On the weaker side of the battlefield were the manufacturers of the traditional calcium-based binders such as calcium acetate (PhosLo), who had to defend themselves against the anti-calcium alliance and its pervasive educational and promotional activities. Some traditionalists did not find the emerging data adequately convincing to so quickly abandon their two-decade-old calcium-based paradigm.

 


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The positive-calcium-balance advocates and their pharmaceutical supporters also intensified their defensive efforts and sponsored a limited number of studies to show that their good old and inexpensive calcium-based binders are still useful.

 

During this phase, several competing pharmaceutical industry sponsored studies yielded contradictory results. Competing companies launched campaigns discrediting each other’s data. These activities led to confusion among both CKD patients and nephrologists, who were not sure as to how to translate calcium-related data into clinical practice. Nevertheless, the new anti-calcemic paradigm appeared to become the dominating clinical trend, and enjoyed the blessing of the 2003 guidelines for bone metabolism issued under the National Kidney Foundation’s Kidney Disease Outcome Initiative.

 

Recently, the once-focused and straightforward war against calcium has become somewhat confounded as several other pharmaceutical products have been finding their ways into the CKD market. Several newer non-calcium-based binders have received or are awaiting approval, including lanthanum carbonate (Fosrenol) and magnesium-based products.

 

These events have led to further confusion as to whether long-term lanthanum or magnesium accumulation or worsening acidemia with sevelamer HCl is hazardous to CKD patients. Sevelamer carbonate is currently undergoing evaluation by the FDA. Additional binders with diverse features are in the pipeline. Fresenius has recently been reported to acquire calcium acetate (PhosLo), which may further confound the situation.

 

Meanwhile, the recent arrival of doxercalciferol (Hectorol) has disrupted the previously focused

message that a third-generation active vitamin D analogue, paricalcitol, is the best. Heightened debate as to whether doxercalciferol status should be regarded an evolved generation

of “active” vitamin D that surpasses calcitriol or a prohormone has only deepened the confusion among nephrologists and dietitians. The competition has become even more complicated as cinacalcet has emerged as a promising intervention to avoid parathyroidectomies.

 

The once unified anti-calcium alliance appears to suffer from worsening infighting among its own members, especially since the once almost-unanimously endorsed motto “the lower calcium, the better outcome” might not quite serve the best interest of all parties involved. Newer epidemiologic analyses have shown that the observed associations between serum calcium and outcome may depend on the methodological tools employed, hence raising questions about the robustness of preliminary observations dependent on baseline values of the retrospective cohorts.

 

Concurrently, recent observational studies in earlier stages of CKD have shown that coronary artery calcification can frequently occur even without high calcium intake or even with low serum calcium levels. Survival data show that any dose of active vitamin D is associated with better survival independent of the level of calcium, phosphorus, or parathyroid hormone (PTH).

 

What next?

There is no denying that the field of kidney bone disease has become complicated in the past few years. That many investigators and opinion leaders in this field may have conflicts of interest that effectively hamper their ability to communicate freely is nothing unprecedented in medical sciences. So what is the best course of action for management of kidney bone disease?

 

A more appropriate approach could be to resist abrupt shifts in practice patterns as long as data are not convincing or as long as higher levels of evidence-based data, such as those from randomized controlled trials, are missing. There are at least 10 fundamental questions to be answered (Table 1) before radical changes in guidelines and practice pattern should be recommended.

 

Old paradigms should be reexamined cautiously instead of being discredited and replaced by new sets of recommendations. The utility of traditional markers of bone disease should be revisited. Recently, a large epidemiologic study found that serum alkaline phosphatase has one of the most linear (incremental) associations with survival in hemodialysis patients when compared to serum levels of PTH, cal-cium or phosphorus.

 

Serum alkaline phosphatase is measured monthly in virtually all maintenance dialysis patients in the United States and is a promising marker to be revisited. More studies are needed to examine whether worsening vascular calcification due to high calcium intake or high serum calcium is related to survival. The question regarding vitamin D deficiency in the CKD population needs more attention. In general, there is a long way to go before the old kidney bone disease paradigms should be considered for radical modifications.

 

Conflict of Interest

Drs. Kalantar-Zadeh and Mehrotra have received honoraria and grants from Genzyme, Inc., the manufacturer of sevelamer hydrochloride (Renagel). Dr. Kalantar-Zadeh has received honoraria and grants from Abbott Laboratories, the manufacturer of paricalcitol (Zemplar). Dr. Mehrotra has received grants from and serves as a consultant for Shire Pharmaceuticals, the manufacturer of lanthanum carbonate (Fosrenol).