Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension

Odanacatib (ODN), a selective oral inhibitor of cathepsin K, was an investigational agent previously in development for the treatment of osteoporosis. In this analysis, the effects of ODN on bone remodeling/modeling and structure were examined in the randomized, double-blind, placebo-controlled, event-driven, Phase 3, Long-term Odanacatib Fracture Trial (LOFT; NCT00529373) and planned double-blind extension in postmenopausal women with osteoporosis. A total of 386 transilial bone biopsies, obtained from consenting patients at baseline (ODN n = 17, placebo n = 23), month 24 (ODN n = 112, placebo n = 104), month 36 (ODN n = 42, placebo n = 41), and month 60 (ODN n = 27, placebo n = 20) were assessed by dynamic and static bone histomorphometry. Patient characteristics at baseline and BMD changes over 5 years for this subset were comparable to the overall LOFT population. Qualitative assessment of biopsies revealed no abnormalities. Consistent with the mechanism of ODN, osteoclast number was higher with ODN versus placebo over time. Regarding bone remodeling, dynamic bone formation indices in trabecular, intracortical, and endocortical surfaces were generally similar in ODN-treated versus placebo-treated patients after 2 years of treatment. Regarding periosteal modeling, the proportion of patients with periosteal double labels and the bone formation indices increased over time in the ODN-treated patients compared with placebo. This finding supported the observed numerical increase in cortical thickness at month 60 versus placebo. In conclusion, ODN treatment for 5 years did not reduce bone remodeling and increased the proportion of patients with periosteal bone formation. These results are consistent with the mechanism of action of ODN, and are associated with continued BMD increases and reduced risk of fractures compared with placebo in the LOFT Phase 3 fracture trial. © 2020 American Society for Bone and Mineral Research.     

Incarceration,Maternal Hardship,and Perinatal Health Behaviors

Parental incarceration is associated with mental and physical health problems in children, yet little research directly tests mechanisms through which parental incarceration could imperil child health. We hypothesized that the incarceration of a woman or her romantic partner in the year before birth constituted an additional hardship for already-disadvantaged women, and that these additionally vulnerable women were less likely to engage in positive perinatal health behaviors important to infant and early childhood development. We analyzed 2006–2010 data from the Pregnancy Risk Assessment and Monitoring System to assess the association between incarceration in the year prior to the birth of a child and perinatal maternal hardships and behaviors. Women reporting incarceration of themselves or their partners in the year before birth of a child had .86 the odds (95 % CI .78–.95) of beginning prenatal care in the first trimester compared to women not reporting incarceration. They were nearly twice as likely to report partner abuse and were significantly more likely to rely on WIC and/or Medicaid for assistance during pregnancy. These associations persist after controlling for socioeconomic measures and other stressors, including homelessness and job loss. Incarceration of a woman or her partner in the year before birth is associated with higher odds of maternal hardship and poorer perinatal health behaviors. The unprecedented scale of incarceration in the US simultaneously presents an underutilized public health opportunity and constitutes a social determinant of health that may contribute to disparities in early childhood development.     

The effect of training in an interactive dynamic stander on ankle dorsiflexion and gross motor function in children with cerebral palsy

Objective: To study the effect of active stretching of ankle plantarflexors using an interactive dynamic stander in children with cerebral palsy (CP).

Methods: Six children in Gross Motor Function Classification System classes I–III, aged 4–10 years, trained intensive active dorsiflexion in an interactive dynamic stander using ankle movement to play custom computer games following a 10-week control period. Gross Motor Function Measure Item Set, gait performance and passive and active dorsiflexion with extended and flexed knee were chosen as outcome parameters.

Results: Median active and passive ankle dorsiflexion increased significantly (5 and 10 degrees, respectively) with extended knee. There was a small but clinically significant increase in gross motor function. The intervention had no effect on temporospatial gait parameters.

Conclusion: In spite of the low number of participants, these results may indicate that intensive active stretching in an interactive dynamic stander could be an effective new conservative clinical treatment of ankle plantarflexor contracture in children with CP.     

GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding,self-association and cellular degradation

GCK-MODY, dominantly inherited mild hyperglycemia, is associated with more than 600 mutations in the glucokinase gene. Different molecular mechanisms have been shown to explain GCK-MODY. Here, we report a Pakistani family harboring the glucokinase mutation c.823C > T (p.R275C). The recombinant and in cellulo expressed mutant pancreatic enzyme revealed slightly increased enzyme activity (k_cat) and normal affinity for α-D-glucose, and resistance to limited proteolysis by trypsin comparable with wild-type. When stably expressed in HEK293 cells and MIN6 β-cells (at different levels), the mutant protein appeared misfolded and unstable with a propensity to form dimers and aggregates. Its degradation rate was increased, involving the lysosomal and proteasomal quality control systems. On mutation, a hydrogen bond between the R275 side-chain and the carbonyl oxygen of D267 is broken, destabilizing the F260-L271 loop structure and the protein. This promotes the formation of dimers/aggregates and suggests that an increased cellular degradation is the molecular mechanism by which R275C causes GCK-MODY.     

Activated platelets promote increased monocyte expression of CXCR5 through prostaglandin E2-related mechanisms and enhance the anti-inflammatory effects of CXCL13

Background

We have previously shown that the homeostatic chemokine CXCL13 is up-regulated in monocytes in atherosclerosis, mediating anti-apoptotic and anti-inflammatory effects.

Objective

To investigate the regulation of CXCL13s receptor, CXCR5.

Methods/patients

In vitro studies in THP-1 and primary monocytes and studies of CXCR5 expression in thrombus material obtained at the site of plaque rupture during myocardial infarction (MI).

Results

Our major findings were: (i) toll-like receptor agonists and particularly β-adrenergic receptor activation and releasate from thrombin-activated platelets increased CXCR5 mRNA levels in monocytes. (ii) The platelet-mediated induction of CXCR5 involved prostaglandin E₂/cAMP/protein kinase A-dependent as well as RANTES-dependent pathways with NFκB activation as a potential common down-stream mediator. (iii) Releasate from thrombin-activated platelets augmented the anti-inflammatory effects of CXCL13 in monocytes at least partly by enhancing the effects of CXCL13 on CXCR5 expression. (iv) We found strong immunostaining of CXCR5 in thrombus material obtained at the site of plaque rupture in patients with ST elevation MI (STEMI) and in unstable carotid lesions, co-localized with platelets.

Conclusion

Our findings suggest that platelet-mediated signaling through CXCR5 may be active in vivo during plaque destabilization, potentially representing a counteracting mechanism to inflammation.