Opioids Increase Risk for Fracture, Especially at Initiation and Reinitiation

The researchers aimed to study how duration of opioid exposure, doses used, and the risk of fracture were associated by using a self-controlled study design in an effort to minimize confounding.

Acute central nervous system effects, including sedation and drowsiness, and bone mineral density changes caused by opioids may increase the risk of fracture, particularly in the first week of treatment, a study in the American Journal of Epidemiology suggests.

This self-controlled case series study evaluated the association between opioids and bone fractures from 2008 to 2017 in 539,369 adult patients registered in the United Kingdom Clinical Practice Research Datalink. The investigators identified fractures with clinical codes for diagnoses, and opioid exposure was defined as the presence of an opioid prescription.

A total of 67,622 patients exposed to opioids experienced fractures and were included in the final analysis. There was an association between an increased risk for fracture and opioid exposure (adjusted incidence rate ratio [aIRR], 3.93; 95% CI, 3.82-4.04).

The risk for fracture was highest in the first 7 days of opioid initiation (aIRR, 7.81; 95% CI, 7.40-8.25) but decreased with increasing duration. The aIRR for days 29 through 365 of opioid use was 1.77 (95% CI, 1.54-2.03) and it was 1.25 (95% CI, 0.86-1.82) after 366 days.

Although the risk for fracture declined as the duration of opioid exposure increased until an exposure gap or cessation, restarting opioids following an exposure gap was associated with a significantly increased risk for fracture on days 1 through 7 of a subsequent use period (aIRR, 5.05; 95% CI, 4.83-5.29) compared with nonuse. Similar to the previous period, fracture risk declined with ongoing opioid use from days 29 through 365 (aIRR, 2.43; 95% CI, 2.30-2.57) and days 366 onwards (aIRR, 1.73; 95% CI, 1.50-1.98).

A limitation of this study was the definition of opioid exposure as an opioid prescription, which could have resulted in exposure misclassification.

The investigators concluded that their “findings highlight the importance of raising awareness of fractures among patients at opioid initiation” and also “demonstrate the utility of self-controlled methods for pharmacoepidemiologic research.”

Disclosure: Some study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Peach EJ, Pearce FA, Gibson J, Cooper AJ, Chen LC, Knaggs RD. Opioids and the risk of fracture: a self-controlled case series study in the Clinical Practice Research Datalink. Published online February 19, 2021. Am J Epidemiol. doi:10.1093/aje/kwab042