A novel magnetic resonance imaging postprocessing technique for the assessment of intervertebral disc degeneration-Correlation with histological grading in a rabbit disc degeneration model.

Introduction:Estimation of intervertebral disc degeneration on magnetic resonance imaging (MRI) is challenging. Qualitative schemes used in clinical practice correlate poorly with pain and quantitative techniques have not entered widespread clinical use. Methods:As part of a prior study, 25 New Zealand white rabbits underwent annular puncture to induce disc degeneration in 50 noncontiguous lumbar discs. At 16 weeks, the animals underwent multi-echo T2 MRI scanning and were euthanized. The discs were stained and examined histologically. Quantitative T2 relaxation maps were prepared using the nonlinear least squares method. Decay Variance maps were created using a novel technique of aggregating the deviation in the intensity of each echo signal from the expected intensity based on the previous rate of decay. Results:Decay Variance maps showed a clear and well demarcated nucleus pulposus with a consistent rate of decay (low Decay Variance) in healthy discs that showed progressively more variable decay (higher Decay Variance) with increasing degeneration. Decay Variance maps required significantly less time to generate (1.0 ± 0.0 second) compared with traditional T2 relaxometry maps (5 (±0.9) to 1788.9 (±116) seconds). Histology scores correlated strongly with Decay Variance scores (r = 0.82, P < .01) and weakly with T2 signal intensity (r = 0.32, P < .01) and quantitative T2 relaxometry (r = 0.39, P < .01). Decay Variance had superior sensitivity and specificity for the detection of degenerate discs when compared to T2 signal intensity or Quantitative T2 mapping. Conclusion:Our results show that using a multi-echo T2 MRI sequence, Decay Variance can quantitatively assess disc degeneration more accurately and with less image-processing time than quantitative T2 relaxometry in a rabbit disc puncture model. The technique is a viable candidate for quantitative assessment of disc degeneration on MRI scans. Further validation on human subjects is needed

Unveiling the Bmp13 Enigma: Redundant Morphogen or Crucial Regulator?

Bone morphogenetic proteins are a diverse group of morphogens with influences not only on bone tissue, as the nomenclature suggests, but on multiple tissues in the body and often at crucial and influential periods in development

EFFECTS OF OP-1 DEVICE ON A POSTEROLATERAL INTER-TRANSVERSE SPINAL FUSION MODEL IN OSTEOPOROTIC RATS

Introduction The present experiment is undertaken to determine if a single dose addition of OP-1 device (rhBMP-7 and TCP-CMC) will enhance posterolateral spinal fusion in an osteoporotic rat mode (estrogen deficiency). Posterolateral intertransverse process spinal fusion using recombinant human osteogenic protein (rhBMP-7) was performed in ovariectomised female rats. OP-1 can be manipulated to enhance fusion rates and fracture healing with or without osteoporosis. Osteoporosis is characterised by low bone mass and micro-architectural deterioration of bone structure, resulting in bone fragility and an increase in susceptibility to fracture. Ovariectomised rats have been used as an osteoporotic model for posterolateral intertransverse process fusion in BMP experimental studies. Many studies have shown rhBMP-7 promotes spinal fusions in posterolateral fusion animal models. Not only is OP-1 able to promote spinal fusion in a standard animal model, but also it has been shown to overcome the inhibitory effects of nicotine in a rabbit posterolateral spinal fusion model. OP-1 Putty (Stryker) is an osteoinductive and osteoconductive bone graft material which consists of the recombinant human Osteogenic Protein (rhBMP-7), and TCP putty containing carboxymethylcellulose sodium (CMC) and tricalcium phosphate. This standard OP-1 device is somewhat different from the one Moazzaz et al used (1). The implication of OP-1 in osteoporotic model will open a new therapeutic window for osteoporotic or osteopaenial patients for the requirements of spinal fusion. Methods In present study, a total of 42 ovariectomised Sprague-Dawley female rats were randomly assigned to groups receiving 30 µg lactose + 400mg TCP-CMC, 90 µg lactose + 400 mg TCP-CMC, 30 µg rhBMP-7 + 400 mg TCP-CMC and 90 µg rhBMP-7 + 400 mg TCP-CMC. There was a group of rats receiving 400 mg TCP-CMC alone. Spinal fusion was evaluated by manual motion testing at each lumbar segment, Faxitron digital X-ray evaluation using the Lenke grading system, CT scans, DEXA scans and histology. Results Ovariectomized rats receiving 30 µg lactose + 400mg TCP-CMC, 90 µg lactose + 400 mg TCP-CMC, and 400 mg TCP-CMC alone did not show spinal fusion. OVX rats receiving 90 µg rhBMP-7 + 400 mg TCP-CMC showed significantly higher fusion rates than other groups (P <0.0001). However, the rats receiving 30 µg rhBMP-7 + 400 mg TCP-CMC did not show solid fusion either radiologically and histologically. Discussion Therefore rhBMP-7, in dose of 90 µg, is able to overcome the inhibitory effects of estrogen deficiency on posterolateral spinal fusion and generate a relatively robust fusion. The effect of the OP-1 on osteoporotic spine is dose-dependent with/without carrier-dependent

BMP-13 Emerges as a Potential Inhibitor of Bone Formation

Bone morphogenetic protein-13 (BMP-13) plays an important role in skeletal development. In the light of a recent report that mutations in the BMP-13 gene are associated with spine vertebral fusion in Klippel-Feil syndrome, we hypothesized that BMP-13 signaling is crucial for regulating embryonic endochondral ossification. In this study, we found that BMP-13 inhibited the osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells (BM MSCs) in vitro. The endogenous BMP-13 gene expression in MSCs was examined under expansion conditions. The MSCs were then induced to differentiate into osteoblasts in osteo-inductive medium containing exogenous BMP-13. Gene expression was analysed by real-time PCR. Alkaline phosphatase (ALP) expression and activity, proteoglycan (PG) synthesis and matrix mineralization were assessed by cytological staining or ALP assay. Results showed that endogenous BMP-13 mRNA expression was higher than BMP-2 or -7 during MSC growth. BMP-13 supplementation strongly inhibited matrix mineralization and ALP activity of osteogenic differentiated MSCs, yet increased PG synthesis under the same conditions. In conclusion, BMP-13 inhibited osteogenic differentiation of MSCs, implying that functional mutations or deficiency of BMP-13 may allow excess bone formation. Our finding provides an insight into the molecular mechanisms and the therapeutic potential of BMP-13 in restricting pathological bone formation

BMP13 Prevents the Effects of Annular Injury in an Ovine Model

Chronic back pain is a global health problem affecting millions of people worldwide and carries significant economic and social morbidities. Intervertebral disc damage and degeneration is a major cause of back pain, characterised by histological and biochemical changes that have been well documented in animal models. Recently there has been intense interest in early intervention in disc degeneration using growth factors or stem cell transplantation, to replenish the diseased tissues. Bone Morphogenetic Proteins (BMPs) have been approved for clinical use in augmenting spinal fusions, and may represent candidate molecules for intervertebral disc regeneration

Intervertebral disc degeneration and how it leads to low back pain

Abstract The purpose of this review was to evaluate data generated by animal models of intervertebral disc (IVD) degeneration published in the last decade and show how this has made invaluable contributions to the identification of molecular events occurring in and contributing to pain generation. IVD degeneration and associated spinal pain is a complex multifactorial process, its complexity poses difficulties in the selection of the most appropriate therapeutic target to focus on of many potential candidates in the formulation of strategies to alleviate pain perception and to effect disc repair and regeneration and the prevention of associated neuropathic and nociceptive pain. Nerve ingrowth and increased numbers of nociceptors and mechanoreceptors in the degenerate IVD are mechanically stimulated in the biomechanically incompetent abnormally loaded degenerate IVD leading to increased generation of low back pain. Maintenance of a healthy IVD is, thus, an important preventative measure that warrants further investigation to preclude the generation of low back pain. Recent studies with growth and differentiation factor 6 in IVD puncture and multi‐level IVD degeneration models and a rat xenograft radiculopathy pain model have shown it has considerable potential in the prevention of further deterioration in degenerate IVDs, has regenerative properties that promote recovery of normal IVD architectural functional organization and inhibits the generation of inflammatory mediators that lead to disc degeneration and the generation of low back pain. Human clinical trials are warranted and eagerly anticipated with this compound to assess its efficacy in the treatment of IVD degeneration and the prevention of the generation of low back pain

Review Article - Prosthetic Lumbar disc replacement for degenerative disc disease

Mechanical articulated device to replace intervertebral disc as a treatment for low back pain secondary to disc degeneration has emerged as a promising tool for selected patients. The potential advantages are prevention of adjacent segment degeneration, maintenance of mobility as well as avoidance of all the complications associated with fusion. The short-term results have been comparable to that of fusion, a few mid-term results have shown mixed outcome, but information on long-term results and performance are not available at present. The rationale for lumbar disc arthroplasty, indications, contraindications, the various artificial devices in the market and the concepts intrinsic to each of them, basic technique of insertion, complications are discussed and a brief summary of our experience with one of the devices is presented

Role of nutritional supplementation in elderly patients with hip fractures

Due to the ageing population there is an increasing incidence of hip fractures in the elderly. Oral nutritional supplements are being widely used to improve clinical outcomes and mortality post-hip fractures. The aim of this study was to review the available literature on the effects of oral nutritional supplements on elderly patients with hip fractures. A search of EMBASE (1988–present) and MEDLINE (1946–present) with the search terms: “nutritional supplement” AND “hip fracture”; “nutritional supplement” AND “femoral neck fracture”; “nutritional supplement” AND “intertrochanteric fracture”; “nutritional supplement” AND “subcapital fracture”; “hip fracture” AND “vitamin supplement”; “hip fracture” AND “protein supplement”; “hip fracture” AND “nutrient supplement” was carried out. Additionally, the reference lists of articles were searched for relevant areas of study. Few studies showed that oral nutritional supplementation led to a more positive clinical outcome amongst elderly patients suffering hip fractures. Most studies found little or nil positive results. Thus, the role of oral nutritional supplementation on post-hip fracture mortality, infection/complication rates, and hospitalisation/rehabilitation time amongst elderly patients is unclear. There is a need for a broader, randomised, placebo-controlled clinical trial on the effect of oral nutritional supplements and particularly on the supplements used commonly

Unveiling the Bmp13 Enigma: Redundant Morphogen or Crucial Regulator?

Bone morphogenetic proteins are a diverse group of morphogens with influences not only on bone tissue, as the nomenclature suggests, but on multiple tissues in the body and often at crucial and influential periods in development. The purpose of this review is to identify and discuss current knowledge of one vertebrate BMP, Bone Morphogenetic Protein 13 (BMP13), from a variety of research fields, in order to clarify BMP13's functional contribution to developing and maintaining healthy tissues, and to identify potential future research directions for this intriguing morphogen. BMP13 is highly evolutionarily conserved (active domain &#62;95%) across diverse species from Zebrafish to humans, suggesting a crucial function. In addition, mutations in BMP13 have recently been associated with Klippel-Feil Syndrome, causative of numerous skeletal and developmental defects including spinal disc fusion. The specific nature of BMP13's crucial function is, however, not yet known. The literature for BMP13 is focused largely on its activity in the healing of tendon-like tissues, or in comparisons with other BMP family molecules for whom a clear function in embryo development or osteogenic differentiation has been identified. There is a paucity of detailed information regarding BMP13 protein activity, structure or protein processing. Whilst some activity in the stimulation of osteogenic or cartilaginous gene expression has been reported, and BMP13 expression is found in post natal cartilage and tendon tissues, there appears to be a redundancy of function in the BMP family, with several members capable of stimulating similar tissue responses. This review aims to summarise the known or potential role(s) for BMP13 in a variety of biological systems.</p

Nociceptive pain assessed by the PainDETECT questionnaire may predict response to opioid treatment for chronic low back pain

Introduction: The pharmacological management of chronic low back pain (LBP) is complex. The World Health Organisation recommends a laddered approach to pain medication usage. The PainDETECT questionnaire distinguishes between neuropathic pain (NeP), nociceptive pain (NoP), and ambiguous pain. By elucidating the difference in medication efficacy between these groups, clinicians can provide a tailored treatment plan to manage patient's pain. This study aimed to investigate the relationship between pharmacological treatments, pain categorizations, and medication efficacy as reported by patients. Methods: A secondary retrospective analysis of a prospectively collected database was conducted involving 318 consecutively recruited patients, aged 18 years and above, who completed PainDETECT, medication history and patient reported medication efficacy questionnaires. Medication history was categorized into four lines of treatment: first line (paracetamol ± non-prescribed anti-inflammatories), second line (prescribed anti-inflammatories), third line (anticonvulsants/neuromodulators) and fourth line (opioids). Medication efficacy was measured using a three-point Likert scale: effective (+2), somewhat effective (+1), no effect (0). Findings: The study included 120, 50, 54 and 94 patients on first line, second line, third line and fourth line treatment, respectively. The NeP group had higher mean numerical rating scale (NRS) compared to NoP group in all four lines of treatment (8.10 ± 1.59 vs. 5.47± 2.27, p < 0.001, 8.64± 1.43 vs. 5.52± 1.86, p < 0.001, 8.00± 1.07 vs. 6.37± 2.39, p < 0.01, and 8.05± 1.73 vs. 7.2± 1.29, p < 0.05). When confounding for severity of LBP as measured by NRS, the distribution of medication efficacy significantly differed amongst the NeP, ambiguous and NoP groups in patients undergoing fourth line pharmacological treatment (r2 = 8.623, p < 0.05). The NoP group exhibited significantly higher medication efficacy compared to the NeP group (U = 14.038, p < 0.05). There was no significant difference in medication efficacy across the pain classifications for first, second- and third-line treatment. Interpretation: Opioids was the only line of treatment more effective in targeting NoP, as determined by the PainDETECT questionnaire, compared to NeP. This pioneering study illustrates the complex nature of pharmacological management for chronic LBP. It underscores the importance of tailoring pharmacological treatment plans to fit individual pain profiles and expectations instead of adopting a blanket approach to pain management