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Abstract
Objectives This cross-sectional study aims to evaluate the association between calcium and vitamin D supplementation for osteoporosis treatment and the development of kidney stones while investigating the impact of urinary calcium excretion on kidney stone risk among patients receiving this supplementation treatment.
Design The study involved collecting data from 204 Chinese Han patients aged 50–89 with osteoporosis in the southwest region of China. These patients had been on daily doses of 600 mg of calcium carbonate and 0.5 µg alfacalcidol for at least 1 year. The study employed univariate analysis and multivariable logistic regression to identify risk factors for kidney stones, with independent t-tests used to compare differences between groups.
Setting Data were collected from patients in the southwest region of China, covering the period from July 2019 to December 2023.
Participants The study included 204 patients with osteoporosis, all of whom had been receiving the specified calcium and vitamin D supplements for the duration of the study.
Results The study found that a history of recurrent kidney stones was an independent risk factor for the development of kidney stones. Patients with kidney stones who had a history of recurrent stones exhibited significantly higher levels of 24-hour urinary calcium excretion (1.00±0.62 vs 0.57±0.54, p=0.026) compared with those without such a history.
Conclusions The results suggest that a history of recurrent kidney stones independently increases the risk of kidney stones in patients undergoing calcium and vitamin D supplementation for osteoporosis, likely due to increased urinary calcium excretion.
- Aging
- Kidney & urinary tract disorders
- Calcium & bone
- Cross-Sectional Studies
Data availability statement
Data are available upon reasonable request. Data are available by corresponding author upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
The objective of this study was to investigate the effects of vitamin D and calcium supplementation on individuals with senile osteoporosis, thereby allowing for specific characteristics of the study group and facilitating generalisation of the results to similar populations.
This study specifically assesses the impact of a history of recurrent kidney stones on the risk of new stone formation, providing valuable insights into how prior stone events influence ongoing risk in relation to calcium and vitamin D supplementation.
The utilisation of strict inclusion and exclusion criteria for individuals as well as an automated biochemistry analyser to measure biochemical markers, improved the accuracy and reliability of the data collected.
As a cross-sectional study design was employed, it was not possible to establish causal relationships; therefore, only assessments of associations could be made, limiting interpretation of the results.
While a sample size consisting of 204 patients may provide preliminary data, it might not be sufficient to fully represent the entire elderly osteoporosis patient population.
Introduction
Idiopathic osteoporosis and kidney stones are significant health concerns with a high incidence and prevalence among adults worldwide.1 Among the recent clinical data, kidney stone formation is closely related to osteoporosis or lower bone mineral density (BMD). On one hand, a meta-analysis including 28 studies with 1595 patients with nephrolithiasis and 3402 healthy controls showed significantly lower T-score values for the spine (Standardized Mean Difference，SMD=−0.69), total hip (SMD=−0.82) or femoral neck (SMD=−0.67), and a fourfold higher risk of developing osteoporosis in patients with nephrolithiasis (OR=4.12).2 On the other hand, an Italian epidemiological survey that included 10 157 patients with osteoporosis showed an increased risk of nephrolithiasis after adjustment (HR=1.33).3
In most patients with osteoporosis, calcium and vitamin D supplement therapy is the basic treatment. The American Association of Clinical Endocrinologists 2020 guidelines recommend a total intake of 1200 mg of calcium and 1000–2000 IU of vitamin D3 per day to prevent bone loss for adults aged 50 years and older.4 Considering that our normal daily diet hardly meets the intake requirements of calcium and vitamin D. Therefore, combining calcium and vitamin D supplements is necessary to treat osteoporosis and reduce the risk of fractures.5 In fact, abundant evidence from Cochrane systematic reviews and meta-analyses supports the beneficial effect of calcium and vitamin D supplementation in improving BMD for both children and older adults.6–9
However, the addition of calcium supplements also raises concerns regarding the potential for an increased risk of hypercalciuria which may contribute to the formation of kidney stones.4 10 Calcium-based kidney stones, which are mainly composed of calcium oxalate (CaOx) crystals and calcium phosphate (CaP), account for nearly 80% of kidney stones and are a major cause of nephrolithiasis.10 In addition to acquired or inherited reasons, most idiopathic CaOx cases develop on the kidney papillary surface attached to a CaP subepithelial plaque, known as Randall’s plaque. Though there still exists debates about the pathophysiology of Randall’s plaque, accumulated evidence has confirmed the central role of calcium excretion in plaque development.11–13 Therefore, calcium supplementation therapy for osteoporosis may potentially elevate the risk of kidney stones. Moreover, vitamin D can enhance intestinal absorption of calcium regardless of its type or dosage, further contributing to the possibility of hypercalciuria and kidney stones.14 15 Despite this, studies regarding the potential risk of calcium and vitamin D supplement therapy on nephrolithiasis in patients with osteoporosis are lacking. Therefore, the aim of the present study was to evaluate the risk associated with the basic treatment for osteoporosis in relation to kidney stone formation, while also examining the influence of urinary calcium excretion on the risk profile of kidney stones among patients with osteoporosis with calcium and vitamin D supplement treatment.
Materials and methods
Study design and participants
The aim of this cross-sectional study was to investigate the potential impact of calcium and vitamin D supplement therapy on kidney stone development in patients with osteoporosis, while also examining the role of urinary calcium excretion in this relationship. The study was conducted by a well-trained team consisting of two endocrinologists, two urological surgeons, a sonographer and a statistician. Written consent was granted by all participants.
The primary data was collected from July 2019 to December 2023, encompassing a total of 1572 patients diagnosed with osteoporosis who were admitted to our hospital in Chongqing, located in the southwest region of China. After being analysed by our team based on the predefined inclusion and exclusion criteria, data from 204 patients with osteoporosis were selected for this study. (figure 1).
Flowchart of population included in our final analysis. BMI, body mass index.
Detailed information regarding the characteristics of the entire sample can be found in the Results section. The inclusion criteria are as follows: (1) Chinese Han individuals with osteoporosis and a body mass index (BMI) ranging from 18.5 to 30 kg/m2; (2) Postmenopausal women or men aged≥50 years who have been diagnosed with osteoporosis according to WHO criteria; (3) Patients who have been receiving a daily dosage of 600 mg calcium carbonate and 0.5 ug alfacalcidol for at least 1 year after menopause (women) or on reaching the age of 50 (men) which continued throughout the study period. The exclusion criteria are as follows: (1) Patients with conditions that may contribute to secondary osteoporosis, such as hyperthyroidism, renal tubular acidosis, rheumatoid arthritis or osteomalacia; (2) Patients with diseases that influence urinary calcium excretion such as renal failure, idiopathic hypercalciuria or multiple myeloma; (3) Except for calcium or vitamin D supplementation, patients were not receiving any medications known to impact bone metabolism or urinary calcium levels like bisphosphonates, glucocorticoids or thiazide diuretics; (4) A history of gout, renal infection and urosepsis; (5) Smoking, alcohol consumption, communication impairments and heart, lung, liver, kidney failure.
Sample size calculation
The sample size calculation was estimated by following the formula for estimating sample size in a proportion difference: 
.
where Z is the standard normal distribution quantile (1.96 for 95% confidence level), p is the expected prevalence of kidney stones and d is the acceptable margin of error. Based on the prevalence of urolithiasis in the southern region of China is 5–10%. Assuming an expected prevalence of p=0.1 (10%) and a margin of error d=0.05 (5%), the required sample size would be n≈138.3. As our study included 204 patients, the sample size was adequate for the primary analysis.
Data measurement
Plasma samples were collected from participants who had undergone a 12-hour fasting period. Participants were instructed to collect their urine over a 24-hour duration for the measurement of volume, calcium and creatinine levels. Urine calcium, urine creatinine, serum calcium, serum inorganic phosphorus and serum uric acid (UA) concentration were quantified using an automated biochemistry analyser. Serum N-terminal propeptide of type I procollagen (PINP) levels and β-crosslaps (β-CTX) levels were determined by ELISA assay. All data measurements and reporting were performed by the laboratory department at our hospital. Serum calcium (Ca) levels were adjusted for serum albumin (Alb) concentrations using the following formula: corrected Ca (mg/dL) = total Ca + 0.8 × (4.0 − Alb), if Alb<4.0 (g/dL). BMD of the lumbar spine or hip was assessed through dual-energy X-ray absorptiometry (Hologic, Boston, Massachusetts, USA). Abdominal sonography was conducted by certified physicians to detect renal stones. Urine calcium to creatinine ratio (UCa/UCr; mg/g Cr) was used as an estimate of urinary calcium excretion.16 The diagnostic criteria used in this study included: (1) Osteoporosis diagnosis according to WHO criteria: T-score ≤−2.5 for osteoporosis. (2) Recurrent kidney stones are defined as experiencing three or more episodes of passing stones within a 5-year period.10 Detailed information on participants’ kidney stone episodes over the past 10 years through questionnaire surveys and medical record reviews. (3) The history of kidney stones was documented based on individuals who had experienced kidney stones in the 10-year period preceding the cross-sectional assessment. (4) Cigarette smoking is defined as the daily consumption of at least one cigarette for 1 year or longer.Alcohol drinking is defined as consuming≥140 g per week within the current or previous 6 months.
Statistical analysis
The statistical analysis was performed using SPSS V.25.0 software (SPSS, Chicago, Illinois, USA), with a significance level set at p<0.05. Continuous variables were presented as mean±SD. Demographic characteristics were compared between groups using independent t-tests for quantitative variables and χ² tests for categorical variables. Univariate and multivariable logistic regression analyses were employed to assess risk factors. Categorical or rank variables were converted into dummy variables prior to regression analysis. All statistical graphs were generated using GraphPad Prism V.8.0.3 (GraphPad Software, USA).
Patient and public involvement statement
None.
Results
Urinary calcium is not associated with kidney stones
The characteristics of the study participants are presented in table 1, which includes a total of 204 individuals aged between 52 and 89 years (mean±SD: 61.84±9.06), comprising 105 males and 99 females. The table demonstrated that the patients with kidney stones had higher mean age (62.92±9.51 years) and BMI (25.31±4.13 kg/m²) compared with those without kidney stones (60.21±7.64 years and 23.92±3.32 kg/m², p=0.047 and p=0.041, respectively). Furthermore, the proportion of recurrent kidney stone formers was higher in the kidney stone group (13/45) compared with the without a current stone group (23/159, p=0.024). These findings suggest that higher age, BMI and a history of recurrent kidney stones may be associated with the presence of kidney stones, aligning with prior research.17
The basic characteristics of the subjects
Sonography examination results revealed kidney stones in 45 individuals, with a history of recurrent stone formation observed in 13 cases. Initially, we hypothesised that patients with kidney stones would exhibit higher urinary calcium excretion. However, our data did not reveal any significant differences in 24-hour urinary calcium between patients with and without current kidney stones (5.30±3.44 mmol vs 5.04±2.78 mmol, respectively; p=0.749). Similarly, there were no significant differences observed in the 24-hour urinary UCa/UCr ratio (0.69±0.57 vs 0.57±0.37, respectively; p=0.161) (figure 2).
The 24-hour urinary calcium and 24-hour urinary UCa/UCr ratio between patients with (n=45) and without (n=159) kidney stones. Data were presented as means±SD. UCa/UCr, urine calcium to creatinine ratio.
Additionally, apart from BMI and the history of recurrent kidney stone formation, there were no statistically significant gender differences or variations in blood levels of calcium, phosphorus, UA, PINP and β-CTX among the patients (table 1). To investigate the relationship between kidney stone formation and these risk factors further, we performed univariate analysis and identified BMI, UCa/UCr ratio, UA and PINP as potential influencing factors for kidney stone formation (table 2).
Univariate analysis of the main variables
Next, we investigated potential independent risk factors for kidney stone formation among them including BMI, UCa/UCr ratio, UA and PINP. However, since age and serum calcium level have been well recognised as important risk factors for kidney stones, we also included both variables to control for confounders and ensure the accuracy and stability of our final model. However, our logistic regression analysis revealed that except for age and BMI, neither showed a potentially predictive effect (table 3).
Multivariate logistic regression analysis of risk factors for kidney stone formation
Calcium level associated with recurrent kidney stones
Table 4 further categorises these patients into four distinct groups: (1) Only Present Stone (patients had kidney stones at present and had no prior history of kidney stones), (2) Only Past Stone (patients currently do not have kidney stones but have a prior history of kidney stones), (3) No Past Stone (patients had no history of kidney stones regardless of currently stones) and (4) No Stone (patients had no current or past history of kidney stones). This refined classification allows for a more exploration of the stone formation risk factors. Specifically, the patients age in the Only Past Stone group (66.43±10.71) was higher than those in the No Past Stone group (61.58±8.90, p=0.02). Similarly, blood calcium levels in the Only Past Stone group (2.42±0.27) were higher than those in the No Past Stone group (2.35±0.12, p=0.04). These findings suggest that age and blood calcium levels may play important roles in the recurrence of kidney stones. Specifically, hypercalciuria is often linked to increased stone formation due to its contribution to the supersaturation of urinary calcium salts, thereby promoting crystal nucleation and aggregation. Though the table does not reveal a statistically significant difference in UCa/UCr among groups, the underlying mechanisms of hypercalciuria may still play a pivotal role in driving stone recurrence, particularly in populations predisposed to recurrent kidney stones.
Comparison of basic characteristics among different groups
Recurrent kidney stones as a risk factor for the formation of kidney stones
Analysis of the theses data indicated significant differences in the history of recurrent kidney stones between other groups. Patients with current kidney stones exhibited a higher prevalence of previous stone formation compared with those without current kidney stones (table 1). Additionally, patients with a history of recurrent kidney stones were found to have higher blood calcium levels compared with those without a history of recurrence (table 4). Previous evidence has also supported the notion that individuals with a prior history of kidney stones are more susceptible to their recurrence.18–20 Therefore, we investigated the association between a history of recurrent kidney stones and the development of new kidney stones at present. The χ² test revealed a significant difference in stone formation between groups (χ2=5.11, p=0.024, table 1), suggesting that a history of recurrent kidney stones may be considered as a risk factor for new stone formation in patients with osteoporosis taking calcium and vitamin D supplements. Subsequently, univariate analysis was conducted to examine this relationship and yielded statistically significant results (Beta=0.154, B=0.167, SE=0.075, T=2.221, p=0.028). Furthermore, logistic regression analysis was employed to confirm this connection which indeed verified that a history of recurrent kidney stones serves as an independent risk factor for new stone development (p=0.024; table 5).
Adjusted multivariate logistic regression analysis of risk factors for kidney stone formation
Increased urinary calcium excretion might contribute to the kidney stone formation
Given the evidence from our data indicating recurrent kidney stone as a risk factor for kidney stones formation in patients with osteoporosis who have undergone calcium and vitamin D supplement treatment, we are further investigating the urinary calcium excretion of these patients. As anticipated, individuals with recurrent kidney stones exhibited a higher 24-hour urinary UCa/UCr ratio compared with those without (1.00±0.62 vs 0.57±0.54, p=0.026, figure 3). Furthermore, no significant differences were observed in other factors including BMI, age, UA, blood levels of calcium, phosphorus, PINP and β-CTX (figure 3).
The age, gender, BMI, 24-hour urinary UCa/UCr ratio, corrected serum calcium, serum phosphorus, uric acid levels as well as PINP and β-CTX levels between kidney stone patients with (n=13) and without (n=32) history of recurrent kidney stones. Data were presented as mean±SD. BMI, body mass index; PINP, N-terminal propeptide of type I procollagen; UCa/UCr, urine calcium to creatinine ratio; β-CTX, β-crosslaps.
Discussion
This cross-sectional study investigated the risk factors for kidney stone formation in patients with osteoporosis receiving calcium and vitamin D supplement treatment. Our findings indicate that a history of recurrent kidney stones is an independent risk factor for kidney stone formation in these patients. Additionally, we observed a significantly higher 24-hour urinary UCa/UCr ratio in patients with kidney stone with recurrent stones compared with those not, suggesting that urinary calcium excretion might be involved in the mechanism of kidney stone formation.
In the pathophysiology of kidney stone formation, urinary supersaturation plays a pivotal role. When the concentration of soluble calcium in urine exceeds its saturation point, crystal nuclei can form within the kidney. Subsequent exposure to supersaturated conditions further facilitates stone growth through encrustation.10 21 Previous studies have indicated a linear increase in the risk of nephrolithiasis with increasing urinary calcium22 and an obvious increase in stone risk is observed when calcium excretion exceeds 200 mg/L per day.21 However, the results regarding the increased risk for individuals who were taking supplementary calcium) or vitamin D were controversial. Aloia conducted measurements of serum and 24-hour urine calcium levels in subjects receiving coadministration of calcium carbonate (1200 mg) with either 10 000 IU or 600 IU of vitamin D3 per day. The results revealed that both groups exhibited hypercalcaemia and hypercalciuria, with the high-dose D group having a 3.6-fold higher OR for developing hypercalciuria.23 A randomised controlled trial (RCT) involving 36 282 participants from 40 Women’s Health Initiative centres found that the incidence of urinary tract stones was higher in women who received a daily dose of 1000 mg calcium and 400 IU vitamin D3 compared with those who received placebo control (HR=1.17).24 On the other side, Malihi conducted an RCT involving 5110 participants to investigate the impact of monthly supplementation with 100 000 IU vitamin D3 on kidney stone formation. The results showed no significant difference (HR=0.90, 95% CI 0.24 to 1.26, p=0.30).25 Ferroni found supplement vitamin D (1000 IU daily or 50 000 IU weekly) had no effect on urine calcium excretion or the supersaturation of calcium salts in known stone formers.26 More interestingly, Reid assessed the effects of calcium supplements using 1 g of elemental calcium daily in an RCT involving 1471 healthy postmenopausal women (732 in the calcium group and 739 in the placebo group). As a result, two subjects in the calcium group developed urinary calculi, as did four subjects allocated to the placebo group.27 Previous studies have examined the factors contributing to these disparate findings, suggesting that variables such as water intake, observation period, dietary sodium, genetic variants and timing of calcium supplementation may exert an influence on the formation of kidney stones.28 Nevertheless, our investigation has not established a correlation between urinary calcium excretion and stone formation in patients with osteoporosis undergoing calcium and vitamin D supplement treatment, thus supporting the safety of this therapy.
We further observed that a subset of patients were identified as having recurrent kidney stones. Accumulated evidence has indicated an increased recurrence rate of kidney stones in patients with a history of kidney stone formation.18–20 A recent study estimated 5-year recurrence rates of 17%, 32%, 47% and 60% after the first, second, third and fourth or higher episodes of kidney stones, respectively.29 Thus, we proceeded to investigate whether a history of recurrent kidney stones serves as a risk factor for patients. As anticipated, our logistic regression analysis confirmed this association. Given that hypercalciuria is the most prevalent metabolic abnormality among individuals with kidney stones,19 we compared calcium excretion levels between those with and without recurrent kidney stones and observed increased calcium excretion in the former group. Studies have determined that various factors may contribute to susceptibility, including younger age, male gender, higher BMI and a family history of stones20 29 which was consistent with our results. However, early data did not establish the utility of 24-hour urine calcium excretion in guiding medical therapy for kidney stones.29–31 Our analysis indicated that the history of recurrent kidney stones could act as a risk factor for kidney stone formation and further found increased urinary calcium excretion in patients with the history, suggesting that increased calcium excretion might be involved in the mechanism of kidney stone formation in patients with osteoporosis who have a history of recurrent kidney stones and experiencing calcium and vitamin D supplement therapy.
This study is subject to certain limitations. First, the recurrence of kidney stones was recorded based on self-reported symptoms or medical records in this cross-sectional study which may have resulted in an underestimation of the number of patients with asymptomatic stones being neglected. Second, it is difficult to calculate salt intake, protein intake, urine volume and vegetable consumption as well as urine oxalate, citrate and phosphate that may affect stone formation in this study. Additionally, the number of eligible participants was relatively small due to stringent inclusion criteria and overlapping conditions. Future research should aim to recruit a larger, more diverse cohort to validate these findings and develop more generalised recommendations. A more rigorous study should also ensure identical observation periods, regions and treatment durations.
Conclusion
In conclusion, our study has found that a history of recurrent kidney stones could act as a risk factor for kidney stone formation in patients with osteoporosis when coadministered with calcium and vitamin D supplement therapy. Increased urinary calcium excretion might be involved in the mechanism. Therefore, caution should be exercised when administering calcium and vitamin D supplements to these patients with osteoporosis and attention should be paid to changes in urinary calcium excretion. The next cohort study or RCT should be conducted to further identify the relationship between the increased risk of kidney stones and elevated urinary calcium excretion in larger population studies.
Data availability statement
Data are available upon reasonable request. Data are available by corresponding author upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
The study was approved by the Human Research Ethics committee of the First Affiliated Hospital of Army Medical University (BIIT20230102).
References
Footnotes
LS and YB are joint first authors.
LS and YB contributed equally.
Contributors LS and JH designed the study. LS, YB and XD conducted the analysis. YB, XD and XX conducted the data collection. LS developed the first draft of the manuscript and edited the paper according to the coauthors’ suggestions. LS and JH drew up the final draft. JH is responsible for the overall content as the guarantor. All authors contributed to the final draft of the manuscript.
Funding This work was supported by National Natural Science Foundation of China grant number 82300992.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.