Kazuyo Yamauchi

Comparison of teriparatide and bisphosphonate treatment to reduce pedicle screw loosening after lumbar spinal fusion surgery in postmenopausal women with osteoporosis from a bone quality perspective.

Study Design. Prospective study. Objective. To examine the efficacy of teriparatide or bisphosphonate treatment to reduce pedicle screw (PS) loosening after instrumented lumbar posterolateral fusion in postmenopausal women with osteoporosis. Summary of Background Data. Failure of fixation caused by loosening of PSs in osteoporosis is a problem in spinal surgery. Oral administration of bisphosphonate or intermittent injection of parathyroid hormone treatment increases bone mass and reduces the risk of osteoporotic vertebral fractures. Although these treatments may be factor in improving bone quality, a clinical study of the efficacy of bisphosphonate or parathyroid hormone for reducing PS loosening that addresses the quality of the bone marrow and pedicle cortex has not yet been reported. Methods. Sixty-two women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 3 groups: a teriparatide group (daily subcutaneous injection of 20 &mgr;g of teriparatide, n = 20), a bisphosphonate group (daily oral administration 2.5 mg of risedronate, n = 20), and a control group (without medication for osteoporosis, n = 22). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Loosening of PSs and surgical outcome were evaluated radiographically, clinically, and by computed tomography 12 months after surgery. Results. At 12-month follow-up, the incidence of PS loosening was 7% to 13% in the teriparatide group, 13% to 26% in the risedronate group, and 15% to 25% in the control group. The incidence of PS loosening in the teriparatide group was significantly lower than that in the risedronate or the control group (P < 0.05). In contrast, the extent of PS loosening in the risedronate group was not significantly different from that in the control group (P > 0.05). Conclusion. Our findings suggest that administration of teriparatide increased the quality of the lumbar spine bone marrow and pedicle cortex. Level of Evidence: 3

Results of surgery for discogenic low back pain: a randomized study using discography versus discoblock for diagnosis.

Study Design. Randomized, controlled study. Objective. To evaluate the diagnosis of discogenic low back pain (LBP) with discography and discoblock. Summary of Background Data. Discogenic LBP is usually diagnosed by magnetic resonance imaging and discography. However, the reliability of discography is controversial. Previously, we reported the usefulness of discoblock with bupivacaine for diagnosis, and discoblock improved the results of anterior interbody fusion surgery. However, that study was not a randomized, controlled study. Therefore, the purpose of the current study was to compare the results of surgery after diagnosis of LBP by discography and discoblock. Methods. Patients (n = 42) with severe LBP showing L4–L5 or L5–S1 disc degeneration on magnetic resonance imaging were evaluated by discography (1.5 mL of contrast medium) or discoblock (intradisc injection of 0.75 mL of 0.5% bupivacaine). We randomized the patients in turn. Anterior discectomy and interbody fusion were performed in patients who responded to the diagnostic procedures. The visual analogue scale score (0, no pain; 100, worst pain), Japanese Orthopedic Association Score (0, worst pain; 3, no pain), Oswestry Disability Index, and patient satisfaction before and 3 years after surgery were recorded and compared between groups. Results. Twelve patients did not show pain provocation by discography or pain relief by discoblock and were excluded. Fifteen patients who showed pain provocation by discography and 15 patients who experienced pain relief with discoblock were evaluated. Rates of improvement in the visual analogue scale score, Japanese Orthopedic Association Score, and Oswestry Disability Index score in the discoblock group were significantly higher than those in the discography group (P < 0.05) from baseline to 3 years after surgery. Three patients were dissatisfied with surgery after discography compared with one patient after discoblock. Conclusion. Pain relief after injection of a small amount of bupivacaine into the painful disc was a useful tool for the diagnosis of discogenic LBP compared with discography.

Teriparatide accelerates lumbar posterolateral fusion in women with postmenopausal osteoporosis: prospective study.

Study Design. Prospective trial. Objective. To examine the clinical efficacy of teriparatide for bone union after instrumented lumbar posterolateral fusion using local bone grafting in women with postmenopausal osteoporosis. Summary of Background Data. Intermittent parathyroid hormone (PTH) treatment increases bone mass and reduces the risk for osteoporotic vertebral fractures. Recombinant human PTH (1–34) has already been approved as a treatment for severe osteoporosis. Preclinical data support the efficacy of PTH for lumbar spinal fusion. However, clinical results of PTH for spinal fusion have not yet been reported. Methods. Fifty-seven women with osteoporosis diagnosed with degenerative spondylolisthesis were divided into 2 treatment groups, a teriparatide group (n = 29; daily subcutaneous injection of 20 &mgr;g of teriparatide) and a bisphosphonate group (n = 28; weekly oral administration of 17.5 mg of risedronate). All patients underwent decompression and 1- or 2-level instrumented posterolateral fusion with a local bone graft. Fusion rate, duration of bone union, and pain scores were evaluated 1 year after surgery. Results. Pain scores improved after surgery; however, no significant difference was noted between the groups after surgery. The rate of bone union was 82% in the teriparatide group and 68% in the bisphosphonate group. Average duration of bone union was 8 months in the teriparatide group and 10 months in the bisphosphonate group. The rate of bone union and average of duration of bone union in the teriparatide group patients were significantly superior to those in the bisphosphonate group. Conclusion. Daily subcutaneous injection of teriparatide for bone union using local bone grafting after instrumented lumbar posterolateral fusion in women with postmenopausal osteoporosis was more effective than oral administration of bisphosphonate.

Risedronate decreases bone resorption and improves low back pain in postmenopausal osteoporosis patients without vertebral fractures.

Elderly postmenopausal women who have osteoporosis sometimes experience low back pain, however, the relationship between low back pain and osteoporosis in the absence of vertebral fractures remains unclear. We examined the relationship between bone mineral density (BMD), bone resorption and low back pain in elderly female patients who did not have osteoporotic vertebral fractures. The average BMD was 0.675 g/cm(2) when assessed by dual-energy X-ray absorptiometry (DEXA). Patients were excluded from the study if they had vertebral fractures revealed by radiography, CT scans or MRI. Bisphosphonate (risedronate) was administered for 4 months. The visual analogue scale (VAS) pain score, Roland Morris Disability Questionnaire (RDQ), Short Form-36 (SF-36) questionnaire, BMD and N-terminal telopeptide of type I collagen (NTx; a marker for bone resorption) were examined before and after treatment. DEXA did not increase significantly, but serum and urinary NTx were decreased (-51.4% and -62.0%, respectively) after 4 months of risedronate treatment (p<0.01). The assessment was repeated using the VAS score, RDQ and SF-36, which revealed an improvement after risedronate treatment (p<0.01). A decrease in serum and urinary NTx was associated with improvement of low back pain, suggesting that despite the absence of vertebral fractures, bone resorption due to osteoporosis may cause low back pain.

Tumor Necrosis Factor-alpha in the Nucleus Pulposus Mediates Radicular Pain, but Not Increase of Inflammatory Peptide, Associated With Nerve Damage in Mice

Study Design. Changes in behavior and the immunohistochemistry of dorsal root ganglion (DRG) neurons were examined using a mouse model of radicular pain. Objective. To examine the effects of TNF-α in the nucleus pulposus (NP) on nerve roots. Summary of Background Data. Radicular pain is induced by mechanical compression and inflammation of nerve roots. Many authors have reported that following disc herniation, producing TNF-α plays a major role in neuropathic pain. Their findings suggest that TNF-α contained in the NP is significant in the development of pain and nerve root degeneration, but it has not been clearly demonstrated. Methods. Wild-type NPs or TNF-KO NPs, which were harvested from C57BL/6 mice (wild-type NP) or TNF-knock-out mice (TNF-KO NP), were applied to the left sciatic nerves of 30 wild-type mice, and the nerves were pinched. Production of hind paw mechanical allodynia, activating transcription factor 3, and calcitonin gene- related peptide (CGRP) were assessed. Results. Animals receiving a NP application demonstrated significant mechanical allodynia compared to the pinch-only and the control groups. The degree of mechanical allodynia was greater in the wild-type than in the TNF-KO group. The number of activating transcription factor 3 immunoreactive neurons was significantly higher in the wild-type than in the TNF-KO group. The number of CGRP-immunoreactive neurons was higher in the wild-type and TNF-KO than in the control groups. However, no significant difference in activity was observed between both CGRP positive groups. Conclusion. In this study TNF-α contained in the NP was important for the production of radicular pain accompanied by long-lasting degeneration of DRG neurons. However, other cytokines in the NP and nerve compression may also play important roles in pain transmission. In this model system, TNF-α in the NP appears to mediate pain, but not cause an increase in CGRP in the DRG neurons.

Diffusion magnetic resonance imaging to differentiate degenerative from infectious endplate abnormalities in the lumbar spine.

Study Design. A retrospective observational study of healthy volunteers and patients with degenerative and infectious endplate abnormalities in the lumbar spine. Objectives. Our purpose was to evaluate the usefulness of diffusion-weighted imaging (DWI) for the differentiation of degenerative and infectious endplate abnormalities using 1.5-T magnetic resonance imaging (MRI). Summary of Background Data. DWI can provide valuable structural information about tissues that may be useful for clinical applications in differentiation between degenerative and infectious endplate abnormalities. Methods. Sixteen consecutive patients with endplate abnormalities that was detected by MRI of the lumbar spine, and 15 healthy volunteers were studied. DWI was performed using whole-body imaging with background body signal suppression with a b value of 1000 s/mm2. Apparent diffusion coefficient values of normal and abnormal vertebral bone marrow were calculated. Results. Twenty-nine vertebral abnormalities were found in 16 patients. Nine vertebral abnormalities in 5 patients were because of infections and 20 vertebral abnormalities in 11 patients were because of degenerative changes; 7 levels were classified as Modic type 1, 7 levels as type 2, and 6 levels as type 3. DWI showed hyperintensity in all patients with infection, similar to that used in positron emission tomography, but not in the intervertebral spaces of any patients with degenerative disease. Apparent diffusion coefficient values of infectious bone marrowwere significantly higher than normal and degenerative bone marrow. Conclusion. DWI is useful for differentiation of degenerative and infectious endplate abnormalities. Moreover, MRI is widely used clinically because of the lack of ionizing radiation, low cost, and fast imaging time as compared with positron emission tomography. Therefore, DWI has the potential to be used as a screening tool.

TNF-alpha in nucleus pulposus induces sensory nerve growth: a study of the mechanism of discogenic low back pain using TNF-alpha-deficient mice.

Study Design. We used retrograde neurotracing with fluoro-gold to investigate the relationship between tumor necrosis factor (TNF-á) and nerve growth into the nucleus pulposus (NP) of wild-type and TNF-&agr;-deficient mice. Objective. To clarify mechanisms underlying nerve growth into the NP and the role of TNF-á in this process. Summary of Background Data. Degeneration of lumbar intervertebral discs is a cause of low back pain. Pathogenesis may involve sensory nerve ingrowth into the inner layers and NP of degenerating discs. We hypothesized that TNF-á in the NP is a major inducer of nerve ingrowth and investigated this hypothesis in vivo using wild-type and TNF-á-deficient mice. Methods. NP was harvested at the L4/5 level from 10 wild-type and 10 TNF-deficient mice. These 20 samples of wild-type NP or TNF-deficient NP were mixed with fluoro-gold and injected into the left quadriceps muscle of 20 other wild-type mice (1 sample per mouse). Five control mice underwent sham operations in which they received similar injections of NP-free fluoro-gold into their left quadriceps muscles to detect whether neurons innervating the muscle establish contact with injected NP. Seven and 14 days after surgery, left L4 dorsal root ganglions were removed and incubated with antibodies against growth-associated protein 43 (GAP43), a marker of axonal growth. We evaluated fluoro-gold-labeled and GAP43-immunoreactive dorsal root ganglions neurons. Results. Within the set of fluoro-gold-labeled neurons, 10% were positive for GAP43 in sham-operated animals, 22% positive in the TNF-deficient NP group, and 38% positive in the wild-type NP group. These intergroup differences in the percentage of GAP43-positive neurons were statistically significant (sham vs. TNF-deficient NP group: P = 0.009; TNF-deficient NP group vs wild-type NP group: P = 0.026). Conclusion. The percentage of fluoro-gold–labeled GAP43-immunoreactive neurons significantly increased after injections of NP harvested from both mouse types. Furthermore, the percentage of GAP43-immunoreactive neurons was significantly higher in mice receiving wild-type NP compared with mice receiving TNF-deficient NP. These findings suggest that TNF-&agr; acts as an inducer of axonal growth into degenerated discs, as evidenced by decreased GAP-43 immunoreactivity in mice receiving TNF-deficient NP injections and even lower GAP-43 immunoreactivity in control mice receiving NP-free fluoro-gold injections.

Nerve growth factor of cultured medium extracted from human degenerative nucleus pulposus promotes sensory nerve growth and induces substance p in vitro.

Study Design. We investigated the mechanism of discogenic low back pain using an in vitro model. Objective. To evaluate the axonal growth and induction of a painful neuropeptide, substance P (SP), using rat dorsal root ganglion (DRG) neurons and degenerated human disc cells in vitro. Summary of Background Data. Degeneration of the lumbar intervertebral disc is a cause of low back pain. The pathologic mechanism is thought to be sensory nerve ingrowth into the inner layers of the degenerated intervertebral disc; however, the precise patho-mechanism has not been clarified. Methods. The nucleus pulposus (NP) and annulus fibrosus (AF) of human intervertebral discs were harvested from patients with discogenic low back pain. Extracted medium from human degenerative intervertebral discs was cultured with neurons of rat DRGs. We evaluated the promotion of axonal growth and SP induction of DRG neurons in extracted medium from the NP and AF using immunocytochemistry. Results. The average length of growing axons in the NP and AF was significantly longer than that in the control (P < 0.005). That in the NP was significantly longer than that in the AF. The average length of growing axons in the NP was significantly shortened after anti-nerve growth factor (NGF)&bgr; treatment (P < 0.005); however, that in the AF was not (P > 0.05). The percentage of SP-immunoreactive cells with growing axons was significantly higher only in the NP group compared with the control and AF groups (P < 0.005), and anti-NGF&bgr; treatment decreased the expression of SP in the NP group (P < 0.05). Conclusion. Extracted medium from the NP and AF promoted axonal growth. Furthermore, NGF from the NP promoted axonal growth and induced SP. These in vitro results may suggest that NGF from the NP promotes the growth of sensory nerve fibers innervating the degenerated intervertebral disc and may induce SP related with pain transmission.

Existence of nerve growth factor receptors, tyrosine kinase a and p75 neurotrophin receptors in intervertebral discs and on dorsal root ganglion neurons innervating intervertebral discs in rats.

Study Design. We evaluated 2 types of nerve growth factor (NGF) receptors on dorsal root ganglion (DRG) cells and nerve fibers innervating rat lumbar intervertebral discs. Objective. To examine the NGF receptors, tyrosine kinase A (TrkA) and p75 neurotrophin receptor (p75NTR) on DRG cells and nerve fibers innervating rat lumbar intervertebral discs using immunohistochemistry and a retrograde neurotracing method. Summary of Background Data. Nerve innervation of intervertebral discs is thought to be a pathology of discogenic low back pain. NGF is also important for mediating inflammatory pain from intervertebral discs via the high affinity receptor, TrkA. Recent research has also revealed that the low affinity NGF receptor, p75NTR plays an important role in inflammatory pain. However, the presence of TrkA and p75NTR-immunoreactive (NTR-IR) DRG neurons innervating the rat L5/6 intervertebral disc, and p75NTR-IR nerve fibers in rat intervertebral discs, has not been explored. Methods. The Fluoro-gold neurotracer was applied to rat L5/6 intervertebral discs to determine the DRG neurons innervating the discs (n = 20). Fourteen days after surgery, bilateral DRG from the L1–L6 levels were harvested, sectioned, and immunostained for TrkA and p75NTR. The percentages of TrkA and p75NTR-IR DRG neurons were counted, and p75NTR-IR nerve fibers in L5/6 discs evaluated. Results. p75NTR-IR nerve fibers were found in superficial layers in the annulus fibrosus in L5/6 intervertebral discs. Fluoro-gold-labeled neurons innervating the L5/6 discs were distributed throughout DRG from the L1–L6 levels. The percentage of TrkA-immunoreactive (TrkA-IR) neurons was 75.1% ± 3.9% (mean ± SE) and that of p75NTR-IR neurons was 75.8% ± 5.1%. These percentages were similar for each level. Conclusion. Rat L5/6 intervertebral discs were innervated by multisegmental levels of DRG. Most DRG neurons innervating the discs were positive for 2 types of NGF receptors.

The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury

In peripheral nerve injury, Schwann cells (SCs) must survive to exert a continuing and essential role in successful nerve regeneration. Herein, we show that peripheral nerve injury is associated with activation of endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR). The UPR culminates in expression of C/EBP homology protein (CHOP), a proapoptotic transcription factor in SCs, unless counteracted by LDL receptor-related protein-1 (LRP1), which serves as a major activator of phosphatidylinositol 3-kinase (PI3K). Sciatic nerve crush injury in rats induced expression of the ER chaperone GRP78/BIP, reflecting an early, corrective phase of the UPR. However, when LRP1 signaling was inhibited with receptor-associated protein, PI3K activity was decreased and CHOP protein expression increased, particularly in myelinating SCs. In cultured SCs, the PKR-like ER kinase target eIF2α was phosphorylated and CHOP was induced by (1) inhibiting PI3K, (2) treating the cells with tumor necrosis factor-α (TNF-α), or (3) genetic silencing of LRP1. CHOP gene deletion in SCs decreased cell death in response to TNF-α. Furthermore, the effects of TNF-α on phosphorylated eIF2α, CHOP, and SC death were blocked by adding LRP1 ligands that augment LRP1-dependent cell signaling to PI3K. Collectively, our results support a model in which UPR-activated signaling pathways represent a major challenge to SC survival in nerve injury. LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, limits SC apoptosis resulting from increased CHOP expression in nerve injury.