Prevalence and progression of radiographic ossification of the posterior longitudinal ligament and associated factors in the Japanese population: a 3-year follow-up of the ROAD study

Summary

The prevalence of radiographic cervical ossification of the posterior longitudinal ligament (OPLL) in 1,562 Japanese from a population-based cohort was 1.9 %. The presence of OPLL showed a significant association with the femoral neck bone mineral density (BMD), presence of diffuse idiopathic skeletal hyperostosis (DISH) and plasma pentosidine levels. Only one new case of radiographic OPLL was detected, but OPLL progressed in all affected subjects.

Introduction

The purpose of this study was to clarify the prevalence and progression of radiographic OPLL and the associated factors, using the population-based cohort Research on Osteoarthritis/osteoporosis Against Disability (ROAD).

Methods

In the ROAD study, 1,690 participants underwent X-ray examination of the entire spine and both knees. Radiographic OPLL, lumbar spondylosis, knee osteoarthritis and DISH were diagnosed by a single, well-experienced orthopaedic surgeon. An interviewer-administered questionnaire and tests for anthropometric measurements were administered, and the BMDs of the lumbar spine and proximal femur were determined. A new OPLL case was considered if heterotopic ossification in the posterior longitudinal ligament was absent at baseline but present during follow-up. Progression was defined as an increase in the maximum length or width of the ossification at follow-up over that at baseline.

Results

Radiographic OPLL was detected in 30 (17 men, 13 women) of 1,562 individuals who underwent X-ray examination of the cervical spine (prevalence?=?1.9 %). Its prevalence was significantly higher in men than in women (p?=?0.007), but no association with age was observed. In a logistic regression analysis, OPLL showed a significant association with the femoral neck BMD, presence of DISH and plasma pentosidine levels. Only one new case of radiographic OPLL was detected, but OPLL progressed in all affected subjects.

Conclusion

This population-based study clarified the prevalence of radiographic OPLL in the Japanese population as well as its progression. OPLL showed significant association with plasma pentosidine levels, BMD and DISH.     

Increased Bone Mineral Density and Decreased Prevalence of Osteoporosis in Cervical Ossification of the Posterior Longitudinal Ligament: A Case–Control Study

Bone and mineral metabolism has been reported to affect the development of the ossification of the posterior longitudinal ligament (OPLL). The aim of this study was to compare bone mineral densities (BMD) and rate of osteoporosis between cervical OPLL and a matched control group. We also investigated the correlation of BMD with the number of cervical spine levels involved with OPLL. From 1999 to August 2011, 178 patients with cervical OPLL underwent dual-energy X-ray absorptiometry (DXA) at our institute. The control group was age-, sex-, and body mass index (BMI)–matched with the OPLL group on a 1:1 basis. BMD was measured at the lumbar spine (L1–L4), femoral neck, and total femur using DXA. Age, sex, and BMI were the same in the OPLL and control groups. BMDs of the OPLL and control groups were significantly different in the lumbar spine, femoral neck, and total femur (p = 0.0001, 0.0001, 0.009, respectively). Rates of osteopenia and osteoporosis were lower in the OPLL than in the control group according to lumbar spine and femoral neck DXA (p = 0.01, 0.03, respectively). A positive correlation was observed between lumbar spine BMD and the number of cervical spine levels involved with OPLL (p = 0.004).     

Co-existence of ossification of the nuchal ligament is associated with severity of ossification in the whole spine in patients with cervical ossification of the posterior longitudinal ligament -A multi-center CT study-

Background

Previous studies have shown that patients with cervical ossification of the posterior longitudinal ligament (OPLL) often have co-existing ossification of the nuchal ligament (ONL). However, no studies have focused on ONL and its relevance to the severity of OPLL or ossification of other spinal ligaments, such as anterior longitudinal ligament (OALL), ligamentum flavum (OLF), and supraspinous/interspinous ligament (OSIL).

A hist-morphometrical study of undecalcified sections of bone obtained in patients with cervical disorders

Histomorphometrical parameters were used to investigate bone metabolism in patients with symptomatic cervical disorders, especially those patients with ossification of the posterior longitudinal ligament (OPLL) of the cervical spine. There were 19 patients in this study. The patients were divided into two groups depending on the presence of OPLL. Six patients had OPLL (OPLL group), 13 patients did not (non-OPLL group). All patients received pre-operative labelling with tetracycline. There was a positive correlation between vertebral body and iliac bone in the parameters of trabecular osteoid specific volume, relative osteoid volume and relative formation surface. The vertebra/ilium ratio of the mineral apposition rate, which suggests bone formation in vertebral body relatively, was higher in OPLL group significantly. The present study concludes that OPLL can be considered a condition of hyperostosis though, bone formation ability in the vertebral body of OPLL is higher than in the ilium.     

Evaluation of bone strength using finite-element analysis in patients with ossification of the posterior longitudinal ligament

BACKGROUND CONTEXTPatients with ossification of the posterior longitudinal ligament (OPLL) are often reported to have increased bone mineral density (BMD). The bone strength of the proximal femur measured by quantitative computed tomography-based finite element analysis (QCT/FEA) is reportedly comparable between healthy subjects with and without OPLL. However, the bone strength in symptomatic OPLL patients remains unknown.PURPOSETo investigate bone strength measured by QCT/FEA in symptomatic patients with OPLL.STUDY DESIGN/SETTINGA single-center prospective observational study.PATIENT SAMPLEA total of 157 patients with cervical or thoracic compressive myelopathy were included in the study.OUTCOME MEASURESWe analyzed patients’ characteristics, Japanese Orthopedic Association (JOA) score, serum laboratory tests including calcium (Ca), inorganic phosphate (Pi), and bone turnover markers, BMD of the proximal femur and lumbar spine measured using dual-energy X-ray absorptiometry, and predicted bone strength (PBS) of the proximal femur and lumbar spine measured using QCT/FEA.METHODSEligible patients were divided into the non-OPLL and OPLL groups. We compared the patients’ characteristics, JOA scores, laboratory data, BMD, and PBS of the proximal femur and lumbar spine between the non-OPLL and OPLL groups among total, male, and female patients by performing Fisher's exact test for categorical variables and the unpaired t test for continuous variables. Then, we used the inverse probability weighted logistic regression model after calculating propensity scores to compare the bone metabolism-associated markers, BMD, and PBS measurements between the groups.RESULTSAmong the eligible 157 patients, 68 were in the non-OPLL group and 89 were in the OPLL group. Compared with the non-OPLL group, the OPLL group had a significantly younger age and higher BMI in the total, male, and female patients. The JOA scores in the total and female patients were significantly higher in the OPLL group than in the non-OPLL group. The OPLL group showed significantly lower Ca levels in the female patients and significantly lower Pi levels in the total or male patients compared with the non-OPLL group in the inverse probability weighting method. The BMD of the proximal femur and lumbar spine and the PBS of the proximal femur were significantly higher in the OPLL group than in the non-OPLL group. There were no significant differences in the PBS and BMD between the male subgroups. However, the BMD and PBS of the proximal femur and lumbar spine were significantly higher in the OPLL females than in the non-OPLL females.CONCLUSIONSHyperostosis of the posterior longitudinal ligament in OPLL was associated with higher bone strength by QCT/FEA, especially in female OPLL patients.     

Association of bone morphogenetic protein-2 gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity in Chinese patients

A case–control study was conducted to examine the association between two single nucleotide polymorphisms (SNPs) in exon 2 of the bone morphogenetic protein-2 gene (BMP-2) and ossification of the posterior longitudinal ligament (OPLL), and to investigate whether SNPs of the Ser37Ala (T/G) and the Ser87Ser (A/G) in the BMP-2 gene are associated with genetic susceptibility to OPLL and its severity in Chinese subjects. The Ser87Ser (A/G) SNP has been implicated in bone mineral density (BMD) and increases the risk of OA in women. The Ser37Ala (T/G) SNP is associated with BMD and the rate of bone loss in osteoporosis and osteoporosis fractures. A total of 57 OPLL patients and 135 non-OPLL controls were studied. Radiographs of the cervical spine were analyzed to determine the presence and the severity of OPLL. The association of two SNPs with the occurrence and the extent of OPLL were statistically evaluated. There was a significant association between the Ser37Ala (T/G) polymorphism and the occurrence of OPLL in the cervical spine. However, no significant association was found between the Ser37Ala (T/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. There was a significant association between the Ser87Ser (A/G) polymorphism and the more number of ossified cervical vertebrae in OPLL patients. However, there was no statistical difference between the Ser87Ser (A/G) SNP and the occurrence of OPLL in the cervical spine. In addition, the Ser87Ser (A/G) polymorphism in male patients and in female patients showed no statistical difference between cases and controls. The present results demonstrate that BMP-2 Gene is not only a factor associated with the occurrence of OPLL, but also a factor related to more extensive OPLL. The “G” allele in the Ser37Ala (T/G) polymorphism is associated with the occurrence of OPLL, but not more extensive OPLL in the cervical spine. The “G” allele in the Ser87Ser (A/G) polymorphism promotes the extent of OPLL, whereas the “A” allele in the Ser87Ser (A/G) polymorphism restricts ectopic ossification in the cervical spine at least in Chinese subjects.     

A radiological population study on the ossification of the posterior longitudinal ligament in the spine

This paper reports the results of a radiological population study on the ossification of the posterior longitudinal ligament (OPLL) in both the cervical and the thoracic spine among Japanese. The study was carried out in the Yachiho-mura district in the central part of Japan, where 5074 people were living. X-ray examinations were made of 1058 of the people; there were 440 men and 618 women, 50 or more years of age. The roentgenograms showed 34 cases of OPLL in the cervical spine (3.2%): 19 men (4.3%) and 15 women (2.4%). The condition was most frequently observed at the level of C-4. Radiological classification showed 18 cases of the segmental type, 11 of the continuous type, and five of a mixed type. There were eight cases of OPLL in the thoracic spine (0.8%), four in men (0.9%) and four in women (0.6%). OPLL in the thoracic spine was most frequently observed at the midthoracic levels. All eight cases showed a continuous type of ossification. There were three subjects with OPLL in both the cervical and the thoracic spine. Therefore, the number of subjects with OPLL in either the cervical or the thoracic spine was 39 (3.7%) total.     

Cervical cord compression from ossification of the posterior longitudinal ligament in non-orientals

We report 14 cases of symptomatic ossification of the posterior longitudinal ligament (OPLL) diagnosed in non-oriental men between 1978 and 1985. All 14 patients had incomplete spinal cord syndromes due to OPLL in the cervical spine and had been referred undiagnosed from other institutions. Twelve had severe myelopathy and seven were wheelchair-bound before OPLL was diagnosed, while six patients had had operations elsewhere for their neurological dysfunction. There was a close association between OPLL and diffuse idiopathic skeletal hyperostosis (Forestier's disease) on plain radiographs, seven patients having both disorders. Enhanced CT scans proved to be the best diagnostic method for the localisation of cord compression, and magnetic resonance imaging, used on four recent cases, provided the best visualisation of the extent of involvement in the sagittal plane. We aim to heighten awareness of OPLL in non-orientals, in whom the clinical features, histological characteristics, and radiographic patterns are very similar to those of oriental patients.     

A radiological population study on the ossification of the posterior longitudinal ligament in the spine

Summary This paper reports the results of a radiological population study on the ossification of the posterior longitudinal ligament (OPLL) in both the cervical and the thoracic spine among Japanese. The study was carried out in the Yachiho-mura district in the central part of Japan, where 5074 people were living. X-ray examinations were made of 1058 of the people; there were 440 men and 618 women, 50 or more years of age.The roentgenograms showed 34 cases of OPLL in the cervical spine (3.2%): 19 men (4.3%) and 15 women (2.4%). The condition was most frequently observed at the level of C-4. Radiological classification showed 18 cases of the segmental type, 11 of the continuous type, and five of a mixed type.There were eight cases of OPLL in the thoracic spine (0.8%), four in men (0.9%) and four in women (0.6%). OPLL in the thoracic spine was most frequently observed at the midthoracic levels. All eight cases showed a continuous type of ossification.There were three subjects with OPLL in both the cervical and the thoracic spine. Therefore, the number of subjects with OPLL in either the cervical or the thoracic spine was 39 (3.7%) total.This study was subsidized by the Japanese Ministry of Public Health and Welfare     

Ossification of the ligamentum flavum of the cervical spine

AIM: Ossification of ligamentum flavum (OLF) mainly occurs in the thoracic spine, and rarely in the cervical spine. To clarify its etiology; the features of OLF in the cervical spine were reviewed in 50 reported cases. METHODS: Age, sex, location of OLF, classification of OLF, radiographic findings, computed tomography (CT) findings, magnetic resonance imaging findings, association of ossification of the posterior longitudinal ligament (OPLL), association of OLF in other spinal regions, and association of diffuse idiopathic skeletal hyperostosis (DISH) were analyzed in 23 detailed cases. RESULTS: Association of OPLL was observed in 7 of 20 cases and 4 of these 7 OPLL cases were at C2-4. Association of OLF in other spinal regions was recognized in 7 of 15 cases. DISH was also present in 3 of 7 cases. Local kyphosis was recognized in 10 of 12 cases by radiography. CT showed facet hypertrophy in 13 of 15 cases and lamina hypertrophy in 14 of 16 cases. Patients with OLF at C2-4 had high rates of local kyphosis and association of hyperostotic state, suggesting both local factors and systemic hyperostotic factors are involved in the formation of OLF of the upper cervical spine. CONCLUSION: Local factors may be strongly related to the formation of OLF of the middle or lower cervical spine.     

An epidemiological survey on ossification of ligaments in the cervical and thoracic spine in individuals over 50 years of age

An epidemiological survey on ossification of the spinal ligaments was performed on a total of 1,058 subjects over the age of 50 years by means of roentgenography of the cervical and thoracic spine. Ossification of the posterior longitudinal ligament (OPLL) of the cervical spine was detected in 34 subjects (3.2%) with a predilection for men, whereas OPLL in the thoracic spine was found in 8 (0.8%). There were 325 cases (30.7%) of ossification of the anterior longitudinal ligament (OALL) of stage II or above by Forestier's classification in the region from the cervical to thoracic vertebrae, and these cases included a significantly greater number of men. Ossification of the ligamenta flava (OLF) was observed in 48 cases (4.5%). As for the coexistence of ossification of these ligaments, 364 individuals (34.4%) had at least one instance of OPLL and OALL (stage II or above) in the region from the cervical to thoracic spine, and OLF in the thoracic spine.     

Predictive biomarkers of ossification progression and bone metabolism dynamics in patients with cervical ossification of the posterior longitudinal ligament

Purpose

This study aimed to establish biomarkers to predict the progression of ossification by examining ossification volume and bone metabolism dynamics in patients with ossification of the posterior longitudinal ligament (OPLL).

Methods

We assessed OPLL progression using computed tomography-based three-dimensional (3D) image analysis and examined bone metabolism dynamics in 107 patients with OPLL (men, 72; women, 35; mean age, 63.6 years). The volume of OPLL was calculated twice during the follow-up period, and OPLL progression was evaluated by the annual rate of ossification increase. Bone metabolism dynamics were assessed by routine blood tests and analysis of various serum biomarkers (including 25-hydroxyvitamin D, intact parathyroid hormone, fibroblast growth factor 23, intact N-terminal propeptide of type 1, tartrate-resistant acid phosphatase isoform 5b, sclerostin, and Dickkopf-1) and bone mineral density (BMD). Patients were classified into the progression (P) or non-progression (NP) group according to the annual rate of increase in previous 3D image analyses, and associated factors between these groups were compared.

Results

The P and NP groups consisted of 29 patients (23 men and 6 women) and 78 patients (49 men and 29 women), respectively. Univariate analysis revealed significant differences in terms of age, body mass index, serum phosphorus, serum sclerostin, and BMD. In multivariate analysis, age, serum phosphorus, and serum sclerostin were identified as independent factors associated with OPLL progression.

Conclusion

Younger age, hypophosphatemia, and high serum sclerostin are risk factors for OPLL progression. Serum phosphorus and sclerostin could serve as important biomarkers for predicting ossification progression.

     

Histopathological study of aging of the posterior portion of human cervical vertebral bodies and discs--with special reference to the early ossification of the posterior longitudinal ligament

Ossification of the posterior longitudinal ligament ( OPLL ) of the cervical spine is a disease causing spinal canal stenosis and, henceforth , spinal cord compression. This ossification is found approximately in three percent of the adult Japanese, but it is also found to be present among Chinese, Korean and other South-East Asians, whereas the incidence among Caucasians was reported to be significantly low. The etiology of this interesting ossification is still unknown although multidisciplinary studies have been carried out in Japan in recent years. The purpose of the present study is to find an early ossification of the posterior longitudinal ligament of the cervical spine and to see its relationship with other chronological changes of the surrounding structures. Material and method: One hundred and forty-one cervical spinal columns were obtained en bloc from C2 to C7 from the autopsied bodies at Juntendo University Hospital and at the Tokyo Metropolitan Medical Examiners' Office. There were 89 males and 52 females with a wide age distribution. A 66 year-old male case with advanced continuous OPLL died at Juntendo University Hospital was added to the study. The specimens were either cross-sectioned or sagittally sectioned, and studied soft-ray-roentgenologically and histopathologically. Results: There were specimens after the third decade of life showing micro-ossification along the midline of the posterior aspect of the vertebral body on cross-section as well as micro-ossification or hyperostosis adjacent to the posterior corner of the vertebral body on sagittal section. These micro-ossification or hyperostosis seemed to be a product of a physiological aging process, but could be considered as a precursor of the OPLL . The periosteum was well demonstrated on the posterior aspect of the vertebral body in the first two decades of life, but it became inconspicuous with age. In the adult spine there was no clear delineation between the deep layer of the posterior longitudinal ligament and the fibrous layer of the periosteum . The cambium layer looked absent on hematoxylin-eosin stain. However, on Giemsa stain there appeared a thin layer which would present increased cellular activity between the body and what appeared to be the fibrous layer of the periosteal. This layer was considered to be a 'sleeping cambium layer' for which it was named 'latent periostium layer (LPL)'.(ABSTRACT TRUNCATED AT 400 WORDS)     

A morphological study of the etiology and growth of ossification of the posterior longitudinal ligament of the spine

To know causative and growth factors of ossification of the posterior longitudinal ligament (OPLL) of the spine, we carried out morphological investigation on 212 cases with OPLL and 9 cases of autopsies without OPLL. The results are as follows: 1) The etiology of OPLL ensued from enchondral ossification of ligamentous fibers has not only its primary source in a hereditary factor of polygenic character, but also anatomical stress, age and sex may be influential in causative factors. 2) When the degree of the hereditary factor is weak, the lesion initiates near the posterior border of the vertebral body and grow into a segmental or localized type of OPLL in the final form. When the degree of the hereditary factor is strong, a wide ossification of a continuous or mixed type of OPLL initiates all at once and grow up with movement of the spine, after which modeling continues to take place. 3) New ossification growth over time will arise from the stress resulting from movement of the spine.     

Association between serum leptin and bone metabolic markers, and the development of heterotopic ossification of the spinal ligament in female patients with ossification of the posterior longitudinal ligament

Obesity is a risk factor for ossification of the posterior longitudinal ligament (OPLL) of the spine, which is characterized by heterotopic bone formation in the posterior longitudinal spinal ligament. Hyperleptinemia is a common feature of obese people and leptin is believed to be an important factor in the pathogenesis of OPLL. However, the association between leptin and bone metabolism and the development of OPLL is not understood fully. The objective of the present study was to determine the association between serum leptin concentration and bone metabolic markers and the extent of heterotopic ossification of the spinal ligament in patients with OPLL. The serum concentrations of leptin, insulin, fructosamine, bone-specific alkaline phosphatase, and carboxyterminal propeptide of type I procollagen, urine deoxypyridinoline levels, and the number of vertebrae with OPLL involvement were measured in 125 (68 males and 57 females) patients with OPLL. The correlation between leptin and these other factors was then examined. Serum leptin and insulin concentrations were increased significantly in OPLL females compared to non-OPLL female controls. In the females with OPLL, serum leptin concentrations corrected for body mass index correlated positively with the number of vertebrae with OPLL involvement. In females, serum leptin levels were significantly higher in patients in whom OPLL extended to the thoracic and/or lumbar spine than in patients in whom OPLL was limited to the cervical spine. Our results suggest that hyperleptinemia, in combination with hyperinsulinemia, may contribute to the development of heterotopic ossification of the spinal ligament in female patients with OPLL.     

Ossification of the spinal ligament. A radiographic reevaluation in Bologna, Italy

A radiographic reevaluation of cervical spine films of 1,258 adult patients and of thoraco-lumbar spine films of 488 of these was performed at the Rizzoli Orthopaedic Institute (Bologne, Italy), in order to detect ossification of the posterior longitudinal ligament (OPLL), the anterior longitudinal ligament (OALL), the yellow ligament (OYL) and the nuchal ligament at the cervical level, and OPLL, OALL and OYL at the thoraco-lumbar level. The incidence of OALL, OYL and ossification of the nuchal ligament corresponded with those previously reported in the literature. Cervical OPLL was found in 1.83%, with a definite prevalence in the 45-64 age group where the figure was 2.83%. This incidence is much higher than that hitherto reported in Caucasians, and is nearly the same as that in Japan. Possible explanations for this discrepancy are proposed.     

颈椎后纵韧带骨化症合并硬膜囊骨化的前路手术治疗

目的 探讨颈椎后纵韧带骨化症合并硬膜囊骨化的影像学表现、前路手术方法 及疗效.方法 2005年1月至2008年3月,前路手术治疗颈椎后纵韧带骨化症合并硬膜囊骨化患者13例.男11例,女2例;年龄43～72岁,平均53.6岁.骨化物分型:局限型3例,分节型2例,连续型5例,混合型3例;骨化物范围涉及1～5椎,平均2.8椎.患者均通过前路椎体次全切除术,切除骨化后纵韧带减压,术中6例患者后纵韧带骨化和硬膜囊骨化得以完全分离,硬膜囊保留完整,另7例患者硬膜囊出现不同程度撕裂或缺损.结果 8例患者术前CT横断面成像上表现为典型的"双影征",2例患者表现为整块骨化物存在中心低密度影,余3例患者表现为椎管狭窄率超过90%的严重后纵韧带骨化.术后5例患者并发脑脊液漏,其中3例经卧床休息、局部加压治疗3～5 d后愈合,另2例患者皮肤愈合后形成间歇性脑脊液囊肿,经反复穿刺抽液治疗1个月后痊愈.随访6个月～2年,平均1年,所有患者JOA评分从术前平均8.1分提高至术后平均13.2分,神经功能恢复率平均57.3%.骨化硬膜囊切除和未切除两组患者的神经功能恢复率差异无统计学意义.结论 CT三维重建检查有助于术前诊断后纵韧带骨化合并硬膜囊骨化,合并硬膜囊骨化并非前路手术的禁忌证,前路手术切除骨化后纵韧带、彻底减压是提高此类患者手术疗效的关键.     

Significance of Serum Levels of Type I Procollagen Peptide and Intact Osteocalcin and Bone Mineral Density in Patients with Ossification of the Posterior Longitudinal Ligaments

This study was performed to evaluate the correlation between serum biochemical marker levels of bone metabolism and bone mineral density (BMD) in patients with ossification of the posterior longitudinal ligaments (OPLL). In addition, the efficacy of these markers in the prediction of the progression of OPLL was also examined. In 40 patients with OPLL, and in age- and gender-matched controls (n= 36), the levels of C-terminal extension peptide of type I procollagen (PICP) and intact osteocalcin were quantitated by a sandwich enzyme-linked immunosorbent assay as serum markers of bone formation. BMD of the whole body was measured using dual-energy X-ray absorptiometry. Serum PICP and intact osteocalcin levels were significantly increased in patients with OPLL. There was a significant correlation between serum bone formation marker levels and BMD in both the OPLL and the control groups. Patients with radiological progression of OPLL showed a level higher than the mean + 2 SD of controls in PICP, intact osteocalcin, and BMD. In addition, the levels of serum PICP and intact osteocalcin increased in correspondence with the progression of OPLL without statistical significance. In patients without any growth of OPLL, however, all the parameters were below the mean + 2 SD of controls. Thus, aggravation of bone formation activity was suggested to be closely correlated with the development of OPLL. In addition, serial measurements of these parameters might be useful for estimating the progression of OPLL. Received: 27 November 1995 / Accepted: 19 February 1996     

Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a disease that causes paralysis by compressing the spinal cord. Based on the fact that the nucleotide pyrophosphatase (Npps) gene is responsible for ectopic ossification in ttw, an OPLL model mouse, the possibility was explored whether the human NPPS gene is associated with susceptibility to and severity of OPLL. First, we screened for single-nucleotide polymorphisms (SNPs) in the human NPPS locus using selected 25 OPLL patients with young onset (< 35 years old) or severe ossification (> 10 ossified vertebrae), and identified three novel SNPs in the locus. A case-control association study between 180 OPLL patients and 265 non-OPLL controls showed that one of these SNPs, IVS15-14T --> C substitution, was more frequently observed in OPLL patients (p = 0.022), especially in those with severe ossification (p < 0.0001) and young onset (p = 0.002), than in controls. A stratified study with the number of ossified vertebrae in OPLL patients revealed that IVS15-14T --> C substitution (p = 0.013) as well as young onset (p = 0.046) and female sex (p = 0.006) were associated with severe ossification. We conclude that the IVS15-14T --> C substitution in the human NPPS gene is associated not only with susceptibility to, but also with severity of OPLL.