Objective

Glucocorticoids (GCs) are commonly prescribed as treatment for chronic inflammatory diseases. Prolonged use of GCs is a common cause of atraumatic osteonecrosis (ON) and secondary osteoporosis. Currently, there is no effective treatment for this disease; therefore, a reliable animal model would be useful to study both the pathology and novel treatment strategies for patients with the disease. The aim of this study was to establish a validated, reproducible model of GC-induced ON and bone loss in two different mouse strains (BALB/c and C57BL/6).

Methods

Seven-week-old male BALB/c (n = 32) and male C57BL/6 mice (n = 32) were randomised into placebo or GC groups and treated with daily 4 mg/L oral dexamethasone in drinking water for 90 days. Study outcome measures included histologic assessment of ON of the distal femur, bone mass and mechanical strength of tibia and lumbar vertebral body, osteoclast number, biochemical measure of bone formation and bone marrow fat quantitation.

Results

GC-induced ON lesions were observed in the distal femur in 47% of the male BALB/c mice and 25% of the male C57BL/6 mice. GC treatment decreased the trabecular bone volume and serum pro-collagen type 1N-protease (P1NP) in BALB/c mice compared with the placebo (p < 0.05) and reduced tibial bone strength in both BALB/c and C57BL/6 mice. GC-treated BALB/c mice had significantly greater marrow fat levels compared to the placebo group.

Conclusion

GC-induced ON was more prevalent in the male BALB/c mice compared to the male C57BL/6 mice. GC treatment significantly reduced bone mass, bone formation measured by P1NP, bone strength and increased marrow fat levels in male BALB/c mice. Therefore, the use of male BALB/c mice strain is recommended for both diagnostic and therapeutic studies for the prevention and treatment of ON and bone loss following prolonged treatment with GCs.

The translational potential of this article

GCs are commonly used to treat patients with various chronic inflammatory diseases, and this is associated with both the development of ON and bone loss. Our study confirmed that the BALB/c mouse strain treated for 90 days with GC may be useful for developing novel treatments for ON.

Objective

Determine if LLP2A-Ale or PTH (1-34) affects the prevalence of glucocorticoid-induced osteonecrosis (ON) in a mouse model.

Methods

Eight-week-old young adult male BALB/cJ mice were weight-randomized into Control (Con), glucocorticoid (GC)-only, or concurrent treatments with GC and LLP2A-Ale (250 μg/kg or 500 μg/kg, IV, Days 1, 14, 28) or parathyroid hormone hPTH (1-34) (40 μg/kg, 5×/week). Mice were necropsied after 45 days for qualitative evaluation of prevalent ON and quantitative evaluation of vascularity in the distal femoral epiphysis (DFE); and quantitative evaluation of bone mass, microarchitecture, and strength in the distal femoral metaphysis and lumbar vertebral body.

Results

The prevalence of ON was 14% in the Con group and 36% in the GC-only group (P = 0.07). The prevalence of ON did not differ among GC-only, GC + LLP2A-Ale, and GC + PTH groups. GC-only mice had significantly lower trabecular and cortical bone strength than Con, while GC + LLP2A-Ale (500 μg/kg) and GC + PTH (1-34) groups had significantly greater trabecular bone strength than the GC-only group. GC + LLP2A-Ale (250 μg/kg and 500 μg/kg) and GC + PTH had significantly higher trabecular bone volume than GC-only mice at the vertebrae, distal femoral epiphyses and distal femoral metaphyses. DFE vascularity was lower in GC-only mice than in all other groups.

Conclusion

Neither LLP2A-Ale nor hPTH (1-34) reduced the prevalence of GC-induced ON, compared to GC-only mice. However, GC-treated mice given LLP2A-Ale or hPTH (1-34) had better bone mass, microarchitecture, and strength in trabecular-rich regions, and higher levels of vascularity than GC-only mice.

Background

Differences in the distribution of individual-level clinical risk factors across regions do not fully explain the observed global disparities in COVID-19 outcomes. We aimed to investigate the associations between environmental and societal factors and country-level variations in mortality attributed to COVID-19 among people with rheumatic disease globally.

Methods

In this observational study, we derived individual-level data on adults (aged 18-99 years) with rheumatic disease and a confirmed status of their highest COVID-19 severity level from the COVID-19 Global Rheumatology Alliance (GRA) registry, collected between March 12, 2020, and Aug 27, 2021. Environmental and societal factors were obtained from publicly available sources. The primary endpoint was mortality attributed to COVID-19. We used a multivariable logistic regression to evaluate independent associations between environmental and societal factors and death, after controlling for individual-level risk factors. We used a series of nested mixed-effects models to establish whether environmental and societal factors sufficiently explained country-level variations in death.

Findings

14 044 patients from 23 countries were included in the analyses. 10 178 (72·5%) individuals were female and 3866 (27·5%) were male, with a mean age of 54·4 years (SD 15·6). Air pollution (odds ratio 1·10 per 10 μg/m³ [95% CI 1·01-1·17]; p=0·0105), proportion of the population aged 65 years or older (1·19 per 1% increase [1·10-1·30]; p<0·0001), and population mobility (1·03 per 1% increase in number of visits to grocery and pharmacy stores [1·02-1·05]; p<0·0001 and 1·02 per 1% increase in number of visits to workplaces [1·00-1·03]; p=0·032) were independently associated with higher odds of mortality. Number of hospital beds (0·94 per 1-unit increase per 1000 people [0·88-1·00]; p=0·046), human development index (0·65 per 0·1-unit increase [0·44-0·96]; p=0·032), government response stringency (0·83 per 10-unit increase in containment index [0·74-0·93]; p=0·0018), as well as follow-up time (0·78 per month [0·69-0·88]; p<0·0001) were independently associated with lower odds of mortality. These factors sufficiently explained country-level variations in death attributable to COVID-19 (intraclass correlation coefficient 1·2% [0·1-9·5]; p=0·14).

Interpretation

Our findings highlight the importance of environmental and societal factors as potential explanations of the observed regional disparities in COVID-19 outcomes among people with rheumatic disease and lay foundation for a new research agenda to address these disparities.

Funding

American College of Rheumatology and European Alliance of Associations for Rheumatology.