In this study, we found that presence of two diseases was associated with an increased risk of postoperative periprosthetic fractures. Peptic ulcer disease increased the risk of periprosthetic fracture by 87% and COPD increased the risk by 62%. This increased risk is significant both statistically and clinically. One key finding to be kept in mind is the robustness of these estimates. For both conditions, the estimates were attenuated only slightly from the univariate models to multivariable-adjusted regression models (adjusted for 16 variables simultaneously). Both conditions were also common in our patient cohort undergoing primary TKA (10% and 13% patients). These findings are important and novel and deserve further discussion.
The observation of association of peptic ulcer disease and periprosthetic fractures leads to additional interesting hypotheses that need to be tested in future studies. Is this association due to peptic ulcer disease? Or is it treatment-related (proton-pump inhibitors versus other therapies)? Emerging evidence in cohorts of postmenopausal women suggests a consistently increased risk of fragility fractures in patients using proton-pump inhibitors (24
), while it is unclear whether histamine-2 receptor blockers are associated with higher or lower fracture risk (24
). It remains to be seen whether these observations made for postmenopausal fragility fractures are true for patients undergoing TKA. These hypotheses need to be tested in TKA patients with periprosthetic fractures in future studies.
The association of COPD with periprosthetic fracture risk is not surprising considering that corticosteroids (inhaled, oral and parenteral) are used not uncommonly in patients with COPD. Some evidence exists in the non-arthroplasty literature regarding similar risks. COPD duration and severity and the use of inhaled corticosteroids were associated with increased risk of vertebral fractures (27
). The lack of availability of medication data in total joint registry limited us from performing additional analyses to investigate whether use of corticosteroids was the underlying reason for the association of COPD with periprosthetic fractures. Studies to examine these hypotheses in a different dataset that provides data on medication use in TKA cohorts are underway to determine the exact nature of this association.
How do these findings help surgeons and patients? Our study examined several diseases as potential predictors of periprosthetic fractures and found that only two comorbidities were associated independently with the risk. The knowledge gained from our study can be incorporated in patient-surgeon discussions regarding this increased risk in patients with peptic ulcer disease or COPD. These findings should also stimulate research into why these associations exist and further research into mechanisms of these associations.
These findings must be interpreted considering study limitations. Misclassification bias for comorbidity is possible, since we used electronically captured diagnoses. This may have biased some estimates towards the null, meaning that we may have missed some significant associations. Thus, our estimates are likely conservative. We may have missed periprosthetic fractures in some patients due to loss to follow-up, despite intensive efforts by dedicated total joint registry staff, and thus the cumulative incidence estimates may be conservative. However, as described earlier, dedicated registry staff makes every attempt to follow each patient prospectively for these outcomes. Another limitation is the inability to control for osteoporosis, an important confounder of association of other comorbidities and fracture risk. The study was not designed to examine operation-technique related factors and postoperative physical activity, covariates that may impact the observed associations. Studies are needed to address if after adjustment for these and other factors, the associations noted in our study hold true. Both loss to follow-up (underreporting of fractures in some patients not reachable through clinic, mail and phone contact) and misclassification of comorbidity and fractures due to capture from medical records (rather than a re-review and validation) likely biased our estimates towards null, making these estimates conservative, where the real associations may be even more impressive. However, there is a rigorous protocol to follow all post-arthroplasty patients for complications, the diagnosis of periprosthetic fractures were based on medical records including the operating room report, an orthopedic surgeon’s clinical note and/or review of outside records or radiographic films in all cases, and Deyo-Charlson comorbidities have been systematically captured in Mayo databases since 1994, a key reason for choosing this time-period for study. These procedures minimize these biases. Selection bias is unlikely to have impacted these results, since the sample consisted of every patient who underwent TKA and provided permission for use of their medical records (>98% of all patients seen at Mayo Clinic provide permission for use of data for research).
Our study has several strengths including use of prospectively collected data from the total joint registry and a large sample size allowing for meaningful analyses. Another strength is the use of multivariable adjusted analyses, that control for multiple important demographic, clinical and implant factors. Our estimates were robust, and showed minor attenuation when adjusted for several variables in multivariable analyses.
In summary, the presence of peptic ulcer disease and chronic obstructive pulmonary disease were associated with higher risk of postoperative periprosthetic fractures after primary TKA. The increase in risk was both statistically and clinically significant indicating by almost doubling of the risk. Surgeons should consider discussing this risk with patients prior to the surgery, considering that both conditions are common in patients undergoing TKA. Future studies should examine whether these associations are related to the disease (peptic ulcer disease or chronic pulmonary disease) or the treatments used for these conditions (proton-pump inhibitors, H2-blockers, corticosteroids etc.).