Bisphosphonates in the management of idiopathic hypercalciuria associated with osteoporosis: a new trick from an old drug

Therapeutic Advances in Musculoskeletal Disease Review Bisphosphonates in the management of idiopathic hypercalciuria associated with osteoporosis: a new trick from an old drug Ther Adv Musculoskel Dis (2010) 2(1) 29 35 DOI: 10.1177/ 1759720X09356399! The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/ journalspermissions.nav Gerolamo Bianchi, Andrea Giusti, Giulio Pioli, Antonella Barone, Ernesto Palummeri and Giuseppe Girasole Abstract: Idiopathic hypercalciuria (IHC) is defined as a 24-hour urinary calcium excretion that exceeds 4 mg/kg/day, regardless of gender and in absence of systemic diseases or pharmacological treatments that may cause normocalcemic hypercalciuria (eg sarcoidosis, normocalcemic primary hyperparathyroidism, vitamin D intoxication, hyperthyroidism). Patients with IHC and nephrolithiasis often present increased bone turnover, decreased bone mineral density (BMD) and increased susceptibility to fragility fractures. Although the pathogenesis of IHC seems complex and multifactorial, recent evidences suggest that cells involved in bone resorption may play a critical role in the chain of events leading to the excessive urinary calcium excretion. Therefore, it has been proposed that bisphosphonates, potent inhibitors of bone resorption, may have beneficial effects in hypercalciuric patients with low BMD. This manuscript reports recent findings regarding the role of bone tissue in the pathogenesis of IHC, and supports the use of bisphosphonates in such conditions. It also reviews the literature on the effects of bisphosphonates in subjects with osteoporosis-associated IHC. Keywords: bisphosphonates, idiopathic hypercalciuria (IHC), osteoporosis, treatment Introduction Idiopathic hypercalciuria (IHC) is defined as a 24-hour urinary calcium excretion that exceeds 4 mg/kg/day, in two consecutive collections, regardless of gender and in the absence of systemic diseases or pharmacological treatments that may cause normocalcemic hypercalciuria (eg sarcoidosis, normocalcemic primary hyperparathyroidism, vitamin D intoxication, hyperthyroidism) [Liebman et al. 2006]. IHC occurs in less than 10% of the general population. Historically, most interest in IHC was related to the risk of nephrolithiasis. IHC, indeed, is found in up to 50% of calcium stone-forming patients [Liebman et al. 2006; Pak et al. 1974; Hodgkinson and Pyrah, 1958]. The excess in urinary calcium excretion, produced by an increase in intestinal calcium absorption and/or by a decrease in renal tubular calcium reabsorption, may lead to increased supersaturation that, in turns, determines the formation of calcium kidney stones. In this context, dietary intervention, thiazide diuretics or indapamide are regarded as the first-line strategy for the management of IHC [Escribano et al. 2009; Pak et al. 2003; Borghi et al. 2002]. In recent years, however, a number of studies have suggested that bone cells involved in bone formation and resorption could play a central role in the chain of events leading to hypercalciuria [Heilberg and Weisinger, 2006; Weisinger et al. 1998; Pacifici, 1997; Pacifici et al. 1990]. Several investigators, in the last 10 years, have reported increased bone turnover and reduced bone mineral density (BMD) in subjects with IHC [Heller et al. 2007; Giannini et al. 2003; Vezzoli et al. 2003; Borghi et al. 1991]. In addition, Melton and colleagues [Melton et al. 1998] demonstrated, in a large population-based retrospective cohort study, a fourfold increase in the risk of vertebral fractures among patients with calcium kidney stones. In summary, whether the decrease in BMD constitutes the primary event responsible for the hypercalciuria, or its consequence, IHC is clearly associated with decreased bone mass, increased Correspondence to: Gerolamo Bianchi, MD La Colletta Hospital, Department of Rheumatology, Via del Giappone 3, Genova 16011, Italy gerolamo_bianchi@tin.it Andrea Giusti Antonella Barone Ernesto Palummeri Department of Gerontology and Musculoskeletal Sciences, Galliera Hospital, Genoa, Italy Giulio Pioli Geriatric Unit, ASMN Hospital, Reggio nell Emilia, Italy Giuseppe Girasole Department of Rheumatology, La Colletta Hospital, Arenzano, Italy http://tab.sagepub.com 29

Therapeutic Advances in Musculoskeletal Disease 2 (1) bone resorption, and may also play a role in the pathogenesis of fragility fracture. Therefore, an ideal approach to IHC should take into account the potential implications for bone strength and fragility fractures, together with the adequate management of urine calcium supersaturation. As noted, thiazide diuretics and indapamide have been largely investigated in the management of hypercalciuric patients. In general, these drugs have been demonstrated to satisfactorily control hypercalciuria and to prevent stone formation, but have only occasionally showed a benefit in BMD [Giusti et al. 2009]. Bisphosphonates are potent inhibitors of bone resorption and are well established as the leading drugs for the treatment of osteoporosis [Russell et al. 2008]. To date, a limited number of studies have investigated the role of bisphosphonates in the treatment of patients with IHC associated with osteoporosis. The purpose of this paper is to review the rationale and current evidence on the use of bisphosphonates in patients with IHC associated with osteoporosis. Methods We searched MEDLINE, EMBASE and PubMed for articles related to the specified diseases (IHC and osteoporosis) and agents (bisphosphonates). The terms searched were: alendronate, clodronate, etidronate, ibandronate, pamidronate, risedronate, zoledronic acid AND IHC, absorptive hypercalciuria, fasting hypercalciuria AND osteoporosis, osteopenia, low bone mass and fracture. All authors reviewed the trials selected. Bone involvement in idiopathic hypercalciuria: the rationale for bisphosphonate use The physiopathology of IHC is highly complex. Several mechanisms and theories related to the calcium phosphorus metabolism have been suggested to explain the pathogenesis of the excessive calcium excretion in IHC. Actually, three different mechanisms are regarded as the main causes of hypercalciuria: a reduction in the tubular reabsorption of calcium, with the emergence of compensatory hyperparathyroidism [Coe et al. 1988]; an increase in the intestinal reabsorption of calcium secondary to high levels or hypersensitivity to calcitriol [Pak, 1979]; and a renal loss of phosphates with secondary increased synthesis of calcitriol and intestinal hyperabsorption [Navarro et al. 1994]. Studies on humans, however, suggest that whereas some patients have a single specific defect resulting in hypercalciuria, most subjects do not have a specific site of mineral ion transport dysregulation. Therefore, IHC seems to be a systemic disorder of mineral ion homeostasis resulting from the interaction of different mechanisms [Heilberg and Weisinger, 2006]. In this context, in vitro and in vivo studies have suggested that increased mobilization of calcium from bone tissue may play a key role in the chain of events leading to hypercalciuria, together with either the excessive intestinal absorption of calcium, or the renal calcium leak due to a tubular disturbance [Heilberg and Weisinger, 2006]. As previously reported, several clinical observations have demonstrated decreased bone formation, increased bone resorption and reduced BMD in subjects with IHC [Heller et al. 2007; Giannini et al. 2003; Vezzoli et al. 2003; Borghi et al. 1991]. In general, this and other retrospective and prospective studies found that the rate of urine calcium excretion was related with bone loss and elevation of bone turnover markers in hypercalciuric patients, defining a link between IHC and bone disease [Vezzoli et al. 2003; Tasca et al. 2002; Giannini et al. 1998; Bataille et al. 1991; Sutton and Walker, 1986; Barkin et al. 1985]. However, a greater insight into the underlying mechanisms linking bone with the excessive calcium excretion in IHC came from in vitro studies. In support of the role of bone in the pathogenesis of IHC, Pacifici and colleagues [Pacifici et al. 1990] demonstrated that mononuclear cells from patients with fasting hypercalciuria had an increased spontaneous production of interleukin-1 (IL-1), a potent stimulator of bone resorption. The authors found significant correlations between IL-1 and hydroxyproline, and IL-1 and vertebral mineral density, measured by quantitative computer tomography. Subsequently, other authors demonstrated that not only IL-1, but also other cytokines such as interleukin-6, and tumor necrosis factor-a (TNF-alpha) had increased expression in hypercalciuric patients, with a significant correlation between in vitro cytokine production and lumbar spine BMD [Weisinger et al. 1996]. The potential role of bone catabolic cytokines in the pathogenesis of IHC associated with osteoporosis has been further confirmed and extended by Ghazali and colleagues [Ghazali et al. 1997] 30 http://tab.sagepub.com

G Bianchi, A Giusti et al. who described, in a of calcium stoneforming patients with IHC and low BMD, a particular profile of peripheral blood monocytes activation, characterized by a spontaneously increased synthesis of IL-1, TNF-alpha, and granulocyte macrophage stimulating factor (GM-CSF). Finally, Gomes and colleagues [Gomes et al. 2008] described, in the bone tissue of hypercalciuric patients, a high expression of receptor activator of nuclear factor kappab ligand (RANKL), suggesting that increased bone resorption in patients with IHC is mediated by the osteoprotegerin/rankl system. In summary, mounting evidences are supporting a primary involvement of bone in IHC, characterized, at least, by an increased reabsorption of calcium from bone, that, in turn, induces a primary decrease in BMD and strength [Grynpas et al. 2009]. Bisphosphonates in idiopathic hypercalciuria: a new trick from an old drug The evidence that, at least in some IHC patients with decreased BMD, the excessive urinary calcium excretion and the bone loss are caused by an enhanced bone resorption, led to the hypothesis that bisphosphonates, potent inhibitors of bone resorption, could have beneficial effects in the management of hypercalciuric patients with osteoporosis. Indeed, the mechanism of action of bisphosphonates and their potent antiresorptive activity could produce a decrease in calcium excretion and an increase in BMD by inhibiting bone cells involved in bone resorption and, in turn, reducing calcium mobilization from the skeleton. In this context, about 10 years ago, Bushinsky and colleagues [Bushinsky et al. 1999] found that alendronate, a potent and widely used bisphosphonate, markedly decreased calcium excretion and urine supersaturation in genetic hypercalciuric stone-forming rats fed with a low calcium diet, an animal model of IHC. This finding indirectly demonstrated the role of bone in the pathogenesis of IHC, and supported the use of bisphosphonates in humans. In the last 10 years, a number of studies have been undertaken to evaluate the beneficial effect of bisphosphonates on 24-hour urinary calcium excretion, bone turnover and BMD in hypercalciuric subjects with low BMD (Table 1). As shown, available trials enrolled small samples of patients, only two studies classified the patients according to the subtypes of hypercalciuria (absorptive or fasting), most of them were observational, and only one was a randomized trial [Giusti et al. 2009; Freundlich and Alon, 2008; Heller et al. 2007; Heilberg et al. 1998; Weisinger et al. 1997]. Moreover, none of them included a control receiving dietetic interventions or a placebo. The first two reports published on the topic were prospective observational studies [Weisinger et al. 1997, 1998; Heilberg et al. 1998]. Weisinger and colleagues [Weisinger et al. 1998] evaluated the effect of alendronate therapy on BMD, urinary calcium excretion and a marker of bone turnover, in 18 hypercalciuric nonosteoporotic subjects and eight normocalciuric matched controls. They demonstrated that alendronate 10 mg daily decreased 24-hour urinary calcium excretion by the end of the first month, reduced bone turnover, and increased lumbar spine BMD after 1 year. No changes from baseline were found at the femoral neck BMD. On the other hand, Heilberg and colleagues [Heilberg et al. 1998] found that etidronate, given to young, calcium stone-forming males presenting with hypercalciuria and osteopenia, led to a significant amelioration of BMD, evident only at the lumbar spine and after the first year of treatment. During the second year of therapy a similar but not significant trend of BMD was reported. In addition, 24-hour urinary calcium excretion showed no changes from baseline over 2 years of treatment. The relative lack of benefit of etidronate in the study by Heilberg was probably related to the very small number of subjects evaluated (seven males) and to the weaker antiresorptive action of the bisphosphonate. Consistent with previous findings, oral alendronate at the dose of 10 mg daily improved BMD [Freundlich and Alon, 2008], and reduced fasting urinary calcium and bone turnover [Freundlich and Alon, 2008; Heller et al. 2007] in other two case series recently published. Both studies included a very small number of subjects. Heller and colleagues examined the physiological effect of a short-term blockade (17 days) of bone resorption by alendronate in nine patients with IHC and low BMD. They found that alendronate was able to correct fasting urinary calcium excretion and reduce bone turnover within 3 weeks, therefore supporting the role of bone resorption in the pathogenesis of IHC. Interestingly, Freundlich and colleagues [Freundlich and Alon, 2008] evaluated the http://tab.sagepub.com 31

Therapeutic Advances in Musculoskeletal Disease 2 (1) Table 1. Bisphosphonates in the management of idiophatic hypercalciuria associated to osteoporosis: summary of studies. References Type of hypercalciuria Study type Sample size (men) Duration (months) Treatment regimen Control regimen Main results Weisinger et al. 1997,1998* Heilberg et al. Fasting (5) and 1998 $ absorptive (2) Heller et al. Fasting (5) and 2007 z absorptive (4) Not reported Prospective, case-control Prospective, not controlled Prospective, not controlled Freundlich and Not reported Retrospective, not Alon, 2008 controlled Giusti A et al. Not assessed Randomized 2009 ô controlled 26 12 ALN oral 10 mg/day 7 (7) 24 ETD oral 400 mg/day 9 (6) 17 days ALN oral 10 mg/day 7 (3) 6 18 ALN oral or ALN oral + ZLD iv 77 12 ALN oral 70 mg/ week + IND 2.5 mg/day IND 2.5 mg/ day or ALN oral 70 mg/ week 24-CaU: Significant decrease from baseline. BMD: Significant increase from baseline at the lumbar spine, no changes at the femoral neck. No changes in the matched controls. BTMs: Significant decrease from baseline. No changes in the matched controls. 24-CaU: No changes from baseline after 1 and 2 years. BMD: Significant increase from baseline at the lumbar spine after 1 year with a similar but not significant trend at 2 year, no changes at the femoral neck. 24-CaU: Not significant decrease versus baseline. Fasting urine Ca/Cr: Significant decrease from baseline. BTMs: Significant reduction versus baseline of bone resorption markers, no change for the bone formation marker. Urine Ca/Cr: Significant decrease from baseline. BMD: Significant increase from baseline at the lumbar spine and femoral neck. BTMs: Significant decrease from baseline. 24-CaU: Significant decrease from baseline in all s. The decrease in the combination (ALN + IND) was significantly greater compared to the other two. BMD: In patients who received ALN, either alone or in combination, BMD increased significantly compared to baseline and to IND at the lumbar spine, femoral neck and total hip. No changes in the IND. The combination showed a significantly higher increase of lumbar spine BMD compared to the ALN alone. BTMs: Significant decrease from baseline in patients treated with ALN either alone or in combination. 24-CaU, 24-hour urinary calcium excretion; ALN, alendronate; BMD, bone mineral density; BTMs, bone turnover markers; ETD, etidronate; IND, indapamide; iv, intravenous; ZLD, zoledronate; Urine Ca/Cr, urine calcium/creatinine ratio. *Overall 26 stone-forming patients were included in the study: 18 presented idiopathic hypercalciuria, the others were normocalciuric and were used as matched controls. All patients received ALN. Results were reported, in two different papers, only for hypercalciuric patients. Neither age nor gender of the subjects was reported. $ The treatment consisted of administration of phosphate 1 g/day for 3 days, followed by ETD 400 mg/day for 14 days and calcium supplementation 1 g/day for 74 days. The treatment cycle was repeated every 91 days for a total of eight cycles in 2 years. z The primary aim of the study was to compare bone histomorphometric characteristics between stone-forming subjects with idiopathic hypercalciuria and healthy matched controls. Secondarily, the authors evaluated the effect of a short-term therapy (17 days) with ALN on fasting hypercalciuria, 24-hour urinary calcium excretion and bone turnover markers in idiopathic hypercalciuria subjects. Freundlich et al. enrolled seven children and the treatment was tailored individually for each patients: six patients received ALN, while one received ALN plus ZLD; in four cases ALN treatment was associated with the previous therapy (thiazide + amiloride in two cases and thiazide + amiloride + citrate in the other two). The doses were weight-adjusted according to the standard adult dose and the length of treatment with the bisphosphonate ranged from 6 to 18 months. ô Patients were randomized to receive ALN 70 mg weekly alone (27 subjects), IND 2.5 mg daily alone (24 patients) or ALN 70 mg weekly plus IND 2.5 mg daily (26 subjects). All subjects received daily calcium supplements to maintain a daily input of 1000 mg, and were instructed to increase water intake up to 2000 ml daily. 32 http://tab.sagepub.com

G Bianchi, A Giusti et al. benefit of alendronate in seven stone-forming children with IHC and decreased BMD. To our knowledge, this clinical series represents the first and unique report regarding children and adolescents demonstrating the beneficial effect of alendronate on BMD, bone turnover and fasting calciuria in that population [Freundlich and Alon, 2008]. In a randomized controlled trial undertaken to evaluate the efficacy of a bisphosphonate in the management of IHC associated with osteoporosis, Giusti and colleagues [Giusti et al. 2009] randomized 77 postmenopausal women with IHC and low BMD to receive alendronate 70 mg weekly alone, indapamide 2.5 mg daily alone or the combination therapy for 1 year. As expected and in agreement with previous reports, the three treatments induced a significant reduction in 24-hour urinary calcium excretion [Heilberg and Weisinger, 2006; Ceylan et al. 2005; Weisinger et al. 1997, 1998]. Interestingly, the authors found that women in the combination therapy (alendronate weekly plus indapamide daily) experienced the highest reduction in urinary calcium excretion, resulting in an additional effect of the two drugs. Once more, the beneficial effect of the bisphosphonate (alendronate alone or in combination) on 24-hour urinary calcium excretion, in the absence of other dietetic or therapeutic intervention, supported the critical role of the skeleton and bone resorption in the pathogenesis of the excessive calcium excretion in IHC. After 1 year, BMD showed a significant increase from baseline in subjects who received alendronate alone or in combination with indapamide, while indapamide failed to improve BMD. Moreover, patients receiving indapamide plus alendronate demonstrated a significantly greater increase of lumbar spine BMD compared to women treated with alendronate alone, with a similar but not significant trend at the femoral neck and total hip BMD. Finally, bone alkaline phosphatase, a marker of bone turnover, decreased significantly from baseline in both s treated with alendronate. It is remarkable that, as previously noted by Heller and coworkers [Heller et al. 2007], alendronate alone produced a slightly nonsignificant increase of parathyroid hormone (PTH), while the combination therapy induced a significant reduction of PTH. The authors suggested that the greatest effect of the combination therapy could be related to the different variations in PTH levels in patients who received alendronate alone or the combination therapy, in agreement with a previous report in postmenopausal nonhypercalciuric women [Barone et al. 2007]. In conclusion, although several limitations (small samples, lack of a placebo, no fracture endpoint) hamper the overall contribution of the above-mentioned studies to the body of evidence, their preliminary findings support a new potential approach with bisphosphonates in the management of IHC associated with osteoporosis. Unresolved issues and future research As evident from this review there are major unresolved issues to be included in the agenda for future research in this area. These include the following: (1) Studies with bisphosphonates alone or in combination with a thiazide diuretic directly assessing fracture risk reduction patients with idiopathic hypercalciuria associated with osteoporosis, rather than assessing surrogate markers such as BMD or bone turnover. (2) Further understanding of the effect and potential benefit of bisphosphonates in the different subtypes of IHC. (3) The potential benefit of bisphosphonates, in combination with thiazide diuretics and dietetic intervention in the prevention of nephrolithiasis in hypercalciuric stone-forming patients. Acknowledgements No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Conflict of interest statement Gerolamo Bianchi has received honoraria and/ or consulting fees from Abbott, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Schering-Plough, Servier, and Wyeth. Andrea Giusti has received consulting fees from Novartis. References Barkin, J., Wilson, D.R., Manuel, M.A., Bayley, A., Murray, T. and Harrison, J. (1985) Bone mineral content in idiopathic calcium nephrolithiasis. Miner Electrolyte Metab 11: 19 24. http://tab.sagepub.com 33

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