Hypercalciuria is the most common metabolic abnormality in patients with calcium kidney stones . Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of calcium throughout the body. This additional urinary calcium source is almost certainly bone, which is the largest calcium store in the body. High calcium stone formers exhibit reduced bone mineral density (BMD), which is associated with increased urinary calcium excretion. Decreased BMD is also associated with increased bone turnover markers and increased fractures. In humans, it is difficult to determine the cause of reduced BMD in high-calcium urinary stone formers. To study the skeletal effects of hypercalciuria, we utilized our genetically hypercalciuric stone-forming (GHS) rats, which were developed by serial inbreeding of the most hypercalciuric Sprague-Dawley rats. GHS rats excreted more urinary calcium than similarly fed controls, and all GHS rats developed kidney stones whereas control rats did not. Hypercalciuria is due to a systemic dysregulation of calcium homeostasis, with increased intestinal calcium absorption, enhanced bone mineral absorption, and decreased renal tubular calcium reabsorption, associated with an increase in the vitamin D receptor in all these target tissues. We recently found that GHS rats fed a calcium-sufficient diet have reduced BMD and their bones are more susceptible to fractures, suggesting that intrinsic disease of the skeleton is not secondary to diet.
Bone resorption in high calcium stone formers
Most people with calcium (Ca)-containing kidney stones are hypercalciuria compared with people who do not form stones [ 1 – 3 ]. Hypercalciuria increases the supersaturation of the calcium dibasic phosphate and calcium oxalate solid phases in the urine, thereby increasing the likelihood of crystal nucleation and growth into clinically significant kidney stones [4]. Patients with hypercalciuria typically excrete more calcium than they absorb, reflecting a net loss of systemic calcium [2,5,6]. In patients with hypercalciuria and nephrolithiapers, a low-calcium diet often results in greater net Ca excretion rather than any increase in Ca absorption, suggesting that the source of this additional urinary (U)Ca is almost certainly bone, which is the largest store of Ca in the body [7]. Spinal bone density was significantly reduced in patients with fasting hypercalciuria [8], Pietschmann et al. found that spine BMD was lower in hypercalciuric patients compared with normocalciuric patients [ 9 ]. However, the bone pathology observed in patients with idiopathic hypercalciuria is unclear.
Bone mineral density (BMD) is inversely related to UCa excretion in male [ 10 ] and female [ 11 ] stone formers, but not in non-stone formers [ 7 ]. Many studies using a variety of methods, including radiodensitometry, quantitative computed tomography (CT), dual-energy X-ray absorptiometry, and single-photon absorptiometry, have demonstrated a reduction in BMD in patients with kidney stones compared with matched controls [ 5 , 9 , 12 – 16 ].
Jaeger et al. Stone formers were found to be slightly shorter and have significantly lower BMD at the tibial diaphysis and tibial epiphysis compared with controls [ 12 ]. Giannini found that 49 patients with recurrent stones with idiopathic hypercalciuria had lower lumbar Z-scores than normal controls [ 13 ]. Misalda Silva et al. examined bone formation and resorption parameters in 40 stone formers and classified 10 as osteopenic [ 14 ]. Tasca et al. found that patients with hypercalciuria had more negative L1–L2 vertebrae Z-scores than controls [ 15 ]. After adjusting for a large number of variables, analysis of the National Health and Nutrition Examination Survey 3 (NHANES III) showed that men with a history of kidney stones had lower femoral neck BMD than men without a history of stones [ 17 ]. Analysis of a large cohort of older men again demonstrated an association between kidney stones and reduced BMD at the femoral neck [ 18 ]. Thus, high-calcium stone formers have reduced bone density in both vertebrae and long bones compared with normal patients; however, it is unclear whether any of these bone types is more affected than the other.
Idiopathic hypercalciuria is associated with increased markers of bone turnover, which may provide a possible explanation for reduced BMD [ 16 , 19 ]. Urinary hydroxyproline levels are elevated in unselected patients with idiopathic hypercalciuria [ 16 ], and serum osteocalcin levels are elevated in stone patients with defective tubular Ca reabsorption, but not in patients with intestinal Ca hyperabsorption alone [ 19 ].Bone turnover studies with 47 Ca show increased bone formation and resorption, with the latter predominating [20]. The cytokine , known to increase bone resorption, has also been shown to be elevated in patients with idiopathic hypercalciuria [8, 14, 21, 22]. Pacifici showed that the cytokine interleukin 1 (IL-1) was elevated in monocyte from patients with fasting hypercalciuria but not in patients with intestinal Ca excess [8]. Weisinger demonstrated an increase in IL-1 and also demonstrated an increase in IL-6 and tumor necrosis factor α (TNF-α) [ 21 ]. Others have made similar observations [ 14 , 22 ]. In several studies examining bone biopsies, a picture consistent with low bone formation and turnover was most consistently observed [16, 23]. A retrospective study of male stone formers with idiopathic hypercalcemia found that the only biological factor associated with low BMD in these patients was fasting hypercalciuria following a 2-day calcium-restricted diet [24]. This suggests that a pathological process independent of parathyroid leads to bone Ca efflux and may be used as a tool to identify patients with hypercalciuria at risk for BMD reduction.
Based on the observed changes in BMD and bone turnover in patients with kidney stones, it may not be surprising that they have higher fracture rates than subjects without kidney stones [16]. In NHANES III, stone formers had an increased risk of wrist and spinal fractures [17], and in a retrospective analysis, stone formers had an increased incidence of vertebral fractures but not other fractures [16]. Changes in fracture rates occurred over a much longer period of time than changes in BMD. Because BMD decreases occur earlier than increases in fracture rates, increased attention has been paid to BMD decreases associated with hypercalciuria and nephrolithiasis in an attempt to understand the underlying mechanisms of skeletal changes that occur due to hypercalciuria. The reduction in BMD associated with idiopathic hypercalciuria in humans may be caused by primary bone formation and/or resorption disorders. Alternatively, the decrease in BMD may be due to differences in the renal processing of dietary components (such as calcium, sodium, and/or the protein ) in stone formers and normal controls, possibly over life. Each of these substances affects urinary calcium excretion [ 25 ] and underlying BMD or bone structure. In humans, it is almost impossible to experimentally identify the primary causative factors responsible for the observed decreases in BMD.
The prevalence of nephrolithiasis has increased over the past few decades [65]. Hypercalciuria leading to nephrolithiasis is a systemic disturbance of calcium homeostasis that is associated with an increased risk of bone disease leading to fractures as well as chronic kidney disease , coronary artery disease, hypertension and other metabolic disorders [66].
The primary endpoint of successful metabolic therapy in patients with calcium-containing kidney stones is a reduction in stone recurrence [ 1 – 3 ]. As mentioned above, stone formers have reduced BMD [5, 9, 12-17, 67] and increased fracture rates [16, 17] compared with non-stone formers. Although reducing recurrent stone formation is an important goal, clinicians should equally focus on maintaining and improving patients' BMD and bone quality [67]. Although acute stone attacks usually resolve quickly, patients may live with pain and reduced function for the rest of their lives due to bone complications associated with fractures [68]. We utilized GHS rats not only to better understand the pathogenesis of hypercalciuria and stone formation but also to study their skeleton. With the knowledge gained from this important model, which closely reflects the physiology of human hypercalciuria and stone formation, we will be able to better understand and treat bone disease in hypercalciuric stone formers and ultimately reduce fractures.
Systemic abnormalities in Ca homeostasis in GHS rats
GHS rats exhibit increased intestinal calcium absorption (αCa), increased bone resorption (Br
Ca ), and decreased renal calcium reabsorption (fr Ca ) compared with control rats fed comparable dietary calcium (D Ca
).Krieger NS, Bushinsky DA. The relation between bone and stone formation. Calcif Tissue Int. 2013 Oct;93(4):374-81. doi: 10.1007/s00223-012-9686-2. Epub 2012 Dec 18. PMID: 23247537; PMCID: PMC3625692.
