Long-term biochemical response after bisphosphonate therapy in Paget's disease of bone. Proposed intervals for monitoring treatment

L. Alvarez1,2, P. Peris3, N. Guañabens2,3, S. Vidal4, Ll. Quintó5, A. Monegal3, F. Pons4, A. M. Ballesta1 and J. Muñoz-Gómez2,3

1 Service of Clinical Biochemistry, Hospital Clinic, Barcelona, 2 Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 3 Service of Rheumatology, Hospital Clinic, Barcelona, 4 Service of Nuclear Medicine, Hospital Clinic, Barcelona and 5 Epidemiology and Biostatistics Unit, Hospital Clinic, Barcelona, Spain.

Correspondence to: L. Alvarez, Servicio Bioquimica Clinica, Hospital Clínic, C/ Villarroel 170, 08036 Barcelona, Spain. E-mail: lalvarez{at}medicina.ub.es


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives. To monitor the long-term evolution of Paget's disease activity after treatment with tiludronate by using serum total alkaline phosphatase (TAP) and more sensitive markers such as bone alkaline phosphatase (BAP), procollagen type I N propeptide (PINP) and urinary N-terminal cross-linking telopeptide of type I collagen (NTX); to analyse the predictors of long-term response to therapy; and to study the most appropriate intervals of time for monitoring the response to therapy.

Methods. Thirty-two patients with Paget's disease were included in the study. All received 400 mg of oral tiludronate daily for 3 months. A total of 21 patients completed the study. In these patients, serum TAP, BAP and PINP and urinary NTX were measured at baseline and at 1, 6, 12 and 24 months after discontinuation of therapy. Quantitative bone scintigraphy was performed at baseline and at 6 and 24 months after the end of treatment, obtaining a scintigraphic activity index (SAI). Patients were classified into two groups depending on the long-term response to treatment: Group 1, patients who presented a persistent and significant decrease in disease activity at this time, n = 12 (57%) and Group 2, patients who presented a relapse in the activity of the disease at 24 months after treatment, n = 9 (43%). The relapse of disease activity was defined as a significant increase of SAI (>13%) between 6 and 24 months after the end of treatment, whereas the response to therapy was defined as a significant reduction in SAI (>13%) at 6 months after the end of treatment. In addition, these results were compared with the biochemical evolution of bone markers.

Results. Biochemical markers and SAI decreased significantly after therapy and the nadir response was observed at 6 months. At this time 100% of patients responded to therapy. The persistent long-term response was associated with lower baseline indices of bone turnover (serum BAP<60 ng/ml or TAP<600 IU/l). The intervals of time for monitoring depended on the marker used: no patient from Group 1 presented a biochemical relapse in serum TAP at 1 and 2 yr after the end of treatment whereas 33 and 45% of these patients showed relapsed serum BAP at these time points. Moreover, all patients from Group 2 presented a biochemical relapse of serum BAP at 2 yr whereas in only 33% of these patients did serum TAP relapse at this time.

Conclusion. Most of the Pagetic patients treated with tiludronate presented a long-term response, which persisted 2 yr after the end of treatment. The nadir response to treatment was observed 6 months after discontinuation of therapy whereas the relapse of disease activity was already observed 1 yr after the end of therapy and depended on both the baseline disease activity and the bone marker used in the evaluation.

KEY WORDS: Treatment, Bone markers


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Paget's disease of bone is a disorder characterized by disorganized bone remodelling starting with a marked increase in osteoclastic bone resorption which can lead to bone pain and deformity [1]. The principal strategies for treating Paget's disease are aimed at suppressing the increased osteoclastic activity and bisphosphonates are the treatment of choice in this disorder. These agents have been shown to effectively decrease the disease activity for prolonged periods of time in a large percentage of patients [2].

Biochemical markers of bone turnover are useful tools for assessing the effect of therapy in this disorder. Bone alkaline phosphatase (BAP) and procollagen type I N propeptide (PINP) as markers of bone formation and N-terminal cross-linking telopeptide of type I collagen (NTX) as a marker of bone resorption have been shown to be the most sensitive markers in monitoring disease activity, especially in low-active and in monostotic disease [3]. Nevertheless serum total alkaline phosphatase (TAP) is still considered to be the standard marker for evaluating bone turnover in most Pagetic patients [4] and the normalization of marker levels is the main therapeutic objective. Since most of the studies that use bisphosphonate therapy have shown a nadir in the response of biochemical markers at 3–6 months after starting therapy, it has been recently recommended [4] that the measurement of bone turnover for monitoring Paget's disease should be carried out every 3 months for the first 6 months of therapy and thereafter at intervals of 6 months, and a change higher than 25% in serum TAP should be considered as a significant treatment response. However, the use of the new more potent bisphosphonates has been associated with prolonged periods of treatment response and the new bone markers have also been shown to be more effective in detecting significant changes in the activity of this process. These considerations point to the need to determine the recommended intervals for monitoring treatment in long-term follow-up studies taking into account the bone markers used in this disorder. Therefore, the aims of this study were (1) to monitor the long-term evolution of Paget's disease activity after 3 months of treatment with tiludronate by using serum TAP and more sensitive markers such as BAP, PINP and NTX, (2) to analyse the predictors of long-term response to therapy and (3) to study the most appropriate intervals of time for monitoring the response to therapy.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Subjects
Thirty-two patients with Paget's disease of the bone, 18 men and 14 post-menopausal women, aged 42–86 yr [mean ± standard error of the mean (SEM) 61.75 ± 2.21 yr] were prospectively included in the study. In all patients, the diagnosis of Paget's disease was documented by plain radiographs and bone scintigraphy. Fifty per cent of patients had polyostotic disease. Patients with skull involvement were not included in the study because it has been shown that this location is associated with differing behaviour of biochemical markers [5]. Liver and kidney function tests were normal in all patients. Those who had been treated with calcitonin during the previous year or with plicamycin or bisphosphonates during the previous 2 yr were not included in the study. All patients included in the study were treated with tiludronate.

Reference values were obtained from a sample of 37 healthy volunteers of similar age and gender (15 men and 22 women, mean ± SEM 65.05 ± 1.54 yr) with no evidence of disturbances of calcium metabolism or metabolic bone disease.

All patients provided informed consent for participation and the Ethics Committee of the hospital approved the study.

Study design
All patients completed treatment with 400 mg/day of oral tiludronate for 3 months. Patients were carefully instructed to take the tiludronate 2 h after breakfast with 200 ml of water, as food may interfere with intestinal absorption, and not to take dairy products or antacids containing calcium, iron, magnesium or aluminium within 2 h of treatment. Laboratory assessment was carried out on each patient before the start of treatment and at 1, 6, 12 and 24 months after discontinuation of therapy. Bone scintigraphy was performed at baseline and at 6 and 24 months after the end of treatment.

Biochemical determinations
Blood and second morning urine samples were obtained from each subject on the same day between 8.00 and 10.00 a.m. after an overnight fast. Serum and centrifuged urine samples were kept frozen at –20°C until analysis.

The serum bone formation markers measured were TAP (spectrophotometric kinetic assay, according to the recommendations of the Scandinavian Committee for Clinical Chemistry and Clinical Physiology, using DEA buffer in a DAX 72 analyser; Bayer Diagnostics Technicon, Tarrytown, NY, USA), BAP (Tandem-R Ostase; Beckman Coulter, Fullerton, CA, USA) and PINP (Intact PINP; Orion, Espoo, Finland). The urinary marker of bone resorption measured was NTX (Osteomark; Ostex International Inc, Seattle, WA, USA). Results of NTX determinations were expressed as a ratio to urinary creatinine. The intra-assay and inter-assay coefficients of variation for each marker were as follows: TAP 0.75 and 3.1%; BAP 3.5 and 8.8%; PINP 4.1 and 5.6% and NTX 5.5 and 9.2%. The intra-individual variabilities of bone markers obtained from patients with stable Paget's disease were as follows: TAP 12.4%; BAP 4.9%; PINP 10% and NTX 15.8%. The critical difference values obtained in these patients for TAP, BAP, PINP and NTX were 35, 25, 35 and 47% respectively [6]. Based on this, a variation higher than 35% for serum TAP and PINP, >25% for BAP and >47% for urinary NTX was considered to be a significant change.

Quantitative bone scintigraphy
Bone scintigraphy was performed 2 h after an intravenous injection of 740 MBq (20 mCi) of 99m-technetium-hydroxymethylene bisphosphonate. Whole-body images were acquired simultaneously in both the anterior and posterior views using a dual-headed gamma camera (Helix, Elscint, Israel) and stored in a 512 x 512 matrix for quantitative analysis. From these data a scintigraphic activity index (SAI), which reflects both the extent and activity of the disease, was obtained as described elsewhere [7]. The intra-individual variability of SAI was 4.5% and the critical difference value for this measurement was 13%. This value has also been referred to as the least significant change.

Assessment criteria
Patients were classified into two groups depending on the long-term response to treatment:

The time point of 6 months was selected because the nadir response to tiludronate therapy was observed at this time. The relapse in disease activity was defined as an increase of SAI of more than 13% between 6 and 24 months after the end of treatment, whereas a response to therapy was defined as a decrease of SAI of less than 13% in values from baseline to 6 months after the end of treatment.

In addition, we evaluated the response to therapy as well as the biochemical relapse for each bone marker analysed in the study.

Statistical analysis
Between-group comparisons were performed using the Mann–Whitney U-test. Differences between proportions were assessed by the {chi}2 test.

Receiver-operating characteristic (ROC) curves, which fit sensitivity against (1–specificity), were constructed using relapse versus no relapse in disease activity classified according to SAI change. From ROC curves, the value with a simultaneous high sensitivity and specificity was selected as the cut-off value to categorize BAP and TAP levels.

In each patient, the evaluation of the relationship between disease response at 24 months after discontinuation of treatment and the type of skeletal involvement (monostotic versus polyostotic) as well as TAP and BAP baseline levels was performed using logistic regression models. Stepwise procedure was used to estimate a multivariate model, with P<0.05 and P>0.10 as enter and out criteria, respectively.

All comparisons were made using a significance level of 0.05.

All statistical analyses were performed using SPSS software for Windows (version 10.0).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Of the 32 patients who underwent treatment four patients withdrew during the study due to the occurrence of adverse effects and seven did not come to the follow-up control. In the end, 21 patients were evaluated (12 monostotic, 9 polyostotic).

At entry Pagetic patients showed higher mean baseline values for all markers compared with controls (Table 1). In addition, four monostotic patients showed serum TAP values within the reference range and four additional patients (two monostotic and two polyostotic) presented slightly increased serum baseline values of this marker (less than 15% above the upper limit of normality).


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TABLE 1. Effect of tiludronate on bone markers and scintigraphic activity indices (SAI). There were significant differences in all bone markers analysed between Pagetic patients at baseline and controls. After therapy, biochemical markers and SAI significantly differed from baseline values in all intervals studied

 
After therapy all biochemical markers analysed in the study as well as SAI showed a significant decrease at the different time points analysed throughout the study period compared with baseline values. The lowest mean values were observed at 6 months after the end of treatment and it was considered to be the time of maximum biochemical response (nadir) (Table 1). At this time, the mean percentage of reduction in serum levels of BAP, PINP and urinary NTX were 69, 68 and 64% respectively, whereas the mean percentage of reduction for serum TAP was 51%. Twenty out of 21 patients (95%) showed a significant response to therapy using serum BAP and PINP and 16 out of 21 patients (76%) also showed a significant response using serum TAP and urinary NTX. In addition, 100% of patients responded to therapy using SAI. Moreover, at this time the percentage of patients with biochemical markers within the normal range were 71% for serum TAP, 76% for serum BAP, 65% for serum PINP and 62% for urinary NTX. Conversely, no patient presented normalized bone SAI.

Differences between patients with inactive and relapsed disease at 24 months after the end of treatment
Twelve patients (57%) (nine monostotic and three polyostotic patients) did not show an increase of disease activity assessed by scintigraphic criteria at 24 months after finishing therapy (Group 1) whereas nine patients (43%) (three monostotic and six polyostotic) showed a relapse in disease activity at this time (Group 2). Although polyostotic patients tended to relapse more frequently than monostotic patients, the differences between both groups were not significant (P = 0.143).

At entry, patients from Group 2 presented significantly higher mean baseline values of serum TAP, BAP and urinary NTX (Fig. 1). At 6 months after the end of treatment serum PINP values were significantly higher in Group 2, whereas at the end of the study the mean values of all markers of bone formation were significantly higher in Group 2 (Fig. 1). No significant differences in SAI values were observed between either group throughout the study. When the mean percentage of reduction at 6 months after the end of treatment was analysed no significant differences in bone markers were observed except for serum BAP, which showed a significantly higher mean percentage of reduction in Group 2 at this time compared with Group 1 (77 vs 62%, P<0.05) (data not shown).



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FIG. 1. Evolution of individual values of bone markers throughout the study in Pagetic patients at 0 (baseline), 1, 6, 12 and 24 months after the end of treatment with tiludronate. Mean values of each group are indicated by thicker lines [broken (Group 2) or unbroken (Group 1)]: *P<0.05, Group 1 versus Group 2; **P<0.001, Group 1 versus Group 2.

 


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FIG. 2. Evolution of individual values of SAI throughout the study in Pagetic patients at 0 (baseline), 1, 6, 12 and 24 months after the end of treatment with tiludronate. Mean values of each group are indicated by thicker lines [broken (Group 1) or unbroken (Group 2)].

 
As shown in Table 2, the biochemical relapse depended on the bone marker, the time point and the group of patients analysed. At 12 months after the end of treatment no patient from Group 1 presented a biochemical relapse in serum TAP and PINP while 33% of patients showed a relapse in serum BAP. At 24 months these values increased to 45 and 50% when analysing serum BAP and PINP respectively. In Group 2, 13% of patients presented a relapse in serum TAP at 12 months while 57% of these patients presented a relapse in serum BAP at the same time point. In addition, all patients from this group presented a relapse in serum BAP values at 24 months whereas only 33% of the patients showed relapsed serum TAP at this time. Conversely, serum PINP and urinary NTX were less sensitive markers in this group of patients (Table 2).


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TABLE 2. Percentage of patients who showed a biochemical relapse in bone markers at 12 and 24 months after the end of treatment

 
Factors related to response to therapy
Both baseline values of serum BAP>60 ng/ml and TAP>600 IU/l were related to the relapse in disease activity at 24 months after the end of therapy with a sensitivity of 66.6% when the specificity was 75%.

Table 3 shows the univariate odds ratios for type of skeletal involvement (monostotic and polyostotic) and baseline values of TAP and BAP after their stratification into <600 and >600 IU/l and <60 and >60 ng/ml respectively. In the multivariate model, serum BAP was the only marker independently related to the relapse in disease activity (P = 0.014) [odds ratio 10.5 99.5%, CI: 1.36; 81.05)].


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TABLE 3. Univariate odds ratios for type of skeletal involvement and baseline values of serum TAP and BAP after data stratification

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study shows that most of Pagetic patients treated with tiludronate at the approved dosage presented a long-term response, which persisted 2 yr after the end of treatment. Nadir values for bone markers were observed at 6 months after completing treatment whereas a relapse of disease activity was already observed 1 yr after and depended on both the baseline activity of the disease and the bone marker used in the evaluation. Long-term response to therapy was associated with lower baseline indices of bone turnover, especially with baseline serum BAP lower than 60 ng/ml or serum TAP lower than 600 IU/l. In addition, the results of the present study suggest that it is appropriate to monitor treatment in these patients at 6 months after the end of therapy and thereafter at intervals of 6 months in more active patients at baseline (those patients with baseline serum TAP >600 IU) and on a yearly basis in the remaining patients if serum TAP is analysed. If a more sensitive marker such as serum BAP is used the monitoring of treatment could be carried out at 6-month intervals, independently of baseline disease activity.

In recent guidelines on the management of Paget's disease [4] it is recommended that bisphosphonates be used as a first option to treat this disorder and that treatment be monitored by the measurement of bone markers every 3 months for the first 6 months of therapy and thereafter at intervals of 6 months [4]. Nevertheless, the new bisphosphonates have shown a long-term response in bone turnover in a high number of patients with a similar percentage of reduction in bone markers after 3–6 months of therapy with oral bisphosphonates such as tiludronate, risedronate or alendronate [3, 4, 810]. In the present study, the nadir response to treatment was observed at 6 months after discontinuation of therapy, with a mean percentage of reduction in serum BAP and TAP values reaching 69 and 51%, respectively. In addition, the treatment was effective in almost all patients. Indeed, nearly 100% of patients showed a significant response using SAI as well as serum BAP and PINP at this time. Although it has generally been accepted that a change of 25% in serum TAP activity is a significant change in the activity of Paget's disease [4], in the present study we considered variations higher than 35% for serum TAP and PINP, 25% for serum BAP and 47% for urinary NTX as the least significant changes. These figures are the critical difference values for these markers that were obtained from a 1-yr follow-up study of a group of untreated Pagetic patients with stable disease [6] and it seems to be the most reliable value for detecting a true change in the activity of the disease.

Whether or not other factors such as anti-resorptive therapy or disease activity influence the critical difference values in Pagetic patients is unknown. Although the optimum levels of reduction in bone turnover have not been fully established, it has been suggested that biochemical markers ideally should be suppressed into the population reference range. Nevertheless, it should be noted that nearly 25% of our patients showed normal or slightly increased serum TAP values at entry, and that although 76% of patients showed normalized serum BAP values at 6 months after the end of treatment none of these patients showed normalized bone SAI at this time. Because of this we evaluated the response to therapy and the relapse in disease activity as a significant change in the SAI and we compared it with the significant changes in bone markers, it being the most common and useful test for monitoring disease activity in these patients. Perhaps the scintigraphic index didn’t normalize because of abnormal bone structure, which may not change or may change very slowly with treatment.

Previous studies have shown a long-lasting remission of disease activity with the new bisphosphonates. Miller et al. [8] showed a persistent remission in Paget's disease activity at 18 months in 53% of patients who had undergone 2 months’ therapy with risedronate. Similarly, in our study 57% of the patients showed a long-term response at 2 yr after the end of therapy. When the factors associated with long-term response to therapy were evaluated, we observed that baseline bone turnover was a factor related to long-term evolution. Patients with baseline serum BAP values higher than 60 ng/ml had a 10.5 times greater probability of relapse in the disease activity at 2 yr than patients with lower values. These results are in agreement with others described in previous studies showing that initial pretreatment bone turnover markers are one of the major determinants in remission of Paget's disease activity [1113]. Nevertheless, and contrary to our data, in these studies the magnitude of response to therapy was another factor related to remission in disease activity. Although the reasons for these discrepancies are unknown the form of administration of the drug may play a role. Indeed, in the present series bisphosphonate was given orally whereas in the other studies it was administered intravenously. All these findings suggest that the dosage and the duration of bisphosphonate therapy should be adjusted to baseline disease activity, since both dosage and duration of treatment do not appear to be effective enough in patients with more active disease and probably need to be evaluated according to the bisphosphonate used. In this sense, Khan et al. [14] found that the long-term response to clodronate in Paget's disease depended on the duration and the dose of the drug administered. In addition, other factors such as the type of bisphosphonate given in therapy and the previous treatment of the patient may play a role [15].

It should be pointed out that the evaluation of relapse in Paget's disease activity clearly depends on the marker used. Indeed, nearly 50% of patients with long-term response presented a biochemical relapse in serum BAP and PINP values at 2 yr after the end of treatment, whereas no patient from this group showed a biochemical relapse in serum TAP. These data indicate that serum BAP and PINP are more sensitive than serum TAP and even more sensitive than the quantitative bone scan in detecting a significant relapse in the activity of the disease. Moreover, serum BAP was the most sensitive marker in identifying patients who showed a significant change in SAI. In fact, of all the markers used serum BAP was the one that showed a biochemical relapse in 100% of these patients at 24 months after the end of treatment, thus confirming its higher sensitivity in monitoring Paget's disease of the bone. In addition, a resorption marker such as NTX seems to offer little clinical benefit in the evaluation of these patients since only 22% of patients who showed a relapse in disease activity at 24 months after the end of therapy had a biochemical relapse in this marker.

In summary, all these data indicate that the recommended time points for monitoring Paget's disease activity clearly depend on the baseline activity of the disease and on the marker used for monitoring, since a more sensitive marker such as serum BAP would detect changes in disease activity earlier than serum TAP, which is a less sensitive marker. From our results we recommend that in Pagetic patients taking tiludronate, bone turnover should be measured at 6 months after the end of therapy (since at this time the nadir response was observed in almost 100% of patients) and thereafter at intervals of 6 months in more active patients at baseline (those patients with baseline serum TAP > 600 IU/l) and on a yearly basis in the remaining patients if only serum TAP is analysed. If a more sensitive marker is used, such as serum BAP, we recommend that treatment be monitored at 6-month intervals, independently of baseline disease activity. The above data may help us to decide what is the best time to retreat patients with Paget's disease of the bone.


    Acknowledgments
 
The authors are grateful to Louise Connolly for reviewing the English.

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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  11. Papapoulos SE, Frolich M. Prediction of the outcome of treatment of Paget's disease of bone with bisphosphonates from short-term changes in the rate of bone resorption. J Clin Endocrinol Metab 1996;81:3993–7.[Abstract]
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Submitted 22 October 2003; revised version accepted 6 February 2004.



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