In recent years, researchers have identified a potential correlation between the occurrence of kidney stones and a decrease in BMD in patients,,. In 2021, Ganesan et al reported that 20% of 531,431 patients with kidney stone disease were subsequently diagnosed with osteoporosis. In a more recent comprehensive analysis that included nine case‒control or cohort studies with a total of 454,464 people, researchers reported a notably greater prevalence of osteoporosis in patients with nephrolithiasis and vice versa9. Another 2011–2018 NHANES cross-sectional study revealed that a low femoral-neck BMD T score was significantly associated with an increased risk of developing kidney stones. However, the main limitation of these studies is that they cannot say whether osteoporosis was a cause or consequence of nephrolithiasis.
Figure 2 Scatter plot of the MR analysis of the effects of kidney stones on the risk of developing osteoporosis.
To our knowledge, this is the first combined NHANES and MR study to investigate whether the presence of kidney stones is causally associated with the risk of developing osteoporosis. The large, nationally representative NHANES-based observational study revealed that the presence of kidney stones was associated with a greater risk of developing osteoporosis. To further explore the causal effect of the presence of kidney stones on the risk of developing osteoporosis, an MR analysis was carried out on the basis of the genetic information from two GWASs. The two-sample bidirectional MR study established a causal relationship between the presence of kidney stones and the risk of developing osteoporosis. This finding provides more support for the results obtained from prior epidemiological investigations20,21,22. The reverse-MR analysis did not provide evidence to support the hypothesis that osteoporosis status could increase the risk of developing kidney stones. The results obtained from both the observational study and MR analysis were in agreement, indicating a high level of reliability and robustness in this discovery. The observational study included the examination of a group of individuals from the United States, whereas the MR analysis was primarily concentrated on individuals from Europe. These findings suggest that there may indeed be an association between the presence of kidney stones and the risk of developing osteoporosis among various populations.
Nephrolithiasis is a systemic metabolic disorder, and its main pathogenic factors include metabolic abnormalities, urinary tract infections, inflammatory reactions and drug factors. Osteoporosis is a long-lasting, metabolic condition affecting the bones of older individuals. It is characterized by a decrease in BMD and a decline in the structure of the bones.
Although the exact mechanism underlying the link between the presence of kidney stones and the risk of developing osteoporosis is still unclear, calcium‒phosphate balance and bone metabolism might be key etiopathogeneses A prior study conducted on a population from Taiwan revealed that persons with kidney stones had a greater likelihood of exhibiting allelic variations in the ALPL gene than did the general population. ALPL encodes a tissue-specific alkaline phosphatase (TNSALP) that hydrolyses phosphate substrates such as pyrophosphate (PPi) and phosphorylated glycoproteins such as osteopontin and releases inorganic phosphate, promoting appropriate calcification. Therefore, individuals with nephrolithiasis may experience inadequate calcification, leading to reduced bone mineralization and an elevated risk of developing osteoporosis. Similarly, multiple investigations have shown the presence of mutations in the CYP24A1 gene among patients diagnosed with hypercalcemia and nephrolithiasis,,. CYP24A1 encodes the enzyme 25(OH)D-24-hydroxylase, which inactivates vitamin D metabolites through the C-24 oxidation pathway. The mutant CYP24A1 enzymes presented a significant reduction in their functional capacity, resulting in the stimulation of osteoclasts because of high levels of 1,25(OH)2D, ultimately leading to a decrease in bone mass.
Inflammatory reactions may also increase the incidence of osteoporosis in kidney stone patients. Patients with nephrolithiasis have significantly increased levels of inflammatory markers, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-α (TNF-α), which have been investigated for their potential role in bone reabsorption. IL-1, also known as "osteoclast-activating factor", has the potential to stimulate osteoclast lineage cells, resulting in increases in both the viability and resorptive capacity of osteoclasts. By increasing both the differentiation and activation of osteoclasts and by stimulating the release of degradative products such as matrix metalloproteinases, IL-1 increases bone resorption. In addition, IL-1 synergistically interacts with other cytokines, such as TNF, IL-6, IL-17, and IL-31, which promote bone resorption and inhibit osteoblasts according to previous studies,.
Moreover, kidney stone patients’ with certain dietary habits (low calcium intake), low physical activity, smoking status and inadequate vitamin D status may increase their chance of developing osteoporosis.
The strengths of this study include the diverse groups of participants and the large sample size, which allowed for the adjustment of potential confounders. Another advantage of our study is the combination of an observational study with an MR analysis. The sole use of an observational study is susceptible to unmeasured confounding and reverse causality. When MR is used alone, the rate of false-negative results is relatively high, despite the ability to control for confounding conditions. Therefore, the combination of the two methods makes the results more convincing.
Our study also has several limitations. First, kidney stone information in the NHANES was self-reported and could not be treated as a continuous variable; therefore, the P-trend and the threshold effect of parameters were missing in our study. Second, the composition of kidney stones was unknown in both the NHANES and the UK Biobank. Calcium-free stones such as uric acid stones, which make up 10–20% of kidney stones, may lead to potential bias. Third, we excluded a significant proportion of patients who lacked information on kidney stones, femoral neck BMD data, or other variables. This exclusion may have introduced possible selection bias. Fourth, potential heterogeneity and pleiotropy should also be noted for MR. Finally, our study is based on Americans and Europeans, which may limit the generalizability of our findings to other populations.