scholarly journals Cortical bone mass is low in boys with Klinefelter Syndrome and improves with oxandrolone

2021 ◽  
Author(s):  
Maria G Vogiatzi ◽  
Shanlee M Davis ◽  
Judith L Ross
Keyword(s):  
Bone Mass ◽  
Bone Health ◽  
Klinefelter Syndrome ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Androgen Treatment ◽  
Increased Risk ◽  
Adolescents And Adults ◽  
Age Appropriate ◽  
Cortical Bone Mass

Abstract Introduction Klinefelter syndrome (KS) is the most common sex aneuploidy in men. Affected males have hypogonadism, and as a result, face an increased risk for osteoporosis and fractures. Androgen therapy is standard in adolescents and adults with KS but has not been used earlier in childhood. Objective To determine the effects of androgen treatment on bone mass in children with KS. Study design Randomized, double-blind, placebo-controlled clinical trial of oxandrolone (OX; 0.06 mg/kg daily; n= 38) versus placebo (PL; n= 40) for 2 years in boys with KS (ages 4- 12 years). Changes in bone mass were examined by digital x-ray radiogrammetry, which determines the Bone Health Index (BHI) and standard deviation scores (BHI SDS). Results BHI SDS was similar between groups at baseline (-0.46±1.1 vs. -0.34±1.0 OX vs. PL, p>0.05) and higher in the OX group at 2 years (-0.1 + 1.3 vs. -0.53 + 0.9, OX vs. PL, p< 0.01). At baseline, BHI SDS values of all subjects were not normally distributed with 25.7% of subjects plotted below -1 SDS (p<0.001), suggesting a deficit in bone mass. 13.5% of subjects had sustained a fracture and their BHI SDS was lower than those with no fractures (-1.6 + 1.3 vs. -0.3 + 1.0, p= 0.004). Conclusions Bone mass using BHI SDS is reduced in some children with KS and improves with OX. Since these individuals are at risk for osteoporosis, age-appropriate androgen replacement and future studies on bone health in children with KS should be further explored.

scholarly journals Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sarfaraz A. Hasni ◽  
Sarthak Gupta ◽  
Michael Davis ◽  
Elaine Poncio ◽  
Yenealem Temesgen-Oyelakin ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Controlled Clinical Trial ◽  
Type I ◽  
Systemic Lupus ◽  
Double Blind ◽  
Premature Cardiovascular Disease ◽  
Increased Risk

AbstractIncreased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity (p = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.

scholarly journals Osteocyte- and late Osteoblast-derived NOTUM Reduces Cortical Bone Mass in Mice

2021 ◽  
Author(s):  
Karin H. Nilsson ◽  
Petra Henning ◽  
Maha El Shahawy ◽  
Jianyao Wu ◽  
Antti Koskela ◽  
...  
Keyword(s):  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Vertebral Fractures ◽  
Volume Fraction ◽  
Substantial Reduction ◽  
Lumbar Vertebrae ◽  
Bone Homeostasis ◽  
Increased Risk ◽  
Cortical Bone Mass

Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on non-vertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1 expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur, but no change in trabecular bone volume fraction (BV/TV) in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared to control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce non-vertebral fracture risk.

scholarly journals Oxandrolone Treatment Results in an Increased Risk of Gonadarche in Prepubertal Boys With Klinefelter Syndrome

2018 ◽  
Vol 103 (9) ◽  
pp. 3449-3455 ◽  
Author(s):  
Shanlee M Davis ◽  
Najiba Lahlou ◽  
Matthew Cox-Martin ◽  
Karen Kowal ◽  
Philip S Zeitler ◽  
...  
Keyword(s):  
Klinefelter Syndrome ◽  
Controlled Trial ◽  
Tertiary Care ◽  
Treated Group ◽  
Pubic Hair ◽  
Serum Concentrations ◽  
Double Blind ◽  
Increased Risk ◽  
Cardiometabolic Disorders ◽  
Prepubertal Boys

Abstract Context Klinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown. Objective To compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl). Design Double-blind, randomized, controlled trial. Setting Single tertiary care referral center. Participants Eighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12). Interventions Ox 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years. Outcome Measures Onset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations. Results Ox-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups. Conclusions Two years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.

scholarly journals Effect of Diabetes Mellitus and Anti-Diabetic Drugs on Bone Health-A Review

2021 ◽  
Vol 8 (2) ◽  
pp. 131-148
Author(s):  
Farah Deeba ◽  
Sidra Younis ◽  
Nida Qureshi ◽  
Tahmina Mustafa ◽  
Nadia Iqbal ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Bone Mass ◽  
Bone Fracture ◽  
Bone Health ◽  
Diabetic Patients ◽  
Mineral Density ◽  
Type 2 Diabetic Patients ◽  
Increased Risk

Osteoporosis and diabetes mellitus (DM) are widespread diseases and have a significant health burden. Type-1 diabetes mellitus (T1DM) and Type-2 diabetes mellitus (T2DM) are associated with an increased bone fracture. In T1DM, the increased risk of bone fracture is associated with low bone mass. In patients with T2DM, the risk of fracture of the bone is increased due to low quality of bone, despite increased bone mineral density (BMD). In type 2 diabetic patients, bone fragility depends on the quality of bone instead of a reduction in bone mass. Thiazolidinediones (TZD) cause differentiation of adipocytes and inhibit differentiation of osteoblast and bone marrow stromal stem cells (BMSC). In this review, we have described the effect of anti-diabetic drugs and diabetes mellitus on bone health and our finding shows that sulfonylureas and metformin have no negative effect on bone health and protect bones against fractures.

scholarly journals Efficacy and safety of Naoxintong Capsule for treating Chronic Stable Angina: study protocol for a randomized controlled trial

2021 ◽  
Author(s):  
Gao Huanjia ◽  
Cai Hairong ◽  
Zhuang Jieqin ◽  
Dai Xingzhen ◽  
Fu Xue ◽  
...  
Keyword(s):  
Angina Pectoris ◽  
Stable Angina ◽  
Cardiovascular Events ◽  
Controlled Trial ◽  
Chronic Stable Angina ◽  
Secondary Outcome ◽  
Controlled Clinical Trial ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Increased Risk

Abstract Background Cardiovascular disease is the leading cause of mortality and morbidity worldwide, Chronic stable angina (CSA) is the main symptom of myocardial ischemia, causes increased risk of major cardiovascular events such as sudden cardiac death and myocardial infarction.Naoxintong (NXT)Capsule is a classical traditional Chinese medication used to treat CSA, however, few evidence to support the wide utility of NXT capsule for the treatment of CSA .We design this study to evaluating the efficacy and safety of NXT capsule versus placebo in patients with CSA. Methods/design This is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 260 eligible participants will be enrolled. The participants will be randomized assigned in an equal ratio to groups receiving either NXT or placebo for 12 weeks. After a 2-week run-in period, they will receive either NXT or placebo (3 pills, 3 times daily) for 12 weeks. The primary outcome is therapeutic efficacy. Secondary outcome measures include the quantitative score of TCM syndromes, severity grading of angina pectoris, the number of angina pectoris per week, nitroglycerin dosage, score of seattle angina scale, serum homocysteine, incidence of cardiovascular events. Safety outcomes and adverse events will be monitored throughout the trial. Discussion We designed this study in accordance with principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide clinical evidence of the efficacy and safety of NXT Capsule in the treatment of CSA. Trial registration: ChiCTR2000034871.

Increased Risk of Recurrent Venous Thromboembolism during Hormone Replacement Therapy

2000 ◽  
Vol 84 (12) ◽  
pp. 961-967 ◽  
Author(s):  
Erik Qvigstad ◽  
Harald Arnesen ◽  
Stig Larsen ◽  
Egil Wickstrøm ◽  
Per Sandset ◽  
...  
Keyword(s):  
Placebo Group ◽  
Hormone Replacement Therapy ◽  
Venous Thromboembolism ◽  
Replacement Therapy ◽  
Hormone Replacement ◽  
Epidemiological Studies ◽  
Sequential Design ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Increased Risk

SummaryRecent observational studies suggest a 2-4 fold increased risk of venous thromboembolism (VTE) in women taking hormone replacement therapy (HRT). The present study was started before publication of these studies, and the aim was to determine if HRT alters the risk of VTE in high risk women. The study was a randomized, double-blind, and placebo-controlled clinical trial with a doubletriangular sequential design. Females with previously verified VTE were randomized to 2 mg estradiol plus 1 mg norethisterone acetate, 1 tablet daily (n = 71) or placebo (n = 69). The primary outcome was recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE). Between 1996 and 1998 a total of 140 women were included. The study was terminated prematurely based on the results of circumstantial evidence emerging during the trial. Eight women in the HRT group and one woman in the placebo group developed VTE. The incidence of VTE was 10.7% in the HRT group and 2.3% in the placebo group. In the HRT group, all events happened within 261 days after inclusion. The sequential design did not stop the study, but strongly indicated a difference between the two groups. Our data strongly suggests that women who have previously suffered a VTE have an increased risk of recurrence on HRT. This treatment should therefore be avoided in this patient group if possible. The results also support those of recent epidemiological studies, which also indicate increased risk of VTE in non-selected female populations during HRT.

scholarly journals Effect of phylloquinone (vitamin K1) supplementation for 12 months on the indices of vitamin K status and bone health in adult patients with Crohn's disease

2014 ◽  
Vol 112 (7) ◽  
pp. 1163-1174 ◽  
Author(s):  
Eibhlís M. O'Connor ◽  
Geraldine Grealy ◽  
Jane McCarthy ◽  
Alan Desmond ◽  
Orla Craig ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Bone Mass ◽  
Bone Turnover ◽  
Vitamin K ◽  
Bone Health ◽  
Adult Patients ◽  
Undercarboxylated Osteocalcin ◽  
Double Blind

Although epidemiological findings support a role for vitamin K status in the improvement of bone indices in adult patients with Crohn's disease (CD), this needs to be confirmed in double-blind, randomised controlled trials (RCT) with phylloquinone (vitamin K1). By conducting two RCT, the present study aimed to first establish whether supplementation with 1000 μg of phylloquinone daily near-maximally suppresses the percentage of undercarboxylated osteocalcin in serum (%ucOC; marker of vitamin K status) in adult patients with CD currently in remission as it does in healthy adults and second determine the effect of supplementation with phylloquinone at this dose for 12 months on the indices of bone turnover and bone mass. The initial dose-ranging RCT was conducted in adult patients with CD (n 10 per group) using 0 (placebo), 1000 or 2000 μg of phylloquinone daily for 2 weeks. In the main RCT, the effect of placebo v. 1000 μg vitamin K/d (both co-administered with Ca (500 mg/d) and vitamin D3 (10 μg/d)) for 12 months (n 43 per group) on the biochemical indices of bone turnover (determined by enzyme immunoassay) and bone mass (determined by dual-energy X-ray absorptiometry) were investigated. At baseline, the mean %ucOC was 47 %, and this was suppressed upon supplementation with 1000 μg of phylloquinone daily ( − 81 %; P< 0·01) and not suppressed further by 2000 μg of phylloquinone daily. Compared with the placebo, supplementation with 1000 μg of phylloquinone daily for 12 months had no significant effect (P>0·1) on bone turnover markers or on the bone mass of the lumbar spine or femur, but modestly increased (P< 0·05) the bone mass of the total radius. Despite near maximal suppression of serum %ucOC, supplementation with 1000 μg of phylloquinone daily (with Ca and vitamin D3) had no effect on the indices of bone health in adult CD patients with likely vitamin K insufficiency.

scholarly journals Impact of hydroxyurea on clinical events in the BABY HUG trial

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4304-4310 ◽  
Author(s):  
Courtney D. Thornburg ◽  
Beatrice A. Files ◽  
Zhaoyu Luo ◽  
Scott T. Miller ◽  
Ram Kalpatthi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Acute Chest Syndrome ◽  
Controlled Clinical Trial ◽  
Phase 3 ◽  
Double Blind ◽  
Clinical Events ◽  
Serious Infection ◽  
Increased Risk

Abstract The Pediatric Hydroxyurea Phase 3 Clinical Trial (BABY HUG) was a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of hydroxyurea in infants (beginning at 9-18 months of age) with sickle cell anemia. An important secondary objective of this study was to compare clinical events between the hydroxyurea and placebo groups. One hundred and ninety-three subjects were randomized to hydroxyurea (20 mg/kg/d) or placebo; there were 374 patient-years of on-study observation. Hydroxyurea was associated with statistically significantly lower rates of initial and recurrent episodes of pain, dactylitis, acute chest syndrome, and hospitalization; even infants who were asymptomatic at enrollment had less dactylitis as well as fewer hospitalizations and transfusions if treated with hydroxyurea. Despite expected mild myelosuppression, hydroxyurea was not associated with an increased risk of bacteremia or serious infection. These data provide important safety and efficacy information for clinicians considering hydroxyurea therapy for very young children with sickle cell anemia. This clinical trial is registered with the National Institutes of Health (NCT00006400, www.clinicaltrials.gov).

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