Author: Daniela Barros
Medscape News Global
Even low doses of prednisone increase the risk for fracture, with clinically meaningful harm emerging within months rather than years. Daily doses of 2.5-7.5 mg raise the risk for fracture as early as 5-6 months after treatment initiation, according to an international review published in The Lancet Diabetes & Endocrinology.
These findings have immediate implications for clinicians who routinely prescribe glucocorticoids. The review challenges the long-standing assumption that low-dose therapy is safe for bone health and supports earlier fracture risk assessment and treatment, particularly in individuals at a very high risk for glucocorticoid-induced osteoporosis.
By integrating epidemiologic evidence, mechanistic data, randomized clinical trials, and international guidelines, the authors showed that skeletal damage occurs earlier and more severely than previously recognized.
The review was conducted by an international group of experts from the Technische Universität Dresden, Dresden, Germany; University of Cambridge, Cambridge, England; and University of Alabama at Birmingham.
Drawing on population-level data indicating that approximately 3% of adults receive chronic glucocorticoid therapy, the authors demonstrated that bone injury begins at doses well below those once considered clinically acceptable.
No Safe Dose
Speaking with Medscape’s Portuguese edition, Charlles Heldan de Moura Castro, MD, rheumatologist and adjunct professor of rheumatology at Escola Paulista de Medicina-Universidade Federal de São Paulo (EPM-UNIFESP), São Paulo, Brazil, reinforced this paradigm shift already evident in clinical practice. No glucocorticoid dose could be considered safe for the skeleton.
This review refutes the concept of the Cushing threshold, above which glucocorticoid toxicity becomes clinically relevant. Instead, it describes a continuous dose-response relationship, with the risk for fracture increasing even at low daily doses and rising further with cumulative exposure.
Marise Lazaretti-Castro, MD, endocrinologist and adjunct associate professor and head of the Osteometabolic Diseases Unit at EPM-UNIFESP, emphasized that decades of clinical observation support these conclusions. “Excessive glucocorticoid exposure is extremely harmful to the bone. This was described by Cushing at the beginning of the last century, and today we know that doses as low as 5 mg/d of prednisolone for more than 3 months increase fracture risk,” she explained.
Early and Cumulative Risk
The epidemiologic data summarized in the review indicated that daily doses above 7.5 mg/d increased the risk for vertebral fracture by up to fivefold and the risk for hip fracture by 2.2-fold.
Large cohort studies from the US, Europe, and Japan have further demonstrated that cumulative exposure substantially increases the risk for fractures.
“All patients who have used daily doses of 2.5 mg or more of prednisone for 3 months or longer should be evaluated for fracture risk,” said de Moura Castro. He noted that access to bone densitometry remains limited in Brazil but emphasized that screening should not be delayed.
At the mechanistic level, this review describes a cascade of deleterious skeletal effects, including increased bone resorption mediated by receptor activator of nuclear factor kappa B ligand, marked suppression of bone formation, apoptosis and senescence of osteoblasts and osteocytes, expansion of bone marrow adiposity, reduced insulin-like growth factor 1, inhibition of Wnt signaling, and loss of type H vessels, which are essential for vascular bone coupling.
Extraskeletal effects further contribute to the risk for fracture, including accelerated muscle loss, hypogonadism, suppression of insulin-like growth factor 1, and alterations in calcium metabolism.
According to Lazaretti-Castro, these mechanisms explain why fractures often occur despite apparently normal bone mineral density (BMD). “In glucocorticoid-induced osteoporosis, bone densitometry must be interpreted with caution. Fractures occur even when values remain within the normal range because microarchitecture has already deteriorated.”
Although bone densitometry remains the standard diagnostic tool, the review emphasizes that BMD alone underestimates the risk for fracture. The adjustment of the Fracture Risk Assessment Tool, use of the trabecular bone score, and screening for asymptomatic vertebral fractures are considered essential complementary tools.
The trabecular bone score offers complementary information to BMD by capturing aspects of bone microarchitecture that the standard T-score may miss. Because it assesses bone quality independently of BMD, it can reveal early microstructural deterioration before measurable declines appear in conventional bone density tests.
According to de Moura Castro, the adjusted Fracture Risk Assessment Tool evaluation should be routine. “Assessment of absolute risk for fracture using the Fracture Risk Assessment Tool is essential in people older than 40 years of age, always with dose adjustments for glucocorticoids. In practice, this changes clinical decision-making.”
Anabolic Shift
Randomized trials have demonstrated the superiority of teriparatide compared with alendronate for preventing vertebral fractures and increasing BMD. Over 18 months, teriparatide increased lumbar spine BMD by 7.2% compared with 3.4% with alendronate and reduced vertebral fracture incidence from 6.1% to 0.6%. Trials comparing teriparatide and risedronate have also shown substantial gains in trabecular BMD and structural strength. Denosumab was superior to risedronate for BMD gains over 24 months.
Castro emphasized that the preference for anabolic therapy in individuals at extremely high fracture risk is supported by robust evidence. “Teriparatide is the only anabolic medication tested specifically for conditions of excessive glucocorticoids. It proved superior to bisphosphonates in preventing fractures in people at very high risk and should be followed by antiresorptive therapy after 24 months.”
International guidelines converge in the same direction: initiating evaluation when glucocorticoids are prescribed, using anabolic agents in high-risk cases, and avoiding treatment delays.
The 2022 American College of Rheumatology (ACR) guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis recommend teriparatide, abaloparatide, and romosozumab as first-line treatments for very high-risk patients.
The European Calcified Tissue Society (ECTS) 2024 guidelines prioritize anabolic agents, such as teriparatide, for patients with very high-risk glucocorticoid-induced osteoporosis, followed by sequential antiresorptive therapy.
The UK National Osteoporosis Guideline Group 2024 guidelines make similar recommendations, emphasizing fracture risk assessment and anabolic therapy for very high-risk cases with imminent fracture risk.
In contrast, Brazilian guidelines have only partially incorporated this approach.
According to de Moura Castro, access remains the primary barrier to care. “The ACR and ECTS recommendations have already been incorporated into rheumatology practice. The gap lies in access: anabolic agents like teriparatide remain underutilized in the Brazilian Unified Health System (SUS) and supplementary health insurance due to recent exclusions, high costs, and limited SUS incorporation for osteoporosis.”
Implications for Practice
The review highlighted three clinically relevant conclusions: the risk for fracture begins earlier and at lower doses than previously recognized; microstructural damage explains fractures despite normal BMD; and anabolic therapies are more effective than antiresorptive agents in individuals at a very high risk. However, these findings require a review of the protocols and greater integration between specialties.
Lazaretti-Castro highlighted a persistent challenge in Brazil. “It is common for individuals to use glucocorticoids without medical supervision. Many patients present to the clinic with multiple fractures. Awareness needs to increase.”
Balancing disease control and bone protection remains a complex task. The GLORIA study demonstrated bone loss even with a low dose of 2.5 mg/d of prednisolone.
In contrast, emerging data on biological agents, JAK inhibitors, and Bruton tyrosine kinase inhibitors suggest that targeted therapies may reduce the reliance on glucocorticoids and mitigate the risk for fractures.
Future therapeutic strategies include bispecific antibodies targeting both sclerostin and Dickkopf-1, such as AGA2118; selective glucocorticoid receptor modulators, including vamorolone; and new treatment sequencing approaches.
These advances may ultimately decouple anti-inflammatory efficacy from skeletal toxicity.
According to de Moura Castro, public policy is critical. “We need to expand physician education across specialties to reduce underdiagnosis and increase pharmacologic prevention, which currently reaches fewer than 20% of eligible patients.”
Lazaretti-Castro also emphasized interdisciplinary care. “Endocrinologists and rheumatologists need to work together. However, prevention often fails. Fractures compromise the quality of life more than the underlying disease itself,” she concluded.