Journal of Clinical and Diagnostic Research, ISSN - 0973 - 709X

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Dr Bhanu K Bhakhri

"The Journal of Clinical and Diagnostic Research (JCDR) has been in operation since almost a decade. It has contributed a huge number of peer reviewed articles, across a spectrum of medical disciplines, to the medical literature.
Its wide based indexing and open access publications attracts many authors as well as readers
For authors, the manuscripts can be uploaded online through an easily navigable portal, on other hand, reviewers appreciate the systematic handling of all manuscripts. The way JCDR has emerged as an effective medium for publishing wide array of observations in Indian context, I wish the editorial team success in their endeavour"



Dr Bhanu K Bhakhri
Faculty, Pediatric Medicine
Super Speciality Paediatric Hospital and Post Graduate Teaching Institute, Noida
On Sep 2018




Dr Mohan Z Mani

"Thank you very much for having published my article in record time.I would like to compliment you and your entire staff for your promptness, courtesy, and willingness to be customer friendly, which is quite unusual.I was given your reference by a colleague in pathology,and was able to directly phone your editorial office for clarifications.I would particularly like to thank the publication managers and the Assistant Editor who were following up my article. I would also like to thank you for adjusting the money I paid initially into payment for my modified article,and refunding the balance.
I wish all success to your journal and look forward to sending you any suitable similar article in future"



Dr Mohan Z Mani,
Professor & Head,
Department of Dematolgy,
Believers Church Medical College,
Thiruvalla, Kerala
On Sep 2018




Prof. Somashekhar Nimbalkar

"Over the last few years, we have published our research regularly in Journal of Clinical and Diagnostic Research. Having published in more than 20 high impact journals over the last five years including several high impact ones and reviewing articles for even more journals across my fields of interest, we value our published work in JCDR for their high standards in publishing scientific articles. The ease of submission, the rapid reviews in under a month, the high quality of their reviewers and keen attention to the final process of proofs and publication, ensure that there are no mistakes in the final article. We have been asked clarifications on several occasions and have been happy to provide them and it exemplifies the commitment to quality of the team at JCDR."



Prof. Somashekhar Nimbalkar
Head, Department of Pediatrics, Pramukhswami Medical College, Karamsad
Chairman, Research Group, Charutar Arogya Mandal, Karamsad
National Joint Coordinator - Advanced IAP NNF NRP Program
Ex-Member, Governing Body, National Neonatology Forum, New Delhi
Ex-President - National Neonatology Forum Gujarat State Chapter
Department of Pediatrics, Pramukhswami Medical College, Karamsad, Anand, Gujarat.
On Sep 2018




Dr. Kalyani R

"Journal of Clinical and Diagnostic Research is at present a well-known Indian originated scientific journal which started with a humble beginning. I have been associated with this journal since many years. I appreciate the Editor, Dr. Hemant Jain, for his constant effort in bringing up this journal to the present status right from the scratch. The journal is multidisciplinary. It encourages in publishing the scientific articles from postgraduates and also the beginners who start their career. At the same time the journal also caters for the high quality articles from specialty and super-specialty researchers. Hence it provides a platform for the scientist and researchers to publish. The other aspect of it is, the readers get the information regarding the most recent developments in science which can be used for teaching, research, treating patients and to some extent take preventive measures against certain diseases. The journal is contributing immensely to the society at national and international level."



Dr Kalyani R
Professor and Head
Department of Pathology
Sri Devaraj Urs Medical College
Sri Devaraj Urs Academy of Higher Education and Research , Kolar, Karnataka
On Sep 2018




Dr. Saumya Navit

"As a peer-reviewed journal, the Journal of Clinical and Diagnostic Research provides an opportunity to researchers, scientists and budding professionals to explore the developments in the field of medicine and dentistry and their varied specialities, thus extending our view on biological diversities of living species in relation to medicine.
Knowledge is treasure of a wise man. The free access of this journal provides an immense scope of learning for the both the old and the young in field of medicine and dentistry as well. The multidisciplinary nature of the journal makes it a better platform to absorb all that is being researched and developed. The publication process is systematic and professional. Online submission, publication and peer reviewing makes it a user-friendly journal.
As an experienced dentist and an academician, I proudly recommend this journal to the dental fraternity as a good quality open access platform for rapid communication of their cutting-edge research progress and discovery.
I wish JCDR a great success and I hope that journal will soar higher with the passing time."



Dr Saumya Navit
Professor and Head
Department of Pediatric Dentistry
Saraswati Dental College
Lucknow
On Sep 2018




Dr. Arunava Biswas

"My sincere attachment with JCDR as an author as well as reviewer is a learning experience . Their systematic approach in publication of article in various categories is really praiseworthy.
Their prompt and timely response to review's query and the manner in which they have set the reviewing process helps in extracting the best possible scientific writings for publication.
It's a honour and pride to be a part of the JCDR team. My very best wishes to JCDR and hope it will sparkle up above the sky as a high indexed journal in near future."



Dr. Arunava Biswas
MD, DM (Clinical Pharmacology)
Assistant Professor
Department of Pharmacology
Calcutta National Medical College & Hospital , Kolkata




Dr. C.S. Ramesh Babu
" Journal of Clinical and Diagnostic Research (JCDR) is a multi-specialty medical and dental journal publishing high quality research articles in almost all branches of medicine. The quality of printing of figures and tables is excellent and comparable to any International journal. An added advantage is nominal publication charges and monthly issue of the journal and more chances of an article being accepted for publication. Moreover being a multi-specialty journal an article concerning a particular specialty has a wider reach of readers of other related specialties also. As an author and reviewer for several years I find this Journal most suitable and highly recommend this Journal."
Best regards,
C.S. Ramesh Babu,
Associate Professor of Anatomy,
Muzaffarnagar Medical College,
Muzaffarnagar.
On Aug 2018




Dr. Arundhathi. S
"Journal of Clinical and Diagnostic Research (JCDR) is a reputed peer reviewed journal and is constantly involved in publishing high quality research articles related to medicine. Its been a great pleasure to be associated with this esteemed journal as a reviewer and as an author for a couple of years. The editorial board consists of many dedicated and reputed experts as its members and they are doing an appreciable work in guiding budding researchers. JCDR is doing a commendable job in scientific research by promoting excellent quality research & review articles and case reports & series. The reviewers provide appropriate suggestions that improve the quality of articles. I strongly recommend my fraternity to encourage JCDR by contributing their valuable research work in this widely accepted, user friendly journal. I hope my collaboration with JCDR will continue for a long time".



Dr. Arundhathi. S
MBBS, MD (Pathology),
Sanjay Gandhi institute of trauma and orthopedics,
Bengaluru.
On Aug 2018




Dr. Mamta Gupta,
"It gives me great pleasure to be associated with JCDR, since last 2-3 years. Since then I have authored, co-authored and reviewed about 25 articles in JCDR. I thank JCDR for giving me an opportunity to improve my own skills as an author and a reviewer.
It 's a multispecialty journal, publishing high quality articles. It gives a platform to the authors to publish their research work which can be available for everyone across the globe to read. The best thing about JCDR is that the full articles of all medical specialties are available as pdf/html for reading free of cost or without institutional subscription, which is not there for other journals. For those who have problem in writing manuscript or do statistical work, JCDR comes for their rescue.
The journal has a monthly publication and the articles are published quite fast. In time compared to other journals. The on-line first publication is also a great advantage and facility to review one's own articles before going to print. The response to any query and permission if required, is quite fast; this is quite commendable. I have a very good experience about seeking quick permission for quoting a photograph (Fig.) from a JCDR article for my chapter authored in an E book. I never thought it would be so easy. No hassles.
Reviewing articles is no less a pain staking process and requires in depth perception, knowledge about the topic for review. It requires time and concentration, yet I enjoy doing it. The JCDR website especially for the reviewers is quite user friendly. My suggestions for improving the journal is, more strict review process, so that only high quality articles are published. I find a a good number of articles in Obst. Gynae, hence, a new journal for this specialty titled JCDR-OG can be started. May be a bimonthly or quarterly publication to begin with. Only selected articles should find a place in it.
An yearly reward for the best article authored can also incentivize the authors. Though the process of finding the best article will be not be very easy. I do not know how reviewing process can be improved. If an article is being reviewed by two reviewers, then opinion of one can be communicated to the other or the final opinion of the editor can be communicated to the reviewer if requested for. This will help ones reviewing skills.
My best wishes to Dr. Hemant Jain and all the editorial staff of JCDR for their untiring efforts to bring out this journal. I strongly recommend medical fraternity to publish their valuable research work in this esteemed journal, JCDR".



Dr. Mamta Gupta
Consultant
(Ex HOD Obs &Gynae, Hindu Rao Hospital and associated NDMC Medical College, Delhi)
Aug 2018




Dr. Rajendra Kumar Ghritlaharey

"I wish to thank Dr. Hemant Jain, Editor-in-Chief Journal of Clinical and Diagnostic Research (JCDR), for asking me to write up few words.
Writing is the representation of language in a textual medium i e; into the words and sentences on paper. Quality medical manuscript writing in particular, demands not only a high-quality research, but also requires accurate and concise communication of findings and conclusions, with adherence to particular journal guidelines. In medical field whether working in teaching, private, or in corporate institution, everyone wants to excel in his / her own field and get recognised by making manuscripts publication.


Authors are the souls of any journal, and deserve much respect. To publish a journal manuscripts are needed from authors. Authors have a great responsibility for producing facts of their work in terms of number and results truthfully and an individual honesty is expected from authors in this regards. Both ways its true "No authors-No manuscripts-No journals" and "No journalsNo manuscriptsNo authors". Reviewing a manuscript is also a very responsible and important task of any peer-reviewed journal and to be taken seriously. It needs knowledge on the subject, sincerity, honesty and determination. Although the process of reviewing a manuscript is a time consuming task butit is expected to give one's best remarks within the time frame of the journal.
Salient features of the JCDR: It is a biomedical, multidisciplinary (including all medical and dental specialities), e-journal, with wide scope and extensive author support. At the same time, a free text of manuscript is available in HTML and PDF format. There is fast growing authorship and readership with JCDR as this can be judged by the number of articles published in it i e; in Feb 2007 of its first issue, it contained 5 articles only, and now in its recent volume published in April 2011, it contained 67 manuscripts. This e-journal is fulfilling the commitments and objectives sincerely, (as stated by Editor-in-chief in his preface to first edition) i e; to encourage physicians through the internet, especially from the developing countries who witness a spectrum of disease and acquire a wealth of knowledge to publish their experiences to benefit the medical community in patients care. I also feel that many of us have work of substance, newer ideas, adequate clinical materials but poor in medical writing and hesitation to submit the work and need help. JCDR provides authors help in this regards.
Timely publication of journal: Publication of manuscripts and bringing out the issue in time is one of the positive aspects of JCDR and is possible with strong support team in terms of peer reviewers, proof reading, language check, computer operators, etc. This is one of the great reasons for authors to submit their work with JCDR. Another best part of JCDR is "Online first Publications" facilities available for the authors. This facility not only provides the prompt publications of the manuscripts but at the same time also early availability of the manuscripts for the readers.
Indexation and online availability: Indexation transforms the journal in some sense from its local ownership to the worldwide professional community and to the public.JCDR is indexed with Embase & EMbiology, Google Scholar, Index Copernicus, Chemical Abstracts Service, Journal seek Database, Indian Science Abstracts, to name few of them. Manuscriptspublished in JCDR are available on major search engines ie; google, yahoo, msn.
In the era of fast growing newer technologies, and in computer and internet friendly environment the manuscripts preparation, submission, review, revision, etc and all can be done and checked with a click from all corer of the world, at any time. Of course there is always a scope for improvement in every field and none is perfect. To progress, one needs to identify the areas of one's weakness and to strengthen them.
It is well said that "happy beginning is half done" and it fits perfectly with JCDR. It has grown considerably and I feel it has already grown up from its infancy to adolescence, achieving the status of standard online e-journal form Indian continent since its inception in Feb 2007. This had been made possible due to the efforts and the hard work put in it. The way the JCDR is improving with every new volume, with good quality original manuscripts, makes it a quality journal for readers. I must thank and congratulate Dr Hemant Jain, Editor-in-Chief JCDR and his team for their sincere efforts, dedication, and determination for making JCDR a fast growing journal.
Every one of us: authors, reviewers, editors, and publisher are responsible for enhancing the stature of the journal. I wish for a great success for JCDR."



Thanking you
With sincere regards
Dr. Rajendra Kumar Ghritlaharey, M.S., M. Ch., FAIS
Associate Professor,
Department of Paediatric Surgery, Gandhi Medical College & Associated
Kamla Nehru & Hamidia Hospitals Bhopal, Madhya Pradesh 462 001 (India)
E-mail: drrajendrak1@rediffmail.com
On May 11,2011




Dr. Shankar P.R.

"On looking back through my Gmail archives after being requested by the journal to write a short editorial about my experiences of publishing with the Journal of Clinical and Diagnostic Research (JCDR), I came across an e-mail from Dr. Hemant Jain, Editor, in March 2007, which introduced the new electronic journal. The main features of the journal which were outlined in the e-mail were extensive author support, cash rewards, the peer review process, and other salient features of the journal.
Over a span of over four years, we (I and my colleagues) have published around 25 articles in the journal. In this editorial, I plan to briefly discuss my experiences of publishing with JCDR and the strengths of the journal and to finally address the areas for improvement.
My experiences of publishing with JCDR: Overall, my experiences of publishing withJCDR have been positive. The best point about the journal is that it responds to queries from the author. This may seem to be simple and not too much to ask for, but unfortunately, many journals in the subcontinent and from many developing countries do not respond or they respond with a long delay to the queries from the authors 1. The reasons could be many, including lack of optimal secretarial and other support. Another problem with many journals is the slowness of the review process. Editorial processing and peer review can take anywhere between a year to two years with some journals. Also, some journals do not keep the contributors informed about the progress of the review process. Due to the long review process, the articles can lose their relevance and topicality. A major benefit with JCDR is the timeliness and promptness of its response. In Dr Jain's e-mail which was sent to me in 2007, before the introduction of the Pre-publishing system, he had stated that he had received my submission and that he would get back to me within seven days and he did!
Most of the manuscripts are published within 3 to 4 months of their submission if they are found to be suitable after the review process. JCDR is published bimonthly and the accepted articles were usually published in the next issue. Recently, due to the increased volume of the submissions, the review process has become slower and it ?? Section can take from 4 to 6 months for the articles to be reviewed. The journal has an extensive author support system and it has recently introduced a paid expedited review process. The journal also mentions the average time for processing the manuscript under different submission systems - regular submission and expedited review.
Strengths of the journal: The journal has an online first facility in which the accepted manuscripts may be published on the website before being included in a regular issue of the journal. This cuts down the time between their acceptance and the publication. The journal is indexed in many databases, though not in PubMed. The editorial board should now take steps to index the journal in PubMed. The journal has a system of notifying readers through e-mail when a new issue is released. Also, the articles are available in both the HTML and the PDF formats. I especially like the new and colorful page format of the journal. Also, the access statistics of the articles are available. The prepublication and the manuscript tracking system are also helpful for the authors.
Areas for improvement: In certain cases, I felt that the peer review process of the manuscripts was not up to international standards and that it should be strengthened. Also, the number of manuscripts in an issue is high and it may be difficult for readers to go through all of them. The journal can consider tightening of the peer review process and increasing the quality standards for the acceptance of the manuscripts. I faced occasional problems with the online manuscript submission (Pre-publishing) system, which have to be addressed.
Overall, the publishing process with JCDR has been smooth, quick and relatively hassle free and I can recommend other authors to consider the journal as an outlet for their work."



Dr. P. Ravi Shankar
KIST Medical College, P.O. Box 14142, Kathmandu, Nepal.
E-mail: ravi.dr.shankar@gmail.com
On April 2011

Important Notice

Reviews
Year : 2010 | Month : February | Volume : 4 | Issue : 1 | Page : 2089 - 2097

Biochemical Markers of Bone Remodeling in Osteoporosis - Current Concepts

INDUMATI V*, PATIL V S **

*M.D Biochemistry, Associate professor, Dept of Biochemistry, Vijayanagara Institute of Medical sciences, Bellary, Karnataka. **M.D Biochemistry, Assistant professor, Dept of Biochemistry, SDM College of Medical Sciences and **Hospital, Dharwad-580009, Karnataka.

Correspondence Address :
Dr. Indumati.V,Associate professor, Dept of Biochemistry,Vijayanagara Institute of Medical Sciences ,Civil Hospital, Bellary.Karnataka.e-mail: bioindu@yahoo.co.in,Phone: 9480755564

Abstract

Biochemical markers of bone remodeling have been developed over the past 20 years, which are more specific for bone tissue than the conventional ones. They have been widely used in clinical research and in the clinical trials of new therapies as secondary endpoints of treatment efficacy. Most of the interest has been devoted to their use in postmenopausal osteoporosis, a condition which is characterized by the subtle modification of bone metabolism that cannot readily be detected by conventional markers of bone turnover. Biochemical markers that reflect remodeling and can be measured in blood or urine include resorption markers (eg: pyridinoline, deoxypyridinoline, collagen cross links) and formation markers (eg: alkaline phosphatase, osteocalcin).
The new bone remodeling markers have been found to be more sensitive in
1) Monitoring bone loss
2) To see the antiresorptive treatment efficacy
3) To predict fracture risk.

Keywords

Biochemical markers of bone remodeling, N-telopeptide, Osteoporosis, Osteocalcin, Pyridinoline.

Introduction
Bones are in a dynamic metabolic state throughout life. They are continuously resorbed and formed in a finely regulated process known as remodeling. Through childhood and early adulthood, their formation exceeds resorption so that bone density increases and then plateaus until the age of 30-40 years. After that, resorption exceeds formation and bone density decreases through the rest of life, which in turn may lead to osteoporosis (1). Osteoporosis is a condition which is characterized by enhanced bone fragility, leading to pain, increase in fracture risk and skeletal deformity as the skeleton is unable to sustain ordinary stress. It has been estimated that about 30% of elderly women and 20% of elderly men have osteoporosis. This silently progressing metabolic bone disease is widely prevalent in India and osteoporotic fractures are a common cause of morbidity and mortality in adult Indian men and women (2). In India, about 60 million adults have osteoporosis and approximately 2-3 million cases are being added annually (3). Hip fractures occur at a relatively earlier age in Indians as compared to western people. It is possible that a dietary deficiency of calcium, beginning early in life, leads to a low peak bone mass and consequently leads to osteoporosis at an earlier age. Malabsorption of calcium due to the deficiency of vitamin D also contributes towards osteoporosis (2).

The process of bone remodeling from resorption to matrix synthesis to mineralization normally takes about 8 months--a slow but constant process. Bones in older persons just aren’t as efficient as bones in younger persons at maintaining themselves, since there is decreased activity of osteoblasts and the decreased production of growth factors and bone matrix. (Table/Fig 1) illustrates changes in bone density with aging in women.

The normal curve (A) steepens following menopause, but even by old age, the risk for fracture is still low. A woman who begins with diminished bone density (B) even before menopause is at great risk, particularly with a more accelerated rate of bone loss. Interventions such as postmenopausal oestrogen (with progesterone) therapy, the use of drugs such as the non hormonal compound Alendronate that diminishes osteoclast activity and the use of diet and exercise regimens can help to slow bone loss (C), but will not stop bone loss completely or restore prior bone density (4).

Osteoporosis can be classified as primary or secondary. Primary osteoporosis is simply the form which is seen in older persons and women who are past menopause, in which bone loss is accelerated over that predicted for age and sex. Secondary osteoporosis results from a variety of identifiable conditions that may include metabolic bone disease such as hyperparathyroidism, neoplasia as with multiple myeloma or metastatic carcinoma, malnutrition, drug therapy as with corticosteroids, prolonged immobilization and weightlessness with space travel.

Aetiology: The risk factors for osteoporosis include: Female sex, age > 70 years, Caucasian or Asian race, early onset of menopause, longer postmenopausal interval, inactivity, especially lack of weight bearing exercise. Modifiable risk factors that may potentiate osteoporosis include: Smoking, alcohol abuse, excessive caffeine consumption, lack of dietary calcium and lack of sunlight exposure (to generate endogenous vitamin D) (4).

Diagnosis: The diagnosis of osteoporosis is made by three methods:
1. Bone mineral density measurement by Dual energy X-ray absorptiometry (DXA)
2. Laboratory biochemical markers
3. Bone biopsy with pathological assessment

Of these three, the best method is radiographical bone mineral density measurement (BMD). A variety of techniques are available including single-photon absorptiometry, dual-photon absorptiometry, quantitative computed tomography, dual energy x-ray absorptiometry and ultrasonography. Most often, site specific measurements are performed. The most common sites which are analyzed are those with the greatest risk for fracture: hip, wrist and vertebrae (4).

Clinical Value Of Biochemical Markers
Metabolites of bone remodeling in serum and urine can serve as markers for monitoring bone loss, bone reformation and the effectiveness of therapy in patients with osteoporosis. More than 50 yrs ago, Fuller Albright, the father of metabolic bone diseases, noted that postmenopausal women were losing excessive amounts of calcium in their urine. He correctly deduced that the resulting negative calcium balance led to osteoporotic fractures. He is credited with introducing the use of biochemical markers into the clinical arena5. Bone turnover markers now appear promising for defining the skeletal status of postmenopausal women. Bone diseases like osteoporosis have a high prevalence in adults; so the clinical challenge is to identify individual patients with high turnover and to monitor interventions to slow bone loss and prevent complications. This will eventually help in improving the quality of life.

Three current indications for using bone markers in clinical practice are:
1) To monitor bone loss in the premenopausal or postmenopausal period
2) To monitor skeletal response to treatment.
3) To predict fracture risk (5).

Classification And Nomenclature Of Bone Turnover Markers

Bone turnover markers are broadly classified as markers of bone formation and markers of bone resorption. (Table/Fig 2) Classification of bone turnover markers (6).

Bone – specific proteins (eg, osteocalcin, bone specific alkaline phosphatase, procollagen – I extension peptide) are synthesized by mature osteoblasts and find their way from the skeleton into the circulation. These peptides can be measured by sensitive radioimmunoassay or by enzyme linked immunosorbent assays. Similarly, osteoclasts induce bone degradation, releasing skeletal specific matrix products into the interstitium. These products enter the circulation and often clear the kidney without being metabolised. These fragments include collagen cross-links, which are small amino acids that bridge collagen fibrils and add support to the tertiary collagen structure. Cross-links are added during the final stages of collagen synthesis and are the first segments to be hydrolysed by proteases during bone resorption.

Depending on the exact site of cleavage, the cross-links found in urine include free pyridinoline and deoxypyridinoline, N-telopeptides and C-telopeptides. Cross-links can also be found in low concentration in the serum, and several assays have recently been developed to measure serum N-telopeptides and C-telopeptides (5).

Measuring Bone Formation
1) Alkaline phosphatase (ALP) is a ubiquitous enzyme that plays an important role in osteoid formation and mineralization. Bone specific ALP can distinguish the osteoporotic ones from normal postmenopausal women. This is measured by heat denaturation, electrophoresis, lectin precipitation, selective inhibition and more recently, immunoassays (6).

2) Osteocalcin (bone Gla-protein/OC) is a small (49 amino acids) hydroxyapatite-binding protein synthesized by osteoblasts, odontoblasts and to a lesser extent by hypertrophic chondrocytes. It is a vitamin K dependent protein. It contains three gamma-carboxyglutamic acid (Gla) residues which are responsible for the calcium binding properties of the protein. OC is involved in bone remodeling via a negative feedback mechanism. It is predominantly synthesized by the osteoblasts and is incorporated into the extracellular matrix of bone. Serum OC is considered to be a specific marker of osteoblast function, as its levels correlate with bone formation rates. However, this peptide is rapidly degraded in serum and both intact peptides and OC fragments of various sizes coexist in the circulation. Assays that measure both the intact molecule and the large N-mid fragment of OC (1-43) appear to be more stable and reproducible (6). Measurement of decarboxylated osteocalcin levels have been shown to be a good predictor of hip fracture in elderly women (7). Serial measurements of OC have been shown to be an excellent marker to assess the long term effects of antiresorptive therapy (1).

3) Procollagen I Extension Peptides (PICP) (PINP): Collagen is synthesized as procollagen containing peptide extensions in both C and N terminal ends. These are cleared from the rest of the molecule before its incorporation into the collagen fibrils. Byproducts of type 1 collagen synthesis are the amino- and carboxy-terminal procollagen 1 extension peptides (PINP and PICP). PINP is an elongated protein of 35 kDa. PICP is a globular protein of 1000 kDa and contains disulfide bonds (8). Procollagen peptides are produced in equimolar ratios to collagen and are then released into the circulation (1). Both propeptides may be measured by specific polyclonal based immunoassays (6). A cut off level of >45.0µg/L for PINP, as measured by Orion diagnostica RIA assay had a diagnostic sensitivity of 83% and a specificity of 64% for identifying women with decreased BMD, with an overall diagnostic efficiency of 73% (9).

Measuring Bone Resorption
Most biochemical markers of bone resorption are degradation products of bone collagen, but noncollagenous proteins such as bone sialoprotein or tartarate-resistant acid phosphatase are being investigated.

1) Hydroxyproline: Hydroxyproline is mainly found in collagens, comprising about 13% of the amino acid content of these proteins. About 90% of the hydroxyproline released by the breakdown of collagen in the tissues, especially during bone resorption, is degraded to the free amino acid form that readily passes through the glomerulus. It is eventually completely oxidized and catabolised in the liver to form urea and carbon dioxide. The remaining 10% is released as small poly peptide chains that are excreted in urine without any further metabolism. Since half of the human collagen resides in bone, excretion of hydroxyproline in urine is regarded as a marker of bone resorption (10),(11).

Urinary hydroxyproline(OHPr) is thus considered as an index of bone resorption and a major determinant of bone status. Monitoring bone status through the urinary excretion of OHPr could serve as a surveillance measure in the early intervention against excessive bone loss. There is therefore, the need to establish normal acceptable ranges for the urinary excretion of OHPr in various communities beyond which individuals will be at a risk of excessive bone loss and may consequently be predisposed to fractures (12).

Hydroxylysine glycosides are integral parts of bone collagen and occur in two forms:- Glycosyl –galactosyl-hydroxylysine (Glc-Gal-Hyl) and galactosyl-hydroxylysine (Gal-hyl). Both components are released into the circulation during collagen degradation and may be measured in urine by HPLC6. Gal-hyl appears to be specific for bone collagen degradation. It is a more sensitive marker than hydroxyproline, since it is not metabolised further, not reutilised by the body nor is affected by diet13. It’s major disadvantage is the lack of immunoassay format (6).

2) Pyridinoline And Deoxypyridinoline: The hydroxypyridinium cross links of collagen, pyridinoline (PYD) and deoxypyridinoline(DPD) are formed during the extracellular maturation of fibrillar collagens and are released upon the degradation of mature collagens (6). Post translational modification of lysine and hydroxylysine produces the nonreducible pyridinium cross-links. Both PYD and DPD are released from bones in a ratio of approximately 3:1. DPD is relatively specific for bone. PYD is also found in articular cartilage and in soft tissues. Approximately 60% of the cross links released during resorption are bound to protein, with the remaining 40% being free. PYD and DPD can be measured in urine by HPLC or chemiluminescence immunoassay (8),(14). Total, free or protein bound PYD and DPD can be measured as bone resorption markers. Urinary PYD and DPD levels increase to 50%-100% with menopause and return to premenopausal levels with hormone replacement therapy (HRT)(13).

3) Cross-Linked Telopeptides: In the process of bone resorption, the amino- and carboxy-terminal fragments of collagen are released, with cross-links attached. These fragments with attached cross-links are called telopeptides. N-telopeptides (NTX) and C-telopeptides (CTX/crosslaps) are excreted in urine (8). Since more than 90% of the organic matrix of bone consists of type I collagen, measuring its degradation products in urine makes crosslaps a potential specific marker of bone resorption (1). Several studies have shown that NTXs and CTXs are reportedly specific and sensitive for the resorption of bone tissues, because nonskeletal type I collagen- containing tissues are not actively degraded by osteoclasts and therefore, different fragments are formed in the degradation of other tissues which are comprised of type I collagen (10),(15). The overall diagnostic efficiency of a single NTX measurement for identifying women with low BMD was 89% (9).

A pronounced and significant increase (47-142%) in crosslaps at menopause indicates that it is a very sensitive marker of metabolic bone changes taking place at menopause. Crosslaps has a specificity of 80% and a sensitivity of more than 70%. It can thus be used as a potentially useful screening parameter in the risk assessment of postmenopausal osteoporosis and Paget’s disease. Crosslaps values decreases substantially in response to replacement therapies, thus suggesting its usefulness in monitoring treatment efficacy (1). CTX and NTX can be measured by specific immunoassays (15),(16).

4) Bone Sialoprotein (BSP): It accounts for 5-10% of the non-collagenous matrix of bone. The protein has been shown to be a major synthetic product of active osteoblasts and odontoblasts. BSP may play an important role in cell-matrix adhesion processes and in the supramolecular organization of the extracellular matrix of mineralized tissues. It is measured by immunoassay (6).

5) Tartrate-Resistant Acid Phosphatase: (TRACP) exists in two sub-iso forms named 5a and 5b, of which only TRACP-5b has been shown to be characteristic for osteoclasts (6).

6) Vitamin D: It plays a critical role in the maintenance of strong bones and teeth and in promoting calcium uptake fromm diet. Vitamin D deficiency is an unrecognized epidemic in the middle aged and the old population. The risk factors that put people at vitamin D related health problems are - post menopause, improper diet, lack of sun exposure, high cholesterol, advancing age, high blood pressure, smoking, diabetes and corticosteroid drug use.

Vitamin D insufficiency is associated with secondary hyperparathyroidism, which is further amplified by inadequate calcium intake. Serum 25 hydroxy vitamin D [25(OH)D] is the most reliable indicator of vitamin D levels of an individual. When there are low 25(OH)D levels, the effective calcium absorption from the gut is reduced. This leads to increased mobilisation of minerals and matrix from bone and hence, increased risk of fracture, especially in postmenopausal women and elderly patients (15) . Given the many variables that can affect serum 25(OH)D levels and the positive outcome effects of treatment, it is reasonable to conclude that physicians should evaluate 25(OH)D levels for patients at risk for osteoporosis and hypovitaminosis (1).

Several prospective studies have noted that turnover markers in the elderly increase during the winter months. This increase which isattributed to a decline in serum levels of 25(OH)D caused by reduced exposure to sunlight, leads to secondary hyperparathyroidism, which then causes an increase in bone turnover (5).

One of the studies suggests that bone resorption markers are more efficient than bone formation markers in the diagnosis of postmenopausal osteoporosis. Urinary DPD/creatinine ratio has the highest diagnostic value (18).

Monitoring Bone Loss
In general, women lose about 1% of their spinal bone density per year during and after menopause. However, nearly 35% of women lose bone at a faster rate during the late perimenopausal period. Biochemical markers can detect women who are considered “rapid losers” (i.e., those who lose 3% to 5% of bone per year) (5) .

Biochemical markers provide a more representative index of the overall skeletal bone loss than would be obtained by measuring the rates of changes in bone mineral density (BMD) at specific skeletal sites containing different ratios of cancellous to cortical component with different metabolic rates (6). Measurements of specific biochemical markers of bone turnover (urinary N-telopeptide crosslinks, free pyridinoline, total deoxypyridinoline, hydroxyproline, serum osteocalcin, bone-specific ALP) are correlated with longitudinal bone loss in elderly women (>65 yrs). These markers may help identify women who are at a greatest risk for bone loss, who would benefit most from therapeutic Interventions (19). The results of several studies of bone loss at the forearm, support the view that 80% of patients having increased biochemical markers in the early postmenopausal years are confirmed 2-12 years later as ‘fast bone losers’, based on BMD measurements (6). For the screening of bone turnover in women at menopause and for the assessment of the levels of bone turnover in elderly women with vertebral osteoporosis, serum osteocalcin and urinary PYD and DPD appear to be the markers which are used so far (20),(21).

Monitoring The Effects Of Therapy:
Follow-up bone mineral density measurements (BMD) using T score (T Score < -2.5 indicates osteoporosis) by Dual-energy X-ray absorptiometry is the “gold standard” for assessing the effects of treatment on bone mass. Treatment related changes in BMD occur very slowly. This fact, coupled with the precision of BMD technologies, suggests that BMD cannot be reliable until at least two years. In contrast, changes in bone turnover markers can be anticipated after 3 months of therapy. Therefore, bone turnover markers may be assessed at diagnosis to provide a baseline, followed by repeat assay at 3 months to determine the response to therapy(5),(6).

Since the current therapy for osteoporosis centers on inhibiting bone turnover with agents such as calcium, calcitonin, oestrogens or bisphosphonates, the measurement of baseline and follow-up biochemical markers of turnover could be particularly useful.

Review of studies in healthy, early postmenopausal women showed that the percent change in N-telopeptides from the baseline to 6 months, was the strongest predictor of subsequent spinal bone mineral density. Similarly, bone turnover marker declined by 50% to 100% in postmenopausal women who were treated with HRT for at least 6months.On treatment with bisphosphonate, urinary markers of resportion declined by at least 50% within 3 months of therapy (5). Women on active treatment with alendronate / HRT/ combination therapy, with the greatest decrease in turnover markers (NTX, Bone ALP,OC) at 6 months, had the greatest increase in spine and hip bone density at 3 years (21). Urinary NTX and serum OC provide the greatest sensitivity and specificity for change in bone density, with either calcium supplementation or hormone replacement therapy (23). Greater short term changes in turnover with parathyroid hormone therapy (especially bone formation-PINP) are associated with greater 1-year increases in spine and hip BMD among postmenopausal osteoporotic women (24). Bjarnason and Christiansen measured U-CTX and BMD levels after 3 years following HRT. The maximum decrease in CTX levels occurred at 6 months, which was significantly correlated to a 3 year bone mass response (25). Treatment with nasal calcitonin also decreased markers. Even bone formation markers decreased after 3 months of treatment with bisphosphonates (alendronate sodium Fosamax) (6).

Hence, short term changes in biochemical markers of bone turnover have been suggested as predictors of long term response in bone mass during antiresorptive therapy. The bone markers predicted a change in spine BMD to be greater than 0%, with a high positive predictive value and specificity (26).

(Table/Fig 3) Sensitivity, Specificity, Positive predictive value (PPV) and Negative predictive values (NPV) of bone turnover markers in monitoring the effects of therapy.

Predicting Fracture Risk
Bone resorption markers and fracture risk are consistent. Riis et al reported that within 3 years of menopause, women classified as ‘fast bone losers’ had a 2 fold higher risk of sustaining vertebral and peripheral fracture during a 15 year follow up than women who were classified as ‘normal’or ‘slow’losers (6).

Women with both a low BMD and a fast rate of bone loss after menopause had a higher risk of subsequently sustaining fracture, than women with only one of the two risk factors. Concordant results have been obtained in four prospective studies (EPIDOS, Rotterdam, OFELY and the Hawaii Osteoporosis Study), thus indicating that increased levels of bone resorption markers are associated with increased risk of hip, vertebral and non-hip and non-vertebral fracture over follow up periods ranging from 1.8 – 5years. Increased levels of bone resorption markers and ucOC have been shown to predict the risk of fracture independently of the level of BMD (6).

The practical outcome of such a strategy is that the number of women who need to be treated to avoid one hip fracture is significantly reduced, which could result in a more cost-effective approach of treatment strategy. In the OFELY study, those women with both low hip BMD and high S-CTX had a probability of fracture over 5 years of 55% i.e., higher than the probability of fracture associated with low BMD alone (39%) or with high CTX alone (25%) (27).Combination of bone mineral density (BMD) and bone turnover markers to predict the risk of fractures in postmenopousal women: the OFELY Study (27) [Table/Fig 4].

Limitations of Biochemical Markers: Biochemical markers of bone turnover can differ in response to specific osteoporosis therapies and may even vary in the same patient. For example, bisphosphonates increase the urinary excretion of peptide-bound collagen products without significantly changing free cross-link excretion. On the other hand, oestrogen suppresses both free and peptide bound cross links to the same degree. The inherent problem of the biological variation for markers like non uniform rates of bone turnover, time of the day and season, remains a major concern. In general, serum markers of bone formation vary by less than 10% within a given patient. However, measurements of urinary markers can differ by as much as 30% in one person, even on the same day. Changes due to seasonal effects, like greater bone resorption during winter than summer months, must be considered. However, most patients have a 50% or greater decline in bone resorption markers during treatment with calcitonin, oestrogen, or the bisphosphonates (5).

Recent Developments
Since 1994, much interest is shown in identifying the genes which are involved in the regulation of bone mass- Vitamin D receptor (VDR) gene, parathyroid hormone and its receptor, oestrogen receptor gene and collagen type I receptor gene (1).

Conclusions
These current biochemical markers allow clinicians to evaluate the risk of bone loss and to provide insight into the response to therapy. As technology improves, tests for these markers will become more reliable and more widely available. Efforts to reduce costs will almost certainly enhance utilization. As the familiarity with the value of biochemical markers grows, the use of these tests will no doubt expand.

Recommendations for research (6)
1 Normal values should be established for all bone markers in large samples (150-200 women) of healthy premenopausal women who are 30-45 years old, with normal BMD at the spine and hip as measured by DXA. Potential differences in normal values across geographical areas and races should be searched. The vitamin D status [serum 25(OH)D levels] of the population should be studied and further remedial measures have to be undertaken.
2 Quality control programs of bone marker measurements should be established and widely implemented, as already done for other biological tests in clinical chemistry.
3 The association between bone markers and the probability of fractures should be explored in large clinical trials.
4 Cut off values should be established for defining responders and non-responders using the same therapeutic regimens.
5 The ability to monitor treatment with bone markers to improve compliance and treatment efficacy should be tested prospectively.

Clearly, the onus is now on the manufacturers of assays to optimize their in-house quality control and to demonstrate to the research and ultimately, the clinical community that they have reached acceptable standards with reagents and reagent sets in which the assay methods have been optimized. Clinical chemists will have to demonstrate that their application of these methods meets acceptable proficiency standards. While this is going on, the previously skeptical clinician will need to critically review the published research concerning what biochemical markers of bone turnover can and cannot do when measured with proper standardization, accuracy, and precision. We will all need to keep open minds as this quality improvement is progressing and will be in a position to put bone turnover markers into practice just as soon as this final crucial piece of the puzzle has been solved to everyone’s satisfaction! (28).

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