An investigation of the differential therapeutic effects of romosozumab on postmenopausal osteoporosis patients with or without rheumatoid arthritis complications: a case-control study.

The impact of ROMO on the width of anabolic windows and the increase in BMD was reduced in the RA group compared to the non-RA group, and this reduction was associated with correlations to RA-related factors. PURPOSE: To investigate the effects of romosozumab (ROMO) in postmenopausal osteoporosis, with and without comorbid rheumatoid arthritis (RA). METHODS: In this retrospective, case-controlled, multicenter study, 171 postmenopausal patients who did not receive oral glucocorticoid, comprising 59 in the RA group and 121 in the non-RA group, received uninterrupted ROMO treatment for 12 months. Propensity score matching was employed to ensure comparability in clinical backgrounds, resulting in 41 patients in each group. Baseline characteristics were as follows: overall (mean age, 76.3 years; T-score of lumbar spine (LS), - 3.0; 45.1% were treatment-naive for osteoporosis); RA group (anti-cyclic citrullinated peptide antibody (ACPA) positivity, 80.5%; titer, 206.2 U/ml; clinical disease activity index (CDAI), 13.6; health assessment questionnaire disability index (HAQ-DI), 0.9). Bone mineral density (BMD) and serum bone turnover markers were monitored over a 12-month period. RESULTS: The rate of increase in the bone formation marker, PINP, and the rates of decrease in the bone resorption marker, TRACP-5b, exhibited a trend toward smaller changes in the RA group compared to the non-RA group, implying a smaller anabolic window. After 12 months, the RA group displayed lower BMD increases in the LS (9.1% vs. 12.6%; P = 0.013) and total hip (2.4% vs. 4.8%; P = 0.025) compared to the non-RA group. Multiple regression analysis in the all RA group (n = 59) for the association between RA-specific factors and 12-month BMD changes revealed negative correlations between ACPA titer and LS BMD and between HAQ-DI and femoral neck BMD. CONCLUSIONS: The efficacy of ROMO may be attenuated by RA-related factors.

Genetic insights into ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.

Baseline serum PINP level is associated with the increase in hip bone mineral density seen with Romosozumab treatment in previously untreated women with osteoporosis.

Baseline serum PINP value was significantly and independently associated with the increased bone mineral density (≥ 3%) in both total hip and femoral necks by 12 months of romosozumab treatment in patients with treatment-naive postmenopausal osteoporosis. PURPOSE: Some patients fail to obtain a sufficiently increased hip bone mineral density (BMD) by romosozumab (ROMO) treatment. This study aimed to investigate the prognostic factor for increased hip BMD with ROMO in patients with treatment-naive postmenopausal osteoporosis. METHODS: This prospective, observational, and multicenter study included patients (n = 63: mean age, 72.6 years; T-scores of the lumbar spine [LS], - 3.3; total hip [TH], - 2.6; femoral neck [FN], - 3.3; serum type I procollagen N-terminal propeptide [PINP], 68.5 µg/L) treated by ROMO for 12 months. BMD and serum bone turnover markers were evaluated at each time point. A responder analysis was performed to assess the patient percentage, and both univariate and multivariate analyses were performed to investigate the factors associated with clinically significant increased BMD (≥ 3%) in both TH and FN. RESULTS: Percentage changes of BMD from baseline in the LS, TH, and FN areas were 17.5%, 4.9%, and 4.3%, respectively. In LS, 96.8% of patients achieved ≥ 6% increased LS-BMD, although 57.1% could not achieve ≥ 3% increased BMD in either TH or FN. Multiple regression analysis revealed that only the baseline PINP value was significantly and independently associated with ≥ 3% increased BMD in both TH and FN (p = 0.019, 95% confidence interval = 1.006-1.054). The optimal cut-off PINP value was 53.7 µg/L with 54.3% sensitivity and 92.3% specificity (area under the curve = 0.752). CONCLUSIONS: In a real-world setting, baseline PINP value was associated with the increased BMD of TH and FN by ROMO treatment in treatment-naive patients.

Preoperative Risk Factors Affecting Outcome in Surgically Treated Pyogenic Spondylodiscitis.

STUDY DESIGN: Retrospective study. OBJECTIVE: The primary aim of this study was to investigate the predictors of severe complications in patients following surgery for pyogenic spondylodiscitis (PS) using a surgeon-maintained database. The secondary aim was to investigate the predictors of early recovery. METHODS: We introduced a surgeon-maintained database of prospectively collected multicenter data that mainly focused on perioperative complications in 2012. Our surgeon-maintained database allows the retrospective collection of detailed data. We analyzed 143 patients who underwent surgery for PS from the 19,056 patients in the prospective surgeon-maintained database at 27 affiliated institutions between 2013 and 2017. Data relating to preoperative patient factors, infection factors, surgical factors, and pre- and postoperative blood tests was retrospectively collected. We performed multivariate regression analysis to evaluate the predictors of postoperative severe complications and early recovery in patients with PS. RESULTS: High updated Charlson comorbidity index (uCCI), chronic pulmonary disease, diabetes, Gram-negative bacteria, pyogenic osteoarthritis, high preoperative white blood cell count, and low preoperative platelet count were significantly associated with severe complications in patients undergoing surgery for PS. A high uCCI was the sole independent negative predictor on early recovery. CONCLUSION: Careful perioperative management is necessary if surgery is performed on patients who are at a high risk of life-threatening events.

Development of Atypical Ulnar Fracture is Associated with Bisphosphonate Therapy and Severe Spinal Deformity: A Case Report.

Atypical ulna fracture (AUF) is relatively rare and is known to be associated with prolonged bisphosphonate (BP) use. The developmental mechanism remains unclear. We report a patient with an AUF associated with BP and severe spinal deformity. The patient was an 85-year-old woman receiving oral alendronate for 8 years without vitamin D supplementation. During regular kitchen work, she needed left upper limb support. She presented with atraumatic pain over the ulna. Radiographs revealed a transverse fracture in the proximal ulna and ulna bowing deformity. Whole-spine standing radiographs showed severe degenerative kyphoscoliosis. The skin induration with pigmentation on her left elbow that suggested prolonged overload and during standing work, coincided exactly with fracture location. This report suggests that 'direct stress', with persistent local overload on the proximal ulna, is one of the developmental mechanisms of AUF, in addition to persistent suppression of bone remodelling by prolonged BP use and vitamin D deficiency. Level of Evidence: Level V (Therapeutic).

Assessment of bone health in patients with prostate cancer using cancer staging computed tomography.

PURPOSE: To evaluate the utility of vertebral Hounsfield unit (HU) values from computed tomography (CT) in cancer staging as a supplementary screening tool for bone health among prostate cancer (PCa) patients. METHODS: T-scores of bone mineral density (BMD) in each lumbar vertebra (L1-L4) and hip for newly diagnosed PCa patients (N = 139) were measured using dual-energy X-ray absorptiometry (DXA). The degenerative changes in each lumbar vertebra were assessed, and the HU values of trabecular bone in axial CT images of each vertebral body (vertebral CT-HU value) were measured using staging CT. RESULTS: 556 vertebrae were analyzed. 326 of 556 (59%) lumbar vertebrae had degenerative changes. The vertebral CT-HU value was positively correlated with the lumbar BMD T-score, with higher correlation coefficients observed in vertebrae without degenerative changes (r = 0.655, N = 230) when compared to vertebrae with degenerative changes (r = 0.575, N = 326). The thresholds matching BMD T-scores of - 2.0 and - 1.5 set by cancer treatment-induced bone loss guidelines were 95 HU and 105 HU, respectively. Based on the intervention threshold (lumbar BMD T-score < - 1.5), 15.1% of PCa patients required osteoporosis treatment; and, this value increased to 30.9% when L1-L4 CT-HU thresholds that corresponded to BMD T-score < - 1.5 were used. CONCLUSION: Lumbar BMD values from DXA may not reflect true bone health in PCa patients who often have lumbar degenerative diseases. Thresholds based on the vertebral CT-HU value can be used as a supplementary method to identify PCa patients who need anti-osteoporosis drugs.

Relationship between distal radius fracture severity and 25-hydroxyvitamin-D level among perimenopausal and postmenopausal women.

AIMS: Low-energy distal radius fractures (DRFs) are the most common upper arm fractures correlated with bone fragility. Vitamin D deficiency is an important risk factor associated with DRFs. However, the relationship between DRF severity and vitamin D deficiency is not elucidated. Therefore, this study aimed to identify the correlation between DRF severity and serum 25-hydroxyvitamin-D level, which is an indicator of vitamin D deficiency. METHODS: This multicentre retrospective observational study enrolled 122 female patients aged over 45 years with DRFs with extension deformity. DRF severity was assessed by three independent examiners using 3D CT. Moreover, it was categorized based on the AO classification, and the degree of articular and volar cortex comminution was evaluated. Articular comminution was defined as an articular fragment involving three or more fragments, and volar cortex comminution as a fracture in the volar cortex of the distal fragment. Serum 25-hydroxyvitamin-D level, bone metabolic markers, and bone mineral density (BMD) at the lumbar spine, hip, and wrist were evaluated six months after injury. According to DRF severity, serum 25-hydroxyvitamin-D level, parameters correlated with bone metabolism, and BMD was compared. RESULTS: The articular comminuted group (n = 28) had a significantly lower median serum 25-hydroxyvitamin-D level than the non-comminuted group (n = 94; 13.4 ng/ml (interquartile range (IQR) 9.8 to 17.3) vs 16.2 ng/ml (IQR 12.5 to 20.4); p = 0.005). The AO classification and volar cortex comminution were not correlated with the serum 25-hydroxyvitamin-D level. Bone metabolic markers and BMD did not significantly differ in terms of DRF severities. CONCLUSION: Articular comminuted DRF, referred to as AO C3 fracture, is significantly associated with low serum 25-hydroxyvitamin-D levels. Therefore, vitamin D3 supplementation for vitamin D deficiency might prevent articular comminuted DRFs. Nevertheless, further studies must be conducted to validate the results of the current study. Cite this article: Bone Jt Open 2022;3(3):261-267.

Tolerability of the first infusion of once-yearly zoledronic acid within one to two weeks after hip fracture surgery.

OBJECTIVE: Once-yearly infusions of zoledronic acid (ZA) 5 mg may be optimal for secondary fracture prevention after hip fracture (HF), but there are crucial side effects of ZA. This study assessed the tolerability of the first infusion of once-yearly ZA within one to two weeks after HF surgery and to identify risk factors for acute-phase reactions (APRs) and the decrease in serum calcium (Ca) concentration. METHODS: We analyzed 84 patients (average age: 83 years, 18 men and 66 women) who met the inclusion criteria. The patients underwent the first infusion of ZA one to two weeks after HF surgery and received antipyretic analgesics and active vitamin D analog. RESULTS: APRs occurred in ten patients (11.9%) and all these patients had pyrexia (>37.5 °C) and/or other symptoms. The asymptomatic hypocalcemia (serum Ca < 8.3 mg/dL) incidence was 6.0% at 7 days after ZA infusion. Compared with female patients without APRs, female patients with APRs had significantly higher levels of serum 25-dihydroxyvitamin D at baseline and serum C-reactive protein on the day ZA was administered (day 0). Multiple linear regression analyses showed that serum level of tartrate-resistant acid phosphatase-5b were significantly associated with an absolute decrease in serum corrected Ca from day 0 to day 7. CONCLUSIONS: The first infusion of ZA within one to two weeks after HF surgery was well tolerated with the combined use of antipyretic analgesics and active vitamin D analog. Higher inflammatory condition after surgery which is more likely sensitized by ZA administration may increase the risk of APRs, and high bone turnover may increase hypocalcemia risk.

Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with postmenopausal osteoporosis.

OBJECTIVES: To investigate the effects of prior treatment and determine the predictors of a 12-month treatment response of romosozumab (ROMO) in 148 patients with postmenopausal osteoporosis. METHODS: In this prospective, observational, and multicenter study, treatment naïve patients (Naïve; n=50) or patients previously treated with bisphosphonates (BP; n=37) or denosumab (DMAb; n=45) or teriparatide (TPTD; n=16) (mean age, 75.0 years; T-scores of the lumbar spine [LS] -3.2 and total hip [TH] -2.6) were switched to ROMO due to insufficient effects of prior treatment. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 12 months. RESULTS: At 12 months, changes in LS BMD were Naïve (18.2%), BP (10.2%), DMAb (6.4%), and TPTD (11.2%) (P<0.001 between groups) and changes in TH BMD were Naïve (5.6%), BP (3.3%), DMAb (0.6%), and TPTD (4.4%) (P<0.01 between groups), respectively. In all groups, the LS BMD significantly increased from baseline at 6 and 12 months, although only the DMAb group failed to obtain a significant increase in TH BMD during 12-month treatment. Mean values of N-terminal type I procollagen propeptide (PINP; µg/L) from baseline → 1 month → 12 months were Naïve (67.9 → 134.1 → 51.0), BP (32. 2 → 81.7 → 40.9), DMAb (30.4 → 56.2 → 75.3), and TPTD (97.4 → 105.1 → 37.1), and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b; mU/dL) were Naïve (500.4 → 283.8 → 267.1), BP (273.4 → 203.1 → 242.0), DMAb (220.3 → 246.1 → 304.8), and TPTD (446.6 → 305.1 → 235.7), respectively. Multiple regression analysis revealed that the significant predictors of BMD change at 12 months were difference of prior treatment (r=-2.8, P<0.001) and value of PINP at 1 month (r=0.04, P<0.01) for LS, and difference of prior treatment (r=-1.3, P<0.05) and percentage change of TRACP-5b at 1 month (r=-0.06, P<0.05) for TH. CONCLUSIONS: The early effects of ROMO on LS and TH BMD increase at 12 months were significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers.

Direct Involvement of Concomitant Foraminotomy for Radiculomyelopathy in Postoperative Upper Limb Palsy in Cervical Laminoplasty.

OBJECTIVE: Although concomitant foraminotomy has been reported to increase the risk of postoperative upper limb palsy (ULP) in cervical laminoplasty, the specific effects of concomitant foraminotomy on ULP remain uncertain. This study aimed to clarify the effect of concomitant foraminotomy on ULP in cervical laminoplasty. METHODS: We identified 19 patients who developed ULP after laminoplasty with concomitant foraminotomy for radiculomyelopathy with nerve root impingement (laminoplasty with concomitant foraminotomy group [F-group]) from 4080 patients who underwent primary cervical laminoplasty at 27 affiliated institutions between 2012 and 2018. An age- and sex-matched control group comprised patients who developed ULP after laminoplasty without concomitant foraminotomy (n = 76, 4:1 ratio with F-group). Collected data included the time of onset and distribution of ULP (side and level). The site of foraminotomy was recorded in the F-group. RESULTS: The F-group showed a significantly higher incidence of ULP than the candidates for the control group (15.1% vs. 3.1%, P < 0.001). The site of foraminotomy was consistent with the distribution of ULP in 79% (15 of 19 patients) of the F-group. The F-group showed a significantly higher proportion of preoperative upper-limb muscle weakness (74% vs. 37%, P = 0.005) and early-onset ULP occurring by postoperative day 1 (63% vs. 33%, P = 0.02) compared with the control group. CONCLUSIONS: Our results indicate that the foraminotomy procedure in the stenotic foramen is directly involved in ULP. Combined with a previous report suggesting that early-onset ULP is associated with thermal nerve damage, our results indicate that thermal nerve damage partly explains the increased incidence of ULP in the F-group.

Effects of follow-on therapy after denosumab discontinuation in patients with postmenopausal osteoporosis.

OBJECTIVES: To clarify the effects of follow-on therapy after denosumab (DMAb) discontinuation. METHODS: In this retrospective, multicenter study, postmenopausal patients with osteoporosis who were previously treated by oral bisphosphonates (BP) (n = 26) or teriparatide (TPTD) (n = 27) were switched to DMAb (administered 2.6 times), and then discontinued. Patients (73.1 years, T-scores of the lumbar spine [LS] - 2.7 and femoral neck [FN] - 2.2) were switched to either (1) raloxifene (RAL) (n = 13) or BP [(2) weekly or monthly BP (wmBP) (n = 29) or (3) zoledronate (ZOL) (n = 11)], based on each physician's decision (mean interval after final DMAb administration was 7.2 months). Bone mineral density (BMD) at final DMAb administration were set as baseline. RESULTS: Changes in LS BMD at 1.5 years after final DMAb administration were -2.7% in the RAL, 0.7% in the wmBP, and 1.9% in the ZOL (p = .31 between groups), and in FN BMD were -3.8%, -0.8%, and 1.8%, respectively (p = .02 between the RAL and ZOL; p = .048 between the RAL and BP). Clinical vertebral fracture incidence during 1.5 years after final DMAb administration was 23.1% in the RAL, 3.4% in the wmBP, and 0.0% in the ZOL (p = .048 between the RAL and ZOL; p = .015 between the RAL and BP). No significant differences were observed in these parameters between the wmBP and ZOL. CONCLUSION: These results may contribute to the selection of adequate follow-on therapy after DMAb discontinuation, although further investigations are required.

Risk factor analysis of surgery-related complications in primary cervical spine surgery for degenerative diseases using a surgeon-maintained database.

AIMS: This study, using a surgeon-maintained database, aimed to explore the risk factors for surgery-related complications in patients undergoing primary cervical spine surgery for degenerative diseases. METHODS: We studied 5,015 patients with degenerative cervical diseases who underwent primary cervical spine surgery from 2012 to 2018. We investigated the effects of diseases, surgical procedures, and patient demographics on surgery-related complications. As subcategories, the presence of cervical kyphosis ≥ 10°, the presence of ossification of the posterior longitudinal ligament (OPLL) with a canal-occupying ratio ≥ 50%, and foraminotomy were selected. The surgery-related complications examined were postoperative upper limb palsy (ULP) with a manual muscle test (MMT) grade of 0 to 2 or a reduction of two grade or more in the MMT, neurological deficit except ULP, dural tear, dural leakage, surgical-site infection (SSI), and postoperative haematoma. Multivariate logistic regression analysis was performed. RESULTS: The significant risk factors (p < 0.050) for ULP were OPLL (odds ratio (OR) 1.88, 95% confidence interval (CI) 1.29 to 2.75), foraminotomy (OR 5.38, 95% CI 3.28 to 8.82), old age (per ten years, OR 1.18, 95% CI 1.03 to 1.36), anterior spinal fusion (OR 2.85, 95% CI 1.53 to 5.34), and the number of operated levels (OR 1.25, 95% CI 1.11 to 1.40). OPLL was also a risk factor for neurological deficit except ULP (OR 5.84, 95% CI 2.80 to 12.8), dural tear (OR 1.94, 95% CI 1.11 to 3.39), and dural leakage (OR 3.15, 95% CI 1.48 to 6.68). Among OPLL patients, dural tear and dural leakage were frequently observed in those with a canal-occupying ratio ≥ 50%. Cervical rheumatoid arthritis (RA) was a risk factor for SSI (OR 10.1, 95% CI 2.66 to 38.4). CONCLUSION: The high risk of ULP, neurological deficit except ULP, dural tear, and dural leak should be acknowledged by clinicians and OPLL patients, especially in those patients with a canal-occupying ratio ≥ 50%. Foraminotomy and RA were dominant risk factors for ULP and SSI, respectively. An awareness of these risks may help surgeons to avoid surgery-related complications in these conditions. Cite this article: Bone Joint J 2021;103-B(1):157-163.

Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis.

PURPOSE: To investigate the effects of prior treatment and the predictors of early treatment response to romosozumab (ROMO) in patients with postmenopausal osteoporosis. METHODS: In this prospective, observational, multicenter study, 130 treatment-naïve patients (Naïve; n = 37) or patients previously treated with bisphosphonates (BP; n = 33), denosumab (DMAb; n = 45), or teriparatide (TPTD; n = 15) (age, 75.0 years; T-scores of the lumbar spine [LS] -3.2 and femoral neck [FN] -2.9) were switched to ROMO based on their physician's decision. Bone mineral density (BMD) and serum bone turnover markers were evaluated for six months. RESULTS: At six months, LS BMD changes were 13.6%, 7.5%, 3.6%, and 8.7% (P < .001 between groups) and FN BMD changes were 4.2%, 0.4%, 1.6%, and 1.5% (P = .16 between groups) for Naïve, BP, DMAb, and TPTD groups, respectively. Changes in N-terminal type I procollagen propeptide (PINP; µg/L) levels from baseline â†’ one month were 72.7 â†’ 139.0, 33.5 â†’ 85.4, 30.4 â†’ 54.3, and 98.4 â†’ 107.4, and those of isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b) (mU/dL) were 474.7 â†’ 270.2, 277.3 â†’ 203.7, 220.3 â†’ 242.0, and 454.1 â†’ 313.0 for Naïve, BP, DMAb, and TPTD groups, respectively. Multivariate regression analysis revealed that significant predictors of LS BMD change at six months were prior treatment difference (r = -3.1, P = .0027) and TRACP-5b percentage change (r = -2.8, P = .0071) and PINP value at one month (r = 3.2, P = .0021). CONCLUSION: Early effects of ROMO on the increase in LS BMD are significantly affected by the difference of prior treatment and are predicted by the early change in bone turnover markers. MINI ABSTRACT: Early effects of ROMO on the increase in LS BMD at six months is significantly affected by the difference of prior treatment and also predicted by the early change of bone turnover markers in patients with postmenopausal osteoporosis.

Combined effect of teriparatide and an anti-RANKL monoclonal antibody on bone defect regeneration in mice with glucocorticoid-induced osteoporosis.

OBJECTIVE: The purpose of this study was to examine the effect of single or combination therapy of teriparatide (TPTD) and a monoclonal antibody against the murine receptor activator of nuclear factor κB ligand (anti-RANKL Ab) on cancellous and cortical bone regeneration in a mouse model of glucocorticoid-induced osteoporosis (GIOP). METHODS: C57BL/6 J mice (24 weeks of age) were divided into five groups: (1) the SHAM group: sham operation + saline; (2) the prednisolone (PSL) group: PSL + saline; (3) the TPTD group: PSL + TPTD; (4) the Ab group: PSL + anti-RANKL Ab; and (5) the COMB group: PSL + TPTD + anti-RANKL Ab (n = 8 per group). With the exception of the SHAM group, 7.5 mg of PSL was inserted subcutaneously into mice, to generate a mouse model of GIOP. Four weeks after insertion, bone defects with a diameter of 0.9 mm were created to assess bone regeneration on both femoral metaphysis (cancellous bone) and diaphysis (cortical bone). After surgery, therapeutic intervention was continued for 4 weeks. Saline (200 µl) or TPTD (40 µg/kg) was injected subcutaneously five times per week, whereas the anti-RANKL Ab (5 mg/kg) was injected subcutaneously once on the day after surgery. Subsequently, the following analyses were performed: microstructural assessment of bone regeneration and bone mineral density (BMD) measurement via micro-computed tomography, and histological, histomorphometrical, and biomechanical analyses with nanoindentation. RESULTS: The COMB group showed the highest lumbar spine BMD increase (vs. the PSL, TPTD, and Ab groups). The volume of regenerated cancellous bone at the bone defect site was higher in the COMB group compared with the PSL, TPTD, and Ab group. The volume of the regenerated cortical bone was significantly higher in the COMB group compared with the PSL group, and its hardness was significantly higher in the COMB group compared with the PSL and TPTD groups. CONCLUSION: In a mouse model of glucocorticoid-induced osteoporosis, the combination therapy of TPTD plus the anti-RANKL Ab increased bone mineral density in the lumbar spine and regenerated cancellous bone volume compared with single administration of each agent, and also increased regenerated cortical bone strength compared with single administration of TPTD.

Romosozumab was not effective in preventing multiple spontaneous clinical vertebral fractures after denosumab discontinuation: A case report.

Discontinuation of denosumab is associated with the increase of bone turnover markers to above-baseline levels (so-called rebound in bone turnover) and rapid bone loss. Several studies have reported vertebral fractures (VFs), particularly multiple spontaneous clinical VFs (MSCVFs), occurring after discontinuation of denosumab. There is currently no recommendation for the management of VFs including MSCVFs. Presently, romosozumab is the strongest anti-osteoporotic agent that inhibits sclerostin and rapidly increases bone mass, but it is uncertain that romosozumab is an effective treatment choice to treat VFs occurring after discontinuation of denosumab. Herein we reported a novel case of a 60-year-old woman who was treated with romosozumab after discontinuation of denosumab and subsequently suffered MSCVFs under romosozumab treatment. She had a history of two osteoporotic VFs (T6 and T8) and received five doses of 60 mg denosumab every 6 months following the osteoporosis diagnosis. As per the patient's convenience, the sixth denosumab injection was postponed. To improve the persistent low bone mass in the lumbar spine (T-score -3.8), 210 mg romosozumab was administered monthly after 9 months following the last denosumab injection. At the first romosozumab injection, she had no clinical symptoms such as low back pain, but her bone formation and resorption marker levels elevated compared with those treated with denosumab. After three doses of romosozumab, spontaneous severe low back pain occurred, and time-course radiographs revealed five new VFs (T12, L2, L3, L4, and L5). Romosozumab administration had no suppressive effect on bone resorption during the rebound in bone turnover after discontinuation of denosumab. This case suggests that romosozumab is not effective in preventing VFs or MSCVFs after denosumab discontinuation.

Utility of Distal Forearm DXA as a Screening Tool for Primary Osteoporotic Fragility Fractures of the Distal Radius: A Case-Control Study.

BACKGROUND: Osteoporotic fragility fractures frequently occur at the distal part of the radius. This suggests that initial osteoporosis evaluation at this site may inform screening and treatment to prevent additional fractures. The purpose of this study was to investigate the utility of distal forearm dual x-ray absorptiometry (DXA) as a screening tool to assess the risk of fragility fractures at the distal part of the radius. METHODS: This retrospective, case-control study included postmenopausal women who had sustained a distal radial fracture (fracture group, n = 110) and postmenopausal women with no history of fracture (control group, n = 95). DXA measurements at the spine, hip, and distal part of the forearm (ultra-distal, mid-distal, and one-third distal sections) were compared between the groups on the basis of bone mineral density (BMD), T-score, and the proportion of patients with a T-score of ≤-2.5 standard deviations (SD). We also investigated the regional differences on the basis of T-score among the skeletal sites. Furthermore, the reliability of distal forearm DXA measurements was validated by assessing the statistical correlation (r) with volumetric BMD by computed tomography (CT). RESULTS: Compared with the control group, the fracture group showed significantly lower BMD and T-scores and higher proportions of patients with a T-score of ≤-2.5 SD at the ultra-distal, mid-distal, and one-third distal forearm; however, the spine and hip measurements did not differ significantly between the 2 groups. With respect to regional differences, in the fracture group, T-scores were significantly lower and the proportions of patients with a T-score of ≤-2.5 SD were significantly higher for the 3 distal forearm sites compared with the spine and hip. DXA measurements at all 3 of the distal forearm regions exhibited high correlation with volumetric BMD by CT (r = 0.83 to 0.92). CONCLUSIONS: Some postmenopausal women were found to exhibit bone loss preferentially at the distal part of the radius, which may render them vulnerable to fragility fractures. Forearm DXA for the assessment of local bone loss may demonstrate benefit in screening for those at risk for distal radial fractures and facilitate the early identification of patients who require intervention for osteoporosis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Comparison in the same intervertebral space between titanium-coated and uncoated PEEK cages in lumbar interbody fusion surgery.

BACKGROUNDS: Disadvantages of polyetheretherketone (PEEK) cages are their smooth and hydrophobic surfaces and their lack of osteoconductivity. Titanium (Ti) coated PEEK cage has been innovated to overcome these potential concerns. However, few well-designed studies have investigated the efficacy of Ti-coated PEEK cage on interbody fusion in humans. This study aimed to evaluate the efficacy of Ti coating on bone ongrowth at bone-implant surface by simultaneously comparing Ti-coated and uncoated PEEK cages in the same intervertebral space. METHODS: This study is a prospective comparative study for the two different cages. Twenty-six subjects who underwent one-level instrumented posterior lumbar interbody fusion (PLIF) were included. Two PEEK cages [a plasma-sprayed Ti-coated (PTC-PEEK) and an uncoated PEEK cage] were inserted in the same intervertebral space. Fusion rates, cage subsidence, and vertebral cancellous condensation (VCC) around the cage, which indicates bone growth on the surface of each cage, were assessed by thin-slice computed tomography (CT) immediately (within 1 week) and at 3 months postoperatively. A functional radiograph was obtained at 3 and 12 months postoperatively. RESULTS: Twenty-three subjects showed solid fusion at 3 months postoperatively (fusion rate, 88%). Cage subsidence was not observed. VCC was often observed around the PTC-PEEK cage as evaluated by completely synchronized CT images between immediately and at 3 months postoperatively. Quantified VCC around the cage was significantly larger in the PTC-PEEK cage than in the uncoated PEEK cage (P = 0.01). CONCLUSIONS: The Ti-coated PEEK cage exhibits radiographic signs, suggesting bone ongrowth, as represented by VCC around the cage compared with that around the uncoated PEEK cage. The Ti-coated PEEK cage has the potential to promote solid fusion and to improve clinical outcomes in lumbar interbody fusion surgery.

Risk factors for in-hospital mortality after spine surgery: a matched case-control study using a multicenter database.

BACKGROUND/CONTEXT: It is yet unclear what preoperative and intraoperative factors affect mortality after spine surgery. PURPOSE: To identify the preoperative and intraoperative risk factors for in-hospital mortality after spine surgery using a matched case-control study based on a multicenter database. STUDY DESIGN/SETTING: A retrospective matched case-control study based on a registry of prospectively collected multicenter data. PATIENT SAMPLE: We identified 25 patients who died in the hospital (the mortality group) from the 26,604 patients in the database who underwent spine surgery at our 27 affiliated institutions between 2012 and 2018. An age-, sex-, spinal disease-, and surgical procedure-matched control group of patients (n=100, 4:1 ratio with the mortality group) was selected from the same database. OUTCOME MEASURES: Data relating to comorbidities, preoperative blood tests, operative factors, and perioperative complications. METHODS: We retrospectively reviewed all the medical records of each patient in the two groups to nullify the effects of overt risk factors such as age, sex, diseases, and surgical procedures. Risk factors for in-hospital mortality were initially evaluated by univariate analysis. Then, multivariate logistic regression models were generated to analyze independent risk factors for in-hospital mortality. RESULTS: The overall in-hospital mortality rate was 0.09% (25/26,604). Mortality was lowest in patients with degenerative cervical (0.04%, 2/5,027) or lumbar disease (0.03%, 5/15,630). In contrast, mortality was highest in patients with dialysis-related spondyloarthropathy (3.0%, 3/99), patients with infectious spondylodiscitis (1.5%, 6/401), and patients with metastatic spinal tumors (0.9%, 3/334). Multivariate logistic regression analysis revealed that massive intraoperative hemorrhage (>2 L) (odds ratio [OR], 28.2; 95% confidence interval [CI], 2.27-349), preoperative renal comorbidity (OR, 4.33; 95% CI, 1.38-13.6), and elevated preoperative aspartate aminotransferase levels (OR, 1.51 per 10 units; 95% CI, 1.04-2.20) were risk factors. CONCLUSIONS: Spine surgery for patients with dialysis-dependency, infectious diseases or metastatic tumors had much more potential of in-hospital mortality compared with those for patients with degenerative diseases. Massive intraoperative hemorrhage and preoperative renal and liver comorbidities were identified as risk factors for in-hospital mortality in patients who underwent spine surgery.

The combined effects of teriparatide and anti-RANKL monoclonal antibody on bone defect regeneration in ovariectomized mice.

OBJECTIVE: The purpose of this study was to investigate the combined effects of teriparatide (TPTD) and anti-murine receptor activator of nuclear factor-κB ligand monoclonal antibody (anti-RANKL Ab) on both cancellous and cortical bone healing in ovariectomized mice. METHODS: Thirteen-week-old mice were divided into the sham-operated group (n=11) or the ovariectomized group (n=44). At 1 month post-operation, all mice underwent bone defect surgery on the left femoral metaphysis (cancellous bone healing model) and right femoral mid-diaphysis (cortical bone healing model). After creating the bone defects, all ovariectomized mice were assigned to one of four groups to receive 1) saline (5 times a week; CNT group), 2) TPTD (40µg/kg 5 times a week; TPTD group), 3) anti-RANKL Ab (5mg/kg once; Ab group), or 4) a combination of TPTD and anti-RANKL Ab (COMB group). The following analyses were performed: Time-course microstructural analysis of healing in both cancellous and cortical bone in the bone defect, measuring the volumetric bone mineral density and the cortical bone thickness of the tibia as a representative of whole body bone with the use of micro-computed tomography, and histological analysis. RESULTS: Regeneration of cancellous bone volume in the COMB group was the highest among the four groups, and combined treatment accelerated the formation of medullary callus during the early phase of bone regeneration. On the other hand, there were no significant differences in the regeneration of cortical bone volume during the early phase of bone regeneration among the four groups. Furthermore, lamellar bone was not well identified in the all four groups. Volumetric bone mineral density in the tibia in the COMB group was significantly higher compared with that in the CNT and TPTD groups and tended to be higher compared with that in the Ab group. The mean values of cortical bone thickness in the TPTD and COMB groups were significantly higher than that in the CNT group. CONCLUSION: In a mouse model of postmenopausal osteoporosis, combination therapy of TPTD and anti-RANKL Ab accelerates regeneration of cancellous bone more effectively than either agent alone during the early phase of bone regeneration.