Urolithiasis is known for its high prevalence and recurrence rate; therefore, close follow-up is important for preventing stone relapse and symptomatic events for better patient care [1,2] In this study, we tried to investigate the relationship between the BMD and follow-up outcomes of patients with urolithiasis in clinical practice. Patients at high risk of urolithiasis, such as those with metabolic syndrome and metabolic abnormalities [16] should be carefully evaluated and followed-up; we speculate that the screening of BMD could be useful for reduce urinary risk factors including hypocitraturia and future symptom onset.
The relationship between urolithiasis and BMD was first reported in 1976 by Alhava et al. [17]. In their cohort of 21 male and 54 female participants, they found that the BMD was statistically lower in patients with urolithiasis than in healthy controls of both sexes. Since then, the association of urolithiasis with hypercalciuria and low BMD, particularly in postmenopausal women, has been recognized [18]. The main concern regarding bone metabolism in patients with urolithiasis is not only about having a higher chance of recurrence but also having a potential risk for fractures. A retrospective cohort study in the United Kingdom demonstrated that urolithiasis was associated with higher fracture risk, especially in adolescent boys and older women [19]. Similarly, two large cohort studies in the United States revealed that nephrolithiasis was associated with a markedly high risk of wrist fractures in both men and women (relative risk: 1.20) [20]. Interestingly, the Women’s Health Initiative report indicated a significant association between urolithiasis and incidental total fractures in postmenopausal women by unadjusted analyses; however, covariate-adjusted analyses revealed no statistical association between them [21]. Although there is no absolute conclusion, a recent meta-analysis suggested that patients with nephrolithiasis had significantly lower T-scores, was four times more likely to have osteoporosis, and had a potentially increased risk of fractures [7].
The low BMD in patients with urolithiasis, especially calcium-containing stone formers, is caused by calcium metabolism disorders including hypercalciuria [6,22]. In fact, patients with urolithiasis have a high occurrence rate of hypercalciuria, up to 50% reported in the literature [23]. Unlike the results of previous reports from Europe and the United States [9,24], our cohort had only 8.6% hypercalciuria in both men and women but had a higher prevalence of hypocitraturia. Similar to our study cohort, a Japanese cohort also had a lower prevalence of hypercalciuria [18]. Low BMD is found to be associated with hypercalciuria; this could be an independent risk factor for developing urolithiasis [25–27]. Owing to our unique demography, a low prevalence of hypercalciuria was observed in those with low BMD and postmenopausal women; we hypothesize that a different mechanism from hypercalciuria may cause a lower BMD in Japanese patients with urolithiasis. This needs further essential investigation. Our study also demonstrated the demographic differences between premenopausal and postmenopausal women with urolithiasis. Despite the relatively low number of patients in our study, the finding that postmenopausal women had a higher prevalence of hypertension, lower BMD, and hypocitraturia was consistent with current evidence [28], implying that postmenopausal status was associated with a higher risk of urolithiasis.
The current study also demonstrated some correlation between BMD and urinary parameters, such as hyperphosphaturia and hypocitraturia. There was a positive association between T-scores and urinary phosphate excretion in men and postmenopausal women with urolithiasis. Although no prior research directly detected this relationship, a few papers indicated the relationship between low BMD and phosphaturia [29,30]. Since the bone resorption mechanism involves phosphate metabolism, which is also regulated by the intestinal phosphate absorption, hyperphosphaturia in urolithiasis may be linked to lower BMD; this may explain the risk for stone development. Furthermore, we found that urinary citrate excretion was positively associated with T-scores in men and premenopausal women with urolithiasis. Citrate is considered to decrease with acidosis under circumstances of increasing bone resorption; therefore, patients with urolithiasis with osteopenia or osteoporosis tend to have hypocitraturia [24,31]. In fact, some papers indicated that potassium citrate treatment reversed low BMD [32,33]. Such evidence suggests that awareness of urinary citrate levels is essential for evaluating stone development risk factors, including BMD.
Most importantly, logistic regression analyses revealed that female sex was associated with a decreased odds ratio for stone recurrence, whereas osteoporosis status (T-score <−2.5) was associated with an increased odds ratio for developing stone symptoms; however, hyperoxaluria was associated with a decreased odds ratio for developing stone symptoms. Interestingly, this result of association between T-scores <-2.5 and symptomatic stones was not observed on univariate analysis; this was probably due to the presence of confounders such as age, BMI, sex, and presence of urinary abnormalities. Examining BMD in patients with urolithiasis is important for effective follow-up; therefore, in real-world practice, this BMD evaluation may be performed in patients with a high-risk of urolithiasis at initial metabolic evaluation.
This study has several limitations, the primary being the study design. Although we could capture a large number of follow-up patients with urolithiasis who had both BMD and 24-hour urine examinations, this single-center retrospective cohort study may not reflect daily practice data around the world. As described above, the prevalence of hypercalciuria was quite low, unlike previously reported rates among other ethnicities, suggesting a potential difference in calcium metabolism between the Asian population and others. Additionally, there is a lack of evidence regarding the stone composition and dietary/fluid records, which affect data interpretation. Preventive measures, such as bisphosphonates and NaKCit, may be biased by the preferences of physicians who diagnose and record the appropriate disease codes for connecting with the national insurance system. Lastly, our study did not include some bone turnover markers [6,9] such as osteocalcin, β-cross-laps, and 25-hydroxy vitamin D, useful for evaluating bone metabolism; however, we believe that the current data set represents real-world data more accurately than currently available data.