To clarify the pathomechanisms of discogenic low back pain, the sympathetic afferent discharge originating from the L5-L6 disc via the L2 root were investigated neurophysiologically in 31 Lewis rats. Sympathetic afferent units were recorded from the L2 root connected to the lumbar sympathetic trunk by rami communicantes. The L5-L6 discs were mechanically probed, stimulated electrically to evoke action potentials and, finally, treated with chemicals to produce an inflammatory reaction. We could not obtain a response from any units in the L5-L6 discs using mechanical stimulation, but with electrical stimulation we identified 42 units consisting mostly of A-delta fibres. In some experiments a response to mechanical probing of the L5-L6 disc was recognised after producing an inflammatory reaction. This study suggests that mechanical stimulation of the lumbar discs may not always produce pain, whereas inflammatory changes may cause the disc to become sensitive to mechanical stimuli, resulting in nociceptive information being transmitted as discogenic low back pain to the spinal cord through the lumbar sympathetic trunk. This may partly explain the variation in human symptoms of degenerate discs

A rat model of lumbar root constriction with an additional sympathectomy in some animals was used to assess whether the sympathetic nerves influenced radicular pain. Behavioural tests were undertaken before and after the operation. On the 28th post-operative day, both dorsal root ganglia and the spinal roots of L4 and L5 were removed, frozen and sectioned on a cryostat (8 μm to 10 μm). Immunostaining was then performed with antibodies to tyrosine hydroxylase (TH) according to the Avidin Biotin Complex method. In order to quantify the presence of sympathetic nerve fibres, we counted TH-immunoreactive fibres in the dorsal root ganglia using a light microscope equipped with a micrometer graticule (10 x 10 squares, 500 mm x 500 mm). We counted the squares of the graticule which contained TH-immunoreactive fibres for each of five randomly-selected sections of the dorsal root ganglia. The root constriction group showed mechanical allodynia and thermal hyperalgesia. In this group, TH-immunoreactive fibres were abundant in the ipsilateral dorsal root ganglia at L5 and L4 compared with the opposite side. In the sympathectomy group, mechanical hypersensitivity was attenuated significantly. We consider that the sympathetic nervous system plays an important role in the generation of radicular pain

In a study on ten fresh human cadavers we examined the change in the height of the intervertebral disc space, the angle of lordosis and the geometry of the facet joints after insertion of intervertebral total disc replacements. SB III Charité prostheses were inserted at L3-4, L4-5, and L5-S1. The changes studied were measured using computer navigation sofware applied to CT scans before and after instrumentation. After disc replacement the mean lumbar disc height was doubled (p < 0.001). The mean angle of lordosis and the facet joint space increased by a statistically significant extent (p < 0.005 and p = 0.006, respectively). By contrast, the mean facet joint overlap was significantly reduced (p < 0.001). Our study indicates that the increase in the intervertebral disc height after disc replacement changes the geometry at the facet joints. This may have clinical relevance

It has been thought that lumbar intervertebral discs were innervated segmentally. We have previously shown that the L5-L6 intervertebral disc in the rat is innervated bilaterally from the L1 and L2 dorsal root ganglia through the paravertebral sympathetic trunks, but the pathways between the disc and the paravertebral sympathetic trunks were unknown. We have now studied the spines of 17 rats to elucidate the exact pathways. We examined serial sections of the lumbar spine using immunohistochemistry for calcitonin gene-related peptide, a sensory nerve marker. We showed that these nerve fibres from the intervertebral disc ran through the sinuvertebral nerve into the rami communicantes, not into the corresponding segmental spinal nerve. In the rat, sensory information from the lumbar intervertebral discs is conducted through rami communicantes. If this innervation pattern applies to man, simple decompression of the corresponding nerve root will not relieve discogenic pain. Anterior interbody fusion, with the denervation of rami communicantes, may be effective for such low back pain

Our study establishes a rabbit model of disc degeneration which requires neither a chemical nor physical injury to the disc. Disc degeneration similar to that seen in man was created at levels proximal (L4-L5) and caudal (L7-S1) to a simulated lumbar fusion and was studied for up to nine months after arthrodesis. Loss of the normal parallel arrangement of collagen bundles within the annular lamellae was observed in intervertebral discs adjacent to the fusion at three months. By six months there was further disorganisation as well as loss of distinction between the lamellae themselves. By nine months the structure of the disc had been replaced by disorganised fibrous tissue, and annular tears were seen. There was an initial cellular proliferative response followed by loss of chondrocytes and notochordal cells in the nucleus pulposus. Degeneration was accompanied by a decrease in the monomer size of proteoglycans. Narrowing of the disc space, endplate sclerosis and the formation of osteophytes at adjacent disc spaces were observed radiologically

We performed a biomechanical study on human cadaver spines to determine the effect of three different interbody cage designs, with and without posterior instrumentation, on the three-dimensional flexibility of the spine. Six lumbar functional spinal units for each cage type were subjected to multidirectional flexibility testing in four different configurations: intact, with interbody cages from a posterior approach, with additional posterior instrumentation, and with cross-bracing. The tests involved the application of flexion and extension, bilateral axial rotation and bilateral lateral bending pure moments. The relative movements between the vertebrae were recorded by an optoelectronic camera system. We found no significant difference in the stabilising potential of the three cage designs. The cages used alone significantly decreased the intervertebral movement in flexion and lateral bending, but no stabilisation was achieved in either extension or axial rotation. For all types of cage, the greatest stabilisation in flexion and extension and lateral bending was achieved by the addition of posterior transpedicular instrumentation. The addition of cross-bracing to the posterior instrumentation had a stabilising effect on axial rotation. The bone density of the adjacent vertebral bodies was a significant factor for stabilisation in flexion and extension and in lateral bending

Dorsal root ganglion neurones with dichotomising axons are present in several species and are considered to play a role in referred pain. Clinically, patients with lesions in the lower lumbar discs occasionally complain of pain in the groin. We investigated the existence of dichotomising afferent neurones projecting axons both to the lumbar disc and to the groin skin, using the double fluorescent-labelling technique in rats. We observed neurones labelled with a tracer applied at the ventral portion of the L5-L6 disc and another tracer placed on the groin skin in L1 and L2 dorsal root ganglia. Our results showed that the double-labelled neurones had peripheral axons which dichotomised into both the L5-L6 disc and the groin skin, indicating the convergence of afferent sensory information from the disc and groin skin. Our findings provide a possible neuroanatomical mechanism for referred groin pain in patients with disc lesions

Based on a study using a retrograde neurotracer, we have previously found that the dorsal portion of the L5/6 disc in the rat is multisegmentally innervated by dorsal root ganglia (DRG) from the level of T13 to L6, and that sensory nerve fibres from DRG of T13, L1 and L2 pass through the paravertebral sympathetic trunks. In this study in newborn rats, we injected crystals of 1,1′-dioctadecyl-3,3,3′,3′-tetramethylinedocarbocyanine perchlorate (DiI) into the DRG of T13, L1 and L2 and showed DiI-labelled sensory nerve fibres in the dorsal portion of the discs from the level of T13/L1 to L5/6. Our results show that the dorsal portion of the lumbar discs is innervated by the DRG from levels T13 to L2

We have examined the process of fusion of the intertransverse processes and bone graft in the rabbit by in situ hybridisation and evaluated the spatial and temporal expression of genes encoding pro-α1 (I) collagen (COL1A1), pro-α1 (II) collagen (COL2A1) and pro-α1 (X) collagen (COL10A1).

Beginning at two weeks after operation, osteogenesis and chondrogenesis occurred around the transverse process and the grafted bone at the central portion of the area of the fusion mass. Osteoblasts and osteocytes at the newly-formed woven bone expressed COL1A1. At the cartilage, most chondrocytes expressed COL2A1 and some hypertrophic chondrocytes COL10A1. In some regions, co-expression of COL1A1 and COL2A1 was observed. At four weeks, such expressions for COL1A1, COL2A1 and COL10A1 became prominent at the area of the fusion mass. From four to six weeks, bone remodelling progressed from the area of the transverse processes towards the central zone. Osteoblasts lining the trabeculae expressed a strong signal for COL1A1. At the central portion of the area of the fusion mass, endochondral ossification progressed and chondrocytes expressed COL2A1 and COL10A1.

Our findings show that the fusion process begins with the synthesis of collagens around the transverse processes and around the grafted bone independently. Various spatial and temporal osteogenic and chondrogenic responses, including intramembranous, endochondral and transchondroid bone formation, progress after bone grafting at the intertransverse processes. Bone formation through cartilage may play an important role in posterolateral spinal fusion.

Objectives. Several genome-wide association studies (GWAS) of bone mineral density (BMD) have successfully identified multiple susceptibility genes, yet isolated susceptibility genes are often difficult to interpret biologically. The aim of this study was to unravel the genetic background of BMD at pathway level, by integrating BMD GWAS data with genome-wide expression quantitative trait loci (eQTLs) and methylation quantitative trait loci (meQTLs) data. Method. We employed the GWAS datasets of BMD from the Genetic Factors for Osteoporosis Consortium (GEFOS), analysing patients’ BMD. The areas studied included 32 735 femoral necks, 28 498 lumbar spines, and 8143 forearms. Genome-wide eQTLs (containing 923 021 eQTLs) and meQTLs (containing 683 152 unique methylation sites with local meQTLs) data sets were collected from recently published studies. Gene scores were first calculated by summary data-based Mendelian randomisation (SMR) software and meQTL-aligned GWAS results. Gene set enrichment analysis (GSEA) was then applied to identify BMD-associated gene sets with a predefined significance level of 0.05. Results. We identified multiple gene sets associated with BMD in one or more regions, including relevant known biological gene sets such as the Reactome Circadian Clock (GSEA p-value = 1.0 × 10. -4. for LS and 2.7 × 10. -2. for femoral necks BMD in eQTLs-based GSEA) and insulin-like growth factor receptor binding (GSEA p-value = 5.0 × 10. -4. for femoral necks and 2.6 × 10. -2. for lumbar spines BMD in meQTLs-based GSEA). Conclusion. Our results provided novel clues for subsequent functional analysis of bone metabolism, and illustrated the benefit of integrating eQTLs and meQTLs data into pathway association analysis for genetic studies of complex human diseases. Cite this article: W. Wang, S. Huang, W. Hou, Y. Liu, Q. Fan, A. He, Y. Wen, J. Hao, X. Guo, F. Zhang. Integrative analysis of GWAS, eQTLs and meQTLs data suggests that multiple gene sets are associated with bone mineral density. Bone Joint Res 2017;6:572–576

Objectives. The aim of the current study was to assess whether calcaneal broadband ultrasound attenuation (BUA) can predict whole body and regional dual-energy x-ray absorptiometry (DXA)-derived bone mass in healthy, Australian children and adolescents at different stages of maturity. Methods. A total of 389 boys and girls across a wide age range (four to 18 years) volunteered to participate. The estimated age of peak height velocity (APHV) was used to classify children into pre-, peri-, and post-APHV groups. BUA was measured at the non-dominant heel with quantitative ultrasonometry (QUS) (Lunar Achilles Insight, GE), while bone mineral density (BMD) and bone mineral content (BMC) were examined at the femoral neck, lumbar spine and whole body (DXA, XR-800, Norland). Associations between BUA and DXA-derived measures were examined with Pearson correlations and linear regression. Participants were additionally ranked in quartiles for QUS and DXA measures in order to determine agreement in rankings. Results. For the whole sample, BUA predicted 29% of the study population variance in whole body BMC and BMD, 23% to 24% of the study population variance in lumbar spine BMC and BMD, and 21% to 24% of the variance in femoral neck BMC and BMD (p < 0.001). BUA predictions were strongest for the most mature participants (pre-APHV R. 2. = 0.03 to 0.19; peri-APHV R. 2. = 0.05 to 0.17; post-APHV R. 2. = 0.18 to 0.28) and marginally stronger for girls (R. 2. = 0.25-0.32, p < 0.001) than for boys (R. 2. = 0.21-0.27, p < 0.001). Agreement in quartile rankings between QUS and DXA measures of bone mass was generally poor (27.3% to 38.2%). Conclusion. Calcaneal BUA has a weak to moderate relationship with DXA measurements of bone mass in children, and has a tendency to misclassify children on the basis of quartile rankings. Cite this article: B. K. Weeks, R. Hirsch, R. C. Nogueira, B. R. Beck. Is calcaneal broadband ultrasound attenuation a valid index of dual-energy x-ray absorptiometry-derived bone mass in children? Bone Joint Res 2016;5:538–543. DOI: 10.1302/2046-3758.511.BJR-2016-0116.R1

Aims. We aimed to evaluate the temperature around the nerve root during drilling of the lamina and to determine whether irrigation during drilling can reduce the chance of nerve root injury. Materials and Methods. Lumbar nerve roots were exposed to frictional heat by high-speed drilling of the lamina in a live rabbit model, with saline (room temperature (RT) or chilled saline) or without saline (control) irrigation. We measured temperatures surrounding the nerve root and made histological evaluations. Results. In the control group, the mean temperature around the nerve root was 52.0°C (38.0°C to 75.5°C) after 60 seconds of drilling, and nerve root injuries were found in one out of 13 (7.7%) immediately, three out of 14 (21.4%) at three days, and 11 out of 25 (44.0%) at seven days post-operatively. While the RT group showed a significantly lower temperature around the nerve root compared with the control group (mean 46.5°C; 34.5°C to 66.9°C, p < 0.001), RT saline failed to significantly reduce the incidence of nerve root injury (ten out of 26; 38.5%; odds ratio (OR) 0.96; 95% confidence interval (CI) 0.516 to 1.785; p = 0.563). However, chilled saline irrigation resulted in a significantly lower temperature than the control group (mean 39.0°C; 35.3°C to 52.3°C; p < 0.001) and a lower rate of nerve root injury (two out of 21; 9.5%, OR 0.13; 95% CI 0.02 to 0.703, p = 0.010). Conclusion. Frictional heat caused by a high-speed drill can cause histological nerve root injury. Chilled saline irrigation had a more prominent effect than RT in reducing the incidence of the thermal injury during extended drilling. Cite this article: Bone Joint J 2017;99-B:554–60

Using the transverse processes of fresh porcine lumbar spines as an experimental model we evaluated the heat generated by a rotating burr of a high-speed drill in cutting the bone. The temperature at the drilled site reached 174°C with a diamond burr and 77°C with a steel burr. With water irrigation at a flow rate of 540 ml/hr an effective reduction in the temperature was achieved whereas irrigation with water at 180 ml/hr was much less effective. There was a significant negative correlation between the thickness of the residual bone and the temperature measured at its undersurface adjacent to the drilling site (p < 0.001). Our data suggest that tissues neighbouring the drilled bone, especially nerve roots, can be damaged by the heat generated from the tip of a high-speed drill. Nerve-root palsy, one of the most common complications of cervical spinal surgery, may be caused by thermal damage to nerve roots arising in this manner

We have studied the mechanosensitive afferent units in the lateral ligament of the ankle of the cat, with reference to the causes of lateral instability after injury, using electrophysiological recording from the lumbar dorsal rootlets. We identified 30 mechanosensitive units in the lateral ligament; 28 (93%) were located near the attachment to the fibula and calcaneus, which included both low-threshold group-II units and low- and high-threshold group-III units. Our results indicate that there are both proprioceptors and nociceptors in the lateral ligament of the cat ankle, and confirm that afferent fibres from the lateral ligament may contribute to the stability of the joint by regulation of position and movement

Recent studies of the fibroblast growth factor receptor 3 (FGFR3) gene have established that achondroplasia and hypochondroplasia are allelic disorders of different mutations. To determine whether the genotype could be distinguished on the basis of the phenotype, we analysed height, arm span, and skeletal radiographs from 23 patients with achondroplasia and the G380R mutation of FGFR3 and eight with hypochondroplasia and the N540K mutation. Both conditions share the classical pathological features of micromelic short stature, reduced or unchanged interpedicular distances in the lumbar spine, disproportionately long fibulae, and squared and shortened pelvic ilia. These were significantly more severe in the G380R patients than in the N540K patients. Our findings have shown a firm statistical correlation between the genotype and the phenotype, although there were a few exceptional cases in which there was phenotypic overlap between the two conditions

Immobilisation causes denervation-like changes in the motor endplates, decreases the content of IGF-I, and increases the number of IGF-I receptors in the spinal cord. In the rat we investigated whether similar changes occur after a fracture of the midshaft of the femur which had been treated by intramedullary fixation with adequate or undersized pins. A more pronounced reduction in muscle wet weight was seen after fixation by undersized pins as well as decreased ash density of the ipsilateral tibia which did not completely return to normal within the 12-week experimental period. The nicotinic cholinergic receptors in the motor endplates of tibialis anterior were increased (p < 0.01) and there was a significant increase (p < 0.02) in IGF-I receptors in the lumbar spinal cord ipsilateral to the fracture after treatment by undersized nails. These changes may be associated with the impaired proprioception, co-ordination and motor activity which are sometimes seen after fractures

We investigated the distribution of compressive ‘stress’ within cadaver intervertebral discs, using a pressure transducer mounted in a 1.3 mm diameter needle. The needle was pulled along the midsagittal diameter of a lumbar disc with the face of the transducer either vertical or horizontal while the disc was subjected to a constant compressive force. The resulting ‘stress profiles’ were analysed in order to characterise the distribution of vertical and horizontal compressive stress within each disc. A total of 87 discs from subjects aged between 16 and 87 years was examined. Our results showed that age-related degenerative changes reduced the diameter of the central hydrostatic region of each disc (the ‘functional nucleus’) by approximately 50%, and the pressure within this region fell by 30%. The width of the functional annulus increased by 80% and the height of compressive ‘stress peaks’ within it by 160%. The effects of age and degeneration were greater at L4/L5 than at L2/L3, and the posterior annulus was affected more than the anterior. Age and degeneration were themselves closely related, but the stage of degeneration had the greater effect on stress distributions. We suggest that structural changes within the annulus and endplate lead to a transfer of load from the nucleus to the posterior annulus. High ‘stress’ concentrations within the annulus may cause pain, and lead to further disruption

Objectives

Degenerative disc disease (DDD) and osteoarthritis (OA) are relatively frequent causes of disability amongst the elderly; they constitute serious socioeconomic costs and significantly impair quality of life. Previous studies to date have found that aggrecan variable number of tandem repeats (VNTR) contributes both to DDD and OA. However, current data are not consistent across studies. The purpose of this study was to evaluate systematically the relationship between aggrecan VNTR, and DDD and/or OA.

Objectives

Osteoporosis has become an increasing concern for older people as it may potentially lead to osteoporotic fractures. This study is designed to assess the efficacy and safety of ten therapies for post-menopausal women using network meta-analysis.