Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

Accuracy of cup placement and pelvic motion in total hip arthroplasty in the lateral decubitus position using a new computed tomography-based navigation system with augmented reality technology.

INTRODUCTION: This study aimed to investigate the accuracy of cup position and assess the changes in pelvic tilt during primary total hip arthroplasty (THA) in the lateral decubitus position using a new computed tomography (CT)-based navigation system with augmented reality (AR) technology. MATERIALS AND METHODS: There were 37 cementless THAs performed using a CT-based navigation system with AR technology in the lateral decubitus position and 63 cementless THAs performed using manual implant techniques in the lateral decubitus position in this retrospective study. Postoperative cup radiographic inclination and anteversion were measured using postoperative CT, and the proportion of hips within Lewinnek's safe zone was analyzed and compared between the two groups. The mean absolute values of navigation error were assessed. Intraoperative pelvic tilt angles were also recorded using navigation system. RESULTS: The percentage of cups inside Lewinnek's safe zone was 100% in the navigation group and 35% in the control group (p < 0.001). The mean absolute values of navigation error in inclination and anteversion were 2.9° ± 2.1° and 3.3° ± 2.4°, respectively. The mean abduction angle of the pelvis was 5.1° ± 4.8° after placing the patients in the lateral decubitus position and 4.1° ± 6.0° after cup placement. The mean posterior tilt angle was 6.8° ± 5.1° after placing the patients in the lateral decubitus position and 9.3° ± 5.9° after cup placement. The mean internal rotation angle was 14.8° ± 7.4° after cup placement. There were no correlations between the navigation error in inclination or anteversion and the absolute values of changes of the pelvic tilt angle at any phase. CONCLUSIONS: Although progressive pelvic motion occurred in THA in the lateral decubitus position, especially during cup placement, the CT-based navigation system with AR technology improved cup placement accuracy.

Two- and three-dimensional measurements of leg length change using an accelerometer-based portable navigation system in total hip arthroplasty.

BACKGROUND: The aim of this study was examining the accuracy of accelerometer-based portable navigation systems (HipAlign) when measuring leg length changes using two-dimensional (2D) and three-dimensional (3D) methods. METHODS: Inclusion criteria were patients ≥ 20 years old with symptomatic hip disease who underwent primary total hip arthroplasty (THA) in the supine position using HipAlign between June 2019 and April 2020. The exclusion criteria were patients who underwent THA via a posterior approach. We examined correlations between the leg length change measurement with HipAlign and either 2D or 3D measurement. We performed a multivariate analysis to determine which factors may have influenced the absolute error results. RESULTS: This study included 34 patients. The absolute error in leg length change between the HipAlign and 3D measurement (4.0 mm) was greater than the HipAlign and 2D measurement (1.7 mm). There were positive correlations between leg length change with HipAlign and 2D and 3D measurements. Male patients had larger errors with 2D measurement. No significant factors were identified for 3D measurement. CONCLUSION: HipAlign provided acceptable measurement accuracy for leg length changes.

Long-term results of hemi-resurfacing and metal-on-metal hip resurfacing for osteonecrosis of the femoral head.

PURPOSE: Hemi-resurfacing arthroplasty (Hemi) and metal-on-metal hip resurfacing arthroplasty (HR) were proposed as alternatives to conventional total hip arthroplasty (THA) for patients with osteonecrosis of the femoral head (ONFH). Long-term results were evaluated. METHODS: Twenty-three hips with ONFH were treated, using Hemi in 12 and HR in 11. Mean follow-up was 15 years in the Hemi group and 10 years in the HR group. Long-term outcomes were reviewed retrospectively. RESULTS: In the Hemi group, 8 hips showed acetabular protrusion and were revised to THA. One of the 8 hips showed femoral loosening. In the HR group, pseudotumor was detected in 4 hips (36%), and 1 hip was revised due to symptomatic pseudotumor. No evidence of any femoral or acetabular loosening was seen in the HR group. Ten-year survival rates were 64.2% and 90.9% in the Hemi and HR groups, respectively. Survival rate in the Hemi group dropped to 22.9% at 15 years. CONCLUSIONS: Long-term results of Hemi for patients with ONFH were very poor, and Hemi should not continue to be used. Although HR had a concern of pseudotumor, it could offer attractive indications for 10 years.

High rates of outliers in computer-assisted high tibial osteotomy with excellent mid-term outcomes.

PURPOSE: The primary aim was to evaluate the accuracy of navigation in opening wedge high tibial osteotomy (HTO). The secondary aim was to examine mid-term outcomes after HTO. METHODS: Inclusion criteria were patients with medial compartment knee osteoarthritis who underwent computer-assisted HTOs. Mechanical axis (MA), percentage MA (%MA), and change in posterior tibial slope (ΔPTS) were displayed on the navigation screen. Radiographic examinations included hip-knee-ankle (HKA) angle, medial proximal tibial angle (MPTA), joint line convergence angle (JLCA), and PTS. Preoperative and 5 weeks postoperative standing radiographs of the whole lower extremity and knee were used. Clinical evaluations were performed using American Knee Society knee score and function score both preoperatively and at last follow-up. Radiographic evaluations were performed by orthopedic surgeons. Intraoperative navigation after osteotomy and postoperative standing radiograph were compared. MA (HKA), %MA, and ΔPTS were compared. Outliers were defined as > 3° in MA, > 10% in %MA, and > 10° in ΔPTS. Outlier and non-outlier groups were compared. The rate of conversion to arthroplasty was examined. RESULTS: This study involved 38 patients (44 knees) and last follow-up was at a mean of 5 years (range, 1-9 years). Mean American Knee Society knee score and function score improved significantly from 59 to 69 preoperatively to 95 and 85 at last follow-up, respectively. Absolute values of mean errors for MA, %MA, and ΔPTS were 2.1°, 9.3%, 1.2°, respectively. Outlier rates were 18% in MA, 39% in %MA, and 5% in ΔPTS. No significant factors were found in MA and ΔPTS. In %MA, preoperative JLCA was significantly higher in the outlier group compared to the non-outlier group. No knees underwent conversion to total knee arthroplasty. No differences in outcomes were found between outlier and non-outlier groups. CONCLUSION: Although rates of outlier values in computer-assisted opening wedge HTO were high, mid-term outcomes were excellent. LEVEL OF EVIDENCE: IV.

Predicting outcomes after total knee arthroplasty using intraoperative knee kinematics measured by navigation.

OBJECTIVES: The objective of the study is to evaluate the relationship between clinical results following posterior-stabilized total knee arthroplasty (TKA) and intraoperative kinematic pattern determined from navigation. METHODS: Participants were patients with knee osteoarthritis and varus deformity who underwent primary posterior-stabilized TKA. Preoperative and post-implantation kinematic data were recorded, and all kinematic patterns were divided into two types: medial pivot (MP) or non-MP. Knees with MP and non-MP patterns after implantation were compared in terms of postoperative flexion angle, pain, patient satisfaction, expectations, and activity using the new Knee Society Score 2011 at 1 year postoperatively. RESULTS: This study involved 55 patients (12 men, 43 women) with a mean age of 73.1 years and mean body mass index of 26.5 kg/m2. Preoperative kinematic measurements showed MP in 23 knees and non-MP in 32 knees. After implantation, navigation showed MP in 25 knees and non-MP in 30 knees. No significant differences were found between kinematic patterns preoperatively and after implantation. Postoperative flexion angle, pain, patient satisfaction, expectations, and activity using Knee Society Score 2011 showed no differences between MP and non-MP knees. CONCLUSION: Intraoperative knee kinematics as measured by navigation could not predict postoperative outcomes of TKA.

Accuracy of a novel accelerometer-based navigation (Naviswiss) for total hip arthroplasty in the supine position.

BACKGROUND: This study aimed to determine the accuracy of acetabular cup insertion using a novel accelerometer-based navigation system in total hip arthroplasty (THA). METHODS: A single-surgeon study was conducted in which 62 prospective patients with navigation and 42 retrospective patients without navigation in a supine position were compared. Absolute values for errors of radiographic inclination and anteversion were calculated. Navigation error was also calculated. Factors that affected absolute value of navigation error in cup alignment were determined. RESULTS: In the navigation group, mean absolute errors for radiographic inclination and anteversion were 4.1° and 4.3°, respectively. In the control group, mean absolute errors were 6.6° in inclination (p < 0.01) and 5.9° in anteversion (p = 0.04). Mean absolute values of navigation error were 2.8° in inclination and 2.8°in anteversion. Factors affecting navigation errors were not found. CONCLUSION: This novel accelerometer-based navigation system significantly increased the accuracy of cup placement during THA in the supine position.

Preoperative pain catastrophizing affects pain outcome after total knee arthroplasty.

BACKGROUNDS: Preoperative widespread pain sensitization or pain catastrophizing could be associated with chronic pain after total knee arthroplasty (TKA). The aim of the present study was to examine the association between postoperative pain in patients undergoing TKA and preoperative factors, including patient characteristics and preoperative central sensitization as well as pain catastrophizing. METHODS: Preoperative TKA patients were evaluated using the Central Sensitization Inventory (CSI)-9 and Pain Catastrophizing Scale (PCS). Postoperative knee pain was evaluated using a numerical rating scale (NRS) 6 months after TKA. Statistical analyses were performed to assess the relationship between NRS 6 months after TKA and preoperative factors, including patient characteristics, CSI-9, and PCS. RESULTS: We enrolled 58 consecutive patients with osteoarthritis who underwent TKA. Using cutoff of 14, postoperative NRS was higher in the patients with ≥14 than the patients with <14 in CSI (p = 0.025). Postoperative NRS was higher in the patients with ≥30 than the patients with <30 in PCS (p = 0.043). Preoperative PCS was a significant risk factor of postoperative pain using a multivariate analysis. CONCLUSIONS: Surgeon should recognize preoperative PCS could affect postoperative pain 6 months after TKA.

Accuracy of acetabular cup insertion in an anterolateral supine approach using an accelerometer-based portable navigation system.

The purpose of this study was to determine the accuracy of acetabular cup insertion during total hip arthroplasty (THA) in a supine position using an accelerometer-based portable navigation system. A single-surgeon study was conducted in which 62 prospective patients with navigation and 42 retrospective patients without navigation as historical controls were compared. The patients underwent THA via an anterolateral supine approach. The absolute values of errors of radiographic inclination and anteversion were calculated. The navigation error was also calculated. The factors that affected the absolute values of errors of cup alignment were determined. The mean absolute error of the postoperative CT measurement from the target angle for radiographic inclination was 3.8° in the navigation group and 6.6° in the control group (P < 0.001). The mean absolute error for anteversion was 3.3° in the navigation group and 5.9° in the control group (P < 0.001). The mean absolute values of navigation error were 3.7° ± 2.8° in inclination and 3.0° ± 2.6° in anteversion. Changes in the pelvic tilt angle among preoperative, intraoperative, and postoperative were the significant risk factors for the absolute values of navigation error of anteversion relative to the anterior pelvic plane. Other factors affecting the absolute values of errors in the navigation group were not found for radiographic inclination and anteversion. The portable navigation system significantly improved the accuracy of cup inclination and anteversion. Changes in the pelvic tilt were the risk factors for the error of anteversion relative to the anterior pelvic plane.

The accuracy of acetabular cup placement in primary total hip arthroplasty using an image-free navigation system.

BACKGROUND: Intraoperative navigation systems have been shown to improve the accuracy of acetabular component insertion in total hip arthroplasty (THA). The purpose of this study was to investigate the accuracy of cup orientation in primary THA using an image-free navigation system. METHODS: A total of 107 consecutive cementless THAs using an image-free navigation system were performed from February 2017 to March 2020 (the navigation group). As a control group, 77 retrospective consecutive cases who underwent THAs with manual implant-techniques between February 2012 and April 2017 were included. Postoperative cup radiographic inclination and radiographic anteversion relative to the functional pelvic plane were assessed using a 3D-template system after computed tomography (CT) examination. RESULTS: The mean absolute errors of the postoperative measured angles from the target angles in inclination were 3.4° ± 3.0° in the navigation group and 8.4° ± 6.6° in the control group (p < 0.001). The mean absolute errors in anteversion were 5.1° ± 3.6° in the navigation group and 10.8° ± 6.5° in the control group (p < 0.001). The percentage of cups inside the Lewinnek safe zone was 93% in the navigation group and 44% in the control group (p < 0.001). The mean absolute values of navigation error were 3.3° ± 2.8° in inclination and 5.8° ± 4.9° in anteversion. Among the cases of osteoarthritis, the inclination error was significantly higher in Crowe group 2 to 4 than in Crowe group 1 (5.1° ± 3.5° and 3.0° ± 2.5°, respectively, p < 0.05). The percentage of hips with inclination error over 10° in Crowe group 2 to 4 was significantly higher than in Crowe group 1 (17 and 1%, respectively, p < 0.05). CONCLUSIONS: The image-free navigation system improved the accuracy of cup orientation. The accuracy of cup position was less in Crowe group 2 to 4 than in Crowe group 1.

Accuracy of image-free navigation in intraoperative leg length change from total hip arthroplasty using evaluations from 2D and 3D measurements.

BACKGROUND: Leg length discrepancy is one of the most common problems after total hip arthroplasty (THA). The aim of this study was to investigate the accuracy of image-free navigation in intraoperative leg length change (LLC) using evaluations from anteroposterior radiographs (2D measurement) and 3D bone models using CT data (3D measurement). METHODS: One hundred THAs with cementless cups and stems were performed using an image-free navigation system in our hospital. We evaluated the accuracy of image-free navigation based on LLC from 2D and 3D measurements. Furthermore, we also investigated error in absolute value and correlations between 2D and 3D measurements in LLC. RESULTS: The accuracy of image-free navigation based on 2D measurement was 94% within 5 mm and 76% within 3 mm. The accuracy of image-free navigation based on 3D measurement was 92% within 5 mm and 81% within 3 mm. The error in absolute value in LLC between 2D and 3D measurements was 1.7 ± 1.4 mm (range, 0 to 6 mm). A strong correlation was observed between 2D and 3D measurements in the LLC. CONCLUSIONS: In the present study, good accuracy of image-free navigation in intraoperative LLC was confirmed for both evaluation methods from 2D and 3D measurements. In addition, the error in absolute value in the LLC between 2D and 3D measurements was very small, and we observed a strong correlation between 2D and 3D measurements. Based on these results, evaluation of LLC from radiographs was considered sufficient if radiographs can be taken accurately.

Minimum 10-Year Follow-Up of Cementless Total Hip Arthroplasty With a 32-mm Cobalt-Chromium Head on Highly Cross-Linked Polyethylene and a Tapered, Fiber Metal Proximally Coated Femoral Stem.

BACKGROUND: The clinical and radiographic results of cementless total hip arthroplasty using a 32-mm cobalt-chromium head on remelted highly cross-linked polyethylene (HXLPE) and a tapered, fiber metal proximally coated femoral stem were evaluated at a mean follow-up of 12 years. METHODS: A total of 57 cementless total hip arthroplasties using remelted HXLPE combined with a 32-mm cobalt-chromium head, and a tapered, fiber metal proximally coated femoral stem were performed from October 2004 to December 2006. Clinical evaluation was performed using the Merle d'Aubigné and Postel scoring system. Standardized anteroposterior and lateral radiographs of the pelvis and femur without weight-bearing were analyzed. Radiographic measurements of two-dimensional femoral head penetration into the polyethylene were performed with a computerized method. The steady-state wear rates were measured based on the radiographs from the first year after surgery to the final follow-up. RESULTS: The mean Merle d'Aubigné and Postel score improved significantly from 10.7 points preoperatively to 15.6 postoperatively (P < .001). No osteolysis was found around the implant. Stem fixation in all cases showed stable bone ingrowth. Third-degree stress shielding was found in 46% of all stems. The total head penetration rate was 0.05 mm/y, and the steady-state wear rate was 0.01 mm/y. The Kaplan-Meier survivorship with the end point of revision was 95% (95% confidence interval, 85%-98%) at 12 years. CONCLUSION: A 32-mm cobalt-chromium head on remelted HXLPE demonstrated low wear properties, and a tapered, fiber metal proximally coated femoral stem showed good results at long-term follow-up.

Minimum ten-year results in revision total hip arthroplasty using titanium fully porous long stem.

PURPOSE: The fully porous long stem could be used for diaphyseal locking and achieve bypass fixation in revision total hip arthroplasty (THA). This study evaluated long-term results for fully porous long stems made of titanium alloy in revision THA. METHODS: Between 2003 and 2010, 45 consecutive femoral revisions were performed using fully porous long stems. Thirty-eight hips had complete clinical and radiographic data for a mean of 13.8 years (range, 10-16.7 years). Femoral bone loss was Paprosky type II in 14 hips, type IIIA in 18 hips, and type IIIB in six hips. Clinical results were analyzed using the Merle d'Aubigné and Postel scoring system. Femoral stress shielding was graded. Radiological loosening of the femoral component was evaluated. Kaplan-Meier survival analysis was performed with revision for any reason as the end-point. RESULTS: Mean Merle d'Aubigné and Postel score improved significantly from 10.7 before revision to 14.5 at latest follow-up (p < 0.001). Third-degree stress shielding was found in seven hips, and fourth degree in 11 hips. Radiological femoral loosening occurred in one hip, which was revised. Another hip was revised for stem fracture. Kaplan-Meier cumulative survival rate was 94.7% at both ten and 15 years. CONCLUSION: Although stress shielding is a concern with fully porous stems, this stem was useful in revision THA and provided satisfactory long-term results in hips with Paprosky types II, IIIA, and IIIB.

Use of antibiotic-impregnated hydroxyapatite for infection following total knee arthroplasty.

OBJECTIVES: Antibiotic-impregnated hydroxyapatite (HA) is an emerging drug delivery system for the treatment of periprosthetic joint infection (PJI) of the knee. The aim of this study was to evaluate the clinical results of this treatment in patients with PJI following total knee arthroplasty (TKA). METHODS: Participants comprised 14 consecutive patients with PJI of the knee who were scheduled to undergo two-stage knee revision. In the first stage, all components were removed with thorough debridement, and antibiotic-impregnated HA was inserted in the bone and joint space. In the second stage, revision TKA was performed after the eradication of infection. The mean period from the removal of all components and treatment with antibiotic-impregnated HA to revision TKA was 3.4 months. Clinical and radiographic evaluations were performed after a mean follow-up of 6.1 years following revision TKA. Predictors of reinfection were evaluated. RESULTS: Eleven patients had no recurrent infection, whereas 3 patients showed recurrent infection. Knee Society knee score and function score, as well as flexion angles, improved significantly postoperatively. No knees showed osteolysis or loosening after revision TKA. The present study identified no predictors of reinfection. CONCLUSION: Antibiotic-impregnated HA could be effective in treating knee PJI.

Thirteen-year results of cementless total hip arthroplasty with zirconia heads on highly cross-linked polyethylene.

OBJECTIVES: Zirconia ceramic was introduced for femoral heads because of its mechanical strength and fracture toughness. Highly cross-linked polyethylene has been shown to achieve wear reduction compared to conventional polyethylene. The purpose of this study was to investigate the long-term results of cementless total hip arthroplasty with zirconia femoral heads on highly cross-linked polyethylene. METHODS: Radiographic measurements of two-dimensional femoral head penetration into the polyethylene were performed with a computerized method (PolyWare) in 93 hips at a mean follow-up of 13 years. The steady-state wear rates were measured based on the radiographs from the first year after surgery to the final follow-up. RESULTS: The mean Merle d'Aubigné and Postel score had improved significantly from 10.9 points preoperatively to 15.3 postoperatively (p < 0.001). Osteolysis was not found around the implant, and no zirconia heads had fractures. The total head penetration rate was 0.04 mm/year, and the steady-state wear rate was 0.02 mm/year. Kaplan-Meier survivorship with the endpoint of revision was 97% (95% confidence interval [CI], 92% to 99%) at 10 years. CONCLUSION: Zirconia on highly cross-linked polyethylene demonstrated extremely low wear properties at long-term follow-up.

Prevention of bone loss and improvement of pain-related behavior in hind limb-unloaded mice by administration of teriparatide and bisphosphonate.

OBJECTIVES: There are few reports on the comparison between teriparatide (PTH) and bisphosphonate (BP) in terms of osteoporosis pain-related behavior and immunohistochemical findings. The aims of this study were to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effect of PTH and BP on pain and bone loss in hind limb-unloaded (HU) mice. The mechanism of osteoporotic pain in HU mice was evaluated by examining pain-related behavior and immunohistochemical findings. The effects of PTH and alendronate (ALN), a potent osteoclast inhibitor, on these parameters were also assessed. METHODS: Eight-week-old male ddY mice were tail-suspended for 2 weeks and assigned to four groups: hind limb-loaded (HL) mice with only tail suspension treated with vehicle; HU mice with tail suspension treated with vehicle; HU mice treated with PTH; and HU mice treated with ALN. Starting immediately after reloading, vehicle, PTH, or ALN was injected subcutaneously. After a 2-week treatment, mechanical sensitivity was examined using von Frey filaments. Bilateral hind limbs were removed for micro-computed tomography, immunohistochemical analysis, and messenger RNA (mRNA) expression analysis. RESULTS: HU mice with tail suspension developed bone loss and mechanical hyperalgesia in the hind limbs. The HU mice showed an increased osteoclasts and sclerostin-positive cells in the hind limb bone. Furthermore, PTH and ALN both prevented HU-induced bone loss and mechanical hyperalgesia in the osteoporotic animal models. Histological examination of the hind limb bone revealed that, similar to ALN, PTH inhibited the osteoclasts and sclerostin-positive cells. The mRNA levels of TNFα and IL-6 tended to decrease with ALN or PTH treatment compared with those without any treatment. CONCLUSIONS: Treatment with PTH as well as BP prevented bone loss, mechanical hyperalgesia, osteoclast increase, and osteocyte increase. Similar to BP, the inhibitory effect of PTH on osteoclasts might contribute to the improvement of skeletal pain.

CTLA-4Ig Improves Hyperalgesia in a Mouse Model of Osteoporosis.

This study aimed to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effects of cytotoxic T lymphocyte-associated antigen-4Ig (CTLA-4Ig) administration in ovariectomized (OVX) mice. Eight-week-old female ddY mice were assigned to three groups: sham-operated mice (SHAM) treated with vehicle, OVX mice treated with vehicle (OVX), and OVX mice treated with CTLA-4Ig (CTLA-4Ig). Vehicle or CTLA-4Ig was injected intraperitoneally, starting immediately after surgery. After 4 weeks of treatment, mechanical sensitivity was examined, and the bilateral hind limbs were removed and evaluated by micro-computed tomography, immunohistochemical analyses, and messenger RNA expression analysis. Ovariectomy induced bone loss and mechanical hyperalgesia in the hindlimbs. CTLA-4Ig treatment prevented bone loss in the hindlimbs compared to vehicle administration in the OVX group. Moreover, mechanical hyperalgesia was significantly decreased in the CTLA-4Ig treatment group in comparison to the OVX group. The expression levels of tumor necrosis factor-α (TNF-α) and sclerostin (SOST), as well as the number of osteoclasts, were increased, and the expression level of Wnt-10b was decreased in the OVX group compared with the SHAM group, whereas these parameters were improved in the CTLA-4Ig group compared with the OVX group. The novelty of this research is that CTLA-4Ig administration prevented bone loss and mechanical hyperalgesia induced by ovariectomy in the hindlimbs.

Functional Block of Interleukin-6 Reduces a Bone Pain Marker but Not Bone Loss in Hindlimb-Unloaded Mice.

Interleukin-6 (IL-6) is widely accepted to stimulate osteoclasts. Our aim in this study was to examine whether the inhibitory effect of IL-6 on bone loss and skeletal pain associated with osteoporosis in hindlimb-unloaded (HU) mice in comparison with bisphosphonate. Eight-week-old male ddY mice were tail suspended for 2 weeks. Starting immediately after reload, vehicle (HU group), alendronate (HU-ALN group), or anti-IL-6 receptor antibody (HU-IL-6i group) was injected subcutaneously. After a 2-week treatment, pain-related behavior was examined using von Frey filaments. The bilateral distal femoral and proximal tibial metaphyses were analyzed three-dimensionally with micro-computed tomography. Calcitonin gene-related peptide (CGRP) expressions in dorsal root ganglion (DRG) neurons innervating the hindlimbs were examined using immunohistochemistry. HU mice with tail suspension developed bone loss. The HU mice showed mechanical hyperalgesia in the hindlimbs and increased CGRP immunoreactive neurons in the L3-5 DRG. Treatment with IL-6i and ALN prevented HU-induced mechanical hyperalgesia and upregulation of CGRP expressions in DRG neurons. Furthermore, ALN but not IL-6i prevented HU-induced bone loss. In summary, treatment with IL-6i prevented mechanical hyperalgesia in hindlimbs and suppressed CGRP expressions in DRG neurons of osteoporotic models. The novelty of this research suggests that IL-6 is one of the causes of immobility-induced osteoporotic pain regardless improvement of bone loss.

Interleukin-6 Inhibitor Suppresses Hyperalgesia Without Improvement in Osteoporosis in a Mouse Pain Model of Osteoporosis.

The aim of this study was to evaluate skeletal pain associated with osteoporosis and examine the inhibitory effect of interleukin-6 (IL-6) on pain in ovariectomized (OVX) mice. The mechanism of osteoporotic pain in OVX mice was evaluated by examining pain-related behavior and immunohistochemistry. The effects of IL-6 receptor inhibitor (IL-6i) on these parameters were also assessed. Eight-week-old female ddY mice were ovariectomized and assigned to three groups: OVX mice treated with vehicle (OVX); OVX mice treated with alendronate (OVX-ALN); and OVX mice treated with anti-IL-6 receptor (anti-IL-6R) antibody (OVX-IL6i). Sham-operated mice were treated with vehicle. Immediately after surgery, vehicle, ALN, or anti-IL-6R antibody was injected subcutaneously. After a 4-week treatment, mechanical sensitivity was examined using von Frey filaments. The bilateral distal femoral metaphyses and proximal tibial metaphyses were analyzed three-dimensionally with micro-computed tomography. Calcitonin gene-related peptide (CGRP) expression in L3-L5 dorsal root ganglion (DRG) neurons was examined using immunohistochemistry. Ovariectomy induced bone loss and mechanical hyperalgesia in the hindlimbs with upregulation of CGRP expression in the DRG neurons innervating the hindlimbs. ALN treatment prevented bone loss, but anti-IL-6R antibody treatment had no effect on bone morphometry compared with that of the OVX group. However, mechanical hyperalgesia and CGRP expression were significantly decreased in the OVX-IL6i and OVX-ALN groups compared with those in the OVX group. Although anti-IL-6R antibody treatment had no effect on ovariectomy-induced bone loss, the treatment prevented ovariectomy-induced mechanical hyperalgesia in the hindlimbs and suppressed CGRP expression in DRG neurons. The results suggest that IL-6 is one of the causes of postmenopausal osteoporotic pain, and anti-IL-6R antibody might preserve bone health and decrease osteoporotic pain.