Improvement in health status and quality of life in patients with osteoporosis treated with denosumab: results at a mean follow-up of six years.

OBJECTIVE: The clinical efficacy and tolerability of denosumab in severe osteoporosis are well-known. However, the evaluation on general health and quality of life over time and compared to population norms is still lacking. We aimed at evaluating denosumab effectiveness in a real-world clinical sample with a 6-years average follow-up. PATIENTS AND METHODS: In this retrospective-matched study with prospective data collection, a total of 101 patients affected by severe osteoporosis and treated with denosumab between 2014 and 2020 were evaluated. All patients completed the self-perceived quality of life (36-Item Short Form - SF-36) survey and visual analogue scale (VAS) before and after treatment. RESULTS: Overall, 13 patients died of causes unrelated to the procedure, 12 stopped therapy with denosumab, and 30 did not participate in the follow-up; thus, 46 patients completed the study. There were 44 (95.7%) women and 93.4% of patients reported history of osteoporotic fractures. The mean follow-up was 59±17.8 months and the mean age at follow-up was 73.9±10.6 years. We found a significant improvement in bodily pain (baseline 53.8±33.4, follow-up 62.7±26.6; p=0.002) and in general health (baseline 35±25.4, follow-up 41.7±24.2; p=0.002) over time. The bodily pain score at follow-up was similar to the mean of the age-matched healthy population (62.7±26.6 vs. 67.6±26, p=0.374). The MCS-36 scores were higher than the normative values before treatment and at follow-up (51.6±9.8 vs. 45.8±9, p=0.004 and 50.6±11.7 vs. 45.8±9, p=0.030, respectively). The PCS-36 score at follow-up was comparable to the normative values (39.4±10.4 vs. 42.7±9, p=0.107). CONCLUSIONS: Denosumab is effective to improve bone health and global mental and physical wellbeing, and quality of life over time.

Conventional progesterone receptors (PR) B and PRA are expressed by human chondrocytes and can be involved in the pathogenesis of osteoarthritis.

To evaluate the expression, location and role of progesterone receptors (PRs) A and B in human chondrocytic cell lines, Western blotting, real time PCR analyses, transmission electron microscopy and immunogold assays were performed. By transfection and co-transfection assays, the influence of progesterone (OHPg) on estrogen receptor alpha (ERα) promoter activity was investigated. MTT and pAKT documented OHPg effects on chondrocytes survival. The PR-B and PR-A were both observed in human chondrocytes. The PR-B was evidenced both in the nucleus and in the cytosol of the cells. OHPg, through PR-B, induced ERα expression by acting at the ER promoter level affecting chondrocytes survival. We reported for the first time the expression of PRs in human chondrocytes. Interestingly, we described a novel mechanism via progesterone induction of ERα, which may explain, at least in part, the dramatic rise in OA prevalence among postmenopausal women.

Cervical spondylodiscitis mimicking Pott's disease: a case report.

INTRODUCTION: The leading cause of pyogenic vertebral osteomyelitis is Staphylococcus aureus, and its incidence is rising, particularly in the elderly. We report an unusual case of cervical spondylodiscitis and epidural abscess mimicking Pott's disease. CASE REPORT: A 67-year-old man was admitted to our institution with a 15-day history of neck pain radiating to the head, shoulders and left arm that was associated with weakness and paresthesia. Laboratory tests showed a mild leucocytosis and high levels of inflammatory markers. The MRI showed contrast enhancement of C6-C7 with an abscess infiltration extending to the intervertebral disc, the anterior epidural space, and the medullary cord. The patient had a medical history of a positive Mantoux tuberculin skin test 25 years prior, and the interferon-gamma release assay (IGRA) was positive for the identification of latent tuberculosis infection. All other examinations for diagnosis of spinal tuberculosis were inconclusive. Intravenous antibiotic therapy was initiated with teicoplanin 800 mg and levofloxacin 750 mg daily with a fast recovery of symptoms. CONCLUSIONS: Cervical spondylodiscitis can be an unusual cause of severe neck pain with a challenging differential diagnosis. Conservative treatment should always be considered for patients without neurological symptoms as long as close follow-up evaluations are performed.

Urinary tract infections after early removal of urinary catheter in total joint arthroplasty.

OBJECTIVE: Postoperative urine retention (POUR) is a well-known complication after total joint arthroplasty (TJA). POUR is most commonly managed with an indwelling catheter. However, indwelling catheters have been associated with a substantial risk of urinary tract infection (UTI). The purpose of this study was to (1) evaluate the incidence of UTI and POUR in patient with indwelling urinary catheter after TJA, (2) identify the microorganisms responsible for catheter colonization, and (3) assess preoperative risk factors (gender, body mass index, hypertension, diabetes mellitus, smoking) associated with catheter colonization. PATIENTS AND METHODS: Patients undergoing primary TJA with no preoperative bacteriuria were enrolled. Prior to the draping of the surgical site, each patient received an indwelling catheter that was inserted under sterile conditions and remained in place for 24 hours. Urine and tip catheter cultures were performed after catheter removal. RESULTS: 55 patients (38 females and 17 males) were recruited (26 total knee and 29 total hip arthroplasties). POUR was not reported in any patient, and only 1 patient (1.8%) had UTI. Cultures of catheter tips were positive in 16 patients (29.1%). Only 1 of these patients had a positive urine culture. Enterococcus faecalis was the most common pathogen isolated. None of the preoperative variables was associated with the risk of catheter colonization. CONCLUSIONS: Data from this study support early catheter removal after TJA. Predominant catheter-isolated bacteria are enteric species. The culture of a catheter tip specimen should be discouraged for the diagnosis of UTI within the firsts 24 hours after surgery.

Tantalum monoblock cups in total hip arthroplasty: clinical results and outcome predictors.

This study aims to report the minimum 2-year follow-up results of the tantalum monoblock cup in primary THA and to identify possible outcome predictors. Eighty-eight porous tantalum monoblock acetabular cup in primary THA were reviewed. The Harris Hip Score (HHS) and the Short Form-36 Health Survey (SF-36) were used for the evaluation of outcomes. Radiographic evaluation included acetabular component orientation, presence of bone gaps, radiolucent lines, new bone formation and heterotopic ossifications. After a mean follow-up of 55.4±19.5 months, no component revision was noted. The HHS improved from 43.6±14.6 to 88.3±8.4 (P less than 0.001). The mean physical domain of the SF-36 did not significantly differ from that of age-matched, healthy subjects (P=0.072); the mean mental component of the SF-36 was significantly higher than that of age-matched, healthy subjects (P less than 0.001). Negative determinants of postoperative HHS (total adjusted R2=0.328) using tantalum monoblock cups were age at surgery (R2=0.164, P less than 0.001), female sex (R2=0.103, P less than 0.001), and acetabular inclination (R2=0.084, P equals 0.003).

Reinfusion-drains reduce blood transfusions in total joint arthroplasty.

This study aims to evaluate the effect of postoperative blood recovery with reinfusion drains on hematologic parameters and blood transfusion rate in patients undergoing total joint arthroplasty. Three-hundred-and-forty-four patient records were reviewed and 271 patients were included in the study; 56.8% of patients were treated with postoperative cell salvage procedure using reinfusion drains (PCS) and 43.2% had closed-suction drain (CSD) postoperatively. In comparison to the CSD group, the PCS group showed higher hemoglobin (Hb) levels on the first and second days postoperatively but no statistical differences were noted at the day of discharge. 75.2% and 37.7% of patients required blood transfusions in the CSD and PCS groups, respectively. The PCS group had a lower number of blood transfusions than the CSD group. At multivariate analysis, Hb loss rate was related to preoperative Hb values, total amount of drained blood and chronic antiplatelet therapy. The number of blood transfusions was related to preoperative Hb values, closed-suction drains, preoperative platelet count, TKA surgery and BMI. This study supports the use of PCS with reinfusion drains after THA and TKA at least for the short-term.

C3f is a potential tool for the staging of osteoarthritis.

An attractive method for osteoarthritis (OA) staging is the measurement of biochemical markers in biological fluids, which could reflect dynamic and quantitative changes in joint remodeling and therefore disease progression. Proteome analysis has been recognized as one of the most effective tools to explore biomarkers as it can furnish a wealth of information in both diagnosis and prognosis of diseases. We have recently described an innovative tool for peptidome and lipidome profiling of fluids based on mesoporous aluminosilicate (MPAS) and Matrix-Assisted Laser Desorption/Ionization time-of-flight Mass Spectrometry (MALDI-TOF MS). The aim of this study was to analyze peptide profiles of human synovial fluid in patients with different grade of OA using MALDI-TOF-MS technique in order to identify potential markers of disease progression. Twenty-five patients older than 50 years and affected by primary knee OA diagnosed according to clinical and radiological criteria were enrolled. For each patient a synovial fluid sample was aspirated from the affected knee and analyzed using MALDI-TOF-MS technique. A statistically significant difference in the normalized area of two peaks (m/z=1865 and m/z=2021) was detected among different stages of OA. The 2 peaks were identified as Complement C3 peptide fragments: C3f and C3f Des-Arg. The expression levels of these two peptides (m/z=1865 and 2021) decreased with the progression of OA degrees severity (ρs=-0.434, p=0.03, and ρs=-0.532, p=0.006, respectively). This marker may be a useful tool for assessing the severity of knee OA and it may be a novel target for drug discovery, specifically for the development of disease modifying OA drugs. However further studies are required to clarify the role of C3f in OA pathogenesis.

PTEN ELEVATION, AUTOPHAGY AND METABOLIC REPROGRAMMING MAY BE INDUCED IN HUMAN CHONDROCYTES DURING STEROIDS OR NUTRIENT DEPLETION AND OSTEOARTHRITIS.

The exact mechanisms controlling the development and progression of osteoarthritis have not yet been clarified. Our aim was to investigate new pathomechanisms, with an emphasis on novel molecular targets that might regulate human chondrocytes in osteoarthritis. As a model for studying cell survival and metabolism, C-28/I2 and T/C-28a4 human chondrocytes were grown in complete medium, in dex-tran-coated charcoal treated medium and in serum-free medium. Healthy and osteoarthritic human cartilage samples were obtained from discarded surgical material. Cell survival, PTEN, AKT, Beclin1, AMBRA, AMPK and glucose/triglyceride metabolism were evaluated by immunoblotting and spectro-photometric assays. Starvation and steroids depletion decreased cell survival concomitantly with PTEN elevation, repression of the PI3K/AKT signaling axis and autophagy activation. These experimental conditions promoted the accumulation of glucose, decreased levels of G6PDH and resulted in differen-tial expression of OXPHOS complexes. Furthermore, they induced the expression of AMPK, reduced triglyceride levels and increased lipase activity, which was accompanied by a change in chondrocytes toward a fibroblast-like morphology. In osteoarthritic human cartilage, increased PTEN, AMPK and autophagy reflected the chondrocyte responses observed during starvation and steroids depletion. In conclusion, we defined the metabolic phenotype of human chondrocytes, in which both starvation and steroids depletion induce the activation of PTEN, AMPK and autophagy signaling, concomitant with metabolic reprogramming. Our data may aid in the development of novel in vitro models for the discovery and design of drugs or nutraceuticals capable of ameliorating the course of osteoarthritis.

The effects of nonsteroidal anti-inflammatory drugs on clinical outcomes, synovial fluid cytokine concentration and signal transduction pathways in knee osteoarthritis. A randomized open label trial.

OBJECTIVE: We investigated the effects of celecoxib, diclofenac, and ibuprofen on the disease-specific quality of life, synovial fluid cytokines and signal transduction pathways in symptomatic knee osteoarthritis (OA). DESIGN: Ninety patients scheduled for a total knee arthroplasty (TKA) were randomized to six groups that were treated with low and high dosages of celecoxib, diclofenac or ibuprofen. At the time of the first admission (T0) and at surgery (T1 = 14 days after beginning of the nonsteroidal anti-inflammatory drugs (NSAIDs)), samples of knee synovial fluid were obtained from each patient for analysis. During the surgery the synovial tissue was harvested from the knee of patients. The Western Ontario and McMaster universities (WOMAC) score was used to evaluate the patient disease-specific quality of life at T0 and T1. Microarray tests performed at T0 and T1 were used to evaluate the effects of NSAIDs on Tumor necrosis factor (TNF)-alpha, Interleukin-6 (IL-6), IL8 and Vascular endothelial growth factor (VEGF) concentration in the synovial fluid. Western blot assays evaluated the effects of NSAIDs on MAP kinase (MAPK) signal transduction pathway in the synovial membrane. RESULTS: NSAID treatment induced a statistically significant improvement in the WOMAC score and a statistically significant decrease in the IL-6, VEGF and TNF-alpha concentration in the synovial fluid. Higher dosages of NSAIDs provided a greater improvement in the disease-specific quality of life of patients and lower concentrations of pro-inflammatory cytokines in the synovial fluid. Inhibition of MAPKs was noted after NSAID treatment. CONCLUSION: Short-term NSAID treatment improves the patient disease-specific quality of life with a parallel decrease in pro-inflammatory synovial fluid cytokine levels in knee OA. Signal transduction pathways may be involved in regulating the anti-inflammatory effects of NSAIDs. ClinicalTrial.gov: NCT01860833.

Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis.

BACKGROUND AND OBJECTIVE: Ibuprofen is a non-selective cyclo-oxygenase (COX)-1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800 mg/day to 1800 mg/day) administered in patients affected by severe knee OA. METHODS: Ibuprofen was administered for 7 days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7 days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. RESULTS: Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. CONCLUSION: Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution.

Physical, mechanical and pharmacological properties of coloured bone cement with and without antibiotics.

Coloured bone cements have been introduced to make the removal of cement debris easier at the time of primary and revision joint replacement. We evaluated the physical, mechanical and pharmacological effects of adding methylene blue to bone cement with or without antibiotics (gentamicin, vancomycin or both). The addition of methylene blue to plain cement significantly decreased its mean setting time (570 seconds (SD 4) vs 775 seconds (SD 11), p = 0.01), mean compression strength (95.4 MPa (SD 3) vs 100.1 MPa (SD 6), p = 0.03), and mean bending strength (65.2 MPa (SD 5) vs 76.6 MPa (SD 4), p < 0.001) as well as its mean elastic modulus (2744 MPa (SD 97) vs 3281 MPa (SD 110), p < 0.001). The supplementation of the coloured cement with vancomycin and gentamicin decreased its mean bending resistance (55.7 MPa (SD 4) vs 65.2 MPa (SD 5), p < 0.001).The methylene blue significantly decreased the mean release of gentamicin alone (228.2 µg (SD 24) vs 385.5 µg (SD 26), p < 0.001) or in combination with vancomycin (498.5 µg (SD 70) vs 613 µg (SD 25), p = 0.018) from the bone cement. This study demonstrates several theoretical disadvantages of the antibiotic-loaded bone cement coloured with methylene blue.

Regulatory functions of insulin-like growth factor binding proteins in osteoarthritis.

Insulin-like growth factor binding proteins (IGFBPs) are a group of secreted proteins, which bind to IGF-I (and IGF-II) with high affinity and modulate the biological actions of IGFs. Abundant evidence points the importance of the IGF-I/IGFBP system on both cell growth and differentiation. A role for the IGF-I/IGFBP system in the regulation of normal human cartilage has been previously reported. In this context, recent studies suggest an emerging role for IGFBPs in the failure of cartilage during osteoarthritis (OA). Indeed, increased IGFBP levels have been reported in both the articular cartilage and synovial fluid from patients with OA. Overexpression of IGFBPs, by altering the bioavailability and function of IGFs, is likely to deliver IGFs-independent signals for chondrocyte survival. This, at least in part, might explain the degenerative changes of the cartilage in OA. Further studies are necessary to clarify the mechanisms that cause the overexpression of IGFBPs in patients with OA. Advances in our understanding of the relationship between osteoarthritis and the IGF-I/IGFBP system may lead to new treatment strategies for this degenerative disease.

Pathological findings in subsynovial connective tissue in idiopathic carpal tunnel syndrome.

Recent studies suggest that in patients with carpal tunnel syndrome, pathological changes occur in the subsynovial connective tissue. Such changes are non-inflammatory synovial fibrosis and vascular proliferation. Thickening of the tendon sheet may cause an increase of canal pressure and damages to the median nerve in the wrist; however, the causes of such events still remain to be clarified. We examined synovial specimens from 26 patients operated on for idiopathic carpal tunnel syndrome. Analysis included histological, ultrastructural and immunohistochemical examination in order to establish a pathological underlying pattern. An explanation for the pathogenesis of the found changes suggested. Our data confirm the presence of a non-inflammatory fibrosis with irregular bundles of collagen. De novo blood vessel formation was also noted. Interestingly the neo-angiogenesis consists of anomalous vessels and may be triggered from various cell types secreting vascular endothelial growth factor (VEGF), including macrophage-like elements similar to endothelial progenitor cells. Therefore, we believe that in the future a non-surgical management of carpal tunnel syndrome might be conjecturable via anti-VEGF drugs.

The functional relevance of neurological recovery after lumbar discectomy: a follow-up of more than 20 years.

We have studied 180 patients (128 men and 52 women) who had undergone lumbar discectomy at a mean of 25.4 years (20 to 32) after operation. Pre-operatively, most patients (70 patients; 38.9%) had abnormal reflexes and/or muscle weakness in the leg (96 patients; 53.3%). At follow-up 42 patients (60%) with abnormal reflexes pre-operatively had fully recovered and 72 (75%) with pre-operative muscle impairment had normal muscle strength. When we looked at patient-reported outcomes, we found that the Short form-36 summary scores were similar to the aged-matched normative values. No disability or minimum disability on the Oswestry disability index was reported by 136 patients (75.6%), and 162 (90%) were satisfied with their operation. The most important predictors of patients' self-reported positive outcome were male gender and higher educational level. No association was detected between muscle recovery and outcome. Most patients who had undergone lumbar discectomy had long-lasting neurological recovery. If the motor deficit persists after operation, patients can still expect a long-term satisfactory outcome, provided that they have relief from pain immediately after surgery.

Minimum 20-year follow-up results of Harrington rod fusion for idiopathic scoliosis.

We evaluated the outcome of spinal fusion with a single Harrington distraction rod in patients with idiopathic scoliosis. At follow-up visits a minimum of 20 years post-surgery, we studied 24 patients who had been operated on by the same surgeon. The Scoliosis Research Society (SRS) Instrument and an additional questionnaire of our own, along with an invitation for a follow-up visit, were originally mailed to 28 consecutive patients of the surgeon. The SRS Instrument has seven domains dealing with back pain, general self-image, self-image after surgery, general function, function in terms of level of activity, function after surgery, and degree of satisfaction with the surgery. The length of time between surgery and the follow-up visit averaged 22.9 years (20.2-27.3). The mean age at surgery and follow-up were 15.8 (13-22) and 38.8 (35-48) years, respectively. Twenty-four patients sent back the completed questionnaires and 16 of them participated in the clinic and radiographic follow-up. To assess the meaning of the questionnaires' results, a control group of the same sex, age and geographic provenance was selected from our outpatients without scoliosis. The average follow-up score on the SRS Instrument for the patients was 100.8 (78-110). When we compared the study and control groups, no significant differences in the single SRS domain scores were observed. The mean Cobb angle and rib cage deformity before surgery were 70.46 degrees (40-120) and 36.4 mm (20-60 mm), respectively, whereas on follow-up they were 41.23 degrees (16-75) and 22.3 mm (5-50 mm), respectively. These long-term results lead us to consider Harrington fusion a procedure that produces a long-lasting high degree of self-reported post-operative satisfaction.