossiﬁ cation of ligaments has been found to progress even after operative treatment.

Postoperative progression of ossifi cation is associated with the recurrence or onset of neurological symptoms due to ossifi cation 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 ossifi cation is greatly desired.

The pathophysiology of OPLL, which is described in detail elsewhere, may be interpreted as a type of hetero- topic ossiﬁ cation. There are no drugs, except EHDP,

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

0 20 40

33.3%

37.9%

58.3%

57.7%

P = 0.012

60 80 100

Control (n = 123)

200 mg (n = 24)

1000 mg (n = 18) 600 mg

(n = 29)

t value for Placebo vs

t value for ( Placebo + 200 mg ) vs ( 600 mg + 1000 mg ) : 2.588

t value for ( Placebo + 200 mg + 600 mg ) vs 1000 mg : 1.717

( max t method )

(vs Placebo, Fisher’s exact probability test ) Cochran Armitage trend test: P = 0.009

(vs Placebo, Fisher’s exact probability test )

P = 0.086

P = 0.091

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 ossiﬁ cation progress of OPLL in analysis of integrated data from Studies 1 and 2

Control 200 mg 600 mg 1000 mg

All patients

Median (mm) 1.95 1.90 1.70 1.75

25% percentile (mm) 1.30 1.30 1.20 0.60

75% percentile (mm) 4.20 4.10 3.60 3.10

Average (mm) 3.8 4.1 2.4 2.2

Male patients

Median (mm) 2.40 2.15 1.60 1.10

25% percentile (mm) 1.30 1.65 1.20 0.60

75% percentile (mm) 4.70 5.35 3.00 3.10

Average (mm) 4.2 4.8 2.3 2.0*

Female patients

Median (mm) 1.8 1.35 2.85 2.65

Maximum (mm) 11.4 10.8 7.1 6.1

*P= 0.020 vs Control, Wilcoxon two-sided rank-sum test

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indicated for the treatment of heterotopic ossifi cation because of EHDP’s direct pharmacologic actions on ossifi cation. EHDP was approved by the U.S. Food and Drug Administration (FDA) for treating Paget’s disease in 1977 and for heterotopic ossifi cation 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 ossifi ca- tion 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 effi cacy of EHDP in the treatment of OPLL.

In this study, EHDP failed to demonstrate effi cacy in preventing the progression of ossifi cation after pos- terior decompression at the predetermined level of statistical signifi cance. However, in male patients, the drug demonstrated a tendency toward signifi cance (P = 0 .063) in the results of the max t-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 signifi cant 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 efﬁ cacy 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 ossifi cation, which may be associated with more severe ossifi cation progression, are also known to have higher serum estrogen levels than those with segmental-type ossifi ca- tion. Interestingly, high-affi nity estrogen receptors have been identifi ed 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 ossiﬁ cation; and possibly they have an effect on the efﬁ cacy of EHDP in OPLL.

The results of the present study did not provide con- vincing evidence of the therapeutic effi cacy of EHDP in the treatment of OPLL. However, in male patients, the drug seems to have a potential to prevent the progres- sion of ossifi cation, and further studies are necessary to verify the effi cacy of the drug in men. On the other hand, OPLL has not yet been etiologically or patho- physiologically defi ned. Because progression is mild in most cases, it is not always easy to assess the progress of ossifi cation accurately. OPLL is a rare disease, and it is diffi cult to recruit a suffi cient 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 ossifi cation, 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 ossifi cation, and successful development of OPLL- preventive drug is greatly needed.

Greatest ossification progress (mm)

Max.

Min.

75%

percentile

25%

percentile Median Average

Control

( n = 102 )

–2 0 2 4 6 8 10 12 14 16

62.9 36.3

P = 0.126 P = 0.020

200 mg

( n = 24 )

600 mg

( n = 29 )

1000 mg

( n = 18 )

( Wilcoxon two-sided rank-sum test )

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

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Acknowledgments. The authors express sincere thanks

to the members of The Ossiﬁ cation Evaluation Com- mittee, 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 mea- suring, these studies could not be completed.

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