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Modern image analysis enables the accurate quantification of knee osteoarthritis (OA) bone using MRI. We hypothesised that three-dimensional changes in bone would be characteristic of OA and provide a responsive measure of progression. 1312 participants with radiographic knee OA, and 885 non-OA controls with MRIs at baseline, 1, 2 and 4 years were selected from the NIH Osteoarthritis Initiative. Automated segmentation of all knee bones and calculation of bone area was performed using active appearance models. In a subset of 352 participants, responsiveness of bone area change was compared with change in radiographic joint space width (JSW) and MRI cartilage thickness over a 2-year period. All OA knee compartments showed increased bone area over time compared with non-OA participants: for example, the 4-year percentage change from baseline in medial femur area for OA (95% CI) was 1.87(0.13), non-OA 0.43 (0.07); p<0.0001. Bone area change was more responsive than cartilage thickness or JSW; 2-year SRM for bone area in the medial femur was 0.83, for the most responsive cartilage thickness measure central medial femorotibial composite (cMFTC): 0.38, JSW: 0.35. Almost half of all knees had change greater than smallest detectable difference at 2 years. Body mass index, gender and alignment had only a small effect on the rate of change of bone area. Changes in bone area discriminated people with OA from controls and was more responsive than the current and impending standards for assessing OA progression. The shape change in OA bone provides a new window on OA pathogenesis and a focus for clinical trials.

High-resolution peripheral quantitative computed tomography (HR-pQCT) captures novel aspects of bone geometry, volumetric bone mineral density and offers the ability to measure bone microarchitecture, but data relating measures obtained from this technique to diabetic status are inconsistent in women and lacking in men. Here, we report an analysis from the Hertfordshire Cohort Study, where we were able to study associations between bone microarchitecture from HR-pQCT of distal radius and distal tibia in 332 participants (177 men and 155 women) aged 72.1–81.4 years with or without diabetes mellitus (DM); n  = 29 (18 men and 11 women) and n  = 303, respectively. Statistical analyses were performed separately for women and men. The mean (SD) age of participants was 76.4 (2.6) and 76.1 (2.5) years in women and men, respectively. Participants with DM differed significantly in terms of weight in both women (70.4 ± 12.3 vs. 80.3 ± 18.3 kg; p  = 0.015) and men (81.7 ± 11.4 vs. 92.8 ± 16.3 kg; p  < 0.001) but no differences were found in height, smoking status, alcohol intake, social class and physical activity among women or men. Analyses in women revealed that cortical pore volume (Ct.Po.V) was higher in participants with DM and close to statistical significance for cortical porosity (Ct.Po) ( β  = 0.76 [0.12, 1.41] z -score, p  = 0.020 and β  = 0.62 [−0.02, 1.27] z -score, p  = 0.059, respectively) at the distal radius. Adjustment for weight did not materially affect the relationship described for Ct.Po.V ( β  = 0.74 [0.09, 1.39], p  = 0.027) and Ct.Po ( β  = 0.65 [−0.01, 1.30], p  = 0.053) at the distal radius. After adjustment for weight, analyses in men revealed that Ct.Po and Ct.Po.V were higher in participants with DM ( β  = 0.57 [0.09, 1.06] z -score, p  = 0.021 and β  = 0.48 [0.01, 0.95] z -score, p  = 0.044, respectively) at the distal tibia. Analyses of distal radial and tibial trabecular bone parameters according to diabetic status revealed no significant differences among men or women after adjustment for weight. We found higher cortical porosity and cortical pore volume at the distal tibia in men with DM and higher cortical pore volume at the distal radius in women with a non-significant tendency for higher cortical porosity. The results of our study suggest that deficits in cortical bone exist both in older men and women with DM.

Background Human bone marrow is a source of mesenchymal stem cells (MSCs), other progenitor cells, and factors with anti-inflammatory and regenerative capacity. Though the fraction of MSCs out of the nucleated cells is very small, bone marrow aspirate (BMA) for osteoarthritis (OA) has noteworthy effects. BMA is usually collected from the posterior or anterior iliac crest, and rarely from the proximal tibia. We investigated the clinically beneficial concentration of ex vivo MSCs, derived from BM harvested from the posterior iliac crest and proximal tibia by Marrow Cellution™ Aspiration System, and their phenotypic differences, in comparison to autologous Platelet-Rich Plasma (PRP) treatment prepared with a manual, closed system. Methods A single-center, parallel, randomized controlled study was designed to investigate the efficacy of BMA from the posterior iliac crest compared to BMA from the proximal tibia, against a control group treated with PRP, in knee OA. Thirty patients with knee OA grade I-IV, according to Kellgren-Lawrence (KL), were distributed into each group. Visual Analog Scale (VAS) and Western Ontario & McMaster Universities Arthritis Index (WOMAC) score were used for clinical outcome evaluation. Results Data from an intermediate analysis of 6-months follow-up, involving 15 patients in each arm, showed that the posterior iliac crest was significantly more densely populated with mononuclear cells, than the proximal tibia (p = 0.005). Flow cytometric analysis on ex vivo BMA showed a significantly greater number of MSCs in the BM-derived from the posterior iliac crest when compared with the proximal tibia (p < 0.001), together with a significantly higher number of platelets (PLTs) (p < 0.001). Surprisingly, despite these differences in cells number, the improvement in early pain and function scores, after each treatment, were statistically significant within each of the three arms. BM from the proximal tibia showed the highest ΔWOMAC, while BM from the posterior iliac crest showed the highest ΔVAS; however, these differences were not statistically significant across the three arms (p > 0.05). A better outcome, in terms of ΔVAS, was observed in patients classified as KL I-II, when treated with BMA from crest (p < 0.001) and PRP (p = 0.004). Moreover, the effect of BMA treatment on ΔVAS depends on MSCs % only in the Tibia Arm (r = -0.59, p = 0.021), where we also found a correlation between ΔWOMAC and monocytes (r = 0.75, p = 0.016). Conclusion The results indicate that the iliac crest yields a higher concentration of MSCs compared to the proximal tibia, however both BM, independently of the MSCs concentration, show a beneficial clinical outcome in the treatment of knee OA. Furthermore, BMA is not superior to PRP treatment.

Background Mesenchymal stem cells (MSCs) have been proposed to treat osteoarthritis (OA) for many years. However, clinical outcomes have been inconsistent due to biological variation between patients, differences in tissue source and preparation of the MSCs, and type of donor (e.g. allogenic versus autologous). Here, we test the hypothesis that inconsistent clinical outcomes are related to variations in the stemness and senescence of the injected autologous adipose-derived (AD) MSCs. Methods In the prospective randomized trial, 45 knee OA patients were divided into two groups: Group 1 (n = 22) patients treated with high tibial osteotomy (HTO) alone and Group 2 (n = 23) patients treated with HTO followed by intra-articular injection of autologous AD-MSCs (HTO + AD-MSCs). MRI and X-ray were performed pre-operation and 12 months post-operation. WOMAC and VAS score were collected four times, every 6 months over a 24-month follow-up. We observed the proliferation and stemness of AD-MSCs selected from the 5 patients showing the most improvement and from the 5 patients with the least improvement, and completed further in vitro experiments including beta-galactosidase activity, reactive oxygen species and bioinformatic analysis. Results The results showed that patients treated with HTO + AD-MSCs had a significant reduction in knee OA severity as compared to patients treated with HTO alone. Moreover, we discovered that proliferation and colony forming efficiency of AD-MSCs selected from the 5 patients showing the most improvement performed significantly better than cells selected from the 5 patients with the least improvement. AD-MSCs from the patients with the most improvement also had lower amounts of senescent cells and intracellular reactive oxygen species. Conclusions Clinical outcomes of autologous AD-MSCs therapy in knee osteoarthritis are correlated with stem cell stemness and senescence. Our study highlights emerging opportunities and trends in precision medicine that could potentially improve autologous MSC-based therapies.

Background A recent publication on efficacy of Sprifermin for knee osteoarthritis (OA) using quantitatively MRI-defined central medial tibio-femoral compartment cartilage thickness as the structural primary endpoint reported no statistically significant dose response. However, Sprifermin was associated with statistically significant, dose-dependent reductions in loss of total and lateral tibio-femoral cartilage thickness. Based on these preliminary promising data a post-hoc analysis of secondary assessment and endpoints was performed to evaluate potential effects of Sprifermin on semi-quantitatively evaluated structural MRI parameters. Aim of the present analysis was to determine effects of sprifermin on several knee joint tissues over a 12 month period. Methods 1.5 T or 3 T MRIs were acquired at baseline and 12 months follow-up using a standard protocol. MRIs were read according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) scoring system (in 14 articular subregions) by four muskuloskeletal radiologists independently. Analyses focused on semiquantitative changes in the 100 μg subgroup and matching placebo of multiple MRI-defined structural alterations. Analyses included a delta-subregional and delta-sum approach for the whole knee and the medial and lateral tibio-femoral (MTFJ, LTFJ), and patello-femoral (PFJ) compartments, taking into account number of subregions showing no change, improvement or worsening and changes in the sum of subregional scores. Mann–Whitney − Wilcoxon tests assessed differences between groups. Results Fifty-seven and 18 patients were included in the treatment and matched placebo subgroups. Less worsening of cartilage damage was observed from baseline to 12 months in the PFJ (0.02, 95 % confidence interval (CI) (−0.04, 0.08) vs. placebo 0.22, 95 % CI (−0.05, 0.49), p  = 0.046). For bone marrow lesions (BMLs), more improvement was observed from 6 to 12 months for whole knee analyses (−0.14, 95 % CI (−0.48, 0.19) vs. placebo 0.44, 95 % CI (−0.15, 1.04), p  = 0.042) although no significant effects were seen from the baseline visit, or in Hoffa-synovitis, effusion-synovitis, menisci and osteophytes. Conclusions In this post-hoc analysis cartilage showed less worsening from baseline to 12 months in the PFJ, and BMLs showed more improvement from 6 to 12 months for the whole knee. Trial registration ClinicalTrials.gov identifier: NCT01033994 .

Summary Strontium ranelate appears to influence more than alendronate distal tibia bone microstructure as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and biomechanically relevant parameters as assessed by micro-finite element analysis (μFEA), over 2 years, in postmenopausal osteoporotic women. Introduction Bone microstructure changes are a target in osteoporosis treatment to increase bone strength and reduce fracture risk. Methods Using HR-pQCT, we investigated the effects on distal tibia and radius microstructure of strontium ranelate (SrRan; 2 g/day) or alendronate (70 mg/week) for 2 years in postmenopausal osteoporotic women. This exploratory randomized, double-blind trial evaluated HR-pQCT and FEA parameters, areal bone mineral density (BMD), and bone turnover markers. Results In the intention-to-treat population ( n  = 83, age: 64 ± 8 years; lumbar T-score: −2.8 ± 0.8 [DXA]), distal tibia Cortical Thickness (CTh) and Density (DCort), and cancellous BV/TV increased by 6.3%, 1.4%, and 2.5%, respectively (all P  < 0.005), with SrRan, but not with alendronate (0.9%, 0.4%, and 0.8%, NS) ( P  < 0.05 for all above between-group differences). Difference for CTh evaluated with a distance transformation method was close to significance ( P  = 0.06). The estimated failure load increased with SrRan (+2.1%, P  < 0.005), not with alendronate (−0.6%, NS) (between-group difference, P  < 0.01). Cortical stress was lower with SrRan ( P  < 0.05); both treatments decreased trabecular stress. At distal radius, there was no between-group difference other than DCort ( P  < 0.05). Bone turnover markers decreased with alendronate; bALP increased (+21%) and serum-CTX-I decreased (−1%) after 2 years of SrRan (between-group difference at each time point for both markers, P  < 0.0001). Both treatments were well tolerated. Conclusions Within the constraints of HR-pQCT method, and while a possible artefactual contribution of strontium cannot be quantified, SrRan appeared to influence distal tibia bone microstructure and FEA-determined biomechanical parameters more than alendronate. However, the magnitude of the differences is unclear and requires confirmation with another method.

After acute spinal cord injury (SCI), rapid depletion of the sublesional skeleton occurs, particularly at the distal femur and proximal tibia. Subsequently, fragility fractures of the knee may occur. We determined the efficacy of zoledronic acid to prevent sublesional bone mineral density (BMD) loss at 6 and 12 months after acute SCI. Thirteen subjects with acute motor-complete SCI were prospectively studied: 6 patients received zoledronic acid (5 mg) and 7 subjects did not receive the drug (controls). Zoledronic acid was administered intravenously within 16 weeks of acute injury. Areal BMD was performed by dual energy X-ray absorptiometry at baseline, 6, and 12 months after administration of drug. The treatment group demonstrated sparing of BMD at the total hip at month 6 ( p  < 0.0006) and at month 12 ( p  < 0.01). In contrast to the findings at the hip, the treatment group had a greater loss of BMD compared to the control group at the distal femur and proximal tibia at month 6 (−7.9 % ± 3.4 vs.−2.7 % ± 5.0, respectively, p  = 0.054; and −10.5 % ± 6.4 vs. −4.8 % ± 6.8, respectively, p  = NS) and at month 12 (−18.5 % ± 3.9 vs. −8.4 % ± 7.2, respectively, p  = 0.01; and −20.4 % ± 8.8 vs.−7.9 % ± 12.3, respectively, p  = 0.06). A single dose of zoledronic acid administered soon after acute SCI reduced the %BMD loss at the hip, but appeared to have no effect to prevent %BMD loss at the knee, the site where fracture risk is greatest in persons with SCI.

During the healing process after bone fracture, soft callus forms adjacent to the fracture site, is replaced by hard callus, and is finally remodeled to the original bone configuration. Although the cambium layer of the periosteum is reported to play an essential role in callus formation, we still lack direct in vivo evidence of this. To investigate the cell lineage of the soft callus, we analyzed the process of fracture healing in Prx1 - Cre;ROSA26 reporter ( R26R ), Col1a1(3.6   kb) - Cre;R26R , Col1a1(2.3   kb) - Cre;R26R , Sox9 - CreERT2;R26R , and Sox9 - LacZ mice with X-gal staining. In the Prx1 - Cre;R26R , in which the cells of the periosteum stained for X-gal before fracture, all cells in the soft callus were X-gal positive, whereas in the Col1a1(3.6   kb) - Cre;R26R mice, the cells in the periosteum before fracture stained for X-gal and the soft callus was partly composed of X-gal-positive cells. In contrast, in the Col1a1(2.3   kb) - Cre;R26R mice, in which the mature osteoblasts in the cambium layer of the periosteum were marked before fracture, no cells in the soft callus at the fracture site were X-gal positive. These results suggest that most of the cells in the soft callus are derived from the mesenchymal progenitors in the periosteum, and not from mature osteoblastic cells. Interestingly, in the Sox9 - LacZ mice, Sox9 -expressing X-gal-positive cells emerged in the periosteum adjacent to the fracture site 3 days after fracture. We demonstrated this by injecting tamoxifen into the Sox9 - CreERT2;R26R mice for 3 days after fracture, so that these Sox9 -expressing periosteal cells gave rise to cells in the soft and hard calli. Our findings show that the periosteal cells in which Sox9 expression is induced just after fracture are the major source of the chondrocytes and osteoblasts in the fracture callus.

Objective We aimed to apply 3D MRI-based measurement technology to studying 2-year change in quantitative measurements of meniscus size and position. Methods Forty-seven knees from the Osteoarthritis Initiative with medial radiographic joint space narrowing had baseline and 2-year follow-up MRIs. Quantitative measures were obtained from manual segmentation of the menisci and tibia using coronal DESSwe images. The standardized response mean (SRM = mean/SD change) was used as measure of sensitivity to longitudinal change. Results Medial tibial plateau coverage decreased from 34.8 % to 29.9 % (SRM -0.82; p  < 0.001). Change in medial meniscus extrusion in a central image (SRM 0.18) and in the central five slices (SRM 0.22) did not reach significance, but change in extrusion across the entire meniscus (SRM 0.32; p  = 0.03) and in the relative area of meniscus extrusion (SRM 0.56; p  < 0.001) did. There was a reduction in medial meniscus volume (10 %; p  < 0.001), width (7 %; p  < 0.001), and height (2 %; p  = 0.08); meniscus substance loss was strongest in the posterior (SRM -0.51; p  = 0.001) and weakest in the anterior horn (SRM -0.15; p  = 0.31). Conclusion This pilot study reports, for the first time, longitudinal change in quantitative 3D meniscus measurements in knee osteoarthritis. It provides evidence of improved sensitivity to change of 3D measurements compared with single slice analysis. Key Points • First longitudinal MRI-based measurements of change of meniscus position and size . • Quantitative longitudinal evaluation of meniscus change in knee osteoarthritis . • Improved sensitivity to change of 3D measurements compared with single slice analysis .

After an anterior cruciate ligament (ACL) injury, a majority of patients have a traumatic bone marrow lesion (BML, or bone bruise). The clinical relevance of posttraumatic lesions remains unclear.   To explore the cross-sectional associations between traumatic BML volume and self-reported knee pain and symptoms among individuals within 4 weeks of ACL injury.   Cross-sectional exploratory analysis of a randomized clinical trial.   Orthopaedic departments at 2 hospitals in Sweden.   As part of a randomized trial (knee anterior cruciate ligament nonoperative versus operative treatment [KANON] study), 121 young active adults (74% men, age = 26 ± 5 years, height = 1.8 ± 0.1 m, weight = 76 ± 13 kg) with an ACL tear were studied.   The BML volume in the proximal tibia and distal femur was segmented using magnetic resonance images obtained within 4 weeks of injury. A radiologist evaluated the presence of depression fractures on the images. Pain and symptoms of the injured knee (Knee Injury and Osteoarthritis Outcome Score [KOOS] pain and symptoms subscales) were obtained the same day as imaging. We used linear regression models to assess the associations.   Most knees had at least 1 BML (96%), and the majority (57%) had a depression fracture. Whole-knee BML volume was not related to knee pain for the entire cohort (β = -0.09, P = .25). Among those without a depression fracture, larger whole-knee BML volume was associated with increased knee pain (β = -0.46, P = .02), whereas no association was found for those with a depression fracture (β = 0.0, P = .96). Larger medial (β = -0.48, P = .02) but not lateral (β = -0.03, P = .77) tibiofemoral BML volume was associated with greater pain. We found no association between BML volume and knee symptoms.   We confirmed the absence of relationships between whole-knee BML volume and pain and symptoms within 4 weeks of ACL injury. Our findings extend previous reports in identifying weak associations between larger BML volume in the medial compartment and greater pain and between BML volume and greater pain among those without a depression fracture.