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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 29  |  Issue : 3  |  Page : 145-150

Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study


1 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan
2 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
3 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
5 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, Kaohsiung Municipal Siaogang Hospital; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
6 Department of Urology, Kaohsiung Medical University Hospital; Department of Urology, Kaohsiung Municipal Siaogang Hospital; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

Date of Web Publication27-Jun-2018

Correspondence Address:
Tsu-Ming Chien
Department of Urology, Kaohsiung Medical University, Hospital, Hospital No. 100, Tz-You 1st Road, Kaohsiung 807
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_20_17

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  Abstract 

Objective: We aimed to determine whether urolithiasis is a warning sign indicating long-term osteoporosis. Controls were matched for age, sex, and other comorbidities, including hypertension, diabetes mellitus, dyslipidemia, liver disease, and cardiovascular disease. Materials and Methods: Data were obtained from the Longitudinal Health Insurance Database (LHID2000) of Taiwan, Republic of China, compiled by the NHI from 1996 to 2013. We further evaluated potential risk factors stratified by different comorbidities. Results: After performing the propensity score matching (urolithiasis: control; ratio, 1:3), we included a total of 104,900 patients, including 26,225 patients with urolithiasis and 78,675 control patients. There was a significant difference between the incidence of osteoporosis between the urolithiasis and control groups (adjusted hazard ratio 1.20, 95% confidence interval [CI]: 1.15–1.27, P < 0.001). Interestingly, the impact of urolithiasis on osteoporosis was more prominent in the younger patient population (age < 40 years, adjusted hazard ratio 1.4, 95% CI: 1.12–1.75, P = 0.003; 40–59 years, adjusted hazard ratio 1.3, 95% CI: 1.20–1.40, P < 0.001), than in the older patient population (age >60 years, adjusted hazard ratio 1.13, 95% CI: 1.05–1.21, P = 0.001; P = 0.015 for interaction). We also observed that urolithiasis had an impact on hypertension-free patients (hypertension free, adjusted hazard ratio 1.28, 95% CI: 1.20–1.36, P < 0.001; hypertension, adjusted hazard ratio 1.12, 95% CI: 1.03–1.22, P = 0.006, P = 0.020 for interaction). Conclusion: In conclusion, on the basis of our results, an association exists between urolithiasis patients and subsequent osteoporosis diagnosis. Although the clinical mechanisms are not fully understood, patients who had urolithiasis history may need regular follow-up of bone marrow density.

Keywords: Osteoporosis, risk factors, urolithiasis


How to cite this article:
Lu YM, Chien TM, Li CC, Chou YH, Wu WJ, Huang CN. Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study. Urol Sci 2018;29:145-50

How to cite this URL:
Lu YM, Chien TM, Li CC, Chou YH, Wu WJ, Huang CN. Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study. Urol Sci [serial online] 2018 [cited 2018 Jul 20];29:145-50. Available from: http://www.e-urol-sci.com/text.asp?2018/29/3/145/232251


  Introduction Top


Urolithiasis is considered an important public health issue with a substantial burden on human health and considerable national economic consequences.[1] The prevalence of symptomatic kidney stones in Taiwan is approximately 9.6% of the general population throughout their lifetime.[2] In addition, evidence has shown a marked increase in stone disease in the past 15 years, compared with the 3rd National Health and Nutrition Examination Survey cohort.[3]

Calcium stones account for more than 80% of urolithiasis cases, and the percentage is even higher among patients with first-time symptomatic kidney stones (>90%).[3],[4] It is difficult to predict the composition of the stone until it is collected. Therefore, estimating stone composition and predicting the recurrence rate is nearly impossible.

Previous studies have shown that a relationship exists between the loss of bone mineral density and calcium urolithiasis.[5],[6],[7] It is also commonly known that calcium urolithiasis occurs in patients with idiopathic hypercalciuria.[6],[8] Furthermore, researchers using dual-energy X-ray absorptiometry reported that recurrent calcium urolithiasis and fasting hypercalciuria is linked to an increased incidence of bone mineral density loss, and therefore, a greater risk for osteopenia and osteoporosis.[6]

Although urolithiasis and osteoporosis are two distinct pathological entities, they are both characterized by higher complications, especially in older patients. This is considered an important public health issue, with a substantial burden on human health and considerable national economic consequences. Osteoporosis, which decrease bone strength, is one of the main risk factors associated with bone fracture in elderly patients. Typically, there are no obvious symptoms of osteoporosis until a patient has a bone fracture. In menopausal women, bone loss occurs even faster due to a decrease in estrogen.

There are many factors that increase the risk for urolithiasis, including family heredity, dietary habit, hydration status, different lifestyle, and environmental factors. Calcium hemostasis, substantial amount of consumption and excretion, in the body is also affected by multiple factors. In a previous study,[9] researchers showed that urolithiasis and bone disease, including osteoporosis, had similarities in bone metabolism pertaining to pathogenesis. Alternating bone resorption and increasing calcium loss through urine excretion increases urine supersaturation, and has been suggested to be associated with an elevated risk for urolithiasis.[8] In a recent population-based study, researchers showed that nephrolithiasis is associated with a higher risk of wrist fractures.[7] Osteoporosis is a risk factor associated with osteoporotic fractures, and to our knowledge, few studies have focus on the relationship between urolithiasis and osteoporosis.

Furthermore, published reports have almost exclusively focused on Caucasian populations; studies evaluating the Asian population are rare. In the present study, we used the Taiwan National Health Insurance (NHI) database to determine whether urolithiasis is a warning sign indicating long-term osteoporosis. Controls were matched for age, sex, and other comorbidities, including hypertension, diabetes mellitus, dyslipidemia, liver disease, and cardiovascular disease. To our knowledge, this is one of the largest cohorts examining the association between osteoporosis and prior urolithiasis.


  Materials and Methods Top


Data were obtained from the Longitudinal Health Insurance Database (LHID2000) of Taiwan, Republic of China, compiled by the NHI from 1996 to 2013. In Taiwan, <2% of the population is not covered by this insurance system (n = 23.7 million). Hence, the database is presumed to include >98% of hospital admission records. The LHID2000 includes the medical records of 1,000,000 individuals randomly sampled from all NHI enrollees. Many researchers in Taiwan use the LHID2000 database for scientific studies. The present study was supervised by the review board of Kaohsiung Medical University Hospital. De-identified secondary data from the LHID2000 were released to the researchers for study purposes.

This retrospective study consisted of a study group and a comparison group. Patients were diagnosed with renal stones based on two criteria, (1) The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic code 592, and (2) The code was assigned by urologists or nephrologist. Patients were diagnosed with osteoporosis using claims data containing ICD-9-CM diagnostic code 733.0. In Taiwan, osteoporosis is defined as a T-score ≤−2.5 measured using dual-energy X-ray absorptiometry at the spine, hip, or forearm. Exclusion criteria were patients aged <18 years, a diagnosis of osteoporosis before the index stone date, incomplete demographic data, <90 days of follow-up, or osteoporosis occurring within 90 days after the first stone episode. Among the remaining patients with renal stones, we defined the index date as the date of the first ambulatory care visit or hospitalization. In the control group, we included patients without renal stones and matched for age, sex, and other comorbidities between January 2000 and December 2003.

Statistical analysis

Differences between categorical parameters were assessed using the χ2 or Fisher's exact test. Basic social demographic data including age, sex, urbanization level, monthly income, and selected comorbidities were considered risk factors for the incidence of urolithiasis. We included data pertaining to comorbidities including hypertension, diabetes mellitus, dyslipidemia, liver disease, and cardiovascular disease because they are potential risk for osteoporosis. Therefore, we adjusted for these potential confounders in our study cohort. Propensity score matching was used to reduce the bias of confounding variables that could be found in the treatment effect, which were obtained by simply comparing outcomes among units that received Kaplan–Meier analysis was applied to estimate the effect of urolithiasis on osteoporosis-free rates. Follow-up was terminated with the last NHI record, death, or osteoporosis diagnosis. Urolithiasis was studied as a time-dependent covariate in a Cox proportional hazard model to estimate the hazard ratio and 95% confidence intervals (CI) for the effect of osteoporosis in patients after urolithiasis. We also adjusted the significant interaction effect in the saturated model for interaction analyses. Statistical significance was set at P < 0.05. We used SPSS 20.0 (SPSS Inc., Chicago, IL, USA) for all statistical analyses.


  Results Top


The sample population from the LHID2000 database identified 69,177 patients aged < 18 years between January 1, 2001, and December 31, 2003. We first excluded these patients because of the relatively low disease prevalence in this age group, and the possibility of congenital or nutritional problems. Then, 8901 patients with a history of osteoporosis before their index date were excluded. An additional 29 patients with incomplete demographic data were excluded. After performing the propensity score matching (urolithiasis: control; ratio, 1:3), we included a total of 104,900 patients, including 26,225 patients with urolithiasis and 78,675 control patients. [Table 1] shows the basic characteristics and comorbidities in both groups. The mean age for the entire cohort was 45.8 ± 15.6 years. There was no difference in age, sex, monthly income, or comorbidities between the groups.
Table 1: Basic characteristics between urolithiasis and control groups (n=104,900)

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As shown in [Table 2], there was a significant difference between the incidence of osteoporosis between the urolithiasis and control groups (adjusted hazard ratio 1.20, 95% CI: 1.15–1.27, P < 0.001). The incidence rate of osteoporosis during the follow-up period was 9.25/1000 person-years in the urolithiasis group, and 7.79/1000 person-years in the control group. We further evaluated these findings using a Kaplan–Meier survival analysis of osteoporosis. [Figure 1] shows that the urolithiasis group had poorer osteoporosis-free rates than the control group (P = 0.012) using the log-rank test. The overall average follow-up time was 9.0 ± 2.5 years in the urolithiasis group and 9.1 ± 2.4 years in the control group. There was no significant difference in follow-up time between groups [Table 1]. The average patient age at the onset of osteoporosis after the occurrence of an index stone was 4.1 ± 3.0 years and 4.0 ± 2.9 years in the urolithiasis and control groups, respectively. No significant differences were seen in the timing of osteoporosis onset between groups [Table 1].
Table 2: The risk of osteoporosis between urolithiasis and control groups stratified by comorbidities (n=104,900)

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Figure 1: Kaplan–Meier estimate of absence of osteoporosis in patients with urolithiasis history and control patients

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We further evaluated potential risk factors stratified by different comorbidities. Interestingly, the impact of urolithiasis on osteoporosis was more prominent in the younger patient population (age <40 years, adjusted hazard ratio 1.4, 95% CI: 1.12-1.75, P = 0.003; 40–59 years, adjusted hazard ratio 1.3, 95% CI: 1.20–1.40, P < 0.001), than in the older patient population (age > 60 years, adjusted hazard ratio 1.13, 95% CI: 1.05–1.21, P = 0.001; P = 0.015 for interaction). We also observed that urolithiasis had an impact on hypertension-free patients (hypertension free, adjusted hazard ratio 1.28, 95% CI: 1.20–1.36, P < 0.001; hypertension, adjusted hazard ratio 1.12, 95% CI: 1.03–1.22, P = 0.006, P = 0.020 for interaction). Urolithiasis status in a patient without dyslipidemia or cardiovascular disease did not affect the rate of osteoporosis.


  Discussion Top


Age

The prevalence of osteoporosis becomes higher with age. In a previous report, researchers showed that 2%–8% of men and 9%–38% of women aged ≥50 years living in industrialized countries are affected depending on the examination of diagnosis. Almost half of the older patients – especially those >60 years – may experience a decrease in bone density.[10] The results of our study confirm that the incidence of osteoporosis gradually increases with age. Approximately 20% of patients were diagnosed with osteoporosis. Although the incidence of osteoporosis is low, the impact of prior urolithiasis history seems to be significant. In previous studies,[11],[12] researchers identified underlying secondary causes for osteoporosis, including chronic inflammatory, endocrine, neuromuscular, metabolic, or medications, in a young population of patients with osteoporosis or clinical fractures associated with osteoporosis.[13] Therefore, treating the underlying disease may also improve bone mass. Data from a recent report indicated that family history of stones was strongly associated with a more severe clinical course in young patients with calcium urolithiasis. We have traditionally considered that abnormal urinary metabolic factors are strong risk factors for stone recurrence in clinical practice. However, the current study [14] showed that urinary chemistries were unaffected in young patients. The pathophysiology of young patients with urolithiasis is complex, and so far, no conclusive theory has been reached. Further studies are warranted to evaluate the interaction between osteoporosis and prior urolithiasis in young patients.

Sex

Researchers of the osteoporotic fractures in men study (MrOS)[15] showed that trabecular and cortical volumetric bone mineral density appear to differ in older men. They also reported that urolithiasis is one of the most significant negative risk factors for osteoporosis. In the CHAMP study,[16] researchers showed that a history of kidney stones is associated with lower bone mineral density in the hip of men. Conversely, the impact of urolithiasis history on bone mineral density is still diverse for women in different reports.[7],[11],[13],[17],[18],[19] In postmenopausal women, estrogen deficiency may cause accelerated bone turnover rate, which in turn may contribute to osteoporosis. Recent data on postmenopausal women taking hormone therapy from the Cochrane database,[20] demonstrated a significant decrease in the incidence of fractures with a long-term use. In another study, researchers evaluated the relationship between osteoporosis and prior urolithiasis. They concluded that urolithiasis was not linked to changes in bone marrow density at any skeletal site in postmenopausal women.[17] However, Taylor et al.[7] demonstrated that a history of urolithiasis was strongly associated with wrist fractures in women. In addition, they found that the discrepancy may vary at different skeletal sites. Our results showed the incidence of osteoporosis is much higher in women with urolithiasis than in men with the disease. Another clinical trial [21] showed that hormone therapy increases the risk for nephrolithiasis in healthy postmenopausal women. The underlying mechanism of action of estrogen supplementation as it relates to osteoporosis and urolithiasis in postmenopausal women remains unsolved. Therefore, estrogen use still needs to be considered in clinical decision-making for these patients.

Hypertension

Some known factors such as older age, menopausal status, diabetes, hypertension, smoking, diet, and physical activity are related to bone and cardiovascular health.[22] Hypertension has been shown to be an independent risk factor for bone fractures (adjusted hazard ratio 1.49, 95% CI: 1.13–1.96).[23] One review article showed that bone and cardiovascular health may be linked because all cardiovascular drugs used in patients with hypertension seemed to have beneficial effects on bone marrow density in vitro and in vivo. In human studies, they were associated with increases (or preservation) in bone marrow density, and/or a reduction in osteoporotic fractures.[24] The authors also recommended against the use of loop diuretics, due to its possible negative effects on bone health, in patients with a high risk of fractures and who need hypertension drugs. In addition, other agents such as thiazides, cardioselective beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors all have equal benefits to improve bone marrow density. In our report, patients with hypertension were classified using ICD-9-CM diagnostic codes 401–405 for hypertension medication use, including ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta-blockers, and diuretics. Prior history of urolithiasis influences the occurrence of osteoporosis in patients without hypertension, and the effects are not so obvious in hypertension patients.

Dyslipidemia

Until now, limited studies have invested lipid metabolism and the risk for fractures or bone loss. It has been reported that the differentiation of osteoblast is affected by adipose tissue. Adami et al.[25] showed that lipid profiles are associated with bone mass in men and women. Increased mass of adipose tissue may increase the risk for osteoporosis.[26] Osteoblast differentiation may be inhibited by increased oxidative stress through lipid oxidation,[27] as well as proinflammatory adipokines, which may enhance osteoclast differentiation.[28] Yamaguchi et al.[29] showed that plasma low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were inversely and positively correlated with bone marrow density plasma values, but that triglycerides levels seem to have a protective effect on vertebral fractures in postmenopausal women. The actual mechanisms of action are not definite. However, observational studies have shown that using statin, a 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitor, that blocks the synthesis of mevalonate and isoprenoids, may be beneficial in patients with osteoporosis by inhibiting osteoclast activity and osteoblast apoptosis.[27],[30],[31] The second speculated mechanism of action pertains to the anti-inflammatory action to protect from inflammation, which is a main determinant of osteoporosis. There is an elevation in inflammatory cytokines in postmenopausal women; statins may alleviate such influence through anti-inflammatory activities.[31] Meta-analysis results showed that statins may help improve and maintain bone marrow density in the lumbar spine, hip, and femoral neck of patients, especially in Caucasians and Asians.[32] Based on these data, statin therapy may represent a potential alternative target for the treatment of patients with osteoporosis. In our study cohort, patients with dyslipidemia were not influenced by prior stone history for consequent osteoporosis. Treating patients with dyslipidemia may also treat osteoporosis, irrespective of previous history of urolithiasis.

Limitations

There are several limitations in our study. First, this was a retrospective analysis using the NHI database. As with most retrospective studies, data may be subject to incomplete, missing, or inaccurate reporting of events. Second, the urolithiasis and osteoporosis diagnoses were based on ICD-9-CM codes released by NHI. Accurate diagnoses were not confirmed by standard criteria. Third, the database did not record stone size or the numbers of stone episodes; therefore, stone burden may not be the same between groups. Fourth, we did not adjust for other predisposing factors, such as smoking, family history, body mass index, obesity, and dietary habits, other endocrine problems, because these data were not recorded in the NHI database. Fifth, clinical decision-making was often performed by a clinical physician, and selection bias might have occurred. Despite these limitations, this study is based on one of the largest longitudinal database in the world.


  Conclusion Top


On the basis of our results, an association exists between urolithiasis patients and subsequent osteoporosis diagnosis. Although the clinical mechanisms are not fully understood, patients who had urolithiasis history may need regular follow-up of bone marrow density.

Acknowledgements

Yu-Han Chang analyzed and interpreted the data.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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