Trends in osteoporosis care patterns during the COVID-19 pandemic in Alberta, Canada.

PURPOSE/INTRODUCTION: The objective of this study was to describe osteoporosis-related care patterns during the coronavirus disease 2019 (COVID-19) pandemic in Alberta, Canada, relative to the 3-year preceding. METHODS: A repeated cross-sectional study design encompassing 3-month periods of continuous administrative health data between March 15, 2017, and September 14, 2020, described osteoporosis-related healthcare resource utilization (HCRU) and treatment patterns. Outcomes included patients with osteoporosis-related healthcare encounters, physician visits, diagnostic and laboratory test volumes, and treatment initiations and disruptions. The percent change between outcomes was calculated, averaged across the control periods (2017-2019), relative to the COVID-19 periods (2020). RESULTS: Relative to the average control March to June period, all HCRU declined during the corresponding COVID-19 period. There was a reduction of 14% in patients with osteoporosis healthcare encounters, 13% in general practitioner visits, 9% in specialist practitioner visits, 47% in bone mineral density tests, and 13% in vitamin D tests. Treatment initiations declined 43%, 26%, and 35% for oral bisphosphonates, intravenous bisphosphonates, and denosumab, respectively. Slight increases were observed in the proportion of patients with treatment disruptions. In the subsequent June to September period, HCRU either returned to or surpassed pre-pandemic levels, when including telehealth visits accounting for 33-45% of healthcare encounters during the COVID periods. Oral bisphosphonate treatment initiations remained lower than pre-pandemic levels. CONCLUSIONS: This study demonstrates the COVID-19 pandemic and corresponding public health lockdowns further heightened the "crisis" around the known gap in osteoporosis care and altered the provision of care (e.g., use of telehealth and initiation of treatment). Osteoporosis has a known substantial care and management disparity, which has been classified as a crisis. The COVID-19 pandemic created additional burden on osteoporosis patient care with healthcare encounters, physician visits, diagnostic and laboratory tests, and treatment initiations all declining during the initial pandemic period, relative to previous years.

Trends in osteoporotic fracture and related in-hospital complications during the COVID-19 pandemic in Alberta, Canada.

Fragility fractures (i.e., low-energy fractures) account for most fractures among older Canadians and are associated with significant increases in morbidity and mortality. Study results suggest that low-energy fracture rates (associated with surgical intervention and outcomes) declined slightly, but largely remained stable in the first few months of the COVID-19 pandemic. PURPOSE/INTRODUCTION: This study describes rates of low-energy fractures, time-to-surgery, complications, and deaths post-surgery in patients with fractures during the coronavirus disease (COVID-19) pandemic in Alberta, Canada, compared to the three years prior. METHODS: A repeated cross-sectional study was conducted using provincial-level administrative health data. Outcomes were assessed in 3-month periods in the 3 years preceding the COVID-19 pandemic and in the first two 3-month periods after restrictions were implemented. Patterns of fracture- and hospital-related outcomes over the control years (2017-2019) and COVID-19 restrictions periods (2020) were calculated. RESULTS: Relative to the average from the control periods, there was a slight decrease in the absolute number of low-energy fractures (n = 4733 versus n = 4308) during the first COVID-19 period, followed by a slight rise in the second COVID-19 period (n = 4520 versus n = 4831). While the absolute number of patients with low-energy fractures receiving surgery within the same episode of care decreased slightly during the COVID-19 periods, the proportion receiving surgery and the proportion receiving surgery within 24 h of admission remained stable. Across all periods, hip fractures accounted for the majority of patients with low-energy fractures receiving surgery (range: 58.9-64.2%). Patients with complications following surgery and in-hospital deaths following fracture repair decreased slightly during the COVID-19 periods. CONCLUSIONS: These results suggest that low-energy fracture rates, associated surgeries, and surgical outcomes declined slightly, but largely remained stable in the first few months of the pandemic. Further investigation is warranted to explore patterns during subsequent COVID-19 waves when the healthcare system experienced severe strain.

Off-target profiling of janus kinase (JAK) inhibitors in rheumatoid arthritis: A computer-based approach for drug safety studies and repurposing

Background: The JAK inhibitors (JAKi's) tofacitinib and baricitinib are new alternatives for treating rheumatoid arthritis. Safety concerns associated with JAKi's, such as the increased risk for thrombosis and viral infections, have emerged worldwide. The underlying explanatory mechanisms remain unknown, suggesting the elevated risk is likely due to underlying confounding or an off-target binding effect. Computational approaches can explore the potential for a small molecule drug to interact with previously unknown biological targets and identify potential safety-related concerns, and open doors for potential drug repurposing. Objectives: To identify and characterize the off-target binding effects of baricitinib and tofacitinib, with a focus on targets related to thrombosis and viral infection Methods: Potential targets of baricitinib and tofacitinib were predicted using two neural-network-based systems (TIGER[1] and SPiDER[2]). Targets were considered relevant if they had (1) a SPiDER confidence with p<0.05, or (2) a TIGER score >1. Selected targets related to the outcome of interest were experimentally evaluated at Eurofins Cerep (France-Celle L'Evescault, www.eurofins. com) if commercial available. Compounds were tested at (1) single concentration (30 μM) with technical replicates, using radioligand or enzymatic assays, or (2) multiple concentrations (30 μM highest concentration;dilution factor in a logscale) with technical replicates, using calcium flux or inhibition of [cAMP] assays. Observed activity of ≥50% inhibition or stimulation on the target was considered active, between 25 to 50% inhibition (or a dissociation constant [Kd] from 1 to 10 μM) was considered as moderate activity, and lower than 25% was considered inactive. Dose-response curve were performed on active and moderate targets for IC50 / EC50 (half maximal inhibitory / effective concentration) determination. Results: TIGER and SPiDER suggested a total of 99 off-target binding effects (baricitinib n=41;tofacitinib n=58), of which 17 targets had potential impact on thrombosis or viral infection (baricitinib n=5 and 4, respectively;tofacitinib n=5 and 3, respectively). Commercial testing was available on 11 targets (Adenosine Receptor A2A [AA2AR], Epidermal growth factor receptor, induclible NOS, PI3 Kinase (p110b/p85a), Phosphodiesterase 10A2 [PDE10A2] and Protein Kinase N2 [PKN2] for baricitinib;and Adenosine receptor A3, 15-Lipoxygenase [15-LO], PKN2, Transient receptor potential cation channel [TRPM6] and AA2AR for tofacitinib). Of these, 5 targets showed active or moderately active binding activity (baricitinib n=2;tofacitinib n=3), and were tested for dose-response curves. Test results confirmed ligand-binding activity with IC50 on nanomolar (PKN2), and micromolar ranges (PDE10A2 and TRPM6). Conclusion: The results suggest both baricitinib and tofacitinib are promiscuous binders with effects on several families. Although it may lead to side effects, off-target binding also represents a potential opportunity for drug repurposing. Besides on-target effects, both drugs are under clinical investigation for the treatment of COVID-19 due to off-target interactions. The proposed pharmacological off-target effects of those with active binding include attenuation of pulmonary vascular remodeling, anti-fibrotic and anti-psychotic activities (PDE10A2), modulation of viral response (PKN2), and hypomagnesaemia (TRPM6), which is involved in cardiovascular diseases. This study supports tofacitinib and baricitinib as candidates for drug repurposing (e.g., in COVID-19, Hepatitis C virus, and pulmonary hypertension). We did not identify active off-target interactions linked to thrombosis to explain the elevated risk observed in clinical practice. Further research is required to elucidate the underlying patient-specific factors (confounders) that could explain this safety concern.