Summary Objective To assess whether synovial mesenchymal stem cells (SMSCs) from patients with osteoarthritis (OA) or rheumatoid arthritis (RA) can be used as an alternative cell source for cartilage ...repair using allogenic tissue engineered construct (TEC). Methods Twenty-five patients (17 female, average age 61.8 years) were divided according to their pathology (control trauma group; N = 6, OA group; N = 6) and RA patients were subdivided into two groups to evaluate the impact of biologics in accordance with whether treated with biologics Bio(+)RA; N = 7 or not Bio(−)RA; N = 6. We compared the following characteristics among these groups: (1) The cell proliferation capacity of SMSCs; (2) The influence of passage number on features of SMSCs; (3) The weight and volume of TEC from the same number of SMSCs; (4) Inflammatory cytokine gene expressions levels of TEC; (5) The chondrogenic potential of TEC; and (6) Osteochondral repair using TEC in athymic nude rats. Results SMSCs from the four groups exhibited equivalent features in the above evaluation items. In in vivo studies, the TEC-treated repair tissues for all groups exhibited significantly better outcomes than those for the untreated group and no significant differences among the four TEC groups. Conclusion SMSCs from OA or RA patients are no less appropriate for repairing cartilage than those from trauma patients and thus, may be an effective source for allogenic cell-based cartilage repair.
Summary
In biologic-naïve female RA patients, switching oral BPs to DMAb significantly reduced radiographic joint destruction compared to continuing oral BPs or switching to TPTD at 12 months, which ...were significantly associated with a decrease of a bone resorption marker at 6 months.
Introduction
The aim of this study was to clarify the effects of switching oral bisphosphonates (BPs) to denosumab (DMAb) or daily teriparatide (TPTD) on the progression of radiographic joint destruction in patients with biologic-naïve rheumatoid arthritis (RA).
Methods
A retrospective, case-controlled study involving 90 female RA patients (mean age 68.2 years, 96.7% postmenopausal, disease activity score assessing 28 joints with CRP (DAS28-CRP) 2.4, methotrexate treatment 81.1%, prednisolone treatment 68.9%, and prior BP treatment 44.8 months), who were allocated depending on each patient’s and physician’s wishes, to (1) the BP-continue group (
n
= 30), (2) the switch-to-DMAb group (
n
= 30), or (3) the switch-to-TPTD group (
n
= 30), was conducted. Patients were retrospectively selected to minimize the difference of possible clinical backgrounds that may affect the joint destruction of RA. The primary endpoint was to clarify the change of the modified total Sharp score (mTSS) from baseline to 12 months.
Results
After 12 months, the mean changes of the modified Sharp erosion score were significantly lower in the switch-to-DMAb group (0.2 ± 0.1; mean ± standard error) than in the switch-to-TPTD group (1.3 ± 0.5;
P
< 0.05), and mTSS was significantly lower in the switch-to-DMAb group (0.3 ± 0.2) than in the BP-continue group (1.0 ± 0.3;
P <
0.05) and the switch-to-TPTD group (1.7 ± 0.6;
P
< 0.05). The logistic regression analysis showed that mTSS changes were significantly associated with the percent changes of TRACP-5b at 6 months (
β
= 0.30, 95% CI = 0.002–0.016;
P <
0.01).
Conclusions
Changes of systemic bone turnover induced by switching BPs to DMAb or TPTD may affect not only systemic bone mass, but also local joint destruction, and its clinical relevance should be considered comprehensively.
Summary
In patients with postmenopausal osteoporosis, prior osteoporosis treatment affected the bone mineral density increase of following treatment with 12 months of romosozumab, although it did not ...affect that of following treatment with 12 months of denosumab after romosozumab.
Purpose
To investigate the effects of prior osteoporosis treatment on the response to treatment with romosozumab (ROMO) followed by denosumab (DMAb) in patients with postmenopausal osteoporosis.
Methods
In this prospective, observational, multicenter study, treatment-naïve patients (Naïve;
n
= 55) or patients previously treated with bisphosphonates (BP;
n
= 37), DMAb (DMAb;
n
= 45) or teriparatide (TPTD;
n
= 17) (mean age, 74.6 years; T-scores of the lumbar spine LS − 3.2 and total hip TH − 2.6) were switched to ROMO for 12 months, followed by DMAb for 12 months. Bone mineral density (BMD) and serum bone turnover markers were evaluated for 24 months.
Results
A BMD increase was observed at 12 and 24 months in the following patients: Naïve (18.2% and 22.0%), BP (10.2% and 12.1%), DMAb (6.6% and 9.7%), and TPTD (10.8% and 15.0%) (
P
< 0.001 between the groups at both 12 and 24 months) in LS and Naïve (5.5% and 8.3%), BP (2.9% and 4.1%), DMAb (0.6% and 2.2%), and TPTD (4.3% and 5.4%) (
P
< 0.01 between the groups at 12 months and
P
< 0.001 at 24 months) in TH, respectively. The BMD increase in LS from 12 to 24 months was negatively associated with the levels of bone resorption marker at 24 months. Incidences of major fragility fractures for the respective groups were as follows: Naïve (5.5%), BP (16.2%), DMAb (11.1%), and TPTD (5.9%).
Conclusions
Previous treatment affected the BMD increase of following treatment with ROMO, although it did not affect that of following treatment with DMAb after ROMO.
Summary
Patients with rheumatoid arthritis showed greater response to 18-month administration of daily teriparatide especially in the increase of bone formation markers at 1 month and femoral neck ...bone mineral density at 18 months compared to postmenopausal osteoporosis patients.
Introduction
The aim of this study was to evaluate the effects of 18-month administration of daily teriparatide (TPTD) in osteoporosis patients with rheumatoid arthritis (RA) by comparing that of postmenopausal osteoporosis patients (Porosis).
Methods
The effects of TPTD were examined between RA (
n
= 70; age 68.4 years; disease activity score assessing 28 joints with CRP DAS28-CRP 2.8; rheumatoid factor RF positivity 75.5 %) with 77.1 % of prior bisphosphonate (BP), 84.3 % of oral prednisolone (PSL) (4.4 mg/day at baseline), 25.7 % of biologics, and Porosis (
n
= 62; age 71.3 years) with 77.4 % of prior BP.
Results
Femoral neck (FN) bone mineral density (BMD) increase at 18 months was significantly greater in RA compared to Porosis (4.7 vs. 0.7 %,
P
= 0.038), whereas it was 9.7 versus 7.9 % (
P
= 0.736) in the lumbar spine (LS). The increase of bone formation markers (bone alkaline phosphatase bone ALP and N-terminal type I procollagen propeptide PINP) at 1 month were all significantly greater in RA compared to Porosis. A multivariate logistic regression analysis revealed that the significant indicator of 18-month BMD increase in RA was a 3-month increase of under-carboxylated osteocalcin (ucOC) for LS (
β
= 0.446,
P
= 0.005) and baseline ucOC for FN (
β
= 0.554,
P
= 0.001), in which both showed significant negative correlation with baseline PSL dose.
Conclusions
RA showed greater response to daily TPTD administration, especially in the increase of bone formation markers at 1 month and FN BMD increase at 18 months compared to Porosis.
Summary
To elucidate mutation spectrum and genotype-phenotype correlations in Japanese patients with OI, we conducted comprehensive genetic analyses using NGS, as this had not been analyzed ...comprehensively in this patient population. Most mutations were located on
COL1A1
and
COL1A2
. Glycine substitutions in
COL1A1
resulted in the severe phenotype.
Introduction
Most cases of osteogenesis imperfecta (OI) are caused by mutations in
COL1A1
or
COL1A2
, which encode α chains of type I collagen. However, mutations in at least 16 other genes also cause OI. The mutation spectrum in Japanese patients with OI has not been comprehensively analyzed, as it is difficult to identify using classical Sanger sequencing. In this study, we aimed to reveal the mutation spectrum and genotype-phenotype correlations in Japanese patients with OI using next-generation sequencing (NGS).
Methods
We designed a capture panel for sequencing 15 candidate OI genes and 19 candidate genes that are associated with bone fragility or Wnt signaling. Using NGS, we examined 53 Japanese patients with OI from unrelated families.
Results
Pathogenic mutations were detected in 43 out of 53 individuals. All mutations were heterozygous. Among the 43 individuals, 40 variants were identified including 15 novel mutations. We found these mutations in
COL1A1
(
n
= 30, 69.8%),
COL1A2
(
n
= 12, 27.9%), and
IFITM5
(
n
= 1, 2.3%). Patients with glycine substitution on
COL1A1
had a higher frequency of fractures and were more severely short-statured. Although no significant genotype-phenotype correlation was observed for bone mineral density, the trabecular bone score was significantly lower in patients with glycine substitutions.
Conclusion
We identified pathogenic mutations in 81% of our Japanese patients with OI. Most mutations were located on
COL1A1
and
COL1A2
. This study revealed that glycine substitutions on
COL1A1
resulted in the severe phenotype among Japanese patients with OI.
Summary
Oxygen ultra-fine bubbles (OUB) saline injection prevents bone loss of glucocorti\coid-induced osteoporosis in mice, and OUB inhibit osteoclastogenesis via RANK-TRAF6-c-Fos-NFATc1 signaling ...and RANK-p38 MAPK signaling in vitro.
Introduction
Ultra-fine bubbles (<200 nm in diameter) have several unique properties, and they are tested in various medical fields. The purpose of this study was to investigate the effects of oxygen ultra-fine bubbles (OUB) on glucocorticoid-induced osteoporosis (GIO) model mice.
Methods
Prednisolone (PSL, 5 mg) was subcutaneously inserted in 6-month-old male C57BL/6J mice, and 200 μl of saline, OUB-diluted saline, or nitrogen ultra-fine bubbles (NUB)-diluted saline was intraperitoneally injected three times per week for 8 weeks the day after operations. Mice were divided into four groups; (1) control, sham-operation + saline; (2) GIO, PSL + saline; (3) GIO + OUB, PSL + OUB saline; (4) GIO + NUB, PSL + NUB saline. The effects of OUB on osteoblasts and osteoclasts were examined by serially diluted OUB medium in vitro.
Results
Bone mass was significantly decreased in GIO bone volume/total volume (%): control vs. GIO 12.6 vs. 7.9;
p
< 0.01 while significantly preserved in GIO + OUB (GIO vs. GIO + OUB 7.9 vs. 12.9;
p
< 0.05). In addition, tartrate-resistant acid phosphatase (TRAP)-positive cells in the distal femur mean osteoclasts number/bone surface (mm
−1
) was significantly increased in GIO (control vs. GIO 6.8 vs. 11.6;
p
< 0.01) while suppressed in GIO + OUB (GIO vs. GIO + OUB 11.6 vs. 7.5;
p
< 0.01). NUB did not affect these parameters. In vitro experiments revealed that OUB significantly inhibited osteoclastogenesis by inhibiting RANK-TRAF6-c-Fos-NFATc1 signaling, RANK-p38 MAPK signaling, and TRAP/Cathepsin K/DC-STAMP mRNA expression in a concentration-dependent manner. OUB did not affect osteoblastogenesis in vitro.
Conclusions
OUB prevent bone loss in GIO mice by inhibiting osteoclastogenesis.
Currently, biological disease-modifying anti-rheumatic drugs (bDMARDs) with different modes of action tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL-6Ri), or cytotoxic ...T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig) are used in clinical practice to treat rheumatoid arthritis (RA). However, it is unclear which type of bDMARD is the most efficacious for a specific clinical situation. C-reactive protein (CRP) is an acute-phase reactant driven by IL-6 signalling. Here, we aimed to establish whether therapeutic efficacy differs between IL-6Ri and other bDMARDs with alternative modes of action in RA patients according to their CRP level.
RA patients treated with bDMARDs were enrolled from an observational multicentre registry in Japan. Patients were classified into three groups according to baseline CRP tertiles. The overall 3 year retention rates of each bDMARD category were assessed. The Clinical Disease Activity Index (CDAI) was also assessed before and 3, 6, and 12 months after bDMARD initiation.
A total of 1438 RA patients were included and classified into three groups according to tertiles of baseline CRP levels (CRP
1
, 0-0.3; CRP
2
, 0.3-1.8; CRP
3
, 1.8-18.4 mg/dL). In CRP
3
, the overall 3 year drug retention rates were significantly higher for IL-6Ri than for TNFi and CTLA4-Ig (77.5 vs 48.2 vs 67.3, respectively). No significant difference was evident in terms of CDAI 12 months after bDMARD initiation in CRP
1
-CRP
3
.
IL-6Ri may be a favourable therapeutic option over TNFi and CTLA4-Ig in RA patients with high CRP levels.
Summary
Switching weekly ALN or RIS to monthly MIN in patients with RA, of whom two-thirds were treated with low-dose PSL, significantly decreased bone turnover markers and increased BMD at ...12 months, suggesting that monthly MIN may be an effective alternative treatment option of oral bisphosphonate treatment.
Introduction
The aim of this prospective, observational study was to evaluate the effects of switching weekly alendronate (ALN 35 mg) or risedronate (RIS 17.5 mg) to monthly minodronate (MIN 50 mg) in patients with rheumatoid arthritis (RA).
Methods
Patient characteristics were as follows:
n
= 172; 155 postmenopausal women, age 65.5 (44–87) years; T-score of lumbar spine (LS), −1.4; total hip (TH), −1.8; femoral neck (FN), −2.1; dose and rate of oral prednisolone (2.3 mg/day), 69.1 %; prior duration of ALN or RIS, 46.6 months; were allocated, based on their preference, to either the (1) continue group (
n
= 88), (2) switch-from-ALN group (
n
= 44), or (3) switch-from-RIS group (
n
= 40).
Results
After 12 months, increase in BMD was significantly greater in group 3 compared to group 1: LS (4.1 vs 1.2 %;
P
< 0.001), TH (1.9 vs −0.7 %;
P <
0.01), and FN (2.7 vs −0.5 %;
P <
0.05); and in group 2 compared to group 1: LS (3.2 vs 1.2 %;
P <
0.05) and TH (1.5 vs −0.7 %;
P <
0.01). The decrease in bone turnover markers was significantly greater in group 3 compared to group 1: TRACP-5b (−37.3 vs 2.5 %;
P <
0.001), PINP (−24.7 vs −6.2 %;
P <
0.05), and ucOC (−39.2 vs 13.0 %;
P <
0.05); and in group 2 compared to group 1: TRACP-5b (−12.5 vs 2.5 %;
P <
0.05) at 12 months.
Conclusions
Switching weekly ALN or RIS to monthly MIN in patients with RA may be an effective alternative treatment option of oral bisphosphonate treatment.
In end-stage arthritis indicated for total ankle arthroplasty (TAA), full-thickness cartilage damage, subchondral bone defect/shaving, and fluttering of the talar dome occur, shortening the distance ...between the tibial and talar insertions of ligaments and leading to laxity of ligaments surrounding the ankle joint. Under such conditions, medial ligaments (including the deltoid ligament) would not be expected to function properly. To stabilize the ankle joint during the stance phase, medial ligament function under tension is important. This study therefore examined whether TAA contributes to lengthening of the medial tibio-talar joint as evaluated radiographically, as a preferable method for achieving tensile effects on medial ligaments.
Twenty-four feet with end-stage varus deformity of the ankle joint that underwent TAA were retrospectively investigated, excluding cases with any malleolar osteotomy or fracture. Distance between proximal and distal insertions of medial ligaments, lateralization of the talus, and talar tilt angle under valgus/varus stress condition were evaluated pre- and postoperatively.
Distance between proximal and distal insertions of medial ligaments was significantly elongated after TAA. At the same time, the talus showed significant lateralization. Furthermore, talar tilt under valgus/varus stress conditions was also significantly reduced after TAA.
TAA affects distal translation and lateralization of the talus in cases of varus ankle deformity. These effects might contribute to re-providing tensile force on lax medial ligaments, improving ligament function.
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