Association between meaningful activities at home and subjective well-being in older adults with long-term care needs: A cross-sectional study.

For this study, we examined whether engaging in meaningful activities at home is associated with subjective well-being (SWB) in older adults with long-term care needs according to their preference for going out. We distributed a self-administered questionnaire to long-term care facilities in Japan and performed a linear mixed-effects model regression analysis of the responses. The dependent variable was SWB, and the independent variables were the number of meaningful home activities, preference for going out, and the interaction between them. In our survey (n = 217), we found that both number of meaningful home activities (B = 0.43; 95%CI: 0.17, 0.70) and its interaction with preference (B = -0.43; 95%CI: -0.79, -0.08) were associated with SWB. These results suggest the importance of engaging in meaningful activities at home for older adults who do not prefer going out. We should encourage older adults to participate in activities that match their preference.

Rheumatoid factor value for determining the first biologic agent to use for non-systemic juvenile idiopathic arthritis.

OBJECTIVES: Currently, no indicators on which biologic disease-modifying anti-rheumatic drugs (bDMARDs) should be used first for juvenile idiopathic arthritis (JIA) have been established. Thus, this study aimed to determine the useful biomarkers in JIA to enable the best selection of the first bDMARDs without primary failure. METHODS: This retrospective study used data of patients examined for JIA between 2015 and 2021 at Kagoshima University Hospital in Japan. RESULTS: Altogether, 67 cases of non-systemic JIA were analyzed, excluding cases that had been treated for <6 months. Of the 67 cases, 52 were treated with bDMARDs and all rheumatoid factor (RF)+ types (32 cases) were treated with bDMARDs. Eleven cases (31.4&) (all were RF+ types and used anti-tumor necrosis factor (TNF)α agents) switched to other bDMARDs because of primary failure, and nine cases had secondary failure (6;anti-TNF, 3;anti-Interleukin-6). A significant difference in pre-treatment RF values (177.9 vs 25.7 IU/ml, p = 0.002) and presence (Odds Ratio 1.952,p = 0.004) were observed between the primary failure group and effective group. CONCLUSIONS: RF+ JIA required bDMARDs with high probability. JIA with high titre of RF tends to be refractory to anti-TNFα agents. Tocilizumab or abatacept could be a first-choice bDMARD in such cases.

Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear. OBJECTIVES: This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. METHODS: Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases. RESULTS: Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients' monocytes and B cells after IFN-γ stimulation. CONCLUSIONS: Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.

Clinical practice guidance for childhood-onset systemic lupus erythematosus-secondary publication.

Childhood-onset systemic lupus erythematosus (cSLE) has been recognised as a more acute and severe autoimmune disease than adult-onset SLE. With the development of medications for the disease and supportive therapy, the mortality rate associated with cSLE has drastically improved; the 10-year survival rate among patients with cSLE between 1995 and 2006 in Japan was 98.3%. However, the 10-year survival rate without any permanent functional impairment remained low at 66.1%. Therefore, the current treatment goal for cSLE is to ensure that they can perform normal daily activities throughout their lives by preventing the occurrence and/or progression of organ damage. For this purpose, appropriate treatments and evaluations are required according to the severity and risk of organ damage; however, there are no established guidelines for cSLE. Therefore, the Pediatric Rheumatology Association of Japan and the Pediatric Rheumatology Subcommittee in the Japan College of Rheumatology developed a comprehensive guidance for clinical practice based on cSLE-related data collected from Japanese national surveys and relevant articles from both domestic and international sources. However, due to the lack of indications for defined and objective evidence quality levels, this guidance should be used on the basis of the judgement of the attending physicians for individual patients.

Clinical practice guidance for juvenile idiopathic arthritis (JIA) 2018.

Juvenile idiopathic arthritis (JIA) is the most common disease in pediatric rheumatism. There is no specific symptom or examination finding for JIA, and the diagnosis is made by exclusion and differentiation. Because non-pediatric rheumatologists are sometimes involved in medical care, 'proposal for JIA guidance on diagnosis and treatment for primary care pediatricians and non-pediatric rheumatologists' was first published in 2007. In these 10 years, a number of new findings on pathophysiology and treatment of JIA have been published; therefore, we propose this guidance of 2018th edition aiming at updating and standardization of JIA medical care in Japan. This edition included the management of uveitis, macrophage activation syndrome, infectious diseases before and during treatment. Moreover, details of biologics are also described. Although this guidance is tailored to adaptation of examinations and drugs, we do not purpose to limit the physicians' discretion in clinical practice. This guidance should be viewed as recommendations and be individualized according to the condition of the patient. We hope that medical care for JIA will advance and more patients will get benefit based on this guidance. Then, further revisions are needed due to changes in future conditions.

Early prediction for over two years efficacy of the first biologic agent for polyarticular juvenile idiopathic arthritis: A multi-institutional study in Japan.

OBJECTIVE: To estimate target of treatment for long-term efficacy of the first biologic agent used to treat polyarticular juvenile idiopathic arthritis (pJIA). METHODS: A retrospective cohort of patients with pJIA treated at six medical institutions in Japan between 1 March 2005 and 31 October 2014 was identified. The patients were divided by 2-year treatment periods with the first biologic agent into continuous treatment group and switching group. Three markers were examined: matrix metalloproteinase-3 (MMP-3), erythrocyte sedimentation rate (ESR), and disease activity score (DAS) 28-ESR. RESULTS: Thirty-two pJIA patients (8 boys, 24 girls) from 43 recruited patients were included in this study. The treatment periods with the first biologic agent in continuous treatment group (24 patients, 75%) was 40 months (median, range 24-119) and switching group (8 patients; 25%) was 9.5 months (median, 6-18). Markers [odds ratio (95% confidence interval)] at 3 months were MMP-3 [1.02 (0.99-1.05), p = .219], ESR [1.00 (0.78-1.30), p = .998], and DAS28-ESR [13.9 (2.08-409.82), p = .035]. The cut-off point for DAS28-ESR at 3 months to distinguish the two groups was 2.49 (sensitivity, 87.5%; specificity, 87.5%). CONCLUSION: DAS28-ESR of 2.49 at 3 months after initiating the first biologic agent can be a target of sustained treatment in pJIA patients.

Prediction of long-term remission of oligo/polyarticular juvenile idiopathic arthritis with S100A12 and vascular endothelial growth factor.

OBJECTIVES: This study aimed to evaluate the usefulness of S100A12 and vascular endothelial growth factor (VEGF) for predicting the stability of remission for discontinuing methotrexate (MTX) and/or biological agents in Japanese patients with oligo/polyarticular juvenile idiopathic arthritis (JIA). METHODS: Forty-four patients with oligo/polyarticular JIA who received MTX with or without biological agents were enrolled. Serum concentration of both S100A12 and VEGF were simultaneously evaluated by ELISA in active and in remission phase determined by activity markers including DAS-28. RESULTS: S100A12 and VEGF were correlated with DAS-28. Of the 22 patients with oligo/polyarticular JIA in clinical remission, 13 patients with low S100A12 and VEGF concentrations could discontinue treatment without relapse over 2 years. However, nine patients without low S100A12 and VEGF concentrations relapsed afterwards, even though they had been in clinical remission. The cut-off levels of S100A12 and VEGF for division into two groups of the maintenance remission and relapse groups were 177 ng/ml and 158 pg/ml, respectively. CONCLUSIONS: S100A12 and VEGF are useful markers for assessing disease activity of oligo/polyarticular JIA in remission phase. These markers should be kept low when clinicians consider tapering or discontinuing treatments in oligo/polyarticular JIA patients.

The safety and effectiveness of HBV vaccination in patients with juvenile idiopathic arthritis controlled by treatment.

OBJECTIVES: To evaluate the safety and effectiveness of hepatitis B virus (HBV) vaccination in patients with juvenile idiopathic arthritis (JIA) controlled by treatment. METHODS: Among 49 patients with juvenile idiopathic arthritis (JIA) at the outpatient clinic of Kagoshima University Hospital, we enrolled 25 who were controlled by treatment. All children were unimmunized and were vaccinated against HBV according to the schedule. Their responses to the vaccine and vaccine adverse events were examined during their visits. RESULTS: Nineteen of the 25 patients with JIA controlled by treatment developed effective antibody responses (76%). All eight patients with JIA below 10 years of age achieved seroconversion. The seroconversion was not influenced by biologics. Five adverse events were observed (6.7%). The rate of all adverse events did not surpass that of a previous report, and all adverse events were immediately resolved. None of the patients with JIA experienced a flare-up or clinical deterioration related to the vaccination. CONCLUSIONS: HBV vaccination is safe and effective. Pediatric rheumatologists should consider HBV vaccination for unimmunized patients with JIA, because the response to HBV vaccine might be influenced by age, and children have a higher risk for potential HBV infection than adults.

Disease activity score in 28 joints at 3 months after the initiation of biologic agent can be a predictive target for switching to the second biologic agent in patients with polyarticular juvenile idiopathic arthritis.

OBJECTIVE: To clarify polyarticular juvenile idiopathic arthritis (pJIA) patients who failed to maintain prolonged remission with the first biologic agent. METHODS: Fourteen pJIA patients were observed for 47.5 months (median) after initiating the first biologic agent. RESULTS: Eight maintained sustained clinical remission (median 47 months) with the first biologic agents, while the six switched to the second one due to lack of efficacy, thereafter. Receiver operating characteristic (ROC) analysis revealed that disease activity score in 28 joints (DAS28) of 2.37 at 3 months could distinguish between the two patient groups (p = 0.001). CONCLUSION: pJIA patients with DAS28 >2.37 at 3 months of the initial biologic therapy may be considered to switch to the second biologics.

Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

To assess the role of IL-6/IL-18 in the pathogenesis of systemic juvenile idiopathic arthritis (s-JIA) and to investigate the clinical significance of serum IL-18 levels for predicting macrophage activation syndrome (MAS) development, we measured the serum IL-6/IL-18 levels in 76s-JIA patients, including 15 with MAS, and compared them with the clinical features. We identified 2 distinct subsets on the basis of serum IL-6/IL-18 levels. The IL-18-dominant subset had more patients who developed MAS. Serum IL-18 levels during active phase in patients with MAS were significantly higher than those without MAS. The cutoff value of serum IL-18 levels for predicting MAS development was 47750 pg/ml. The patients with IL-18 dominant subset at their disease onset were significantly more likely to develop MAS after TCZ therapy started. IL-18 might have a key role in the pathogenesis of MAS. Serum IL-18 levels >47750 pg/ml might be useful to predict MAS development.

Treatment for macrophage activation syndrome associated with systemic juvenile idiopathic arthritis in Japan.

OBJECTIVES: To clarify how pediatric rheumatologists treat systemic juvenile idiopathic arthritis (s-JIA) associated macrophage activation syndrome (MAS) in the real world and to assess the efficacy and safety of dexamethasone palmitate (DEX-P) in the treatment of s-JIA-associated MAS. METHODS: This multicenter, retrospective study was conducted at 13 pediatric rheumatology institutes in Japan. This study included 28 patients with s-JIA-associated MAS. Clinical findings, such as treatment details and adverse events, were evaluated. RESULTS: Methylprednisolone (mPSL) pulse therapy was selected as the first-line treatment in more than half of the patients with MAS. Cyclosporine A (CsA) was used as first-line therapy in combination with corticosteroids in half of the patients with MAS. DEX-P and/or CsA were selected as the second-line therapy in 63% of patients with corticosteroid-resistant MAS. Plasma exchange was selected as the third-line therapy for DEX-P and CsA-resistant MAS. All patients improved and there were no characteristically severe adverse events associated with DEX-P. CONCLUSIONS: The first-line treatment for MAS in Japan is mPSL pulse therapy and/or CyA. DEX-P could be an effective and safe therapeutic option for patients with corticosteroid-resistant MAS.

A case of cryopyrin-associated periodic fever syndrome during canakinumab administration complicated by inflammatory bowel disease.

Cryopyrin-associated periodic fever syndrome (CAPS) is a highly debilitating disorder, which is characterized by unregulated interleukin-1ß production driven by autosomal dominantly inherited mutations in the NLRP3 gene. Patients with CAPS often present with early-onset episodes of fever and rash. These patients also present with variable systemic signs and symptoms, such as arthritis, sensorineural hearing loss, chronic aseptic meningitis, and skeletal abnormalities, but minimal gastrointestinal symptoms. Recently, effective therapies for CAPS targeted against interleukin-1 have become available. We report a case of a young Japanese woman with CAPS who developed inflammatory bowel disease during canakinumab therapy. The patient had colostomy after intestinal perforation and changed canakinumab to infliximab. To the best of our knowledge, this is the first report of a case of inflammatory bowel disease secondary to CAPS complicated by gastrointestinal symptoms and arthritis which canakinumab could not control. Patients with CAPS who have symptoms that cannot be controlled by canakinumab should be considered for possible co-morbidities.

Pediatric Dual-Energy X-Ray Absorptiometry in Japan: A Proposal for Shared Access to Equipment.

BACKGROUND: Regular assessment of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is essential for detecting glucocorticoid-induced osteoporosis in juvenile-onset autoimmune diseases. Z-score is used to standardize osteoporosis assessment in children and is evaluated with only one of three devices in Japan. The purpose of this study was to determine how many Japanese medical facilities for pediatric rheumatic diseases were unable to use Z-scores to evaluate osteoporosis. METHODS: Electronic questionnaires were distributed between 2017 and 2019 to hospitals belonging to the Pediatric Rheumatology Association of Japan and to university hospitals and public children's hospitals that provide medical care for pediatric rheumatic diseases. The questionnaire inquired about the location of DXA measurement, manufacturer (Hologic, GE healthcare, Hitachi), and measurement site, and the answers were collected using Google Forms. Statcel 4 was used for analysis. RESULTS: Overall, 120 facilities responded to the survey, of which 117 had DXA. In the remaining three facilities, DXA was not installed in two and was out of order in one. Bone loss in childhood was evaluated using a Z-score calculated from age-based reference values; however, 30% of hospitals without HOLOGIC DXA could not evaluate osteoporosis by Z-score in Japanese childhood. The characteristics of the hospitals enrolled in this study did not bias the selection of Hologic DXA. CONCLUSIONS: Neighboring institutions should consider sharing access to Hologic DXA equipment, to ensure use of uniform reference values. GE BMD reference values should be established for Japanese children.

Tocilizumab modifies clinical and laboratory features of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

BACKGROUND: This study aimed to determine the influence of tocilizumab (TCZ) in modifying the clinical and laboratory features of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Furthermore, we assessed the performance of the 2016 MAS classification criteria for patients with s-JIA-associated MAS while treated with TCZ. METHODS: A panel of 15 pediatric rheumatologists conducted a combination of expert consensus and analysis of real patient data. Clinical and laboratory features of s-JIA-associated MAS in 12 TCZ-treated patients and 18 untreated patients were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented full-blown MAS. RESULTS: Clinically, the TCZ-treated patients with s-JIA-associated MAS were less likely febrile and had significantly lower ferritin, triglyceride, and CRP levels than the untreated patients with s-JIA-associated MAS. Other laboratory features of MAS including lower platelet counts and lower fibrinogen were more pronounced in TCZ-treated patients. The TCZ-treated patients with s-JIA-associated MAS were less likely to be classified as MAS based on the MAS classification criteria (25% vs 83.3%, p < 0.01). This is ascribed to the absence of fever or insufficient ferritin elevation, compared with the untreated patients. CONCLUSION: TCZ could modify the clinical and laboratory features of s-JIA-associated MAS. When evaluating the s-JIA patients while treated with TCZ, it is not applicable to use MAS classification criteria. Care must be taken to not underdiagnose MAS based on the MAS classification criteria.

S100A12 and vascular endothelial growth factor can differentiate Blau syndrome and familial Mediterranean fever from systemic juvenile idiopathic arthritis.

OBJECTIVES: Systemic juvenile idiopathic arthritis (sJIA) has recently become regarded as one of the autoinflammatory syndromes (AIS). However, other AIS, such as familial Mediterranean fever (FMF) and Blau syndrome, have been initially misdiagnosed as sJIA because of the clinical similarities. Making the correct diagnosis in the early stage of these AIS is desirable. Therefore, we evaluated serum S100A12 and vascular endothelial growth factor (VEGF) levels to determine if they could be biomarkers for differentiating these AIS. METHOD: Serum S100A12 and VEGF levels were examined in patients with Blau syndrome (n = 4), FMF (n = 4), and sJIA (n = 11) in the active and inactive phases. RESULTS: In the active phase, S100A12 levels were significantly higher in patients with sJIA and FMF compared with those with Blau syndrome (p < 0.001). VEGF levels of patients with sJIA were significantly higher than those of patients with others (p = 0.001). In the inactive phase, there was no significant difference in VEGF levels. However, colchicine-resistant patients or patients without treatment with FMF showed high levels of S100A12 compared with others. CONCLUSIONS: Measuring both serum S100A12 and VEGF levels may be useful for differentiating patients with Blau syndrome and FMF from those with sJIA at the early stage.

Clinical features and characteristics of uveitis associated with juvenile idiopathic arthritis in Japan: first report of the pediatric rheumatology association of Japan (PRAJ).

BACKGROUND: Although there are many reports on Juvenile Idiopathic arthritis-associated uveitis (JIA-U) from various countries, especially from Europe and North America, there are few reports from Asia. Our aim was to investigate the epidemiology, characteristics and predictors of JIA-U in Japan. METHODS: Data were retrospectively collected on 726 patients with JIA from medical records as of April 2016 at 15 medical centers specialized in pediatric rheumatic diseases. Of these, patients with uveitis were further investigated for the specific characteristics of this manifestation. RESULTS: The prevalence of uveitis was 6.1% in the 726 JIA patients examined. Incidence of uveitis was significantly higher in patients with an earlier arthritis onset (2.6-vs.-5.8 years, P < 0.0001), oligoarthritis (16.1%-vs.-1.6%, P < 0.001), or anti-nuclear antibodies. On the contrary, it was significantly less common in patients with rheumatoid factor or anti-cyclic citrullinated peptide antibodies. A history of using methotrexate (MTX), infliximab or adalimumab was also associated with uveitis occurrence. The median age at uveitis diagnosis was 5 years, and the median time from arthritis onset to uveitis diagnosis was 2 years. The occurrence of anterior and bilateral uveitis was 79.3 and 53.7%, respectively. There were no symptoms at uveitis diagnosis in 58.5% of cases. Complications arising between the time of uveitis diagnosis and the last observation increased from 31.7 to 56.1%; in particular, cataract was increased 3-fold. While no patients lost their vision, 61.9% did not recover normal vision (≥ 1.0), and in many cases active uveitis persisted, especially in males. In addition to steroid eye drops (97.6%) and MTX (15.4%), biological agents were used for treating the uveitis in 41.5% of patients. CONCLUSIONS: The epidemiology, characteristics and predictors of JIA-U in Japan are described here for the first time. Although the prevalence of JIA-U in Japan is lower than in predominantly Caucasian cohorts, as reported from North America and Europe, the epidemiology, characteristics and predictors were found to be similar.

Validation of Classification Criteria of Macrophage Activation Syndrome in Japanese Patients With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world. METHODS: A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. A total of 65 profiles comprised 18 patients with systemic JIA-associated MAS and 47 patients with active systemic JIA without evidence of MAS. From these profiles, 10 patient data points for full-blown MAS, 11 patient data points for MAS onset, and 47 patient data points for acute systemic JIA without MAS were evaluated. RESULTS: Evaluation of the classification criteria to discriminate full-blown MAS from acute systemic JIA without MAS showed a sensitivity of 1.000 and specificity of 1.000 at the time of full-blown MAS. Sensitivity was 0.636 and specificity was 1.000 at the time of MAS onset. The number of measurement items that fulfilled the criteria increased in full-blown MAS compared to that at MAS onset. At MAS onset, the positive rates of patients who met the criteria for platelet counts and triglycerides were low, whereas those for aspartate aminotransferase were relatively high. At full-blown MAS, the number of patients who met the criteria for each measurement item increased. CONCLUSION: The classification criteria for MAS complicating systemic JIA had a very high diagnostic performance. However, the diagnostic sensitivity for MAS onset was relatively low. For the early diagnosis of MAS in systemic JIA, the dynamics of laboratory values during the course of MAS should be further investigated.

Treatable renal disease in children with silent lupus nephritis detected by baseline biopsy: association with serum C3 levels.

Lupus nephritis is identified in up to 75% of patients with juvenile systemic lupus erythematosus and may present with abnormal urinary findings (overt lupus nephritis) or be apparent only upon renal biopsy (silent lupus nephritis). We investigated whether serum complement levels correlate with renal pathology in pediatric patients with silent lupus nephritis. We performed baseline renal biopsy in 45 children diagnosed with juvenile systemic lupus erythematosus who were admitted to Kagoshima University Hospital between January 2000 and June 2015. Patients were classified as having overt or silent lupus nephritis based on urinary findings at renal biopsy. Silent lupus nephritis was identified in 55.5% (25/45) of cases. Of these, 6 (13.3%) were classified as class III nephritis, according to the International Society of Nephrology/Renal Pathology Society criteria. Decreased serum C3 levels were associated with the renal pathology classification for patients with silent but not with overt lupus nephritis. No differences in serum C4 levels were identified between cases of silent and overt lupus nephritis. Baseline renal biopsy is a critical component of the work-up of juvenile systemic lupus erythematosus as treatable renal pathology may be present in the absence of urinary signs. Serum C3 may be an important marker of the progression of silent lupus nephritis.

Effectiveness of vitamin K2 on osteoporosis in adults with cerebral palsy.

BACKGROUND: Osteoporosis can lead to spontaneous fractures in adults with cerebral palsy (CP). Undercarboxylated osteocalcin (ucOC) is a useful marker for vitamin K insufficiency in osteoporosis. The primary objective of this study was to determine the effect of vitamin K2 on bone mineral density (BMD) in adults with CP and vitamin K insufficiency. METHODS: Sixteen adults, median age of 56years, with CP and osteoporosis in whom the serum ucOC concentration exceeded 4.5ng/mL were included. All patients received 45mg of vitamin K2 per day. BMD was measured and presented as a percentage of the young adult mean (%YAM). Serum levels of ucOC and BMD were measured at baseline and after 6 and 12months. RESULTS: Serum levels of ucOC decreased from 7.8ng/mL (range, 4.9-32) at baseline to 3.9ng/mL (range, 1.9-6.8) after 6months (P=0.001). BMD increased from 59%YAM (range, 45-67) at baseline to 68%YAM (range, 50-79) after 12months (P=0.003). CONCLUSIONS: Vitamin K2 had a positive effect on BMD in osteoporotic adults with CP and high serum concentrations of ucOC, and might be useful as a first line treatment for osteoporotic adults with CP and vitamin K insufficiency.