Bone health in patients with kidney stones Miguel Angel Arrabal-Polo and Miguel Arrabal-Martin

The presence of urolithiasis has been shown to be associated with an increased risk of bone fracture in men and women, particularly in adolescent males and females aged 30–39 years and 70–79 years. This increased risk of fracture in patients with urolithiasis may have important implications for public health. Arrabal-Polo, M. A. & Arrabal-Martin, M. Nat. Rev. Urol. 12, 9–10 (2015); published online 9 December 2014; doi:10.1038/nrurol.2014.333

In a recent article published in the Clinical Journal of the American Society of Nephrology, Denburg et al.1 analysed the prevalence of bone fracture in patients with a history of urolithiasis. The retrospective study was performed using data from The Health Improvement Network (THIN) database to compare the prevalence of bone fracture in patients with (n = 51,785) and without (n = 517,267) urolithiasis. The most relevant finding from this study was that there is an increased incidence of frac­ ture in patients with urolithiasis, in both men and women. In men, the overall hazard ratio (HR) for fracture associated with urolithi­asis was 1.10 (95% CI 1.05–1.16); the risk was found to be highest during adolescence (HR 1.55; 95% CI 1.07–2.25). In women aged 30–79 years, the overall HR ranged from 1.17 to 1.52, being highest in women aged 30–39 years (HR 1.52; 95% CI 1.23–1.87). Denburg and colleagues’ study is impor­ tant because it confirms the results of pre­ vious work showing that the incidence of vertebral fractures and wrist fractures is higher in patients with a history of uroli­ thiasis. 2,3 Thus, according to these three articles,1–3 nephrolithiasis can be consid­ ered a risk factor for osteoporosis and osteo­porotic fracture. However, it is impor­ tant to analyse the various limitations of the study. One of the main limiting factors of the study is that the researchers did not investigate whether the incidence of bone fracture in patients with urolithiasis was due to the presence of osteoporosis, as data on bone mineral density loss measured with


…hypocitraturia in combination with hypercalciuria can increase the risk of nephrolithiasis…


bone densito­metry were not available. Thus, it could not be determined whether the fractures in patients with urolithiasis were due to osteoporosis or due to other causes such as trauma. It is striking that in men, the greatest risk of fracture is among adoles­ cents, even though the incidence of osteo­ porosis is low in this patient group. Another limit­ing factor of the study is that the THIN database did not include much data regard­ ing the presence of metabolic abnormalities (such as hypercalciuria, hypocitraturia and hyperoxaluria) in patients with urolithiasis, so the researchers could not identify which predisposing causes of urolithiasis were related to bone fracture. In order to explain the loss of bone mineral density, the pres­ ence of osteoporosis and later osteoporotic fracture in a patient with urolithiasis, it is necessary to analyse and properly study the pathophysiology of the process from the occurrence of calcium stones to the loss of bone mineral density. Nephrolithiasis is a multifactorial disease that depends on anatomical, hormonal, metabolic and endocrine factors; hyper­ calciuria is the main metabolic abnormal­ ity in the urine. In most cases where there is no obvious organic cause, bone mineral density loss in a patient with urolithiasis occurs as a result of an intrinsic metabolic bone disorder, which is expressed by the


occurrence of hypercalciuria, elevated levels of bone resorption markers, an elevated calcium:creatinine fasting ratio and often hypocitraturia and an elevated calcium:citrate ratio. 4–6 In a patient with recurrent calcium nephrolithiasis, a com­ plete blood and urine metabolic screen should be performed to investigate the pres­ ence of metabolic alterations that enable the physician to suspect bone mineral density loss; such suspicion should be con­ firmed with bone densitometry. Various studies have shown that that osteoporosis is an independent risk factor for nephro­ lithiasis,7 so bone mineral density should be m­easured on a case-by-case basis. Calciuria, citraturia and calcium-­to-­creatinine and calcium:citrate ratios are the metabolic profiles that must be investigated to suspect the presence of bone mineral density loss; a fasting calcium:creatinine ratio >0.25 is associated with an increased risk of osteo­ paenia in a patient with calcium nephroli­ thiasis8 and a calcium:citrate ratio >0.25 is associ­ated with an increased of loss of bone mineral density in a patient with recurrent calcium stones.9 The presence of idiopathic hypercalciuria in a patient with recurrent calcium stones is classified as absorptive hypercalciuria (fasting calcium:creatinine ratio 0.11).9 In the case of fasting hypercalciuria, we must suspect the presence of idiopathic loss of bone mineral density associated with calcium stones, but it must be confirmed by bone densitometry and the identifi­ cation of bone remodelling markers in blood or urine, findings that will be useful in treatment and follow-up.9 Furthermore, hypo­citraturia in combination with hyper­ calciuria can increase the risk of nephro­ lithiasis and also decrease bone mineral density, because in many circumstances there is a latent state of metabolic acidosis that induces increased bone resorption.9,10 In clinical practice, a complete meta­ bolic study should be performed in patients with recurrent calcium stones. This study should include a 24 h urinary study including calcium levels, citrate levels and fasting calcium:creatinine ratio, ruling out any abnormalities in the levels of parathyroid hormone and vitamin D, VOLUME 12  |  JANUARY 2015

© 2015 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS and in the case of fasting hypercalciuria (calcium:creatinine ratio >0.11), analy­ sis of bone mineral density with bone densito­metry and measure­ment of serum or urinary markers of bone turnover (Figure 1). Such an indivi­dualized diag­ nostic procedure will enable appropriate treatment to be administered to the patient in order to reduce stone recurrence and reduce the risk of osteoporosis and osteo­ porotic fracture. Further treatment might also include dietary recom­m endations and administration of thiazide, citrate or bisphosphonates,10 which, properly admin­ istered, can improve bone mineral density,

reduce hypercalciuria, increase citraturia and reduce the risk of recurrent stones. The article by Denburg et al. confirms the relationship between nephrolithi­asis and bone fracture risk in patients with kidney stones, indicating that bone mineral density should be observed in patients with r­ecurrent nephrolithiasis. Urology Department, La Inmaculada Hospital, Doctora Ana Parra Avenue, 04600 Huercal-Overa, Almeria, Spain (M.A.A.‑P.). Urology Department, San Cecilio University Hospital, Doctor Oloriz Avenue, 18012 Granada, Spain (M.A.‑M.). Correspondence to: M.A.A.‑P. [email protected]

Recurrent calcium stones

Serum and 24 h urine metabolic study

Absorptive hypercalciuria


Calcium:creatinine ratio 0.11

Fasting hypercalciuria

Normal levels

Bone densitometry Bone remodelling markers (e.g. osteocalcin, alkaline phosphatase, β-crosslaps)

Abnormal levels

Investigate other causes Individualized treatment and follow-up

Figure 1 | Diagnostic algorithm in patients with recurrent calcium nephrolithiasis to suspect Nature Reviews | Urology bone mineral density loss. Abbreviation: iPTH, intact parathyroid hormone.

JANUARY 2015  |  VOLUME 12

Competing interests The authors declare no competing interests. 1.

Denburg, M. R. et al. Risk of fracture in urolithiasis: a population-based cohort study using the Health Improvement Network. Clin. J. Am. Soc. Nephrol. 10.2215/CJN.04340514. 2. Lauderdale, D. S. et al. Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey. J. Bone Miner. Res. 16, 1893–1898 (2001). 3. Melton, L. J. 3rd et al. Fracture risk among patients with urolithiasis: a population-based cohort study. Kidney Int. 53, 459–464 (1998). 4. Krieger, N. S. & Bushinsky, D. A. The relation between bone and stone formation. Calcif. Tissue Int. 93, 374–381 (2013). 5. Asplin, J. R. et al. Bone mineral density and urine calcium excretion among subjects with and without nephrolithiasis. Kidney Int. 63, 662–669 (2003). 6. Arrabal-Polo, M. A. et al. Mineral density and bone remodelling markers in patients with calcium lithiasis. BJU Int. 108, 1903–1908 (2011). 7. Chou, P. S. et al. Osteoporosis and the risk of symptomatic nephrolithiasis: a populationbased 5 year follow-up study in Taiwan. Calcif. Tissue Int. 95, 317–322 (2014). 8. Letavernier, E. et al. Determinants of osteopenia in male renal‑stone‑disease patients with idiopathic hypercalciuria. Clin. J. Am. Soc. Nephrol. 6, 1149–1154 (2011). 9. Arrabal-Polo, M. A. et al. Calcium nephrolithiasis and bone demineralization: pathophysiology, diagnosis, and medical management. Curr. Opin. Urol. 24, 633–638 (2014). 10. Sakhaee, K. et al. Nephrolithiasis-associated bone disease: pathogenesis and treatment options. Kidney Int. 79, 393–403 (2011). © 2015 Macmillan Publishers Limited. All rights reserved

Stones: Bone health in patients with kidney stones.

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