From Pathophysiology to Clinical Practice
Critical Choices in Chronic Heart Failure Management

Managing Bone and Mineral Metabolism Disorders in Chronic Kidney Disease

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

39th Annual Meeting and Scientific Exhibition of the American Society of Nephrology

San Diego, California / November 14-19, 2006

Disorders in bone and mineral metabolism are virtually synonymous with chronic kidney disease (CKD), especially end-stage renal disease (ESRD). “The problem with bone does not start at dialysis,” indicated Dr. Hartmut Malluche, Professor and Chief of Nephrology, University of Kentucky A. B. Chandler Medical Center, Lexington. Rather, patients develop metabolic abnormalities when they have lost about 50% of their kidney function. At that point, patients are still exposed to the same amount of phosphorus as before, but because the body does not tolerate hyperphosphatemia well, “each remaining nephron has to excrete double the amount of phosphorus to avoid it,” he noted.

During the early stage of CKD, the kidney is already working overtime to maintain serum phosphorus levels within the normal range. In recent years, nephrologists are observing more adynamic bone disease, a condition characterized by low bone turnover. This is now clearly associated with an increased risk of vascular calcification. As Dr. Malluche explained, “If bone doesn’t turn over, it can’t pick up calcium, it can’t pick up phosphorus, therefore minerals have a much higher tendency to be shifted to the soft tissues and vessels, and the patient is primed to develop arterial calcification.”

Dr. Stuart Sprague, Professor of Medicine, Northwestern University Feinberg School of Medicine, Evanston, Illinois, agreed that CKD patients are in a “very bad physiological milieu” that predisposes them to form calcium deposits within vascular spaces.

According to several studies cited by Dr. Sprague, vascular calcification is both highly prevalent in the CKD population and is rapidly progressive. Depending on whether patients are new to dialysis or are well-established with the treatment, vascular calcification can be detected in between 40 and 80% of dialysis patients. Treatment of hyperphosphatemia with a calcium-containing binder also appears to make vascular calcification worse. In another study that he mentioned, patients treated with a calcium-containing binder showed a marked increase in coronary artery calcification compared with those who received a non-calcium- containing binder over a period of 76 weeks.

Whether or not the presence of vascular calcification in CKD patients increases overall mortality has not been clearly demonstrated, cautioned Dr. Sprague. For example, in the DCOR (Dialysis Clinical Outcomes Revisited) study, all-cause mortality was not significantly reduced at the end of two years in patients receiving sevelamer compared with those receiving a calcium-containing binder.

Adjusted data from DOPPS (Dialysis Outcome Practice Patterns Study), which assessed the impact of sevelamer vs. calcium-based binders, reflected similar results. Findings showed that they did not support a mortality advantage for either all-cause or cardiovascular disease (CVD) mortality of one agent over the other.

Nevertheless, as Dr. Sprague reminded the audience, patients with vascular calcification will undoubtedly progress if they continue to take a calcium-containing binder. “Thus, in patients with or at risk for vascular calcification, it would seem prudent to limit calcium exposure,” he suggested.

What does appear to extend longevity in hemodialysis patients is vitamin D. As cited by Dr. Dennis Andress, Clinical Professor of Medicine, University of Washington, Seattle, a study by Teng et al. (J Am Soc Nephrol 2005;16:1115-25) compared survival in 173 patients who received intravenous (i.v.) vitamin D sterols with that of approximately 14,000 historical controls who did not receive an activated i.v. vitamin D.

t the end of two years, patients who had been treated with i.v. vitamin D had an adjusted two-year survival advantage of 20% compared with historical controls. This benefit was demonstrated even in patients with low parathyroid hormone (PTH) levels as well as those with elevated levels of calcium and phosphorus.

K/DOQI Recommendations

Evidence linking hyperphosphatemia with increased morbidity and mortality in stage V CKD patients argue clearly in favour of careful phosphate control through dietary measures, dialysis and the use of phosphate binders. The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines indicate that serum phosphorus should be in the range of 1.13 to 1.78 mmol/L in patients undergoing dialysis but it is generally accepted that only about 30 to 40% of dialysis patients actually achieve recommended levels. Failure to attain K/DOQI phosphate goals may reflect the substantial pill burden associated with conventional phosphate-binding regimens.

According to Dr. Rajnish Mehrotra, Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, the average number of pills that ESRD patients take is approximately 20, “and the single largest contributor to that is the phosphate binder.” This high pill burden in turn impedes patient adherence to their regimen. Indeed, up to 40% of patients will admit to taking less than 80% of the required doses and when directly measured, compliance is much lower, noted Dr. Mehrotra.

Consequently, an inherently desirable property of any new phosphate binder would be a reduction in pill burden. Even in its original formulation, lanthanum carbonate was associated with a significantly lower pill burden than other phosphate binders. In a study undertaken by the South Florida Nephrology Group, Coral Springs, conversion to the original formulation of lanthanum carbonate, in doses of 250 to 500 mg, led to significant reductions in the mean daily tablet burden and total daily dose for the same phosphate control as was achieved with previous phosphate-binder therapy. At the end of the 12-week titration period, 73% of patients reported that they preferred lanthanum carbonate over their previous phosphate binder and some 83% of physicians also indicated the same preference. Approximately 40% of patients receiving lanthanum carbonate continued to achieve K/DOQI targets for serum phosphorus with the significantly reduced pill burden.

In the US, the original lanthanum carbonate has now been reformulated into higher-strength tablets of 750 and 1000 mg. The new 750-mg tablet is smaller than the original 500-mg tablet, as is the new 500-mg reformulated binder. The new 1000-mg tablet is identical in size to the original 500-mg tablet.

The efficacy and safety of the reformulated higher-strength binder preparations has also been evaluated in a multicentre study involving two cohorts of patients. Group A consisted of patients who achieved K/DOQI targets for serum phosphorus after four weeks of treatment at doses of lanthanum carbonate ranging from 1500 to 3000 mg/day. This group continued to receive the same dose for another four weeks. Cohort B included patients who were not at K/DOQI targets after four weeks and their dose was titrated up to 3000, 3750 or 4500 mg/day. As Dr. Mehrotra and colleagues reported, 54% of patients receiving the initial doses of the phosphate binder achieved serum phosphorus levels of <1.77 mmol/L at the end of four weeks. There was a 16-week extension phase of this study as well, for a total treatment interval of 24 weeks.

For those in cohort A, mean serum phosphorus remained at 1.77 mmol/L or lower through to week 24. Patients who did not achieve K/DOQI targets after four weeks subsequently responded to 3000-, 3750- and 4500-mg doses by week 8 with reductions in serum phosphorus of 0.07, 0.19 and 0.24 mmol/L, respectively. Overall, approximately 60% of the cohort involved in the study achieved K/DOQI targets by study end, “which is substantially higher than what we know most patients achieve with other phosphate binders,” observed Dr. Mehrotra.

Importantly, the safety profile of the higher doses used in cohort B was no different than that for the lower doses, the most common adverse effects being nausea, vomiting and diarrhea.

“The 750-mg and the 1000-mg tablets of lanthanum carbonate made a simplified treatment regimen possible which for most patients consisted of one tablet per meal (three tablets per day),” investigators noted, adding that this reduction in pill burden might increase patient adherence and thus improve serum phosphorus control.

As was the case for the original formulations of lanthanum carbonate, patients and their physicians have expressed an overwhelming preference for the new, high-strength formulations. In the same efficacy and safety study, Dr. Mehrotra and colleagues collected scores for patient and physician satisfaction at baseline and at several time points out to week 24. Responses indicated patients and physicians alike expressed increased satisfaction at all time points beyond baseline, with satisfaction generally “consistently high” throughout the first eight weeks of the study. Compared with previous phosphate binders, “the greatest increase in satisfaction was for the number of tablets, followed by ‘rarely missed dose’ and then ‘easy-to-take medication,’” Dr. Mehrotra observed, “and that translated into a greater degree of overall satisfaction.”

Long-term Safety Profile

The fact that there has been no evidence of adverse effects of lanthanum carbonate on the liver for patients receiving up to six years of treatment is reassuring. The biliary system is the predominant route of elimination for this agent. In a poster presented by Dr. Alastair Hutchison, Honorary Lecturer in Medicine, University of Manchester, UK, liver enzyme test results were reviewed across all studies with additional open-label extensions for up to six years of treatment. Some 93 patients completed six years of follow-up.

A comparison of median values of liver enzymes in this group showed that AST and ALT levels of 15.0 U/L and 12.0 U/L after six years of treatment were not different from baseline levels of 17.0 U/L and 14.0 U/L, respectively. Nine patients did experience liver or biliary system disorders during up to six years of treatment, but none were considered treatment-related.

A review of the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS)—a post-marketing surveillance database—identified 154 individual reports of intestinal obstruction and perforation during treatment with sevelamer. The same review identified seven similar reports for lanthanum carbonate and none for calcium acetate. Of the 59 sevelamer-treated patients who developed a gastrointestinal (GI) obstruction or perforation, five died, 12 had a life-threatening event, four required hospitalization, three required intervention and the outcome was unknown in 35 patients. “We don’t know exactly why sevelamer would cause these complications but we postulate that it might be because the molecule is anhydrous and when it hits intestinal fluids, it gets hydrated and swells to about six to eight times its original volume, causing a mechanical obstruction [leading to perforation],” observed Dr. Charles Nolan, Professor of Medicine, University of Texas Health Science Center, San Antonio.

Many CKD patients have altered GI motility, he indicated, and this might explain some of the GI complications reported for sevelamer. The molecule may also dehydrate the bowel wall and lead to ischemia. “The AERS is just a warning system that should alert the FDA to demand additional studies be done to define the safety of the drug, but at a minimum, physicians ought to be aware that if their patients have unusual GI side effects, they should think about this possibility,” Dr. Nolan advised. The FDA estimates that AERS data represent at most 1% of actual adverse events.


Bone and mineral disorders are key drivers of much of the morbidity and mortality seen among ESRD patients. Among the most important of these disorders is hyperphosphatemia. Unfortunately, most phosphate binders, whether or not they are calcium-containing, are associated with a large pill burden, making compliance difficult. New higher-strength formulations of lanthanum carbonate, a non-calcium-containing binder, significantly reduce pill burden and may provide adequate phosphate control with a single tablet taken with meals. The simplified regimen should make adherence easier and patients may thus achieve better phosphate control.

Questions and Answers

The following section is based on discussions with Dr. Hartmut Malluche, Professor and Chief of Nephrology, University of Kentucky A. B. Chandler Medical Center, Lexington, during the scientific sessions.

Q: How can physicians make optimal use of calcium-containing phosphate binders?

A: We have enough data indicating that the use of calcium-containing phosphate binders in doses sufficient to control phosphorus requires the total amount of calcium. Unfortunately, that exceeds what you need to give patients. I still agree with the K/DOQI guidelines that state that patients can get 1 or 1.2 g of calcium a day—including the diet—if the patient is on vitamin D. If the patient is not on vitamin D, you might go up to 2 g, again including the diet. But if you subtract 800 mg [patients get from their diet], you only have 1200 mg available for phosphorus binding and that is not sufficient to do it, so we need a non-calcium-containing binder. In addition, we have diabetics who are at very high risk for low bone turnover to begin with, and you don’t want to further suppress this turnover. For these patients, calcium-containing binders should be avoided as first-line choice.

Q: Should patients with adynamic bone disease receive vitamin D?

A: Bone cells need vitamin D to be active but in cases of severe adynamic state, there are no cells that can respond to that vitamin D. While vitamin D will improve intestinal calcium absorption, if you can’t get that into the bone, it will get into the soft tissue. That is the reason why I feel that if the patient has clearly adynamic bone, I would rather take steps to raise the bone turnover at least temporarily before I give vitamin D.

Q: Is there any evidence that the phosphate binders improve bone balance?

A: In a study we did with lanthanum carbonate, we looked at renal osteodystrophy over one and two years and compared it to standard phosphate binders. Whether patients lost or gained bone, bone balance was improved in 54% with the non-calcium-containing phosphate binder compared with only 33% of the calcium-containing binder group. Most excitingly, after two years, one could see an increase in bone volume and the biochemical evidence for increased bone formation was confirmed histologically. Controlling serum phosphorus and avoiding calcium load may lead to an increase in bone volume.

Note: At the time of printing, lanthanum carbonate is not available in Canada.

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