Towards the revival of alkaline phosphatase for the management of bone disease, mortality and hip fractures.

The story of alkaline phosphatase in the management of mineral and bone disorder (MBD) in patients with chronic kidney disease (CKD) is an interesting and educational part of the history of nephrology. Circulating alkaline phosphatase, a marker of bone turnover, was among the first bone markers used for the detection and management of ‘renal osteodystrophy’, a term previously used by clinicians and researchers since the 1970s. However, by the mid-1990s and early 2000s alkaline phosphatase fell out of favor, when commercial parathyroid hormone (PTH) assays become available. At the same time, the first Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines on CKD–MBD chose not to mention alkaline phosphatase, as target ranges were uncertain [1]. A rise in serum alkaline phosphatase, known as hyperphosphatasemia or hyperphosphatasia, is an expected finding in progressive CKD with worsening kidney function [2]. Elevated serum alkaline phosphatase concentrations in CKD patients with otherwise intact liver and biliary systems usually result from excess of the bone isoforms of the enzyme [3–5]. Specific detection of the bone isoform may not have clinical utility, since it was found not to correlate with inflammation or mortality risk [6]. The recent data suggest that a rise in alkaline phosphatase in dialysis patients is associated with worsening bone mineral density [7], and worse responsiveness to erythropoiesis stimulating agents [8]. The existence of an incremental and strictly linear associations between higher serum alkaline phosphatase (>120 U/L) and worse mortality was reported first in hemodialysis patients [9, 10], and more recently in peritoneal dialysis patients [11] as well as in non-dialysis dependent CKD patients [12–14]. At least in dialysis patients, these findings are in sharp contradistinction to the mortality predictability of serum PTH, which has a U-shaped relationship in that both high and low PTH are associated with higher death risk [10]. Even more importantly, the alkaline phosphatase-death association persists even across different PTH strata including when PTH is <150 pg/mL [9, 10]. Interestingly, a low alkaline phosphatase level is associated with greater survival, a finding that appears to question the harmfulness of adynamic bone disease. These studies suggest that alkaline phosphatase is more than a mere marker of high-turnover bone disease and may serve a reliable mortality predictor. Hence, modulating alkaline phosphatase via interventions such as improving CKD care, better dialysis treatment, or therapy with vitamin D agents or calcimimetics, may improve not only bone health but also survival of CKD patients. Higher circulating alkaline phosphatase may increase hydrolysis of pyrophosphate [15, 16], which is a potent inhibitor of vascular calcification [17–19]. The modulatory effect of alkaline phosphatase on pyrophosphate could be the link as to why lower levels of the former are associated with an incremental drop in mortality [20]. Consistent with this notion, a recent epidemiologic study found that higher levels of alkaline phosphatase (and not PTH, calcium or phosphorus) were associated with coronary artery calcification in hemodialysis patients [21]. Higher alkaline phosphatase levels are also associated with lower 25(OH) vitamin D level [22–24], which is per se associated with increased mortality [25]. In this issue of Nephrology Dialysis Transplantation, Maruyama et al. [26] examined the baseline data in 185 277 prevalent hemodialysis patients in Japan and related them to 1-year mortality and incident hip fracture events through calendar year 2010. They found that patients in the highest quartile of serum alkaline phosphatase had 46% and 25% higher all-cause and cardiovascular death risk, respectively, as well as a 71% higher incidence of hip fracture events, than those within the lowest quartile [26]. Whereas the mortality predictability of alkaline phosphatase is a well-known finding, this is the first report of such an association in a large cohort of Japanese dialysis patients. It is important to note that Japanese dialysis patients have by far the best survival among all known dialysis patients in the world, usually <10% per year, when compared with European and US dialysis patients who have an annual mortality of 15–20% or higher [26]. Japan is also the nation with the longest life expectancy of 92 years. Maruyama et al. reported an annual mortality of 7.9% in their IN F O C U S