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REVIEWS ARTICLES
Biochemical Markers : Diagnostic Considerations and Clinical Applications for Osteoporosis Assessment
Vipla Puri
Bone is in a dynamic metabolic state throughout life. It is continuously resorbed and formed in a finely regulated process known as remodeling. Through childhood and early adulthood, formation exceeds resorption so that bone density increases and then plateaus until the age of 30 to 40 years. After that, resorption exceeds formation and bone density decreases through the rest of life, which in turn may lead to osteoporosis. Osteoporosis is a condition characterized to enhanced bone fragility and a consequent increase in fracture risk since skeleton is unable to sustain ordinary stresses.
Over the past 30 years there have been significant advances in our understanding about the aetiology of osteoporosis. A number of dietary, non-dietary and genetic factors contribute to the development of such a condition as osteoporosis. The dietary factors include limited lifelong calcium intake, excessive fibre intake which can interfere with calcium absorption, high sodium levels particularly in association with a low calcium intake, excessive caffeine consumption and a high protein intake without an increase in phosphorus.
The non-dietary factors are age, sex, race, body built, family history, premature menopause, nulliparity, limited exercise, use of cigarettes, alcohol consumption and prolonged use of exogenous thyroid hormones. Menstrual status is a major determinant of osteoporosis risk in women. Any interruption of menstruation for an extended period results in bone loss. There is currently much interest in genetic aspects of osteoporosis as it is believed that identification of the genes involved and knowledge of their subsequent function ultimately result in either improved diagnostic or novel treatment options for osteoporotic patients.
In assessing osteoporosis, biochemical test panel incorporating resorption marker and a formation marker can provide the non-invasive assessment of overall bone turnover. Bone resorption markers are released in circulation as byproducts of osteoclast action on bone and include cross-links for collagen type I. Bone formation markers are released during osteoblast synthesis of new bone protein matrix, which can be assessed by measuring circulating osteocalcin.
Bone diseases 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 for populations’ worldwide. Invasive techniques measuring bone turnover provides useful information but all have limitations. This has led to many challenges in the field of non-invasive biochemical markers of bone remodeling, requiring newer tests with improved sensitivity and specificity relative to the old standard serum alkaline phosphatase or urinary hydroxyproline.
Since bones are composed of several types of cells that coexist in a constant equilibrium between two conflicting processes of resorption and formation, we describe here the potential markers which would give most useful information about the bone turnover process (Table ).
Biochemical markers of bone turnover Formation Serum ResorptionUrine a. Osteocalcin (bone Gla-protein) a. Type 1 collagen N and C- telopeptide
breakdown products (Crosslaps).b. Alkaline phosphatase (Total and bone specific) b. Urinary Pyridinoline and Deoxypyridinoline c. Procollagen 1 carboxy and N-terminal extension peptides c. Fasting urinary calcium and hydroxyproline. Measuring bone formation
Serum osteocalcin
Osteocalcin is a vitamin K dependent protein. Also known as bone Gla-protein, Osteocalcin is a small non-collagenous protein that is specific for bone tissue and dentine. It is predominantly synthesized by the osteoblasts and incorporated into extracellular matrix of bone. Osteocalcin synthesis is known to be modulated by Vitamin D. Since Vitamin D deficiency remains unrecognized over a long period of time, it may be appropriate to monitor both Vitamin D and osteocalcin levels in patients at risk of developing osteoporosis. Serum osteocalcin levels correlate well with iliac crest histomorphometry and calcium kinetic data. Measurement of decarboxylated osteocalcin has been shown to be a good predictor of hip fracture in elderly women. Serial measurements of osteocalcin levels have been shown to be an excellent marker to assess long term effects of antiresorptive therapy.
Serum total and bone alkaline phsophatase
Total alkaline phsophatase comprises the serum of skeletal, intestinal and hepatic components and therefore lacks specificity for identifying abnormalities in bone remodeling. Bone specific alkaline phosphatase can distinguish between osteoporotic from normal postmenopausal women if measured by specific RIA, since other methods like electrophoresis, heat inactivation, lectin precipitation lack desired sensitivity and specificity.
Procollagen 1 Extension Peptides (PICPs)
Collagen is synthesized as procollgen containing peptide extensions in both the C and N terminal ends. These are cleaved from the rest of the molecule before its incorporation into collagen fibrils. Procollagen peptides are produced in equimolar ratios to collagen and are then released into circulation. Although the metabolic fate of these peptides are not fully known, radioimmunoassays to measure blood levels have been developed which reflect osteoblastic collagen synthesis. Since the development of RIA for PICP is new, definite statements about its predictive value in osteoporosis awaits further studies although correlation of PICP levels with histological indices of bone formation and calcium kinetics have been reported.
Measuring Bone Resorption
Crosslaps
Crosslaps is degradation products of type 1 collagen, which can be measured in urine with specific RIA and ELISAs. Since more than 90% of the organic matrix of bone consists of type 1 collagen, measuring its degradation products in urine makes crosslaps a potential specific marker of bone resorption. A pronounced and significant increase (47-142%) in Crosslaps at menopause indicate that it is a very sensitive marker of metabolic bone changes taking place at menopause. The correlation between crosslaps and the rate of loss measured by single photon absorptiometry has been shown to be much higher than with Pyridinoline and Deoxypyridinoline. Crosslaps has also been used to predict the rate of bone loss considering a bone loss of more than 3% per year. Crosslapse 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.
Pyridinoline and Deoxypyridinoline (Pyr and D-Pyr)
Pyridinoline cross links are released into the circulation during bone resorption and are excreted as both free and bound to C and N terminal ends of type 1 collagen. These are measured by different methods, the most sensitive being HPLC that limits its widespread clinical utility. More recently sensitive chemiluminescence based assays have also been made available.
Fasting urinary calcium and hydroxyproline
Fasting urinary calcium measured in a morning sample and corrected for creatinine excretion is the cheapest marker of bone resorption. It is useful to detect marked changes in bone resorption but lacks sensitivity especially in conditions characterized by subtle alteration of bone turnover such as osteoporosis. Hydroxyproline is found mainly in collagen and represents about 13% of the amino acid content of the molecule. Hydroxyproline is highly metabolized before being excreted and is poorly correlated with bone resorption as assessed by calcium kinetic and bone histomorphometry.
Other biochemical factors affecting bone turnover
Systemic hormones
(a) Gonadal hormones
(b) Parathyroid hormone (PTH)
(c) Vitamin D
Local factors
(a) Interleukin-1
(b) Interluekin-6
(c) Tumour necrosis factor (TNF-a)
Of all the factors, we now know that Vitamin D is absolutely necessary for the efficient absorption of calcium and phosphorus from our diet as well for normal metabolism. It has been established beyond doubt that calcium mal absorption is a primary contributor to the development of osteoporosis. Vitamin D deficiencies and the incidence of osteoporosis, rickets and osteomalacia are all well documented. Vitamin D plays a critical role in maintenance of strong bones and teeth and promoting calcium uptake from diet.
Why test Vitamin D levels?
Vitamin D deficiency is an unrecognized epidemic in middle aged and older population. The conditions or 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
*Corticosteroid drug use
Vitamin D deficiency is an unrecognized epidemic in our middle aged and older population
Given the many variables that can effect serum Vitamin D levels and the positive outcome effects of treatment, it is reasonable to conclude that physicians should evaluate Vitamin D levels for patients at risk for osteoporosis and hypovitaminosis. Thus the optimal combination of markers for bone resorption and bone formation may be useful to target patients at highest risk for fracture resulting in a more cost effective treatment strategy. Because of the relatively small change in bone mass in patients treated with anti-resorptive therapy, monitoring the efficacy of treatment using Dual X-ray absorptiometry in the individual patient is a challenge. Repeated bone marker measurements during treatment is likely to improve the management of osteoporotic patients, including the assessment of compliance.
Recent developments in the genetic arena of osteoporosis
Since 1994, much interest has centred on identifying the genes involved in the regulation of bone mass. Early association studies focussed on the Vitamin D Receptor (VDR) gene but recently a number of other additional candidate genes like parathyroid hormone and its receptor, oestrogen receptor gene, collagen type 1 receptor gene, have also been studied. These studies have opened a new vista for osteoporosis evaluation, which, together with BMD, biochemical markers indices and hormonal profile correlation studies, will prove to be an efficient diagnostic protocol for osteoporotic diagnosis and evaluation at a preventable stage. With the imminent completion of a “first draft” of the human genome, these are therefore exciting and challenging times for genetic research into complex disorders such as osteoporosis.
REFERENCES
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VIAGRA SWELLS DIAGNOSIS RATES FOR ERECTILE DYSFUNCTION
Diagnoses of erectile dysfunction more than doubled after Viagra (Sildenafil) was introduced in Britain. In a cross sectional study. Kaye and Jick reviewed a UK general practice research database for cases of erectile dysfunction among men 40-80 years of age, before and after Viagra was introduced in 1998. The annual incidence of erectile dysfunction gradually increased during the 1990s, then rose almost twofold during 1998 to 2000, for all age groups. The prevalence of ischaemic heart disease, a major contraindication for sildenafil, also decreased during the period after Viagra was first introduced and promoted.
BMJ, February, 2003; 326 : 424.
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