Osteopenia and fragility fractures have been associated with human immunodeficiency virus (HIV) infection. Tenofovir, a common antiviral in HIV treatment, also leads to increases in bone catabolism markers and decreased BMD in children and young adults. In murine models and human cell lines, tenofovir inhibits adenosine triphosphate release and decreases extracellular adenosine levels. Adenosine and adenosine A2A receptor inhibit osteoclast formation, and increase local adenosine concentration with dipyridamole, an agent that blocks adenosine cellular uptake and stimulates new bone formation as well as bone morphogenic protein 2. We hypothesized that tenofovir regulates bone resorption by diminishing endogenous adenosine levels and questioned whether dipyridamole may be a useful treatment to counteract the deleterous bone effects of tenofovir. Primary murine osteoclasts were induced by M‐CSF/RANKL, and the number of TRAP‐positive‐cells was studied after challenge with tenofovir alone or in combination with dipyridamole. Differentiation markers were studied by RT‐PCR and MAPK/NFkB expression by Western blot. Male C57Bl/6 mice were treated as follows: saline 0.9% (control), tenofovir 75 mg/kg/day, dipyridamole 25 mg/kg/day, combination tenofovir/dipyridamole (n = 10, 4 weeks). Calcein/Alizarin Red‐labeling of newly formed bone was used, and long bones were prepared for micro‐computed tomography (μCT)/histology. Tenofovir produced a dose‐dependent increase in osteoclast differentiation (EC50 = 44.5nM) that was reversed by dipyridamole (IC50 = 0.3 μM). Tenofovir increased cathepsin K and NFATc1 mRNA levels and dipyridamole reversed the effect. Dipyridamole reversed the effect of tenofovir on pERK1/2, pp38, and NFkB nuclear translocation. Mice treated with tenofovir lost nearly 10% of their body weight (p < 0.001). μCT revealed decreased BMD and altered trabecular bone in tenofovir‐treated mice, reversed by dipyridamole. TRAP‐staining showed increased osteoclasts in tenofovir‐treated mice (p < 0.005), an effect reversed by dipyridamole. Similar results were obtained for cathepsin K and CD68. RANKL‐positive cells were increased in tenofovir‐treated mice, whereas osteoprotegerin‐positive cells were decreased; both effects were reversed by dipyridamole. These results suggest that treatment with agents that increase local adenosine concentrations, like dipyridamole, might prevent bone loss following tenofovir treatment. © 2019 American Society for Bone and Mineral Research.

Joint prosthesis failure is mainly related to aseptic loosening and prosthetic joint infections, both of which are associated with high morbidity and substantial costs for patients and health systems. The development of a biomaterial that is capable of stimulating bone growth while minimizing bacterial adhesion would reduce the incidence of prosthetic failure. We report antibacterial and osteostimulatory effects in a novel fluorine-phosphorus (F-P)-doped TiO2 oxide film grown on Ti-6Al-4V alloy with a nanostructure of bottle-shaped nanotubes (bNT) using five bacterial species (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia) and MCT3T3-E1 osteoblastic cells. The interaction between the bacteria and bNT Ti-6Al-4V was complex, as the adhesion of four bacterial species decreased (two staphylococcus species, E. coli, and S. maltophilia), and the viability of staphylococci and S. maltophilia also decreased because of the aluminum (Al) released by bNT Ti-6Al-4V. This released Al can be recruited by the bacteria through siderophores and was retained only by the Gram-negative bacteria tested. P. aeruginosa showed higher adhesion on bNT Ti-6Al-4V than on chemically polished (CP) samples of Ti-6Al-4V alloy and an ability to mobilize Al from bNT Ti-6Al-4V. The cell adhesion and proliferation of MCT3T3-E1 osteoblastic cells significantly increased at 48 and 168 h, as did the matrix mineralization of these cells and the gene expression levels of three of the most important markers related to bone differentiation. According to our results, the bNT Ti-6Al-4V alloy could have clinical application, preventing infection and stimulating bone growth and thus preventing the two main causes of joint prosthesis failure. IMPORTANCE This work evaluates F-P-doped bNT Ti-6Al-4V from microbiological and cellular approaches. The bacterial results highlight that the antibacterial ability of bNT Ti-6Al-4V is the result of a combination of antiadhesive and bactericidal effects exerted by Al released from the alloy. The cell results highlight that F-P bNT Ti-6Al-4V alloy increases osseointegration due to modification of the chemical composition of the alloy resulting from P incorporation and not due to the nanostructure, as reported previously. A key finding was the detection of Al release from inside the bNT Ti-6Al-4V nanostructures, a result of the nanostructure growth during the anodizing process that is in part responsible for its bactericidal effect.

Background and aimsLow back pain is the leading cause of years lived with disability worldwide. Chiropractors employ different interventions to treat low back pain, including spinal manipulative therapy, although the mechanisms through which chiropractic care improves low back pain are still unclear. Clinical research and animal models suggest that spinal manipulation might modulate plasma levels of inflammatory cytokines, which have been involved in different stages of low back pain. More specifically, serum levels of Tumor Necrosis Factor-alpha (TNF-α) have been found to be elevated in patients with chronic low back pain. We aimed to investigate whether urine from chronic low back pain patients could be an appropriate medium to measure concentrations of TNF-α and to examine possible changes in its levels associated to chiropractic care.MethodsUrine samples were collected from 24 patients with chronic low back pain and TNF-α levels were analyzed by ELISA before and after 4–6 weeks of care compared to a reference value obtained from 5 healthy control subjects, by means of a Welch’s t-test. Simultaneously, pain intensity and disability were also evaluated before and after care. Paired t-tests were used to compare mean pre and post urinary concentrations of TNF-α and clinical outcomes.ResultsSignificantly higher baseline levels of urinary TNF-α were observed in chronic low back pain patients when compared to our reference value (p &lt; 0.001), which were significantly lower after the period of chiropractic treatment (p = 0.03). Moreover, these changes were accompanied by a significant reduction in pain and disability (both p &lt; 0.001). However, levels of urinary TNF-α were not correlated with pain intensity nor disability.ConclusionThese results suggest that urine could be a good milieu to assess TNF-α changes, with potential clinical implications for the management of chronic low back pain.

Plasma levels of adenosine deaminase (ADA), an enzyme that deaminates adenosine to inosine, are increased during inflammation. An increase in ADA activity occurs with lower human immunodeficiency virus (HIV) viral load and higher CD4+ T cell counts. We aimed to investigate the role of plasma ADA as a biomarker of inflammation in treatment-naïve HIV patients who received tenofovir or another nucleoside analog for comparison. Ninety-two treatment-naïve patients were included in the study and grouped by treatment, i.e., tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) or Triumeq. ADA activity was measured in plasma and cytokines were analyzed by MILLIPLEX® MAP-Luminex® Technology. Plasma concentration of monocytes and neutrophils was measured at 0, 3, and 12 months post-treatment. Treatment-naïve HIV patients had increased ADA concentrations (over 15 U/L) that decreased after treatment with TAF and Triumeq, though this did not occur in TDF-treated patients. However, all groups exhibited a pro-inflammatory systemic profile at 12 months of treatment. Plasma GM-CSF levels decreased after 12 months of treatment in the TDF group, with a concomitant decrease in blood monocyte count, and a negative correlation with ADA values was found. In conclusion, ADA levels may be modulated by antiretroviral therapy in HIV patients, possibly affecting inflammatory status.

Background In March 2020, the COVID‐19 pandemic forced the Spanish government to declare a state of emergency. A stringent lockdown was enforced, restricting access to healthcare services, including chiropractic. Reduced access to care provision in combination with psychological stress, social isolation and physical inactivity during the lockdown were shown to negatively influence pain conditions. However, data on strategies to mitigate the impact of the pandemic on these conditions are lacking. Methods Upon easing of restrictions in May 2020, 51 chiropractic clinics throughout Spain pseudo‐randomly invited patients, recruiting a total of 385 participants. During a 14‐day period, participants were exposed to in‐person chiropractic care in either one ( n = 177) or multiple encounters ( n = 109) or to no care ( n = 99). The effects of access to chiropractic care on patients’ pain‐related and psychological outcomes were assessed online through validated self‐reported questionnaires before and after the period of care. Coprimary outcomes included pain intensity, pain interference and pain cognitions. Results When comparing to participants without access to care, pain intensity and interference were significantly decreased at follow‐up, irrespective of the number of encounters. Kinesiophobia was also significantly reduced at follow‐up, though only after multiple encounters. The relationship between fear of movement, changes in pain intensity and interference was mediated by catastrophizing. Conclusion Access to in‐person chiropractic care may provide pain relief, associated with reductions in interference and pain cognitions. Prioritizing in‐person care for patients with maladaptive pain cognitions may help dampen the detrimental consequences of the pandemic on physical and psychological well‐being.

Osteoarthritis (OA) is a degenerative disease characterized by injury of all joint tissues. Our previous study showed that in experimental osteoporosis, chiropractic manipulation (CM) exerts protective effects on bone. We here assessed whether CM might ameliorate OA by improving subchondral bone sclerosis, cartilage integrity and synovitis. Male New-Zealand rabbits underwent knee surgery to induce OA by anterior cruciate ligament injury. CM was performed using the chiropractic instrument ActivatorV 3 times/week for 8 weeks as follows: force 2 setting was applied to the tibial tubercle of the rabbit right hind limb (TM-OA), whereas the corresponding left hind limb received a false manipulation (FM-OA) consisting of ActivatorV firing in the air and slightly touching the tibial tubercle. After sacrifice, subchondral bone integrity was assessed in the tibiae by microCT and histology. Cartilage damage and synovitis were estimated by Mankin's and Krenn's scores, respectively, and histological techniques. Bone mineral density and content in both cortical and trabecular compartments of subchondral bone decreased in OA rabbits compared to controls, but partially reversed in the TM-OA group. Trabecular bone parameters in the latter group also showed a significant improvement compared to FM-OA group. Moreover RANKL, OPG, ALP and TRAP protein expression in subchondral bone significantly decreased in TM-OA rabbits with respect to FM-OA group. CM was associated with lower Mankin's and Krenn's scores and macrophage infiltrate together with a decreased protein expression of pro-inflammatory, fibrotic and angiogenic factors, in TM-OA rabbits with respect to FM-OA. Our results suggest that CM may mitigate OA progression by improving subchondral bone as well as cartilage and synovial membrane status. Osteoarthritis (OA) is one of the most common chronic diseases affecting all anatomical structures of the joint, namely cartilage, subchondral bone and synovial membrane 1. This disease affects about 15% of the population aged 25-75 years, and its prevalence significantly increases with age, affecting 70% of the population over 65 years 2. Although OA has been described as a cartilage disorder, changes in the underlying (subchondral) bone also occur in this disease 3. In this sense, different molecular alterations associated with the latter bone remodeling, e.g., in expression of nuclear factor ligand receptor kappa B (RANKL) and osteoprotegerin (OPG), have been described in OA 4-7. Preclinical and clinical studies point to the observed alterations in subchondral bone as an important OA pathogenic factor 8. In fact, studies in animal models of combined osteoporosis (OP) and OA (OPOA) demonstrate that OP induces cartilage damage 9. In this setting, the observed significant correlation between deterioration of subchondral bone and cartilage injury indicates that alterations in subchondral microstructure aggravate cartilage damage 10 .

IntroductionLow bone mineral density (BMD) has been described as a non-AIDS-related event in human immunodeficiency virus (HIV)-patients, but it is poorly studied by dual-energy X-ray absorptiometry (DXA) and trabecular bone score (TBS) in young HIV-infected men who have received no previous antiretroviral treatment (ART).Material and methodsA retrospective study of 56 naïve-HIV-infected men under 50 years old with recently diagnosed HIV infection, between May 2012 and July 2017.ResultsThe mean age was 33.11 ±6.6 years, and they were 56.4% Caucasian and 43.6% Latin American. Regarding lifestyle and risk factors, 57% had previous exposure to tobacco and 31% reported drug use. Low BMD (Z-score < –2.0) was found in 21.4% of the patients, and partially degraded and degraded in 25% and 1.7%, respectively in TBS. We find significative prevalence of bone involvement among naïve HIV-infected men under 50 years old.ConclusionsFurther studies are necessary to evaluate if BMD assessment should be recommended in young HIV-infected patients.

Background Low BMD (bone mineral density) has been described as a non–AIDS (Acquired Immune Deficiency Syndrome)-related event in HIV (human immunodeficiency virus)-patients but it is poorly studied in young HIV-infected men who have received no previous antiretroviral therapy. Methods A cross-sectional study of 245 naïve-HIV-infected men over 21 and under 50 years old who voluntary attended the Infectious Disease Division appointment in Hospital Fundación Jimenez Díaz in Madrid, from January 1st, 2014 to September 30th, 2017. All subjects underwent a baseline DXA scan (dual energy x-ray absorptiometry) performed prior to start antiretroviral treatment. Further, all patients who started treatment between May 1st and September 30th, 2017 were invited to participate in a substudy on bone mineral metabolism. All the information was collected through clinical history and complementary questionnaire. Results The mean age was 36.4 years, been 68% Caucasian, 29.3% Latin American and 2.7% African race. At the time of diagnosis, 91% of patients had stage-A (median CD4+ T-cell 481cells/μL, IQR, 320–659). 10% had a count below 200 CD4 cells/μL, and 40% had a CD4/CD8 cell-count-ratio below 0.4. Regarding lifestyle and risk factors, 14.1% presented underweight, 36.1% were not engage in any regular exercise, 51.9% were active smokers and 35.3% reported drug use. Low levels of vitamin D were seen in 87.6% of the study participants. Low BMD (Z-score <- 2.0) was found in 22.8% of the patients. It was only observed a significant association of Z-score in lumbar spine (LS) with CD8 and the CD4/CD8 ratio, and with alcohol for femoral neck (FN) measurement. Conclusions We find prevalence of increased bone involvement among naïve HIV-infected men under 50 years old. Further studies are necessary to evaluate if changes in actual guidelines are needed to assess BMD measurements in HIV-infected adult male patients under 50.