Is BMD measurement still useful with the advent of the FRAX® fracture risk assessment tool?



1. M. Chandran,Singapore
2. F. S. Hough, South Africa
3. J. K. Lee, Malaysia
4. W. Lems, The Netherlands
5. R. Nuti, C. Caffarelli, and S. Gonnelli, Italy
6. M. E. Simões, Portugal
7. G. Skarantavos, Greece
8. S. Waikakul, Thailand
9. C. Horváth, Hungary

1. M. Chandran, Singapore

Manju CHANDRAN, MD, FACP, FACE, CCD
Consultant Endocrinologist, Director
Osteoporosis and Bone Metabolism Unit
Singapore General Hospital
SINGAPORE
(e-mail: manju.chandran@sgh.com.sg)

Though estimating relative risks and lifetime risk of fractures is of value in evaluating the burden of osteoporosis in populations and the effects of intervention strategies, they are less relevant with regard to individual risk assessment. The FRAX® tool computes the 10-year probability of fractures from clinical risk factors with or without the measurement of femoral neck bone mineral density (BMD).

When discussing the reasons why BMD measurement is still useful even in the era of FRAX®, thought has to be given to the distinction between diagnosis of osteoporosis and assessment of fracture risk. This in turn implies a distinction between diagnostic and intervention thresholds. FRAX® is meant to be a fracture risk assessment tool. However, BMD measurement using dual-energy x-ray absorptiometry (DXA) remains the core concept in osteoporosis diagnosis and is the most clinically recognized and validated method currently. The World Health Organization (WHO) definition of osteoporosis is based on the results of BMD. The International Osteoporosis Foundation and the National Osteoporosis Foundation suggest that individuals with a history of fragility fracture have high osteoporotic risk and should receive BMD examination. In women aged 70-80 years, the “BMD screening for all” strategy has been found to be more cost effective in preventing hip fracture than either no screening or screening in women with at least one risk factor.1

A low BMD is an important risk factor for future fractures. Many prospective studies with DXA indicate that the risk of fracture approximately doubles for each standard deviation (SD) reduction in BMD. The increase in fracture risk for a specific change in BMD depends on the technique used formeasuring BMD, the site measured, and the fracture of interest.

The ability to predict hip fracture—for instance, by BMD measurement— is as good as that of blood pressure in predicting stroke and better than the use of serum cholesterol to predict coronary artery disease.2 BMD measurement may also help in identifying individuals, especially premenopausal women and men who have experienced a fragility fracture and who are likely to have a secondary cause of osteoporosis. Differing levels of BMD—for instance, low Z scores less than –1—could indicate the possibility of a secondary cause. BMD is also a good indicator when monitoring treatment response. The Fracture Intervention Trial (FIT) has shown that women whose BMD increased by more than 3% in the first 1 to 2 yearsof alendronate treatment were found to have the lowest incidence of new vertebral fractures.3 The Spinal Osteoporosis Therapeutic Intervention (SOTI) and TReatment Of Peripheral OSteoporosis (TROPOS) studies have shown that the beneficial effects of strontium ranelate in fracture risk reduction are related to the increases in BMD seen with this agent.4,5

Even given all the above, however, the sensitivity of BMD measurement is low, and approximately 50% of all fractures would be missed if BMD measurement alone is relied upon, since they occur in patients who have a BMD T-score in the osteopenic or normal range. The predictive value of BMD can be enhanced by the use of other clinical factors, such as age, previous fragility fracture, premature menopause, a family history of hip fracture, the use of oral corticosteroids, etc. FRAX® puts low BMD into perspective as one of the many risk factors for fractures. Though FRAX® assessment without BMD is of some value with the performance characteristics being similar to the use of DXA for the prediction of nonhip fractures, the value of BMD in case finding is improved when combined with the use of clinical risk factors with the FRAX® algorithm.6

In conclusion, even in this current era of fracture risk assessment using FRAX®, measurement of BMD still plays a very important role in the diagnosis of osteoporosis for fracture prediction (in which case it’s value can be enhanced by combining it with other clinical risk factors) and for the follow-up and management of treated patients.Where facilities for BMD testing are limited, consideration should be given to the judicious and selective use of this important tool, so as to optimally deploy resources and appropriately identify individuals above or below an intervention threshold. _

References

1. Schott AM, Ganne C, Hans D, et al.Which screening strategy using BMD measurements would be most cost effective for hip fracture prevention in elderly women? A decision analysis based on a Markov model. Osteoporos Int. 2007;18; 143-151.
2. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: technical report series 843. Geneva, Switzerland: WHO; 1994.
3. Hochbery MC, Ross PD, Black D, et al; Fracture Intervention Trial Research Group. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Arthritis Rheum. 1999;42:1246-1254.
4. Bruyere O, Roux C, Detilleux J, et al. Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab. 2007;92:3076-3081.
5. Bruyere O, Roux C, Badurski J, et al. Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate. Curr Med Res Opin. 2007;23:3041-3045.
6. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures inmen and women. Osteoporos Int. 2007:18:1033-1046.

2. F. S. Hough, South Africa

Stephen HOUGH, MBChB, Hons BSc,
MMed, FCP(SA), MD
Professor of Medicine and Endocrinology
Division of Endocrinology, Department
of Medicine, Stellenbosch University
Tygerberg, 7505, Western Cape
SOUTH AFRICA
(e-mail: fsh@sun.ac.za)

Will the addition of BMD measurements improve identification of those at risk of osteoporotic fractures?

The World Health Organization (WHO) diagnosis of osteoporosis is largely based on the DXA (dual-energy x-ray absorptiometry) assessment of central bone mineral density (BMD). Despite a specificity of 85%, DXA has a poor sensitivity, and numerous studies have shown that less than 50% of fragility fractures occur in subjects with DXAconfirmed osteoporosis (T-score <–2.5). The WHO classification also does not take cognizance of causes of a low BMD other than osteoporosis, nor does it recognize the importance of bone quality or extraskeletal factors, like falls, in the development of fracture.

The knowledge that many women at risk of fracture will not be identified on the basis of a BMD measurement has rekindled interest in clinical risk factors (CRFs). Advanced age, a previous fragility fracture, a family history, excessive leanness, bone toxins, and certain diseases have been shown to predispose to fracture, largely independent of BMD. FRAX®, the latest fracture risk assessment tool, uses these CRFs.1 Vertebral fracture (not included in FRAX®), age, and BMD have the highest gradient of risk and may predict fracture risk as well as, if not better than, FRAX®.2,3 Moreover, the lack of country-specific data on the epidemiology of osteoporosis seriously limits the scientific use of risk assessment tools like FRAX®. There can be little doubt that the combined use of two independent fracture risk factors like BMD and CRFs will complement our ability to identify those at risk of an osteoporotic fracture.

Will it alter your decision to intervene with a bone-active drug?

The efficacy of pharmacologic intervention has largely been demonstrated in patients with a low BMD or a prior fracture, but their efficacy in patients with other CRFs remain unknown. The history of a major osteoporotic fracture is an important predictor of fracture and would negate the need for a BMD measurement before initiating therapy. The mere presence of a number of CRFs in the absence of significant fracture or low BMD would, however, support the need for a BMD measurement in order to decide on pharmacological intervention.

Will it influence treatment?

BMD data have had little influence on the type of osteoporosis treatment. Although bisphosphonates have been shown to be effective in patients selected solely on the basis of prior fractures, risedronate was ineffective in preventing fracture in elderly women with a BMD T-score above –2.5, suggesting that alternative therapeutic strategies may have to be considered in those with CRFs and less severe bone loss. Conversely, an extremely low BMD (eg, T-score –4.0) may argue against the use of antiresorptive agents, which only modestly increase BMD, and instead suggest the use of anabolic agents.

Will it impact on compliance and adherence?

Little evidence exists that compliance can be improved with reinforcement in subjects who have already sustained a fracture. However, in those without a history of fracture, reinforcement strategies using BMD data do suggest that adherence can be improved.

Will it influence monitoring of treatment?

Changes in BMD following initiation of treatment with antiresorptive agents (ARAs) account for <20% of the variance in fracture risk reduction. BMD monitoring is therefore of limited value in subjects treated with ARAs. Drugs with anabolic actions, however, significantly increase BMD. Changes in BMD following treatment with strontium ranelate have been shown to explain 75% of the antifracture efficacy of this drug.4

Summary

Osteoporosis is a complex syndrome which is best managed when CRFs, a history of prior fracture, and BMD measurements are combined to optimize treatment. The need to determine the importance of different CRFs in a community and to establish local intervention thresholds is emphasized. _

References

1. Kanis JA, Johnell O, Oden A, et al. FRAXTM and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
2. Chen P, Krege JH, Adachi JD, et al. Vertebral fracture status and the World Health Organization risk factors for predicting osteoporotic fracture risk. J Bone Miner Res. 2009;24:495-502.
3. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007;18:1033-1046.
4. Kendler DL, Adachi JD, Josse RG, Slosman DO. Monitoring strontium ranelate therapy in patients with osteoporosis. Osteoporos Int. 2009;20:1101-1106.

3. J. K. Lee, Malaysia

Joon Kiong LEE, MBBS (Mal), FRCS (Edin),
M.S.ORTHO. (Mal), A.M. (Mal)
Orthopaedic and Traumatology
No.923A, Jalan 17/38
46400 Petaling Jaya, Selangor
MALAYSIA
(e-mail: osteoporosis_jklee@yahoo.com)

Osteoporosis is defined in terms of bone mineral density (BMD) and microarchitectural deterioration of bone tissue. BMD measurement can be used in untreated individuals as a diagnostic tool. Dual-energy x-ray absorptiometry (DXA) is the most widely used bone densitometric technique in measuring BMD. It can be used to assess bone mineral content of the whole skeleton as well as of specific sites, including thosemost vulnerable to fracture.1 In 1994, an expert panel of the World Health Organization (WHO) recommended thresholds for BMD in women to define osteoporosis.2 A relatively high Z-score (lower than –2.0) also indicates the possibility of secondary causes.

Low BMD has been shown to be a strong predictor of osteoporosis fracture.3 Many cross-sectional prospective population studies indicate that the risk of fracture increases by a factor of 1.5 to 3.0 for each standard deviation decrease in BMD.3 Fracture risk varies markedly in different populations with a similar T-score of –2.5, eg, individuals at age 50 compared with those at the age of 80. Therefore, the use of BMD measurement alone to predict osteoporosis fracture risk is no longer appropriate.1 Other factors such as presence of clinical risk factors, high indices of bone turnover, and the absolute risk of various fragility fractures should be considered.

Poor adherence to medication leads on to failure of treatment in patients with both osteoporosis or osteopenia. Patients may be encouraged to adhere to treatment when presented with measurement of biochemical markers of bone turnover or their BMD results, together with an explanation of how these measures relate to risk reduction.4 Correct DXA interpretation by physicians may lead to higher treatment rates and better compliance, and patients who understand their BMD results also have a higher rate of treatment continuity.5

Improvement in vertebral stiffness and strength after vertebroplasty has been found to depend highly on BMD.6 Individuals with higher BMD might have a higher leakage rate when given a higher cement volume; whereas ex vivo biomechanical study showed that low BMD (<0.7 g/cm2) may have least improvement in mechanical properties after vertebroplasty.6 The cement volume should be restricted to the amount needed for fracture reduction only.6 Therefore, it might be appropriate for patients with osteoporotic fractures with different BMDs to receive different treatment strategies to prevent recurrent fracture and subsequent complications.6

FRAX® only provides us with the ten-year fracture probability or absolute risk to assist us in deciding whether to initiate treatment in an untreated individual. The value of absolute risk before initiating treatment is useful for clinicians. However, in clinical practice, many patients do not appreciate a single value for the absolute fracture risk or the 10-year probability of them sustaining fractures. Comparisons of absolute risk cannot be calculated in treated individuals based on FRAX®, as FRAX® is only applicable in untreated individuals.

The use of clinical risk factors together with BMD improves sensitivity of fracture prediction without adverse effects on specificity and provides a mechanism for the effective and efficient delivery of health care to individuals at high risk and the avoidance of unnecessary treatment to others.6 There are other clinical uses of BMD measurement which are not possible and cannot be replaced with FRAX®. Therefore, themeasurement of BMD, wherever it is available and accessible, is still very important in managing our patients with osteoporosis. _

References

1. Genant HK, Engelke K, Fuerst T, et al. Noninvasive assessment of bone mineral and structure: state of the art. J Bone Miner Res. 1996;11:707-730.
2. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Technical report series 843. Geneva, Switzerland: World Health Organization; 1994.
3. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312: 1254-1259.
4. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;19:399-428.
5. Pickney CS, Arnason JA. Correlation between patient recall of bone densitometry results and subsequent treatment adherence. Osteoporos Int. 2005;16: 1156-1160.
6. Graham J, Ahn C, Hai N, et al. Effect of bone density on vertebral strength and stiffness after percutaneous vertebroplasty. Spine. 2007;32:E505-E511.

4. W. Lems, The Netherlands

Willem F. LEMS, MD, PhD
Rheumatologist, Professor
Department of Rheumatology, 3A61
VU Medical Center, Postbox 7057
1007 MB Amsterdam, THE NETHERLANDS
(e-mail: wf.lems@vumc.nl)

Bone mineral density (BMD) measurement is advocated in elderly patients with clinical risk factors for osteoporotic fractures, such as low body mass index, familiar osteoporosis, the use of glucocorticoids, etc. Usually, in the work-up of patients with (possible) osteoporosis, a dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine and the hips is performed. Suppose that a 61-yearold woman with a height of 165 cm and a body weight of 59 kg—without other obvious causes of (secondary) osteoporosis— has T-scores of –1.8 for the lumbar spine and of –2.6 for the hips. Should you treat her with antiosteoporotic drugs or not? Because the T-score of the hips is lower than –2.5, the diagnostic threshold for osteoporosis, many of our colleagues would start antiosteoporotic treatment, but is that realistic? What is her fracture risk and what is the risk reduction that can be expected, based on the literature? For the first question, the FRAX® scoring system1 is very helpful: for this patient, the 10-year probability of having a major fracture is 9.9% and her 10-year hip fracture risk is 2.8%. A lot of our colleagues and several patients are probably hesitating about whether their preliminary treatment decision based on low BMD is correct.

The FRAX® scoring system is particularly useful for both physicians and patients to get information about the future untreated fracture risk.2,3 It has been suggested that, since compliance with antiosteoporotic drugs is low, a model of shared decision-making between physician and patient with the use of the absolute future fracture risk may be helpful.

Unfortunately, there are limitations with the use of absolute fracture risk according to FRAX®:
_ Although 90% of nonvertebral fractures are related to falls, falls are not included in the algorithm;
_ Vertebral morphometric deformities are also not included in the algorithm;
_ The use of glucocorticoids (GCs) is a yes-no phenomenon, which is certainly also a limitation since GCs are prescribed in different dosages in clinical practice and the side effects of GC on bone are dose-related;
_ The FRAX® database is based on several cohorts from 9 countries: other countries have been encouraged to submit their country-specific data, if available, to the FRAX® organizers; and
_ The most important limitation is that consensus about the thresholds for both diagnosing and treating osteoporosis are lacking. It has been suggested that a pharmacoeconomic analysis should be made for each country.

It is possible to calculate an absolute fracture risk score according to FRAX® with or without BMD measurement. Obviously, this is an advantage in countries in which DXA is not available. The question is, however, whether it is useful to performa DXAmeasurement in patients for whoma FRAX® score has already been determined, if DXA machines are widely available. There are four reasons that support additional DXA measurements in these patients:

1. Measuring BMD gives additional information about future fracture risk, making the risk score more precise. That can easily be seen in the model: low T-scores are associated with slightly higher fracture risk scores for major fractures and for hip fractures, etc.
2. With a DXA measurement at baseline, the possibility of performing repeated measurements after some years to evaluate the effect of (drug) treatment in the individual patient remains;
3. Since modern DXA machines are also equipped with lateral vertebral assessment (LVA), it is possible to perform additional morphometry of vertebrae height in the thoracolumbar spine; and
4. A low BMD measurement can confirm a diagnosis of osteoporosis, which might be important in patients with a high trauma fracture. In contrast, a finding of normal BMD in a patient with a vertebral or nonvertebral fracture may induce hesitation about whether or not antiosteoporotic treatment is indicated.
_

References

1. FRAX®: http:www.shef.ac.uk.FRAX/index.htm
2. Watts NB, Ettinger B, LeBoffMS. FRAX facts. J BoneMiner Res. 2009;24:975-979.
3. Kanis JA, McCloskey EV, Johansson H, Ström O, Borgström F, Oden A; National Osteoporosis Guideline Group. Case finding for the management of osteoporosis with FRAX. Osteoporos Int. 2008;19:1395-1408.

5. R. Nuti, C. Caffarelli, and S. Gonnelli , Italy

Ranuccio NUTI, MD
Carla CAFFARELLI
Stefano GONNELLI, MD
Professor, Department of Internal Medicine
Endocrine-Metabolic Science and Biochemistry
University of Siena, Policlinico Le Scotte
Viale Bracci 2, 53100 Siena, ITALY
(e-mail: nutir@unisi.it)

For at least two decades, bone mineral density (BMD) has formed the cornerstone not only for the diagnosis of osteoporosis, but also for the assessment of fracture risk and the monitoring of treatment. However, although the risk of fractures approximately doubles for each SD reduction in BMD, there is a growing conviction that assessment with BMD alone captures a minority of the fracture risk. In fact, half or more osteoporosis-related fractures occur in patients with T-scores better than –2.5, which are in the osteopenic or normal range.

The use of clinical risk factors (CRFs) that add information on fracture risk independently of BMD improves the sensitivity of fracture risk assessment. The FRAX® tool computes the 10-year probability of a major osteoporotic fracture or a hip fracture on the basis of CRFs identified from baseline and follow- up data fromten prospective population-based European cohorts. These CRFs comprise a prior history of fragility fracture, body mass index, parental history of hip fracture, longterm use of glucocorticoids, rheumatoid arthritis, current smoking, and alcohol intake of 3 or more units daily. BMD can be included, but the model also works without it.

The development of the WHO FRAX® calculator represents a major achievement and is currently the gold standard fracture model.1 FRAX® may be one of the few resources available for fracture risk assessment in countries where facilities for BMD measurement are limited (for example, India where dual-energy x-ray absorptiometry [DXA] equipment was limited to 6 towns in 2004).

At this point, it is crucial to correctly define the real value of FRAX® assessment without BMD. A recent study examined the effects of using CRFs alone, BMD alone, or a combination of both in FRAX® to detect women at risk of hip fractures.2 The use of BMD alone showed improved sensitivity with respect to CRFs, but at the expense of a reduction in predictive value, positive predictive value, and an increase in the number needed to treat (NNT) value. In this study, the combination of CRFs and BMD selected women at higher risk than either CRFs or BMD alone, yielding the lowest NNT.

Moreover, the combined test identified women with a lower mean T-score than BMD tests alone and a substantially lower T-score than with CRFs alone.2

These findings support the view that fracture risk is optimally characterized when BMD results are used with FRAX®. However, where facilities for BMD are limited, as happens in most European countries, it has been suggested that a triage system might be utilized. According to this approach, BMD testing would not be necessary in individuals categorized by CRFs to be way above or way below a threshold risk for fractures, whereas BMD would be measured in individuals categorized as being close to the threshold risk. In these cases, the inclusion of BMD for a better classification of fracture risk is supported by the fact that BMD reflects several important and independent risk factors for fracture that are not included in FRAX®, such as vitamin D status, bone turnover, previous treatment for osteoporosis, and medication that induces bone loss (antiepileptic drugs and aromatase inhibitors).3

Traditionally, a limitation of FRAX® without BMD was that patients identified on the basis of CRFs with FRAX® would not respond to pharmacological interventions. Nevertheless, two recent studies showed that in patients treated with clodronate or bazedoxifene, high FRAX® probabilities were associated with higher efficacy, even when BMD was not used to characterize the fracture risk.4,5 Finally, BMD testing continues to be the best method for following up patients treated with antiosteoporotic drugs.

In conclusion, the use of FRAX® with BMD increases the performance characteristics of fracture risk assessment compared with the use of CRFs alone. Further studies are needed to define the cost-effectiveness of such a strategy, which on the one hand requires more resources, but on the other improves the budget impact by limiting treatment only to highrisk patients. _

References

1. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
2. Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E. BMD, clinical risk factors and their combination for hip fracture prevention. Osteoporos Int. 2009; 20:1675-1682.
3. Kanis JA, Oden A, Johansson H, Borgström F, Ström O, McCloskey E. FRAX® and its applications to clinical practice. Bone. 2009;44:734-743.
4. McCloskey EV, Johansson H, Oden A, et al. Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from a double-blind, placebo-controlled randomised study. Osteoporos Int. 2009;20:811-817.
5. Kanis JA, Johansson H, Oden A, McCloskey EV. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX®. Bone. 2009;44:1049-1054.

6. M. E. Simões, Portugal

Maria Eugénia C. SIMÕES, MD
Rheumatologist, Osteo-Metabolic Disease Unit
Portuguese Institute of Rheumatology
Apartado 13051, 1050 Lisboa
PORTUGAL
(e-mail: eugenia.simoes@netcabo.pt)

In the last 15 years, our medical rationale for evaluating fracture risk has been bone mineral density (BMD)–based. According to the dual-energy x-ray absorptiometry (DXA) operational definition of osteoporosis, we tended to classify, and therefore to treat, individuals with T-scores lower than –2.5 as osteoporotic and consequently at high risk of fracture. After a while, this approach was demonstrated to be inefficient and inappropriate; a great part of the population classified as being osteopenic would miss out on treatment if medical thinking was based uniquely on DXA. In fact, we now know, thanks to the results of epidemiological studies like the National Osteoporosis Risk Assessment (NORA) study,1 that in a real population, the majority of fractures develop in individuals classified as osteopenic (partially because this is the real state of the majority of the fracture population).

Perhaps the bigger issue is that low BMD is only one of the risk factors for fracture; other factors like bone architecture, quality, and bone remodeling (all difficult to quantify) were not taken into account in our clinical judgement previously. Last but not least, clinical risk factors for osteoporosis and fractures were used in an empirical and unorganized manner and tended to be put at the back of the stage when compared with the importance of DXA. This bias has also been demonstrated not to be very correct, as the majority of opinion leaders on osteoporosis now believe that osteoporosis clinical risk factors account for about 60% of the osteoporotic fracture determinism.2 In fact, all the local and best known osteoporosis guidelines draw attention to clinical risk factors for osteoporosis and the need, for accessibility and economic reasons, to limit BMD testing in clinical prescreened populations.3

In this scenario, the appearance of a diagnostic and evaluating tool in which clinical risk factors were put in their right place and weighed according to their relative importance was anxiously awaited by the scientific and clinical community. FRAX® emerged to answer the majority of these questions;4 in fact, it is simple, validated, available, and adjustable (for some countries), allowing the calculation of risk, and thus an intervention threshold, in osteoporosis. It allows us to calculate fracture risk in the presence or absence of BMD values. Applying FRAX® and accepting that our ten-year intervention threshold risk of hip fracture is at least 3% (and perhaps a total risk of 10%)5 may shift our therapeutic intervention toward patients who really do need it; itmeans, for instance, not treating perimenopausal women without clinical risk factors just because they have low BMD. Why test it in the first place? It also means treating all women if they are over 76, regardless of BMD (as age is a big determinant of risk fracture). Finally, it means treating women with low-energy fractures, even if the T-score is –2.

But, as with other subjects in medicine, not everything is purely black or white…there is a “twilight” zone. Because FRAX® is not perfect, there are some factors that are underweighted by this tool: falls, number of fractures, magnitude and duration of smoking and drinking, vitamin D status, bone remodeling, and vertebral osteoporosis…. And it is for these twilight zone cases that measuring BMD can be useful; for those individuals considered at intermediate risk when calculating FRAX®, for all cases of secondary osteoporosis (this is one area that FRAX® underestimates), probably for everyone above 65 years of age, and whenever the clinician believes that reassessing fracture risk could be useful. In addition, monitoring BMD during osteoporosis treatment is considered a valuable process according the majority of guidelines. We must always remember that there is no guideline, guidance, or tool that should overrule good clinical judgement! _

References

1. Chesnut CH III. Osteoporosis, an underdiagnosed disease. JAMA. 2001;286: 2865-2866.
2. Kanis JA, Johnnel O, Oden A, et al. Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis. Bone. 2000;27: 585-590.
3. Gennant H, Cooper C, Poor G, Reid I. Interim report and recommendations of a World Health Organization task force on osteoporosis. Osteoporos Int. 1999; 10:259-264.
4. Kanis JA, Borgström F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int. 2005;16:581-589.
5. Tosteson AN, Melton LJ III, Dawson-Hughes B, et al. Cost-effective osteoporosis treatment thresholds: the United States perspective. Osteoporos Int. 2008; 19:437-447.

7. G. Skarantavos, Greece

Grigoris N. SKARANTAVOS, MD
Rheumatologist Director
1st Orthopedic Clinic University of Athens
Attikon General University Hospital
Haidari, Rimini 1, 12462 GREECE
(e-mail: skarant@hol.gr)

The World Health Organization (WHO) Consensus Conference defines osteoporosis as a condition of bone deterioration in which individuals have “a bone mineral density (BMD) that lies 2.5 standard deviations or more below the average value for young healthy women,”1 and the Surgeon General’s report adds to this definition increased risk of fracture.2 BMD, while associated with fracture risk, is not fully predictive of who will experience a low impact fracture. Large epidemiological studies have shown that BMD accounts for only H60% of the fracture risk3 and have suggested that other “bone quality” parameters may account for why two individuals with similar lifestyles and equivalent BMDs may have different fragility fracture histories. Although measurable decreases in BMD in untreated patients have been associated with increased risk of fragility fracture, areal BMD changes account for less than half of the improvement in fracture risk seen in osteoporotic patients treated with anticatabolic and anabolic agents.4

FRAX® is a computer based algorithm that provides models for the assessment of fracture probability in men and women. 5 The approach uses easily obtained clinical risk factors to estimate 10-year fracture probability. Clinical risk factors include age, low body mass index (BMI), previous fracture, parent’s osteoporotic fracture, corticosteroid use, rheumatoid arthritis, secondary osteoporosis, low BMD, excess alcohol consumption, and smoking. The estimate can be used alone or with femoral neck BMD to enhance fracture risk prediction.

The use of FRAX® with the generation of a number does not, however, replace clinical judgment. For example, several of the clinical risk factors identified take no account of dose– response, but give risk ratios for an average dose or exposure. By contrast, there is good evidence that the risk associated with excess alcohol consumption, cigarette smoking, and the use of glucocorticoids is dose-responsive. In addition, the risk of fracture increases progressively with the number of prior fractures. These limitations should be recognized when interpreting a FRAX® result in the clinic. It should also be acknowledged that there are many other risk factors for fracture that are not incorporated into assessment algorithms. Examples include the biochemical markers of bone turnover.

The obvious application of FRAX® is in the assessment of individuals to identify those who would be candidates for pharmacological intervention. Experts in the care of patients with osteoporosis are used to integrating information derived from multiple risk factors. By contrast, primary care physicians in most countries have little expert knowledge, and it is for this constituency that FRAX® has been primarily designed. Physicians should not consider the FRAX® tool as a gold standard, but rather as a platform technology on which to build as new validated risk indicators become available.

In clinical practice, areal BMD can only be useful in determining if a patient is healthy, osteopenic, or osteoporotic at first visit according to the WHO criteria, but does not answer questions about the patient’s fracture risk and treatment decisions. The FRAX® model is an aid to enhance patient assessment by the integration of clinical risk factors alone and/or in combination with BMD.6 Other tools, such as determination of bone turnover, can provide physicians with further valuable information for treatment, when available. _

References

1. World Health Organization. Prevention and management of osteoporosis. WHO technical report series 921. Geneva, Switzerland: World Health Organization; 2003.
2. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285: 785-795.
3. Siris ES, Brenneman SK, Miller PD, et al. Predictive value of low BMD for 1-year fracture outcomes is similar for postmenopausal women ages 50-64 and 65 and Older: results from the National Osteoporosis Risk Assessment (NORA). J Bone Miner Res. 2004;19:1215-1220.
4. Hillier TA, Stone KL, Bauer DC, et al. Evaluating the value of repeat bone mineral density measurement and prediction of fractures in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167:155-160.
5. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey EV. FRAX™ and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
6. Kanis JA, Oden A, Johansson H, Borgström F, Ström O, McCloskey EV. FRAX® and its applications to clinical practice. Bone. 2009:44:734-743.

8. S. Waikakul, Thailand

Saranatra WAIKAKUL, BSc, MD,
FRCOST, FIMS
Professor, 59/2 Soi Charoenjai
Ekamai Road, Wattana
Bangkok 10110, THAILAND
(e-mail: sisvk@mahidol.ac.th)

Identification of population at risk is the most important step in the management of osteoporosis,1 and bone mineral density (BMD) is just one tool that has been used for the diagnosis of osteoporosis and fracture prediction in the last decade. However, BMD alone might not be a good fracture predictor, as low energy fractures can be found quite often in osteopenia patients with BMDs between –1.5 and –2.5. Furthermore, BMD does not directly determine bone architecture and bone strength, which are the most important factors effecting bone fragility.2 Recently, Kanis JA et al presented an algorithm of their fracture risk assessment tool (FRAX®) for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density.3 The clinical risk factors include age (between 40 and 90 years), sex, weight, height, previous fracture in adult life, parent with fractured hip, current smoking, glucocorticoid administration, rheumatoid arthritis, secondary osteoporosis, and consumption of 3 or more units of alcohol per day.

Bone mineral density is not included in the clinical risk factors. However, BMD is still an important investigation point for the diagnosis and planning the management of osteoporosis. In sensitivity analyses, the positive predictive value and number needed to treat were always better for the combination of BMD with CRFs than for either BMD or CRFs alone, across all ages studied (50 to 70 years).4 When using FRAX® in a relatively young population—50 to 55 years old— the probability of fracture doses not change much, whether BMD is used or not. On the other hand, in an older population aged between 80 to 85 years old, low BMD can increase the probability of fracture by more than 7%, which may affect the clinical outcome.5 In patients who have premenopausal or secondary osteoporosis, BMD is a useful tool for decision making about treatment and follow-up. With the recent development of bone turnover markers, better monitoring of bone physiology can be carried out during medical treatment of osteoporosis in short-term follow-up.6 When the osteoporotic patient information from these three independent tools—clinical risk factors, bone turnover markers, and BMD—is coevaluated, a more accurate probability of fracture in a particular patient can be predicted. For now, BMD is still being used in clinical practice. Patients who have low BMD, ie, T-score <–2.5, usually have lower quality of life than comparable patients with osteopenia and a BMD >–2.5. Most of the research into the management of osteoporosis use pain, BMD, and bone turnovermarkers as outcomemeasurements. Thus, BMD is still a useful tool in the management of osteoporosis._

References

1. Borgström F, Kanis JA. Health economics of osteoporosis. Best Pract Res Clin Endocrinol Metab. 2008;22:885-900.
2. Griffith JF, Genant HK. Bone mass and architecture determination: state of the art. Best Pract Res Clin Endocrinol Metab. 2008;22:737-764.
3. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
4. Kanis JA, Torgerson D, van Staa T, Watts NB, Yoshimura N. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007;18:1033-1046.
5. Fujiwara S, Nakamura T, Orimo H, Kanis JA. Development and application of a Japanese model of the WHO fracture risk assessment tool (FRAX™). Osteoporos Int. 2008;19:429-435.
6. Reginster JY, Collette J, Neuprez A, Zegels B, Deroisy R, Bruyere O. Role of biochemical markers of bone turnover as prognostic indicator of successful osteoporosis therapy. Bone. 2008;42:832-836.

9. C. Horváth, Hungary

Csaba HORVÁTH, MD, PhD, DSc
1st Department of Medicine
Semmelweis University, Koranyi 2/a
H-1083 Budapest, HUNGARY
(e-mail: horcsa@bel1.sote.hu)

Osteoporosis is a collective name for diseases with different pathomechanisms, but with a common clinical output: fragility fracture. Bone fragility is predominantly determined by mineral content, but other bone properties also contribute toward ensuring mechanical competence. The collagen network, microstructure of bone tissue, trabecular network, and size and macrostructure of bones are accepted as important, while the role of elasticity, the osteocyte network (vectorially governing bone turnover), and other contributors to bone quality are only recently becoming clear. As most of these factors cannot be evaluated in daily practice, the link between pathophysiological knowledge and patient management remains a point of controversy. Little is known about the relation of bone properties to widely used clinical risk factors (CRFs), while bonemineral density (BMD) hasmore or less of an impact on bone quality.

Until now, the diagnostic criteria for osteoporosis (T-score <–2.5) has also been used as an intervention threshold. This method has poor cost-effectiveness. The risk/benefit ratio has also proven inappropriate as half of fractures occur in patients with normal BMD or osteopenia. FRAX®, the new 10- year fracture risk assessment tool, has provided an elegant solution to this problem, with a limited number of CRFs tested on robust databases of thousands of people.1 Using this tool new health economic strategies can be formulated for each country and more precise treatment decisions can be made for individual patients. While FRAX® is convincing and accepted worldwide, some limitations have been highlighted by the original authors and others.

Firstly, one needs to recognize that BMD is not the main point of a FRAX® calculation. Only hip BMD is involved and, moreover, a fracture probability can even be obtained without BMD at all. Does this suggest that BMD will be unnecessary with the advent of FRAX®?

First of all, BMD is still an existing basis for the definition of osteoporosis (T-score <–2.5), like blood pressure measurement is for the diagnosis of hypertension. This is not a medical, but a financial way of selecting patients for treatment at a currently acceptable level of cost-effectiveness.2 A relationship between BMD measured and fracture risk (twofold increase per T-score SD) also exists. Moreover, fluctuations and variability in BMD of different bones depend on a patient’s genetic profile and individual lifestyle (physical activity). This is why the International Society for Clinical Densitometry (ISCD) recommends testing BMD in a range of bones and using the lowest value for diagnosis. Young postmenopausal women with low vertebral but normal femoral BMD provide a good example of why this recommendation exists.3

The clinical risk factors of FRAX® have been carefully evaluated for their relationships to BMD. Thanks to these associations, FRAX® provides a more relevant indication for intervention in osteopenia, which is a big step forward in osteoporosis management. However, BMD can help in cases where FRAX® has limitations, eg, dosage of glucocorticoids or severity of previous fractures (site, number, and type). The exclusive role of hip BMD was due to technical limitations, so the involvement of other bones remains to be evaluated. A more promising approach is the use of nonmass methods like quantitative bone ultrasound (elasticity+trabecular integrity), for which the 10-year fracture probability has been calculated by Kanis et al.4 Involving turnover markers seems to be an exciting step, too. Risk due to vitamin D deficiency has also not been incorporated in FRAX®, but is partly reflected by BMD. Bone density has an effect on fracture risk independent of some clinical risk factors, but related to others. Not surprisingly, the fracture probability calculated from clinical factors and BMD T-score <–2.0 was higher than the probability calculated using only clinical risk factors. In contrast, a normal or slightly decreased BMD (T-score >–2.0) decreases calculated fracture risk (unpublished results of our study).

In summary, the advent of FRAX® does not mean the end of BMD. In fact, wider use of BMD and nonmass bone testing methods could help FRAX® provide a more precise risk assessment. _
References
1. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey EV. FRAX® and the assessment of fracture probability in men and women from the UK. Osteoporosis Int. 2008;19:385-397.
2. Tosteson AN, Melton LJ III, Dawson-Hughes B, et al. Cost-effective osteoporosis treatment thresholds: the United States perspective. Osteoporosis Int. 2008; 19:437-447.
3. Roux C, Thomas T. Optimal use of FRAX®. Joint Bone Spine. 2009;76:1-3. Editorial.
4. Kanis JA, Johnell O, Oden A, de Laet C, de Terlizzi F. Ten-year probabilities of clinical vertebral fractures according to phalangeal quantitative ultrasound. Osteoporosis Int. 2005;16:1065-1070.