Abstract:Proton pump inhibitors (PPIs) belong to the most common medication in geriatric medicine. They are known to reduce osteoclast activity and to delay fracture healing in young adult mice. Because differentiation and proliferation in fracture healing as well as pharmacologic actions of drugs markedly differ in the elderly compared to the young, we herein studied the effect of the PPI pantoprazole on bone healing in aged mice using a murine fracture model. Bone healing was analyzed by biomechanical, histomorphomet… Show more
“…Of interest, we failed to observe a significant difference of serum calcium level and amount of daily calcium intake among non-user, PPI user, and H2RA user, but our result still showed an association of PPI use with lower BMD. A recent study demonstrated that pantoprazole accelerated bone turnover by affecting the number of osteoclasts and decreased the expression of bone morphogenetic protein-4 (BMP-4) in aged mice, indicating PPIs may affect bone metabolism by regulating bone formation ( 27 ).…”
Aims: The association of acid suppressants use with bone mineral density (BMD) is still unclear, especially in older adult with prolonged use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs). In this study, our aim was to investigate the association between PPI or H2RA use and BMD in general US older adults.Methods: We conducted a cross-sectional study on a sample from National Health and Nutrition Examination Survey. Association between long-term use of PPIs or H2RAs and lumber spine BMD in elderly was evaluated using weighted multivariate linear regression models. Sensitive and subgroup analysis were also performed in this study.Results: Long-term PPI use is correlated with lower lumber spine BMD in our multivariable regression model after adjusting for known confounding factors. Further analysis showed PPI use with a duration over 1 year was negatively associated with lumber spine BMD in male, elderly aged over 70 years, and white elderly. There is no significant association between long-term H2RA use and lumber spine BMD.Conclusions: Our results indicated that the association between long-term use of PPI and lumber spine BMD differed by gender. Long term use of PPIs would reduce lumber spine BMD in older men, while H2RA use is not significantly linked with lumber spine BMD. Patients that are at high risk of bone loss should shortened the duration of PPI use (<1 year) or use H2RAs as alternative if possible.
“…Of interest, we failed to observe a significant difference of serum calcium level and amount of daily calcium intake among non-user, PPI user, and H2RA user, but our result still showed an association of PPI use with lower BMD. A recent study demonstrated that pantoprazole accelerated bone turnover by affecting the number of osteoclasts and decreased the expression of bone morphogenetic protein-4 (BMP-4) in aged mice, indicating PPIs may affect bone metabolism by regulating bone formation ( 27 ).…”
Aims: The association of acid suppressants use with bone mineral density (BMD) is still unclear, especially in older adult with prolonged use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs). In this study, our aim was to investigate the association between PPI or H2RA use and BMD in general US older adults.Methods: We conducted a cross-sectional study on a sample from National Health and Nutrition Examination Survey. Association between long-term use of PPIs or H2RAs and lumber spine BMD in elderly was evaluated using weighted multivariate linear regression models. Sensitive and subgroup analysis were also performed in this study.Results: Long-term PPI use is correlated with lower lumber spine BMD in our multivariable regression model after adjusting for known confounding factors. Further analysis showed PPI use with a duration over 1 year was negatively associated with lumber spine BMD in male, elderly aged over 70 years, and white elderly. There is no significant association between long-term H2RA use and lumber spine BMD.Conclusions: Our results indicated that the association between long-term use of PPI and lumber spine BMD differed by gender. Long term use of PPIs would reduce lumber spine BMD in older men, while H2RA use is not significantly linked with lumber spine BMD. Patients that are at high risk of bone loss should shortened the duration of PPI use (<1 year) or use H2RAs as alternative if possible.
“…The CD-1 outbred mouse has been used in a variety of experimental studies to investigate the effects of pharmacological substances on fracture healing [7][8][9] and develop novel treatment strategies to facilitate bone regeneration [10,11]. Additionally, CD-1 mice have been successfully applied in orthopedic research, which focuses on fracture healing in aged animals [12,13]. However, to our knowledge, no study has yet compared the radiographic, biomechanical and histological healing properties of aged animals with those of young adult CD-1 mice.…”
With a gradually increasing elderly population, the treatment of geriatric patients represents a major challenge for trauma and reconstructive surgery. Although, it is well established that aging affects bone metabolism, it is still controversial if aging impairs bone healing. Accordingly, we investigated fracture healing in young adult (3–4 months) and aged (16–18 months) CD-1 mice using a stable closed femoral fracture model. Bone healing was analyzed by radiographic, biomechanical and histological analysis at 1, 2, 3, 4 and 5 weeks after fracture. Our results demonstrated an increased callus diameter to femoral diameter ratio in aged animals at later time points of fracture healing when compared to young adult mice. Moreover, our biomechanical analysis revealed a significantly decreased bending stiffness at 3 and 4 weeks after fracture in aged animals. In contrast, at 5 weeks after fracture, the analysis showed no significant difference in bending stiffness between the two study groups. Additional histological analysis showed a delayed endochondral ossification in aged animals as well as a higher amounts of fibrous tissue at early healing time points. These findings indicate a delayed process of callus remodeling in aged CD-1 mice, resulting in a delayed fracture healing when compared to young adult animals. However, the overall healing capacity of the fractured femora was not affected by aging.
“…Noteworthy, the intrinsic angiogenic response was sufficient for adequate vascularization during non-union formation, however, the failure of fracture healing was associated with a decreased expression of the pro-osteogenic proteins BMP-2 and BMP-4 [ 79 ]. Moreover, our own recent investigation on the effects of pantoprazole on fracture healing in aged mice demonstrated that impaired bone healing is associated with a decrease in the protein expression ratio of pro-osteogenic to pro-angiogenic growth factors, such as VEGF and cysteine rich protein(CYR)61 [ 80 ]. Fig.…”
Despite major research efforts to elucidate mechanisms of non-union formation, failed fracture healing remains a common complication in orthopedic surgery. Adequate vascularization has been recognized as a crucial factor for successful bone regeneration, as newly formed microvessels guarantee the supply of the callus tissue with vital oxygen, nutrients, and growth factors. Accordingly, a vast number of preclinical studies have focused on the development of vascularization strategies to stimulate fracture repair. However, recent evidence suggests that stimulation of blood vessel formation is an oversimplified approach to support bone regeneration. This review discusses the role of vascularization during bone regeneration and delineates a phenomenon, for which we coin the term “the vascularization paradox of non-union-formation”. This view is based on the results of a variety of experimental studies that suggest that the callus tissue of non-unions is indeed densely vascularized and that pro-angiogenic mediators, such as vascular endothelial growth factor, are sufficiently expressed at the facture site. By gaining further insights into the molecular and cellular basis of non-union vascularization, it may be possible to develop more optimized treatment approaches or even prevent the non-union formation in the future.
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