Pradeesh Sivapalan, MD, PhD, on How Corticosteroid Dosage Affect Bone Turnover Markers

A shorter course of corticosteroids may have bone safety benefits for patients experiencing chronic obstructive pulmonary disease (COPD) exacerbations, according to a new study.¹

Long-term corticosteroid use is associated with bone density loss, and patients with COPD have a higher risk of osteoporosis. In an effort to decrease this burden on this patient population, a research team examined whether high-dose corticosteroid therapy impacts bone turnover markers to a greater extent than low-dose corticosteroid therapy.

The team was led by Pradeesh Sivapalan, MD, PhD, who is a respiratory trainee in the Department of Internal Medicine at Zealand University Hospital in Roskilde, Denmark and is a post-doctoral researcher in the Respiratory Medicine Section at the Herlev-Gentofte Hospital in Denmark.

Pulmonology Consultant reached out to Dr Sivapalan to find out more about this study and its findings.

Pulmonology Consultant: For your study, you and your colleagues determined whether high-dose corticosteroid therapy affected bone turnover markers to a greater extent than low-dose corticosteroid therapy. Why is this objective important to study?

Pradeesh Sivapalan: When COPD patients are hospitalized with exacerbations, the standard treatment is corticosteroid treatment for 5 to 7 days, which can lead to adverse effects such as adrenal insufficiency, worsening of diabetes, and decreased bone density. The altered bone density as a consequence of the treatment increases the patient’s risk of fractures, avascular necrosis, as well as corticosteroid-induced osteoporosis. Therefore, it is relevant to investigate how corticosteroid therapy in these patients may be altered in order to avoid these frequent adverse effects.

In the CORTICO-COP study,² we investigated how a different treatment algorithm of corticosteroids for COPD exacerbation affects the number of days the patient is without hospitalization within 14 days. In addition, a number of other outcomes included mortality, readmission, worsening of diabetes, antibiotic-demanding infections, as well as parathyroid hormone and vitamin D levels were examined. Patients were divided into 2 groups, which received different treatments: the low-dose group received treatment when the number of blood eosinophilic granulocytes exceeded a certain limit, and the high-dose group (controls) received standard treatment of corticosteroids for 5 days. With special focus on the effect on bone remodeling, we performed a substudy that, using biomarkers, examined how bones were affected in the 2 groups, to provide insight into whether low-dose treatment can treat COPD exacerbation without inappropriate effect on bones.

In the CORTICO-COP study, there were no significant differences between the 2 patient groups, indicating that low-dose treatment has the same effect on COPD exacerbations while exposing patients to less total corticosteroids. In relation to negative outcomes, there were also no significant differences in the frequency with COPD readmissions, new-onset of diabetes, or death within 30 days, just as there was no difference in parathyroid hormone level, vitamin D level, and frequency with antibiotic-demanding infections after 90 days.

In the field of diabetes, there was a significant difference between the 2 groups. The number of patients with diabetes whose diabetes worsened after 30 days was significantly higher in the high-dose control group compared with the low-dose group, which in turn speaks for the eosinophil-controlled treatment. In summary, the eosinophil-guided corticosteroid treatment led to patients receiving an approximately 60% lower accumulated dose of systemic corticosteroids (ie, corticosteroid reduction from 5 days to 2 days of treatment for COPD exacerbation without worsening the treatment effect). Therefore, if you use such a method, we should expect far fewer long-term adverse effects of corticosteroids in vulnerable patients with COPD.

Hence, we investigated whether 5 days of corticosteroid treatment was associated with more adverse effects compared with 2 days of treatment. Our first substudy, the present study,¹ was planned to determine the effects of these 2 treatments on bone metabolism.

PULM CON: To examine this association, your team compared the levels of C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) in 318 patients with COPD during acute exacerbations and at 1- and 3-month follow-up visits. What is the significance of these bone turnover markers?

PS: To look at bone remodeling, we selected 2 relevant biomarkers: CTX and P1NP. CTX is released during bone resorption, so a decrease means decreased bone resorption. Conversely, P1NP is released during bone formation, so an increase means increased bone formation. Measurements were made at baseline and at follow-up after 1 and 3 months. Vitamin D, parathyroid hormone, calcium, and fasting blood glucose levels were also measured over these time periods.

These bone turnover markers are very sensitive to bone formation or bone resorption activity. Therefore, they are also used in the monitoring and treatment of osteoporosis. They are not used for screening for osteoporosis. Dual-energy x-ray absorptiometry scanning is still the right choice there.

PULM CON: Overall, your analysis showed that CTX had decreased and P1NP had increased significantly over time in both treatment groups. How do these findings impact clinical practice and how COPD exacerbations are managed?

PS: In this study, we have shown that there is no major detrimental short-term effect on bone metabolism by using a 2- or 5-day regimen to treat COPD exacerbations. However, we cannot comment on the accumulated effect in patients receiving frequent prednisolone regimens. At the same time, it is important to emphasize that corticosteroids have many other adverse effects, which is why corticosteroids still need to be used with caution. Currently, the guidelines recommend 5 days of treatment with corticosteroids for COPD exacerbations. Therefore, there is no benefit in treating for longer periods.

PULM CON: You also noted that no significant differences were seen between the high- and low-dose groups at 1- or 3-months follow-up for P1NP, but a significant decrease was seen in CTX at 3 months for the high-dose group. How might this finding help improve patient care in the future?

PS: Overall, this shows that the low-dose treatment was no more bone-friendly than the standard treatment but also is no more harmful at 3-month follow-up.

PULM CON: What is the overall key take-home message from your study for practicing health care providers who manage patients with COPD and acute exacerbations?

PS: Using eosinophil-controlled corticosteroid therapy, there was no increase in mortality or COPD readmission rates, but there were fewer diabetic exacerbations. In terms of bone remodeling, the treatment was not beneficial, but neither was it more harmful. Therefore, the low-dose treatment could potentially be used to reduce the amount of corticosteroids and reduce other adverse effects. The latter requires further study of the long-term effects.

References:

1. Sivapalan P, Jørgensen NR, Mathioudakis AG, et al. Bone turnover biomarkers in COPD patients randomized to either a regular or shortened course of corticosteroids: a substudy of the randomized controlled CORTICO-COP trial. BMC Respir Res. 2020;12(1):263. https://doi.org/10.1186/s12931-020-01531-9
2. Sivapalan P, Lapperre TS, Janner J, et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial. Lancet Respir Med. 2019;7(8):699-709. https://doi.org/10.1016/S2213-2600(19)30176-6