JBJS | Insulin Secretory Response Is Positively Associated with the Extent of Ossification of the Posterior Longitudinal Ligament of the Spine

The Journal of Bone & Joint Surgery, Volume 83, Issue 10

Scientific Article | October 01, 2001

Insulin Secretory Response Is Positively Associated with the Extent of Ossification of the Posterior Longitudinal Ligament of the Spine

Toru Akune, MD; Naoshi Ogata, MD; Atsushi Seichi, MD; Isao Ohnishi, MD; Kozo Nakamura, MD; Hiroshi Kawaguchi, MD

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Investigation performed at the Department of Orthopaedic Surgery, University of Tokyo, Tokyo, Japan
Toru Akune, MD
Naoshi Ogata, MD
Atsushi Seichi, MD
Isao Ohnishi, MD
Kozo Nakamura, MD
Hiroshi Kawaguchi, MD
Department of Orthopaedic Surgery, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail address for H. Kawaguchi: kawaguchi-ort@h.u-tokyo.ac.jp

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Funds were received in total or partial support of the research or clinical study presented in this article. The funding sources were a Grant-in-Aid from the Investigation Committee on the Ossification of Spinal Ligaments, Japanese Ministry of Public Health and Welfare; a Grant-in-Aid (#11470301) for Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture; the Bristol-Myers Squibb/Zimmer Unrestricted Research Grant; and the Uehara Memorial Foundation.

The Journal of Bone & Joint Surgery. 2001; 83:1537-1544

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Abstract

Background: Glucose intolerance is frequently found in patients with ossification of the posterior longitudinal ligament of the spine. This study was undertaken to examine the relationship between glucose intolerance and the extent of ossification in patients with ossification of the posterior longitudinal ligament.

Methods: A total of 100 patients with ossification of the posterior longitudinal ligament (the overall study group), including fifty-two inpatients who were scheduled to have an operation (the inpatient group) and forty-eight outpatients who had undergone an operation, were analyzed. Indices of glucose metabolism—fasting plasma glucose and serum insulin levels, hemoglobin A1c level, and insulinogenic index (a ratio of the increment of the serum level of insulin to that of glucose)—as well as age and body-mass index were correlated with the extent of ossification, as determined by the number of vertebral levels affected with ossification of the posterior longitudinal ligament (extent of ossification), in the inpatient group. In addition, a similar analysis was performed in twenty-eight inpatients (the selected inpatient group) whose ages and body-mass indices were within one standard deviation of the mean values of those of the inpatient group. Association of a polymorphism in the gene of insulin receptor substrate-1, an essential substrate in insulin signaling, with the extent of ossification was evaluated with genomic DNA extracted from the overall study group.

Results: Multiple-regression analysis revealed direct correlations of age (p = 0.038), body-mass index (p = 0.006), and insulinogenic index (p = 0.0003) with the extent of ossification of the posterior longitudinal ligament in the inpatient group. The fasting plasma glucose level, the hemoglobin A1c level, and the stage of glucose tolerance were not associated with the extent of ossification. In the analysis of the selected inpatient group, only the insulinogenic index was correlated with the extent of ossification (p = 0.002). However, no significant association was seen between the insulin receptor substrate-1 polymorphism and the extent of ossification.

Conclusions: The insulin secretory response was associated with the extent of ossification of the posterior longitudinal ligament. Since insulin receptor substrate-1 is expressed both in the spinal ligament and in the tissues regulating glucose metabolism, we speculate that some other molecules related to insulin signaling that are impaired only in the tissues regulating glucose metabolism may be responsible for the progression of ossification. We also speculate that the upregulation of insulin production due to the impairment of insulin action may stimulate osteoprogenitor cells in the ligament to induce ossification.

Clinical Relevance: The insulinogenic index may be useful as a serum marker for the prediction of progression of ossification of the posterior longitudinal ligament. This study may serve as a stimulus for evaluation of the use of various drugs that may improve the response to insulin in the tissues regulating glucose metabolism to prevent the progression of ossification.

Figures in this Article

Introduction

Introduction | Materials and Methods | Results | Discussion | References

Ossification of the posterior longitudinal ligament is a disease that involves ectopic ossification in this ligament of the spine^1-3. There is a prevalence of 2% to 4% in Asian countries (mostly in patients older than forty years), while a lower prevalence has been reported in non-Asian countries⁴. Although the extent of ossification is minimal in most affected patients and most patients are asymptomatic, severe paralysis can develop when the ossification progresses and causes compression of the spinal cord^1-3. The prognosis is worse when the ossification extends over multiple levels^5,6. However, there is no treatment to prevent the progression of this disease and no diagnostic marker to predict recurrence or progression. Therefore, it is clinically important to elucidate the pathophysiology of the progression of the ossification to prevent severe myelopathy and to improve the clinical course.

Patients with ossification of the posterior longitudinal ligament have greater systemic bone mineral density⁷ and sometimes have endocrinological disorders (specifically, in the metabolism of glucose and calcium)^8-16. Patients with severe ossification and those with diffuse idiopathic skeletal hyperostosis have been noted to have associated obesity and glucose intolerance^{9,10,14,15,17,18}. The prevalence of ossification of the posterior longitudinal ligament is high in patients with non-insulin-dependent diabetes mellitus^10,15. Because patients who are obese and have this type of diabetes mellitus often exhibit increased secretion and impaired action of insulin, it is possible that changes in the secretion or action of insulin may play a role in the progression of the disease. Insulin is known to induce a wide variety of growth and metabolic responses and to play important roles in the anabolic regulation of bone metabolism^19,20. Insulin initiates a cellular response by binding not only to its own endogenous tyrosine kinase receptor²¹ but also to the receptor of insulin-like growth factor-I (IGF-I), a potent anabolic factor for bone formation^22,23. A major substrate of insulin and IGF-I receptor tyrosine kinase is insulin receptor substrate-1 (IRS-1), which rapidly becomes phosphorylated on multiple tyrosine residues following ligand stimulation²⁴. We recently reported that IRS-1 is essential to maintain bone turnover in mice lacking the IRS-1 gene²⁵. A molecular scanning study of the human IRS-1 gene revealed several polymorphisms resulting in amino-acid substitutions (so-called missense polymorphisms); the most common of these was a glycine (Gly) to arginine (Arg) substitution at codon 972²⁶. This Arg⁹⁷² mutation in the IRS-1 locus has been reported to impair insulin-stimulated signaling and to be twice as prevalent in patients with non-insulin-dependent diabetes mellitus as it is in control subjects^26,27.

The current study was undertaken to examine the relationship between glucose intolerance and the extent of ossification of the posterior longitudinal ligament. Since we suspected that the association of non-insulin-dependent diabetes mellitus and ossification of the posterior longitudinal ligament can be ascribed to the disorder of a common molecule, IRS-1, we investigated further the association of this missense polymorphism in the IRS-1 locus with the extent of ossification of the posterior longitudinal ligament by analyzing genomic DNA extracted from patients with this disease.

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Fig. 1:: Correlation between the extent of ossification of the posterior longitudinal ligament (OPLL extent) and each of the other factors—age (A), body-mass index (BMI) (B), fasting plasma glucose level (FPG) (C), hemoglobin A1c level (Hb A1c) (D), fasting serum insulin level (E), and insulinogenic index (F)—in the inpatient group of fifty-two patients.

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Fig. 2:: Correlation between the extent of ossification of the posterior longitudinal ligament (OPLL extent) and each of the other factors—age (A), body-mass index (BMI) (B), fasting plasma glucose level (FPG) (C), hemoglobin A1c level (HB A1c) (D), fasting serum insulin level (E), and insulinogenic index (F)—in the selected inpatient group of twenty-eight patients whose ages and body-mass indices were within one standard deviation of the mean value of those of the entire group of fifty-two inpatients.

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Fig. 3:: Correlation of the extent of ossification of the posterior longitudinal ligament (OPLL extent) and insulinogenic index with each stage of glucose tolerance—normal glucose tolerance (NGT), impaired glucose regulation (IGR), and diabetes mellitus (DM)—in the inpatient group of fifty-two patients (A and C) and in the selected inpatient group of twenty-eight patients (B and D). In A and B, closed circles indicate patients with a higher-than-average insulinogenic index (17.9 and 15.4 U/mol, respectively) while open circles indicate those with a lower insulinogenic index. In C and D, closed circles indicate patients with a greater-than-average extent of ossification (5.58 and 4.61 vertebrae, respectively) while open circles indicate those with a lower extent of ossification. Bars indicate the mean and the standard deviation for each group. *The value is significantly higher than that for patients with diabetes mellitus (p < 0.05). #The value is significantly higher than that for patients with diabetes mellitus (p < 0.01).

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Fig. 4:: The mean values for the extent of ossification of the posterior longitudinal ligament (OPLL extent) in patients with each genotype of insulin receptor substrate-1 (IRS-1) polymorphism. The allele that could be digested by the restriction enzyme is expressed as a lowercase "b" (translated into Arg⁹⁷²), while the allele that could not be digested is expressed as an uppercase "B" (translated into Gly⁹⁷²). Bars and error bars indicate the mean and the standard error of the mean, respectively, for the number of patients indicated in parentheses. There was no patient with a homozygous bb genotype. No significant difference in extent of ossification was seen between the two genotypes.

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TABLE I: Results of a Multiple-Regression Analysis with the Extent of Ossification of the Posterior Longitudinal Ligament as the Outcome Variable in the Inpatient Group of Fifty-two Patients (R² = 0.59)

Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.116	0.054	—0.235	0.038
Body-mass index	0.454	0.160	0.339	0.006
Fasting plasma glucose	—0.666	0.596	—0.114	0.269
Hemoglobin A1c	0.686	0.964	0.075	0.480
Fasting serum insulin	—0.092	0.090	—0.127	0.310
Insulinogenic index	0.157	0.040	0.456	0.0003

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Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.116	0.054	—0.235	0.038
Body-mass index	0.454	0.160	0.339	0.006
Fasting plasma glucose	—0.666	0.596	—0.114	0.269
Hemoglobin A1c	0.686	0.964	0.075	0.480
Fasting serum insulin	—0.092	0.090	—0.127	0.310
Insulinogenic index	0.157	0.040	0.456	0.0003

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TABLE II: Results of a Multiple-Regression Analysis with the Extent of Ossification of the Posterior Longitudinal Ligament as the Outcome Variable in the Selected Inpatient Group of Twenty-eight Patients (R² = 0.49)

Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.070	0.103	—0.118	0.503
Body-mass index	0.037	0.268	0.027	0.891
Fasting plasma glucose	—0.173	0.692	—0.047	0.805
Hemoglobin A1c	0.846	1.233	0.141	0.500
Fasting serum insulin	—0.018	0.099	—0.036	0.857
Insulinogenic index	0.191	0.055	0.654	0.002

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Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.070	0.103	—0.118	0.503
Body-mass index	0.037	0.268	0.027	0.891
Fasting plasma glucose	—0.173	0.692	—0.047	0.805
Hemoglobin A1c	0.846	1.233	0.141	0.500
Fasting serum insulin	—0.018	0.099	—0.036	0.857
Insulinogenic index	0.191	0.055	0.654	0.002

Materials and Methods

Introduction | Materials and Methods | Results | Discussion | References

Patients

A total of 100 patients (eighty-nine men and eleven women) with ossification of the posterior longitudinal ligament were analyzed. These patients, who made up the overall study group, ranged in age from thirty-two to eighty years, with a mean age of 58.1 years. Fifty-two of the patients (the inpatient group) were scheduled to undergo decompression surgery at our hospital between 1994 and 1999, and the remaining forty-eight patients had previously undergone the operation between 1989 and 1993. The glucose metabolism of the fifty-two inpatients (forty-seven men and five women, with an age range of thirty-two to seventy-eight years and a mean age of 57.4 years) was analyzed. The extent of ossification was determined on the basis of the number of vertebral levels affected on lateral radiographs of the cervical, thoracic, and lumbar spine made just before the decompression surgery. Tomograms were made of the lower cervical and upper thoracic areas in which lesions could not be detected on plain radiographs. The associations between the extent of the ossification and indices of glucose metabolism were determined. To study these associations in the middle range of ages and body-mass indices, we selected a subset of twenty-eight patients (the selected inpatient group of twenty-six men and two women) whose ages and body-mass indices were within one standard deviation of the mean value of those of the entire inpatient group (57.4 ± 9.5 years and 25.1 ± 3.5 kg/m², respectively), and a similar analysis was performed. To analyze the genetic polymorphism in the IRS-1 locus, the overall study group (inpatients and outpatients) was evaluated. The study protocol was approved by the committee on ethics of human research at our institute, and informed consent was obtained from each subject.

Analysis of Glucose Metabolism

Within one week before the operation, a 75-g oral glucose-tolerance test was administered to the inpatient group, and plasma glucose, hemoglobin A1c, and serum immunoreactive insulin levels were measured. Glucose tolerance was classified into three stages according to the 1998 criteria of the World Health Organization²⁸: normal glucose tolerance, impaired glucose regulation, and diabetes mellitus. Normal glucose tolerance was defined as a fasting plasma glucose level of <6.1 mmol/L and a level of <7.8 mmol/L two hours after the oral glucose-tolerance test. Diabetes mellitus was defined as a fasting plasma glucose level of 7.0 mmol/L or a level of 11.1 mmol/L two hours after the oral glucose-tolerance test. Patients who did not meet the criteria for normal glucose tolerance or diabetes mellitus were classified as having impaired glucose regulation.

The insulinogenic index was calculated as follows: (serum insulin level at thirty minutes — serum insulin level at zero minutes)/(plasma glucose level at thirty minutes — plasma glucose level at zero minutes).

Analysis of Genetic Polymorphism

Because the change in the insulin secretory response can be ascribed to an abnormality of the response to insulin in its target tissues regulating glucose metabolism (including liver, muscle, and adipose tissues), it was speculated that the abnormality of some molecules related to the insulin signaling may be involved in regulating the extent of ossification. We therefore sought to determine the association of the most common polymorphism (Gly to Arg substitution at codon 972) in the gene of IRS-1²⁶, an essential substrate in insulin signaling^24,25, with the extent of ossification of the posterior longitudinal ligament. To analyze this association, peripheral blood samples were obtained from all 100 patients. Genomic DNA was extracted from leukocytes and amplified by polymerase chain reaction with use of the sense primer 5¢-CTTCTGTCAGGTGTCCATCC (A = adenine, T = thiamine, G = guanine, and C = cytosine) and the antisense primer 5¢-TGGCGAGGTGTCCACGTAGC, and a 263-base-pair polymerase chain-reaction product was obtained. Because the polymorphism is a restriction fragment length (the size of DNA digested by the restriction enzyme) polymorphism by BstNI restriction endonuclease, this enzyme digestion was carried out as described previously²⁶, and the allele that could be digested by the enzyme was expressed as a lowercase "b" (translated into Arg⁹⁷²), while the allele that could not be digested was expressed as an uppercase "B" (translated into Gly⁹⁷²). The association of the genotype with the extent of ossification was then investigated.

Statistical Analysis

Pearson correlation coefficients between the extent of ossification and each of the other factors—age, body-mass index, and the indices of glucose metabolism—were calculated. Multiple-regression analysis was also used to assess the association between the extent of ossification (the outcome variable) and the other measured variables. Independent variables were age, body-mass index, and the indices of glucose metabolism. The mean extent of ossification and the mean insulinogenic index were correlated with the glucose-tolerance stage with use of analysis of variance. The extents of ossification were compared between the genotypes with use of analysis of variance. The significance of differences was determined with post-hoc testing and Bonferroni’s method. A p value of less than 0.05 was considered significant.

Results

Introduction | Materials and Methods | Results | Discussion | References

Correlation of the Extent of Ossification in the Inpatient Group

The extent of ossification was inversely correlated with age (r = —0.52, p < 0.0001) and was positively correlated with body-mass index (r = 0.57, p < 0.0001) (Fig. 1, A and B) in the inpatient group of fifty-two patients. There was an inverse correlation between age and body-mass index (r = —0.39, p = 0.004). These results show that younger patients not only had a higher body-mass index but also had more severe ossification, suggesting the existence of a group with onset of ossification of the posterior longitudinal ligament at a younger age, a higher body-mass index, and severe ossification in this disease population. Among the indices of glucose metabolism, neither the fasting plasma glucose level (r = —0.20, p = 0.151) nor the hemoglobin A1c level (r = —0.07, p = 0.641) was associated with the extent of ossification (Fig. 1, C and D). However, the extent of ossification had a significant association with the fasting serum insulin level (r = 0.35, p = 0.012) and an even stronger association with the insulinogenic index (r = 0.67, p < 0.0001) (Fig. 1, E and F). These results suggest that the extent of ossification is not correlated with the severity of glucose intolerance but is strongly associated with the insulin secretory response expressed by the insulinogenic index. To exclude possible bias effects among these factors, multiple-regression analysis with the extent of ossification as the outcome variable was performed. Among independent variables, age (p = 0.038), body-mass index (p = 0.006), and insulinogenic index (p = 0.0003), but not fasting plasma glucose, hemoglobin A1c, or fasting serum insulin level, showed direct univariate associations with the extent of ossification after an adjustment for other factors (Table I).

Correlation of the Extent of Ossification in the Selected Inpatient Group

In the selected group of twenty-eight inpatients whose ages and body-mass indices were within one standard deviation of the mean value of those of the entire group of fifty-two inpatients, neither age (r = —0.09, p = 0.664) nor body-mass index (r = 0.12, p = 0.534) was found to be associated with the extent of ossification (Fig. 2, A and B). Similarly, the fasting plasma glucose (r = —0.23, p = 0.236), hemoglobin A1c (r = 0.19, p = 0.335), and fasting serum insulin levels (r = 0.31, p = 0.104) were not found to be associated with the extent of ossification (Fig. 2, C, D, and E). However, the insulinogenic index did have a strong association with the extent of ossification (r = 0.68, p < 0.0001) (Fig. 2, F). Multiple-regression analysis revealed that, among these variables, only the insulinogenic index had a direct univariate association with the extent of ossification after an adjustment for other factors (age, body-mass index, fasting plasma glucose, hemoglobin A1c, and fasting serum insulin level) (p = 0.002) (Table II). The fact that this index is more representative of the responsive ability of pancreatic b-cells to secrete insulin than of the fasting serum insulin level indicates that, among the indices of glucose metabolism, the insulin secretory response was most strongly associated with the extent of ossification, independent of age and obesity.

Association of the Extent of Ossification and the Insulinogenic Index with Each Stage of Glucose Tolerance in the Entire and the Selected Inpatient Groups

More than 80% of the fifty-two inpatients were classified either as having normal glucose tolerance (48% [twenty-five] of the fifty-two inpatients and 43% [twelve] of the twenty-eight selected inpatients) or as having impaired glucose regulation (39% [twenty] and 39% [eleven], respectively), with <20% of the patients classified as having diabetes mellitus (Fig. 3, A through D). Interestingly, both the extent of ossification and the insulinogenic index of patients with diabetes mellitus were lower than those of patients with normal glucose tolerance or impaired glucose regulation in both populations. These findings confirm that the severity of glucose intolerance is inversely related to the extent of ossification. Furthermore, among the patients with normal glucose tolerance or impaired glucose regulation, most of those with a higher-than-average insulinogenic index (closed circles in Fig. 3, A and B) had a greater extent of ossification than did those with a lower insulinogenic index. Conversely, the patients with a greater-than-average extent of ossification (closed circles in Fig. 3, C and D) had a higher insulinogenic index than did those with a lower extent of ossification in both populations. Both the extent of ossification and the insulinogenic index of all patients with diabetes mellitus were less than the average values in the two populations. Therefore, it appears that patients with severe ossification of the posterior longitudinal ligament have milder glucose intolerance and a greater insulin secretory response.

Association of the Extent of Ossification with Genetic Polymorphism of IRS-1 in the Overall Study Group

In the overall study group of 100 patients, the distribution of each genotype was bb in no patients, Bb in thirteen, and BB in eighty-seven. With the numbers available, no significant difference in the extent of ossification was seen between the Bb and BB genotypes of the patients (Fig. 4). This result was reproducible when the inpatient group of fifty-two patients was analyzed (data not shown). Therefore, the polymorphism of IRS-1 gene locus that has been reported to be associated with non-insulin-dependent diabetes mellitus^29,30 was shown not to be associated with the extent of ossification, indicating the involvement of different genetic backgrounds in the etiology of these two diseases.

Discussion

Introduction | Materials and Methods | Results | Discussion | References

We investigated the relationship between the extent of ossification of the posterior longitudinal ligament and several indices of glucose metabolism in patients with considerable ossification who were scheduled to undergo surgical decompression. Insulin secretory response as determined with the insulinogenic index was strongly associated with the extent of ossification, while the severity of glucose intolerance was not associated with it or was inversely associated with it. The association between the insulinogenic index and the extent of ossification was found to be independent of both age and obesity.

Histological studies of tissues from patients with ossification of the posterior longitudinal ligament have revealed that undifferentiated mesenchymal cells in the ligament differentiate into chondrocytes, followed by endochondral ossification^2,3,31,32. Because insulin is well known to be a potent bone anabolic factor^19,20, we suspected that exposure of mesenchymal cells to high levels of insulin causes ossification. This upregulation of insulin level may be due to the augmentation of insulin secretion from pancreatic β-cells to compensate for the impairment of response to insulin in the tissues regulating glucose metabolism such as liver, muscle, and adipose tissues.

It is interesting that the severity of glucose intolerance as assessed with use of the oral glucose-tolerance test was inversely related to the extent of ossification and the insulinogenic index, both of which were lowest in the patients with diabetes mellitus (a fasting plasma glucose level of 7.0 mmol/L or a level of 11.1 mmol/L two hours after the oral glucose-tolerance test). The relationship between the severity of glucose intolerance and insulin secretion is regulated by complicated mechanisms³³. As a nondiabetic individual begins to become diabetic and the fasting plasma glucose level rises, the pancreatic β-cells recognize the disruption of the glucose homeostasis and augment insulin secretion in an attempt to compensate for the disturbance in glucose metabolism. Thus, at the early stage of glucose intolerance, insulin secretion is upregulated. However, once the β-cells can no longer maintain this accelerated rate of insulin secretion, the secretion slows, finally leading to a marked deficiency in secretion in patients with severe diabetes. It should be noted that some patients with normal glucose tolerance as well as those with impaired glucose regulation showed that a high insulinogenic index was associated with a greater extent of ossification. These results strongly suggest that ossification is dependent on the responsive insulin secretion from healthy β-cells and not on the severity of glucose intolerance.

Because we suspected the involvement of some molecule or molecules related to insulin signaling in the progression of ossification, we examined a genetic polymorphism of a major substrate of insulin receptor tyrosine kinase: IRS-1. However, we found that it was not associated with the extent of ossification. Since this polymorphism is reported to be directly related to the IRS-1 function and to be associated with the prevalence of non-insulin-dependent diabetes mellitus^26,27, we believe that the lack of association strongly suggests the absence of involvement of the abnormality of the IRS-1 molecule in the extent of ossification. IRS-1 is expressed not only in the tissues regulating glucose metabolism but also in the spinal ligament²⁴. We therefore speculate that some other molecules in insulin signaling that are impaired only in the tissues regulating glucose metabolism—such as liver, muscle, and adipose tissues—may be responsible for the ossification.

Ossification of the posterior longitudinal ligament is a common disease whose etiology involves a multiplicity of genetic and environmental factors. The prevalence of the disease increases with age, implying the involvement of environmental factors that accumulate with aging. However, this study clearly demonstrated that there is a subgroup of patients with ossification of the posterior longitudinal ligament who have onset at a young age, obesity, and severe ossification. It is likely that genetic background contributes much more strongly to the ossification in this subgroup of patients than in patients with an older age at onset and milder ossification. Although this study failed to identify the responsible gene locus, several previous studies have suggested candidate genes such as nucleotide pyrophosphatase (NPPS)^34,35 and collagen 11A2³⁶. Because the ossification type varies, the etiology of ossification of the posterior longitudinal ligament likely involves a multiplicity of genetic factors, and progression may be regulated by different genetic factors from those regulating its incidence.

In addition to demonstrating the relationship of insulin secretory response to the pathophysiology of progression of ossification of the posterior longitudinal ligament, the results of this study might also be applied to the diagnosis and treatment of the disease. The postoperative course of patients with ossification of the posterior longitudinal ligament is not always satisfactory, and one of the reasons is the recurrence or progression of the ossification around the site of the operation. Therefore, some diagnostic marker to predict the progression of ossification may be useful to determine the surgical method and the extent of decompression. The insulinogenic index may be a serum marker for this condition. Currently, there is no treatment to prevent the progression of ossification of the posterior longitudinal ligament. Drugs to improve the response to insulin in its target tissues regulating glucose metabolism could provide a novel treatment.

We conclude that the upregulation of insulin production due to the impairment of insulin response in tissues regulating glucose metabolism may act on osteoprogenitor cells in the spinal ligament to induce ossification. Additional screening studies on variations in the genes related to insulin signaling may identify the genetic background of the progression of ossification of the posterior longitudinal ligament.

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Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.116	0.054	—0.235	0.038
Body-mass index	0.454	0.160	0.339	0.006
Fasting plasma glucose	—0.666	0.596	—0.114	0.269
Hemoglobin A1c	0.686	0.964	0.075	0.480
Fasting serum insulin	—0.092	0.090	—0.127	0.310
Insulinogenic index	0.157	0.040	0.456	0.0003

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Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.116	0.054	—0.235	0.038
Body-mass index	0.454	0.160	0.339	0.006
Fasting plasma glucose	—0.666	0.596	—0.114	0.269
Hemoglobin A1c	0.686	0.964	0.075	0.480
Fasting serum insulin	—0.092	0.090	—0.127	0.310
Insulinogenic index	0.157	0.040	0.456	0.0003

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Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.070	0.103	—0.118	0.503
Body-mass index	0.037	0.268	0.027	0.891
Fasting plasma glucose	—0.173	0.692	—0.047	0.805
Hemoglobin A1c	0.846	1.233	0.141	0.500
Fasting serum insulin	—0.018	0.099	—0.036	0.857
Insulinogenic index	0.191	0.055	0.654	0.002

Add to My JBJS

Variable	Regression Coefficient	Standard Error	Standardized Regression Coefficient	P Value
Age	—0.070	0.103	—0.118	0.503
Body-mass index	0.037	0.268	0.027	0.891
Fasting plasma glucose	—0.173	0.692	—0.047	0.805
Hemoglobin A1c	0.846	1.233	0.141	0.500
Fasting serum insulin	—0.018	0.099	—0.036	0.857
Insulinogenic index	0.191	0.055	0.654	0.002