Calcium nephrolithiasis and bone demineralization: pathophysiology, diagnosis, and medical management

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1 REVIEW C URRENT OPINION Calcium nephrolithiasis and bone demineralization: pathophysiology, diagnosis, and medical management Miguel A. Arrabal-Polo a, María del Carmen Cano-García a, Benjamin K. Canales b, and Miguel Arrabal-Martín c Purpose of review To establish the relationship between calcium nephrolithiasis, bone densitometry scoring, and bone mineral density (BMD) loss according to bone turnover markers (BTMs) and urinary metabolites. Recent findings Patients with recurrent calcium nephrolithiasis and idiopathic fasting hypercalciuria (urinary calcium/ creatinine ratio >0.11) are more likely to have BMD loss that may lead to osteopenia or osteoporosis. In these patients, BTMs may be used as a surrogate for both bone health and stone recurrence. Suspect higher lithogenic states when calcium stone formers have serum beta-crosslaps (resorptive marker) greater than ng/ml, serum osteocalcin (formative marker) greater than 13.2 ng/ml, and beta-crosslaps/ osteocalcin ratio greater than Summary Patients with recurrent calcium nephrolithiasis and fasting hypercalciuria have a higher incidence of osteopenia and osteoporosis, measured by the dual-energy X-ray absorptiometry. These patients present not only with hypercalciuria and increased BTMs (mainly resorptive), but also up to 30% have hypocitraturia and increased urinary calcium/citrate ratio (>0.25). On the basis of these results, a diagnostic algorithm was created, classifying hypercalciurics according to their fasting calcium/creatinine and calcium/citrate ratio. Medical therapy for these patients is aimed at improving the dietary habits (normocalcemic, low salt, low animal protein diet), prescribing combinations of potassium citrate, thiazides, and bisphosphonates, and correcting bone and urinary abnormalities that may lower future skeletal and kidney stone risk. Keywords bone mineral density, bone turnover markers, calcium nephrolithiasis, hypercalciuria, hypocitraturia INTRODUCTION Calcium nephrolithiasis is a highly prevalent disease with recurrence rates as high as 50% within 5 years [1 & ]. Up to 60% of calcium stone formers are hypercalciuric a number that increases even further when the stone former has concomitant bone mineral density (BMD) loss [2]. Since the 1970s, a variety of authors have elegantly demonstrated the relationship between calcium nephrolithiasis, hypercalciuria, and the development of osteopenia, osteoporosis, and even fracture [3]. This relationship, not surprisingly, is affected by a number of dietary, endocrine, and immunological factors [3,4]. Additionally, experimental data in hypercalciuric, genetically predisposed animals suggest that some BMD loss occurs through pathways independent of all external factors, including diet. It is likely, therefore, that some portion of intrinsic bone phenotype is associated with genetic factors that may predispose a subset of patients to hypercalciuria, renal stones, osteopenia, and osteoporosis [5]. This review will highlight the pathophysiology of bone and stone disease, summarize the advances in markers and medical therapies for hypercalciuric stone formers, and end by proposing a screening a Urology Department, Hospital La Inmaculada, Huercal-Overa, Almeria, Spain, b Department of Urology, University of Florida, Gainesville, Florida, USA and c Urology Department, San Cecilio University Hospital, Granada, Spain Correspondence to Miguel A. Arrabal-Polo, PhD, Virgilistreet, 9, Huercal- Overa, Almeria, Spain. arrabalp@ono.com Curr Opin Urol 2014, 24: DOI: /MOU ß 2014 Wolters Kluwer Health Lippincott Williams & Wilkins

2 Bone health in urologic patients KEY POINTS Bone mineral density loss occurs in patients with recurrent calcium stones, in particular those with hypercalciuria. Bone densitometry and bone turnover markers may be useful tools to diagnose and follow bone and stone health in these patients. The treatment of patients with calcium stones and BMD loss is most successful by decreasing bone resorption (bisphosphonates) and reducing calciuria (thiazides). occurrence of local inflammatory processes induced by osteogenic phenomena associated with the synthesis of certain proteins such as osteopontin, osteocalcin and some others may produce papillary mineralization and calcification, inducing lesions that precede the onset of Randall s plaque [9]. In 2002, 20 patients with nephrolithiasis or loss of BMD were found to be heterozygous for the renal sodium phosphate cotransporter (NaPi-2a) mutation, which can lead to urinary phosphate wasting and hypophosphatemia in patients with calcium nephrolithiasis or loss of BMD [10]. algorithm for high-risk stone formers who may be at risk for BMD loss. PATHOPHYSIOLOGY OF BONE MINERAL DENSITY LOSS IN STONE FORMERS A variety of factors and pathophysiological mechanisms may be involved and altered in the development of osteopenia and osteoporosis in patients with calcium lithiasis. Role of cytokines Immunological processes and cytokines may be responsible for the decreased BMD in patients with lithiasis, with particular emphasis on the increased levels of IL-1 that stimulate prostaglandin production and increase bone resorption. Other cytokines, such as IL-6, TNF-alpha, and Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), may also be involved in these processes [4,6]. A 1997 study showed that patients with lithiasis and idiopathic fasting hypercalciuria had higher levels of IL-1 beta and TNF-alpha (compared with controls) and higher levels of GM-CSF when compared with stone formers with absorptive hypercalciuria. These findings suggest that monocyte activation may induce BMD loss through the onset of inflammatory phenomena [7]. Considering the studies conducted to date, the relationship between the osteoprotegerin Receptor Activator for Nuclear Factor kb Ligand molecular system and the onset of osteopenia osteoporosis in patients with calcium nephrolithiasis remains unclear [4]. The role of phosphate and renal sodium cotransporter Extracellular pyrophosphate plays a key role in bone mineralization and, when it reaches the kidney, can accumulate at the interstitial level, producing calcium pyrophosphate deposits [8]. Also, the The role of genetics In 2009, a genome-wide association study showed synonymous variants in the CLDN14 gene which were associated with nephrolithiasis. Approximately, 62% of the study population was homozygous for this variant with an increased risk of calcium nephrolithiasis up to 1.64 times. This same variant was observed in patients with loss of BMD in spine and hip [11], confirming the importance of genetics in calcium lithiasis and BMD loss. The Wnt signaling pathway facilitates osteoblast growth and development and overall bone metabolism. When this pathway is inhibited, calcium could be released from bone and BMD could be lost. A recent retrospective study of 184 mixed calcium stone formers and 46 age-matched controls demonstrated that serum Dickkopf-1 (DKK1), an antagonist of the Wnt signaling pathway involved in negative feedback, was 2 3 fold higher in stone formers than controls [51]. The authors speculated that excessive serum DKK1 in these stone formers could have led to higher urinary calcium excretion [51]. Although DKKI may be associated with idiopathic hypercalciuria, this study was limited by the absence of serum calcium levels and bone densitometry measurements, by the use of spot urinary assays to estimate urine calcium, and by the lack of correlation of DKK1 to urinary calcium/creatinine excretion. The role of vitamin D and parathyroid hormone Hypercalciuria is technically defined as the excretion of urinary calcium over 250 mg per 24 h in women and 300 mg per 24 h in men [12]. Although a number of mechanisms may be responsible for this excretion, hypercalciuria resulting from the intestinal overabsorption of calcium may be because of an alteration in the metabolism of vitamin D [13]. Although several studies have suggested that activated vitamin D levels may be altered in patients with hypercalciuria, no direct relationship has Volume 24 Number 6 November 2014

3 Nephrolithiasis and bone demineralization Arrabal-Polo et al. been found between this and the amount of osteopenia and osteoporosis of these patients [12]. In a 2007 study, 51 stone formers were reported to have higher mean 25-OH vitamin D levels, lower serum parathyroid hormone (PTH), and lower calcium intake than controls [14]. The authors speculated that the increased serum vitamin D levels resulted from decreased calcium intake, not from the genetic differences between the patients [14]. Hypercalciuric, experimental rats with normal serum vitamin D levels have been found to express higher numbers of intestinal vitamin D receptors and to increase both intestinal calcium absorption and bone resorption, resulting in decreased serum PTH. In humans, although polymorphisms in the vitamin D receptor that affect calcium absorption and bone buffering have been described, serum vitamin D levels do not appear to significantly impact bone health in stone formers [12]. In fact, BMD loss is felt to be primarily related to the onset of fasting hypercalciuria, which is completely independent of serum PTH levels [13] (Fig. 1). However, when hypercalciuric stone formers are compared to those without, vitamin D does appear to be mediating the increased intestinal calcium absorption. This phenomenon is even more pronounced when stone formers have Z-scores less than -2 SD [15], making it possible to have different patterns of intestinal calcium absorption [16]. The role of PTH in stone disease is felt to be marginal and limited only to cases of primary hyperparathyroidism. The role of diet In addition to the previously described factors, diet plays a key role in the development of nephrolithiasis and in the onset of hypercalciuria. Stone formers are typically advised to be on a normocalcemic diet ( mg/day dietary calcium) in order to avoid bone demineralization and PTH increase. Sodium intake must be limited, as it directly increases calciuria. Last, dietary protein intake, in particular animal proteins, may indirectly produce metabolic acidosis and must be closely controlled, as acidosis is a known risk factor for bone resorption and may precipitate the development of osteopenia or osteoporosis [2,4,14,17]. Recurrent calcium kidney stones Serum and 24 hour urine metabolic study Hypercalciuria, normal range urine sodium If normal, check clinic spot urine (8 hour fast) for calcium, creatinine, and citrate. Serum vitamin D and PTH Fasting urine Ca/creatinine ratio > 0.11 Fasting urine Ca/creatinine ratio < 0.11 If abnormal, refer to endocrine for further evaluation. Idiopathic fasting hypercalciuria. High suspicion of BMD loss. Refer to endocrine for BTM, bone densitometry, and lumbar spine morphometric absorptiometry. Absorptive hypercalciuria. Check history for sarcoidosis or oral dietary calcium excess. Consider dietary restriction or thiazide diuretic. Urine Ca/citrate ratio > 0.25 Check history and serum labs for causes of bicarbonate loss. Consider potassium citrate. FIGURE 1. Diagnostic algorithm to classify hypercalciuric types according to the fasting calcium/creatinine ratio after 8 h of nocturnal fast. When the fasting calcium/creatinine ratio is above 0.11, suspect bone mineral density loss and request bone turnover markers and bone densitometry ß 2014 Wolters Kluwer Health Lippincott Williams & Wilkins 635

4 Bone health in urologic patients BIOCHEMICAL MARKERS TO DIAGNOSE LITHIASIS AND OSTEOPOROSIS Although bone densitometry is the gold standard noninvasive test of choice to measure BMD, a number of different serum biochemical markers and urinary metabolites can be used as a screening tool for BMD loss in stone formers. Bone mineral density in patients with calcium nephrolithiasis BMD in calcium stone formers may be decreased in both men and women, although, surprisingly, it is felt to affect women to a lesser extent [18]. In a study carried out in the year 2001 using National Health and Nutrition Examination Survey III database, male stone formers had decreased femoral neck BMD loss compared with controls after adjusting for age, race, BMI, and other factors. Furthermore, these stone-forming men were found to have a higher lumbar spine and wrist fracture rate than those without stones. In women, this effect was not much pronounced [18]. In a follow-up study done in the year 2003 that included 196 idiopathic calcium stone formers with bone densitometry, 54% of patients had osteopenia and 14% had osteoporosis. Hypercalciuria, identified in 21.7% of patients, was not directly correlated with BMD loss [19]. In diseases associated with lithiasis, such as distal renal tubular acidosis (drta), a study from 2012 showed that drta is not a determining factor in the loss of BMD in patients with lithiasis, as this problem is also found in patients without drta [20]. In a series of studies carried out by the same team of researchers [21 23], it is observed that men and women with recurrent calcium lithiasis and severe lithogenic activity have greater loss of BMD in lumbar spine, as well as in femoral neck and hip, reaching 50% in hip and 70% in lumbar spine [22]. The loss of BMD has been identified not only in adults, but also in children, where decreased Z-scores have been seen in both stone-forming children and hypercalciuric children without lithiasis [24,25]. Overall, patients with recurrent calcium lithiasis and hypercalciuria show greater BMD loss than controls without stones or stone formers without hypercalciuria. Bone markers in patients with calcium lithiasis As bone resorption and formation are tightly coupled processes, levels of specific bone cell activity can be assessed by bone turnover marker (BTM) assays, including breakdown products of matrix resorption, such as type 1 collagen or the amino acid crosslinks (also known as beta-crosslaps), that hold collagen peptides together. In contrast, bone formation markers include byproducts of de novo collagen synthesis or osteoblast-related proteins, such as osteocalcin or alkaline phosphatase. In nephrolithiasis, most studies demonstrate higher levels of BTMs in patients with active calcium stones than in controls [26]. In a study done in the year 2002 that included 70 hypercalciuric stone formers, patients with fasting hypercalciuria (fasting urinary calcium/creatinine ratio greater than 0.11 Fig. 1) had higher alkaline phosphatase (formative) and hydroxyproline (resorptive) when compared with controls [27]. BTMs, primarily those of bone resorption, were highest in patients with recurrent calcium lithiasis and severe lithogenic activity [28]. One of the most studied markers over the last 3 years, the resorptive marker beta-crosslaps, was found to be higher in recurrent calcium stone formers than controls, correlating significantly with the degree of calciuria [29 31]. A direct relationship between BTMs and lithogenic activity in patients with calcium lithiasis and osteopenia osteoporosis has also been observed. More specifically, calcium stone formers with serum beta-crosslaps greater than ng/ml, serum osteocalcin (formative marker) greater than 13.2 ng/ml, and a beta-crosslaps/osteocalcin ratio greater than may indicate a higher state of lithogenic activity and should be followed more closely for stone recurrence [32 && ]. Urinary markers in patients with calcium lithiasis and bone mineral density loss Calciuria is certainly the most frequent alteration in patients with calcium lithiasis and the alteration which is most frequently associated with BMD loss [33]. When the origin of hypercalciuria is unrelated to diet, BMD loss can affect up to 65% of patients [34], a phenomenon more commonly seen in women [33,34]. Calciuria has also been shown to correlate with BMD loss [21,35] and is an excellent predictor of BMD changes in Z-score in femoral neck and lumbar spine [36]. In addition, measurement of 24-h calciuria can be replaced by fasting calciuria in monitored patients, as it has an excellent linear correlation, making the follow-up and therapeutic control even easier [37]. The classification of hypercalciuria in absorptive or fasting, depending on the calcium/creatinine fasting ratio, is a key issue in patients with recurrent calcium lithiasis. Specifically, absorptive hypercalciuria is defined as fasting calcium/creatinine ratio below 0.11, and fasting hypercalciuria when it is above 0.11 (Fig. 1). For example, in one study of calcium stone formers, a Volume 24 Number 6 November 2014

5 Nephrolithiasis and bone demineralization Arrabal-Polo et al. fasting calcium/creatinine ratio higher than 0.25 mmol/mmol was associated with a 3.8 times greater risk of BMD [38]. In addition, fasting calcium/creatinine ratio is negatively correlated with the T-score of bone densitometry in hip and lumbar spine of patients with calcium lithiasis. Therefore, the higher the fasting calcium/creatinine ratio is, the lower the T-score and the greater the loss of BMD by densitometry [30]. In Fig. 1, we observe the algorithm follow-up to diagnose patients with recurrent calcium stones. For the practitioner suspicious for BMD loss in his or her stone former, we propose a patient care algorithm, stratified by fasting calcium/creatinine ratio. In addition to this, our group observed that 32% of our calcium stone formers with osteopenia and osteoporosis had reduced urinary excretion of citrate, a potent inhibitor of crystallization [39]. In 2013, we published that a calcium/citrate ratio greater than 0.25 may be indicative of severe lithogenic activity and BMD loss, and feel that it may also be an early marker for BMD loss [39]. MEDICAL THERAPY FOR STONES, OSTEOPENIA, AND OSTEOPOROSIS A variety of drugs have been shown to be useful to decrease calcium stone recurrence. These drugs can also be used to improve BMD, so treatments should be tailored to the specific disease of each individual patient. Potassium citrate In a study carried out with 21 lithiasic patients treated with potassium citrate supplements, an improvement in BMD was observed at L2 L4, slowing demineralization yet controlling the lithiasic activity [40]. In addition to producing an improvement in hip and lumbar spine BMD, supplementation raised urinary citrate excretion, increased serum ph, and reduced BTM in urine [41]. Used as either monotherapy or combined with thiazides, potassium citrate appears to be effective in improving BMD as measured by the dual X-ray densitometry [42]. Thiazides and its derivatives In the experimental studies carried out in rats with lithiasis and a genetic predisposition to hypercalciuria, it has been observed that thiazides therapy decreases calciuria, increases trabecular bone mineralization, and improves the connectivity, strength, and compressibility of the vertebrae [43]. In humans, the beneficial effect of thiazides on bone has been proven in adults [42,45 47], but is still considered investigational in children [44]. In adult stone formers, the effect of thiazides on skeletal health bones is similar to the effect produced by the administration of calcium with vitamin D. Therefore, it is an effective alternative for these patients [46], producing an improvement in BMD [47], while also controlling nephrolithiasisassociated hypercalciuria. In addition, thiazides have been shown to have a protective effect on osteoporotic hip fractures an effect which disappeared 4 months after discontinuing the treatment [45]. Bisphosphonates Bisphosphonates are potent inhibitors of bone resorption, which are used in patients with calcium nephrolithiasis, hypercalciuria, and osteopenia osteoporosis [48]. A decrease in calcium/creatinine ratio and calciuria is observed, whether the bisphosphonates are administered alone or in association with indapamide [49] or thiazides [50]. Overall, the most beneficial effect of bisphosphonate therapy has been observed when alendronate sodium was combined with thiazides. This combination treatment most successfully reduced calciuria, improved BMD loss, and decreased kidney stone recurrence [50]. CONCLUSION Recurrent calcium nephrolithiasis, mainly occurring with hypercalciuria, is related to BMD loss and is expressed by a decrease in the densitometric T-score and Z-score, an increase in BTMs (mostly resorption), an increase in calciuria and fasting calcium/creatinine ratio, and a decrease in urinary citrate. Treating these patients with citrate, thiazides, and bisphosphonates either alone or in combination can effectively control both stone and bone diseases. Acknowledgements Funding by Fundacion Progreso y Salud. Junta de Andalucia. Proyecto Investigacion n8 0766/2013. Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Arrabal-Polo MÁ, Sierra Girón-Prieto M, Orgaz-Molina J, et al. Calcium renal & lithiasis and bone mineral density. Importance of bone metabolism in urinary lithiasis. Actas Urol Esp 2013; 37: Bone markers are altered in patients with idiopathic calcium nephrolithiasis principally with fasting hypercalciuria. Bone mineral density loss is present in patients with recurrent calcium stones ß 2014 Wolters Kluwer Health Lippincott Williams & Wilkins 637

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