Review of Bone Turn over Biomarkers for Early Diagnose of Osteoporosis

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1 Journal of Advances in Medicine and Medical Research 26(8): 1-8, 2018; Article no.jammr ISSN: (Past name: British Journal of Medicine and Medical Research, Past ISSN: , NLM ID: ) Review of Bone Turn over Biomarkers for Early Diagnose of Osteoporosis Afshan Iftikhar 1*, Syed Tousif Ahmed 1 and Tayeb Asim 1 1 Ziauddin Medical University, Karachi, Pakistan. Authors contributions This work was carried out in collaboration between all authors. Author AI did the conception of idea, methodology and paper writing. Author STA performed the literature search, methodology and review of 2nd draft. Author TA performed the methodology, review of 1st draft and final editing. All authors read and approved the final manuscript. Article Information DOI: /JAMMR/2018/41718 Editor(s): (1) Rui Yu, Environmental Sciences & Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, USA. Reviewers: (1) Pouran Famili, University of Pittsburgh, USA. (2) Ali Al Kaissi, Orthopaedic Hospital Speising, Austria. Complete Peer review History: Mini-review Article Received 14 th March 2018 Accepted 22 nd May 2018 Published 30 th May 2018 ABSTRACT Introduction: Osteoporosis is a worldwide major burden among postmenopausal women. Not only the women, men are also prone to osteoporosis and fragility fractures with increasing age. The underlying pathology of osteoporosis is actually an imbalance among bone turnover cells including osteoblasts and osteoclasts. The rate of bone formation and resorption can be either measured by using urinary excretion of different biochemical markers or their presence in serum as well. Objective: The aim of this review article was to collate all the osteoporotic biomarkers, their role in assessing risk of fractures, and monitoring of treatment potency. Methodology: A web-based search was used and online data bases from PUBMED and MEDLINE were searched for osteoporosis. Studies from the year of 2000 up to 2017 were included. A total of 28 studies were included in the review which fulfilled the study parameters. Results: Bone turnover biomarkers are not only helpful in early identification of the osteoporosis and fracture risk but also for the follow-up purpose after the antiresorptive treatment. These are also helpful in identifying over suppression of bone turn over after taking long term treatment of osteoporosis so beneficial in monitoring of patient taking long term treatment or who are on treatment holiday. The including biomarkers are bone-specific alkaline phosphatase, Procollagen *Corresponding author: dr_afshan_iftikhar@hotmail.com;

2 type 1 amino-terminal propeptide, Osteocalcin, Procollagen type 1 carboxy-terminal propeptide, receptor activator of nuclear factor NF-κB ligand, Osteoprotegerin, Carboxy-terminal telopeptide cross-linked type 1 collagen, type 1 collagen amino-terminal telopeptide, deoxypyridinoline, tartrate-resistant acid phosphatase, Cathepsin K and hydroxylysine. Conclusion: At the end of this mini-review, it can be concluded that the bone biomarkers have enough potential to act as an indicator in early prediction of the risk of osteoporosis and fracture along with the follow up after osteoporosis therapy. Multiple studies are going on to introduce novel biomarkers using genomic and proteomic approaches. Keywords: Bone turnover biomarkers; osteoporosis; fracture risk. 1. INTRODUCTION Osteoporosis is a worldwide major burden among postmenopausal women [1]. Not only the women, men are also prone to osteoporosis and fragility fractures with increasing age, about 1 in 2 women and 1 in 5 men has the probability to develop osteoporotic fractures [2,3]. So overall osteoporotic fracture have high morbidity and mortality among both men as well as women [1]. The underlying pathology of osteoporosis is actually an imbalance among bone turnover cells including osteoblasts and osteoclasts [4]. In postmenopausal women, there is excessive activation of osteoclastic cells leads to bone demineralization because of the estrogen deficiency, the net effect is more bone resorption than the bone formation [5-7]. The rate of bone formation and resorption can be either measured by using urinary excretion of different biochemical markers or their presence in serum as well. In past few decades, a wide range of immunoassays have been identified in vitro as well as in vivo investigations. These immunoassays are helpful not only for diagnostic purpose but for the research purpose as well as to understand the pathogenesis of osteoporotic mechanism and to evaluate the multiple treatment modalities. So the aim of this review article was to collate all the osteoporotic biomarkers, their role in assessing risk of fractures, and monitoring of treatment potency. 2. METHODS This is a mini-review. A web based search was used and online databases from PUBMED and MEDLINE were searched for osteoporosis biomarkers. The key words used for the search were osteoporosis, osteoporosis induced fracture risk, biomarkers for osteoporosis, osteoblast markers, osteoclast markers and individually searched by using the biomarker name. The search results showed about 73 studies done on bone biomarkers while considering biomarkers in osteoporosis only 28 studies left. Studies from the year of 2000up to 2018 were included in the review. The current review included those particular articles that show only the biomarkers that appear in osteoporosis and the articles that available in English. 2.1 Composition of Bone Basically bone is composed of three main components including collagen fibers type I, hydroxyapatite crystals [3Ca 3 (PO 4 ) 2 (OH) 2 ], and ground substance. On the structural basis the bone is divided into outer thick part, named as cortical bone and the inner thin part, known as trabecular bone. The cortical bone is made up of a dense layer of calcified tissue while the trabecular bone is comprising of flexible framework of thin trabeculae [8-10]. During the process of bone turnover both the osteoblast and osteoclast cells are interconnected by Basic Multicellular Unit (BMU), so the old bone is replaced by the new bone of same weight. In premenopausal women the osteoblast and osteoclast cells work in a balanced way so the net effect of bone resorption and formation is zero [10]. However, after menopause, there is an imbalance in bone remodeling that is the bone resorption is more than the bone formation. This resulting in loss of bone mass and deterioration of bone microarchitecture, so that the bones become porous and fragile, increases the overall risk of fractures [6,11]. 2.2 Biochemical Markers According to WHO, the osteoporosis can be diagnosed by using bone mineral density (BMD) of hip or spine and considered dual-energy X-ray absorptiometry (DXA) as a gold standard technique [12,13]. When comparing with biomarkers, the BMD changes appear late and is expensive to test, while biomarkers not only 2

3 detect early changes but can also be repeated with small intervals, as it gives a representative index of overall bone loss [14,15]. But on the other hand, some of the studies considered BMD as a better indicator for the diagnosis of osteoporosis and bone turn over biomarkers for the treatment efficacy [16,17]. Bone turnover biomarkers are not only helpful in early identification of the osteoporosis and fracture risk but also for the follow-up purpose after the antiresorptive treatment [18,19]. These are also helpful in identifying over suppression of bone turn over after taking long-term treatment of osteoporosis so beneficial in the monitoring of patient taking long-term treatment or who are on treatment holiday [20,21]. These biomarkers are actually produced either as a result of the enzymatic activity of osteoclast or osteoblast cells or osteolytic metabolites, found either in the serum or in urine [14,18]. The including biomarkers are bone-specific alkaline phosphatase, Procollagen type 1 amino-terminal propeptide, Osteocalcin, Procollagen type 1 carboxy-terminal propeptide, receptor activator of nuclear factor NF-κB ligand, Osteoprotegerin, Carboxy-terminal telopeptide cross-linked type 1 collagen, type 1 collagen amino-terminal telopeptide, deoxypyridinoline, tartrate-resistant acid phosphatase, Cathepsin K and hydroxylysine [18] Osteoblast biomarkers (Formation markers) 1. Bone-specific Alkaline Phosphatase: There are multiple isoforms of serum alkaline phosphatase which are synthesized by various tissues including liver, bone, spleen, kidney, intestine and placenta, among them bone is the major factory of about 40-50% of total alkaline phosphatase [22]. Bone-specific Alkaline Phosphatase (BALP) can be measured either by using enzyme-linked immunosorbent assay (ELISA), which detects the BALP enzymatic activity or by using immunoradiometric assay (IRMA), which detect BALP in protein mass unit. Literature review recommends the BALP testing at baseline before the initiation of osteoporosis treatment and then repeat after 3-6 month of the start of therapy [23]. The strength of the test is its little affected by demographic variables like age, gender, ethnicity and diurnal variation [16] but on the other hand, having some limitations including cross-reactivity with the alkaline phosphatase so contradicted in patients of liver diseases [20,24]. 2. Procollagen type 1 amino-terminal propeptide: Procollagen type 1 amino-terminal propeptide (P1NP) is synthesized mainly by the osteoblast while a small amount is by skin, cartilage and tendon, as these tissues also contain type 1 collagen. It is considered as a sensitive as well as a specific marker for bone formation and is particularly used for follow-up purpose after giving bone formation therapy [25, 26]. ELISA or the radioimmunoassay is used to detect the P1NP by introducing anti-p1np antibodies. Like BALP, it is also recommended to test P1NP at baseline before the initiation of therapy and then after 3-6 month for follow-up [23]. The advantage of the test is its accuracy without fasting, prior to specimen collection and is little affected by diurnal variation [16] but only limitation is its expensiveness [20,24]. The International Federation of Clinical Chemistry (IFCC) and National Bone Health Alliance (NBHA) have recommended P1NP as a reference biomarker to evaluate bone formation [27,28]. 3. Osteocalcin: Osteocalcin also known as bone gamma-carboxyglutamic acid-containing protein (gla protein), is synthesized mainly by osteoblast but other than that a small quantity is also synthesized by odontoblast and hypertrophic chondroblast. It is the major constituents of noncollagenous part of bone matrix [29]. In bone OC plays an important role in mineralization of bone and homeostasis of calcium ion. It is a specific marker of osteoblast activity so aid in interpretation of rate of bone formation after osteoporosis treatment. Like P1NP, the Osteocalcin can also be detected by ELISA or radioimmunoassay [23]. The strength of the biomarker is its specificity, wide availability and low variability [16]. 4. Procollagen type 1 carboxy-terminal propeptide: Procollagen type 1 carboxy-terminal propeptide (P1CP) is formed by osteoblast during the process of collagen fibers assembly, like P1NP a small amount of P1CP is also synthesized by skin, cartilage tendon and fibroblast. Its level can be assessed by using ELISA or radioimmunoassay, same as other biomarkers [23,24,30]. 5. Receptor activator of nuclear factor NF-κB ligand: Receptor activator of nuclear factor NFκB ligand (RANKL) is a part of tumor necrosis factor (TNF) family and is released by osteoblast cells and T-lymphocytes. Its receptors are located on osteoclast cells so is the major 3

4 mediator of activation and differentiation of osteoclast cells [31-33]. Studies manifested that expression of RANKL has an inverse association with 17β estradiol while significant correlation with resorption markers, so can be used to measure the osteoclast activity [34]. 6.Osteoprotegerin: Osteoprotegerin (OPG) is synthesized by a number of tissues including bone, liver, stomach and intestine. Looking over the bone, it is secreted by osteoblast cells, after secretion it binds to RANKL so inhibiting the activation and differentiation of osteoclast cells, overall act as an inhibitor of osteoclastogenesis [35,36]. Unlike RANKL, OPG has a significant correlation with estrogen level [37]. It is measured in serum using sandwich ELISA assays. The OPG to RANKL ratio is an important predictor of osteoclast activity rather than individual interpretation of these two markers [34] Osteoclast biomarkers (Resorption markers) 1. Carboxy-terminal telopeptide cross-linked type 1 collagen: As the name indicates, Carboxy-terminal telopeptide cross-linked type 1 collagen (CTX) is a fragment of peptide which is formed from the carboxy-terminal of type 1 collagen during the osteoclastic activity. It is a sensitive as well as specific marker, the level can be determined by doing serum or urine ELISA [23]. The strength of the biomarker is its highest sensitivity after the specific osteoporosis treatment like bisphosphonate therapy [16]. Looking over the limitations, sampling require prior fasting, need repeated sampling because of large circadian rhythm and its instability require immediate freezing of sample [20,38]. 2. Type 1 collagen amino-terminal telopeptide: Type 1 collagen amino-terminal telopeptide (NTX) is a peptide, formed from the amino-terminal of type 1 collagen. It can be detected in urine as well as in serum by using competitive inhibition ELISA or by chemiluminescence assay [24]. Literature reported the 50% decline in NTX level within 3 months after the initiation of bisphosphonate therapy, so it is suggested as a good follow-up tool in osteoporosis that should measure before the initiation of osteoporosis therapy and 3-6 months post-therapy [23] NTX testing is preferred over CTX as it is not altered by food intake. 3. Deoxypyridinoline: Deoxypyridinoline (dpyr)is an indicator of bone matrix degradation as it is the part of the degradation product, released from the type 1 collagen [23]. dpyr has a function of developing a cross-linkage between two collagen polypeptides, that is the reason of its presence in the mature form of type 1 collagen. dpyr level in serum as well as in urine is detected by competitive ELISA or by highperformance liquid chromatography (HPLC)(1). It is not a specific test for osteoporosis as there are many other diseases that can raise the urine dpyr level, including osteomalacia, hyperparathyroidism, thyrotoxicosis and certain inflammatory conditions like Paget s disease, metastatic cancers and in the patients with immobilization. But a decrease in 30% after the initiation of osteoporosis therapy is the indicator of good treatment response [23]. 4. Tartrate-resistant acid phosphatase: Tartrate-resistant acid phosphatase (TRAcP) is produced by osteoclast, dendritic cells and macrophages. It has two forms 5a and 5b, these activate phosphatase activity in turn leads to the formation of reactive oxygen species [39]. The osteoclast cells produce isoform 5b, so this isoform represents the number of osteoclasts rather than its resorption activity [40,41]. It has good sensitivity and is highly specific. Usually, its level is measured in serum, increasing with age, even more after menopause [42]. 5. Cathepsin K: Cathepsin K is one of the members of protease family synthesized by osteoclast cells. It has a major role in the degradation of collagen type 1 cells that is involving in organic phase degradation [43,44]. The most important prerequisite for Cathepsin K induced degradation is low ph after the completion of the degradation of inorganic phase. The level of Cathepsin K is directly measured in a serum sample [45]. 6. Hydroxylysine: Hydroxylysine (HYL) is the product of post-translational modification of lysine. There are two forms of HYL, including galactosylhydroxylysine (GHYL) and glucosylgalactosyl-hydroxylysine (GGHYL). GHYL having more specificity as compare to the GGHYL, because of its secretion during bone degradation while GGHYL released from the other tissues other than the bone including skin and the C1Q complement molecule [46,47]. The literature reported increases in urinary GHYL concentration after bone fracture, that is an indicator of collagen defect. So it is considered 4

5 as a good biomarker of bone resorption. But the very small number of studies have been done to evaluate GHYL in osteoporosis and this limits its use [48,49]. The major limitation of the test is that it can only be done by HPLC [50] Variability in biomarkers There are various factors that can affect the level of biomarkers, including the collection or storage of specimen [16,51-54], variability in the method of interpretation [16,52], diurnal, menstrual or seasonal variations [16,51-54], demographic variations like age, gender or ethnicity [51,53, 54], if patient is taking any medication other than therapy for osteoporosis such as hormone replacement therapy (HRT), glucocorticoids, gonadotropin releasing hormone (GnRH), contraceptives or anticonvulsants [51] and the other factors like some diseases involving liver diseases, renal instability, diabetes, osteomalacia, thyroid diseases, systemic inflammatory responses, or eating disorders [51, 53,54]. Bone turn over follows a circadian rhythm as osteoclast cells having peak activity at night and early morning while resting of the day counter-balanced by antiresorptive cells [23]. Markers in the serum show less variability than that of urine [16]. Because of wide variations, test specific reference ranges should be established for the early diagnosis of the risk of osteoporosis, fracture and treatment response [55-57]. 3. CONCLUSION At the end of this mini-review, it can be concluded that the bone biomarkers have enough potential to act as an indicator in early prediction of the risk of osteoporosis and fracture along with the follow up after osteoporosis therapy. Among the bone formation biomarkers, the BALP and CTX are the most prevalent. Multiple studies are going on to introduce novel biomarkers using genomic and proteomic approaches. CONSENT It is not applicable. ETHICAL APPROVAL It is not applicable. COMPETING INTERESTS Authors have declared that no competing interests exist. REFERENCES 1. Leeming D, Alexandersen P, Karsdal M, Qvist P, Schaller S, Tanko L. An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice. European Journal of Clinical Pharmacology. 2006;62(10): Banu J. Causes, consequences, and treatment of osteoporosis in men. Drug Design, Development and Therapy. 2013;7: Greenblatt MB, Tsai JN, Wein MN. Bone turnover markers in the diagnosis and monitoring of metabolic bone disease. Clinical Chemistry. 2017;63(2): Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinology and Metabolism Clinics. 2005;34(4): Horowitz MC, Xi Y, Wilson K, Kacena MA. Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. Cytokine & Growth Factor Reviews. 2001;12(1): Lerner U. Bone remodeling in postmenopausal osteoporosis. Journal of Dental Research; McNamara L. Perspective on postmenopausal osteoporosis: establishing an interdisciplinary understanding of the sequence of events from the molecular level to whole bone fractures. Journal of the Royal Society Interface. 2010; 7(44): Baron R. Anatomy and biology of bone matrix and cellular elements. Primer on the metabolic bone diseases and disorders of mineral metabolism American Society for Bone and Mineral Research, Washington. 2003; Lian J, Stein G, Aubin J. Anatomy and biology of bone matrix and cellular elements. Bone Formation: Maturation and Functional Activities of Osteoblast Lineage Cells American Society for Bone and Mineral Research, Primer, Section. 2003; 1: Katagiri T, Takahashi N. Regulatory mechanisms of osteoblast and osteoclast differentiation. Oral Diseases. 2002; 8(3):

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