Integral pharmacological management of bone mineral disorders in chronic kidney disease (part II): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification

ABSTRACT

Introduction: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are associated with costly complications and dismal hard-outcomes.

Areas covered: In two comprehensive articles we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (part 1) and hyperparathyroidism (this part 2), taking into account CKD-accelerated cardiovascular calcification (CVC) processes.

Expert opinion: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Here, initial guidance to control hyperparathyroidism is provided, taking into account the presence/absence of CVC. We include also measures for patients at risk of adynamic bone disease or suffering from calciphylaxis. Many epidemiological studies (relating to vitamin D) and thorough analyses of recent randomized clinical trials (of cinacalcet) point towards benefits of attempting to improve biochemical parameters while trying to, at least, avoid progression of CVC by more rational use of intestinal P-binders and low-dose vitamin D derivatives and/or calcimimetics. This approach does not seem to be far away from significantly improving hard-outcomes, at least in the dialysis population. The availability of new drugs and the performance of randomized clinical trials should ultimately lead to define earlier, clearer, and more cost-effective patient stratification and biochemical targets with consequent significant clinical improvements.

KEYWORDS:

• Chronic kidney disease
• CKD-MBD
• phosphate
• secondary hyperparathyroidism
• vascular calcification
• calcium receptor
• vitamin D
• paricalcitol
• cinacalcet
• calcimimetics
• etelcalcetide
• adynamic bone disease

Article highlights

• CKD is linked to an extremely important and independent increase in mortality, and mineral and bone disorders (MBD) explain at least part of this disproportionate risk

• Treatment of CKD-MBD requires an integral approach, addressing all 3 components of the CKD-MBD triad (including the presence of CVC)

• CKD-MBD and secondary hyperparathyroidism are common and costly manifestations of CKD

• Vitamin D deficiency is common both in the general population and in patients with CKD, and it is associated with poor outcomes

• There is no proof that supplementation with vitamin D improves survival, although guidelines recommend treatment of vitamin D deficiency

• Vitamin D receptor activators are used to reduce PTH secretion and have been associated with improved outcomes in observational studies and meta-analyses, but not in RCTs

• Selective activators of the vitamin D receptor (i.e. paricalcitol vs calcitriol) seem to have a wider therapeutic window (less hypercalcemic and hyperphosphatemic episodes) and have also been associated with improved survival in dialysis patients in retrospective studies

• Calcimimetics provide a completely different means to control secondary hyperparathyroidism in dialysis patients, controlling PTH synthesis and secretion and decreasing calcium and phosphate levels.

• The ADVANCE and EVOLVE RCTs provide important clues towards improvement of hard outcomes in dialysis patients

• Etelcalcetide represents a novel iv agonist of the calcium-sensing receptor

• Combination of anti-parathyroid agents is a feasible clinical option

• Low PTH levels (< 2 times the upper limit of normality for the assay) should be avoided since adynamic bone disease is associated to poor outcomes

• Increasing trends in PTH levels should be treated and PTH levels > 9 times the upper limit of normality should be definitely avoided

• Therapeutic nihilism while awaiting the results of new RCTs does not seem to be justified

This box summarizes key points contained in the article.

CKD: chronic kidney disease; MBD: mineral and bone disorders; CKD–MBD: chronic kidney disease-mineral and bone disorder; CVC: cardiovascular calcification; PTH: parathyroid hormone; RCT: randomized clinical trial.

Acknowledgments

We thank Ricardo Pellejero for his invaluable bibliographic assistance. J Bover belongs to the Spanish National Network of Kidney Research RedinRen (RD06/0016/0001 and RD12/0021/0033) and the Spanish National Biobank network RD09/0076/00064. He also belongs to the Catalan Nephrology Research Group AGAUR 2009 SGR-1116. J Bover and M.M. Diaz-Encarnacion collaborate with the Spanish ‘Fundación Iñigo Alvarez de Toledo’ (FRIAT).

Declaration of interests

J Bover has received speaking honoraria from Abbvie, Amgen, Genzyme, and Shire; fees as a consultant for Abbvie, Amgen, Vifor/Fresenius-Pharma, Chugai, Medice and Genzyme/Sanofi. M.M. Diaz-Encarnacion and J Bover received a research grant from Abbvie. P Ureña-Torres reports personal fees and grants from Amgen, Abbvie, Genzyme-Sanofi, Medice, Hemotech, and Fresenius. E Fernández has received speaking honoraria from Abbvie, Amgen, Genzyme, and Shire; fees as a consultant for Abbvie, Amgen, Vifor/Fresenius-Pharma. E Fernández received a research grant from Abbvie. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.