Chronic Kidney Disease


In addition to the mortality studies, there are a number of trials that have investigated the effects of sevelamer versus calcium binders on progression of vascular calcification. In the Treat to goal (TTG) study, 200 prevalent hemodialysis patients were randomized to either calcium acetate or sevelamer and calcification of the coronary arteries and thoracic aorta were determined by electron beam computed tomography (EBCT). Sevelamer and calcium provided equivalent control of serum phosphate, whereas calcium concentrations were significantly higher and hypercalcemia was more common in subjects receiving calcium-containing binders.26


In subjects with pre-existing vascular


calcification, the median percentage change in coronary artery and aortic calcium score was significantly greater with calcium than with sevelamer; however, the development of vascular calcifications was similar in those who entered the study without pre-existing vascular calcification. In the Renagel in new dialysis (RIND) study, 129 incident hemodialysis patients were randomized to receive calcium-containing phosphate binders or sevelamer hydrochloride. Subjects underwent EBCT at entry into the study and again at six, 12, and 18 months. All subjects with baseline coronary artery calcification scores >30 demonstrated progression of vascular calcifications. The progression was more rapid in the subjects receiving calcium-based phosphate binders versus sevelamer but the difference was not significant until 18 months of therapy.27


Meta-analysis of current studies does, however,


support a trend toward decreased vascular calcification with sevelamer though this is not statistically significant.25


The effects of sevelamer HCl on bone compared to calcium-based binders have also been evaluated. Raggi and colleagues compared the effects of the two binders in changes on bone attenuation in the thoracic spine using electron beam CT. Compared to sevelamer, subjects treated with calcium showed decreases in both trabecular and cortical bone attenuation, a surrogate of bone mineral density.28


A subsequent study compared the


effects of the two binders on bone histomorphometry. Patients were randomized to either calcium or sevelamer and bone biopsies were performed at baseline and following one year. Compared to baseline values, there were no differences for either group in mineralization or measures of bone turnover. Sevelamer, however, resulted in increased bone formation and improved trabecular architecture.29


Lanthanum Carbonate


Lanthanum is a rare earth metal and, like lanthanum carbonate, is a non-calcium, non-resin phosphate binder. It dissociates in an acid environment of the upper GI tract to release trivalent cations that bind dietary phosphate into an insoluble complex.30


Its theoretical benefit


over other binders lies in its potent phosphate binding independent of pH. In addition, it is chewable and its formulation seems to allow for a reduced pill burden to achieve similar control of phosphate as compared to sevelamer and calcium-based binders. However, the incidence of adverse events—predominantly GI upset—requiring discontinuation is high (up to 14 %). There are no studies to date evaluating the impact of lanthanum on mortality or vascular calcification compared with the other phosphate binders.


A crossover comparison of lanthanum carbonate and sevelamer hydrochloride was performed in hemodialysis patients.31


Following washout, patients with serum phosphate of 6 mg/dl or greater and serum 18 Emerging Therapies


Several non-calcium-based phosphate binders are under investigation. Fermagate contains magnesium and ferric iron held in an insoluble hydrotalcite structure. The iron and magnesium are held in a tight, crystalline-layered structure, with carbonate groups, which are exchanged for phosphate, lying between the layers. In a Phase II trial, 1 g given three times daily before meals was associated with reduced serum phosphate levels, but a higher dose (6 g per day) was associated with adverse GI events.35


A novel approach has been developed based on the large amount of phosphate found in salivary excretion that occurs in patients with CKD


US NEPHROLOGY


calcium 8.4 mg/dl or greater were randomized (1:1) to receive lanthanum (2,250–3,000 mg/day) or sevelamer (4,800–6,400 mg/day) for four weeks. Patients underwent a second washout and then switched to the alternative binder for four weeks. At the end of treatment, lanthanum had reduced serum phosphorus by 1.7 + 0.1 mg/dl, compared with 1.4 + 0.1 mg/dl for sevelamer; the difference was not statistically significant in the primary analysis. However, the reduction with lanthanum was significantly greater than with sevelamer in a pre-specified key secondary analysis of patients who completed four weeks of treatment with each binder (0.5 mg/dl difference; p=0.007). The reduction of serum phosphorus was also greater with lanthanum than sevelamer after one week of treatment (p=0.024).31


Lanthanum is the most extensively studied phosphate binder in regards to effects on bone. The effects of lanthanum compared with calcium-based binders on the development of renal osteodystrophy were determined after one and two years of treatment. Bone biopsies were performed at baseline and one year in one study and at baseline, one, and two years in the other study. Both studies demonstrated that lanthanum did not result in osteomalacia or adynamic bone disease. In fact, there were an increased number of patients who developed adynamic bone disease (20 % at baseline to 30 % at one year) in the calcium-treated subjects. Alternatively, in those who received lanthanum, there was a decrease in patients with low bone turnover (36 to 18 %).


Further analysis revealed that lanthanum showed greater improvement, as compared with calcium, in osteoblast activity and overall measures of bone turnover.32,33


In the two-year study, the percentage of patients after one year of lanthanum therapy showed improvement in bone turnover as measured by activation frequency and bone formation rate, which was significantly higher than in the standard therapy group (52 and 41.9 %, respectively, versus 23.3 and 15.6 %, respectively). The percentage of patients with increased bone volume was significantly higher in the subjects who received lanthanum for two years compared with those who received standard therapy.34


Magnesium Salts


Magnesium hydroxide and carbonate have been used as alternatives or adjuncts to calcium-based phosphate binders. However, because of the risk for adverse GI side effects and hypermagnesemia, oral magnesium binders have not gained widespread clinical use as phosphate binders. As such, no studies evaluating magnesium-based binders have measured clinical end points or histological features of bone.


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68