Most of the data in the literature concern the use of bone markers in postmenopausal osteoporosis, a condition with a high social impact both for its prevalence in the general population and for the importance of its most dreaded consequence: fracture.

Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and macro and microarchitectural qualitative alterations accompanied by increased bone fragility.

According to the criteria of the World Health Organization, the diagnosis of osteoporosis is based on the assessment of bone mineral density through radiographic techniques, among which the most widely used is represented by the Dual-Energy X-ray Absorptiometry (DEXA), compared to the average of healthy adults of the same sex reached the peak of bone mass, i.e., around 20 years of age. The unit of measurement is the standard deviation from the mean peak bone mass (T-score). The risk of fracture begins to increase exponentially with densitometric values of T-score  < −2.5 SD, the threshold value for diagnosing the presence of osteo porosis. However, skeletal and extra-skeletal factors must be considered in assessing individual fracture risk. Notably, osteoporotic fractures are demonstrated even in subjects with normal densitometry, and this supports the hypothesis that the deterioration of the architecture of the bone trabeculae also contributes to increasing the fragility of the skeleton. These pathogenetic mechanisms represent the rationale behind using biochemical markers to evaluate osteoporosis patients.

Prediction of Bone Loss

 There is no doubt that in many clinical situations, it is very important to identify patients with a high rate of bone loss, a condition predisposing to increased bone fragility and an increased risk of fracture. The most common condition in this sense is certainly represented by the early postmenopausal period in women. The alterations typical of the involutional age, when the entity of osteoclastic resorption prevails over the new formation determining a progressive, albeit slow, loss of bone mass, are made more evident in women starting from menopause due to the loss of inhibition of osteoclastic activity exerted by estrogen. In the estrogenic deficiency, besides the prevalence of osteoclastic resorption over osteoblastic formation at the level of the single remodeling unit, an increased activation frequency and an increase in the number of the units themselves can occur. All this can result in two very different conditions in terms of prognosis: a condition of slow losers, in which the loss of bone mass is slow, and a condition of fast losers, in which the loss of bone mass can reach 2% per year in the first 3 years of menopause. Women categorized as fast losers might be candidates for antiresorptive therapy. Numerous studies have supported the hypothesis that bone marker values measured in women at the onset of menopause may predict the extent of bone loss in subsequent years, thus helping in deciding whether or not to undertake antiresorptive therapy and the extent of recovery after therapy. However, in order to make the use of markers in daily clinical practice effective, it is necessary to take into account the restrictive criteria used for the selection of patients that characterize such studies (age of the subjects studied, the magnitude of the risk calculated a priori, number of determinations made to obtain an average value) and apply them to individual patients.

Fracture Risk Prediction

 Measurement of bone mineral density (BMD) by X-ray or ultrasound techniques demonstrates high specificity towards fracture risk assessment but relatively low sensitivity, meaning that many individuals who will fracture cannot be identified as high risk by BMD determination alone. This is because the risk of fracture is determined not only by the bone mass at the time of measurement but also by the bone loss over time. Emerging data from several prospective studies have found that biochemical markers of bone remodeling have a strong potential to predict fracture risk. The predictive value appears independent of bone mass values obtained by densitometry, age, and other clinical risk factors. In particular, an increase of the markers beyond the typical values of the pre-menopausal age, considered as reference, is associated with a doubled risk of encountering vertebral and non- vertebral fractures, particularly of the femur.

In order to identify all patients at risk of fracture and to undergo therapy, some algorithms have been developed in recent years that include, in addition to bone densitometry, the most important factors that contribute to an increase in the risk of fracture, including gender, age, previous fractures, family history, dietary habits, use of glucocorticoids. In 2008 a commission of the World Health Organization developed an algorithm known as FRAX® (http://www.shef.ac.uk/ FRAX), which integrates multiple clinical risk factors. This tool calculates the probability of a patient sustaining a hip or other bone site fracture in the next 10 years. However, FRAX® presents some application issues. For this reason, national versions have been developed, such as the DeFRA by the Scientific Society for the Study of Skeletal Diseases (SIOMMMS; https://defra- osteoporosi.it). The inclusion in these algorithms for the determination of biochemical markers would increase their clinical sensitivity.

Therapy Monitoring

Osteoporosis is diagnosed with the determination of BMD by radiographic techniques, the most widely used of which is DEXA. Most of the antiresorptive drugs used for osteoporosis therapy produce a significant increase in bone mineral density shown by DEXA. However, for evaluating the effects of antiresorptive therapy, this procedure is of limited utility since at least 1–2 years must have elapsed since the start of treatment before the efficacy of any treatment can be defined with certainty. In addition, BMD does not provide information about the speed of bone remodeling, which may be necessary for choosing the most effective treatment for the individual patient. The measurement of BMD can therefore be complemented by determining biochemical markers of bone remodeling. The most validated indication for the use of bone markers concerns the assessment of the effectiveness of antiresorptive therapy with bisphosphonates or hormone replacement. The evaluation of bone markers can evidence a significant change in the efficacy of the treatment before and after just 3–6 months from the start of treatment; therefore, many months before any improvement in bone density is observed with DEXA, for which 2 years are required. Estrogen deficiency causes a rapid increase in bone remodeling, evidenced by increased circulating biochemical markers of bone formation and resorption. Hormone replacement therapy decreases biochemical markers that are dose- dependent and reaches a plateau maintained throughout treatment. Following discontinuation of treatment, biochemical markers return to baseline values. Numerous studies have documented these changes by demonstrating an initial significant decrease in reabsorption markers (3–6 months) followed by a decrease in formation markers that reach a plateau after 6–12 months of treatment.

Assessment of Adherence to Therapy

 Oral bisphosphonates are first-line drugs for osteoporosis and, therefore, widely prescribed. Despite this, at least 1 in 2 patients who begin treatment do not show adequate compliance and even discontinue therapy altogether within 1 year of initiation.

This behavior, typical of many patients with chronic dis eases, compromises the effectiveness of therapies and, in the case of osteoporosis, cancels the beneficial effect of therapy and exposes patients to high fracture risk. For this reason, the experts of the International Osteoporosis Foundation- European Calcified Tissue Society propose not to limit themselves to prescribing drugs but to carefully monitor adherence to therapy through the measurement of markers of bone remodeling in patients who have begun treatment with oral bisphosphonates for postmenopausal osteoporosis.

These recommendations stem from the results of the TRIO trial, a randomized, controlled trial that studied the effects of three oral bisphosphonates, alendronate, ibandronate, and risedronate, on biochemical markers and bone mineral density. Specifically, the authors recommend measuring serum PINP and CTX levels at baseline and 3 months after starting treatment. This time interval is optimal because the first few weeks after starting treatment are critical for non- adherence. When the reduction of these two markers does not reach significance, a reduction of 38% for PINP and 56% for CTX, respectively, it is necessary to evaluate patient compliance or investigate the presence of a secondary cause of osteoporosis.

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مواضيع ذات صلة

Biochemical Markers of Bone Remodeling in Different Clinical Conditions Affecting Bone Tissue Metabolism

Free Radicals & Antioxidant Nutrients

Vitamin B12 is Found only in Foods of Animal Origin

Vitamin B6 is important in Amino Acid & Glycogen Metabolism & in Steroid Hormone Action

Niacin is not Strictly A Vitamin

Bone Tissue Biochemistry

Vitamin K is required for synthesis of blood-clotting proteins

Vitamin E does not have a precisely defined metabolic function

Vitamin D is really a hormone

Two groups of compounds have vitamin A activity

Protein & Amino acid requirements

Energy balance: over & undernutrition