It is a well-known fact that bone is affected by chronic kidney disease (CKD). CKD affects not only bone turnover, but also bone mineralisation and bone mass. Morbidity and mortality related to chronic kidney disease – mineral bone disorder (CKD-MBD) is significant and the assessment of bone turnover is one of the most important diagnostic tools in the management of CKD-MBD.
Histological procedures are the gold standard to assess bone turnover however bone biopsies are invasive and the procedures are performed in specialised centres. It is therefore more practical and cost effective to use bone biomarkers for both diagnosis and monitoring of bone turnover.
The recommendations published in 2009 by KDIGO (Kidney Disease Improving Global Outcomes) suggest that measurements of serum parathormone (PTH) and bone specific alkaline phosphatase (b-ALP) could be used to evaluate bone disease because markedly high or low values predict underlying bone turnover.
The International Osteoporosis Foundation and the International Federation of Clinical Chemistry and Laboratory Medicine recommend that a marker of bone formation (serum procollagen type I N-propeptide, PINP) and a marker of bone resorption (serum C-terminal telopeptide of the type I collagen, CTX) should be used as reference analytes for bone turnover markers in non-CKD populations. These are still being investigated for use in CKD-MBD, as is another interesting marker of bone resorption, TRAP-5B (tartrate-resistant acid phospatase 5B).
Recent reports of several bone derived substances, some of which have hormonal properties, have shed new light on the bone-cardiovascular axis. Connections can be made to cardiovascular morbidity and mortality, and also chronic kidney disease. FGF23, Sclerostin, DKK1 and osteocalcin are all biomarkers of interest to researchers in the field of CKD-MBD.
In the circulation PINP is rapidly bound and internalised by the endothelial cells of the liver. When present in the serum it exists in 2 forms – monomeric and trimeric. The proportion of monomeric PINP is elevated in patients with CKD.
There is limited literature on the use of this biomarker in CKD but it has been shown that serum PINP values correlate significantly more strongly than serum b-ALP with all bone resorption markers.
CTX are fragments formed as a result of the degradation of type I collagen that are released during osteoclastic resorption. A decrease in CTX has been shown to correlate with an increase in bone mass during osteoporosis therapy.
TRAP-5B is secreted in the circulation by osteoclasts during bone resorption. It is a “true” non-collagen bone resorption marker as it correlates significantly with histological indices of osteoclast number.
The key physiological role of FGF23 is to maintain balance of phosphorous and vitamin D. It also reduces the production and secretion of parathyroid hormone and interferes with the metabolism of vitamin D.
Epidemiological and experimental data suggest that increases in FGF23 are directly involved in the dismal clinical outcome in CKD.
Sclerostin is a potent inhibitor of Wnt signalling, and plays an important role in osteoblast maturation.
- Serum levels are significantly elevated in post-menopausal women, in patients with immobilisation-induced bone loss, and in patients with multiple myeloma.
- Circulating sclerostin serum levels are reduced by PTH therapy and oestrogen.
- he development of neutralising antibodies to sclerostin and DKK1 are found to be promising therapeutic agents in diseases with elevated bone resorption.
A potent inhibitor of Wnt signalling that pays an important role in osteoblast maturation.
Increased circulating DKK1 levels have been reported in clinical situations characterised by:
- Markedly depressed bone formation, as in multiple myeloma
- Bone metastases from breast, prostate or lung cancer
- Rheumatoid arthritis.
Osteocalcin is a calcium-binding bone-matrix protein produced by osteoblasts and is one of the most abundant non-collagen proteins in bone. It is regulated by vitamin D and parathyroid hormone.
In CKD or vitamin K deficiency, the amount of uncarboxylated osteocalcin increases, negatively affecting insulin secretion and sensitivity, promoting cardiovascular disease.
Oxford Biosystems offers ELISA and RIA kits for a wide range of bone biomarkers covering all those listed above and others such as Cathepsin K, free sRANKL and Osteoprotegerin.
Can we use circulating biomarkers to monitor bone turnover in CKD haemodialysis patients?
Hypothesis and facts.
Pierre Delanaye, Jean-Claude Souberbielle, Marie-Helene Lafage-Proust, Gillaume Jean, Etienne Cavalier
Nephrol Dial Transplant (2013)
Is chronic kidney disease-mineral bone disorder (CKD-MBD) really a syndrome?
Mario Cozzolino, Pablo Urena- Torres, Marc G. Vervloet, Vincent Brandenburg, Jordi Bover, David Goldsmith, Tobias E. Larsson, Ziad A. Massey and Sandro Mazzaferro on behalf of the CKD-MBD Working Group of ERA-EDTA
Nephrol Dial Transplant (2014)
Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders.
Marc G. Vervloet, Ziad A. Massey, Vincent Brandenburg, Sandro Mazzaferro, Mario Cozzolino, Pablo Urena- Torres, Jordi Bover, David Goldsmith on behalf of the CKD-MBD
Working Group of ERA-EDTA
Lancet Diabetes Endocrinol2014; 2:427-36