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What is the role of DXA, QUS and bone markers in fracture prediction, treatment allocation and monitoring?
Best Practice & Research Clinical Rheumatology Vol. 19, No. 6, pp. 951–964, 2005 doi:10.1016/j.berh.2005.06.004 available online at http://www.sciencedirect.com
5 What is the role of DXA, QUS and bone markers in fracture prediction, treatment allocation and monitoring? Karine Briot
MD
Assistant Professor
Christian Roux*
MD, PhD
Professor of Rheumatology De´partement de Rhumatologie, Hoˆpital Cochin, 27 Rue du Faubourg St Jacques, 75014 Paris, France
There is evidence that treatment can decrease the risk of fractures in osteoporotic patients, and screening of these patients is therefore relevant. Diagnosis of osteoporosis is based on the T-score calculated from bone mineral density (BMD) measurements. BMD measurements have been widely used for the management of osteoporosis, and a low BMD is a strong risk factor for fractures. But BMD measurement has several limitations in both diagnosis, prediction of fracture risk, and treatment follow-up. Quantitative ultrasound (QUS) parameters, an alternative to BMD in the assessment of bone, are independent risk factors for osteoporotic fracture. However, the use of QUS cannot be recommended for both allocation and monitoring of treatment. Biochemical markers of bone remodelling can be useful for both prediction of fracture risk and monitoring of treatment if sources of variability are controlled. Key words: osteoporosis; fracture; bone mineral density; ultrasound; bone turnover markers.
Osteoporotic fractures represent a major health problem worldwide, leading to significant morbidity and mortality, reducing the quality of life, and being responsible for major costs in health-care systems.1,2 Because effective treatments are available, the identification of women at high risk of fractures is relevant. Both quantitative and qualitative parameters are determinants of bone strength. In routine practice these parameters can be assessed by bone mineral density (BMD), quantitative ultrasound (QUS) parameters, and markers of bone remodelling measurements. Dual-energy X-ray absorptiometry (DXA) is the most relevant method for BMD measurement and is considered as the gold standard for * Corresponding author. E-mail address: [email protected] (C. Roux).
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the diagnosis of osteoporosis, the prediction of fractures and the follow-up of patients. The WHO (World Health Organization) definition of osteoporosis is based on the results of BMD.3 Osteoporosis is defined as BMD more than 2.5 SD below the mean value of young adults, i.e. peak bone mass. However, because of the low sensitivity of the method, other bone evaluation methods can be considered for clinical decisions.
ROLE OF DXA DXA and prediction of fracture risk Clinical studies BMD measurements can estimate fracture risk. Low BMD is associated with all types of fractures (except skull, hands and toes).4 In prospective studies, the risk of fracture approximately doubles for each decrease in BMD of 1 SD.5,6 There is no threshold below which fracture risk increases, indicating that there is rather a gradient of risk of fracture with decrease in BMD.7 The performance in predicting fracture risk is similar for all sites and types of BMD measurement. However, hip BMD measurement is the best predictor of hip fracture, and is particularly useful in women older than 65 years.8 Hip and spine BMDs have similar value for predicting vertebral fractures. The ability of the method to predict fracture is similar at all ages, including elderly women, but the interpretation of the Tscore varies according to age. Limits of the use of BMD in the prediction of fracture risk In the National Osteoporosis Risk Assessment (NORA), a longitudinal study of 140 000 women, new fractures during 1 year were reported in 2259 women; however, only 6. 4% had a baseline T-score of K2.5 or less, indicating that the sensitivity of this measurement is low. A proportion of fractures occurs in patients with osteopenia rather than osteoporosis.9 Between 10 and 44% of fractures are attributable to low BMD.4 This populationattributable risk (PAR) varies according to the analysed fracture, but is 15% on average for all types of fracture. This PAR is comparable with the PAR reported for hypertension or lipid profiles and cardiovascular disease, but lower than the PAR reported for smoking and lung cancer. DXA and treatment decision-making Several treatments have shown their effectiveness in postmenopausal women with low BMD (T-score %K2 or K2.5 at femoral neck or spine) and/or vertebral fractures.10–14 There is no evidence that anti-osteoporotic treatment is able to reduce the risk of fractures in women having only clinical risk factors for fractures. Thus, BMD measurement is useful for treatment decision-making. However, the diagnostic threshold is not equivalent to a ‘treatment decision threshold’. The number of women—aged 65 years on average—who need to be treated to prevent one of them having a fracture is on average 10 if patients have prevalent vertebral fractures and 35 if they have no fractures but T-score !K2.5 at the hip. At the same age, if
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K1.6!T!K2, this number is 363.11 At 50 years old, in a population with a T-score of K1.5, maybe 2000 women should be treated to prevent one fracture. Thus, BMD measurement is useful for treatment decision-making, and is even sufficient in cases of very low BMD. However, in most cases other parameters must also be used.7,15 Fracture risk indices have been proposed using both BMD and clinical risk factors for fracture (i.e. age, prevalent fractures, family history of fractures, low body mass index, increased risk of falls, etc) and in some studies biochemical markers of turnover. These combinations allow the estimation of a probability of fracture in a 5-year or 10-year period. Such data will be proposed under the auspices of WHO in 2006. DXA and monitoring osteoporosis The ultimate goal of anti-osteoporotic treatment is to reduce the risk of fractures, but this effect cannot be measured directly in individuals. BMD is the most often used surrogate measurement for evaluating the bone effect. Interpretation of BMD changes The precision of DXA is better than most of the biological markers providing that there is quality control of the device and the measurements. The changes can be related to the biological changes and/or measurement error. Precision is usually given as coefficient of variation of repeated measurements. Actually clinical use needs to calculate the least significant change (LSC: 2.77!the coefficient of variation)16 or the smallest detectable difference (SDD).17 Expressed in SDD, BMD changes of at least 0.05 g/cm2 and 0.04 g/cm2 at the spine and hip, respectively, are significant.17,18 Using the LSC or the SDD is mandatory to avoid misinterpretation related to variability of the measurement or regression to the mean.19 Clinical relevance of the monitoring Increase in BMD is the consequence of anti-osteoporotic treatment, but the change is a function of the drug, duration of treatment and sites of measurement. The mean increase at the lumbar spine is 2.6% after 4 years with raloxifene, 10–15% after 7–10 years of bisphosphonates, 13% after 18 months of teriparatide, and 14.5% after 3 years of strontium ranelate.12,14,20–25 Taking into account the precision of the measurement, these expected changes give an estimate of the time interval for a follow-up measurement. All these treatments are able to reduce vertebral fracture risk by about 30–50%. However, a small proportion of reduction in risk of vertebral fractures is explained by the increase in BMD: 18–28% for the risedronate26,27, 16% for the alendronate28, and only 4% for the raloxifene.29 Even for large increases, it has not been shown that BMD gain is a determinant of the treatment effectiveness.24 Baseline BMD is a stronger predictor of vertebral fracture risk than change in BMD under treatment. On the other hand, some data suggest a better relationship between BMD increase and reduction of the risk of non-vertebral fractures.30 Each 1% increase in spine BMD at 1 year was associated with an 8% reduction in non-vertebral fracture risk (PZ0.02). Similar results were observed with the hip BMD. Finally, there is no evidence that serial BMD measurements increase the persistence of the treatment. The follow-up BMD result is obtained too late to be of any use in this field. Patients usually stop taking treatment in the first year; in the FIT study, 76% of the patients who stopped alendronate did so in the first year.
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In summary, follow-up using DXA measurement is possible providing that there is adequate quality control. The aim of this follow-up is to check for the absence of bone loss. Its timing is a function of expected change under treatment.
ROLE OF QUS QUS measurements have been proposed as an alternative to BMD assessment. Numerous ultrasound parameters used to characterize bone have been proposed, including broadband ultrasound attenuation (BUA), speed of sound (SOS), combined index, amplitude-dependent speed of sound (AD-SoS), etc. There are various QUS devices available with a number of differences, coupling methods, sites of measurement, parameters calculation. Most of the measurements are performed at os calcis or phalanx. In theory, QUS has the ability to provide additional information about bone structure, trabecular orientation and micro-architecture that is independent of bone mass and density.31,32 Moreover, QUS instruments have advantages compared with DXA: they are radiation-free, portable, and inexpensive.33 A low QUS result is an indicator of low bone strength and is an independent risk factor for osteoporotic fracture in postmenopausal women. But the clinical use of QUS is difficult because of the absence of diagnostic criteria. A T-score threshold of K2.5 is inappropriate for the diagnosis of osteoporosis by QUS.34 In the study of Frost et al, a T-score of K1.8 for QUS resulted in the same percentage of postmenopausal women classified as osteoporotic as a T-score !K2.5 for BMD measurements.34 Moreover, the threshold was shown to be different among parameters and instruments: K1.6 and K1.9 for BUA and SOS measured at the os calcis with a dry system, and K1.5 and K2.1 for BUA and SOS at the os calcis with another device. Knapp et al assessed the appropriate equivalent T-score thresholds for SOS measurements at tibia, radius, phalanx and metatarsal in a population of 278 healthy premenopausal women, 194 postmenopausal women and 115 women with vertebral fracture. They showed different T-score cut-off values for each skeletal site measured by QUS.35 Because of the technological differences between devices, results cannot be extrapolated from one device to another. QUS and prediction of risk of fracture Cross-sectional studies Numerous cross-sectional studies have examined the relationship between QUS and fracture. They found a lower36, an equal37, or a higher38 prediction value than the one obtained with DXA. In the Osteoporosis and Ultrasound Study (OPUS), Glue¨r et al compared the performance of five QUS devices with DXA for discrimination of women with and without osteoporotic vertebral fractures. The calcaneus QUS was as good as axial DXA in discriminating women with vertebral fracture; the OR was 1.2–1.4 for BUA, 1.4– 1.5 or SOS, and 1.4–1.6 for lumbar and femoral BMD.39 Broadband ultrasound attenuation imaging improves the reproducibility of ultrasound measurements.40 Prospective studies The EPIDOS and SOF, two large prospective longitudinal studies, investigated the effectiveness of calcaneus QUS with regards to fracture risk prediction. The results are close to those obtained in cross-sectional studies.
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In the EPIDOS study, 5662 women (median age 80.4 years) were followed for 2 years. The risk of hip fractures increases for each SD decrease in BUA by a factor of 2 (1.6–2.4) and of 1.7 (1.4–2.1) for SOS.41 The results are similar to the predictive value of BMD, and they remain significant after adjustment for BMD. This result can be related to the exploration of either a non-quantitative bone parameter or of a non-axial site of measurement. In the SOF (Study of Osteoporotic Fracture), Bauer et al studied 6189 women (mean age 76 years) for 2 years. They showed that each SD reduction of QUS increases the risk of hip (RRZ2; CI 95% 1.5–2.7) and vertebral (RRZ1.3; CI 95% 1.3–1.5) fractures.42 However, in this study, the risk of hip fracture is greater for hip BMD (RRZ 2.6) than that observed with the BUA (RRZ2.0). In a population of 432 peri- and postmenopausal women (range 53.7–63.3), although a small number of fractures was observed, the ability of QUS to predict fractures was similar to that of BMD.43 In none of the studies, the combination of QUS and BMD was superior to the use of QUS or BMD alone.41 Prediction fracture and site of measurement Njeh et al evaluated the abilities of six devices measuring QUS at os calcis to discriminate between controls and women with hip fractures. The variability ranged from 3.14 to 5% for SOS, and from 2.45 to 6% for BUA.44 All QUS devices showed similar diagnostic sensitivity and gave similar hip fracture discrimination. Results concerning the discrimination power of the QUS of phalanges are conflicting. In a crosssectional and retrospective study of 7562 Swiss women, the two heel QUS (BUA and SOS) had a significantly higher discrimination power than QUS of the phalanges with ORs adjusted ranging from 2.1 to 2.7 (95% CIZ1.6–3.5) compared with 1.4 (95% CIZ 1.1–1.7) for the AD-SoS.45 The phOS study, performed on 10 000 women, showed the effectiveness of the QUS at phalanges in detecting postmenopausal vertebral fractures with an OR for AD-SoS of 1.7 (1.5–1.8).46 In summary, a low QUS value is an independent risk factor for osteoporotic fracture in peri- and postmenopausal women. QUS and treatment allocation QUS is not recommended for therapeutic decision-making as none of the treatments has shown efficacy in a population selected on QUS data only. Currently QUS result can be considered as an additional risk factor for fracture, and further studies are needed to evaluate the role of QUS in a multifactorial index of fracture risk and the costeffectiveness of such a strategy. QUS and monitoring Monitoring bone changes In contrast to BMD, very few longitudinal studies have been performed with QUS. The QUS measurements decline with age, particularly SOS and stiffness index. Van Daele et al examined changes in QUS in 323 women with a mean follow-up of 1.4 years; calcaneal SOS and stiffness decreased by 2.2 and 0.9%, respectively.47 No study has evaluated the relationship between serial changes in QUS and fractures, and no study
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has demonstrated the benefit of serial measurements of QUS in the evaluation of individuals at risk of osteoporosis. Monitoring treatment There is no prospective placebo-controlled study for anti-osteoporotic treatment using QUS as the main efficacy criterion. Most of the studies are open-labelled showing that postmenopausal women with treatment have higher QUS values than untreated women.48 There is still limited experience in monitoring osteoporotic therapy and bone changes.49 At present, monitoring by QUS cannot be recommended for individuals. Reproducibility of QUS There are several sources of variability of QUS measurements: position of the measured bone, cleanliness and temperature of the skin, presence of oedema, composition of soft tissue, technician training, etc. The device must be controlled by an appropriate phantom. The published coefficient of variation (CV) ranges from 1 to 6% for BUA and from 0.25 to 0.5% for SOS.50 For technological reasons, it is not possible to compare the different machines, and there is a need for standardization of procedures acquisition and evaluation.39
ROLE OF BONE MARKERS Biological bone markers are aimed at non-invasive evaluation of bone remodelling. Some are specific for bone formation (osteocalcin, bone alkaline phosphatase, peptides of type 1 procollagen). Others are specific for bone resorption (deoxypyridinoline and its free or peptide-bound forms) (Table 1). Their main applications are the prediction of fracture risk and the follow-up of anti-osteoporotic treatments. The markers cannot be used for diagnosis of osteoporosis. Clinical use of bone markers must take into account their variability. Problems arising from the interpretation of the markers Quality of measurements has been improved with the introduction of automated immunoassay analysers.51 Numerous factors affect the variability of bone marker measurements. Some controllable factors can be reduced by standardization; others, uncontrollable, must be assessed before interpretation. Uncontrollable factors of variability Age, gender, ethnicity, menopause status, diseases, recent fractures, immobility and treatments can influence the levels of bone markers.52 Moreover, appropriate reference ranges are necessary for interpretation. Controllable factors of variability Circadian variability is an important factor of variability.53 The timing of sample collection must be tightly controlled to reduce its effect. The bone markers must be measured at a fixed time in the morning before nine o’clock.
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Table 1. Biochemical markers of bone turnover. Formation
Resorption
Serum Total ALP Bone ALP OC PINP PICP
Serum TRACP NTX CTX
Urine PYD DPD NTX CTX Hydroxyproline Galactosyl hydroxylysine ALP, alkaline phosphatase; OC, osteocalcin; PINP, procollagen type-1 N propeptide; PICP, procollagen type-1 C propeptide; TRACP, tartrate-resistant acid phosphatase; NTX, N-terminal cross-linking telopeptide of type 1 collagen; CTX, C-terminal cross-linking telopeptide of type 1 collagen; PYD, pyridinoline; DPD, deoxypyridinoline.
Bone markers and fracture risk prediction Markers of bone formation The results of the prospective studies are contradictory. In the EPIDOS study, with a follow-up of 2 years, there is no significant association between osteocalcin, bone alkaline phosphatase and the risk of hip fracture.54 In contrast, in the OFELY study, including a large number of younger postmenopausal women (50–89 years), a high value of bone alkaline phosphatase was associated with an increase in the fracture risk, independent of the BMD value.55 In this population, bone formation and bone resorption markers remain stable over 4 years.56 The difference between the studies may be related to the characteristics of the population, the studied fractures and the duration of the follow-up. Markers of bone resorption Concordant results were obtained in numerous prospective studies of postmenopausal women of various ages (EPIDOS, OFELY, Rotterdam and Hawai Osteoporosis study). In the EPIDOS study, conducted in the 1980s, the increase in the urinary CTX (above the upper limit of the range in premenopausal women) was associated with an increase in hip fracture risk [ORZ2.2 (CI 95% 1.3–3.6)].54 In the OFELY study, including a large number of postmenopausal women 50–89 years old, the increase in the serum CTX was associated with the risk of fracture with an OR of 2 (95% 1.2–3.8).55 In these studies, the prediction of the risk of fracture is independent of BMD value, indicating that the excess of bone resorption is an added factor of deterioration of bone strength.
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Clinical use of the bone markers for the evaluation of the risk of fracture The combination of bone resorption markers and BMD could be used to improve the prediction of the risk of fracture. In the EPIDOS study, Garnero et al showed that among women who had low BMD (T-score %K2.5) and an increase in urinary CTX, the risk of hip fracture increased by 4.8 (CI 95% 2.4–9.5), whereas the risk increased by 2.2 if they had high urinary CTX and by 2.7 (CI 95% 1.5–5.0) if they had low BMD.57 In the OFELY study, women who had both low hip BMD (T-score %K2.5) and high serum CTX values had a risk of fracture of 55% at 5 years, significantly higher than the risk associated with a low density (39%) or high value of CTX (25%).55 These results suggest that the combination could be useful in some circumstances for the identification of women at high risk of fracture. Bone markers and allocation of treatment Even if it’s logical to hypothesize that patients with accelerated bone turnover will have greater benefits from anti-resorptive treatment and patients with low bone turnover should receive an anabolic agent, clinical data have not confirm this. The efficacy of risedronate in reducing incident vertebral fractures in women with postmenopausal osteoporosis is independent of pretreatment bone resorption marker levels (urinary DPD).58 Similar results have been shown for teriparatide efficacy.59 Bone markers and monitoring treatment Effects of anti-osteoporotic treatment on bone markers The bone marker values change rapidly after the beginning of a treatment. The magnitude of the changes in bone markers depends on the sensitivity of the marker, the drug, and the duration, potency and route of administration of the treatment. These early changes might be used as a surrogate marker for treatment efficacy. Oral treatment with bisphosphonates induces a decrease in bone turnover, especially for the cross-link-related peptides (serum and urinary CTX, serum NTX), which can be seen after 1 month and which reaches a plateau at 3 months.60 Alendronate induces a 70% decrease in urinary NTX and CTX, and a 50% decrease in total D-Pyr. The decrease in bone formation markers is observed later, after 6–12 months. This effect on bone remodelling is sustained during long-term treatment (10 years). After discontinuation of alendronate therapy, levels of the markers increase but remain below pretreatment levels.21 Risedronate induces a 60% decrease in bone resorption markers in 3–6 months.61 After stopping risedronate treatment, there is an immediate increase in bone resorption markers, indicating a difference in the permanent effect of these two bisphosphosnates. Hormone replacement therapy (HRT) induces a large and rapid decrease in bone markers with a plateau from 3–6 months onwards. The decrease in bone formation is delayed, with a plateau within 6–12 months. When HRT is discontinued, a rapid increase in bone markers ensues, similar to that seen after menopause.62
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Raloxifene induces a smaller decrease in bone remodelling than HRT and the bisphosphonates, with a reduction of 30–40% in resorption markers (urinary CTX) and of 20–30% in formation markers.23 Teriparatide induces a large and rapid increase in bone formation markers assessed by the increase in osteocalcin (C55%), whereas the bone resorption assessed by the measurement of cross-link-related peptides increase by 20%.13,24 In contrast, very small changes are induced by strontium ranelate (an average of 10% of increase in bone formation and decrease in bone resorption).14 Prediction of BMD changes by bone markers Several studies of anti-resorptive treatments have shown that short-term reduction in bone turnover markers is associated with long-term increase in BMD, especially at the spine and radius. With alendronate, a short-term decrease (3–6 months) of at least 65% for NTX, 55% for CTX and 40% for osteocalcin can predict a gain of BMD of 3% at 2 years.63 Prediction of fracture risk under anti-osteoporotic treatment This is certainly the most important criterion of clinical utility of the markers. Among women with at least one prevalent vertebral fracture treated with risedronate, the short-term decrease at 3–6 months in urinary CTX (median 60%) and urinary NTX (median 51%), was significantly associated with a reduction in vertebral fracture at 1 year (75%) and at 3 years (50%).61 The 3–6-month changes in resorption markers accounted for one half of the risedronate’s effect (CTX, 55%; NTX, 49%) at 1 year and for two thirds over 3 years (CTX, 67%; NTX 66%). The proportion of the effect of risedronate on non-vertebral fractures explained by changes in bone resorption over 3 years was 54% for NTX and 77% for CTX. The relationships between the levels of resorption markers and the risk of vertebral fracture were not linear, suggesting the existence of a threshold for decrease in bone resorption markers below which there is no increase in anti-fracture benefit.61 In the FIT study, after 1 year of treatment, alendronate-treated women with at least a 30% reduction in bone alkaline phosphatase (ALP) had a lower risk of non-spine (RRZ 0.72, CI 95% 0.55–0.92) and hip fractures (RRZ0.26, CI 95% 0.08–0.83).64 In the MORE study, changes in bone markers of formation (ostecalcin and bone ALP) observed after 1 year of raloxifene were correlated with the decrease in risk of new vertebral fracture over 3 years.65 Use of biochemical markers and persistence of treatment Monitoring anti-osteoporotic treatment using bone markers may be useful to improve persistence of the treatment and thus its effectiveness.66,67 Indeed the biochemical changes are rapid and are a convenient way to show the bone effect of the treatment.
WHICH STRATEGY IN DAILY CLINICAL PRACTICE? BMD measurement by DXA is the gold standard for the management of osteoporosis (diagnosis, treatment decision, monitoring therapy) but has several limitations.
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Even if BMD is a strong risk factor for fracture, it explains only part of the individual’s fracture risk. The risk of fracture, like the risk of stroke, is multifactorial. Other risk factors are consistently associated with fracture: age, low body mass index, prior fractures, maternal hip history, risk of falls, and use of steroids.7 Several fracture indices, combining clinical risk factors and BMD measurement, have been developed to predict the risk of fracture in individuals.15 With simple scoring systems, it’s easier to assess which women require treatment to reduce fracture risk. Bone markers of resorption and QUS measurements are also associated with an increase in the risk of fracture but cannot routinely be used alone. Combining markers of resorption with QUS or BMD and/or clinical risk factor may improve the prediction of the risk.57 BMD measurement is useful for treatment decision-making, and is even sufficient in cases of very low BMD. There is no evidence that anti-osteoporotic treatment is able to reduce the risk of fractures in women having only clinical risk factors for fractures, low QUS measurements or high bone turnover. The BMD measurement and the bone markers can be used for monitoring therapy, providing that there is quality assurance of the measurements. There is no direct link between the increase in BMD and the decrease in vertebral fracture risk. Moreover, time interval between two BMD measurements is a function of the treatment, but cannot be less than 18 months (anabolic agents) or even more (anti-resorptive agents). Bone marker changes can be assessed in the short term (i.e. after 3–6 months of treatment). They are not yet recommended routinely today, but are useful in situations of poor compliance and difficulties in management of treatment.
SUMMARY BMD measurements have been widely used for the management of osteoporosis. Low BMD is a strong risk factor for fractures, but it explains only a part of an individual’s fracture risk because of its low sensitivity. Combining BMD with other risk factors is a relevant method to predict the risk of fracture in individuals. BMD measurement is useful for treatment decision-making and is even sufficient in cases of very low BMD. BMD measurement can be used for monitoring therapy, and can be repeated 2 years later (on average, depending on the treatment), provided that there is quality assurance of the measurements. A low QUS value is an independent risk factor for osteoporotic fracture in postmenopausal women. However, in the absence of a diagnostic threshold, and with the lack of standardization, the use of QUS alone cannot be recommended for the allocation and monitoring of treatment. Biochemical markers of bone remodelling can be useful for the prediction of fracture risk. A combined approach with BMD and/or clinical factors could improve fracture prediction. Bone markers can be measured in the short term (i.e. after 3–6 months of treatment) for monitoring anti-osteoporotic drugs. The clinical use of these markers requires the control of sources of variability.
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Practice points † BMD measurement by DXA is the gold standard for the management of osteoporosis † low BMD is a strong risk factor for fractures, but because of its low sensitivity it explains only a part of an individual’s fracture risk † BMD measurement is useful for treatment decision-making † BMD measurement can be used for monitoring therapy, and the follow-up measurement is a function of precision of the measure, sensitivity to change of the measured site, and expected change induced by the treatment † QUS alone cannot be recommended for the allocation and monitoring of treatment † increase in bone markers is a risk factor of osteoporotic fracture in postmenopausal women † bone marker changes can be assessed in the short term for monitoring antiosteoporotic treatment
Research agenda † fracture risk index combining BMD and other risk factors must be developed and validated in order to estimate the individual’s absolute risk of fracture † the usefulness of the bone markers for monitoring osteoporotic drugs needs to be well established
REFERENCES 1. Ray NF, Chan JK, Thamer M & Melton LJ. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. Journal of Bone and Mineral Research 1997; 12: 24–35. 2. Riggs BL & Melton 3rd. LJ. The worldwide problem of osteoporosis: insights afforded by epidemiology. Bone 1995; 17: 505S–511S. 3. Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO study group. Osteoporosis International 1994; 4: 368–381. 4. Stone KL, Seeley DG, Lui LYet al. Osteoporotic Fractures Research Group. BMD at multiple sites and risk of fracture of multiple types: long-term results from the study of osteoporotic fractures. Journal of Bone and Mineral Research 2003; 18: 1947–1954. 5. Marshall D, Johnell O & Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. British Medical Journal 1996; 312: 1254–1259. 6. Dargent-Molina P, Schott AM, Hans D et al. Separate and combined value of bone mass and gait speed measurements in screening for hip fracture risk: results from the EPIDOS study. Epide´miologie de l’oste´oporose. Osteoporosis International 1999; 9: 188–192. 7. Kanis JA. Osteoporosis; diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002; 359: 1929–1936. 8. Cummings SR, Black DM, Nevitt MC et al. Bone density at various sites for prediction of hip fractures. The study of osteoporotic fractures research group. Lancet 1993; 341: 72–75. 9. Siris ES, Chen YT, Abbott TA et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Archives of Internal Medicine 2004; 164: 1108–1112.
962 K. Briot and C. Roux 10. Black DM, Cummings SR, Karpf DB et al. Randomised trial of the effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996; 348: 1535–1541. 11. Harris ST, Watts NB & Genant HK. Effects of risedronate treatment on vertebral and non vertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. The Journal of the American Medical Association 1999; 282: 1344–1552. 12. Ettinger B, Black DM, Mitlak BH et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple outcomes of raloxifene evaluation (MORE) investigators. The Journal of the American Medical Association 1999; 282: 637–645. 13. Neer RM, Arnaud CD, Zanchetta JR et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. The New England Journal of Medicine 2001; 344: 1434–1441. 14. Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. The New England Journal of Medicine 2004; 350: 459–468. 15. Black DM, Steinbuch M, Palermo L et al. An assessment tool for predicting fracture risk in postmenopausal women. Osteoporosis International 2001; 12: 519–528. 16. Gluer CC, Blake G, Lu Y et al. Accurate assessment of precision errors: how to measure the reproducibility of bone densitometry techniques. Osteoporosis International 1995; 5: 262–270. 17. Ravaud P, Reny JL, Giraudeau B et al. Smallest detectable difference in individual bone mineral density measurements. Journal of Bone and Mineral Research 1999; 14: 1449–1456. 18. Lodder MC, Lems WF, Ader HJ et al. Reproducibility of bone mineral density measurement in daily practice. Annals of the Rheumatic Diseases 2004; 63: 285–289. 19. Cummings SR, Palermo L, Browner W et al. Monitoring osteoporosis therapy with bone densitometry. Misleading changes and regression to the mean. The Journal of the American Medical Association 2000; 283: 1318–1321. 20. Liberman UA, Weiss SR, Bro¨ll J et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The alendronate phase III osteoporosis treatment study group. The New England Journal of Medicine 1995; 333: 1437–1443. 21. Bone HG, Hosking D, Devogelaer JP et al. Ten years’experience with alendronate for osteoporosis in postmenopausal women. The New England Journal of Medicine 2004; 350: 1189–1199. 22. Harris ST. Bisphosphonates for the treatment of postmenopausal osteoporosis: clinical studies of etidronate and alendronate. Osteoporosis International 2002; 12: S11–S16. 23. Delmas PD, Bjarnason NH, Mitlak BH et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. The New England Journal of Medicine 1997; 337: 1641–1647. 24. Marcus R, Wang O, Satterwhite J & Mitlak B. The skeletal response to teriparatide is largely independent of age, initial bone mineral density, and prevalent vertebral fractures in postmenopausal women with osteoporosis. Journal of Bone and Mineral Research 2003; 18: 18–23. 25. Delmas PD, Ensrud KE, Adachi JD et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. Journal of Clinical Endocrinology and Metabolism 2002; 87: 3609–3617. 26. Watts NB, Cooper C, Linday R et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate. Journal of Clinical Densitometry 2004; 7: 255–261. 27. Li Z, Meredith MP & Hoseyni MS. A method to assess the proportion of treatment effect explained by a surrogate end-point. Statistics in Medicine 2001; 112: 281–289. 28. Cummings SR, Karpf DB, Harris F et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. The American Journal of Medicine 2002; 112: 281–289. 29. Sarkar S, Mitlak BH, Wong M et al. Relationship between bone mineral density and incident vertebral fracture risk raloxife`ne therapy. Journal of Bone and Mineral Research 2002; 17: 1–10. 30. Hochberg MC, Greenspan S, Wasnich RD et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. Journal of Clinical Endocrinology and Metabolism 2002; 87: 1586–1592. 31. Glu¨er CC, Cummings SR, Bauer DC et al. Association of recent fractures with quantitative US findings. Radiology 1996; 199: 25–32.
Role of DXA, QUS and bone markers 963 32. Hans D, Arlot ME, Schott AM et al. Do ultrasound measurements on the os calcis reflect more the microarchitecture than the bone mass? A two-dimensional histomorphometric study. Bone 1995; 16: 295–300. 33. Baran DT. Quantitative ultrasound: a technique to target women with low bone mass for preventive therapy. The American Journal of Medicine 1995; 98: 48S–51S. 34. Frost ML, Blake GM & Foelman I. Can the WHO criteria for diagnosing osteoporosis be applied to calcaneal quantitative ultrasound? Osteoporosis International 2000; 11: 321–330. 35. Knapp KM, Blake GM, Spector TD et al. Can the WHO definition of osteoporosis be applied to multi-site axial transmission quantitative ultrasound? Osteoporosis International 2004; 15: 367–374. 36. Cepollaro C, Gonnelli S, Pondrelli C et al. The combined use of ultrasound and densitometry in the prediction of vertebral fracture. The British Journal of Radiology 1997; 70: 691–696. 37. Bauer DC, Gluer CC, Genant HK et al. Quantitative ultrasound and vertebral fracture in postmenopausal women. Fracture intervention trial research group. Journal of Bone and Mineral Research 1995; 10: 353– 358. 38. Ross P, Huang C, Davis J et al. Predicting vertebral deformity using bone densitometry at various skeletal sites and calcaneus ultrasound. Bone 1995; 16: 325–332. 39. Glu¨er CC, Eastell R, Reid DM et al. Association of five quantitative ultrasound devices and bone densitometry with osteoporotic vertebral fractures in population-based sample: the OPUS study. Journal of Bone and Mineral Research 2004; 19: 782–793. 40. Roux C, Fournier B, Laugier P et al. Broadband ultrasound attenuation imaging: a new imaging method in osteoporosis. Journal of Bone and Mineral Research 1996; 11: 1112–1118. 41. Hans D, Dargent-Molina P, Schott AM et al. Ultrasonographic heel measurements to predict hip fracture in erderly women: the EPIDOS prospective study. Lancet 1996; 348: 511–514. 42. Bauer DC, Glu¨er CC, Cauley JA et al. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women: a prospective study. Archives of Internal Medicine 1997; 157: 629–634. 43. Huopio J, Kroger H, Honkanen R et al. Calcaneal ultrasound predicts early postmenopausal fractures as well as axial BMD. A prospective study of 422 women. Osteoporosis International 2004; 15: 190–195. 44. Njeh CF, Hans D, Li J et al. Comparison of six calcaneal quantitative ultrasound devices: precision et and hip fracture discrimination. Osteoporosis International 2000; 11: 1051–1062. 45. Krieg MA, Cornuz J, Cruffieux C et al. Comparison of three bone ultrasounds for the discrimination of subjects with and without osteoporotic fractures among 7562 elderly women. Journal of Bone and Mineral Research 2003; 18: 1261–1266. 46. Wuster C, Albanese C, De Aloysio D et al. Phalangeal osteosonogrammetry study: age-related changes, diagnostic sensitivity, and discrimination power. The Phalangeal osteosonogrammetry study group. Journal of Bone and Mineral Research 2000; 12: 1280–1288. 47. Van Daele PL, Burger H, De Laet CE et al. Longitudinal changes in ultrasound parameters of the calcaneus. Osteoporosis International 1997; 7: 207–212. 48. Hadji P, Hars O, Schuler M et al. Assessment by quantitative ultrasonometry of the effects of hormon ereplacement therapy on bone mass. American Journal of Obstetrics and Gynecology 2000; 182: 529–534. 49. Gonnelli S, Cepollaro C, Montagnani A et al. Heel ultrasonography in monitoring alendronate therapy: a four-year longitudinal study. Osteoporosis International 2002; 13: 415–421. 50. Schott AM, Hans D, Garnero P et al. Age-related changes in os calcis ultrasonic indices: a 2 year prospective study. Osteoporosis International 1995; 5: 478–483. 51. Garnero P, Borel O & Delmas PD. Evaluation of a fully automated serum assay for C-terminal crosslinking telopeptide of type I collagen in osteoporosis. Clinical Chemistry 2001; 47: 694–702. 52. Qvist P, Christgau S, Pedersen BJ et al. Circadian variation in the serum C-terminal telopeptide of type I collagen (serum CTX): effects of gender, age, menopausal status, posture, daylight, serum cortisol and fasting. Bone 2002; 31: 57–61. 53. Blumsohn A, Herrington K, Hannon RA et al. The effect of calcium supplementation on the circadian rhythm of bone resorption. Journal of Clinical Endocrinology and Metabolism 1994; 79: 730–735. 54. Garnero P, Hausherr E, Chapuy MC et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. Journal of Bone and Mineral Research 1996; 11: 1531–1538.
964 K. Briot and C. Roux 55. Garnero P, Sornay-Rendu E, Claustrat B & Delmas PD. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. Journal of Bone and Mineral Research 2000; 15: 1526–1536. 56. Garnero P, Mulleman D, Munoz F et al. Long-term variability of markers of bone turnover in postmenopausal women and implications for their clinical use: the OFELY study. Journal of Bone and Mineral Research 2003; 18: 1789–1794. 57. Garnero P, Dargent-Molina P, Hans D et al. Do markers of bone resorption add to bone mineral density and ultrasonographic heel measurement for the prediction of hip fracture in elderly women? The EPIDOS prospective study. Osteoporosis International 1998; 8: 563–569. 58. Seibel MJ, Naganathan V, Barton I & Grauer A. Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic women treated with risedronate. Journal of Bone and Mineral Research 2004; 19: 394–401. 59. Delmas Pd, Chen P, Misurski DA et al. Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover. Journal of Bone and Mineral Research 2004; 19: S44. 60. Garnero P, shih WJ, Gineyts E et al. Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. Journal of Clinical Endocrinology and Metabolism 1994; 79: 1693–1700. 61. Eastell R, Barton I, Hannon RA et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. Journal of Bone and Mineral Research 2003; 18: 1051–1056. 62. Tremollieres F, Pouilles JM & Ribot C. Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. Osteoporosis International 2001; 12: 385–390. 63. Delmas PD. How does antiresorptive therapy decrease the risk of fracture in women with osteoporosis. Bone 2000; 27: 1–3. 64. Bauer DC, Black DM, Garnero P et al. Change in bone turnover and hip, non spine, and vertebral fracture in alendronate-treated women. Journal of Bone and Mineral Research 2004; 19: 1250–1258. 65. Bjarnason NH, Christiansen C, Sarkar S et al. 6 months changes in biochemical markers predict 3-year response in vertebral fracture rate in postmenopausal, osteoporotic women: results from the MORE study. Osteoporosis International 2001; 12: 922–930. 66. Clowes JA, Peel NF & Eastell R. The impact of monitoring on adherence and presistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. Journal of Clinical Endocrinology and Metabolism 2004; 89: 1117–1123. 67. Chapurlat RD & Cummings SR. Does follow-up of osteoporotic women treated with antiresorptive therapies improve effectiveness? Osteoporosis International 2002; 13: 738–744.
5 What is the role of DXA, QUS and bone markers in fracture prediction, treatment allocation and monitoring? Karine Briot
MD
Assistant Professor
Christian Roux*
MD, PhD
Professor of Rheumatology De´partement de Rhumatologie, Hoˆpital Cochin, 27 Rue du Faubourg St Jacques, 75014 Paris, France
There is evidence that treatment can decrease the risk of fractures in osteoporotic patients, and screening of these patients is therefore relevant. Diagnosis of osteoporosis is based on the T-score calculated from bone mineral density (BMD) measurements. BMD measurements have been widely used for the management of osteoporosis, and a low BMD is a strong risk factor for fractures. But BMD measurement has several limitations in both diagnosis, prediction of fracture risk, and treatment follow-up. Quantitative ultrasound (QUS) parameters, an alternative to BMD in the assessment of bone, are independent risk factors for osteoporotic fracture. However, the use of QUS cannot be recommended for both allocation and monitoring of treatment. Biochemical markers of bone remodelling can be useful for both prediction of fracture risk and monitoring of treatment if sources of variability are controlled. Key words: osteoporosis; fracture; bone mineral density; ultrasound; bone turnover markers.
Osteoporotic fractures represent a major health problem worldwide, leading to significant morbidity and mortality, reducing the quality of life, and being responsible for major costs in health-care systems.1,2 Because effective treatments are available, the identification of women at high risk of fractures is relevant. Both quantitative and qualitative parameters are determinants of bone strength. In routine practice these parameters can be assessed by bone mineral density (BMD), quantitative ultrasound (QUS) parameters, and markers of bone remodelling measurements. Dual-energy X-ray absorptiometry (DXA) is the most relevant method for BMD measurement and is considered as the gold standard for * Corresponding author. E-mail address: [email protected] (C. Roux).
1521-6942/$ - see front matter Q 2005 Published by Elsevier Ltd.
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the diagnosis of osteoporosis, the prediction of fractures and the follow-up of patients. The WHO (World Health Organization) definition of osteoporosis is based on the results of BMD.3 Osteoporosis is defined as BMD more than 2.5 SD below the mean value of young adults, i.e. peak bone mass. However, because of the low sensitivity of the method, other bone evaluation methods can be considered for clinical decisions.
ROLE OF DXA DXA and prediction of fracture risk Clinical studies BMD measurements can estimate fracture risk. Low BMD is associated with all types of fractures (except skull, hands and toes).4 In prospective studies, the risk of fracture approximately doubles for each decrease in BMD of 1 SD.5,6 There is no threshold below which fracture risk increases, indicating that there is rather a gradient of risk of fracture with decrease in BMD.7 The performance in predicting fracture risk is similar for all sites and types of BMD measurement. However, hip BMD measurement is the best predictor of hip fracture, and is particularly useful in women older than 65 years.8 Hip and spine BMDs have similar value for predicting vertebral fractures. The ability of the method to predict fracture is similar at all ages, including elderly women, but the interpretation of the Tscore varies according to age. Limits of the use of BMD in the prediction of fracture risk In the National Osteoporosis Risk Assessment (NORA), a longitudinal study of 140 000 women, new fractures during 1 year were reported in 2259 women; however, only 6. 4% had a baseline T-score of K2.5 or less, indicating that the sensitivity of this measurement is low. A proportion of fractures occurs in patients with osteopenia rather than osteoporosis.9 Between 10 and 44% of fractures are attributable to low BMD.4 This populationattributable risk (PAR) varies according to the analysed fracture, but is 15% on average for all types of fracture. This PAR is comparable with the PAR reported for hypertension or lipid profiles and cardiovascular disease, but lower than the PAR reported for smoking and lung cancer. DXA and treatment decision-making Several treatments have shown their effectiveness in postmenopausal women with low BMD (T-score %K2 or K2.5 at femoral neck or spine) and/or vertebral fractures.10–14 There is no evidence that anti-osteoporotic treatment is able to reduce the risk of fractures in women having only clinical risk factors for fractures. Thus, BMD measurement is useful for treatment decision-making. However, the diagnostic threshold is not equivalent to a ‘treatment decision threshold’. The number of women—aged 65 years on average—who need to be treated to prevent one of them having a fracture is on average 10 if patients have prevalent vertebral fractures and 35 if they have no fractures but T-score !K2.5 at the hip. At the same age, if
Role of DXA, QUS and bone markers 953
K1.6!T!K2, this number is 363.11 At 50 years old, in a population with a T-score of K1.5, maybe 2000 women should be treated to prevent one fracture. Thus, BMD measurement is useful for treatment decision-making, and is even sufficient in cases of very low BMD. However, in most cases other parameters must also be used.7,15 Fracture risk indices have been proposed using both BMD and clinical risk factors for fracture (i.e. age, prevalent fractures, family history of fractures, low body mass index, increased risk of falls, etc) and in some studies biochemical markers of turnover. These combinations allow the estimation of a probability of fracture in a 5-year or 10-year period. Such data will be proposed under the auspices of WHO in 2006. DXA and monitoring osteoporosis The ultimate goal of anti-osteoporotic treatment is to reduce the risk of fractures, but this effect cannot be measured directly in individuals. BMD is the most often used surrogate measurement for evaluating the bone effect. Interpretation of BMD changes The precision of DXA is better than most of the biological markers providing that there is quality control of the device and the measurements. The changes can be related to the biological changes and/or measurement error. Precision is usually given as coefficient of variation of repeated measurements. Actually clinical use needs to calculate the least significant change (LSC: 2.77!the coefficient of variation)16 or the smallest detectable difference (SDD).17 Expressed in SDD, BMD changes of at least 0.05 g/cm2 and 0.04 g/cm2 at the spine and hip, respectively, are significant.17,18 Using the LSC or the SDD is mandatory to avoid misinterpretation related to variability of the measurement or regression to the mean.19 Clinical relevance of the monitoring Increase in BMD is the consequence of anti-osteoporotic treatment, but the change is a function of the drug, duration of treatment and sites of measurement. The mean increase at the lumbar spine is 2.6% after 4 years with raloxifene, 10–15% after 7–10 years of bisphosphonates, 13% after 18 months of teriparatide, and 14.5% after 3 years of strontium ranelate.12,14,20–25 Taking into account the precision of the measurement, these expected changes give an estimate of the time interval for a follow-up measurement. All these treatments are able to reduce vertebral fracture risk by about 30–50%. However, a small proportion of reduction in risk of vertebral fractures is explained by the increase in BMD: 18–28% for the risedronate26,27, 16% for the alendronate28, and only 4% for the raloxifene.29 Even for large increases, it has not been shown that BMD gain is a determinant of the treatment effectiveness.24 Baseline BMD is a stronger predictor of vertebral fracture risk than change in BMD under treatment. On the other hand, some data suggest a better relationship between BMD increase and reduction of the risk of non-vertebral fractures.30 Each 1% increase in spine BMD at 1 year was associated with an 8% reduction in non-vertebral fracture risk (PZ0.02). Similar results were observed with the hip BMD. Finally, there is no evidence that serial BMD measurements increase the persistence of the treatment. The follow-up BMD result is obtained too late to be of any use in this field. Patients usually stop taking treatment in the first year; in the FIT study, 76% of the patients who stopped alendronate did so in the first year.
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In summary, follow-up using DXA measurement is possible providing that there is adequate quality control. The aim of this follow-up is to check for the absence of bone loss. Its timing is a function of expected change under treatment.
ROLE OF QUS QUS measurements have been proposed as an alternative to BMD assessment. Numerous ultrasound parameters used to characterize bone have been proposed, including broadband ultrasound attenuation (BUA), speed of sound (SOS), combined index, amplitude-dependent speed of sound (AD-SoS), etc. There are various QUS devices available with a number of differences, coupling methods, sites of measurement, parameters calculation. Most of the measurements are performed at os calcis or phalanx. In theory, QUS has the ability to provide additional information about bone structure, trabecular orientation and micro-architecture that is independent of bone mass and density.31,32 Moreover, QUS instruments have advantages compared with DXA: they are radiation-free, portable, and inexpensive.33 A low QUS result is an indicator of low bone strength and is an independent risk factor for osteoporotic fracture in postmenopausal women. But the clinical use of QUS is difficult because of the absence of diagnostic criteria. A T-score threshold of K2.5 is inappropriate for the diagnosis of osteoporosis by QUS.34 In the study of Frost et al, a T-score of K1.8 for QUS resulted in the same percentage of postmenopausal women classified as osteoporotic as a T-score !K2.5 for BMD measurements.34 Moreover, the threshold was shown to be different among parameters and instruments: K1.6 and K1.9 for BUA and SOS measured at the os calcis with a dry system, and K1.5 and K2.1 for BUA and SOS at the os calcis with another device. Knapp et al assessed the appropriate equivalent T-score thresholds for SOS measurements at tibia, radius, phalanx and metatarsal in a population of 278 healthy premenopausal women, 194 postmenopausal women and 115 women with vertebral fracture. They showed different T-score cut-off values for each skeletal site measured by QUS.35 Because of the technological differences between devices, results cannot be extrapolated from one device to another. QUS and prediction of risk of fracture Cross-sectional studies Numerous cross-sectional studies have examined the relationship between QUS and fracture. They found a lower36, an equal37, or a higher38 prediction value than the one obtained with DXA. In the Osteoporosis and Ultrasound Study (OPUS), Glue¨r et al compared the performance of five QUS devices with DXA for discrimination of women with and without osteoporotic vertebral fractures. The calcaneus QUS was as good as axial DXA in discriminating women with vertebral fracture; the OR was 1.2–1.4 for BUA, 1.4– 1.5 or SOS, and 1.4–1.6 for lumbar and femoral BMD.39 Broadband ultrasound attenuation imaging improves the reproducibility of ultrasound measurements.40 Prospective studies The EPIDOS and SOF, two large prospective longitudinal studies, investigated the effectiveness of calcaneus QUS with regards to fracture risk prediction. The results are close to those obtained in cross-sectional studies.
Role of DXA, QUS and bone markers 955
In the EPIDOS study, 5662 women (median age 80.4 years) were followed for 2 years. The risk of hip fractures increases for each SD decrease in BUA by a factor of 2 (1.6–2.4) and of 1.7 (1.4–2.1) for SOS.41 The results are similar to the predictive value of BMD, and they remain significant after adjustment for BMD. This result can be related to the exploration of either a non-quantitative bone parameter or of a non-axial site of measurement. In the SOF (Study of Osteoporotic Fracture), Bauer et al studied 6189 women (mean age 76 years) for 2 years. They showed that each SD reduction of QUS increases the risk of hip (RRZ2; CI 95% 1.5–2.7) and vertebral (RRZ1.3; CI 95% 1.3–1.5) fractures.42 However, in this study, the risk of hip fracture is greater for hip BMD (RRZ 2.6) than that observed with the BUA (RRZ2.0). In a population of 432 peri- and postmenopausal women (range 53.7–63.3), although a small number of fractures was observed, the ability of QUS to predict fractures was similar to that of BMD.43 In none of the studies, the combination of QUS and BMD was superior to the use of QUS or BMD alone.41 Prediction fracture and site of measurement Njeh et al evaluated the abilities of six devices measuring QUS at os calcis to discriminate between controls and women with hip fractures. The variability ranged from 3.14 to 5% for SOS, and from 2.45 to 6% for BUA.44 All QUS devices showed similar diagnostic sensitivity and gave similar hip fracture discrimination. Results concerning the discrimination power of the QUS of phalanges are conflicting. In a crosssectional and retrospective study of 7562 Swiss women, the two heel QUS (BUA and SOS) had a significantly higher discrimination power than QUS of the phalanges with ORs adjusted ranging from 2.1 to 2.7 (95% CIZ1.6–3.5) compared with 1.4 (95% CIZ 1.1–1.7) for the AD-SoS.45 The phOS study, performed on 10 000 women, showed the effectiveness of the QUS at phalanges in detecting postmenopausal vertebral fractures with an OR for AD-SoS of 1.7 (1.5–1.8).46 In summary, a low QUS value is an independent risk factor for osteoporotic fracture in peri- and postmenopausal women. QUS and treatment allocation QUS is not recommended for therapeutic decision-making as none of the treatments has shown efficacy in a population selected on QUS data only. Currently QUS result can be considered as an additional risk factor for fracture, and further studies are needed to evaluate the role of QUS in a multifactorial index of fracture risk and the costeffectiveness of such a strategy. QUS and monitoring Monitoring bone changes In contrast to BMD, very few longitudinal studies have been performed with QUS. The QUS measurements decline with age, particularly SOS and stiffness index. Van Daele et al examined changes in QUS in 323 women with a mean follow-up of 1.4 years; calcaneal SOS and stiffness decreased by 2.2 and 0.9%, respectively.47 No study has evaluated the relationship between serial changes in QUS and fractures, and no study
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has demonstrated the benefit of serial measurements of QUS in the evaluation of individuals at risk of osteoporosis. Monitoring treatment There is no prospective placebo-controlled study for anti-osteoporotic treatment using QUS as the main efficacy criterion. Most of the studies are open-labelled showing that postmenopausal women with treatment have higher QUS values than untreated women.48 There is still limited experience in monitoring osteoporotic therapy and bone changes.49 At present, monitoring by QUS cannot be recommended for individuals. Reproducibility of QUS There are several sources of variability of QUS measurements: position of the measured bone, cleanliness and temperature of the skin, presence of oedema, composition of soft tissue, technician training, etc. The device must be controlled by an appropriate phantom. The published coefficient of variation (CV) ranges from 1 to 6% for BUA and from 0.25 to 0.5% for SOS.50 For technological reasons, it is not possible to compare the different machines, and there is a need for standardization of procedures acquisition and evaluation.39
ROLE OF BONE MARKERS Biological bone markers are aimed at non-invasive evaluation of bone remodelling. Some are specific for bone formation (osteocalcin, bone alkaline phosphatase, peptides of type 1 procollagen). Others are specific for bone resorption (deoxypyridinoline and its free or peptide-bound forms) (Table 1). Their main applications are the prediction of fracture risk and the follow-up of anti-osteoporotic treatments. The markers cannot be used for diagnosis of osteoporosis. Clinical use of bone markers must take into account their variability. Problems arising from the interpretation of the markers Quality of measurements has been improved with the introduction of automated immunoassay analysers.51 Numerous factors affect the variability of bone marker measurements. Some controllable factors can be reduced by standardization; others, uncontrollable, must be assessed before interpretation. Uncontrollable factors of variability Age, gender, ethnicity, menopause status, diseases, recent fractures, immobility and treatments can influence the levels of bone markers.52 Moreover, appropriate reference ranges are necessary for interpretation. Controllable factors of variability Circadian variability is an important factor of variability.53 The timing of sample collection must be tightly controlled to reduce its effect. The bone markers must be measured at a fixed time in the morning before nine o’clock.
Role of DXA, QUS and bone markers 957
Table 1. Biochemical markers of bone turnover. Formation
Resorption
Serum Total ALP Bone ALP OC PINP PICP
Serum TRACP NTX CTX
Urine PYD DPD NTX CTX Hydroxyproline Galactosyl hydroxylysine ALP, alkaline phosphatase; OC, osteocalcin; PINP, procollagen type-1 N propeptide; PICP, procollagen type-1 C propeptide; TRACP, tartrate-resistant acid phosphatase; NTX, N-terminal cross-linking telopeptide of type 1 collagen; CTX, C-terminal cross-linking telopeptide of type 1 collagen; PYD, pyridinoline; DPD, deoxypyridinoline.
Bone markers and fracture risk prediction Markers of bone formation The results of the prospective studies are contradictory. In the EPIDOS study, with a follow-up of 2 years, there is no significant association between osteocalcin, bone alkaline phosphatase and the risk of hip fracture.54 In contrast, in the OFELY study, including a large number of younger postmenopausal women (50–89 years), a high value of bone alkaline phosphatase was associated with an increase in the fracture risk, independent of the BMD value.55 In this population, bone formation and bone resorption markers remain stable over 4 years.56 The difference between the studies may be related to the characteristics of the population, the studied fractures and the duration of the follow-up. Markers of bone resorption Concordant results were obtained in numerous prospective studies of postmenopausal women of various ages (EPIDOS, OFELY, Rotterdam and Hawai Osteoporosis study). In the EPIDOS study, conducted in the 1980s, the increase in the urinary CTX (above the upper limit of the range in premenopausal women) was associated with an increase in hip fracture risk [ORZ2.2 (CI 95% 1.3–3.6)].54 In the OFELY study, including a large number of postmenopausal women 50–89 years old, the increase in the serum CTX was associated with the risk of fracture with an OR of 2 (95% 1.2–3.8).55 In these studies, the prediction of the risk of fracture is independent of BMD value, indicating that the excess of bone resorption is an added factor of deterioration of bone strength.
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Clinical use of the bone markers for the evaluation of the risk of fracture The combination of bone resorption markers and BMD could be used to improve the prediction of the risk of fracture. In the EPIDOS study, Garnero et al showed that among women who had low BMD (T-score %K2.5) and an increase in urinary CTX, the risk of hip fracture increased by 4.8 (CI 95% 2.4–9.5), whereas the risk increased by 2.2 if they had high urinary CTX and by 2.7 (CI 95% 1.5–5.0) if they had low BMD.57 In the OFELY study, women who had both low hip BMD (T-score %K2.5) and high serum CTX values had a risk of fracture of 55% at 5 years, significantly higher than the risk associated with a low density (39%) or high value of CTX (25%).55 These results suggest that the combination could be useful in some circumstances for the identification of women at high risk of fracture. Bone markers and allocation of treatment Even if it’s logical to hypothesize that patients with accelerated bone turnover will have greater benefits from anti-resorptive treatment and patients with low bone turnover should receive an anabolic agent, clinical data have not confirm this. The efficacy of risedronate in reducing incident vertebral fractures in women with postmenopausal osteoporosis is independent of pretreatment bone resorption marker levels (urinary DPD).58 Similar results have been shown for teriparatide efficacy.59 Bone markers and monitoring treatment Effects of anti-osteoporotic treatment on bone markers The bone marker values change rapidly after the beginning of a treatment. The magnitude of the changes in bone markers depends on the sensitivity of the marker, the drug, and the duration, potency and route of administration of the treatment. These early changes might be used as a surrogate marker for treatment efficacy. Oral treatment with bisphosphonates induces a decrease in bone turnover, especially for the cross-link-related peptides (serum and urinary CTX, serum NTX), which can be seen after 1 month and which reaches a plateau at 3 months.60 Alendronate induces a 70% decrease in urinary NTX and CTX, and a 50% decrease in total D-Pyr. The decrease in bone formation markers is observed later, after 6–12 months. This effect on bone remodelling is sustained during long-term treatment (10 years). After discontinuation of alendronate therapy, levels of the markers increase but remain below pretreatment levels.21 Risedronate induces a 60% decrease in bone resorption markers in 3–6 months.61 After stopping risedronate treatment, there is an immediate increase in bone resorption markers, indicating a difference in the permanent effect of these two bisphosphosnates. Hormone replacement therapy (HRT) induces a large and rapid decrease in bone markers with a plateau from 3–6 months onwards. The decrease in bone formation is delayed, with a plateau within 6–12 months. When HRT is discontinued, a rapid increase in bone markers ensues, similar to that seen after menopause.62
Role of DXA, QUS and bone markers 959
Raloxifene induces a smaller decrease in bone remodelling than HRT and the bisphosphonates, with a reduction of 30–40% in resorption markers (urinary CTX) and of 20–30% in formation markers.23 Teriparatide induces a large and rapid increase in bone formation markers assessed by the increase in osteocalcin (C55%), whereas the bone resorption assessed by the measurement of cross-link-related peptides increase by 20%.13,24 In contrast, very small changes are induced by strontium ranelate (an average of 10% of increase in bone formation and decrease in bone resorption).14 Prediction of BMD changes by bone markers Several studies of anti-resorptive treatments have shown that short-term reduction in bone turnover markers is associated with long-term increase in BMD, especially at the spine and radius. With alendronate, a short-term decrease (3–6 months) of at least 65% for NTX, 55% for CTX and 40% for osteocalcin can predict a gain of BMD of 3% at 2 years.63 Prediction of fracture risk under anti-osteoporotic treatment This is certainly the most important criterion of clinical utility of the markers. Among women with at least one prevalent vertebral fracture treated with risedronate, the short-term decrease at 3–6 months in urinary CTX (median 60%) and urinary NTX (median 51%), was significantly associated with a reduction in vertebral fracture at 1 year (75%) and at 3 years (50%).61 The 3–6-month changes in resorption markers accounted for one half of the risedronate’s effect (CTX, 55%; NTX, 49%) at 1 year and for two thirds over 3 years (CTX, 67%; NTX 66%). The proportion of the effect of risedronate on non-vertebral fractures explained by changes in bone resorption over 3 years was 54% for NTX and 77% for CTX. The relationships between the levels of resorption markers and the risk of vertebral fracture were not linear, suggesting the existence of a threshold for decrease in bone resorption markers below which there is no increase in anti-fracture benefit.61 In the FIT study, after 1 year of treatment, alendronate-treated women with at least a 30% reduction in bone alkaline phosphatase (ALP) had a lower risk of non-spine (RRZ 0.72, CI 95% 0.55–0.92) and hip fractures (RRZ0.26, CI 95% 0.08–0.83).64 In the MORE study, changes in bone markers of formation (ostecalcin and bone ALP) observed after 1 year of raloxifene were correlated with the decrease in risk of new vertebral fracture over 3 years.65 Use of biochemical markers and persistence of treatment Monitoring anti-osteoporotic treatment using bone markers may be useful to improve persistence of the treatment and thus its effectiveness.66,67 Indeed the biochemical changes are rapid and are a convenient way to show the bone effect of the treatment.
WHICH STRATEGY IN DAILY CLINICAL PRACTICE? BMD measurement by DXA is the gold standard for the management of osteoporosis (diagnosis, treatment decision, monitoring therapy) but has several limitations.
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Even if BMD is a strong risk factor for fracture, it explains only part of the individual’s fracture risk. The risk of fracture, like the risk of stroke, is multifactorial. Other risk factors are consistently associated with fracture: age, low body mass index, prior fractures, maternal hip history, risk of falls, and use of steroids.7 Several fracture indices, combining clinical risk factors and BMD measurement, have been developed to predict the risk of fracture in individuals.15 With simple scoring systems, it’s easier to assess which women require treatment to reduce fracture risk. Bone markers of resorption and QUS measurements are also associated with an increase in the risk of fracture but cannot routinely be used alone. Combining markers of resorption with QUS or BMD and/or clinical risk factor may improve the prediction of the risk.57 BMD measurement is useful for treatment decision-making, and is even sufficient in cases of very low BMD. There is no evidence that anti-osteoporotic treatment is able to reduce the risk of fractures in women having only clinical risk factors for fractures, low QUS measurements or high bone turnover. The BMD measurement and the bone markers can be used for monitoring therapy, providing that there is quality assurance of the measurements. There is no direct link between the increase in BMD and the decrease in vertebral fracture risk. Moreover, time interval between two BMD measurements is a function of the treatment, but cannot be less than 18 months (anabolic agents) or even more (anti-resorptive agents). Bone marker changes can be assessed in the short term (i.e. after 3–6 months of treatment). They are not yet recommended routinely today, but are useful in situations of poor compliance and difficulties in management of treatment.
SUMMARY BMD measurements have been widely used for the management of osteoporosis. Low BMD is a strong risk factor for fractures, but it explains only a part of an individual’s fracture risk because of its low sensitivity. Combining BMD with other risk factors is a relevant method to predict the risk of fracture in individuals. BMD measurement is useful for treatment decision-making and is even sufficient in cases of very low BMD. BMD measurement can be used for monitoring therapy, and can be repeated 2 years later (on average, depending on the treatment), provided that there is quality assurance of the measurements. A low QUS value is an independent risk factor for osteoporotic fracture in postmenopausal women. However, in the absence of a diagnostic threshold, and with the lack of standardization, the use of QUS alone cannot be recommended for the allocation and monitoring of treatment. Biochemical markers of bone remodelling can be useful for the prediction of fracture risk. A combined approach with BMD and/or clinical factors could improve fracture prediction. Bone markers can be measured in the short term (i.e. after 3–6 months of treatment) for monitoring anti-osteoporotic drugs. The clinical use of these markers requires the control of sources of variability.
Role of DXA, QUS and bone markers 961
Practice points † BMD measurement by DXA is the gold standard for the management of osteoporosis † low BMD is a strong risk factor for fractures, but because of its low sensitivity it explains only a part of an individual’s fracture risk † BMD measurement is useful for treatment decision-making † BMD measurement can be used for monitoring therapy, and the follow-up measurement is a function of precision of the measure, sensitivity to change of the measured site, and expected change induced by the treatment † QUS alone cannot be recommended for the allocation and monitoring of treatment † increase in bone markers is a risk factor of osteoporotic fracture in postmenopausal women † bone marker changes can be assessed in the short term for monitoring antiosteoporotic treatment
Research agenda † fracture risk index combining BMD and other risk factors must be developed and validated in order to estimate the individual’s absolute risk of fracture † the usefulness of the bone markers for monitoring osteoporotic drugs needs to be well established
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