Proton pump inhibitors and fracture risk: response to comments.

Abstract

Dear Editor, We are delighted by the interest shown by Dr. Sugiyama and colleagues in our recent article [1, 2]. They agreed with our suggestion that calcium malabsorption would not be a major cause of the association between proton pump inhibitor (PPI) use and an increased fracture risk and Dr. Sugiyama also discussed this topic further from a different point of view. The biologic mechanisms through which PPIs may increase the risk of fracture are still unknown. It has been hypothesized that PPI reduces calcium absorption, eventually leading to a decreased bone mineral density (BMD), which increases the risk of fractures [3]. However, neither impaired calcium absorption nor BMD decline has been confirmed in patients taking PPIs [4, 5]. Sugiyama et al. provided the evidence that the effects of calcium intake on a real BMD and fracture risk are limited. In addition, they also provided some data regarding the association of vitamin D and BMD. Vitamin D treatment could significantly increase the levels of serum 25-hydroxyvitamin D, however, could not change BMD [6]. These data support our suggestion that calcium malabsorption would not be a major cause of the association with PPI use. And Sugiyama and colleagues speculated that the effect of osteoporosis therapy might be limited by skeletal adaptation to the mechanical environment, thus, Bmild^ mineral-related changes in bone material stiffness by PPI therapy did not exert significant effects. In our meta-analysis, short-term PPI use (<1 year) was also found to be associated with an increased risk of hip fracture, which may not support a link between PPI use and increased fracture risk through biochemical mechanisms. And we speculate that there may be other mechanisms that have direct effects upon bone mineralization or bone quality [2]. The latest article about the relation of PPIs and fractures in young adults showed that PPI use was associated with a significantly increased risk for fracture in young adults, but not in children [7]. Compared to older adults, a larger proportion of fractures in young adults are related to sports and relatively high-impact falls and other injuries. Thus, the results of this study support the possibility that PPIs act on the bone to increase fracture risk through the mechanisms that are independent of osteoporosis. Future research is needed to further understand the underlying mechanisms through which PPI use leads to an increased risk of fractures, as this area is still poorly understood and controversial. We again thank Sugiyama et al. for their interest in our study. They and other readers are welcome to contact us for more discussion on it.