- Email: [email protected]
Single infusion of zoledronate in Paget’s disease of bone: a placebo-controlled, dose-ranging study
Bone Vol. 24, No. 5, Supplement May 1999:81S– 85S
Single Infusion of Zoledronate in Paget’s Disease of Bone: A Placebo-Controlled, Dose-Ranging Study H. BUCKLER,1 W. FRASER,2 D. HOSKING,3 W. RYAN,4 M. J. MARICIC,5 F. SINGER,6 M. DAVIE,7 I. FOGELMAN,8 C. A. BIRBARA,9 A. M. MOSES,10 K. LYLES,11 P. SELBY,12 P. RICHARDSON,13 J. SEAMAN,13 K. ZELENAKAS,13 and E. SIRIS14 1
Hope Hospital, Salford, UK Department of Clinical Chemistry, Royal Liverpool University Hospitals, Liverpool, UK 3 Nottingham City Hospital, Nottingham, UK 4 Rush Presbyterian–St. Luke’s Medical Center, Chicago, IL, USA 5 University of Arizona Health Sciences Center, Tucson, AZ, USA 6 John Wayne Cancer Institute, Santa Monica, CA, USA 7 Robert Jones and Agnes Hunt Hospital, Oswestry, Shropshire, UK 8 Osteoporosis Unit, Nuclear Medicine Department, Guy’s Hospital, London, UK 9 University of Massachusetts Medical School, Worcester, MA, USA 10 State University of New York Health Science Center, Syracuse, NY, USA 11 Duke University Medical Center and VA Medical Center, Durham, NC, USA 12 University of Manchester, Manchester, UK 13 Clinical Research, Novartis Pharmaceuticals, East Hanover, NJ, USA 14 Columbia University College of Physicians and Surgeons, New York, NY, USA 2
ical response to bisphosphonate therapy and the duration of remission achieved. More complete effects suppress bone resorption, as reflected in nadir and plateau levels of biochemical indices of bone turnover, such as urinary hydroxyproline excretion and alkaline phosphatase, which are usually associated with a longer duration of remission.9,13 However, prolonging duration of therapy does not appear to compensate for the less marked suppression of disease activity seen with lower doses of bisphosphonates.2 Sustained and effective suppression of osteoclast activity of sufficient degree and duration might prevent recruitment of new pagetic osteoclasts with eventual destruction of the abnormal osteoclast population.5 Thus, more potent antiresorptive drugs offer the possibility of greater suppression of abnormal osteoclast function, thereby eliminating the need for continuing treatment for long time periods. Zoledronate is a heterocyclic nitrogen-containing bisphosphonate with antiresorptive potency that is at least 120 times greater than that of pamidronate.10 The relatively low doses that are clinically active are expected to have little adverse effect on mineralization and potentially reduced side effects compared with other bisphosphonate compounds requiring higher dose regimens. The present study was conducted to assess the doseresponse effects of zoledronate administered as a single 1 h infusion on biochemical markers of bone turnover in patients with Paget’s disease of bone.
Introduction Paget’s disease of bone is a unifocal or multifocal bone remodeling disorder characterized by dramatic increases in osteoclast size, number, and activity. Increased bone resorption coupled with increased osteoblast-mediated new bone formation produce structurally inferior bone at the affected sites. Pagetic lesions are most frequently found in the pelvis, spine, skull, femur, and tibia.5 The most common clinical complications of Paget’s disease are pain, bone deformity, fractures, and syndromes of neurological compression.16 Clinical symptoms are usually accompanied by marked abnormalities in biochemical markers of bone resorption and bone formation. As potent inhibitors of bone resorption, bisphosphonates are now commonly used to treat patients with Paget’s disease. Substantial reductions in biochemical indices of disease activity as well as symptomatic relief have been demonstrated with a number of bisphosphonates.3,6 – 8,14 Treatment effects generally last for several months or longer following a course of therapy. The various bisphosphonate compounds that have been evaluated for clinical use vary widely in potency due to differences in side-chain structure.15,17 For example, the newer amino- and nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate) have potent antiresorptive activity at doses that do not produce mineralization defects, as may be seen with etidronate. However, the aminobisphosphonates may be associated with other side effects: fever, malaise, lymphopenia, hypocalcemia, and esophagitis.1 There is a positive relationship between the initial biochem-
Materials and Methods We studied 176 patients with Paget’s disease of bone (108 males and 68 females, mean age 71 years) at 20 investigational sites in the United States and the United Kingdom (80 patients in the USA and 96 patients in the UK). One hundred sixty-six patients were white, 7 black, and 3 of other racial origin. The baseline serum alkaline phosphatase concentrations were at least twice the upper limit of the normal reference range (USA 39 –117 IU/L,
Address for correspondence and reprints: Ethel Siris, M.D., Center for the Prevention and Treatment of Osteoporosis, Metabolic Bone Diseases Program, Harkness Pavillion 9-964, 180 Fort Washington Avenue, New York, NY 10032. E-mail: [email protected] © 1999 by Elsevier Science Inc. All rights reserved.
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UK 30 –135 IU/L). No patients had been treated with calcitonin or plycamicin in the 3 months prior to the study or with bisphosphonates in the 6 months prior to the study. One hundred twenty of the patients had been treated with one or more Paget’s disease medications in the past: 112 with a bisphosphonate; 64 with calcitonin; and 6 with plycamicin. X-ray confirmation of Paget’s disease was obtained if there was no previous X-ray record or, in patients with painful lytic disease of the long bones, to rule out impending fractures. Patients with creatinine clearance ,60 mL/min were excluded from the study unless serum creatinine levels were within the normal range; patients with abnormal hepatic function were excluded from the study. The study protocol was approved by the institutional review board at each study site, and informed consent was obtained from all patients prior to enrollment. Following baseline assessment, the patients were randomized in a double-blind manner to receive a single 1 hour intravenous infusion of 50, 100, 200, or 400 mg zoledronate in 60 mL of 5% dextrose in water, or a placebo (60 mL of 5% dextrose in water). Morning fasting blood and 2 h urine samples were obtained between 3 and 14 days prior to infusion (baseline assessment); immediately postinfusion; and at 5, 10, 30, 45, 60, and 90 days postinfusion. Blood measurements included a complete blood count, and serum calcium, phosphate, magnesium, creatinine, blood urea nitrogen, electrolytes, liver function tests, total protein, albumin, urate, total alkaline phosphatase, and bone-specific alkaline phosphatase. Urine was assayed for calcium, creatinine, hydroxyproline, pyridinoline, and deoxypyridinoline. Creatinine clearance based on a 24 h urine collection was determined at baseline and 90 days postinfusion. Serum bone-specific alkaline phosphatase and urinary calcium, creatinine, hydroxyproline, pyridinoline, and deoxypyridinoline assays were performed by Nichols Institute (San Juan Capistrano, CA). Serum bone-specific alkaline phosphatase was measured by a colorimetric assay; urinary calcium was assayed by atomic absorption spectrometry; urinary creatinine and total hydroxyproline were measured by colorimetric assay; total urinary pyridinoline and deoxypyridinoline were assayed by high-performance liquid chromatography (HPLC). Urinary calcium, hydroxyproline, pyridinoline, and deoxypyridinoline were expressed as a ratio to creatinine concentration. Oral temperature was measured immediately prior to infusion, at 1–2 h postinfusion, and at each subsequent evaluation visit. A baseline electrocardiogram (ECG) was obtained if one had not been obtained within 3 months prior to study. All efficacy analyses were based on all randomized patients who had at least one postbaseline measurement (intent-to-treat analysis). Four of the 176 patients did not complete all postbaseline evaluations (one patient treated with 400 mg withdrew due to unsatisfactory therapeutic effect; one patient each, treated with 50, 100, and 400 mg, died during the study of causes related to coexisting conditions). Comparisons between treatment groups were made using summary measures. The primary efficacy variables were serum alkaline phosphatase and urinary hydroxyproline; the criterion for effectiveness was that the maximum percent reduction from baseline (maximum change from pretreatment values) over the entire 3 month trial be statistically significantly greater for zoledronate as compared with placebo. Secondary efficacy variables were bone-specific alkaline phosphatase and urinary pyridinoline, deoxypyridinoline, and calcium. The percent reduction from baseline for all variables at all posttreatment visits was also analyzed. Between-treatment comparisons of the active treatment groups vs. placebo were made using the nonparametric Wilcoxon rank-sum test, with Bonferroni adjustment for multiple compar-
Bone Vol. 24, No. 5, Supplement May 1999:81S– 85S
Figure 1. Median percent changes in urinary hydroxyproline-creatinine following treatment with zoledronate.
isons for statistical significance. For graphical display, all values were expressed as median percent decreases from baseline. The proportion of patients who demonstrated a therapeutic response for serum alkaline phosphatase and urinary hydroxyproline:creatinine ratio was compared between treatment groups, and the comparisons were analyzed using the Fisher exact test. A therapeutic response was defined as a 50% decrease from baseline or normalization at any time posttreatment. Overall comparability among treatment groups was examined at baseline for all intent-to-treat patients by means of Fisher exact, Kruskal–Wallis, and F-tests, for demographic characteristics and biochemical measurements (serum total alkaline phosphatase, serum bone-specific alkaline phosphatase, urinary hydroxyproline:creatinine ratio, urinary calcium:creatinine ratio, urinary pyridinoline:creatinine ratio, and urinary deoxypyridinoline:creatinine ratio). At the end of the trial, patients were grouped into strata based on whether their baseline serum alkaline phosphatase was less than or equal to three times the upper limit of the normal reference range (stratum 1) or greater than three times the upper limit of the normal reference range (stratum 2), for comparison of the analysis of the maximum percent reduction from baseline between the two strata. Results There were no statistically significant differences among groups in key demographics or in biochemical measurements at baseline assessment (Table 1). A rapid reduction in median fasting urinary hydroxyproline: creatinine excretion, which reached a nadir by day 10, was seen in all four treatment groups (Figure 1); this reduction was significantly greater for 200 mg and 400 mg compared with placebo, and for 400 mg compared with the other treatment groups, at all posttreatment visits. This was followed by a fall in
Figure 2. Median percent changes in serum alkaline phosphatase following treatment with zoledronate.
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Table 1. Patient characteristics at baseline for each treatment group Dose of zoledronate Characteristic No. of patients Gender no. of patients (%) Men Women Mean age 6 SD (years) Severity of disease,a no. of patients (%) Stratum 1 Stratum 2 Median serum alkaline phosphatase (U/L) Median urine hydroxyproline:creatinine ratio
50 mg
100 mg
200 mg
400 mg
Placebo
35
38
33
35
35
19 (54) 16 (46) 73 6 7
24 (63) 14 (37) 70 6 8
22 (67) 11 (33) 69 6 10
19 (54) 16 (46) 70 6 8
24 (69) 11 (31) 72 6 11
11 (31) 24 (69) 542 0.108
12 (32) 26 (68) 422 0.097
13 (39) 20 (61) 438 0.081
15 (43) 20 (57) 372 0.112
13 (37) 22 (63) 389 0.085
Severity of disease based on serum alkaline phosphatase level at baseline: stratum 1, #3 times upper limit of normal; stratum 2, .3 times upper limit of normal.
a
serum alkaline phosphatase activity, which, for 50, 100, and 200 mg, reached a nadir by day 60 (Figure 2), but continued to decrease at posttreatment day 90 for 400 mg. This fall in serum alkaline phosphatase activity was significantly greater for all zoledronate treatment groups compared with placebo by posttreatment day 5 and at all subsequent posttreatment visits. The 400 mg treatment was statistically significantly favored over 50 mg and 100 mg by posttreatment day 10. There was evidence of a dose-response relationship. For serum alkaline phosphatase, the maximum reduction over the entire 3 month posttreatment follow-up was significantly greater for all four zoledronate treatment groups over placebo (Figure 2), and also for the higher doses over the lower doses. The maximum reduction over the entire 3 month posttreatment for urinary hydroxyproline:creatinine ratio was significantly greater for 100, 200, and 400 mg over placebo, and also for 400 mg over 50, 100, and 200 mg (Figure 1). There was no difference between stratum 1 (baseline serum alkaline phosphatase three times the upper limit of normal range) and stratum 2 (baseline serum alkaline phosphatase more than three times the upper limit of normal range) in the maximum response in serum alkaline phosphatase in any treatment group. For the maximum response in hydroxyproline:creatinine ratio, 400 mg was statistically superior to all other treatment groups in stratum 2, but only to 100 mg in stratum 1. A dose-response relationship was apparent in the proportion of therapeutic responders (50% decrease from baseline or normalization) for sAP with statistically significant between-treatment differences in favor of 400 mg over placebo, 50, 100, and 200 mg. With 400 mg, a 50% decrease from pretreatment values
was seen in 46% of patients, and normalization of serum alkaline phosphatase values was seen in 20% of patients. The 400 mg treatment was statistically favored over placebo in the proportion of therapeutic responders for urinary hydroxyproline:creatinine ratio; two thirds of patients demonstrated a therapeutic response with 57% of these showing a 50% decrease from pretreatment values, and 43% normalization. The results for other bone metabolic markers were quite consistent with those for serum alkaline phosphatase and urine hydroxyproline:creatinine ratio. The greatest maximum median reduction in urinary pyridinoline:creatinine ratio and urinary deoxypyridinoline:creatinine ratio occurred in the 400 mg group and was 40.2% and 51.8%, respectively, reaching a nadir by 10 days postinfusion. Similarly, the maximum median reduction in bone-specific alkaline phosphatase levels also occurred in the 400 mg group and continued to fall through 90 days postinfusion (Table 2). Zoledronate infusion was well tolerated. Drug-related adverse experiences were reported with comparable frequency with all treatments including placebo. Among the most frequently reported drug-related adverse events were fever, back pain, and skeletal pain, which showed a dose-dependency trend (Table 3). Actual temperature elevations (.1°C) postinfusion were observed in only one patient with 50 mg and in two patients with 200 mg. Dose-related decreases in serum calcium and serum phosphate were observed within the first 3 weeks following zoledronate infusion. Three patients treated with 400 mg developed asymptomatic hypocalcemia (,8 mg/dL) 5–10 days postinfusion, which resolved without treatment; two of these patients also had serum phosphate values of ,2 mg/dL during the
Table 2. Maximum median percent reduction from baseline for primary and secondary bone turnover markers Dose of zoledronate Test
Placebo
50 mg
100 mg
200 mg
400 mg
sAP uOHP P:Cr BSAP Pyd:Cr DPyd:Cr Ca:Cr
26.2 216.7 217.8 216.5 219.5 257.2
210.8 227.6 225.4 222.3 230.9a 234.2
216.8 228.0a 229.2 215.9 222.7 244.4
232.7 237.0a 241.1a 232.3a 233.8a 264.4
246.9a 258.0a 260.8a 240.2 251.8a 279.7a
a
a
a
KEY: BSAP, bone-specific alkaline phosphatase; Ca, calcium; Cr, creatinine; DPyd, deoxypridinoline; P, phosphorus; Pyd, pyridinoline; sAP, serum alkaline phosphatase; uOHP, urinary hydroxyproline. a Statistically significant compared with placebo in favor of the zoledronate treatment after Bonferroni adjustment for multiple comparison (p , 0.0125).
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Table 3. Most frequently reported drug-related adverse events in .10% patients in any treatment group 50 mg
Placebo
100 mg
200 mg
400 mg
Adverse events
N
%
N
%
N
%
N
%
N
%
Fatigue Fever Arthralagia Pain, back Pain, skeletal
0 0 3 1 2
0 0 8.6 2.9 5.7
4 1 4 2 1
11.8 2.9 11.8 5.9 2.9
3 0 5 3 2
7.9 0 13.2 7.9 5.3
2 2 1 4 3
6.1 6.1 3.0 12.1 9.1
3 4 5 5 5
8.6 11.4 14.3 14.3 14.3
postinfusion period. No dose-related abnormal changes in hematological parameters were observed. Discussion This study demonstrates a clear dose-response effect in the biochemical response to zoledronate. Zoledronate’s effects on the primary bone turnover markers, serum alkaline phosphatase, and urinary hydroxyproline:creatinine ratio were consistent with those observed in previous trials of antiresorptive therapy in Paget’s disease.4,12 The fall in urinary hydroxyproline:creatinine ratio, a marker of bone resorption, generally precedes a more gradual decline in serum alkaline phosphatase levels as the rate of new bone formation returns toward normal. In the present study, decreases in urinary hydroxyproline:creatinine ratio were maximal by 10 days after infusion, whereas serum alkaline phosphatase levels declined at a slower rate with maximal or near-maximal changes reached by 60 days posttreatment. The maximum percent reduction of biochemical bone turnover markers observed in patients receiving 400 mg zoledronate approached a 50% decrease from baseline for serum alkaline phosphatase and 60% for urinary hydroxyproline:creatinine ratio, indicating that a maximum effective dose was not achieved in this trial. Suppression of biochemical markers of bone turnover has been shown to be an index of decreased disease activity and may lead to clinical improvement in Paget’s disease patients.13 However, because clinical efficacy was not assessed in this trial, only prudent inferences about clinical improvement can be made. In the 400 mg zoledronate group, the percentage of responders for alkaline phosphatase was greater among stratum 2 patients (55%) than among patients with less severe disease at baseline (33%). These results suggest that the biochemical response to effective doses of zoledronate may be more pronounced when tested in patients with highly active disease. However, in contrast to these results, Bombassei et al.17 reported all patients with initial serum alkaline phosphatase concentrations below 215 U/L had decreases to normal after one 60 mg intravenous infusion of pamidronate, whereas those patients with an initial serum alkaline phosphatase greater than 240 U/L required multiple doses of 60 mg infusions (2–11) given over 4 –18 months to achieve reduction in serum alkaline phosphatase, but not normalization. Changes in other markers of bone resorption and formation in response to zoledronate treatment were consistent with those observed for serum alkaline phosphatase and urinary hydroxyproline:creatinine ratio. Median percent reductions in collagen cross-links, deoxypyridinoline, and pyridinoline (Table 2), were similar in magnitude to those observed for urinary hydroxyproline:creatinine ratio and were also maximal by day 10. Deoxypyridinoline appears to be a more sensitive marker of bone resorption than pyridinoline, because, for all the active treatment doses, the maximum decreases were greater for deoxypyridinoline than for pyridinoline and more closely paralleled the results with urinary hydroxyproline:creatinine ratio. Deoxypyridinoline may prove advantageous over urinary hydroxyproline as a
marker of bisphosphonate effect on bone metabolism due to its bone specificity and less diet-related variability in urinary excretion. Changes in serum bone alkaline phosphatase, a more specific bone formation marker, paralleled those observed for serum alkaline phosphatase; decreases from baseline were evident by day 5, were incremental with time, and appeared to reach a maximum by day 60. Although the maximum reduction in urine calcium:creatinine ratio was significantly greater for the 400 mg zoledronate group compared with placebo (80% vs. 57%), the marked placebo effect suggests that urinary calcium is not a very specific marker for bisphosphonate effects on bone metabolism. The decreases observed in the placebo group may reflect dietary effects. Although fever has been reported as a component of the acute-phase reaction following intravenous administration of aminobisphosphonates,1 no patients in the placebo and 100 mg dose group and one, two, and four patients in the 50, 200, and 400 mg dose groups reported fever following zoledronate infusion. Transient worsening of pain in affected bones was reported in some patients treated with bisphosphonates. The reports of back pain and other areas of skeletal pain occurred more commonly with increasing dose, suggesting that this type of pain exacerbation can also be seen with zoledronate therapy. Mild, transient decreases in serum calcium and phosphate observed following zoledronate infusion were comparable to changes observed after intravenous pamidronate in patients with Paget’s disease. They correlated with the early, antiresorptive effect of these compounds, and generally improved if patients were given calcium with vitamin D. The data obtained in this trial suggest a wide therapeutic index for zoledronate in treatment of Paget’s disease. The most effective doses were 200 and 400 mg, which were safe and well tolerated. Currently, the aim of Paget’s disease therapy is to achieve normalization of biochemical markers of bone turnover (as the maximal therapeutic dose was not achieved). Although the intent of this study was not to normalize, seven (20%) patients in the 400 mg group did achieve normalization of serum alkaline phosphatase. We conclude that zoledronate is an effective agent in the treatment of Paget’s disease. Future investigation is needed to identify a dose that will achieve normalization and long-term remission. References 1. Adami, S., Bhalla, A. K., Dorizzi, R., Montesanti, F., Rosini, S., Salvagno, G., and Lo Cascio, V. The acute phase response after bisphosphonate administration. Calcif Tissue Int 41:326 –331; 1987. 2. Adami, S., Mian, M., Gatti, P., Rossini, M., Zamberlan, N., Bertoldo, F., and Lo Cascio, V. Effects of two oral doses of alendronate in the treatment of Paget’s disease of bone. Bone 15:415– 417; 1994. 3. Adami, S., Salvagno, G., Guarrera, G., Montesanti, F., Garavelli, S., Rosini, S., and Lo Cascio, V. Treatment of Paget’s disease of bone with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. Calcif Tissue Int 39:226 – 229; 1986.
Bone Vol. 24, No. 5, Supplement May 1999:81S– 85S 4. Bombassei, G. I., Yocon, O. M., and Raisz, L. G. Effects of intravenous pamidronate therapy on Paget’s disease of bone. J Med Sci 308:226–233; 1994. 5. Bone, H. G. and Kleerekoper, M. Clinical review 39: Paget’s disease of bone. J Clin Endocrinol Metabol 75:1179 –1182; 1992. 6. Burckhardt, P. and Thiebaud, D. Treatment of Paget’s disease with short courses of bisphosphonates. In: Singer, F. R. and Wallach, S. Eds. Paget’s disease of bone. New York: Elsevier; 1991; 1179 –1182. 7. Cantrill, J. A. and Anderson, D. C. Treatment of Paget’s disease of bone. Clin Endocrinol 32:507–518; 1990. 8. Delmas, P. D., Chapuy, M. C., Vignon, E., Charon, S., Brianc¸on, E., Alexandre, C., Edourd, C., and Meunier, P. J. Long-term effects of dichloromethylene diphosphonate in Paget’s disease of bone. J Clin Endocrinol Metabol 54:837– 844; 1982. 9. Gray, R. E. S., Yates, A. J. P., Preston, C. J., Smith, R., Russell, R. G. G., and Kanis, J. A. Duration of effect of oral diphosphonate therapy in Paget’s disease of bone. Q J Med 64:755–767; 1987. 10. Green, J. R., Mu¨ller, K., and Jaeggi, K. A. Preclinical pharmacology of CGP 42,446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 9:745–751; 1994.
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11. Kanis, J. A. Pathophysiology and Treatment of Paget’s Disease of Bone. London: Martin Dunitz; 1991. 12. Kelepouris, N., Siris, E., Jacobs, T., Altman, R., Ryan, W., Chausmer, A., Shai, F., Lang, R., Whyte, M., Schaffer, V., Heffernan, M., and Zelenakas, K. Comparison of three doses of intravenous pamidronate in the treatment of Paget’s disease of bone. Unpublished data. 13. O’Doherty, D. P., McCloskey, E. V., Vasikaran, S., Khan, S., and Kanis, J. A. The effects of intravenous alendronate in Paget’s disease of bone. J Bone Miner Res 10:1094 –1100; 1995. 14. Preston, C. J., Yates, A. J. P., Beneton, M. N. C., Russell, R. G. G., Gray, R. E. S., Smith, R., and Kanis, J. A. K. Effective short term treatment of Paget’s disease with oral etidronate. Br Med J 292:79 – 80; 1986. 15. Sietsema, W. K. and Ebetino, F. H. Bisphosphonates in development for metabolic bone disease. Exp Opin Invest Drugs 3:1255–1276; 1994. 16. Siris, E. S. Extensive personal experience: Paget’s disease of bone. J Clin Endocrinol Metabol 80:335–338; 1995. 17. Rodan, G. A. and Balena, R. Bisphosphonates in the treatment of metabolic bone diseases. Ann Med 25:373–378; 1993.
Single Infusion of Zoledronate in Paget’s Disease of Bone: A Placebo-Controlled, Dose-Ranging Study H. BUCKLER,1 W. FRASER,2 D. HOSKING,3 W. RYAN,4 M. J. MARICIC,5 F. SINGER,6 M. DAVIE,7 I. FOGELMAN,8 C. A. BIRBARA,9 A. M. MOSES,10 K. LYLES,11 P. SELBY,12 P. RICHARDSON,13 J. SEAMAN,13 K. ZELENAKAS,13 and E. SIRIS14 1
Hope Hospital, Salford, UK Department of Clinical Chemistry, Royal Liverpool University Hospitals, Liverpool, UK 3 Nottingham City Hospital, Nottingham, UK 4 Rush Presbyterian–St. Luke’s Medical Center, Chicago, IL, USA 5 University of Arizona Health Sciences Center, Tucson, AZ, USA 6 John Wayne Cancer Institute, Santa Monica, CA, USA 7 Robert Jones and Agnes Hunt Hospital, Oswestry, Shropshire, UK 8 Osteoporosis Unit, Nuclear Medicine Department, Guy’s Hospital, London, UK 9 University of Massachusetts Medical School, Worcester, MA, USA 10 State University of New York Health Science Center, Syracuse, NY, USA 11 Duke University Medical Center and VA Medical Center, Durham, NC, USA 12 University of Manchester, Manchester, UK 13 Clinical Research, Novartis Pharmaceuticals, East Hanover, NJ, USA 14 Columbia University College of Physicians and Surgeons, New York, NY, USA 2
ical response to bisphosphonate therapy and the duration of remission achieved. More complete effects suppress bone resorption, as reflected in nadir and plateau levels of biochemical indices of bone turnover, such as urinary hydroxyproline excretion and alkaline phosphatase, which are usually associated with a longer duration of remission.9,13 However, prolonging duration of therapy does not appear to compensate for the less marked suppression of disease activity seen with lower doses of bisphosphonates.2 Sustained and effective suppression of osteoclast activity of sufficient degree and duration might prevent recruitment of new pagetic osteoclasts with eventual destruction of the abnormal osteoclast population.5 Thus, more potent antiresorptive drugs offer the possibility of greater suppression of abnormal osteoclast function, thereby eliminating the need for continuing treatment for long time periods. Zoledronate is a heterocyclic nitrogen-containing bisphosphonate with antiresorptive potency that is at least 120 times greater than that of pamidronate.10 The relatively low doses that are clinically active are expected to have little adverse effect on mineralization and potentially reduced side effects compared with other bisphosphonate compounds requiring higher dose regimens. The present study was conducted to assess the doseresponse effects of zoledronate administered as a single 1 h infusion on biochemical markers of bone turnover in patients with Paget’s disease of bone.
Introduction Paget’s disease of bone is a unifocal or multifocal bone remodeling disorder characterized by dramatic increases in osteoclast size, number, and activity. Increased bone resorption coupled with increased osteoblast-mediated new bone formation produce structurally inferior bone at the affected sites. Pagetic lesions are most frequently found in the pelvis, spine, skull, femur, and tibia.5 The most common clinical complications of Paget’s disease are pain, bone deformity, fractures, and syndromes of neurological compression.16 Clinical symptoms are usually accompanied by marked abnormalities in biochemical markers of bone resorption and bone formation. As potent inhibitors of bone resorption, bisphosphonates are now commonly used to treat patients with Paget’s disease. Substantial reductions in biochemical indices of disease activity as well as symptomatic relief have been demonstrated with a number of bisphosphonates.3,6 – 8,14 Treatment effects generally last for several months or longer following a course of therapy. The various bisphosphonate compounds that have been evaluated for clinical use vary widely in potency due to differences in side-chain structure.15,17 For example, the newer amino- and nitrogen-containing bisphosphonates (pamidronate, alendronate, risedronate) have potent antiresorptive activity at doses that do not produce mineralization defects, as may be seen with etidronate. However, the aminobisphosphonates may be associated with other side effects: fever, malaise, lymphopenia, hypocalcemia, and esophagitis.1 There is a positive relationship between the initial biochem-
Materials and Methods We studied 176 patients with Paget’s disease of bone (108 males and 68 females, mean age 71 years) at 20 investigational sites in the United States and the United Kingdom (80 patients in the USA and 96 patients in the UK). One hundred sixty-six patients were white, 7 black, and 3 of other racial origin. The baseline serum alkaline phosphatase concentrations were at least twice the upper limit of the normal reference range (USA 39 –117 IU/L,
Address for correspondence and reprints: Ethel Siris, M.D., Center for the Prevention and Treatment of Osteoporosis, Metabolic Bone Diseases Program, Harkness Pavillion 9-964, 180 Fort Washington Avenue, New York, NY 10032. E-mail: [email protected] © 1999 by Elsevier Science Inc. All rights reserved.
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UK 30 –135 IU/L). No patients had been treated with calcitonin or plycamicin in the 3 months prior to the study or with bisphosphonates in the 6 months prior to the study. One hundred twenty of the patients had been treated with one or more Paget’s disease medications in the past: 112 with a bisphosphonate; 64 with calcitonin; and 6 with plycamicin. X-ray confirmation of Paget’s disease was obtained if there was no previous X-ray record or, in patients with painful lytic disease of the long bones, to rule out impending fractures. Patients with creatinine clearance ,60 mL/min were excluded from the study unless serum creatinine levels were within the normal range; patients with abnormal hepatic function were excluded from the study. The study protocol was approved by the institutional review board at each study site, and informed consent was obtained from all patients prior to enrollment. Following baseline assessment, the patients were randomized in a double-blind manner to receive a single 1 hour intravenous infusion of 50, 100, 200, or 400 mg zoledronate in 60 mL of 5% dextrose in water, or a placebo (60 mL of 5% dextrose in water). Morning fasting blood and 2 h urine samples were obtained between 3 and 14 days prior to infusion (baseline assessment); immediately postinfusion; and at 5, 10, 30, 45, 60, and 90 days postinfusion. Blood measurements included a complete blood count, and serum calcium, phosphate, magnesium, creatinine, blood urea nitrogen, electrolytes, liver function tests, total protein, albumin, urate, total alkaline phosphatase, and bone-specific alkaline phosphatase. Urine was assayed for calcium, creatinine, hydroxyproline, pyridinoline, and deoxypyridinoline. Creatinine clearance based on a 24 h urine collection was determined at baseline and 90 days postinfusion. Serum bone-specific alkaline phosphatase and urinary calcium, creatinine, hydroxyproline, pyridinoline, and deoxypyridinoline assays were performed by Nichols Institute (San Juan Capistrano, CA). Serum bone-specific alkaline phosphatase was measured by a colorimetric assay; urinary calcium was assayed by atomic absorption spectrometry; urinary creatinine and total hydroxyproline were measured by colorimetric assay; total urinary pyridinoline and deoxypyridinoline were assayed by high-performance liquid chromatography (HPLC). Urinary calcium, hydroxyproline, pyridinoline, and deoxypyridinoline were expressed as a ratio to creatinine concentration. Oral temperature was measured immediately prior to infusion, at 1–2 h postinfusion, and at each subsequent evaluation visit. A baseline electrocardiogram (ECG) was obtained if one had not been obtained within 3 months prior to study. All efficacy analyses were based on all randomized patients who had at least one postbaseline measurement (intent-to-treat analysis). Four of the 176 patients did not complete all postbaseline evaluations (one patient treated with 400 mg withdrew due to unsatisfactory therapeutic effect; one patient each, treated with 50, 100, and 400 mg, died during the study of causes related to coexisting conditions). Comparisons between treatment groups were made using summary measures. The primary efficacy variables were serum alkaline phosphatase and urinary hydroxyproline; the criterion for effectiveness was that the maximum percent reduction from baseline (maximum change from pretreatment values) over the entire 3 month trial be statistically significantly greater for zoledronate as compared with placebo. Secondary efficacy variables were bone-specific alkaline phosphatase and urinary pyridinoline, deoxypyridinoline, and calcium. The percent reduction from baseline for all variables at all posttreatment visits was also analyzed. Between-treatment comparisons of the active treatment groups vs. placebo were made using the nonparametric Wilcoxon rank-sum test, with Bonferroni adjustment for multiple compar-
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Figure 1. Median percent changes in urinary hydroxyproline-creatinine following treatment with zoledronate.
isons for statistical significance. For graphical display, all values were expressed as median percent decreases from baseline. The proportion of patients who demonstrated a therapeutic response for serum alkaline phosphatase and urinary hydroxyproline:creatinine ratio was compared between treatment groups, and the comparisons were analyzed using the Fisher exact test. A therapeutic response was defined as a 50% decrease from baseline or normalization at any time posttreatment. Overall comparability among treatment groups was examined at baseline for all intent-to-treat patients by means of Fisher exact, Kruskal–Wallis, and F-tests, for demographic characteristics and biochemical measurements (serum total alkaline phosphatase, serum bone-specific alkaline phosphatase, urinary hydroxyproline:creatinine ratio, urinary calcium:creatinine ratio, urinary pyridinoline:creatinine ratio, and urinary deoxypyridinoline:creatinine ratio). At the end of the trial, patients were grouped into strata based on whether their baseline serum alkaline phosphatase was less than or equal to three times the upper limit of the normal reference range (stratum 1) or greater than three times the upper limit of the normal reference range (stratum 2), for comparison of the analysis of the maximum percent reduction from baseline between the two strata. Results There were no statistically significant differences among groups in key demographics or in biochemical measurements at baseline assessment (Table 1). A rapid reduction in median fasting urinary hydroxyproline: creatinine excretion, which reached a nadir by day 10, was seen in all four treatment groups (Figure 1); this reduction was significantly greater for 200 mg and 400 mg compared with placebo, and for 400 mg compared with the other treatment groups, at all posttreatment visits. This was followed by a fall in
Figure 2. Median percent changes in serum alkaline phosphatase following treatment with zoledronate.
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Table 1. Patient characteristics at baseline for each treatment group Dose of zoledronate Characteristic No. of patients Gender no. of patients (%) Men Women Mean age 6 SD (years) Severity of disease,a no. of patients (%) Stratum 1 Stratum 2 Median serum alkaline phosphatase (U/L) Median urine hydroxyproline:creatinine ratio
50 mg
100 mg
200 mg
400 mg
Placebo
35
38
33
35
35
19 (54) 16 (46) 73 6 7
24 (63) 14 (37) 70 6 8
22 (67) 11 (33) 69 6 10
19 (54) 16 (46) 70 6 8
24 (69) 11 (31) 72 6 11
11 (31) 24 (69) 542 0.108
12 (32) 26 (68) 422 0.097
13 (39) 20 (61) 438 0.081
15 (43) 20 (57) 372 0.112
13 (37) 22 (63) 389 0.085
Severity of disease based on serum alkaline phosphatase level at baseline: stratum 1, #3 times upper limit of normal; stratum 2, .3 times upper limit of normal.
a
serum alkaline phosphatase activity, which, for 50, 100, and 200 mg, reached a nadir by day 60 (Figure 2), but continued to decrease at posttreatment day 90 for 400 mg. This fall in serum alkaline phosphatase activity was significantly greater for all zoledronate treatment groups compared with placebo by posttreatment day 5 and at all subsequent posttreatment visits. The 400 mg treatment was statistically significantly favored over 50 mg and 100 mg by posttreatment day 10. There was evidence of a dose-response relationship. For serum alkaline phosphatase, the maximum reduction over the entire 3 month posttreatment follow-up was significantly greater for all four zoledronate treatment groups over placebo (Figure 2), and also for the higher doses over the lower doses. The maximum reduction over the entire 3 month posttreatment for urinary hydroxyproline:creatinine ratio was significantly greater for 100, 200, and 400 mg over placebo, and also for 400 mg over 50, 100, and 200 mg (Figure 1). There was no difference between stratum 1 (baseline serum alkaline phosphatase three times the upper limit of normal range) and stratum 2 (baseline serum alkaline phosphatase more than three times the upper limit of normal range) in the maximum response in serum alkaline phosphatase in any treatment group. For the maximum response in hydroxyproline:creatinine ratio, 400 mg was statistically superior to all other treatment groups in stratum 2, but only to 100 mg in stratum 1. A dose-response relationship was apparent in the proportion of therapeutic responders (50% decrease from baseline or normalization) for sAP with statistically significant between-treatment differences in favor of 400 mg over placebo, 50, 100, and 200 mg. With 400 mg, a 50% decrease from pretreatment values
was seen in 46% of patients, and normalization of serum alkaline phosphatase values was seen in 20% of patients. The 400 mg treatment was statistically favored over placebo in the proportion of therapeutic responders for urinary hydroxyproline:creatinine ratio; two thirds of patients demonstrated a therapeutic response with 57% of these showing a 50% decrease from pretreatment values, and 43% normalization. The results for other bone metabolic markers were quite consistent with those for serum alkaline phosphatase and urine hydroxyproline:creatinine ratio. The greatest maximum median reduction in urinary pyridinoline:creatinine ratio and urinary deoxypyridinoline:creatinine ratio occurred in the 400 mg group and was 40.2% and 51.8%, respectively, reaching a nadir by 10 days postinfusion. Similarly, the maximum median reduction in bone-specific alkaline phosphatase levels also occurred in the 400 mg group and continued to fall through 90 days postinfusion (Table 2). Zoledronate infusion was well tolerated. Drug-related adverse experiences were reported with comparable frequency with all treatments including placebo. Among the most frequently reported drug-related adverse events were fever, back pain, and skeletal pain, which showed a dose-dependency trend (Table 3). Actual temperature elevations (.1°C) postinfusion were observed in only one patient with 50 mg and in two patients with 200 mg. Dose-related decreases in serum calcium and serum phosphate were observed within the first 3 weeks following zoledronate infusion. Three patients treated with 400 mg developed asymptomatic hypocalcemia (,8 mg/dL) 5–10 days postinfusion, which resolved without treatment; two of these patients also had serum phosphate values of ,2 mg/dL during the
Table 2. Maximum median percent reduction from baseline for primary and secondary bone turnover markers Dose of zoledronate Test
Placebo
50 mg
100 mg
200 mg
400 mg
sAP uOHP P:Cr BSAP Pyd:Cr DPyd:Cr Ca:Cr
26.2 216.7 217.8 216.5 219.5 257.2
210.8 227.6 225.4 222.3 230.9a 234.2
216.8 228.0a 229.2 215.9 222.7 244.4
232.7 237.0a 241.1a 232.3a 233.8a 264.4
246.9a 258.0a 260.8a 240.2 251.8a 279.7a
a
a
a
KEY: BSAP, bone-specific alkaline phosphatase; Ca, calcium; Cr, creatinine; DPyd, deoxypridinoline; P, phosphorus; Pyd, pyridinoline; sAP, serum alkaline phosphatase; uOHP, urinary hydroxyproline. a Statistically significant compared with placebo in favor of the zoledronate treatment after Bonferroni adjustment for multiple comparison (p , 0.0125).
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Table 3. Most frequently reported drug-related adverse events in .10% patients in any treatment group 50 mg
Placebo
100 mg
200 mg
400 mg
Adverse events
N
%
N
%
N
%
N
%
N
%
Fatigue Fever Arthralagia Pain, back Pain, skeletal
0 0 3 1 2
0 0 8.6 2.9 5.7
4 1 4 2 1
11.8 2.9 11.8 5.9 2.9
3 0 5 3 2
7.9 0 13.2 7.9 5.3
2 2 1 4 3
6.1 6.1 3.0 12.1 9.1
3 4 5 5 5
8.6 11.4 14.3 14.3 14.3
postinfusion period. No dose-related abnormal changes in hematological parameters were observed. Discussion This study demonstrates a clear dose-response effect in the biochemical response to zoledronate. Zoledronate’s effects on the primary bone turnover markers, serum alkaline phosphatase, and urinary hydroxyproline:creatinine ratio were consistent with those observed in previous trials of antiresorptive therapy in Paget’s disease.4,12 The fall in urinary hydroxyproline:creatinine ratio, a marker of bone resorption, generally precedes a more gradual decline in serum alkaline phosphatase levels as the rate of new bone formation returns toward normal. In the present study, decreases in urinary hydroxyproline:creatinine ratio were maximal by 10 days after infusion, whereas serum alkaline phosphatase levels declined at a slower rate with maximal or near-maximal changes reached by 60 days posttreatment. The maximum percent reduction of biochemical bone turnover markers observed in patients receiving 400 mg zoledronate approached a 50% decrease from baseline for serum alkaline phosphatase and 60% for urinary hydroxyproline:creatinine ratio, indicating that a maximum effective dose was not achieved in this trial. Suppression of biochemical markers of bone turnover has been shown to be an index of decreased disease activity and may lead to clinical improvement in Paget’s disease patients.13 However, because clinical efficacy was not assessed in this trial, only prudent inferences about clinical improvement can be made. In the 400 mg zoledronate group, the percentage of responders for alkaline phosphatase was greater among stratum 2 patients (55%) than among patients with less severe disease at baseline (33%). These results suggest that the biochemical response to effective doses of zoledronate may be more pronounced when tested in patients with highly active disease. However, in contrast to these results, Bombassei et al.17 reported all patients with initial serum alkaline phosphatase concentrations below 215 U/L had decreases to normal after one 60 mg intravenous infusion of pamidronate, whereas those patients with an initial serum alkaline phosphatase greater than 240 U/L required multiple doses of 60 mg infusions (2–11) given over 4 –18 months to achieve reduction in serum alkaline phosphatase, but not normalization. Changes in other markers of bone resorption and formation in response to zoledronate treatment were consistent with those observed for serum alkaline phosphatase and urinary hydroxyproline:creatinine ratio. Median percent reductions in collagen cross-links, deoxypyridinoline, and pyridinoline (Table 2), were similar in magnitude to those observed for urinary hydroxyproline:creatinine ratio and were also maximal by day 10. Deoxypyridinoline appears to be a more sensitive marker of bone resorption than pyridinoline, because, for all the active treatment doses, the maximum decreases were greater for deoxypyridinoline than for pyridinoline and more closely paralleled the results with urinary hydroxyproline:creatinine ratio. Deoxypyridinoline may prove advantageous over urinary hydroxyproline as a
marker of bisphosphonate effect on bone metabolism due to its bone specificity and less diet-related variability in urinary excretion. Changes in serum bone alkaline phosphatase, a more specific bone formation marker, paralleled those observed for serum alkaline phosphatase; decreases from baseline were evident by day 5, were incremental with time, and appeared to reach a maximum by day 60. Although the maximum reduction in urine calcium:creatinine ratio was significantly greater for the 400 mg zoledronate group compared with placebo (80% vs. 57%), the marked placebo effect suggests that urinary calcium is not a very specific marker for bisphosphonate effects on bone metabolism. The decreases observed in the placebo group may reflect dietary effects. Although fever has been reported as a component of the acute-phase reaction following intravenous administration of aminobisphosphonates,1 no patients in the placebo and 100 mg dose group and one, two, and four patients in the 50, 200, and 400 mg dose groups reported fever following zoledronate infusion. Transient worsening of pain in affected bones was reported in some patients treated with bisphosphonates. The reports of back pain and other areas of skeletal pain occurred more commonly with increasing dose, suggesting that this type of pain exacerbation can also be seen with zoledronate therapy. Mild, transient decreases in serum calcium and phosphate observed following zoledronate infusion were comparable to changes observed after intravenous pamidronate in patients with Paget’s disease. They correlated with the early, antiresorptive effect of these compounds, and generally improved if patients were given calcium with vitamin D. The data obtained in this trial suggest a wide therapeutic index for zoledronate in treatment of Paget’s disease. The most effective doses were 200 and 400 mg, which were safe and well tolerated. Currently, the aim of Paget’s disease therapy is to achieve normalization of biochemical markers of bone turnover (as the maximal therapeutic dose was not achieved). Although the intent of this study was not to normalize, seven (20%) patients in the 400 mg group did achieve normalization of serum alkaline phosphatase. We conclude that zoledronate is an effective agent in the treatment of Paget’s disease. Future investigation is needed to identify a dose that will achieve normalization and long-term remission. References 1. Adami, S., Bhalla, A. K., Dorizzi, R., Montesanti, F., Rosini, S., Salvagno, G., and Lo Cascio, V. The acute phase response after bisphosphonate administration. Calcif Tissue Int 41:326 –331; 1987. 2. Adami, S., Mian, M., Gatti, P., Rossini, M., Zamberlan, N., Bertoldo, F., and Lo Cascio, V. Effects of two oral doses of alendronate in the treatment of Paget’s disease of bone. Bone 15:415– 417; 1994. 3. Adami, S., Salvagno, G., Guarrera, G., Montesanti, F., Garavelli, S., Rosini, S., and Lo Cascio, V. Treatment of Paget’s disease of bone with intravenous 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. Calcif Tissue Int 39:226 – 229; 1986.
Bone Vol. 24, No. 5, Supplement May 1999:81S– 85S 4. Bombassei, G. I., Yocon, O. M., and Raisz, L. G. Effects of intravenous pamidronate therapy on Paget’s disease of bone. J Med Sci 308:226–233; 1994. 5. Bone, H. G. and Kleerekoper, M. Clinical review 39: Paget’s disease of bone. J Clin Endocrinol Metabol 75:1179 –1182; 1992. 6. Burckhardt, P. and Thiebaud, D. Treatment of Paget’s disease with short courses of bisphosphonates. In: Singer, F. R. and Wallach, S. Eds. Paget’s disease of bone. New York: Elsevier; 1991; 1179 –1182. 7. Cantrill, J. A. and Anderson, D. C. Treatment of Paget’s disease of bone. Clin Endocrinol 32:507–518; 1990. 8. Delmas, P. D., Chapuy, M. C., Vignon, E., Charon, S., Brianc¸on, E., Alexandre, C., Edourd, C., and Meunier, P. J. Long-term effects of dichloromethylene diphosphonate in Paget’s disease of bone. J Clin Endocrinol Metabol 54:837– 844; 1982. 9. Gray, R. E. S., Yates, A. J. P., Preston, C. J., Smith, R., Russell, R. G. G., and Kanis, J. A. Duration of effect of oral diphosphonate therapy in Paget’s disease of bone. Q J Med 64:755–767; 1987. 10. Green, J. R., Mu¨ller, K., and Jaeggi, K. A. Preclinical pharmacology of CGP 42,446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 9:745–751; 1994.
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11. Kanis, J. A. Pathophysiology and Treatment of Paget’s Disease of Bone. London: Martin Dunitz; 1991. 12. Kelepouris, N., Siris, E., Jacobs, T., Altman, R., Ryan, W., Chausmer, A., Shai, F., Lang, R., Whyte, M., Schaffer, V., Heffernan, M., and Zelenakas, K. Comparison of three doses of intravenous pamidronate in the treatment of Paget’s disease of bone. Unpublished data. 13. O’Doherty, D. P., McCloskey, E. V., Vasikaran, S., Khan, S., and Kanis, J. A. The effects of intravenous alendronate in Paget’s disease of bone. J Bone Miner Res 10:1094 –1100; 1995. 14. Preston, C. J., Yates, A. J. P., Beneton, M. N. C., Russell, R. G. G., Gray, R. E. S., Smith, R., and Kanis, J. A. K. Effective short term treatment of Paget’s disease with oral etidronate. Br Med J 292:79 – 80; 1986. 15. Sietsema, W. K. and Ebetino, F. H. Bisphosphonates in development for metabolic bone disease. Exp Opin Invest Drugs 3:1255–1276; 1994. 16. Siris, E. S. Extensive personal experience: Paget’s disease of bone. J Clin Endocrinol Metabol 80:335–338; 1995. 17. Rodan, G. A. and Balena, R. Bisphosphonates in the treatment of metabolic bone diseases. Ann Med 25:373–378; 1993.