Previous studies have suggested the possibility of a link between PPI use and fracture risk, but evidence has been inconsistent.
This study, led by Dr Shelly Gray from the University of Washington, Seattle, used data from 161,806 women aged 50-70 years enrolled in the Women's Health Initiative study.
During an average of more than six years of follow-up, the women suffered a total of 21,247 fractures. These included 1,500 hip fractures, 4,881 forearm or wrist fractures and 2,315 clinical spinal fractures.
The researchers found no increased risk of hip fracture among women on PPI therapy.
But PPIs were associated with a 47 per cent increased risk of clinical spine fracture and a 26 per cent increased risk of forearm or wrist fracture.
Overall, there was a 25 per cent increased risk of fracture.
Given the findings, Dr Gray and colleagues believe clinicians should remain cautious about long-term PPI therapy.
'Questions remain regarding the potential risk associated with long-term PPI use and fracture risk; thus, based on the accumulation of evidence, it is prudent for clinicians to periodically re-evaluate the need for long-term PPI therapy,' the researchers said.
'For those older adults who do require long-term PPI therapy, it is reasonable to focus on using the lowest effective dose, ensuring adequate dietary calcium intake and adding calcium supplements when necessary.'
The researchers did not find an increased fracture risk with longer duration of PPI use, although few women in the study took PPIs for more than three years.
The study also failed to find any evidence that the risk of suffering a fracture was mitigated by taking calcium supplements. The researchers said that this raised questions about the hypothesis that raised fracture risk in PPI users was caused by reduced calcium absorption.
PPI use may have different effects on those at high or low risk of fractures as a result of other factors, they said.