Ossification of the posterior longitudinal ligament is linked to heterotopic ossification of the ankle/foot tendons.

INTRODUCTION: Systemic osteogenesis has been speculated to be involved in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL). Our purpose was to compare the radiologic prevalence and severity of heterotopic ossification in foot tendons of Japanese patients with OPLL and to determine their association with systemic heterotopic ossification. MATERIALS AND METHODS: Clinical and radiographic data of 114 patients with OPLL were collected from 2020 to 2022. Control data were extracted from a medical database of 362 patients with ankle radiographs. Achilles and plantar tendon ossification were classified as grades 0-4, and the presence of osteophytes at five sites in the foot/ankle joint was assessed by radiography. Factors associated with the presence and severity of each ossification were evaluated by multivariable logistic regression and linear regression analysis. RESULTS: The prevalence of Achilles and plantar tendon ossification (grade ≥ 2) was 4.0-5.5 times higher in patients with OPLL (40-56%) than in the controls (10-11%). The presence of Achilles tendon ossification was associated with OPLL, age, and coexisting plantar tendon ossification, and was most strongly associated with OPLL (standardized regression coefficient, 0.79; 95% confidence interval, 1.34-2.38). The severity of Achilles and plantar tendon ossification was associated with the severity of ossification of the entire spinal ligament. CONCLUSIONS: The strong association of foot tendon ossification with OPLL suggests that patients with OPLL have a systemic osteogenesis background. These findings will provide a basis for exploring new treatment strategies for OPLL, including control of metabolic abnormalities.

A patient and public involvement study to explore patient perspectives on the efficacy of treatments for pain and numbness derived from ossification of posterior longitudinal ligament of the spine.

BACKGROUND: Chronic pain and numbness are common complaints in patients with ossification of the posterior longitudinal ligament of the spine (OPLL). However, it is unclear whether the current treatments are effective in patients with OPLL in terms of improving pain and numbness. METHODS: A cross-sectional survey of patients with OPLL was conducted to determine patient satisfaction with surgery and drug therapy for pain and numbness, and its association with health-related quality of life. The survey was conducted by a patient association and its members, and anonymized data were analyzed by physicians. Comparisons between groups were made using T-tests or Kruskal-Wallis and Steel-Dwass tests, chi-square tests, and Fisher's exact tests. RESULTS: Data from 121 patients with OPLL (age 69 ± 11 years, 69 males; 43 females; and 7 unknown) who completed a mailed questionnaire were analyzed. Of the 93 patients with a history of surgery for OPLL, 24% and 18% reported much improvement in pain and numbness, respectively. After surgery, 42% and 48% reported some improvement, and 34% and 34% reported no improvement, respectively. Patients whose numbness did not improve with surgery had a significantly poorer health-related quality of life than those who did. Of the 78 patients who received medication, only 2% reported "much improvement," 64% reported "some improvement," and 31% reported "no improvement at all." Compared to patients with OPLL only in the cervical spine, those with diffuse-type OPLL showed poorer improvement in numbness after surgery and poorer quality of life. CONCLUSIONS: The majority of patients with OPLL belonging to the association were unsatisfied with surgery and pharmacotherapy in terms of pain and numbness improvement, indicating that there is an unmet medical need for more effective treatment for chronic pain and numbness in patients with OPLL.

Sagittal alignment cut-off values for predicting future fall-related fractures in community-dwelling osteoporotic women.

PURPOSE: Determining the optimal cut-off value of sagittal alignment for detecting osteoporotic patients at high risk for fall-related fractures is essential for understanding fracture risk and informing clinicians and physical therapists. We determined the optimal cut-off value of sagittal alignment for detecting osteoporotic patients at high risk for fall-related fractures in this study. METHODS: In the retrospective cohort study, we enrolled a total of 255 women aged ≥ 65 years who visited an outpatient osteoporosis clinic. We measured participants' bone mineral density and sagittal alignment, including sagittal vertical axis (SVA), pelvic tilt, thoracic kyphosis, pelvic incidence, lumbar lordosis, global tilt, and gap score at the initial visit. The cut-off value for sagittal alignment that was significantly associated with fall-related fractures was calculated after using multivariate Cox proportional hazards regression analysis. RESULTS: Ultimately, 192 patients were included in the analysis. After a mean follow-up of 3.0 years, 12.0% (n = 23) had fractures due to falls. Multivariate Cox regression analysis confirmed that SVA (hazard ratio [HR] = 1.022, 95% confidence interval [CI] = 1.005-1.039) was the only independent predictor of fall-related fracture occurrence. The predictive ability of SVA for the occurrence of fall-related fractures was moderate (area under the curve [AUC] = 0.728, 95% CI = 0.623-0.834), with a cut-off value of 100 mm for SVA. SVA classified by cut-off value was also associated with an increased risk of developing fall-related fractures (HR = 17.002, 95% CI = 4.102-70.475). CONCLUSION: We found that assessing the cut-off value of sagittal alignment would be useful information in understanding fracture risk in postmenopausal older women.

Does locomotive syndrome severity predict future fragility fractures in community-dwelling women with osteoporosis?

OBJECTIVES: We investigated whether the locomotive syndrome (LS) severity affects future fragility fractures in osteoporosis patients. METHODS: In this retrospective cohort study, 315 women with osteoporosis (mean follow-up period, 2.8 years) were reviewed, of whom 244 were included in the analysis. At baseline, we obtained medical information, bone mineral density of the lumbar spine and femoral neck, and sagittal vertical axis. Additionally, LS risk was assessed using the two-step test, stand-up test, and 25-question geriatric locomotive function scale scores. The LS risk test results were used to classify LS severity, which was rated on a 4-point scale from stage 0 (robust) to 3 (worsening). Cox proportional hazards regression analysis was used to determine the association of the severity with future fragility fracture. RESULTS: Fragility fractures occurred in 37 of 315 participants (11.8%). This study showed that sagittal vertical axis (hazard ratio = 1.014; 95% confidence interval, 1.005-1.023; p value = 0.003) and LS severity (hazard ratio =1.748; 95% confidence interval, 1.133-2.699; p = 0.012) were independent risk factors for incidence of fragility fracture. CONCLUSIONS: This study revealed the LS severity to predicted fragility fractures. We suggested that the progression of LS associated with osteoporosis increases the fracture risk.

Association between obesity and ossification of spinal ligaments in 622 asymptomatic subjects: a cross-sectional study.

INTRODUCTION: Previous studies on patients with symptoms of spinal ligament ossification, including ossification of the posterior longitudinal ligament (OPLL) and ligamentum flavum (OLF), have not clarified whether obesity is a cause or consequence of these diseases and were limited by selection bias. Thus, we investigated the association between obesity and the prevalence of spinal ligament ossification in randomly selected asymptomatic subjects. MATERIALS AND METHODS: Between April 2020 and March 2021, 622 asymptomatic Japanese subjects who underwent computed tomography of neck to pelvis for medical check-up purposes were included. All subjects were divided into the following three groups: normal weight (body mass index [BMI] < 25 kg/m2), obese I (25 ≤ BMI < 30 kg/m2), and obese II (BMI ≥ 30 kg/m2). The relationship between factors affecting the presence of each spinal ligament ossification was evaluated using multivariate logistic regression analysis. RESULTS: The proportion of subjects with thoracic OPLL was significantly higher in the obese II group than in the other two groups (vs. normal weight, P < 0.001; vs. obese I, P < 0.001). BMI was associated with the prevalence of OLF, cervical OPLL, thoracic OPLL, and ossification of the anterior longitudinal ligament (OALL). BMI was most significantly associated with the prevalence of thoracic OPLL (ß, 0.28; 95% confidence interval, 0.17-0.39). CONCLUSION: BMI was associated with the prevalence of OALL, cervical OPLL, thoracic OPLL, and OLF in asymptomatic subjects, suggesting that obesity is associated with the development of heterotopic ossification of the spinal ligaments.

Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis.

INTRODUCTION: Bisphosphonates (BPs) have been shown to reduce the incidence of vertebral fractures during the first year or two of glucocorticoid (GC) treatments and are therefore recommended as a first-line treatment for GC-induced osteoporosis (GIO). However, there are theoretical concerns about the long-term use of BPs in low-turnover osteoporosis caused by chronic GC therapy. MATERIALS AND METHODS: We analyzed the trabecular microarchitecture, bone metabolism, and material strength of iliac crest bone biopsy samples from 10 female patients with rheumatoid arthritis who received an average of 6.7 years of BP therapy for GIO (GIOBP group), compared with those of 10 age- and bone mineral density (BMD)-matched non-rheumatoid arthritis postmenopausal women (reference group). RESULTS: Patients in the GIOBP group had a significantly greater fracture severity index, as calculated from the number and the extent of vertebral fractures compared with the reference patients. Micro-computed tomography analysis showed that the degree of mineralization and trabecular microarchitecture were significantly lower in the GIOBP group than in the reference patients. Patients in the GIOBP group exhibited lower bone contact stiffness, determined by micro-indentation testing, than in the reference group. The contact stiffness of the bone was negatively correlated with the fracture severity index and the daily prednisolone dosage. Immunohistochemistry and serum bone turnover markers showed decreased osteoclastic activity, impaired mineralization, and an increased fraction of empty lacunae in the GIOBP group. CONCLUSION: Our findings indicate that patients receiving long-term BP for GIO are still at high risk for fragility fractures because of poor bone quality.

Genome-wide association study of epilepsy in a Japanese population identified an associated region at chromosome 12q24.

OBJECTIVE: Although a number of genes responsible for epilepsy have been identified through Mendelian genetic approaches, and genome-wide association studies (GWASs) have implicated several susceptibility loci, the role of ethnic-specific markers remains to be fully explored. We aimed to identify novel genetic associations with epilepsy in a Japanese population. METHODS: We conducted a GWAS on 1825 patients with a variety of epilepsies and 7975 control individuals. Expression quantitative trait locus (eQTL) analysis of epilepsy-associated single nucleotide polymorphisms (SNPs) was performed using Japanese eQTL data. RESULTS: We identified a novel region, which is ~2 Mb (lead SNP rs149212747, p = 8.57 × 10-10 ), at chromosome 12q24 as a risk for epilepsy. Most of these loci were polymorphic in East Asian populations including Japanese, but monomorphic in the European population. This region harbors 24 transcripts including genes expressed in the brain such as CUX2, ATXN2, BRAP, ALDH2, ERP29, TRAFD1, HECTD4, RPL6, PTPN11, and RPH3A. The eQTL analysis revealed that the associated SNPs are also correlated to differential expression of genes at 12q24. SIGNIFICANCE: These findings suggest that a gene or genes in the CUX2-RPH3A ~2-Mb region contribute to the pathology of epilepsy in the Japanese population.

Clinical and radiologic comparison of anterior-posterior single-position lateral surgery versus MIS-TLIF for degenerative lumbar spondylolisthesis.

BACKGROUND: The lateral interbody fusion (LIF) has gained popularity for the surgical treatment of lumbar degenerative spondylolisthesis (DS), however, LIF often requires the position change for posterior screwing. We have performed the single-position lateral surgery of oblique lateral interbody fusion (OLIF) and posterior screwing (OLIF-LPF). The present study compared the clinical and radiologic results between OLIF-LPF and minimally invasive transforaminal interbody fusion (MIS-TLIF). METHODS: A total of 142 patients underwent either OLIF-LPF (92 cases) or MIS-TLIF (50 cases) for L3 or L4 DS. The average age was 72 and 70 years old, respectively. The OLIF-LPF was performed in right decubitus position with allograft and percutaneous modified cortical bone trajectory screws (mCBT). The MIS-TLIF utilized a single 4 cm midline incision, allograft, boomerang cage and mCBTs. The operation time, estimated blood loss, and serum CRP levels were recorded. JOABPEQ effectiveness rate (%), Visual Analogue Scale (VAS), fusion rate, segmental radiologic alignment, and complications were also evaluated. RESULTS: Average follow-up period was 31 and 57 months in OLIF-LPF and MIS-TLIF, respectively. The average operation time and estimated blood loss were 108min, 51 ml and 104 min and 69 ml, respectively. OLIF-LPF demonstrated significantly higher values of mental health domain of JOABPEQ effectiveness rate and VAS improvement of leg pain than those in MIS-TLIF. The less correction loss of posterior disc height was demonstrated in OLIF-LPF. The fusion rate and symptomatic adjacent segment degeneration (ASD) were statistically equivalent between two groups. CONCLUSIONS: The single-position surgery of OLIF combined with posterior screwing serves as a safe, minimally invasive and effective surgical modality without the need of position change. It provides comparable fusion rate, segmental radiologic alignment, and symptomatic adjacent segment degeneration to MIS-TLIF surgery.

Clinical characteristics of patients with thoracic myelopathy caused by ossification of the posterior longitudinal ligament.

Although ossification of the posterior longitudinal ligament (OPLL) commonly develops in the cervical spine, it also occurs, albeit less commonly, in the thoracic spine. However, data are scarce regarding the characteristics of patients with thoracic OPLL. In the current study, we performed a cross-sectional study on a total of 133 patients with OPLL to clarify the clinical characteristics of patients with thoracic OPLL compared with those of patients with cervical OPLL. The subjects were divided into four groups according to the main region of OPLL and treatment type: C-OPLL-C, cervical OPLL treated conservatively; C-OPLL-S, cervical OPLL treated via surgery; T-OPLL-C, thoracic OPLL treated conservatively; and T-OPLL-S, thoracic OPLL treated via surgery. Symptoms developed at an earlier age in the T-OPLL-S group than in the C-OPLL groups. Current body mass index (BMI), maximum lifetime BMI, and BMI at the age of 20 years were significantly higher in the T-OPLL-S group than in the C-OPLL groups. Yearly weight gain from the age of 20 years to the age at which maximum body weight was attained was significantly greater in the T-OPLL-S group than in the C-OPLL groups. The T-OPLL group showed a higher rate of co-existence of OPLL at other regions or ossification of the ligamentum flavum compared to the C-OPLL groups. Our findings demonstrate that severe obesity, early-onset of symptoms, and diffuse ossification of spinal ligaments are distinct features of patients with myelopathy caused by thoracic OPLL.

RNF213 Variants, Vasospastic Angina, and Risk of Fatal Myocardial Infarction.

Importance: Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully understood. Objective: To identify genetic factors associated with VSA. Design, Setting, and Participants: This was a case-control genome-wide association study of VSA. Data from Biobank Japan (BBJ; enrolled patients from 2002-2008 and 2013-2018) were used, and controls without coronary artery disease (CAD) were enrolled. Patients from the BBJ were genotyped using arrays or a set of arrays. Patients recruited between 2002 and 2005 were classified within the first dataset, and those recruited between 2006 and 2008 were classified within the second dataset. To replicate the genome-wide association study in the first and second datasets, VSA cases and control samples from the latest patients in the BBJ recruited between 2013 and 2018 were analyzed in a third dataset. Exposures: Single-nucleotide variants associated with VSA. Main Outcomes and Measures: Cases with VSA and controls without CAD. Results: A total of 5720 cases (mean [SD] age, 67 [10] years; 3672 male [64.2%]) and 153 864 controls (mean [SD] age, 62 [15] years; 77 362 male [50.3%]) in 3 datasets were included in this study. The variants at the RNF213 locus showed the strongest association with VSA across the 3 datasets (odds ratio [OR], 2.34; 95% CI, 1.99-2.74; P = 4.4 × 10-25). Additionally, rs112735431, an Asian-specific rare deleterious variant (p.Arg4810Lys) experimentally shown to be associated with reduced angiogenesis and a well-known causal risk for Moyamoya disease was the most promising candidate for a causal variant explaining the association. The effect size of rs112735431 on VSA was distinct from that of other CADs. Furthermore, homozygous carriers of rs112735431 showed an association with VSA characterized by a large effect estimate (OR, 18.34; 95% CI, 5.15-65.22; P = 7.0 × 10-6), deviating from the additive model (OR, 4.35; 95% CI, 1.18-16.05; P = .03). Stratified analyses revealed that rs112735431 exhibited a stronger association in males (χ21 = 7.24; P = .007) and a younger age group (OR, 3.06; 95% CI, 2.24-4.19), corresponding to the epidemiologic features of VSA. In the registry, carriers without CAD of the risk allele rs112735431 had a strikingly high mortality rate due to acute myocardial infarction during the follow-up period (hazard ratio, 2.71; 95% CI, 1.57-4.65; P = 3.3 × 10-4). As previously reported, a possible overlap between VSA and Moyamoya disease was not found. Conclusions and Relevance: Results of this study suggest that vascular cell dysfunction mediated by variants in the RNF213 locus may promote coronary vasospasm, and the presence of the risk allele could serve as a predictive factor for the prognosis.

Decoding triancestral origins, archaic introgression, and natural selection in the Japanese population by whole-genome sequencing.

We generated Japanese Encyclopedia of Whole-Genome/Exome Sequencing Library (JEWEL), a high-depth whole-genome sequencing dataset comprising 3256 individuals from across Japan. Analysis of JEWEL revealed genetic characteristics of the Japanese population that were not discernible using microarray data. First, rare variant-based analysis revealed an unprecedented fine-scale genetic structure. Together with population genetics analysis, the present-day Japanese can be decomposed into three ancestral components. Second, we identified unreported loss-of-function (LoF) variants and observed that for specific genes, LoF variants appeared to be restricted to a more limited set of transcripts than would be expected by chance, with PTPRD as a notable example. Third, we identified 44 archaic segments linked to complex traits, including a Denisovan-derived segment at NKX6-1 associated with type 2 diabetes. Most of these segments are specific to East Asians. Fourth, we identified candidate genetic loci under recent natural selection. Overall, our work provided insights into genetic characteristics of the Japanese population.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E-11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.

Adolescent idiopathic scoliosis (AIS) is a twisting deformity of the spine that occurs during periods of rapid growth in children worldwide. Children with severe cases of AIS require surgery to stop it from getting worse, presenting a significant financial burden to health systems and families. Although AIS is known to cluster in families, its genetic causes and its inheritance pattern have remained elusive. Additionally, AIS is known to be more prevalent in females, a bias that has not been explained. Advances in techniques to study the genetics underlying diseases have revealed that certain variations that increase the risk of AIS affect cartilage and connective tissue. In humans, one such variation is near a gene called Pax1, and it is female-specific. The extracellular matrix is a network of proteins and other molecules in the space between cells that help connect tissues together, and it is particularly important in cartilage and other connective tissues. One of the main components of the extracellular matrix is collagen. Yu, Kanshour, Ushiki et al. hypothesized that changes in the extracellular matrix could affect the cartilage and connective tissues of the spine, leading to AIS. To show this, the scientists screened over 100,000 individuals and found that AIS is associated with variants in two genes coding for extracellular matrix proteins. One of these variants was found in a gene called Col11a1, which codes for one of the proteins that makes up collagen. To understand the relationship between Pax1 and Col11a1, Yu, Kanshour, Ushiki et al. genetically modified mice so that they would lack the Pax1 gene. In these mice, the activation of Col11a1 was reduced in the mouse spine. They also found that the form of Col11a1 associated with AIS could not suppress the activation of a gene called Mmp3 in mouse cartilage cells as effectively as unmutated Col11a1. Going one step further, the researchers found that lowering the levels of an estrogen receptor altered the activation patterns of Pax1, Col11a1, and Mmp3 in mouse cartilage cells. These findings suggest a possible mechanism for AIS, particularly in females. The findings of Yu, Kanshour, Ushiki et al. highlight that cartilage cells in the spine are particularly relevant in AIS. The results also point to specific molecules within the extracellular matrix as important for maintaining proper alignment in the spine when children are growing rapidly. This information may guide future therapies aimed at maintaining healthy spinal cells in adolescent children, particularly girls.

A genome-wide association study identifies a locus associated with knee extension strength in older Japanese individuals.

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10-8). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Interrogating Causal Effects of Body Composition and Puberty-Related Risk Factors on Adolescent Idiopathic Scoliosis: A Two-Sample Mendelian Randomization Study.

Adolescent idiopathic scoliosis (AIS) is the most common form of pediatric musculoskeletal disorder. Observational studies have pointed to several risk factors for AIS, but almost no evidence exists to support their causal association with AIS. Here, we applied Mendelian randomization (MR), known to limit bias from confounding and reverse causation, to investigate causal associations between body composition and puberty-related exposures and AIS risk in Europeans and Asians. For our two-sample MR studies, we used single nucleotide polymorphisms (SNPs) associated with body mass index (BMI), waist-hip ratio, lean mass, childhood obesity, bone mineral density (BMD), 25-hydroxyvitamin D (25OHD), age at menarche, and pubertal growth in large European genome-wide association studies (GWAS), and with adult osteoporosis risk and age of menarche in Biobank Japan. We extracted estimates of the aforementioned SNPs on AIS risk from the European or Asian subsets of the largest multiancestry AIS GWAS (N = 7956 cases/88,459 controls). The results of our inverse variance-weighted (IVW) MR estimates suggest no causal association between the aforementioned risk factors and risk of AIS. Pleiotropy-sensitive MR methods yielded similar results. However, restricting our analysis to European females with AIS, we observed a causal association between estimated BMD and the risk of AIS (IVW odds ratio for AIS = 0.1, 95% confidence interval 0.01 to 0.7, p = 0.02 per SD increase in estimated BMD), but this association was no longer significant after adjusting for BMI, body fat mass, and 25OHD and remained significant after adjusting for age at menarche in multivariable MR. In conclusion, we demonstrated a protective causal effect of BMD on AIS risk in females of European ancestry, but this effect was modified by BMI, body fat mass, and 25OHD levels. Future MR studies using larger AIS GWAS are needed to investigate small effects of the aforementioned exposures on AIS. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Aggravation of Ossified Ligamentum Flavum Lesion Is Associated With the Degree of Obesity.

STUDY DESIGN: Retrospective cross-sectional study. OBJECTIVES: There is insufficient data on the clinical features of ossification of the ligamentum flavum (OLF) of the thoracic spine and the risk of progression of ossified lesions. The link between obesity and ossification of the posterior longitudinal ligament (OPLL), which frequently coexists with OLF, has been demonstrated. However, the link between obesity and OLF has not been recognized. We aimed to determine the prevalence of obesity in thoracic OLF and whether the severity of OLF is associated with the degree of obesity. METHODS: A total of 204 symptomatic Japanese subjects with thoracic OLF and 136 subjects without spinal ligament ossification as controls were included. OLF subjects were divided into 3 groups: 1) localized OLF (OLF <2-intervertebral regions); 2) multilevel OLF (OLF ≥3-intervertebral regions); and 3) OLF + OPLL. The severity of OLF was quantified using the OLF index using computed tomography imaging of the entire spine. RESULTS: The proportion of severely obese subjects (BMI ≥ 30 kg/m2) was significantly higher both in the multilevel OLF group (25.5%) and the OLF + OPLL group (44.3%) than in the localized OLF group (3.6%) and the control group (1.4%) (P < 0.01). BMI, age, and coexistence of cervical OPLL and lumbar OLF were associated with thoracic OLF index in the multiple regression analysis. CONCLUSIONS: Our findings demonstrated that obesity is a distinct feature of multilevel OLF in the thoracic spine and that the severity of OLF is associated with the degree of obesity.

Lumbar ossification of the ligamentum flavum reflects a strong ossification tendency of the entire spinal ligament.

Patients with ossification of the ligamentum flavum (OLF) in the lumbar spine may be at high risk of developing concomitant ossification of the entire spinal ligament, but the etiology remains unclear. We investigated the propensity for spinal ligament ossification in asymptomatic subjects with lumbar OLF using the data of 595 Japanese individuals receiving medical check-ups, including computed tomography (CT) scanning. The severity of OLF (total number of intervertebral segments with OLF) of the entire spine on CT was quantified using an OLF index. Subjects with OLF were grouped according to this index: localized OLF (n = 138), intermediate OLF (n = 70), and extensive OLF (n = 31). The proportion of subjects with lumbar OLF increased with increasing OLF index (localized 13.7%, intermediate 41.4%, and extensive 70.9%). Multiple regression analysis found that lumbar OLF index was associated with thoracic OLF index, and co-existence of ossification of the posterior longitudinal ligament (OPLL) of the thoracic and lumbar spine. This study showed that subjects with more multilevel lumbar OLF were more likely to develop multilevel thoracic OLF and to have coexisting OPLL. Patients with lumbar OLF may be a distinctive subgroup with a strong tendency to ossification of the entire spinal ligament.

High whole-body bone mineral density in ossification of the posterior longitudinal ligament.

BACKGROUND CONTEXT: Recent studies suggest that ossification of the posterior longitudinal ligament (OPLL) is exacerbated by systemic metabolic disturbances, including obesity. However, although an increase in bone mineral density (BMD) measured at the lumbar spine has been reported in patients with OPLL, no studies have investigated the systemic BMD of patients with OPLL in detail. PURPOSE: We investigated whether patients with OPLL develop increased whole-body BMD. STUDY DESIGN: Single institution cross-sectional study. PATIENT SAMPLE: Data were collected from Japanese patients with symptomatic OPLL (OPLL [+]; n=99). Control data (OPLL [-]; n=226) without spinal ligament ossification were collected from patients who underwent spinal decompression, spinal fusion, or hip replacement surgery. OUTCOME MEASURES: Demographic data, including age, body mass index (BMI), comorbidities, history of treatment for osteoporosis, and history of vertebral and nonvertebral fractures, was obtained from all participants. In addition, whole-body BMD, including the lumbar spine, thoracic spine, femoral neck, skull, ribs, entire upper extremity, entire lower extremity, and pelvis, were measured in all participants using whole-body dual-energy X-ray absorptiometry. METHODS: Patient data were collected from 2018 to 2022. All participants were categorized based on sex, age (middle-aged [<70 years] and older adults [≥70 years]), and OPLL type (localized OPLL [OPLL only in the cervical spine], diffuse OPLL [OPLL in regions including the thoracic spine]), and OPLL [-]) and each parameter was compared. The factors associated with whole-body BMD were evaluated via multivariable linear regression analysis. RESULTS: Compared with the OPLL (-) group, the OPLL (+) group of older women had significantly higher BMD in all body parts (p<.01), and the OPLL (+) group of older men had significantly higher BMD in all body parts except the ribs, forearm, and skull (p<.01). The factors associated with increased BMD of both the femoral neck (load-bearing bone) and skull (nonload-bearing bone) were age, BMI, and coexisting diffuse OPLL in women and BMI and coexisting localized OPLL in men. CONCLUSIONS: Patients with OPLL have increased whole-body BMD regardless of sex, indicating that it is not simply due to load-bearing from obesity. These findings suggested that OPLL is associated with a systemic pathology.

Dyslipidemia as a novel risk for the development of symptomatic ossification of the posterior longitudinal ligament.

BACKGROUND CONTEXT: Obesity and visceral fat have been implicated as potential factors in the pathogenesis of the ossification of the posterior longitudinal ligament (OPLL); the details of the factors involved in OPLL remain unclear. PURPOSE: We aimed to determine the association between dyslipidemia and symptomatic OPLL. STUDY DESIGN: Single institution cross-sectional study. PATIENT SAMPLE: Data were collected from Japanese patients with OPLL (n=92) who underwent whole-spine computed tomography scanning. Control data (n=246) without any spinal ligament ossification were collected from 627 Japanese participants who underwent physical examination. OUTCOME MEASURES: Baseline information and lipid parameters, including triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from fasting blood samples were collected to assess the comorbidity of dyslipidemia. METHODS: Patient data were collected from 2020 to 2022. Patients with dyslipidemia were defined as those who were taking medication for dyslipidemia and who met one of the following criteria: TG ≥150 mg/dL, LDL-C ≥140 mg/dL, and/or HDL-C <40 mg/dL. The factors associated with OPLL development were evaluated using multivariate logistic regression analysis. RESULTS: The comorbidity of dyslipidemia in the OPLL group was more than twice that in the control group (71.7% and 35.4%, respectively). The mean body mass index (BMI) of the OPLL group was significantly higher than that of the control group (27.2 kg/m2 and 23.0 kg/m2). Multivariate logistic regression analysis revealed that dyslipidemia was associated with the development of OPLL (regression coefficient, 0.80; 95% confidence interval, 0.11-1.50). Additional risk factors included age, BMI, and diabetes mellitus. CONCLUSIONS: We demonstrated a novel association between dyslipidemia and symptomatic OPLL development using serum data. This suggests that visceral fat obesity or abnormal lipid metabolism are associated with the mechanisms of onset and exacerbation of OPLL as well as focal mechanical irritation due to being overweight.

Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.