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Low-dose glucocorticoid exposure increases osteoporotic fracture risk
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Among patients with various inflammatory conditions, exposure to glucocorticoids at doses as low as 5 mg per day may be associated with increased fracture risk, according to findings published in the Journal of Bone and Mineral Research.
“Fracture risk progressively increased with increasing levels of glucocorticosteroid exposure,” Akhila Balasubramanian, PhD, director with the Center for Observational Research at Amgen Inc., told Endocrine Today. “These trends were seen in the overall population as well as in patients younger than 50 years. We observed that fracture incidence in patients younger than 50 years who were exposed to glucocorticosteroids was as high as that observed in older (> 50 years) unexposed patients. Fracture risk decreased within months of steroid discontinuation.”
Balasubramanian and colleagues utilized the Truven Health MarketScan Commercial Claims and Encounters Database to follow 403,337 patients aged 18 to 64 years with rheumatoid arthritis (10%), asthma/chronic obstructive pulmonary disease (74%), irritable bowel disease (9%), multiple sclerosis, lupus and sarcoidosis. The researchers stratified fracture incidence rates per 1,000 person-years by prednisone-equivalent doses. They used Cox’s proportional hazard models to evaluate risk by daily and cumulative dose, and by time since cessation of glucocorticoids, adjusted for baseline characteristics.
At the end of follow-up, 72% patients had received systematic glucocorticoids during the study, according to researchers, with 69% of those exposed younger than 50 years. Sixty percent of exposed patients received cumulative doses of less than 675 mg (equivalent to 7.5 mg per day for 90 days), and 81% had short-term exposures between 1 and 90 cumulative days. Researchers identified 4,405 post-index fractures in the cohort, including 1,547 clinical vertebral fractures and 685 hip fractures.
Compared with incidence rates during unexposed time, fracture incidence approximately doubled in the presence of glucocorticoid exposures, even at the lowest daily doses of less than 5 mg per day (incidence rate = 9.33 per 1,000 person-years; 95% CI, 7.29-11.77) vs. unexposed (incidence rate = 4.87, 95% CI, 4.72-5.02), according to researchers. Results persisted in patients both older and younger than 50 years.
Unadjusted fracture incidence increased with increasing exposure for all exposure metrics, with very modest increases for peak dose, the researchers wrote.
Fracture incidence in patients with cumulative doses of 5,400 mg or higher (equivalent to 7.5 mg per day for 2 years), or patients with more than 365 days of glucocorticoid exposure, were nearly twice that of patients with cumulative doses ranging from 2,700 mg to 5,400 mg cumulative dose, or 81 to 365 days of glucocorticoid exposure. Fracture incidence in these patients with the highest doses and exposures were nearly triple that of unexposed patients, according to researchers.
Comparable patterns were revealed for clinical vertebral fractures and hip fractures, although daily dose for hip fractures did not exhibit the dose-response trend, the researchers wrote.
Adjusted HRs suggested significantly elevated fracture risk at daily doses as low as less than 5 mg per day, as well as a dose-response increase in fracture risk with increased cumulative dose. The risk at cumulative doses of less than 5,400 mg were roughly 2.5-fold higher vs. no exposure. Adjusted analyses stratified by cumulative dose corroborated the increased fracture risk at daily doses as low as less than 5 mg at cumulative doses greater than 5,400 mg.
Age-stratified descriptive analyses found a dose-dependent increase of fracture incidence with higher cumulative exposure to glucocorticoids in patients younger than 50 years and in patients aged 50 years or older.
In individuals younger than 50 years, there was a fracture incidence rate range of 2.44 per 1,000 person-years in never-exposed patients to five to six per 1,000 person-years in those with the highest cumulative exposures. Patients aged 50 years and older had incidence rate ranges between roughly six and 17 per 1,000 person-years based on exposure levels. There was an increase in fracture incidence rates at the lowest daily doses in both the younger and older patients; however, the older age group only showed a clear dose-response pattern of fracture incidence with higher daily doses. At doses of 5,400 mg or higher, patients younger than 50 years had incidence rates of 5.69 (95% CI, 4.32-7.35), whereas older patients had incidence rates of 17.10 (95% CI, 14.97-19.45).
Fracture risk decreased significantly within months after glucocorticoid discontinuation, according to researchers.
“The literature indicates that bone loss and associated fracture risk is often not well managed among patients using glucocorticosteroid therapy,” Balasubramanian said. “Based on the findings of our study as well as previous studies, physicians treating their patients with glucocorticosteroid therapy would be well advised to monitor and manage the bone health of these patients, including consideration of appropriate treatments for reduction of fracture risk.” – by Jennifer Byrne
For more information:
Akhila Balasubramanian, PhD, can be reached at aromano@webershardwick.com.
Disclosures: Amgen supported this study. Balasubramanian reports she is an employee of and stockholder in Amgen. Please see the study for the other authors’ relevant financial disclosures.
Correction: Sixty-nine percent of those exposed younger than 50 years, and the risk at cumulative doses of less than 5,400 mg were roughly 2.5-fold higher vs. no exposure. Endocrine Today regrets the error.
Perspective
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Glucocorticoids are used to treat many chronic inflammatory conditions. Adverse effects of long-term glucocorticoid therapy include disruption of bone remodeling, decrease in bone mineral density and increased fracture risk. Most patients on glucocorticoids are not being treated to mitigate the undesirable skeletal effects. A better understanding of the skeletal effects of glucocorticoids in diverse groups of patients may lead to more effective treatment.
The report by Balasubramanian and colleagues described the findings of a retrospective analysis of a large administrative claims database with chronic inflammatory diseases. This included more than 400,000 patients who were newly diagnosed with rheumatoid arthritis, asthma/chronic obstructive lung disease, inflammatory bowel disease, multiple sclerosis, lupus or sarcoidosis, 72% of whom had exposure to glucocorticoids.
Over 5 years with more than 2.4 million person-years of observation, 4,405 incident fractures were identified, including 1,547 clinical vertebral fractures and 685 hip fractures. Fracture rates were elevated in patients younger than 50 years of age as well as in those 50 years and older. The risk of fractures was greater with increasing levels of glucocorticoid exposure, but the risk was also elevated with prednisone equivalent doses of less than 5 mg per day. Fracture risk decreased within months of stopping glucocorticoids.
This study adds to the body of knowledge concerning the adverse skeletal effects of glucocorticoids. The findings suggest that we should be vigilant for potential skeletal harm with glucocorticoids, even in younger patients treated with low doses. Pharmacological therapy for glucocorticoid-induced osteoporosis should be used according to well-established guidelines. It is reassuring that fracture risk rapidly diminishes with discontinuation of glucocorticoids.
E. Michael Lewiecki, MD
Director of New Mexico Clinical Research & Osteoporosis Center
Director of Bone Health TeleECHO at University of New Mexico Health Sciences Center
Disclosure: The author has received institutional grant/research support from Amgen, Radius, PFEnex, and Mereo. He has served on scientific advisory boards for Amgen, Radius, Alexion, Ultragenyx, and Sandoz. He serves on speakers’ bureaus for Alexion and Radius. He is a board member of the National Osteoporosis Foundation, International Society for Clinical Densitometry, and Osteoporosis Foundation of New Mexico.
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