Chronic kidney disease (CKD) is common, with an estimated worldwide prevalence of 7% of patients in stage 3–5. In addition, with the aging of society, the incidence of chronic kidney disease, especially ESRD, is gradually increasing (6). Due to the advanced stage of chronic renal disease, renal osteodystrophy often occurs in ESRD patients, and subsequent fractures are common. Renal osteodystrophy usually interferes with bone metabolism and related hormone levels to reduce bone mass, strength and cause abnormal bone remodeling (7, 8). These bone abnormalities are common in most ESRD patients, especially those requiring dialysis (9). Therefore, patients with ESRD have a higher risk of fracture, and the risk of fracture increases as renal function declines. Fragility fractures in ESRD patients are a serious complication, resulting in high morbidity, high mortality (10), increased financial burden and prolonged hospitalization (11, 12). In recent years, there have been relatively few studies on fragility fractures in ESRD patients, and most have focused on cases from Europe and North America. Whether the results can be extrapolated to Asian populations is unclear because of differences in race and social structure. In our study, Chinese patients were the main subjects. Among the 521 patients studied, we found that the incidence of fragility fractures during the follow-up period was 8.4%, proximal femoral fractures and vertebral body fractures were the main types seen. The annual incidence of fragility fractures during follow-up was 2.76‰. Compared with other research, the incidence of fractures was similar, although our study showed an obvious decrease in annual incidence compared with data from the research of Tseng et al. (13 33). This may be related to our workload, which has over 2600 hemodialysis treatments per week. Dialysis patients are treated with high quality normative therapy in our hospital. The dialysis center nursing department has excellent education on the causes of fracture such as falls and dizziness.
Our study found that the FF group patients were significantly more likely to have underlying diseases such as essential hypertension and diabetes than the CG, and our subsequent correlation analysis showed that essential hypertension was an independent risk factor for fragility fractures. This conclusion is consistent with that reported by Yang, Sennerby, and Vestergaard P et al (14–16). We suspect that the reason may be linked to the high incidence of symptoms such as dizziness which occurs with blood pressure fluctuation, and high blood pressure-related urinary calcium loss which can cause bone quality decline. Although our experiment did not investigate this further, a literature search revealed that Rull (17) recommended a 24-hour urinary calcium and empty stomach calcium/creatinine ratio test that could offer better data support. This can be considered in future studies. We also hypothesize that diabetes causes blood glucose fluctuations that may result in symptoms such as dizziness, amaurosis fugax, or nausea and thus increase the risk of falls leading to fractures. Existing research (18–20) has detailed the association between diabetes and osteoporosis. Other results of studies into osteoporosis and fragility fractures are consistent with our research.
In this study, the nutritional indicators including hemoglobin, serum TC and LDL in patients with fragility fractures were significantly lower than those in the CG, while the levels of TG, high-density lipoprotein and apolipoprotein were slightly lower than those in the CG, but there was no statistical significance. This situation suggests a relationship between fragility fractures and nutritional status. The logistic regression analysis in this study suggests higher TC levels may be a protective factor for fractures. Sivas et al. (21) believe that the increase of TC could reduce the risk of vertebral fracture proportionately. Yamaguchi et al.(22) suggested that an increase of one standard deviation of TG reduced the risk of vertebral fracture in perimenopausal women by approximately 50%. However, Wang Y et al. pointed out that although high levels of TG were associated with fragility fractures, there was no relationship between increased TC at standard deviation and fracture susceptibility (23). The study by Trimpou et al. (24) found that high TC was directly associated with fracture susceptibility. We believe that the conflict between the two results achieved from the healthy people and ESRD patients may be the result of significant confounding factors. The relevant serum lipids and bone metabolism which are directly affected by chronic kidney disease and the common effect of statins and double phosphate on bone and lipid metabolism may have introduced biases. We believe that a moderately high level of cholesterol often represents a better nutritional status and is associated with effective dialysis. These patients have a better quality of life and are active so they have better motor strength and coordination of their skeletal muscles, thus reducing the risk of fragility fracture. We recommend a follow-up study with an expanded sample size in ESRD patients to confirm our speculation.
We found that ESRD patients in the FF group had higher serum calcium, serum corrected calcium and alkaline phosphatase levels than the CG, while iPTH levels were lower than the CG. Similarly, in the comparative study based on the levels recommended by KDIGO, the fracture rate of the target level and the high corrected calcium group was higher than that of the low corrected calcium group, and the fracture rate of the low iPTH group was higher than that of the target level and the high iPTH group. The regression analysis also confirmed that fragility fracture was correlated with the low iPTH and a high level of corrected calcium. We speculate that this might be related to low calcium and high phosphatemia in CKD patients, resulting in prescribed calcium supplements or calcitriol. High alkaline phosphatase and high serum calcium not only did not lead to increased bone calcium deposition but also led to excessive inhibition of iPTH and failure of osteoblastic transformation and function. These processes affected the mineralization of bone and led to increased fracture susceptibility. The relationship between low iPTH and fracture has been confirmed in the studies of Matias PJ(25) and Atsumi(26). The study of Maruyama et al. (27) also confirmed that elevated alkaline phosphatase in ESRD patients increased the risk of fracture. In many of the reports we reviewed, the significant effects of hyperphosphatemia on the prognosis of ESRD patients has been repeatedly noted, but in our study, there was no significant difference in serum phosphorus levels between the fracture group and the CG, and further studies have shown no significant difference in fracture incidence among the subgroups of serum phosphorus defined by KDIGO. This may reveal that although hyperphosphatemia is closely related to the prognosis of ESRD patients, it is not a risk factor for brittle fracture. The serum level of vitamin D3 was not included in this study, which may be a confounding factor. Further research will be carried out in follow-up experiments.
In this study, we found that 77.3% of the patients died in the FF group and 25.0% of them died from the cardiovascular event. Both all-cause mortality and the cardiovascular event mortality were higher in the FF group. it was found that the survival rate and life span of patients with fragility fractures decreased significantly. We speculate that the impact of fragility fractures on the risk of death is due firstly, to an increased risk of cardiovascular events. Shantouf et al. (28) showed that high serum alkaline phosphatase may be associated with metastatic calcification of soft tissue. Therefore, high levels of alkaline phosphatase in ESRD patients with fragility fractures may promote arterial and cardiac calcification. In our study, the COX regression analysis showed that high LDL was an independent risk factor for all-cause mortality, and high LDL was also a risk factor for arterial calcification and cardiac valve calcification (29). This study did not confirm the calcification of artery and heart valve in patients, this should be investigated in future studies. Secondly, there may be an increased risk of infection. Fractures can lead to prolonged bed rest, an increased risk of hypostatic pneumonia, and a risk of developing refractory systemic infection, leading to septic shock and systemic multi-organ failure. We found that the fracture group had more deaths from septic shock and multiple organ dysfunction than the CG, which supports our hypothesis. Studies by Groff(30), Dodd(31) and many scholars have also confirmed the association between secondary infection after fracture and patient death.