Fracture risk prediction & kidney function at different stages of chronic kidney disease: A correlation study

Materials & Methods

The non-experimental correlational research was conducted in July-December 2023 in the department of Nephrology, All India Institute of Medical Sciences Jodhpur, a tertiary care teaching hospital in Rajasthan, India. The institute’s ethical clearance was obtained from the Institutional Ethics Committee. The confidentiality and anonymity of the subjects was maintained throughout the study. The non-probability consecutive sampling technique was used to recruit the patients with CKD.

Results

The mean age of the participants was 51.42±9.95 yr. Of the total numbers of CKD patients, 66.3 per cent were between 40-55 yr, 25.3 per cent were 56-70 yr, and 8.4 per cent were ≥70 yr. The number of males was (65.3%), more than females (34.7%). More than half (60%) of total participants were from rural areas. 21.1 per cent, 25.3 per cent, and 53.7 per cent of patients were on CKD stages III, IV and V, respectively. Among laboratory parameters, mean serum creatinine was 5.32±3.19 mg/dl, serum urea level was 86.63±49.81 mg/dl, and mean eGFR was 17.96±13.36 ml/min. Bone mineral markers like serum calcium were 8.38±1.26 mg/dl, phosphorus was 5.28±2.02 mg/dl, serum vitamin D was 17.31±13.17 ng/ml, and iPTH was 349.81±564.71 pg/ml. The average femoral neck BMD of the study participants was 0.69±0.138. Table I presents the baseline characteristics of the study population.

Age was significantly associated with the FRAX-Score for major and hip osteoporotic fracture risk. In addition, occupation, area of residence, and stage of CKD were significantly associated with the FRAX score, as shown in supplementary table I, supplementary figures 1 and 2. Among laboratory parameters, eGFR, serum urea, serum chloride, and BMI were significantly associated with FRAX-Score (Supplementary Table II). In regression analysis, age, occupation, area of residence, and stage of CKD were independently associated with FRAX-Score for major osteoporotic fracture risk in this study (Table II; Fig. 1). Age, occupation, and resident area were significantly associated with the FRAX score for hip fracture risk. Overall, the FRAX-Score for hip fracture risk was not associated with the CKD stage; however, there was a significant increase in the hip fracture risk when stages III and V were compared (Fig. 2; Table III). In the different stages of CKD, the FRAX-Score for major osteoporotic fracture and hip fracture risk, age strongly contributes to fracture risk (Fig. 3 and 4). Table III shows that in CKD stage III, 50 per cent of the participants were normal, 40 per cent had osteopenia, and 10 per cent had osteoporosis. In CKD stage IV, 29.2 per cent of participants were normal, 54.4 per cent had osteopenia, and 16.7 per cent had osteoporosis. Similarly, in CKD stage V, 25.5 per cent had normal BMD, 64.7 per cent had osteopenia, and 9.8 per cent had osteoporosis.

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Fig. 1.

FRAX Score of major osteoporotic fracture among individuals with different stages of CKD. The boxplot diagram shows that the average 10-yr probability of major osteoporotic fracture risk in stage V was observed to be significantly higher (P= 0.018) than that in stage IV and stage III. Further investigation through post hoc testing revealed that there was a statistically significant difference found between major osteoporotic fracture risk for stage IV and stage V patients with CKD (P=0.017) and similarly stage III and stage V patients with CKD (P=0.010).

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Fig. 2.

FRAX Score of hip fracture among individuals with different stages of CKD. The boxplot diagram shows that the average 10-year probability hip fracture risk increases with stage of CKD. Further investigation through post hoc testing revealed that there was a statistically significant difference found between hip fracture risk for stage III and stage V patients with CKD (P= 0.038).

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Fig. 3.

Clustered Boxplot of FRAX-Score for Major Osteoporotic Fracture by Stage of CKD by Age. CKD stage and age significantly impact major osteoporotic fracture risk .

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Fig. 4.

Clustered Boxplot of FRAX-Score for Hip Osteoporotic Fracture risk by stage of CKD by Age. It highlights the impact of CKD and age with different stages and age groups. Both CKD stage and age had significant impacts on Hip osteoporotic fracture risk, especially when comparing stages III and V and age groups 40-55 and >70 yr.

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Discussion

While diabetes, hypothyroidism, and chronic liver disease are recorded as secondary causes of osteoporosis, it is interesting to note that CKD has not been incorporated in the same, despite studies showing a higher risk of fragility fractures. The original FRAX score development dataset included some patients with reduced eGFR, but the number was not significant enough to incorporate CKD as an isolated factor for osteoporosis^17-19. The present study demonstrates that advanced age significantly increases FRAX-scores for major osteoporotic and hip fractures. The association of fractures with age in CKD and the non-CKD population is well established^17,18. This finding is in line with the study done by Li et al²⁰, where the risk of osteoporotic fracture increased in elderly patients. Our findings align with previous studies highlighting age as a critical factor in fracture risk. A study done by Zhang et al²¹ found that patients aged >70 yr had significantly higher fracture risks compared to younger non-CKD patients, which is consistent with our finding of higher major osteoporotic and hip fracture risks in older age groups. A similar study done by Drake et al²² showed that increased age increases the risk of fracture.

Data on socioeconomic factors affecting the FRAX score and fracture risk within the general population is available but absent in CKD patients. The findings of this study revealed that major osteoporotic fracture and hip fracture risks are higher in the urban population than in the rural population, similarly, to the findings of Matsuzaki et al²³. In a systematic review comparing BMD among urban and rural residents, it was noted that BMD was five per cent lower in the urban population in high-income countries; results from low and middle-income countries did not show a significant difference in the pooled analysis. However, there are other studies which have shown urban population has less osteoporosis than rural^24,25. However, the present study is in contrast with the findings by Zheng et al²⁵, which revealed that the prevalence of osteoporosis is higher in rural (10.33%) populations as compared to urban (5.52%). In addition, a systematic review²⁶ analysed the relationship between the risk of osteoporotic fractures and socioeconomic factors - income, education, occupation, area of residence, and marital status. It was observed that there was a strong level of evidence for being married, a low level of evidence for being employed and having a larger house size, and no significant evidence for the level of income or educational qualification for a lower risk of fractures²⁶. In the present study, the type of occupation had an impact on the FRAX-Score, which needs further study to confirm this finding.

In this study using the Indian FRAX calculator, the average probability of major osteoporotic fractures in stage V was significantly higher (P=0.018) compared to stages IV and III. Post hoc testing further indicated a significant difference in the risk of major osteoporotic fractures between CKD stage IV and stage V (P=0.017), as well as between stage III and stage V (P=0.010). Additionally, the average probability of hip fractures was significant between stages III and V (P=0.038) in CKD patients. Our findings align with those of Manda et al², who reported an increase in the 10-year probability of major osteoporotic fractures in CKD stage IV (9.47±2.62%) compared to CKD stage III (1.92±0.8%) (P<0.0001). The results of our study suggest that patients in advanced stages of CKD (stages IV and V) have higher FRAX scores for major osteoporotic fractures compared to those in stage III (P=0.018). This is consistent with a study by Pimental et al²⁷, which found that fracture risk increases as kidney function declines, likely due to the mineral and bone disorders prevalent in advanced CKD.

In our study, 56.8 per cent of CKD participants had osteopenia, and 11.6 per cent had osteoporosis. Osteopenia can develop into osteoporosis if left untreated. The prevalence of osteopenia in our study is consistent with findings from Aggarwal et al²⁸, who reported osteopenia and osteoporosis rates of 42 per cent and 8.5 per cent, respectively. Additionally, research by Akkupalli et al²⁹ found that among CKD patients, the prevalence of osteopenia and osteoporosis was both 33.3 per cent each, respectively. Jha et al³⁰ also noted that the prevalence of osteopenia and osteoporosis in CKD patients was 37 per cent and 12 per cent, respectively. Likewise, Govindarajan et al³¹ reported a prevalence of 23.2 per cent for osteopenia and 8.3 per cent for osteoporosis among CKD patients. Our findings align with those of other earlier research in the Indian CKD population.

The present study did suffer from certain limitations. The study’s cross-sectional nature did not allow estimates of the fracture incidence to be calculated, and the FRAX score was used as a corollary for the same. Additionally, our study was done in an Indian population, limiting generalisability to the entire CKD population. While the FRAX score considers a good number of variables, including BMD at the femoral neck, density only represents the strength of the bone. Other parameters, such as bone quality and turnover, as measured by the trabecular bone score, bone biopsy, and biomarkers, also impact the risk of fractures and were omitted. Newer iterations of the FRAX score, which include the TBS, have also come up but require further validation.

Overall, this study not only validated the use of the FRAX score in the Indian CKD population but also demonstrated the effect of decreasing eGFR on the risk of fragility fractures. Importantly, it also fills the gap in terms of the role that socioeconomic and environmental factors play in the development of fragility fractures. Disparities in terms of area of residence, occupation, and education status are a stark reality in middle-and low-income countries like ours and warrant inclusion into a FRAX score specific to the Indian population. Moreover, long-term follow up studies are needed to establish the connection between CKD and fracture rates.