Recommendations for monitoring antiresorptive therapies in postmenopausal osteoporosis

Joint Bone Spine 72 (2005) 26–31 http://france.elsevier.com/direct/BONSOI/

Review

Recommendations for monitoring antiresorptive therapies in postmenopausal osteoporosis Christian Roux *, Patrick Garnero, Thierry Thomas, Jean-Pierre Sabatier, Philippe Orcel, Maurice Audran, pour le Comité Scientifique du GRIO 1 Groupe de Recherche et d’Information sur les Ostéoporoses (Task Force for Research and Information on Osteoporosis), Hôpital Cochin, 27, rue du Faubourg St Jacques, 75014, Paris, France Received 3 February 2004; accepted 1 July 2004 Available online 11 September 2004

Abstract Antiresorptive agents are effective in preventing and treating postmenopausal osteoporosis, provided they are taken as directed. Regular physical examinations including height measurements may fail to ensure optimal compliance. Bone mineral density (BMD) measurement is indispensable for determining whether treatment is warranted. The measurement can be repeated after 2 years at least, provided qualitycontrol procedures are adequate. BMD changes over time should be compared to the least significant change calculated from the in vivo BMD reproducibility at the measurement center. However, BMD changes are not correlated with the fracture risk reduction induced by antiresorptive treatment. Biochemical markers for bone turnover can be monitored after only 3–6 months provided steps are taken to control for intraindividual variability. They are useful when patient compliance is poor or the treatment response inadequate. © 2004 Published by Elsevier SAS. Keywords: Postmenopausal osteoporosis; Bone markers; Bone densitometry; Estrogens; SERMS; Bisphosphonates

1. Introduction Fracture prevention is the goal of bone resorption inhibitor therapy in patients with osteoporosis. However, a decrease in the fracture rate cannot be used to monitor the effectiveness of treatment in the individual patient. Absence of fractures during the first year is not proof that the treatment is working, and a patient with major bone fragility may continue to experience fractures for several months after starting an effective drug regimen. The need for long-term use, constraints related to administration modalities, and potential side effects of antiresorptive agents can result in poor compliance or in drug discontinuation by the patient. Thus, improving compliance is essential to ensure optimal effectiveness. * Corresponding author. Fax: +33-1-44-07-01-07. E-mail address: [email protected] (C. Roux). 1 GRIO Scientific Committee members: E. Attlan, M. Audran, B. BasseCathalinat, C.L. Benhamou, C. Bergot, B. Cortet, P. Dargent-Molina, E. Drapier-Faure, P. Fardellone, C. Jeandel, P.O. Kotzki, M.A. LimouzinLamothe, X. Marchandise, Y. Maugars, P.J. Meunier, P. Orcel, J. Puget, C. Ribot, C. Roux, J.P. Sabatier, B. Sutter, F. Trémollières, Th. Thomas, M.C. de Vernejoul, G. Weryha. 1297-319X/$ - see front matter © 2004 Published by Elsevier SAS. doi:10.1016/j.jbspin.2004.07.003

Providing patients with evidence that their treatment works when taken as directed is likely to improve compliance. Thus, surrogate effectiveness criteria such as bone mineral density (BMD) and bone turnover markers may be useful. This article presents a literature review on the advantages and limitations of these criteria. We will then suggest recommendations based on the opinion of a panel of experts. 2. Physician visits Regular physician visits are invaluable for gathering data on compliance with the drug dosage and administration modalities and for detecting side effects. In addition, height measurement is useful in postmenopausal women. Although nonspecific, a reduction in height can indicate a vertebral fracture, disk space narrowing, exaggeration of the physiological spinal curvatures, or scoliosis. Standing height should be measured using a stadiometer after checking that the line connecting the tragus to the nose is parallel with the floor. Standing height decreases normally during the day, by about 0.6– 1.0 cm over 12 h [1–3]. The reproducibility of

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height measurements depends on the instrument used. The standard deviation of the mean ranged from 0.9 to 1.7 mm in a study that used Harpenden stadiometers [3]. When two different observers did each measurement twice, the standard deviation ranged from 2.4 to 3.2 mm [4]. Most patients do not know their exact height, and a measurement should be obtained around 50 years of age to serve as a reference. A decrease of more than 3 cm compared to this reference value may warrant investigations, most notably radiographs of the spine [5]. Other cutoffs can be used to monitor individual patients.

3. Bone mineral density measurement BMD measurement is needed to select patients for osteoporosis treatment, as there is no proof that drugs for osteoporosis (other than hormone replacement therapy [HRT]) are beneficial in women with clinical risk factors for fractures but normal BMD values. The use of BMD measurement as a tool for monitoring osteoporosis treatment raises both metrological and clinical issues. 3.1. Metrological properties of bone mineral density measurement Reproducibility is far better for BMD measurement than for most laboratory tests. Reproducibility is usually 1–2% at the spine on anteroposterior images and 2–3% at the proximal femur in individuals with normal BMD values; the difference between the two sites is ascribable to greater difficulties with repositioning and examining the femur, as compared to the spine. However, these data obtained under nearly experimental conditions may not apply to everyday clinical practice. Reproducibility depends heavily on qualityassurance factors, including tests to control the quality and performance of the machine, as well as the experience of the operator. Assessment of machine performance requires daily scanning of a phantom (which may be anthropomorphic or not), followed by calculation of the in vitro coefficient of variation (CV), which serves to evaluate short-term and longterm performance and to detect drift in measurement accuracy. These in vitro data, however, do not necessarily reflect in vivo reproducibility, which should be evaluated at each measurement center. Measurements are obtained either three times in each of 15 patients or twice in each of 30 patients, and the CV (m/r) is calculated from the mean (m) and standard deviation (r) of these repeated measurements. The CV is expressed as a percentage and depends on mean BMD values [6]. The standard deviation reflects measurement error, which is a characteristic of machine performance and is independent from the value measured. It can be used to compute the least significant change (LSC) that characterizes a given measurement center; with a confidence interval of 95%, the LSC is calculated as 2.77r. Thus, in practice, two absolute values (g/cm2) can be compared [7], rather than two

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percentages. When serial measurements are obtained in a patient, only changes greater than the LSC (in g/cm2) can be ascribed to treatment effects. Smaller changes may be related to measurement error. The time interval between two measurements in the same patient must be long enough to allow occurrence of a change greater than the LSC. Therefore, it depends on the expected rate of change, which varies according to whether the measurement site is composed predominantly of trabecular or of cortical bone. At the femoral neck for instance, the LSC is usually about 2.77 × 0.011 g/cm2, i.e., about 30 mg/cm2, and consequently treatment-related changes cannot be evaluated in the short-term. At the lumbar spine on an anteroposterior view, the LSC is usually about 2.77 × 0.009 g/cm2, i.e., about 25 mg/cm2, so that a treatment-induced BMD increase can be detected after 2 years. The small changes induced by raloxifene therapy cannot be detected in individual patients. Although the spine may not be the best site for the diagnosis of osteoporosis given the high prevalence of spinal degenerative disease, it is the most sensitive site for detecting changes over time. Computing the LSC provides a means of accounting for regression toward the mean, which is a common property of variation in biochemical parameters [8]. Regression toward the mean is a statistical phenomenon in which values obtained over time tend to move closer to the mean, as compared to initial values. For instance, within a patient population, those individuals with the largest BMD gains after 1 year will tend to have the smallest gains after 2 years, and vice versa. However, use of the LSC shows that these individual variations are related to fluctuations in measurement error rather than to genuine biological variation [7]. 3.2. Clinical usefulness of bone mineral density measurement The clinical usefulness of serial BMD measurement deserves discussion, in the light of several factors. Given the size of the LSC, serial measurements must be spaced at least 2 years apart to detect variations that are larger than those produced by measurement error. With the exception of HRT, treatment dosages cannot be adjusted on the basis of BMD changes. There is no proof that repeating BMD measurements improves compliance, as most patients discontinue antiresorptive medications after a few months because of administration constraints, side effects, or lack of interest. Above all, BMD is used as a surrogate marker for the fracture risk, yet BMD increases do not reliably reflect a reduction in the fracture risk. Although bisphosphonates, raloxifene, and HRT have not been compared in the same study, they seem to produce comparable reductions in the risk of vertebral fractures, of about 30–50%, whereas BMD changes differ markedly across medications. Studies have shown that BMD gains explain only a small proportion of the vertebral fracture risk reduction: 28% with risedronate [9], 16% with alendronate [10], and 4% with raloxifene [11]. It has been suggested that

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Table 1 Biochemical markers for bone turnover. Markers that can be used in clinical practice are in bold type Bone formation Serum Osteocalcin Total alkaline phosphatase and bone alkaline phosphatase Procollagen I C-terminal and N-terminal propeptides (PICP and PINP)

the percentage of BMD change may be related to the change in the relative risk of fracture [12]. In one study, a linear relationship was found between these two parameters, but a 1% increase in spinal BMD was associated with an only 3% decrease in the relative risk of vertebral fracture [10]. For peripheral fractures, in contrast, the risk reduction is clearly related to the BMD gain [13]. Preliminary data suggesting that the fracture risk may decrease despite a reduction in BMD have not been confirmed [14]. Common sense indicates that a BMD increase during treatment should be preferable over a BMD decrease. However, a prospective study found that the fracture risk was more heavily dependent on BMD at baseline than on BMD changes during treatment [15]. 3.3. Conclusion Serial BMD measurements can be used to monitor current antiresorptive treatments (bisphosphonates, raloxifene, and HRT) provided a number of conditions are met. Adequate quality-control procedures must be used. At each measurement center, the LSC must be calculated from in vivo reproducibility data. The LSC is used to estimate the significance of observed changes, in absolute values. BMD measurements must be spaced at least 2 years apart. The main goal of serial BMD measurement is to check that no further bone loss has occurred; quantitation of BMD gains is the second-

Bone resorption Plasma/serum Tartrate-resistant acid phosphatase (TRAP 5b) N-terminal (NTX) and C-terminal (CTX) telopeptides of type I collagen Urine Free pyridinoline (PYD) et deoxypyridinoline (DPD) Procollagen I N-terminal (NTX) and C-terminal (CTX) propeptides Helical peptide of chain alpha I of collagen type I Urinary calcium excretion Urinary hydroxyproline excretion Galactosyl-hydroxylysine

ary objective. This should be explained to the patients, many of whom expect to recover normal BMD values. Finally, BMD should be measured at completion of a treatment sequence, in order to obtain new reference values.

4. Biochemical markers for bone turnover Table 1 lists the main bone turnover markers. At present, routine assays of bone turnover markers are not recommended as a means of selecting patients for antiresorptive treatment. One study found that the efficacy of antiresorptive treatment was independent from the baseline bone turnover level [16]. When using these markers as treatment monitoring tools, intraindividual variability should be taken into account (Table 2). 4.1. Variability in bone turnover markers Intraindividual variability limits the usefulness of bone turnover markers. However, its impact can be minimized by a careful examination of preanalytical and analytical sources of variability. Manual and/or automated assays are available for most bone turnover markers. Within-run and run-to-run reproducibilities range from 3% to 10% [17]. Several factors responsible for preanalytical variability cannot be controlled, such as age, sex, hormonal status, renal and hepatic function,

Table 2 Intraindividual variability (as the coefficient of variation, CV%) in biochemical markers for bone turnover in untreated postmenopausal women (adapted from Hannon and Eastell [30])

Osteocalcin Bone AP

Bone formation Short-term CV% Long-term CV% (1–5 weeks) (3 months–3 years) Serum 7–13 8 7–13 9

PINP PICP

– 10.6

7.5 8.6

NTX CTX

Total DPD (HPLC) Free DPD (ELISA) CTX NTX

Short-term CV% (1–5 weeks) Serum 3.3 8 (fasting) 14 (nonfasting) Urine 12–24 12 – 10–18

Bone resorption Long-term CV% (3 months–3 years) 7.5 9–18

17–63 9–13 18–24 16–25

PAO: bone alkaline phosphatase; PINP: N-terminal propeptide of collagen type I; PIcP: C-terminal propeptide of collagen type I; DPD: deoxypyridinoline; NTX: N-terminal telopeptide of collagen type I; CTX : C-terminal telopeptide of collagen type I

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comorbidities, a recent history of fracture, and current treatments. These factors should be sought routinely and taken into account when interpreting marker values [18]. Controllable sources of preanalytical variability include sampling time, sample preservation procedures, and food intake. Serum levels of the carboxy-terminal peptide of collagen I (CTX), for instance, vary over the 24-h cycle and are influenced by meals (Fig. 1). This was shown by collecting blood samples at 3-h intervals over two 24-h periods in 11 postmenopausal women. The women fasted throughout one 24-h period and ate normally during the other. Mean variability in CTX values over 24-h was 13.6% without and 34% with food [19]. Therefore, to ensure satisfactory reproducibility of serial measurements in a given patient, serum and urine samples must be collected in the morning after an overnight fast; serum samples should be obtained before 9 A.M., if possible, and urine samples at the first or second voiding in the morning. Urinary values should be normalized for the urinary creatinine level. When these rules are followed, intraindividual variability in untreated postmenopausal women ranges from about 5% to 15% for serum bone formation and resorption markers and from 12% to 25% for urinary bone resorption markers. The LSC of values obtained under optimal conditions can be calculated for each marker. In a follow-up study of over 2000 women given bisphosphonate therapy for osteoporosis, the proportion of patients with a decrease in urinary amino-terminal peptide of collagen I (NTX) exceeding the LSC was 65% after 3 months and 84% after 6 months.

phosphonates). After 6 months of oral treatment with 17 beta-estradiol (2 mg/d), urinary CTX and NTX excretion decreased by about 60% and free urinary deoxypyridinoline by about 30% [20]. Similar variations were noted when 17 beta-estradiol was given percutaneously, transdermally, or intranasally [21,22]. During the first 3 months of treatment, changes in bone formation markers may vary with the route of administration. Thus, serum osteocalcin levels decreased by 30% in women given oral estrogen therapy but showed no change with estrogen therapy given percutaneously or intranasally. This difference has been ascribed to a hepatic firstpass effect, which may modify the biological effect of insulin growth factor-1 [23]. With continuous oral bisphosphonate therapy, decreases are largest for type 1 collagen peptide markers (CTX, NTX, and helical peptide), intermediate for total pyridinoline and deoxypyridinoline excretion, and small or absent for urinary excretion of free pyridinoline and deoxypyridinoline. These differences in response may be ascribable to differences across bisphosphonates regarding effects on the enzymes involved in collagen breakdown and on the renal metabolism of pyridinoline peptides. With oral alendronate, 10 mg/day, urinary CTX and NTX decreased by about 70% and total deoxypyridinoline by about 50%. Oral risedronate, 5 mg/day, decreased peptide pyridinoline markers (urinary NTX and serum CTX) by 35–50%. Reductions in bone resorption markers are similar with daily vs. weekly administration of alendronate or risedronate. After intravenous ibandronate or pamidronate, bone resorption markers drop sharply then increase slowly. The time to, and magnitude of, the increase vary with the dosage and frequency of the injections. Zoledronate induces long-lasting changes in bone resorption markers. Discontinuation of alendronate therapy is followed by an increase in bone remodeling that denotes resumption of bone cell activity. When alendronate was stopped after 5 years, the bone turnover increase was about 20%, so that the therapeutic gains were not entirely lost [24]. This phenomenon should be taken into account when designing treatment strategies. Changes in bone remodeling markers after discontinuation of risedronate are being evaluated. As compared to bisphosphonates or HRT, oral raloxifene induces smaller decreases in bone remodeling markers, of about 30–40% for urinary CTX and 20–30% for bone formation markers [25]. Calcium and vitamin D supplements in physiological dosages induce small but significant decreases in bone resorption markers, of about 10–20% [26].

4.2. Effect of treatments on biochemical markers

4.3. Usefulness of markers in clinical practice

After the initiation of antiresorptive therapy, bone resorption markers decline gradually until they reach a plateau after 3–6 months, whereas bone formation markers decrease later and reached a plateau after 6–12 months. The magnitude of the decreases varies according to the potency of the medication (with bisphosphonates producing the largest reductions), the marker, and the treatment regimen (route of administration of HRT or continuous vs. cyclic administration of bis-

In prospective studies, changes in bone remodeling markers were linked to changes in BMD, although the correlations were weak. It has been suggested that markers may be useful for identifying patients whose BMD fails to increase under treatment. Predicting a BMD gain greater than 3% with 90% specificity requires a 45% decrease in a urinary resorption marker (CTX or NTX) with HRT and a 65% decrease with alendronate. In practice, markers are useful mainly for pre-

Fig. 1. Circadian variations in serum levels of carboxy-terminal peptide of collagen I (CTX) and effects of food intake (from Quest et al. [18]).

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Fig. 2. Use of bone resorption markers (urinary amino- and carboxy-terminal peptides of collagen I, NTX and CTX) for predicting the effectiveness of oral risedronate in decreasing incidence vertebral fractures (from Eastell et al. [28]).

dicting the fracture-preventing effect of treatment. After 6 months of raloxifene therapy, changes in serum osteocalcin or bone alkaline phosphatase were associated with the risk of subsequent vertebral fracture, whereas changes in BMD were not [27]. During risedronate therapy, changes in urinary CTX and NTX after 3 and 6 months explained 50–70% of the reduction in vertebral fractures and 54–74% of the reduction in nonvertebral fractures [28]. In this study, the relation between the magnitude of the marker decrease and the risk of vertebral fractures was not linear (Fig. 2); no additional fracture-preventing effect was obtained beyond a 60% reduction in urinary CTX or a 40% reduction in urinary NTX [28]. This finding of considerable practical relevance indicates a need for similar studies with other antiresorptive medications. A study of alendronate reported in abstract form found that the risk of vertebral fractures over nearly 4 years was significantly correlated with 1-year decreases in bone alkaline phosphatase, procollagen type 1 N-terminal propeptide (PINP), and serum CTX [29].

antiresorptive treatments in patients with postmenopausal osteoporosis. These tests have a number of limitations. For instance, they provide no information on changes in bone microarchitecture, which are currently a focus of methodological and technological research. However, osteoporosis is a chronic disease for which burdensome treatments are given for many years, making intermediate evaluation of treatment effectiveness crucial. BMD and bone remodeling markers will generate even greater interest when anabolic agents become available, as these medications can induce major BMD changes in the short-term and act by stimulating bone remodeling within a few months.

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4.4. Conclusion [3]

Biochemical markers can be used to monitor antiresorptive treatments (bisphosphonates, raloxifene, or HRT) in patients with osteoporosis. Only changes greater than the LSC for the marker of interest indicate treatment-related effects. The marker most relevant to the medication used should be selected for monitoring. Assays of resorption markers should not be done before 3–6 months and those of formation markers before 6 months. Assays of bone remodeling markers are not recommended for routine monitoring but may be useful when poor compliance with the dosage or administration instructions is suspected or when the treatment is ineffective, in order to assist in the selection of the second-line treatment.

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5. Conclusion When used with discernment, absorptiometry and assays of markers for bone remodeling are helpful for monitoring

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