Conversely, the high-turnover state is characterized by increased activity of osteoclasts, while the activity of osteoblasts may be normal or even increased The bone-remodeling process is therefore shifted toward bone resorption, resulting in an imbalance of bone turnover that causes osteoporosis.
High-turnover osteoporosis is the most common form and occurs in postmenopausal women so-called primary type-I osteoporosis or in patients with hyperparathyroidism regardless of their menopausal state Transient osteoporosis, most commonly seen in men, is also a high-turnover state Low-turnover osteoporosis occurs in the elderly so-called age-related osteoporosis, or primary type-II osteoporosis or following drug interventions, including chemotherapy, corticosteroids, and prolonged bisphosphonate treatment 47 , 50 , Bone turnover can be assessed by measuring biochemical bone markers, categorized as bone formation and bone resorption markers Table III , in blood and urine samples.
Assessment of bone turnover should be considered for patients with osteoporosis, with treatment proceeding accordingly to address each patient's metabolic profile. Bone markers are indicative of bone formation and resorption at one time point and can help in the assessment of medication efficacy as described below. When osteoclasts resorb bone, they degrade the extracellular matrix and release a variety of collagen breakdown products into the circulation that are further metabolized by the liver and kidneys.
The collagen degradation products achieve measurable concentrations in both serum and urine Fig. During osteoclast-mediated resorption of bone, the collagen molecule is degraded, producing an aminoterminal or N -telopeptide, a carboxyterminal or C -telopeptide, and a central region of intact triple helix. Cross-linked N-telopeptides and C-telopeptides, known as NTX and CTX, respectively, are specific for bone and achieve a measurable concentration in blood and urine. Osteoclasts produce the acid phosphatase isoenzyme tartrate-resistant acid phosphatase TRAP.
Total TRAP, however, is influenced by enzymes originating from both erythrocytes and platelets, and its measurement can be impeded by various circulating inhibitors Currently, a kinetic assay to measure specifically type-5b TRAP, a desialylated isoenzyme present only in osteoclasts and alveolar macrophages, has been described 53 , Increased type-5b TRAP levels have been described in conditions associated with increased bone resorption such as end-stage renal failure, hemodialysis bone disease, and metastatic bone disease 55 - During bone formation, osteoblasts produce type-I collagen, which is their major synthetic product.
Carboxyterminal propeptide and aminoterminal propeptide of type-I collagen—known as PICP and PINP, respectively—are cleaved from the newly formed collagen molecule and can be measured in serum as indices for type-I collagen biosynthesis. Osteoblasts also secrete a variety of noncollagenous proteins, two of which can be measured clinically as markers of osteoblast activity: bone-specific alkaline phosphatase and osteocalcin. Osteocalcin is a small protein synthesized exclusively by osteoblasts.
It is deposited in the bone matrix and can be released into the circulation. Some in vitro studies, however, have suggested that osteocalcin fragments could also be released from osteoclastic degradation of bone matrix and thus may reflect bone resorption 59 - In addition, serum osteocalcin levels vary substantially with circadian and other biological factors 62 , Therefore, serum osteocalcin is not measured as routinely as are other bone-formation markers.
The half-life of bone-specific alkaline phosphatase is one to two days, making it less sensitive to circadian variation than other markers with a shorter half-life. There are multiple factors that may cause variations in the levels of biochemical bone markers.
Therefore, it is necessary to review certain factors that affect bone marker levels before discussing the specific clinical settings in which their measurement might be useful Table IV. Bed rest, exercise, or fracture-healing can affect the level of bone markers.
A prospective study of bone marker levels in elderly women before and after trauma found that the levels were elevated during fracture repair and remained elevated for up to one year 66 , Many bone marker levels show substantial variations over a twenty-four-hour period 63 , 68 - All of the urinary and serum bone resorption markers have substantial diurnal variations in levels, which peak between a.
For the analysis of urine markers, therefore, it is best to obtain either a twenty-four-hour urine collection or a second morning void sample. In addition, various bone formation or resorption markers have different responses to different disease states and therapies, such as Paget disease, osteomalacia, or glucocorticoid use 51 , 72 , Creatinine excretion also contributes to the overall variability in the levels of urinary bone resorption markers. An alteration in muscle mass, therefore, may alter the urine marker levels.
Finally, urine marker levels are not reliable indicators in patients with chronic renal insufficiency; thus, it is preferable to analyze serum bone marker levels in such patients. Bone markers are also subject to intra-assay and interassay variability. If possible, measurements for each individual should be performed in the same laboratory 74 , Sample conservation is another concern. Serum osteocalcin and TRAP are more labile, whereas collagen peptides and bone-specific alkaline phosphatase are more resistant to degradation Pyridinoline cross-links are light-sensitive and degrade under the influence of intense ultraviolet irradiation Currently the best-established clinical use of bone marker analysis is for monitoring treatment efficacy.
After antiresorptive therapy, there is a substantial reduction in levels of bone resorption markers within four to six weeks and in levels of bone formation markers within two to three months 76 , After treatment, the nadir in bone marker levels generally occurs after two to three months and remains constant as long as the patient continues to receive therapy Therefore, failure to show the expected reduction in levels of bone resorption markers could indicate poor compliance with treatment or an improper use of antiresorptive agents.
The objective of treatment should be the return of bone marker levels to the premenopausal range. However, some patients with osteoporosis present with normal bone marker values because the diagnosis was made at a late stage of their disease. In this instance, the goal should be a decrease in bone marker levels to the least significant change. After treatment with an anabolic agent, levels of bone formation markers increase substantially within four weeks and levels of bone resorption markers increase later, approximately three months following the initial therapy 84 , Prediction of fracture risk is probably the most important potential use of bone marker measurements because turnover alters bone geometry and material properties and thus may affect the susceptibility to fracture.
Several studies have shown that bone turnover may be an independent predictor of fracture risk 86 - In a study of postmenopausal women, of whom had fractures, high levels of the bone turnover marker bone-specific alkaline phosphatase were independently associated with an increased fracture risk, with an age-adjusted hazard ratio of 2.
In the Os des Femmes de Lyon OFELY study, a comparison between baseline bone marker levels in fifty-five women who had a fracture and bone marker levels in women who did not have a fracture within five years before the time of follow-up showed that women with levels of bone resorption markers in the highest quartile had an approximately twofold increased risk of fracture compared with women with levels in the three lowest quartiles.
After adjustment for bone mineral density, bone marker levels were still predictive of fracture risk, with similar relative risks of 1. This finding indicates that bone turnover markers and bone mineral density predict fracture risk independently.
When both factors are altered, the fracture risk is compounded Although bone markers are independent predictors of fracture risk, the optimal use of bone marker measurements alone or in combination with bone mineral density in predicting absolute fracture risk has not yet been established.
Several studies indicate that individuals with the highest levels of bone turnover seem to have the best response to antiresorptive therapy 83 , The relationship between bone marker levels and the response to antiresorptive agents, however, is controversial 93 - The authors of a pharmacoeconomic study concluded that measurement of bone marker levels has the potential to identify a subset of postmenopausal women with bone marker levels within the highest quartile, but who do not have osteoporosis as defined by the World Health Organization, for whom alendronate treatment to prevent fracture is cost-effective In a study assessing the efficacy of risedronate in the treatment of postmenopausal osteoporosis in women, the reduction in the incidence of vertebral fractures was independent of the baseline measurement of the urinary deoxypyridinoline level.
However, the number needed to treat to avoid one vertebral fracture at twelve months was fifteen with high urinary deoxypyridinoline levels and twenty-five with low urinary deoxypyridinoline levels Therefore, from a pharmacoeconomic standpoint, it may be useful to stratify patients by the pretreatment bone resorption rate 93 , With regard to anabolic therapy, a recent post hoc analysis of the data from the Fracture Prevention Trial study, in which teriparatide was used to treat osteoporosis, showed a strong positive correlation between the baseline bone markers PINP, NTX, PICP, bone-specific alkaline phosphatase, and deoxypyridinoline and subsequent increases in lumbar spine bone mineral density at eighteen months Therefore, even patients with high bone turnover rates at baseline could have a robust bone mineral density response to teriparatide treatment Osteoporotic fracture is a common and debilitating problem in the elderly.
However, if physicians can identify patients at risk for fracture, prevention programs may be initiated to reduce the number of fractures sustained.
Although bone mineral density is used for the diagnosis of osteoporosis and to assess fracture risk, it has become increasingly apparent that bone mineral density reflects only one component of bone strength.
Recently, FRAX was developed to calculate age-specific fracture probabilities in men and women on the basis of clinical risk factors and the bone mineral density at the femoral neck. Measurements of biochemical bone marker levels can be used not only to monitor treatment efficacy but also to assess fracture risk and help select patients for therapy. Antiresorptive medications are most appropriate for patients with high bone turnover, while anabolic agents demonstrate efficacy in both low and high-turnover conditions.
It is anticipated that the development of new imaging tools to evaluate bone quality will improve the assessment of a patient's fracture risk and response to treatment in the future. In the meantime, bone strength should be assessed with the use of clinical risk factors as identified in FRAX and measurement of bone turnover marker levels as a supplement to the measurement of bone mineral density to enhance patient evaluation and improve osteoporosis diagnosis and treatment.
National Center for Biotechnology Information , U. J Bone Joint Surg Am. Lane , MD 1. Brian P. Joseph M. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Bone mineral density is considered to be the standard measure for the diagnosis of osteoporosis and the assessment of fracture risk.
Assessment of Bone Quantity: Bone Mineral Density In , the World Health Organization developed a definition of osteoporosis on the basis of studies of women of various ages Open in a separate window. FRAX Model Because of the limitations of dual x-ray absorptiometry, efforts have been made to formulate a system to better predict fracture risk. Clinical Guidelines The application of FRAX includes selecting an appropriate group of patients for osteoporosis treatment.
Assessment of Bone Turnover Bone turnover is the principal factor that controls both the quality and the quantity of bone in the adult skeleton. Bone Resorption Markers When osteoclasts resorb bone, they degrade the extracellular matrix and release a variety of collagen breakdown products into the circulation that are further metabolized by the liver and kidneys. Bone Formation Markers During bone formation, osteoblasts produce type-I collagen, which is their major synthetic product.
Factors Affecting Levels of Bone Formation and Bone Resorption Markers There are multiple factors that may cause variations in the levels of biochemical bone markers. Biological Factors Analytical Factors Circadian rhythm, seasonal variation, bed rest, exercise, fracture-healing, medical conditions diabetes mellitus, thyroid diseases, etc.
Technical variability, sample conservation. Potential Clinical Uses of Measurements of Bone Formation and Resorption Marker Levels Monitoring Effectiveness of Treatment Currently the best-established clinical use of bone marker analysis is for monitoring treatment efficacy.
Prediction of Fracture Risk Prediction of fracture risk is probably the most important potential use of bone marker measurements because turnover alters bone geometry and material properties and thus may affect the susceptibility to fracture. Selection of Patients for Treatment Several studies indicate that individuals with the highest levels of bone turnover seem to have the best response to antiresorptive therapy 83 , Overview Osteoporotic fracture is a common and debilitating problem in the elderly.
References 1. J Bone Miner Res. Improvement in the undertreatment of osteoporosis following hip fracture. Interventions to improve osteoporosis treatment following hip fracture. A prospective, randomized trial.
The management of osteoporosis following hip fracture: have we improved our care? Osteoporos Int. Lack of diagnosis and treatment of osteoporosis in men and women after hip fracture. Hip fracture patients are not treated for osteoporosis: a call to action. Arthritis Rheum. Failure to diagnose and treat osteoporosis in elderly patients hospitalized with hip fracture. Am J Med. In fact, well respected osteoporosis researchers determined that if the FRAX criteria, which are endorsed by the U.
You may want to try my simple but reliable Bone Health Profile to assess the health of your bones and your potential risk of fracture. Ford N. Susan Brown. I am a clinical nutritionist, medical anthropologist, writer, and speaker. Results are presented as box plots, and the line denotes the median value. Analysis Restricted to Major Fractures at Inclusion. The year risk of hip fracture or of major fracture was calculated both before and after the FF.
After patient-years of follow-up median 3 y , recurrent FFs occurred in patients Table 4 ; 12 patients had two recurrent FFs and one patient had three only one recurrent FF was considered.
Rates of recurrence were 2. In the analysis according to the FF site at inclusion, Globally, the risk for a recurrent major FF was 57 per 5. A total of FFs occurred in patients. Only the most significant of multiple recurrent FFs are reported here: hip greater than vertebra greater than proximal humerus greater than wrist greater than minor site. Results are presented as dot plots, and the line denotes the median value.
Similarly, patients with previous FFs at inclusion at least two FFs before the recurrent FF and those already receiving osteoporosis treatment at the time of their initial FF more likely with a previous FF or a more severe disease had a significantly higher risk of recurrent FFs.
In multivariate analyses, a previous FF at baseline was the only significant factor affecting the risk of recurrent FF Table 5. The FRAX-BMI scores were also compared within each clinical subgroup of patients, with low statistical power due to small numbers in each subcategory. To accurately predict each patient's risk for a negative outcome is every clinician's dream. A correct identification of patients at high risk of FFs would allow early treatment and decrease the numbers needed to treat to prevent future injuries.
BMD fails to deliver such precise estimates of risk because more than half of FFs occur in nonosteoporotic patients 3. In population studies, fracture rates closely parallel FRAX predicted rates 8. Most guidelines thus build on FRAX to identify men and women in need for preventive treatment. The low sensitivity of FRAX assessment was not driven by inclusion of incident minor FF in our cohort because the same results were obtained when considering baseline major FF only.
Moreover, over a 4-year follow-up period, one third of the patients who developed a recurrent FF were not estimated at high risk. Limiting analyses to initially untreated patients did not improve FRAX performance. The FRAX model does not account for a number of variables that impact the actual year fracture risk: dose and duration of corticosteroids, levels of alcohol or tobacco consumption, activity or duration of predisposing diseases such as rheumatoid arthritis or endocrinopathies diabetes, hypopituitarism, male hypogonadism , multiple drugs potentially inducing bone loss or increasing fracture risk, and risks associated with falls 10 , Some adjustments have been proposed since the FRAX release in Several studies have suggested that FRAX may not be sufficiently sensitive toward some subgroups of patients.
Our re-FF study results are consistent with the recent report that initial minor FFs increase the risk of recurrent FFs at both major and minor sites A minor FF event provides the opportunity for early pharmacological intervention, at least in the first 3—5 years after the initial FF, during which risk of recurrent FF is maximal 15 , Because the Canadian FRAX seems less sensitive among younger groups, adjustment of the threshold should be considered to trigger treatment in younger FF patients below 65 y , similar to what was proposed in other countries 14 , 22 , However, the degree of adjustment required is not clear, and further studies are needed.
Our study has a number of strengths. First, it represents a relatively large longitudinal cohort of consecutive FF patients with minimal exclusion bias. As such, our cohort differs from administrative cohorts based on BMD testing.
Prevalence of BMD testing varies significantly across geographical areas, socioeconomic status, and age 27 — BMD-based cohorts often consist of younger and healthier individuals, thus underestimating FF rates in the general population. Second, all baseline and most recurrent FFs were documented by radiographs, obviating false-positive fracture reports.
We included the sites of the FFs major vs minor , in addition to treatment, gender, and age, to provide a more detailed analysis. Our study also presents some limitations. Second, our study included only a small number of vertebral FFs, as expected for patients recruited from orthopedic fracture clinics. Systematic detection of vertebral fractures at baseline by radiography would have increased the FRAX scores because vertebral fractures are often asymptomatic 34 , and incorporating vertebral FF might have increased the observed rates of recurrent FF because vertebral FFs are strong predictors of subsequent FFs.
Finally, only patients with FFs were studied. The risk of recurrent fracture is highest in the first years following a FF 15 and may then be transiently increased relative to what can be expected from estimated year FRAX probability, in which risk is considered constant over time As a consequence, the current Osteoporosis Canada recommendations, to restrict pharmacological treatment to FF patients with hip or vertebra or repeat FF and to those with estimated high FRAX or CAROC risk, neglect a significant proportion of patients who will present recurrent fractures.
This restrictive approach may significantly hamper the potential decrease in recurrent FFs that post-FF intervention programs such as Fracture Liaison Services want to attain This study was registered at clinicaltrials.
None of the funding sources had any role in the design of the study, collection, analysis or interpretation of the data, or in the decision to publish this article. Disclosure Summary: M. Epidemiology of osteoporosis. Rheum Dis Clin North Am. Google Scholar. The care gap in diagnosis and treatment of women with a fragility fracture. Osteoporos Int. A meta-analysis of previous fracture and subsequent fracture risk. The population burden of fractures originates in women with osteopenia, not osteoporosis.
Construction and validation of a simplified fracture risk assessment tool for Canadian women and men: results from the CaMos and Manitoba cohorts. Development of prognostic nomograms for individualizing 5-year and year fracture risks. J Bone Miner Res. Chapurlat R. Contribution and limitations of the FRAX tool. Joint Bone Spine. FRAX updates Curr Opin Rheumatol. Predicting fractures in an international cohort using risk factor algorithms without BMD. A review of osteoporosis diagnosis and treatment options in new and recently updated guidelines on case finding around the world.
Curr Osteoporos Rep.
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