Open access Original research

Association between calcium and

vitamin D supplementation and
increased risk of kidney stone formation
in patients with osteoporosis in
Southwest China: a cross-­sectional study
Lingfeng Shi ‍ ‍,1 Yinyin Bao,2 Xiang Deng,2 Xiaoli Xu,3 Jiongyu Hu4

To cite: Shi L, Bao Y, Deng X, ABSTRACT

et al. Association between Objectives This cross-­sectional study aims to evaluate STRENGTHS AND LIMITATIONS OF THIS STUDY
calcium and vitamin D the association between calcium and vitamin D ⇒ The objective of this study was to investigate the
supplementation and increased effects of vitamin D and calcium supplementation
supplementation for osteoporosis treatment and the
risk of kidney stone formation on individuals with senile osteoporosis, thereby al-
development of kidney stones while investigating the
in patients with osteoporosis
impact of urinary calcium excretion on kidney stone risk lowing for specific characteristics of the study group
in Southwest China: a cross-­
sectional study. BMJ Open among patients receiving this supplementation treatment. and facilitating generalisation of the results to sim-
2025;15:e092901. doi:10.1136/ Design The study involved collecting data from 204 ilar populations.
bmjopen-2024-092901 Chinese Han patients aged 50–89 with osteoporosis in ⇒ This study specifically assesses the impact of a his-
the southwest region of China. These patients had been tory of recurrent kidney stones on the risk of new
► Prepublication history for
on daily doses of 600 mg of calcium carbonate and stone formation, providing valuable insights into
this paper is available online.
0.5 µg alfacalcidol for at least 1 year. The study employed how prior stone events influence ongoing risk in
To view these files, please visit
the journal online (https://doi.​ univariate analysis and multivariable logistic regression to relation to calcium and vitamin D supplementation.
org/10.1136/bmjopen-2024-​ identify risk factors for kidney stones, with independent ⇒ The utilisation of strict inclusion and exclusion crite-
092901). t-­tests used to compare differences between groups. ria for individuals as well as an automated biochem-
Setting Data were collected from patients in the istry analyser to measure biochemical markers,
LS and YB contributed equally. southwest region of China, covering the period from July improved the accuracy and reliability of the data
2019 to December 2023. collected.
LS and YB are joint first authors. ⇒ As a cross-­sectional study design was employed, it
Participants The study included 204 patients with
Received 26 August 2024 osteoporosis, all of whom had been receiving the specified was not possible to establish causal relationships;
Accepted 15 January 2025 calcium and vitamin D supplements for the duration of the therefore, only assessments of associations could
study. be made, limiting interpretation of the results.
Results The study found that a history of recurrent kidney ⇒ While a sample size consisting of 204 patients may
stones was an independent risk factor for the development provide preliminary data, it might not be sufficient
of kidney stones. Patients with kidney stones who had a to fully represent the entire elderly osteoporosis pa-
history of recurrent stones exhibited significantly higher tient population.
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. including 28 studies with 1595 patients with
Conclusions The results suggest that a history of nephrolithiasis and 3402 healthy controls
recurrent kidney stones independently increases the risk of showed significantly lower T-­ score values
kidney stones in patients undergoing calcium and vitamin for the spine (Standardized Mean Differ-
D supplementation for osteoporosis, likely due to increased ence，SMD=−0.69), total hip (SMD=−0.82)
urinary calcium excretion. or femoral neck (SMD=−0.67), and a four-
© Author(s) (or their fold higher risk of developing osteoporosis in
employer(s)) 2025. Re-­use
patients with nephrolithiasis (OR=4.12).2 On
permitted under CC BY-­NC. No
commercial re-­use. See rights INTRODUCTION the other hand, an Italian epidemiological
and permissions. Published by Idiopathic osteoporosis and kidney stones survey that included 10 157 patients with oste-
BMJ Group. are significant health concerns with a high oporosis showed an increased risk of nephro-
For numbered affiliations see incidence and prevalence among adults lithiasis after adjustment (HR=1.33).3
end of article. worldwide.1 Among the recent clinical data, In most patients with osteoporosis, calcium
Correspondence to kidney stone formation is closely related to and vitamin D supplement therapy is the
Jiongyu Hu; osteoporosis or lower bone mineral density basic treatment. The American Association
​1417482754@​qq.​com (BMD). On one hand, a meta-­ analysis of Clinical Endocrinologists 2020 guidelines

Shi L, et al. BMJ Open 2025;15:e092901. doi:10.1136/bmjopen-2024-092901 1

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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 osteopo-
rosis 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 forma-
tion 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 nephrolithi-
asis.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 excre-
tion 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
Figure 1 Flowchart of population included in our final
regarding the potential risk of calcium and vitamin D
analysis. BMI, body mass index.
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 204 patients with osteoporosis were selected for this study.
basic treatment for osteoporosis in relation to kidney (figure 1).
stone formation, while also examining the influence of
Detailed information regarding the characteristics of
urinary calcium excretion on the risk profile of kidney
the entire sample can be found in the Results section.
stones among patients with osteoporosis with calcium and
The inclusion criteria are as follows: (1) Chinese Han
vitamin D supplement treatment.
individuals with osteoporosis and a body mass index
(BMI) ranging from 18.5 to 30 kg/m2; (2) Postmeno-
pausal women or men aged≥50 years who have been
MATERIALS AND METHODS
Study design and participants diagnosed with osteoporosis according to WHO criteria;
The aim of this cross-­sectional study was to investigate (3) Patients who have been receiving a daily dosage of
the potential impact of calcium and vitamin D supple- 600 mg calcium carbonate and 0.5 ug alfacalcidol for at
ment therapy on kidney stone development in patients least 1 year after menopause (women) or on reaching
with osteoporosis, while also examining the role of the age of 50 (men) which continued throughout the
urinary calcium excretion in this relationship. The study study period. The exclusion criteria are as follows:
was conducted by a well-­trained team consisting of two (1) Patients with conditions that may contribute to
endocrinologists, two urological surgeons, a sonogra- secondary osteoporosis, such as hyperthyroidism, renal
pher and a statistician. Written consent was granted by all tubular acidosis, rheumatoid arthritis or osteomalacia;
participants. (2) Patients with diseases that influence urinary calcium
The primary data was collected from July 2019 to excretion such as renal failure, idiopathic hypercalci-
December 2023, encompassing a total of 1572 patients uria or multiple myeloma; (3) Except for calcium or
diagnosed with osteoporosis who were admitted to our vitamin D supplementation, patients were not receiving
hospital in Chongqing, located in the southwest region any medications known to impact bone metabolism or
of China. After being analysed by our team based on the urinary calcium levels like bisphosphonates, glucocorti-
predefined inclusion and exclusion criteria, data from coids or thiazide diuretics; (4) A history of gout, renal

2 Shi L, et al. BMJ Open 2025;15:e092901. doi:10.1136/bmjopen-2024-092901

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Table 1 The basic characteristics of the subjects

Patients without kidney stones Patients with kidney stones
at present (mean±SD) at present (mean±SD)
Demographic characteristics n=159 n=45 Statistic value P value
Age (year) 60.21±7.64 62.92±9.51 T=−1.99 0.047
BMI (kg/m2) 23.92±3.32 25.31±4.13 T=−2.05 0.041
UCa/UCr (mg/g) 0.57±0.37 0.69±0.57 T=−1.41 0.161
Ca (mmol/L) 2.36±0.16 2.33±0.08 T=1.76 0.079
P (mmol/L) 1.19±0.24 1.23±0.25 T=−1.00 0.319
25(OH)D (ng/mL) 27.82±2.53 27.67±2.52 T=0.354 0.723
UA (umol/L) 326.72±99.51 357.72±78.56 T=−1.82 0.070
PINP (ng/mL) 48.74±30.17 58.01±52.11 T=1.12 0.264
β-CTX (ng/mL) 0.51±0.38 0.47±0.52 T=0.01 0.998
Gender Female=82, male=77 Female=17, male=28 χ2=2.16 0.141
Recurrent n=23 n=13 χ2=5.11 0.024

BMI, body mass index; Ca, corrected serum calcium; 25(OH)D, 25-­hydroxyvitamin D; PINP, N-­terminal propeptide of type I procollagen;
p, serum inorganic phosphorus; Recurrent, a history of recurrent kidney stone formation; UA, blood uric acid; UCa/UCr, urine calcium to
creatinine ratio; β-CTX, β-crosslaps.

infection and urosepsis; (5) Smoking, alcohol consump- Data measurement

tion, communication impairments and heart, lung, liver, Plasma samples were collected from participants who had
kidney failure. undergone a 12-­hour fasting period. Participants were
instructed to collect their urine over a 24-­hour duration
Sample size calculation for the measurement of volume, calcium and creatinine
The sample size calculation was estimated by following levels. Urine calcium, urine creatinine, serum calcium,
the formula for estimating sample size in a proportion serum inorganic phosphorus and serum uric acid (UA)
difference: ‍n = Z2 × p(1 − p) /d2.‍ concentration were quantified using an automated
where Z is the standard normal distribution quantile biochemistry analyser. Serum N-­terminal propeptide of
(1.96 for 95% confidence level), p is the expected prev- type I procollagen (PINP) levels and β-crosslaps (β-CTX)
alence of kidney stones and d is the acceptable margin levels were determined by ELISA assay. All data measure-
of error. Based on the prevalence of urolithiasis in the ments and reporting were performed by the laboratory
southern region of China is 5–10%. Assuming an expected department at our hospital. Serum calcium (Ca) levels
prevalence of p=0.1 (10%) and a margin of error d=0.05 were adjusted for serum albumin (Alb) concentrations
(5%), the required sample size would be n≈138.3. As our using the following formula: corrected Ca (mg/dL) =
study included 204 patients, the sample size was adequate total Ca + 0.8 × (4.0 − Alb), if Alb<4.0 (g/dL). BMD of
for the primary analysis. the lumbar spine or hip was assessed through dual-­energy

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.

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Table 2 Univariate analysis of the main variables

Variable Standardised coefficient (beta) Unstandardised coefficient (B) SE t-­value P value
Age (year) 0.124 0.006 0.003 1.726 0.086
Gender 0.034 0.028 0.062 0.456 0.649
BMI (kg/m2) 0.104 0.020 0.009 2.182 0.043
UCa/UCr 0.117 0.138 0.068 2.038 0.042
Ca (mmol/L) 0.122 0.339 0.195 1.742 0.083
P (mmol/L) 0.084 0.140 0.119 1.177 0.241
UA (umol/L) 0.201 0.240 0.118 2.048 0.042
PINP (ng/mL) 0.159 0.065 0.031 2.081 0.037
β-CTX (ng/mL) −0.059 −0.066 0.092 −0.714 0.476
BMI, body mass index; Ca, corrected serum calcium; PINP, N-­terminal propeptide of type I procollagen; p, serum inorganic phosphorus; UA,
blood uric acid; UCa/UCr, urine calcium to creatinine ratio; β-CTX, β-crosslaps.

X-­ray absorptiometry (Hologic, Boston, Massachusetts, generated using GraphPad Prism V.8.0.3 (GraphPad Soft-
USA). Abdominal sonography was conducted by certified ware, USA).
physicians to detect renal stones. Urine calcium to creat-
inine ratio (UCa/UCr; mg/g Cr) was used as an estimate Patient and public involvement statement
of urinary calcium excretion.16 The diagnostic criteria None.
used in this study included: (1) Osteoporosis diagnosis
according to WHO criteria: T-­score ≤−2.5 for osteopo-
rosis. (2) Recurrent kidney stones are defined as expe- RESULTS
riencing three or more episodes of passing stones within Urinary calcium is not associated with kidney stones
a 5-­year period.10 Detailed information on participants’ The characteristics of the study participants are presented
kidney stone episodes over the past 10 years through in table 1, which includes a total of 204 individuals
questionnaire surveys and medical record reviews. (3) aged between 52 and 89 years (mean±SD: 61.84±9.06),
The history of kidney stones was documented based on comprising 105 males and 99 females. The table demon-
individuals who had experienced kidney stones in the strated that the patients with kidney stones had higher
10-­year period preceding the cross-­sectional assessment. mean age (62.92±9.51 years) and BMI (25.31±4.13 kg/m²)
(4) Cigarette smoking is defined as the daily consump- compared with those without kidney stones (60.21±7.64
tion of at least one cigarette for 1 year or longer.Alcohol years and 23.92±3.32 kg/m², p=0.047 and p=0.041, respec-
drinking is defined as consuming≥140 g per week within tively). Furthermore, the proportion of recurrent kidney
the current or previous 6 months. stone formers was higher in the kidney stone group
(13/45) compared with the without a current stone group
Statistical analysis
(23/159, p=0.024). These findings suggest that higher
The statistical analysis was performed using SPSS V.25.0
age, BMI and a history of recurrent kidney stones may
software (SPSS, Chicago, Illinois, USA), with a signif-
be associated with the presence of kidney stones, aligning
icance level set at p<0.05. Continuous variables were
with prior research.17
presented as mean±SD. Demographic characteristics
Sonography examination results revealed kidney stones
were compared between groups using independent t-­tests
in 45 individuals, with a history of recurrent stone forma-
for quantitative variables and χ² tests for categorical vari-
tion observed in 13 cases. Initially, we hypothesised that
ables. Univariate and multivariable logistic regression
patients with kidney stones would exhibit higher urinary
analyses were employed to assess risk factors. Categorical
calcium excretion. However, our data did not reveal
or rank variables were converted into dummy variables
any significant differences in 24-­ hour urinary calcium
prior to regression analysis. All statistical graphs were
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 differ-
Table 3 Multivariate logistic regression analysis of risk
factors for kidney stone formation
ences observed in the 24-­hour urinary UCa/UCr ratio
(0.69±0.57 vs 0.57±0.37, respectively; p=0.161) (figure 2).
B (SE) OR (95% CI) P value
Additionally, apart from BMI and the history of recur-
Age −0.051 (0.022) 0.957 (0.910 to 0.993) 0.022 rent kidney stone formation, there were no statistically
BMI 0.108 (0.048) 1.114 (1.014 to 1.224) 0.025 significant gender differences or variations in blood levels
of calcium, phosphorus, UA, PINP and β-CTX among the
B, regression coefficient; BMI, body mass index.
patients (table 1). To investigate the relationship between

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Table 4 Comparison of basic characteristics among different groups

Only Present Only Past Stone Only Past Stone No Past Stone
Stone (n=32) (n=23) P value (n=23) (n=168) P value
Age (year) 62.92±9.51 66.43±10.71 0.02 66.43±10.71 61.58±8.90 0.02
BMI (kg/m2) 25.31±4.13 23.92±3.05 0.24 23.92±3.05 24.14±3.48 0.78
UCa/UCr (mg/g) 0.69±0.57 0.54±0.31 0.79 0.54±0.31 0.58±0.42 0.70
Ca (mmol/L) 2.33±0.08 2.42±0.27 0.19 2.42±0.27 2.35±0.12 0.04
P (mmol/L) 1.23±0.25 1.14±0.19 0.13 1.14±0.19 1.21±0.26 0.19
25(OH)D (ng/mL) 27.67±2.52 27.70±2.51 0.22 27.71±2.51 27.51±2.79 0.25
UA (umol/L) 357.72±78.56 320.75±82.58 0.21 320.74±82.58 331.67±96.37 0.60
PINP (ng/mL) 58.01±52.11 55.17±35.49 0.71 55.17±35.49 50.01±37.41 0.53
β-CTX (ng/mL) 0.47±0.52 0.50±0.40 0.93 0.50±0.40 0.51±0.37 0.92
Only Present Only Past Stone No Stone
Stone (n=45) No Stone (n=136) P value (n=23) (n=136) P value
Age (year) 62.92±9.51 62.00±9.12 0.21 66.43±10.71 62.00±9.12 0.04
BMI (kg/m2) 25.31±4.13 23.92±3.37 0.10 23.92±3.05 23.92±3.37 0.99
UCa/UCr (mg/g) 0.69±0.57 0.57±0.38 0.95 0.54±0.31 0.57±0.38 0.67
Ca (mmol/L) 2.33±0.08 2.35±0.13 0.56 2.42±0.27 2.35±0.13 0.08
P (mmol/L) 1.23±0.25 1.21±0.26 0.05 1.14±0.19 1.21±0.26 0.24
25(OH)D (ng/mL) 27.67±2.52 27.60±2.57 0.23 27.71±2.51 27.60±2.57 0.44
UA (umol/L) 357.72±78.56 326.40±91.27 0.14 320.74±82.58 326.40±91.27 0.78
PINP (ng/mL) 58.01±52.11 47.67±29.20 0.27 55.17±35.49 47.67±29.20 0.27
β-CTX (ng/mL) 0.47±0.52 0.52±0.38 0.76 0.50±0.40 0.52±0.38 0.88
Only Present Only Past Stone Only Past Stone No Past Stone
Stone (n=32) (n=23) P value (n=23) (n=168) P value
Age (year) 62.92±9.51 66.43±10.71 0.02 66.43±10.71 61.58±8.90 0.02
BMI (kg/m2) 25.31±4.13 23.92±3.05 0.24 23.92±3.05 24.14±3.48 0.78
UCa/UCr (mg/g) 0.69±0.57 0.54±0.31 0.79 0.54±0.31 0.58±0.42 0.70
Ca (mmol/L) 2.33±0.08 2.42±0.27 0.19 2.42±0.27 2.35±0.12 0.04
P (mmol/L) 1.23±0.25 1.14±0.19 0.13 1.14±0.19 1.21±0.26 0.19
25(OH)D (ng/mL) 27.67±2.52 27.70±2.51 0.22 27.71±2.51 27.51±2.79 0.25
UA (umol/L) 357.72±78.56 320.75±82.58 0.21 320.74±82.58 331.67±96.37 0.60
PINP (ng/mL) 58.01±52.11 55.17±35.49 0.71 55.17±35.49 50.01±37.41 0.53
β-CTX (ng/mL) 0.47±0.52 0.50±0.40 0.93 0.50±0.40 0.51±0.37 0.92
Only Present No Stone Only Past Stone No Stone
Stone (n=45) (n=136) P value (n=23) (n=136) P value
Age (year) 62.92±9.51 62.00±9.12 0.21 66.43±10.71 62.00±9.12 0.04
BMI (kg/m2) 25.31±4.13 23.92±3.37 0.10 23.92±3.05 23.92±3.37 0.99
UCa/UCr (mg/g) 0.69±0.57 0.57±0.38 0.95 0.54±0.31 0.57±0.38 0.67
Ca (mmol/L) 2.33±0.08 2.35±0.13 0.56 2.42±0.27 2.35±0.13 0.08
P (mmol/L) 1.23±0.25 1.21±0.26 0.05 1.14±0.19 1.21±0.26 0.24
25(OH)D (ng/mL) 27.67±2.52 27.60±2.57 0.23 27.71±2.51 27.60±2.57 0.44
UA (umol/L) 357.72±78.56 326.40±91.27 0.14 320.74±82.58 326.40±91.27 0.78
PINP (ng/mL) 58.01±52.11 47.67±29.20 0.27 55.17±35.49 47.67±29.20 0.27
β-CTX (ng/mL) 0.47±0.52 0.52±0.38 0.76 0.50±0.40 0.52±0.38 0.88
BMI, body mass index; Ca, corrected serum calcium; 25(OH)D, 25-­hydroxyvitamin D; P, serum inorganic phosphorus; PINP, N-­terminal
propeptide of type I procollagen; UA, blood uric acid; UCa/UCr, urine calcium to creatinine ratio; β-CTX, β-crosslaps.

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groups. Patients with current kidney stones exhibited a

Table 5 Adjusted multivariate logistic regression analysis of
risk factors for kidney stone formation higher prevalence of previous stone formation compared
with those without current kidney stones (table 1). Addi-
B (SE) OR (95% CI) P value
tionally, patients with a history of recurrent kidney stones
Age −0.054 (0.022) 0.947 (0.907 to 0.990) 0.016 were found to have higher blood calcium levels compared
BMI 0.104 (0.050) 1.110 (1.007 to 1.223) 0.036 with those without a history of recurrence (table 4).
Recurrent 0.945 (0.419) 2.572 (1.131 to 5.846) 0.024 Previous evidence has also supported the notion that
individuals with a prior history of kidney stones are more
B, regression coefficient; BMI, body mass index; Recurrent, a
susceptible to their recurrence.18–20 Therefore, we inves-
history of recurrent stone formation.
tigated 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
kidney stone formation and these risk factors further, we
in stone formation between groups (χ2=5.11, p=0.024,
performed univariate analysis and identified BMI, UCa/
table 1), suggesting that a history of recurrent kidney
UCr ratio, UA and PINP as potential influencing factors
stones may be considered as a risk factor for new stone
for kidney stone formation (table 2).
formation in patients with osteoporosis taking calcium
Next, we investigated potential independent risk
and vitamin D supplements. Subsequently, univariate
factors for kidney stone formation among them including
analysis was conducted to examine this relationship
BMI, UCa/UCr ratio, UA and PINP. However, since age
and yielded statistically significant results (Beta=0.154,
and serum calcium level have been well recognised as
B=0.167, SE=0.075, T=2.221, p=0.028). Furthermore,
important risk factors for kidney stones, we also included
logistic regression analysis was employed to confirm this
both variables to control for confounders and ensure the
connection which indeed verified that a history of recur-
accuracy and stability of our final model. However, our
rent kidney stones serves as an independent risk factor
logistic regression analysis revealed that except for age
for new stone development (p=0.024; table 5).
and BMI, neither showed a potentially predictive effect
(table 3). Increased urinary calcium excretion might contribute to the
Calcium level associated with recurrent kidney stones kidney stone formation
Table 4 further categorises these patients into four Given the evidence from our data indicating recurrent
distinct groups: (1) Only Present Stone (patients had kidney stone as a risk factor for kidney stones forma-
kidney stones at present and had no prior history of tion in patients with osteoporosis who have undergone
kidney stones), (2) Only Past Stone (patients currently calcium and vitamin D supplement treatment, we are
do not have kidney stones but have a prior history of further investigating the urinary calcium excretion of
kidney stones), (3) No Past Stone (patients had no these patients. As anticipated, individuals with recurrent
history of kidney stones regardless of currently stones) kidney stones exhibited a higher 24-­hour urinary UCa/
and (4) No Stone (patients had no current or past history UCr ratio compared with those without (1.00±0.62 vs
of kidney stones). This refined classification allows for 0.57±0.54, p=0.026, figure 3). Furthermore, no significant
a more exploration of the stone formation risk factors. differences were observed in other factors including BMI,
Specifically, the patients age in the Only Past Stone group age, UA, blood levels of calcium, phosphorus, PINP and
(66.43±10.71) was higher than those in the No Past Stone β-CTX (figure 3).
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, DISCUSSION
p=0.04). These findings suggest that age and blood This cross-­
sectional study investigated the risk factors
calcium levels may play important roles in the recurrence for kidney stone formation in patients with osteoporosis
of kidney stones. Specifically, hypercalciuria is often receiving calcium and vitamin D supplement treatment.
linked to increased stone formation due to its contri- Our findings indicate that a history of recurrent kidney
bution to the supersaturation of urinary calcium salts, stones is an independent risk factor for kidney stone
thereby promoting crystal nucleation and aggregation. formation in these patients. Additionally, we observed
Though the table does not reveal a statistically significant a significantly higher 24-­hour urinary UCa/UCr ratio
difference in UCa/UCr among groups, the underlying in patients with kidney stone with recurrent stones
mechanisms of hypercalciuria may still play a pivotal role compared with those not, suggesting that urinary calcium
in driving stone recurrence, particularly in populations excretion might be involved in the mechanism of kidney
predisposed to recurrent kidney stones. stone formation.
In the pathophysiology of kidney stone formation,
Recurrent kidney stones as a risk factor for the formation of urinary supersaturation plays a pivotal role. When the
kidney stones concentration of soluble calcium in urine exceeds its satu-
Analysis of the theses data indicated significant differences ration point, crystal nuclei can form within the kidney.
in the history of recurrent kidney stones between other Subsequent exposure to supersaturated conditions

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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.

further facilitates stone growth through encrustation.10 21 D were controversial. Aloia conducted measurements
Previous studies have indicated a linear increase in the of serum and 24-­hour urine calcium levels in subjects
risk of nephrolithiasis with increasing urinary calcium22 receiving coadministration of calcium carbonate
and an obvious increase in stone risk is observed when (1200 mg) with either 10 000 IU or 600 IU of vitamin D3
calcium excretion exceeds 200 mg/L per day.21 However, per day. The results revealed that both groups exhibited
the results regarding the increased risk for individuals hypercalcaemia and hypercalciuria, with the high-­dose
who were taking supplementary calcium) or vitamin D group having a 3.6-­ fold higher OR for developing

Shi L, et al. BMJ Open 2025;15:e092901. doi:10.1136/bmjopen-2024-092901 7

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hypercalciuria.23 A randomised controlled trial (RCT) kidney stones and experiencing calcium and vitamin D
involving 36 282 participants from 40 Women’s Health supplement therapy.
Initiative centres found that the incidence of urinary tract This study is subject to certain limitations. First, the
stones was higher in women who received a daily dose recurrence of kidney stones was recorded based on
of 1000 mg calcium and 400 IU vitamin D3 compared self-­reported symptoms or medical records in this cross-­
with those who received placebo control (HR=1.17).24 sectional study which may have resulted in an underes-
On the other side, Malihi conducted an RCT involving timation of the number of patients with asymptomatic
5110 participants to investigate the impact of monthly stones being neglected. Second, it is difficult to calculate
supplementation with 100 000 IU vitamin D3 on kidney salt intake, protein intake, urine volume and vegetable
stone formation. The results showed no significant differ- consumption as well as urine oxalate, citrate and phos-
ence (HR=0.90, 95% CI 0.24 to 1.26, p=0.30).25 Ferroni phate that may affect stone formation in this study. Addi-
found supplement vitamin D (1000 IU daily or 50 000 IU tionally, the number of eligible participants was relatively
weekly) had no effect on urine calcium excretion or small due to stringent inclusion criteria and overlap-
the supersaturation of calcium salts in known stone ping conditions. Future research should aim to recruit a
formers.26 More interestingly, Reid assessed the effects larger, more diverse cohort to validate these findings and
of calcium supplements using 1 g of elemental calcium develop more generalised recommendations. A more
daily in an RCT involving 1471 healthy postmenopausal rigorous study should also ensure identical observation
women (732 in the calcium group and 739 in the placebo periods, regions and treatment durations.
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 CONCLUSION
the factors contributing to these disparate findings, In conclusion, our study has found that a history of recur-
suggesting that variables such as water intake, observa- rent kidney stones could act as a risk factor for kidney
tion period, dietary sodium, genetic variants and timing stone formation in patients with osteoporosis when
of calcium supplementation may exert an influence on coadministered with calcium and vitamin D supplement
the formation of kidney stones.28 Nevertheless, our inves- therapy. Increased urinary calcium excretion might be
tigation has not established a correlation between urinary involved in the mechanism. Therefore, caution should
calcium excretion and stone formation in patients with be exercised when administering calcium and vitamin D
osteoporosis undergoing calcium and vitamin D supple- supplements to these patients with osteoporosis and atten-
ment treatment, thus supporting the safety of this therapy. tion should be paid to changes in urinary calcium excre-
We further observed that a subset of patients were iden- tion. The next cohort study or RCT should be conducted
tified as having recurrent kidney stones. Accumulated to further identify the relationship between the increased
evidence has indicated an increased recurrence rate of risk of kidney stones and elevated urinary calcium excre-
kidney stones in patients with a history of kidney stone tion in larger population studies.
formation.18–20 A recent study estimated 5-­year recurrence
rates of 17%, 32%, 47% and 60% after the first, second, Author affiliations
1
Third Military Medical University Southwest Hospital, Chongqing, China
third and fourth or higher episodes of kidney stones, 2
Third Military Medical University (Army Medical University), Chongqing, China
respectively.29 Thus, we proceeded to investigate whether 3
Department of Endocrinology, First Affiliated Hospital of Third Military Medical
a history of recurrent kidney stones serves as a risk factor University (Army Medical University), Chongqing, China
4
for patients. As anticipated, our logistic regression anal- Department of Endocrinology, Chongqing Medical University, Chongqing, China
ysis confirmed this association. Given that hypercalci-
uria is the most prevalent metabolic abnormality among 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
individuals with kidney stones,19 we compared calcium manuscript and edited the paper according to the coauthors’ suggestions. LS and
excretion levels between those with and without recur- JH drew up the final draft. JH is responsible for the overall content as the guarantor.
rent kidney stones and observed increased calcium excre- All authors contributed to the final draft of the manuscript.
tion in the former group. Studies have determined that Funding This work was supported by National Natural Science Foundation of
various factors may contribute to susceptibility, including China grant number 82300992.
younger age, male gender, higher BMI and a family Competing interests None declared.
history of stones20 29 which was consistent with our results. Patient and public involvement Patients and/or the public were not involved in
However, early data did not establish the utility of 24-­hour the design, or conduct, or reporting, or dissemination plans of this research.
urine calcium excretion in guiding medical therapy for Patient consent for publication Not applicable.
kidney stones.29–31 Our analysis indicated that the history Ethics approval The study was approved by the Human Research Ethics
of recurrent kidney stones could act as a risk factor for committee of the First Affiliated Hospital of Army Medical University (BIIT20230102).
kidney stone formation and further found increased Provenance and peer review Not commissioned; externally peer reviewed.
urinary calcium excretion in patients with the history, Data availability statement Data are available upon reasonable request. Data are
suggesting that increased calcium excretion might be available by corresponding author upon reasonable request.
involved in the mechanism of kidney stone formation in Open access This is an open access article distributed in accordance with the
patients with osteoporosis who have a history of recurrent Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which

8 Shi L, et al. BMJ Open 2025;15:e092901. doi:10.1136/bmjopen-2024-092901

 Open access

permits others to distribute, remix, adapt, build upon this work non-­commercially, 14 Messa P, Castellano G, Vettoretti S, et al. Vitamin D and Calcium
and license their derivative works on different terms, provided the original work is Supplementation and Urolithiasis: A Controversial and Multifaceted
properly cited, appropriate credit is given, any changes made indicated, and the use Relationship. Nutrients 2023;15:1724.
is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. 15 Coe FL, Worcester EM, Evan AP. Idiopathic hypercalciuria and
formation of calcium renal stones. Nat Rev Nephrol 2016;12:519–33.
16 Havens PL, Stephensen CB, Hazra R, et al. Vitamin D3 decreases
ORCID iD
parathyroid hormone in HIV-­infected youth being treated with
Lingfeng Shi http://orcid.org/0000-0002-3115-2520 tenofovir: a randomized, placebo-­controlled trial. Clin Infect Dis
2012;54:1013–25.
17 Wang K, Ge J, Han W, et al. Risk factors for kidney stone disease
recurrence: a comprehensive meta-­analysis. BMC Urol 2022;22:62.
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