- Email: [email protected]
Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study
Urological Science xxx (2017) 1e5
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study Yen-Man Lu a, b, Tsu-Ming Chien a, Ching-Chia Li a, c, d, Yii-Her Chou a, d, Wen-Jeng Wu a, b, c, d, Chun-Nung Huang a, b, d, * a
Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan d Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 February 2017 Received in revised form 6 July 2017 Accepted 27 July 2017 Available online xxx
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% CI 1.15e1.27, 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 1.12e1.75, p ¼ 0.003; 40e59 years, adjusted hazard ratio 1.3, 95% CI 1.20e1.40, p < 0.001), than in the older patient population (age >60 years, adjusted hazard ratio 1.13, 95% CI 1.05e1.21, p ¼ 0.001; p ¼ 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 1.20e1.36, p < 0.001; hypertension, adjusted hazard ratio 1.12, 95% CI 1.03e1.22, p ¼ 0.006, p ¼ 0.020 for interaction). Conclusion: In conclusion, on the basis of our results, an association exists between urolithiasis patients and subsequent osteoporosis diagnosis. Though the clinical mechanisms are not fully understood, patients who had urolithiasis history may need regular follow up of bone marrow density. Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Urolithiasis Osteoporosis Risk factors
1. Introduction 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 (NHANES III) cohort.3
* Corresponding author. Department of Urology, Kaohsiung Medical University Hospital, No. 100, Tz-You 1st Road, Kaohsiung 807, Taiwan. Fax: þ886 7321 1033. E-mail address: [email protected] (C.-N. Huang).
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.5e7 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
http://dx.doi.org/10.1016/j.urols.2017.07.010 1879-5226/Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
2
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
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 via 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. 2. 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. In Taiwan, less than 2% of the population is not covered by this insurance system (n ¼ 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 (DXA) 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 followup, 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. 2.1. Statistical analysis Differences between categorical parameters were assessed using the c2 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 KaplaneMeier 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 timedependent 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. 3. Results The sample population from the LHID2000 database identified 69,177 patients aged <18 years between January 1, 2001 to 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 prior to 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. 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 1.15e1.27, p < 0.001). The incidence rate of osteoporosis during the follow-up period was 9.25 per 1000 person-years in the urolithiasis group, and 7.79 per 1000 person-years in the control group. We further evaluated these findings using a KaplaneMeier survival analysis of osteoporosis. Fig. 1 shows that the urolithiasis group had poorer osteoporosisfree rates than the control group (p ¼ 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). 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 1.12e1.75, p ¼ 0.003;
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
3
Table 1 Basic characteristics between urolithiasis and control groups (N ¼ 104,900). Variables
Age <40 40-59 60 Mean ± SD (years) Gender Female Male Insurance range < NT 14,999 NT 15,000e29,999 SNT 30,000 Comorbidities Diabetes Hypertension Hyperlipidemia Liver disease Cardiovascular disease Average follow up duration Mean ± SD (years) Average HTN new-onset duration Mean ± SD (years)
Overall (N ¼ 104,900)
Urolithiasis group (N ¼ 26,225)
Control group (N ¼ 78,675)
P value
N (%)
N (%)
N (%)
39,959 (38.1) 43,648 (41.6) 21,293 (20.3) 45.8 ± 15.6
10,108 (38.5) 10,886 (41.5) 5231 (19.9) 45.8 ± 15.3
29,851 (37.9) 32,762 (41.6) 16,062 (20.4) 45.8 ± 15.8
0.130
44,655 (42.6) 60,245 (57.4)
11,208 (42.7) 15,017 (57.3)
33,447 (42.5) 45,228 (57.5)
0.523
40,657 (38.8) 36,873 (35.2) 27,370 (26.1)
10,110 (38.6) 9194 (35.1) 6921 (26.4)
30,547 (38.8) 27,679 (35.2) 20,449 (26.0)
0.433
6817 (6.5) 17,864 (17.0) 10,366 (9.9) 7176 (6.8) 843 (0.8)
1736 (6.6) 4452 (17.0) 2648 (10.1) 1834 (7.0) 218 (0.8)
5081 (6.5) 13,412 (17.0) 7718 (9.8) 5342 (6.8) 625 (0.8)
0.358 0.791 0.177 0.259 0.563
9.0 ± 2.5
9.0 ± 2.5
9.1 ± 2.4
0.395
4.0 ± 2.9
4.1 ± 3.0
4.0 ± 2.9
0.897
0.857
Table 2 The risk of osteoporosis between urolithiasis and control groups stratified by comorbidities (N ¼ 104,900).
Osteoporosis Per 1000 person-years Age <40 40-59 60 Gender Female Male Comorbidities Diabetes No Yes Hypertension No Yes Hyperlipidemia No Yes Liver disease No Yes Cardiovascular disease No Yes
Control group
Urolithiasis group
N (%)
N (%)
cHR (95%CI)
Urolithiasis group vs. Control group aHR (95%CI)
5522 (7.0) 7.79
2181 (8.3) 9.25
1.18 (1.13e1.25)
1.20 (1.15e1.27)**
231 (0.8) 2251 (6.9) 3040 (18.9)
119 (0.9) 971 (8.9) 1091 (20.9)
1.51 (1.21e1.89) 1.31 (1.21e1.41) 1.12 (1.01e1.20)
1.40 (1.12e1.75)** 1.30 (1.20e1.40)** 1.13 (1.05e1.21)**
0.015
4003 (12.0) 1519 (3.4)
1593 (14.2) 598 (3.9)
1.21 (1.14e1.28) 1.16 (1.05e1.27)
1.24 (1.17e1.31)** 1.19 (1.08e1.31)**
0.460
4774 (6.5) 748 (14.7)
1890 (7.7) 291 (16.8)
1.17 (1.09e1.25) 1.12 (0.98e1.28)
1.22 (1.16e1.29)** 1.19 (1.04e1.36)*
0.827
3327 (5.1) 2195 (16.4)
1396 (6.4) 785 (17.6)
1.26 (1.18e1.34) 1.08 (0.99e1.17)
1.28 (1.20e1.36)** 1.12 (1.03e1.22)**
0.020
4307 (6.1) 1215 (15.7)
1742 (7.4) 439 (16.6)
1.22 (1.15e1.29) 1.05 (0.94e1.17)
1.25 (1.18e1.32)** 1.10 (0.98e1.22)
0.047
4997 (6.8) 525 (9.8)
1967 (8.1) 214 (11.7)
1.19 (1.13e1.25) 1.19 (1.01e1.39)
1.20 (1.14e1.27)** 1.40 (1.19e1.64)**
0.084
5438 (7.0) 84 (13.4)
2147 (8.3) 34 (15.6)
1.19 (1.13e1.25) 1.15 (0.77e1.72)
1.22 (1.16e1.28)** 1.20 (0.80e1.79)
0.464
p for interaction
cHR: Crude HR. aHR: Adjusted HR. Adjusted age, gender, insurance range, diabetes, hyperlipidemia, hypertension, liver disease, cardiovascular disease. * if p < 0.05, ** if p < 0.01.
40e59 years, adjusted hazard ratio 1.3, 95% CI 1.20e1.40, p < 0.001), than in the older patient population (age >60 years, adjusted hazard ratio 1.13, 95% CI 1.05e1.21, p ¼ 0.001; p ¼ 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 1.20e1.36, p < 0.001; hypertension, adjusted hazard ratio 1.12, 95% CI 1.03e1.22, p ¼ 0.006, p ¼ 0.020 for interaction). Urolithiasis status in patient without dyslipidemia or cardiovascular disease did not affect the rate of osteoporosis.
4. Discussion 4.1. Age The prevalence of osteoporosis becomes higher with age. In a previous report, researchers showed that 2e8% of men and 9e38% of women aged 50 years living in industrialized countries are affected depending on the examination of diagnosis. Almost half of older patientsdespecially those >60 yearsdmay experience a
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
4
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
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 trial21 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. 4.3. Hypertension
Fig. 1. KaplaneMeier estimate of absence of osteoporosis in patients with urolithiasis history and control patients.
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 study14 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. 4.2. 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.7,11,13,17e19 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 long-term use. In another study, researchers evaluated the relationship between osteoporosis and prior urolithiasis. They
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, 1.13e1.96).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 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 to 405 for hypertension medication use, including angiotensin-converting enzyme 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. 4.4. 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 via lipid oxidation,27 as well as proinflammatory adipokines, which may enhance osteoclast differentiation.28 Yamaguchi et al.29 showed that plasma LDL-C and HDL-C 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-hydroxy3methylglutaryl 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 via anti-inflammatory activities.31 Meta-analysis results showed that statins may help improve
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
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. 4.5. 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 decisionmaking 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. 5. Conclusion On the basis of our results, an association exists between urolithiasis patients and subsequent osteoporosis diagnosis. Though the clinical mechanisms are not fully understood, patients who had urolithiasis history may need regular follow up of bone marrow density. Conflicts of interest We declare no conflict of interest. Acknowledgements Yu-Han Chang analyzed and interpreted the data. References 1. Sakhaee K. Nephrolithiasis as a systemic disorder. Curr Opin Nephrol Hypertens 2008;17:304e9. 2. Lee YH, Huang WC, Tsai JY, Lu CM, Chen WC, Lee MH, et al. Epidemiological studies on the prevalence of upper urinary calculi in Taiwan. Urol Int 2002;68: 172e7. 3. Scales Jr CD, Smith AC, Hanley JM, Saigal CS. Urologic diseases in America Project. Eur Urol 2012;62:160e5. 4. Singh P, Enders FT, Vaughan LE, Bergstralh EJ, Knoedler JJ, Krambeck AE, et al. Stone composition among first-time symptomatic kidney stone formers in the community. Mayo Clin Proc 2015;90:1356e65. 5. Arrabal-Polo MA, Arrabal-Martin M, de Haro-Munoz T, Lopez-Leon VM, Merino-Salas S, Ochoa-Hortal MA, et al. Mineral density and bone remodelling markers in patients with calcium lithiasis. BJU Int 2011;108:1903e8. 6. Arrabal-Polo MA, Cano-García Mdel C, Canales BK, Arrabal-Martín M. Calcium nephrolithiasis and bone demineralization: pathophysiology, diagnosis, and medical management. Curr Opin Urol 2014;24:633e8. 7. Taylor EN, Feskanich D, Paik JM, Curhan GC. Nephrolithiasis and risk of incident bone fracture. J Urol 2016;195:1482e6.
5
8. Asplin JR, Donahue S, Kinder J, Coe FL. Urine calcium excretion predicts bone loss in idiopathic hypercalciuria. Kidney Int 2006;70:1463e7. 9. Senzaki H, Yasui T, Okada A, Ito Y, Tozawa K, Kohri K. Alendronate inhibits urinary calcium microlith formation in a three-dimensional culture model. Urol Res 2004;32:223e8. 10. Wade SW, Strader C, Fitzpatrick LA, Anthony MS, O'Malley CD. Estimating prevalence of osteoporosis: examples from industrialized countries. Arch Osteoporos 2014;9:182. 11. Bijelic R, Milicevic S, Balaban J. Correlation of osteoporosis and calcium urolithiasis in adult population. Med Arch 2016;70:66e8. 12. Khosla S, Lufkin EG, Hodgson SF, Fitzpatrick LA, Melton 3rd LJ. Epidemiology and clinical features of osteoporosis in young individuals. Bone 1994;15: 551e5. 13. Ferrari S, Bianchi ML, Eisman JA, Foldes AJ, Adami S, Wahl DA, et al. Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos Int 2012;23:2735e48. 14. Guerra A, Ticinesi A, Allegri F, Nouvenne A, Pinelli S, Lauretani F, et al. Calcium urolithiasis course in young stone formers is influenced by the strength of family history: results from a retrospective study. Urolithiasis 2016 Dec 9. http://dx.doi.org/10.1007/s00240-016-0955-9 [Epub ahead of print]. 15. Cauley JA, Blackwell T, Zmuda JM, Fullman RL, Ensrud KE, Stone KL, et al. Correlates of trabecular and cortical volumetric bone mineral density at the femoral neck and lumbar spine: the osteoporotic fractures in men study (MrOS). J Bone Min Res 2010;25:1958e71. 16. Bleicher K, Cumming RG, Naganathan V, Seibel MJ, Sambrook PN, Blyth FM, et al. Lifestyle factors, medications, and disease influence bone mineral density in older men: findings from the CHAMP study. Osteoporos Int 2011;22: 2421e37. 17. Carbone LD, Hovey KM, Andrews CA, Thomas F, Sorensen MD, Crandall CJ, et al. Urinary tract stones and osteoporosis: findings from the Women's health initiative. J Bone Min Res 2015;30:2096e102. 18. Lauderdale DS, Thisted RA, Wen M, Favus MJ. Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey. J Bone Min Res 2001;16:1893e8. 19. Keller JJ, Lin CC, Kang JH, Lin HC. Association between osteoporosis and urinary calculus: evidence from a population-based study. Osteoporos Int 2013;24: 651e7. 20. Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017 Jan 17;1, CD004143. 21. Maalouf NM, Sato AH, Welch BJ, Howard BV, Cochrane BB, Sakhaee K, et al. Postmenopausal hormone use and the risk of nephrolithiasis: results from the Women's Health Initiative hormone therapy trials. Arch Intern Med 2010;170: 1678e85. 22. von der Recke P, Hansen MA, Hassager C. The association between low bone mass at the menopause and cardiovascular mortality. Am J Med 1999;106: 273e8. 23. Yang S, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Association between hypertension and fragility fracture: a longitudinal study. Osteoporos Int 2014;25:97e103. 24. Ghosh M, Majumdar SR. Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis. Endocrine 2014;46:397e405. 25. Adami S, Braga V, Zamboni M, Gatti D, Rossini M, Bakri J, et al. Relationship between lipids and bone mass in 2 cohorts of healthy women and men. Calcif Tissue Int 2004;74:136e42. 26. Sugimoto T, Sato M, Dehle FC, Brnabic AJ, Weston A, Burge R. Lifestyle-related metabolic disorders, osteoporosis, and fracture risk in asia: a systematic review. Value Health Reg Issues 2016;9:49e56. 27. Tsartsalis AN, Dokos C, Kaiafa GD, Tsartsalis DN, Kattamis A, Hatzitolios AI, et al. Statins, bone formation and osteoporosis: hope or hype? Hormones 2012;11: 126e39. 28. Esposito K, Capuano A, Sportiello L, Giustina A, Giugliano D. Should we abandon statins in the prevention of bone fractures? Endocrine 2013;44: 326e33. 29. Yamaguchi T, Sugimoto T, Yano S, Yamauchi M, Sowa H, Chen Q, et al. Plasma lipids and osteoporosis in postmenopausal women. Endocr J 2002;49:211e7. 30. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone 2007;40:1581e7. 31. Lupattelli G, Scarponi AM, Vaudo G, Siepi D, Roscini AR, Gemelli F, et al. Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women. Metabolism 2004;53:744e8. 32. Liu J, Zhu LP, Yang XL, Huang HL, Ye DQ. HMG-CoA reductase inhibitors (statins) and bone mineral density: a meta-analysis. Bone 2013;54:151e6.
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
Contents lists available at ScienceDirect
Urological Science journal homepage: www.urol-sci.com
Original article
Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study Yen-Man Lu a, b, Tsu-Ming Chien a, Ching-Chia Li a, c, d, Yii-Her Chou a, d, Wen-Jeng Wu a, b, c, d, Chun-Nung Huang a, b, d, * a
Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan d Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 February 2017 Received in revised form 6 July 2017 Accepted 27 July 2017 Available online xxx
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% CI 1.15e1.27, 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 1.12e1.75, p ¼ 0.003; 40e59 years, adjusted hazard ratio 1.3, 95% CI 1.20e1.40, p < 0.001), than in the older patient population (age >60 years, adjusted hazard ratio 1.13, 95% CI 1.05e1.21, p ¼ 0.001; p ¼ 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 1.20e1.36, p < 0.001; hypertension, adjusted hazard ratio 1.12, 95% CI 1.03e1.22, p ¼ 0.006, p ¼ 0.020 for interaction). Conclusion: In conclusion, on the basis of our results, an association exists between urolithiasis patients and subsequent osteoporosis diagnosis. Though the clinical mechanisms are not fully understood, patients who had urolithiasis history may need regular follow up of bone marrow density. Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Urolithiasis Osteoporosis Risk factors
1. Introduction 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 (NHANES III) cohort.3
* Corresponding author. Department of Urology, Kaohsiung Medical University Hospital, No. 100, Tz-You 1st Road, Kaohsiung 807, Taiwan. Fax: þ886 7321 1033. E-mail address: [email protected] (C.-N. Huang).
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.5e7 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
http://dx.doi.org/10.1016/j.urols.2017.07.010 1879-5226/Copyright © 2017, Taiwan Urological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
2
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
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 via 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. 2. 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. In Taiwan, less than 2% of the population is not covered by this insurance system (n ¼ 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 (DXA) 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 followup, 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. 2.1. Statistical analysis Differences between categorical parameters were assessed using the c2 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 KaplaneMeier 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 timedependent 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. 3. Results The sample population from the LHID2000 database identified 69,177 patients aged <18 years between January 1, 2001 to 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 prior to 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. 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 1.15e1.27, p < 0.001). The incidence rate of osteoporosis during the follow-up period was 9.25 per 1000 person-years in the urolithiasis group, and 7.79 per 1000 person-years in the control group. We further evaluated these findings using a KaplaneMeier survival analysis of osteoporosis. Fig. 1 shows that the urolithiasis group had poorer osteoporosisfree rates than the control group (p ¼ 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). 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 1.12e1.75, p ¼ 0.003;
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
3
Table 1 Basic characteristics between urolithiasis and control groups (N ¼ 104,900). Variables
Age <40 40-59 60 Mean ± SD (years) Gender Female Male Insurance range < NT 14,999 NT 15,000e29,999 SNT 30,000 Comorbidities Diabetes Hypertension Hyperlipidemia Liver disease Cardiovascular disease Average follow up duration Mean ± SD (years) Average HTN new-onset duration Mean ± SD (years)
Overall (N ¼ 104,900)
Urolithiasis group (N ¼ 26,225)
Control group (N ¼ 78,675)
P value
N (%)
N (%)
N (%)
39,959 (38.1) 43,648 (41.6) 21,293 (20.3) 45.8 ± 15.6
10,108 (38.5) 10,886 (41.5) 5231 (19.9) 45.8 ± 15.3
29,851 (37.9) 32,762 (41.6) 16,062 (20.4) 45.8 ± 15.8
0.130
44,655 (42.6) 60,245 (57.4)
11,208 (42.7) 15,017 (57.3)
33,447 (42.5) 45,228 (57.5)
0.523
40,657 (38.8) 36,873 (35.2) 27,370 (26.1)
10,110 (38.6) 9194 (35.1) 6921 (26.4)
30,547 (38.8) 27,679 (35.2) 20,449 (26.0)
0.433
6817 (6.5) 17,864 (17.0) 10,366 (9.9) 7176 (6.8) 843 (0.8)
1736 (6.6) 4452 (17.0) 2648 (10.1) 1834 (7.0) 218 (0.8)
5081 (6.5) 13,412 (17.0) 7718 (9.8) 5342 (6.8) 625 (0.8)
0.358 0.791 0.177 0.259 0.563
9.0 ± 2.5
9.0 ± 2.5
9.1 ± 2.4
0.395
4.0 ± 2.9
4.1 ± 3.0
4.0 ± 2.9
0.897
0.857
Table 2 The risk of osteoporosis between urolithiasis and control groups stratified by comorbidities (N ¼ 104,900).
Osteoporosis Per 1000 person-years Age <40 40-59 60 Gender Female Male Comorbidities Diabetes No Yes Hypertension No Yes Hyperlipidemia No Yes Liver disease No Yes Cardiovascular disease No Yes
Control group
Urolithiasis group
N (%)
N (%)
cHR (95%CI)
Urolithiasis group vs. Control group aHR (95%CI)
5522 (7.0) 7.79
2181 (8.3) 9.25
1.18 (1.13e1.25)
1.20 (1.15e1.27)**
231 (0.8) 2251 (6.9) 3040 (18.9)
119 (0.9) 971 (8.9) 1091 (20.9)
1.51 (1.21e1.89) 1.31 (1.21e1.41) 1.12 (1.01e1.20)
1.40 (1.12e1.75)** 1.30 (1.20e1.40)** 1.13 (1.05e1.21)**
0.015
4003 (12.0) 1519 (3.4)
1593 (14.2) 598 (3.9)
1.21 (1.14e1.28) 1.16 (1.05e1.27)
1.24 (1.17e1.31)** 1.19 (1.08e1.31)**
0.460
4774 (6.5) 748 (14.7)
1890 (7.7) 291 (16.8)
1.17 (1.09e1.25) 1.12 (0.98e1.28)
1.22 (1.16e1.29)** 1.19 (1.04e1.36)*
0.827
3327 (5.1) 2195 (16.4)
1396 (6.4) 785 (17.6)
1.26 (1.18e1.34) 1.08 (0.99e1.17)
1.28 (1.20e1.36)** 1.12 (1.03e1.22)**
0.020
4307 (6.1) 1215 (15.7)
1742 (7.4) 439 (16.6)
1.22 (1.15e1.29) 1.05 (0.94e1.17)
1.25 (1.18e1.32)** 1.10 (0.98e1.22)
0.047
4997 (6.8) 525 (9.8)
1967 (8.1) 214 (11.7)
1.19 (1.13e1.25) 1.19 (1.01e1.39)
1.20 (1.14e1.27)** 1.40 (1.19e1.64)**
0.084
5438 (7.0) 84 (13.4)
2147 (8.3) 34 (15.6)
1.19 (1.13e1.25) 1.15 (0.77e1.72)
1.22 (1.16e1.28)** 1.20 (0.80e1.79)
0.464
p for interaction
cHR: Crude HR. aHR: Adjusted HR. Adjusted age, gender, insurance range, diabetes, hyperlipidemia, hypertension, liver disease, cardiovascular disease. * if p < 0.05, ** if p < 0.01.
40e59 years, adjusted hazard ratio 1.3, 95% CI 1.20e1.40, p < 0.001), than in the older patient population (age >60 years, adjusted hazard ratio 1.13, 95% CI 1.05e1.21, p ¼ 0.001; p ¼ 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 1.20e1.36, p < 0.001; hypertension, adjusted hazard ratio 1.12, 95% CI 1.03e1.22, p ¼ 0.006, p ¼ 0.020 for interaction). Urolithiasis status in patient without dyslipidemia or cardiovascular disease did not affect the rate of osteoporosis.
4. Discussion 4.1. Age The prevalence of osteoporosis becomes higher with age. In a previous report, researchers showed that 2e8% of men and 9e38% of women aged 50 years living in industrialized countries are affected depending on the examination of diagnosis. Almost half of older patientsdespecially those >60 yearsdmay experience a
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
4
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
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 trial21 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. 4.3. Hypertension
Fig. 1. KaplaneMeier estimate of absence of osteoporosis in patients with urolithiasis history and control patients.
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 study14 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. 4.2. 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.7,11,13,17e19 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 long-term use. In another study, researchers evaluated the relationship between osteoporosis and prior urolithiasis. They
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, 1.13e1.96).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 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 to 405 for hypertension medication use, including angiotensin-converting enzyme 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. 4.4. 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 via lipid oxidation,27 as well as proinflammatory adipokines, which may enhance osteoclast differentiation.28 Yamaguchi et al.29 showed that plasma LDL-C and HDL-C 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-hydroxy3methylglutaryl 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 via anti-inflammatory activities.31 Meta-analysis results showed that statins may help improve
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010
Y.-M. Lu et al. / Urological Science xxx (2017) 1e5
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. 4.5. 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 decisionmaking 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. 5. Conclusion On the basis of our results, an association exists between urolithiasis patients and subsequent osteoporosis diagnosis. Though the clinical mechanisms are not fully understood, patients who had urolithiasis history may need regular follow up of bone marrow density. Conflicts of interest We declare no conflict of interest. Acknowledgements Yu-Han Chang analyzed and interpreted the data. References 1. Sakhaee K. Nephrolithiasis as a systemic disorder. Curr Opin Nephrol Hypertens 2008;17:304e9. 2. Lee YH, Huang WC, Tsai JY, Lu CM, Chen WC, Lee MH, et al. Epidemiological studies on the prevalence of upper urinary calculi in Taiwan. Urol Int 2002;68: 172e7. 3. Scales Jr CD, Smith AC, Hanley JM, Saigal CS. Urologic diseases in America Project. Eur Urol 2012;62:160e5. 4. Singh P, Enders FT, Vaughan LE, Bergstralh EJ, Knoedler JJ, Krambeck AE, et al. Stone composition among first-time symptomatic kidney stone formers in the community. Mayo Clin Proc 2015;90:1356e65. 5. Arrabal-Polo MA, Arrabal-Martin M, de Haro-Munoz T, Lopez-Leon VM, Merino-Salas S, Ochoa-Hortal MA, et al. Mineral density and bone remodelling markers in patients with calcium lithiasis. BJU Int 2011;108:1903e8. 6. Arrabal-Polo MA, Cano-García Mdel C, Canales BK, Arrabal-Martín M. Calcium nephrolithiasis and bone demineralization: pathophysiology, diagnosis, and medical management. Curr Opin Urol 2014;24:633e8. 7. Taylor EN, Feskanich D, Paik JM, Curhan GC. Nephrolithiasis and risk of incident bone fracture. J Urol 2016;195:1482e6.
5
8. Asplin JR, Donahue S, Kinder J, Coe FL. Urine calcium excretion predicts bone loss in idiopathic hypercalciuria. Kidney Int 2006;70:1463e7. 9. Senzaki H, Yasui T, Okada A, Ito Y, Tozawa K, Kohri K. Alendronate inhibits urinary calcium microlith formation in a three-dimensional culture model. Urol Res 2004;32:223e8. 10. Wade SW, Strader C, Fitzpatrick LA, Anthony MS, O'Malley CD. Estimating prevalence of osteoporosis: examples from industrialized countries. Arch Osteoporos 2014;9:182. 11. Bijelic R, Milicevic S, Balaban J. Correlation of osteoporosis and calcium urolithiasis in adult population. Med Arch 2016;70:66e8. 12. Khosla S, Lufkin EG, Hodgson SF, Fitzpatrick LA, Melton 3rd LJ. Epidemiology and clinical features of osteoporosis in young individuals. Bone 1994;15: 551e5. 13. Ferrari S, Bianchi ML, Eisman JA, Foldes AJ, Adami S, Wahl DA, et al. Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos Int 2012;23:2735e48. 14. Guerra A, Ticinesi A, Allegri F, Nouvenne A, Pinelli S, Lauretani F, et al. Calcium urolithiasis course in young stone formers is influenced by the strength of family history: results from a retrospective study. Urolithiasis 2016 Dec 9. http://dx.doi.org/10.1007/s00240-016-0955-9 [Epub ahead of print]. 15. Cauley JA, Blackwell T, Zmuda JM, Fullman RL, Ensrud KE, Stone KL, et al. Correlates of trabecular and cortical volumetric bone mineral density at the femoral neck and lumbar spine: the osteoporotic fractures in men study (MrOS). J Bone Min Res 2010;25:1958e71. 16. Bleicher K, Cumming RG, Naganathan V, Seibel MJ, Sambrook PN, Blyth FM, et al. Lifestyle factors, medications, and disease influence bone mineral density in older men: findings from the CHAMP study. Osteoporos Int 2011;22: 2421e37. 17. Carbone LD, Hovey KM, Andrews CA, Thomas F, Sorensen MD, Crandall CJ, et al. Urinary tract stones and osteoporosis: findings from the Women's health initiative. J Bone Min Res 2015;30:2096e102. 18. Lauderdale DS, Thisted RA, Wen M, Favus MJ. Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey. J Bone Min Res 2001;16:1893e8. 19. Keller JJ, Lin CC, Kang JH, Lin HC. Association between osteoporosis and urinary calculus: evidence from a population-based study. Osteoporos Int 2013;24: 651e7. 20. Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017 Jan 17;1, CD004143. 21. Maalouf NM, Sato AH, Welch BJ, Howard BV, Cochrane BB, Sakhaee K, et al. Postmenopausal hormone use and the risk of nephrolithiasis: results from the Women's Health Initiative hormone therapy trials. Arch Intern Med 2010;170: 1678e85. 22. von der Recke P, Hansen MA, Hassager C. The association between low bone mass at the menopause and cardiovascular mortality. Am J Med 1999;106: 273e8. 23. Yang S, Nguyen ND, Center JR, Eisman JA, Nguyen TV. Association between hypertension and fragility fracture: a longitudinal study. Osteoporos Int 2014;25:97e103. 24. Ghosh M, Majumdar SR. Antihypertensive medications, bone mineral density, and fractures: a review of old cardiac drugs that provides new insights into osteoporosis. Endocrine 2014;46:397e405. 25. Adami S, Braga V, Zamboni M, Gatti D, Rossini M, Bakri J, et al. Relationship between lipids and bone mass in 2 cohorts of healthy women and men. Calcif Tissue Int 2004;74:136e42. 26. Sugimoto T, Sato M, Dehle FC, Brnabic AJ, Weston A, Burge R. Lifestyle-related metabolic disorders, osteoporosis, and fracture risk in asia: a systematic review. Value Health Reg Issues 2016;9:49e56. 27. Tsartsalis AN, Dokos C, Kaiafa GD, Tsartsalis DN, Kattamis A, Hatzitolios AI, et al. Statins, bone formation and osteoporosis: hope or hype? Hormones 2012;11: 126e39. 28. Esposito K, Capuano A, Sportiello L, Giustina A, Giugliano D. Should we abandon statins in the prevention of bone fractures? Endocrine 2013;44: 326e33. 29. Yamaguchi T, Sugimoto T, Yano S, Yamauchi M, Sowa H, Chen Q, et al. Plasma lipids and osteoporosis in postmenopausal women. Endocr J 2002;49:211e7. 30. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone 2007;40:1581e7. 31. Lupattelli G, Scarponi AM, Vaudo G, Siepi D, Roscini AR, Gemelli F, et al. Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women. Metabolism 2004;53:744e8. 32. Liu J, Zhu LP, Yang XL, Huang HL, Ye DQ. HMG-CoA reductase inhibitors (statins) and bone mineral density: a meta-analysis. Bone 2013;54:151e6.
Please cite this article in press as: Lu Y-M, et al., Urolithiasis is associated with the increased risk for osteoporosis: A nationwide 9-year follow-up study, Urological Science (2017), http://dx.doi.org/10.1016/j.urols.2017.07.010