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Kidney Stone Disease And Osteoporosis

Kidney Stone Disease And Osteoporosis

A substantial proportion of veterans with kidney stones face the prospect of developing fractures or osteoporosis, underscoring the absence of established screening guidelines within this demographic. Through an analysis of nationwide data encompassing 9025 patients, the current investigation seeks to ascertain the potential correlation between diminished levels of urine citrate and an elevated risk of osteoporosis or fractures. Identifying hypocitraturia is a critical determinant, signifying a valuable marker for pinpointing individuals at heightened susceptibility. This research endeavors to contribute insights that inform targeted interventions and screening protocols tailored to the nuanced needs of veterans with kidney stone disease.



Kidney stone disease presents a significant health challenge for veterans, with nearly one in four individuals grappling with both kidney stones and the potential complications of fractures or osteoporosis [1,2]. Despite its prevalence, a conspicuous void exists in established screening guidelines tailored to assess bone health in this population [1,2]. This gap in clinical protocols raises pivotal questions about the identification and management of individuals at risk for skeletal complications within the veteran demographic.

Recent cross-sectional analyses have yielded valuable insights into the intricate interplay between kidney stone disease and bone health. Notably, the exploration of 24-hour urine citrate excretion has revealed an association between diminished citrate levels and prevalent bone diseases among veterans diagnosed with kidney stone disease [2]. The rationale behind this association lies in the potential of low urine citrate excretion to signal an early imbalance in acid-base homeostasis within the body, potentially triggering compensatory mechanisms involving the mobilization of alkali from bone to counteract the acid load, consequently predisposing individuals to bone loss over time [3,4].

The absence of screening guidelines prompts a comprehensive investigation into the clinical utility of hypocitraturia as a potential early marker for identifying individuals at risk of developing osteoporosis or experiencing fractures within the veteran population [5–8]. By addressing this critical gap in knowledge, the study endeavors to contribute nuanced insights that may inform targeted interventions and screening protocols specifically tailored to the unique needs of veterans coping with kidney stone disease.

In summary, the research background underscores the multifaceted nature of the intersection between kidney stone disease and bone health among veterans, emphasizing the imperative need for screening guidelines and proactive management strategies within this high-risk demographic.



The Stanford University School of Medicine research was ethically approved by the institution’s Review Board and the Veterans Affairs Research and Development Committee. The researchers waived informed consent requirements due to the de-identified and aggregate nature of the data. The study utilized national data from the Veterans Health Administration (VHA), sourced from the Corporate Data Warehouse hosted by the Veterans Affairs Informatics and Computing Infrastructure. The study population comprised patients with kidney stone disease who received care at one of 130 VHA establishments across the United States from January 1, 2007, to December 1, 2015.

Patients with kidney stone disease were identified based on specific criteria, including inpatient encounters with ICD-9 & 10 (the International Classification of Diseases, Ninth, and Tenth Revision) codes for kidney or ureteral stones, outpatient encounters for kidney or ureteral stones, or kidney/ureteral stone procedures within one year using Current Procedural Terminology (CPT) codes. Each patient was counted once during their first qualification for kidney stone disease during the observation period. Veterans with incident and recurrent kidney stone disease were included in the study.

The selection criteria were narrowed to patients with kidney stone disease who completed a 24-hour urine citrate measurement within six (6) months of their index stone diagnosis. Covariates encompassed patient demographics, relevant comorbid conditions, and laboratory data. Demographics included age, sex, and race/ethnicity, while comorbid conditions covered diabetes, enteric disease, metastatic cancer, hypogonadism, osteoporosis, and a history of fracture. Laboratory data included serum creatinine, bicarbonate, and potassium concentrations. All serum and urine laboratory measurements were synchronized within a specific timeframe to the completion of a 24-hour urine citrate measurement.

The primary outcome of interest was the time to develop osteoporosis or fracture, with 24-hour urine citrate excretion treated as a categorical variable (<200 mg/d, 200–400 mg/d, and >400 mg/d). This meticulous methodology ensured a comprehensive and detailed exploration of the association between urine citrate levels and bone health outcomes in the veteran population with kidney stone disease.



The study assessed the risk of osteoporosis or fracture based on 24-hour urine citrate levels in veterans with kidney stone disease. Employing Cox proportional hazards regression, patients were categorized by citrate levels, adjusting for demographics, body size, and comorbid illnesses such as type 2 diabetes mellitus, metastatic cancer, hypogonadism, and enteric diseases like Crohn’s, ulcerative colitis, and celiac disease. Additionally, serum measurements were considered, including creatinine, potassium, and bicarbonate concentrations. Subgroup analysis involved individuals with specific urine creatinine excretion levels. Statistical studies were conducted using SAS (Statistical Analysis System), version 9.4, from SAS Institute Inc., Cary, NC, USA. The findings revealed nuanced associations between urine citrate levels and the risk of skeletal complications, providing insights into the complex relationship in veterans with kidney stone disease.



Clinical Characteristics of Patients with Low 24-hour Urine Citrate Excretion:

  – The study included 9025 unique patients with kidney stone disease.

  – Urine citrate levels were categorized into three groups: <200 mg/d (19.4%), 200–400 mg/d (26.3%), and >400 mg/d (54.3%).

  – Patients with urine citrate <200 mg/d were predominantly male (91.6%) with a mean age of 59.9 years. In contrast, those with >400 mg/d had a mean age of 57.2 years, with 92.8% being male.

  – The number of people who were confirmed with type 2 diabetes rose as urine citrate levels dropped. 33.7% for <200 mg/d, 25% for 200–400 mg/d, and 30.4% for >400 mg/d.

  – Enteric disease diagnoses showed a similar pattern: 2.1% for <200 mg/d, 1.2% for 200–400 mg/d, and 0.7% for >400 mg/d.

Association between 24-hour Urine Citrate Excretion and Osteoporosis or Fracture:

  – The study examined incident osteoporosis or fracture in patients based on 24-hour urine citrate levels.

  – 8.7% of patients (756/8674) developed osteoporosis or fracture, with a mean time to event of 2.2 years after the stone diagnosis.

  – Univariate analysis revealed that patients with urine citrate <200 mg/d had a higher risk of osteoporosis or fracture (Hazard Ratio [HR]=1.23; Confidence Interval [CI] 1.03–1.48) compared to those with >400 mg/d.

  – The association became statistically insubstantial after adjusting for demographic factors, comorbid conditions, and laboratory abnormalities (HR=1.18; CI 0.98–1.43).

  – Subgroup analysis, considering patients with adequate 24-hour urine collection, maintained a statistically significant association (HR=1.40; CI 1.06–1.89), even after comprehensive adjustments.

The findings suggest a potential link between low urine citrate levels and an increased risk of osteoporosis or fracture, emphasizing the importance of considering various factors in understanding this association. 



In this expansive analysis of a national cohort of veterans grappling with kidney stone disease, the study delves into the intricate relationship between severe hypocitraturia and the subsequent diagnosis of osteoporosis or fracture within five years of a stone diagnosis. The findings underscore a higher incidence of these bone-related outcomes in veterans exhibiting severe hypocitraturia. Nevertheless, upon meticulous adjustment for demographic factors and comorbid conditions, hypocitraturia alone does not emerge as a robust independent risk factor for the incident development of osteoporosis or fracture ([1–3, 12–14]).


A crucial facet of this association lies in the clinical characteristics of the veterans, revealing intriguing patterns. Those with severe hypocitraturia (urine citrate <200 mg/d) exhibit a distinct profile—they are more likely to be older, female, lean, and carry diagnoses of metastatic cancer or enteric disease compared to counterparts with higher urine citrate levels. It prompts the proposition that the predictive power of hypocitraturia for poor bone health gains prominence when coupled with these specific clinical characteristics. This nuanced understanding emphasizes the need for future prospective research to validate whether urine citrate, in combination with clinical features, effectively stratifies individuals with kidney stone disease for the risk of osteoporosis or fracture ([1–3, 12–14]).

The diagnosis of hypocitraturia holds multifaceted clinical significance. Firstly, it is a valuable tool for identifying patients with kidney stone disease who stand to benefit from alkali supplementation, thereby mitigating the risk of recurrent calcium stones. This preventive approach aligns with prior studies advocating alkali therapy to lower the recurrence risk ([1–3, 12–14]). Secondly, hypocitraturia may be indicative of early acid retention in individuals grappling with chronic kidney disease or gastrointestinal alkali loss. In such scenarios, alkali mobilized from bone for acid buffering compensates for overt metabolic acidosis and poses a potential risk to bone strength. This assertion finds support in existing research correlating lower serum bicarbonate concentration with diminished bone mineral density and highlighting the positive impact of alkali therapy on bone health. Furthermore, the study suggests considering additional indicators, such as low urine pH and citrate, to capture early signals of acid retention or compromised bone health ([1–3, 12–14]).

The strengths of this study lie in its pioneering nature, employing a diverse national cohort and leveraging comprehensive Veterans Health Administration (VHA) data. Including clinical and laboratory characteristics contributes to a nuanced understanding, and statistical analyses, including hazard ratios (HR) with 95% confidence intervals (CI), enhance the robustness of the findings. Furthermore, the attempt to account for 24-hour urine collection adequacy through a subgroup analysis adds depth to the interpretation. However, it is crucial to acknowledge the predominantly male cohort and the reliance on diagnosis codes for kidney stones and fractures as notable study characteristics.

Ultimately, while hypocitraturia alone may not conclusively predict the incident development of osteoporosis or fracture, its consideration alongside specific clinical characteristics underscores its potential clinical relevance. The study posits that personalized risk stratification in kidney stone patients warrants further exploration and validation through prospective studies ([1–3, 12–14]).



Sex Discrepancy: The cohort predominantly comprises male participants, limiting the generalization of findings to females.  

Diagnostic Method: Dependency on diagnosis codes rather than radiologic imaging may lead to potential underreporting, especially for clinically silent cases.

Selection Bias: Including patients who voluntarily completed a 24-hour urine citrate measurement introduces potential selection bias, as this test is not routinely ordered.

Urine Collection Precision: Efforts to assess the adequacy of urine collection may not guarantee precision due to potential under- or overcollection of a 24-hour urine sample.

Limited Treatment Consideration: The study does not account for specific medical treatments, such as alkali or thiazide diuretics, which could influence the risk of bone disease.

Generalizability: The primarily male composition of the cohort may limit the generalization of study findings to a broader population.

Diagnostic Accuracy: Reliance on diagnosis codes rather than radiologic imaging might miss clinically silent cases, leading to potential underreporting.

Selection Bias in Urine Measurement: Including patients who voluntarily completed a 24-hour urine citrate measurement may introduce bias, as this test is not routine.

Potential Collection Precision Issues: Despite efforts to assess urine collection adequacy, precision may be compromised due to potential under- or overcollection of 24-hour urine samples.

Unaccounted Medical Treatments: The study does not consider specific medical treatments, such as alkali or thiazide diuretics, which could impact the risk of bone disease.

Study Population Generalization: The predominantly male composition of the cohort may limit the generalizability of findings to a more diverse population.d: Dependency on diagnosis codes rather than radiologic imaging may lead to potential underreporting, especially for clinically silent cases.



In summation, the findings within a predominantly male cohort reveal a nuanced association between hypocitraturia and the risk of osteoporosis or fracture. While a modest connection is evident, researchers emphasize recognizing that the intricate relationship between kidney stone disease and compromised bone health may involve additional contributing factors. The potential interplay of urine citrate with established bone disease risk factors warrants exploration in future research endeavors. Integrating urine citrate assessment with other known determinants of bone health holds promise for identifying individuals within the kidney stone disease population who may benefit from targeted bone health screening.


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