Atypical femoral fractures (AFF) associated with long-term bisphosphonates (LTB) are a growing concern. Their etiology is unknown, but bone material properties might be deteriorated. In an AFF series, we analyzed the bone material properties by microindentation. Four groups of patients were included: 6 AFF, 38 typical osteoporotic fractures, 6 LTB, and 20 controls without fracture. Neither typical osteoporotic fractures nor controls have received any antiosteoporotic medication. A general laboratory workup, bone densitometry by dual-energy X-ray absorptiometry (DXA), and microindentation testing at the tibia were done in all patients. Total indentation distance (Total ID), indentation distance increase (IDI), and creep indentation distance (Creep ID) were measured (microns). Age-adjusted analysis of covariance (ANCOVA) was used for comparisons. Controls were significantly younger than fracture groups. Bisphosphonate exposure was on average 5.5 years (range 5 to 12 years) for the AFF and 5.4 years (range 5 to 8 years) for the LTB groups. Total ID (microns) showed better material properties (lower Total ID) for controls 36 (AE 6; mean AE SD) than for AFF 46 (AE 4) and for typical femoral fractures 47 (AE 13), respectively. Patients on LTB showed values between controls and fractures, 38 (AE 4), although not significantly different from any of the other three groups. IDI values showed a similar pattern 13 (AE 2), 16 (AE 6), 19 (AE 3), and 18 (AE 5). After adjusting by age, significant differences were seen between controls and typical (p < 0.001) and atypical fractures (p ¼ 0.03) for Total ID and for IDI (p < 0.001 and p < 0.05, respectively). There were no differences in Creep ID between groups. Our data suggest that patients with AFF have a deep deterioration in bone material properties at a tissue level similar to that for the osteoporotic fracture group. The LTB group shows levels that are in between controls and both type of fractures, although not statistically different. These results suggest that bisphosphonate therapy probably does not put the majority of patients at risk for AFF. ß

The World Health Organization has declared the SARS-CoV-2 infection (COVID-19) outbreak as a Public Health Emergency of International Concern and characterized it as a pandemic. 1,2 Since early March, 2020, the Spanish cases curve started to rise, with more than 177 000 people infected in 6 weeks. 3 The reported fatality-rate in the general population with COVID-19 admitted to a large tertiary Spanish Hospital is 20.7%, 34% in the subgroup of age 70-79 years. 4

Blocking the PD-1/PD-L1 pathway has emerged as a potential therapy to restore impaired immune responses in human immunodeficiency virus (HIV)-infected individuals. Most reports have studied the impact of the PD-L1 blockade on effector cells and neglected possible effects on regulatory T cells (Treg cells), which play an essential role in balancing immunopathology and antiviral effector responses. The aim of this study was to define the consequences of ex vivo PD-L1 blockade on Treg cells from HIV-infected individuals. We observed that HIV infection led to an increase in PD-1+ and PD-L1+ Treg cells. This upregulation correlated with disease progression and decreased under antiretroviral treatment. Treg cells from viremic individuals had a particularly high PD-1 expression and impaired proliferative capacity in comparison with Treg cells from individuals under antiretroviral treatment. PD-L1 blockade restored the proliferative capacity of Treg cells from viremic individuals but had no effect on its suppressive capacity. Moreover, it increased the viral production in cell cultures from viremic individuals. This increase in viral production correlated with an increase in Treg cell percentage and a reduction in the CD4/Treg and CD8/Treg cell ratios. In contrast to the effect of the PD-L1 blockade on Treg cells from viremic individuals, we did not observe a significant effect on the proliferative capacity of Treg cells from individuals in whom viremia was controlled (either spontaneously or by antiretroviral treatment). However, PD-L1 blockade resulted in an increased proliferative capacity of HIV-specific-CD8 T cells in all subjects. Taken together, our findings suggest that manipulating PD-L1 in vivo can be expected to influence the net gain of effector function depending on the subject’s plasma viremia.

Osteoporosis is defined as a reduction in bone mass and impairment of bone quality that lead to bone fragility and fracture risk. Bone quality includes a hierarchy of properties from macroscopic to nanoscale level. Several techniques have been developed in an attempt to measure these non-density properties. Densitometry, high-resolution images (radiography, CT scan), and MRI can measure the geometry and microarchitecture of bone. Tissue mineralization and composition can be assessed by use of microradiography, Fourier-transform infrared spectroscopy, or Raman microspectroscopy. Finite-element analysis is an image-based method that enables calculation of bone strength. More recently, microindentation has enabled direct estimation of bone material strength, measured in the cortical bone of the tibia. Most of these techniques are of limited use to clinics, although finite-element analysis and microindentation have high potential for clinical use and can enable more comprehensive and accurate evaluation of bone fragility and fracture susceptibility.