Soluble Biomarkers of Osteoporosis and Osteoarthritis, from Pathway Mapping to Clinical Trials: An Update

Abstract

Serum biomarkers of osteoarticular diseases have been in the limelight of current clinical research trends. Laboratory validation of defined and candidate biomarkers for both osteoarthritis and osteoporosis is of key importance for future decisional algorithms in the diagnosis, monitoring, and prognosis of these diseases. The current guidelines recommend the use of collagen degradation remnants, eg, CTX-I and CTX-II, in the complementary diagnosis of both osteoporosis and osteoarthritis. Besides the collagen degradation markers, enzymes that regulate bone and articular metabolism are useful in the clinical evaluation of osteoarticular pathologies. Along these, several other recommended and new nominee molecules have been recently studied. Wnts and Wnt-related molecules have a cardinal role in the bone-joint homeostasis, making them a promising target not only for pharmaceutical modulation, but also to be considered as soluble biomarkers. Sclerostin and dickkopf, two inhibitor molecules of the Wnt/β-catenin signaling, might have a dual role in the assessment of the clinical manifestations of the osteoarticular unit. In osteoarthritis, besides fragments of collagen type II many pathway-related molecules have been studied and proposed for biomarker validation. The most serious limitation is that a significant proportion of studies lack statistical power due to the reduced number of cases enrolled. Serum biomarkers of bone and joint turnover markers represent an encouraging possibility for the diagnosis and prognosis of osteoarticular diseases, although further studies and laboratory validations should be carried out as to solely rely on them.

Keywords:

• osteoarthritis
• osteoporosis
• biomarkers

Abbreviations

ABPS, Achyrantes bidentata polysaccharides; ALP, alkaline phosphatase; BALP, bone-specific alkaline phosphatase; BEST, Biomarkers, EndpointS, and other Tools Resource glossary; BMD, bone mineral density; BMI, body mass index; BTM, bone turnover marker; C1M, MMP-derived degradation of type I collagen; C2M, MMP-derived degradation of type II collagen; C3M, MMP-derived degradation of type III collagen; CCL2, Chemokine (C-C motif) ligand 2; CCL3, Chemokine (C-C motif) ligand 3; COMP, cartilage oligomeric matrix protein; CTAPIII, Connective tissue-activating peptide III; CTX-I, carboxy-terminal cross-linking telopeptide of type I collagen; CTX-II, carboxy-terminal cross-linking telopeptide of type II collagen; CTX-III, carboxy-terminal cross-linking telopeptide of type III collagen; DKK, dickkopf; DM, diabetes mellitus; DPD, deoxypyridinoline; DXA, dual X-ray absorptiometry; Enho, energy-homeostasis related gene; FNIH, Foundation for the National Institutes of Health; GARP, Genetics, Arthrosis, and Progression Study; HIF, hypoxia inducible factor; hsCRP, high-sensitive C-reactive protein; ICTP, serum cross-linking C-terminal telopeptide; IFCC, International Federation of Clinical Chemistry and Laboratory Medicine; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; IOF, International Osteoporosis Foundation; IU, international units; K-L, Kellgren-Lawrence score; LRP, lipoprotein receptor-related proteins; miR, microRNA; MMP, matrix metalloproteinase; NADPH, Nicotinamide adenine dinucleotide phosphate; NO, nitric oxide; NSAID, non-steroid anti-inflammatory drug; NTX, amino-terminal cross-linking telopeptide of type I collagen; OA, osteoarthritis; OARSI, Osteoarthritis Research Society International; OC, osteocalcin; PICP, procollagen type I C propeptide; PIIANP, serum N-propeptide of collagen IIA; PIIBNP, N-terminal propeptide of collagen type II; PINP, procollagen type I N propeptide; PMOP, postmenopausal period osteoporosis; PYD, pyridinoline; RANK, receptor activator of nuclear factor κB; RUNX, runt-related transcription factor; s-CTX-I, serum carboxy-terminal cross-linking telopeptide of type I collagen; sFRP, soluble Frizzled receptor related proteins; SIRT, sirutin; SOST, sclerostin gene; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TGF, transforming growth factor; TJA, total joint arthroplasty; TNF, tumor necrosis factor; TRACP, tartrate-resistant acid phosphatase; uCol2-1 NO2 - urinary nitrated type II collagen degradation fragment; u-CTX-I, urinary carboxy-terminal cross-linking telopeptide of type I collagen; u-CTX-II, urinary C-terminal cross-linked telopeptide of type II collagen; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Disclosure

The authors report no conflicts of interest in this work.