Comparison of once-weekly teriparatide and alendronate against new osteoporotic vertebral fractures at week 12.

The objective of the present multicenter randomized study was to compare weekly teriparatide with alendronate in their inhibition of vertebral collapse, effects on delayed union, pain relief, and improvement of quality of life (QOL) in women with new osteoporotic vertebral fractures within 1 week after onset of the fracture. Patients were randomly allocated to the teriparatide and alendronate groups. Vertebral collapse, low back pain assessed by a visual analog scale, and QOL assessed by EuroQol 5 dimension at weeks 1, 2, 4, 8, and 12 after the start of the treatment were compared between the groups. Lumbar bone mineral density (BMD) at baseline and week 12 and the rate of delayed union at week 12 were also compared. Each group consisted of 48 subjects. Vertebral collapse progressed over time in both groups, with no significant difference between the groups. Pain on rising up from lying position, turning over in bed, and resting in the lying position improved over time in both groups, with no significant difference between the groups. There were no significant differences in increase in BMD and delayed union. QOL in the teriparatide group showed significant improvement in comparison with that in the alendronate group at week 12. The weekly formulation of teriparatide showed comparable inhibition of vertebral collapse, increase in BMD, promotion of bone union, and improvement of pain and significant improvement of QOL at week 12 in comparison with alendronate in patients with a new osteoporotic vertebral fracture within 1 week after onset of the fracture. The weekly formulation of teriparatide may have improved components of QOL other than pain at week 12.

Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women.

Spinal osteoarthritis including disc degeneration is a very common condition in the axial skeletons of aged people. Recently, spinal osteoarthritis has been shown to be influenced by specific genetic risk factors. Vertebral osteophytes, endplate sclerosis, and intervertebral disc narrowing are recognized as radiographic features of spinal disc degeneration. HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the pathogenesis of cartilage-related diseases such as spinal degeneration. Here, we examine the association between an HAPLN1 gene polymorphism and the radiographic features of spinal degeneration. We evaluated the degree of endplate sclerosis, osteophyte formation, and disc space narrowing in 622 Japanese postmenopausal women. Four SNPs in the HAPLN1 gene-in the 5' flanking region, intron 1, intron 2, and intron 4-were analyzed using the TaqMan polymerase chain reaction method. We found that compared to subjects with the CC or CT genotype, those with the TT genotype for an SNP at intron 2 (rs179851) were significantly overrepresented among the subjects with higher scores for osteophyte formation (P = 0.0001; odds ratio 2.12; 95% confidence interval 1.45-3.11, as determined by logistic regression analysis) and disc space narrowing (P = 0.0057; odds ratio 1.83; 95% confidence interval 1.19-2.83). Consistent with the involvement of the HAPLN1 gene in cartilage metabolism, a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration.

Longitudinal study of risk factors for decreased cross-sectional area of psoas major and paraspinal muscle in 1849 individuals.

This 10-year retrospective observational study investigated longitudinal losses in psoas major and paraspinal muscle area in 1849 healthy individuals (1690 male, 159 female) screened using computed tomography. Logistic regression analysis revealed significant decreases in psoas major and paraspinal muscle area at 10 years relative to the baseline area regardless of age or sex, starting at 30 years of age. Only aging [≥ 50 s (odds ratio [OR]: 1.72; 95% confidence interval [CI] 1.05-2.84; p = 0.03) and ≥ 60 s (OR: 2.67; 95% CI 1.55-4.60; p < 0.001)] was a risk factor for decreases in psoas major area. Age ≥ 60 years (OR: 2.05; 95% CI 1.24-3.39; p = 0.005), body mass index ≥ 25 kg/m2 (OR: 1.32; 95% CI 1.01-1.73; p = 0.04), and visceral fat ≥ 100 cm2 (OR: 1.61; 95% CI 1.20-2.15; p = 0.001) were risk factors for decreases in paraspinal muscle area. Physical activity ≥ 900 kcal/week (OR: 0.68; 95% CI 0.50-0.94; p = 0.02) attenuated paraspinal muscle area loss in male. Our study demonstrated that walking > 45 min daily (Calories = METs (walking: 3.0) × duration of time (h) × weight (60 kg) × 1.05) can reduce paraspinal muscle loss, which may in turn decrease the risk of falls, low-back pain, and sarcopenia.

Association of HTRA1 promoter polymorphism with spinal disc degeneration in Japanese women.

HTRA1 (high-temperature requirement A1) has been implicated in the modulation of various disease pathologies. HTRA1 expression is upregulated in osteoarthritic joints, suggesting that it may contribute to the development of this debilitating disease. Moreover, recent reports have shown that the rs11200638, a single nucleotide polymorphism (SNP) in the promoter region of the HTRA1 gene, is strongly associated with an increased prevalence of age-related macular degeneration (AMD). In the present study, we examined the expression of the HTRA1 in human primary chondrocytes and an association between the rs11200638 SNP and radiographic features of spinal disc degeneration in 513 postmenopausal Japanese women. HTRA1 mRNA was detected and increased by TGF-beta treatment in human primary chondrocytes. As an association study of rs11200638 SNP in the HTRA1 gene, the subjects without the G allele (AA; n = 89) had a significantly higher spinal disc space narrowing score than the subjects bearing at least one G allele (GG + GA; n = 424) (P = 0.0292). We found that subjects without the G allele (AA) were significantly overrepresented in the subjects having a higher (> or =4) disc space narrowing score (P = 0.013; odds ratio 1.97; 95% confidence interval 1.15-3.37 by logistic regression analysis). A genetic variation at the HTRA1 gene promoter locus is associated with spinal disc degeneration, suggesting an involvement of the HTRA1 gene in osteoarthritis.

A Diagnostic Approach to Myelopathy Based on Prognostic Factors in Patients With Lower Extremity Symptoms.

STUDY DESIGN: Case-control study. OBJECTIVE: We aimed to identify predictors for latent myelopathy and to develop a diagnostic protocol based on these factors. SUMMARY OF BACKGROUND DATA: There is no diagnostic protocol for latent myelopathy to avoid misdiagnosis in patients complaining only of lower extremity symptoms. METHODS: This case-control study identified 791 patients discussed at conferences from April 2006 to August 2012. Overall, 460 patients complaining only of lower extremity symptoms and who underwent spine surgery were included as participants; 54 underwent surgery involving the cervical and thoracic vertebrae and were assigned to the cervical-thoracic group (C-T group); 406 underwent lumbar surgery and were assigned to the lumbar group (L group). RESULTS: By univariate analysis, age ≥67 years, patellar tendon (PT) hyperreflexia, Achilles tendon (AT) hyperreflexia, spastic gait, and gait inability were more common in the C-T group than in the L group. By multivariate analysis, age ≥67 years (OR, 8; P = 0.001), AT hyperreflexia (OR, 20.5; P < 0.001), spastic gait (OR, 225; P < 0.001), and gait inability (OR, 64; P < 0.001) were significant predictive factors. In patients with age ≥67 years, PT hyperreflexia, and/or AT hyperreflexia, the sensitivity for myelopathy diagnosis was 98%. In patients with spastic gait or gait inability, the specificity of myelopathy diagnosis was 96%. CONCLUSIONS: We analyzed factors that predict latent myelopathy in patients complaining only of lower extremity symptoms. We believe a diagnostic protocol based on the predictors shown in this study would contribute to the accurate diagnosis of latent myelopathy. LEVEL OF EVIDENCE: 4.

A functional single nucleotide polymorphism in the vitamin-K-dependent gamma-glutamyl carboxylase gene (Arg325Gln) is associated with bone mineral density in elderly Japanese women.

The vitamin-K-dependent gamma-glutamyl carboxylase (GGCX) carboxylates vitamin-K-dependent proteins including bone Gla protein (osteocalcin) and matrix Gla protein, which play important roles in bone metabolism. Therefore, GGCX polymorphism might explain in part individual susceptibility to osteoporosis. In the present study, polymorphisms in the exons of this gene were screened in Japanese elderly women and a non-synonymous single nucleotide polymorphisms (SNP) were found; c.8762 G>A; (Arg325Gln). When the kinetic parameters of GGCX325-Gln and GGCX325-Arg were compared in vitro, Vmax/Km was significantly higher for GGCX325-Gln (944.4+/-9.21 pmol/30 min/mg/mM FLEEL) than for GGCX325-Arg (671.9+10.79 pmol/30 min/mg/mM FLEEL) (p=0.018). Then, association study of this polymorphism with forearm bone mineral density (BMD) of Japanese postmenopausal women (n=500, age 73.6+/-5.74) was conducted. As a result, the body mass index (BMI)-adjusted Z score in the subpopulation older than 75 years (n=207) was higher in those with 325-Gln (0.650+/-0.883, mean+/-SD) than those with 325-Arg/Gln or 325-Arg (0.133+/-0.650) (p=0.0383). This is the first report to demonstrate the different activities of GGCX between the common genotypes and their association with BMD.

Reductions in bone turnover, mineral, and structure associated with mechanical properties of lumbar vertebra and femur in glucocorticoid-treated growing minipigs.

The present study was designed to determine the effects of glucocorticoid (GC) on bone turnover, minerals, structure, and bone mechanical properties in minipigs. Six 8-month-old Göttingen minipigs were subcutaneously injected with prednisolone (PN, 0.5 mg/kg body wt (BW)/day, 5 days/week for 26 weeks (Group GC)), 6 were treated with vehicle alone (Group VC), and 4 were sacrificed at start of the study for baseline controls (Group BC). The increase in BW was similar in all groups. PN significantly reduced serum osteocalcin and urinary type-1 collagen N-telopeptide levels at 13 weeks and thereafter, compared with baseline and control, and also reduced serum bone specific alkaline phosphatase levels relative to baseline. At 26 weeks, the longitudinal axis of the lumbar bone and length of femur were smaller in Group GC than Group VC. The total cross-sectional area of femur, but not the lumbar bone, in Group GC was significantly different from Group VC. BMD of the femur, but not L2, measured by DXA, was lower in Group GC than in Groups BC and VC. The cortical shell structure measured by 2D-micro-CT deteriorated and age-dependent increases in trabecular bone structure 3D micro-CT were reduced by PN. PN also caused deterioration of the cortical structure of the mid-femur. In L2 and femur, PN significantly reduced the ultimate load and maximum absorption energy of the femur and L2 compared with Group VC. The structural modulus in Group GC was lower than in Group BC. Regression analyses revealed that bone minerals, bone structure, and chemical markers correlated with mechanical properties of L2 and mid-femur. Our results indicate that PN reduced systemic bone formation and resorption and suppressed the age-dependent increases in bone minerals, structure, and mechanical properties of L2 and mid-femur. Reduced bone turnover seemed to be associated with a reduction in mechanical properties. The growing minipig could be a suitable model of GCs-induced osteoporosis in humans.

The relationship between back pain and future vertebral fracture in postmenopausal women.

STUDY DESIGN: Cross sectional and prospective observational study in Japanese postmenopausal women. OBJECTIVE: The aim of the study was 2-fold. The first was to investigate what kind of comorbidities could be found in conjunction with back pain in Japanese postmenopausal women. The second was to investigate whether significant relationship between baseline back pain and future fracture exists or not. SUMMARY OF BACKGROUND DATA: Back pain has been reported to be associated with vertebral degeneration or vertebral fracture. However, there has been no available data that indicates the relationship between back pain and future fracture risks. METHODS: The subjects who visited their practitioner were examined for their prevalent back pain or pains in other site. Bone mineral density, body height, body weight, and serum parameter were measured at baseline, and comorbidities were investigated by interview. Fragility fractures were also assessed at baseline and then followed up with 1- to 2-year intervals. The correlation between back pain and baseline characteristics was investigated by logistic regression analysis. The hazard ratio of back pain to future vertebral fracture was estimated by multivariate Cox regression analysis. RESULTS: A total of 899 postmenopausal ambulatory women (62.5 +/- 10.3 years old) were enrolled and 81 subjects were dropped out from the study within 1 year. The remaining 818 postmenopausal women (62.1 +/- 10.3 years) were followed-up for 5.7 +/- 3.5 years. Compared to the group without pain, the group with back pain had significantly higher age, lower bone mineral densities at lumbar spine and hip, and higher number of prevalent vertebral fractures. The back pain was significantly associated with rheumatic arthritis (odds ratio [OR]: 2.01, P < 0.05), prevalent vertebral fracture (OR: 4.60, P < 0.001) and osteoporosis (OR: 2.14, P < 0.001). A total of 189 future fractures were observed, of which the most frequent was vertebral fractures (78.3%). The fact that baseline back pain was a significant risk factor for time-dependent vertebral fractures (hazard ratio: 1.62, 95% confidence interval: 1.16-2.27, P = 0.005) was demonstrated by the Cox hazards model after adjusting for traditional risk factors, such as age, bone mineral density, and prevalence of vertebral fractures. CONCLUSION: The data obtained in this study indicated that the back pain is significantly associated with osteoporosis and rheumatoid arthritis and that it can be useful predictor for future vertebral fracture risk in Japanese postmenopausal women in clinical settings.

Association of a single nucleotide polymorphism in the insulin-like growth factor-1 receptor gene with spinal disc degeneration in postmenopausal Japanese women.

STUDY DESIGN: An association study investigating the genetic etiology for spinal disc degeneration. OBJECTIVE: To determine the association of single-nucleotide polymorphism (SNP) in the insulin-like growth factor-1 receptor (IGF1R) with spinal disc degeneration. SUMMARY OF BACKGROUND DATA: Insulin-like growth factor-1 (IGF-1) signaling pathway is involved in cartilage development and homeostasis, suggesting that genetic variations of genes involved in this pathway may affect the pathogenesis of cartilage-related diseases, such as disc degeneration. METHODS: We evaluated the presence of endplate sclerosis, osteophytes, and narrowing of disc spaces in 434 Japanese postmenopausal women. A SNP in the IGF1R gene at intron 1 was determined using TaqMan polymerase chain reaction method. RESULTS: We compared those who carried the G allele (GG or GC, n = 290) with those who did not (CC, n = 144). We found that the subjects with the G allele (GG or GC) were significantly over-represented in the subjects having higher disc narrowing score (P = 0.0033; odds ratio, 2.04; 95% confidence interval, 1.27-3.29 by logistic regression analysis). CONCLUSION: We suggest that a genetic variation at the IGF1R gene locus is associated with spinal disc degeneration, in line with the involvement of the IGF1R gene in the cartilage metabolism.

Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women.

The Wnt-beta-catenin signaling pathway that regulates bone density is also involved in cartilage development and homeostasis in vivo. Here, we assumed that genetic variation in Wnt-beta-catenin signaling genes can affect the pathogenesis of cartilage related diseases, such as osteoarthritis. Wnt-1-induced secreted protein 1 (WISP1) is a target of the Wnt pathway and directly regulated by beta-catenin. In the present study, we analyzed the association of a single nucleotide polymorphism (SNP) in the WISP1 3'-UTR region with the development of radiographically observable osteoarthritis of the spine. For this purpose, we evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 304 postmenopausal Japanese women. We compared those who carried the G allele (GG or GA, n = 184) with those who did not (AA, n = 120). We found that the subjects without the G allele (AA) were significantly over-represented in the subjects having higher endplate sclerosis score (P = 0.0069; odds ratio, 2.91; 95% confidence interval, 1.34-6.30 by logistic regression analysis). On the other hand, the occurrence of disc narrowing and osteophyte formation did not significantly differ between those with and without at least one G allele. Thus, we suggest that a genetic variation in the WISP1 gene locus is associated with spinal osteoarthritis, in line with the involvement of the Wnt-beta-catenin-regulated gene in bone and cartilage metabolism.

Q89R polymorphism in the LDL receptor-related protein 5 gene is associated with spinal osteoarthritis in postmenopausal Japanese women.

STUDY DESIGN: An association study investigating the genetic etiology for spinal osteoarthritis. OBJECTIVE: To determine the association of single-nucleotide polymorphism (SNP) causing an amino-acid change (Q89R) in the low-density lipoprotein receptor-related protein 5 (LRP5) coding region with spinal osteoarthritis. SUMMARY OF BACKGROUND DATA: Wnt/beta-catenin signaling pathway regulates bone density through a Wnt coreceptor LRP5. This pathway is also involved in cartilage development and homeostasis, suggesting that genetic variation in LRP5 gene may affect the pathogenesis of cartilage-related diseases, such as osteoarthritis. METHODS: We evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 357 Japanese postmenopausal women. Missense coding SNP for Q89R of LRP5 gene was determined using TaqMan polymerase chain reaction (PCR) method. RESULTS: We found that subjects without the R allele (QQ; n = 321) had a significantly lower osteophyte formation score than did subjects bearing at least one R allele (QR + RR; n = 36) (7.80 vs. 10.89, P = 0.0019 by analysis of covariance). CONCLUSIONS: We suggest that a genetic variation at the LRP5 gene locus is associated with spinal osteoarthritis, in line with the involvement of the LRP5 gene in the bone and cartilage metabolism.

Enlargement of cervical spinal cord correlates with improvement of motor function in upper extremities after laminoplasty for cervical myelopathy.

OBJECTIVE: The correlation between postoperative spinal cord enlargement at the most compressive disc level and clinical outcome is controversial. The relationship between spinal cord enlargement at neurologically symptomatic disc level and clinical recovery has not been explored. The purpose of this study was to clarify the relationship between postoperative spinal cord enlargement at neurologically symptomatic disc level and neurologic outcome. METHODS: We studied 55 consecutive patients between 1995 and 2002. All patients underwent preoperative neurologic examination to determine the neurologically symptomatic disc level of the spinal cord and computed tomographic myelography twice before and 4 weeks after laminoplasty. The cross-sectional areas of both spinal cord and dural sac from C3/4 to C7/T1 disc levels were measured on computed tomographic myelography images. The Japanese Orthopedic Association scoring system was used for clinical evaluation before and 1 year after surgery. RESULTS: Total score improved significantly from 10.2+/-2.8 (SD) to 13.0+/-3.0 after operation. Motor and sensory function scores of upper and lower extremities also improved significantly. The enlargement of spinal cord area at the neurologically symptomatic disc level correlated significantly with improvement in motor function scores of upper extremities (rs=0.421 P=0.0052). However, there were no significant relationships between the enlargement of the spinal cord at the most compressive disc level or that at the dural sac and any categories of Japanese Orthopedic Association scoring system. CONCLUSION: Postsurgical enlargement of the cervical spinal cord at the neurologically symptomatic disc level at 4 weeks postoperatively correlated with recovery of motor function of the upper extremities at 1 year.