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Biochemical markers of bone turnover in predicting response to clodronate therapy in Paget’s disease
68S
Established therapies: Abstracts
Bone Vol. 24, No. 5, Supplement May 1999:67S– 68S
Table 1.
Group NPBT Intravenous pamidronate Oral alendronate Intravenous pamidronate Oral alendronate
n 5 4 4 4
Baseline ALP 303 6 96 259 6 61 568 6 155 846 6 339
Three month ALP as % of baseline 47 6 8
% patients normalizing ALP 100
44 6 6
75PIPT
67 6 11
0
32 6 6
50
KEY: ALP, alkaline phosphatase; NPBT, no previous bisphosphonate treatment; PIPT; previous intravenous pamidronate treatment. These early results suggest that: (a) in NPBT patients the three monthly dosage regimens are comparable; and (b) for intravenous pamidronate patients, oral alendronate may be advantageous. Relative osteoclastic resistance to one aminobisphosphonate (in this study, intravenous pamidronate) may not imply a poor response to all. Acknowledgments: Partially supported by the Arthritis Foundation of Australia. Address for correspondence and reprints: D. H. Gutteridge, Sir Charles Gairdner Hospital, Perth, Australia. PII S8756-3282(99)00064-2
Treatment of Paget’s Disease With Tiludronate W. D. FRASER1 University of Liverpool, Liverpool, UK
1
Tiludronate (4-chlorophenyl-thiomethylene-bisphosphonate) in a tablet formulation has recently been licensed for use in the treatment of Paget’s disease in several countries. Double-blind placebo-controlled studies performed in the UK and the USA have established that a 3 month course of 400 mg of tiludronate daily results in the best therapeutic/side-effect profile. As with most oral bisphosphonates the main side effects are gastrointestinal, which increase in frequency with higher doses of tiludronate. Oral tiludronate is efficient in reducing biochemical indices of disease activity with a 50% reduction in total alkaline phosphatase (TAP) observed at 6 months in 60.3% and 70.1% of patients who received 400 mg tiludronate daily for 3 and 6 months, respectively. Comparisons with etidronate treatment have found that only 25.3% of patients receiving etidronate demonstrate the same reduction in TAP. Radiographic improvement has been observed in 60% of patients treated with tiludronate, whereas progression was observed in 33% of placebo-treated patients during the same period. Ongoing long-term follow-up of tiludronate-treated patients has indicated that median time to retreatment following a 3 month 400 mg dose is .756 days and the incidence of fracture rate in such patients is low (0.70 – 0.86 per 100 patient-years). Repeated courses of tiludronate have been well tolerated and reduced efficacy has not usually been observed. Tiludronate does not impair mineralization of bone. Address for correspondence and reprints: Dr. William D. Fraser, University of Liverpool, Liverpool L69 3GA, UK. PII S8756-3282(99)00065-4
Long-lasting Suppression of Paget’s Disease Activity With Cyclical Tiludronate Treatment J. D. RINGE1 and O. WIEDEMANN2 Klinikum Leverkusen, University of Cologne, Cologne, Germany and 2 Sanofi Winthrop, Munich, Germany
1
According to an own epidemiological study, the prevalence of Paget’s disease of bone in the German population of age $40 amounts to 1.8%. This frequent, localized bone disease was treated in Germany over the last two decades, mainly with calcitonins, oral etidronate, or intravenous pamidronate. When tiludronate was
approved for this indication 3 years ago, we started a long-term clinical trial to evaluate the efficacy of this new oral bisphosphonate on the clinical and biochemical course of Paget’s disease. Up to now, 41 patients (24 men and 17 women) have been included in our prospective, single-center, open study. Eighteen cases suffered from monostotic disease and 23 from polyostotic disease. The mean age of all patients was 67.5 years. The diagnosis was based on radiologic lesions characteristic of Paget’s disease of bone and increased concentrations of serum alkaline phosphatase (AP). In some patients, the diagnosis had to be proven by bone biopsy. The treatment consisted of a 3 month cycle of daily 400 mg tiludronate. There were no significant side effects. In symptomatic patients we observed a significant decrease in pain and an amelioration of mobility. AP decreased by an average of 53% after month 3 (end of treatment), and showed further moderate decreases in most patients at months 6 and 9. At month 12, 40% of patients still showed a decreasing tendency of AP, whereas 60% reincreased. In four cases, a second tiludronate cycle had to be started. The first results of this ongoing study indicate that cyclical tiludronate is a safe, well-tolerated, and very effective treatment for Paget’s disease of bone. Address for correspondence and reprints: Prof. J. D. Ringe, Med. Klinik IV, Klinikum Leverkusen, 9-51375 Leverkusen, Germany. PII S8756-3282(99)00066-6
Biochemical Markers of Bone Turnover in Predicting Response to Clodronate Therapy in Paget’s Disease C. R. PARKER, P. J. BLACKWELL, N. LAWSON, and D. J. HOSKING Division of Mineral Metabolism, City Hospital, Nottingham, UK Total alkaline phosphatase (TALP) is widely used as a serum marker to monitor disease activity and response to treatment in Paget’s disease of bone. We examined the role of TALP, bone-specific alkaline phosphatase (BALP), osteocalcin (OC), hydroxyproline (Hypro), and deoxypyridinoline (DPD) in predicting extent and rate of response to bisphosphonate treatment. We studied 21 patients (10 male, 11 female; median age 74 years, range 49 – 86 years) with symptomatic Paget’s disease; all had a baseline TALP of .1.5 times the upper limit of normal. Subjects were randomized in a double-blind fashion to a single infusion of clodronate, 1500 mg or placebo. At 12 weeks, 13 patients who had not responded were treated with an infusion of 1500 mg clodronate. Subjects were followed-up for 12 months. At each visit all patients had measurements of TALP and BALP, OC, Hypro, DPD and alanine aminotransferase as an indicator of hepatic function. Baseline (pretreatment) and nadir (lowest posttreatment) values were determined once the investigators were unblinded to treatment allocation. In one case, nadir DPD could not be identified satisfactorily. Using linear regression analysis, we examined the relationship between baseline, nadir, and half life (T1/2) of the biochemical variables. Probability values are shown in Table 1.
Table 1. Probability results
Baseline nadir Baseline T1/2 Nadir T1/2
BALP
TALP
OC
Hypro
DPD
0.0001 0.1 0.0006
<0.0001 0.23 0.002
<0.0001 0.77 0.77
0.04 0.45 0.05
0.02 0.09 0.57
KEY: BALP, bone-specific alkaline phosphatase; DPD, deoxypyridinoline; Hypro, hydroxyproline; OC, osteocalcin; TALP, total alkaline phosphatase. Values in bold type indicate significance levels equal to or less than p 5 0.05. Baseline values of all the formation markers were strongly predictive of nadir values. Although pretreatment values did not directly predict rate of response (T1/2), nadir values of BALP and TALP were strongly predictive. The weaker performance of the resorption markers may be accounted for by the greater difficulty in accurately identifying nadir values. These findings, if reproducible with other bisphosphonates, suggest that, for a given treatment protocol, pretreatment values of either BALP or TALP may be used to predict degree and rate of response. This may be utilized when initiating therapy to adjust treatment dose and duration, particularly as normalization of bone turnover has been shown to prolong remission. Address for correspondence and reprints: Dr. C. R. Parker, Division of Mineral Metabolism, City Hospital, Nottingham, UK. PII S8756-3282(99)00067-8
Established therapies: Abstracts
Bone Vol. 24, No. 5, Supplement May 1999:67S– 68S
Table 1.
Group NPBT Intravenous pamidronate Oral alendronate Intravenous pamidronate Oral alendronate
n 5 4 4 4
Baseline ALP 303 6 96 259 6 61 568 6 155 846 6 339
Three month ALP as % of baseline 47 6 8
% patients normalizing ALP 100
44 6 6
75PIPT
67 6 11
0
32 6 6
50
KEY: ALP, alkaline phosphatase; NPBT, no previous bisphosphonate treatment; PIPT; previous intravenous pamidronate treatment. These early results suggest that: (a) in NPBT patients the three monthly dosage regimens are comparable; and (b) for intravenous pamidronate patients, oral alendronate may be advantageous. Relative osteoclastic resistance to one aminobisphosphonate (in this study, intravenous pamidronate) may not imply a poor response to all. Acknowledgments: Partially supported by the Arthritis Foundation of Australia. Address for correspondence and reprints: D. H. Gutteridge, Sir Charles Gairdner Hospital, Perth, Australia. PII S8756-3282(99)00064-2
Treatment of Paget’s Disease With Tiludronate W. D. FRASER1 University of Liverpool, Liverpool, UK
1
Tiludronate (4-chlorophenyl-thiomethylene-bisphosphonate) in a tablet formulation has recently been licensed for use in the treatment of Paget’s disease in several countries. Double-blind placebo-controlled studies performed in the UK and the USA have established that a 3 month course of 400 mg of tiludronate daily results in the best therapeutic/side-effect profile. As with most oral bisphosphonates the main side effects are gastrointestinal, which increase in frequency with higher doses of tiludronate. Oral tiludronate is efficient in reducing biochemical indices of disease activity with a 50% reduction in total alkaline phosphatase (TAP) observed at 6 months in 60.3% and 70.1% of patients who received 400 mg tiludronate daily for 3 and 6 months, respectively. Comparisons with etidronate treatment have found that only 25.3% of patients receiving etidronate demonstrate the same reduction in TAP. Radiographic improvement has been observed in 60% of patients treated with tiludronate, whereas progression was observed in 33% of placebo-treated patients during the same period. Ongoing long-term follow-up of tiludronate-treated patients has indicated that median time to retreatment following a 3 month 400 mg dose is .756 days and the incidence of fracture rate in such patients is low (0.70 – 0.86 per 100 patient-years). Repeated courses of tiludronate have been well tolerated and reduced efficacy has not usually been observed. Tiludronate does not impair mineralization of bone. Address for correspondence and reprints: Dr. William D. Fraser, University of Liverpool, Liverpool L69 3GA, UK. PII S8756-3282(99)00065-4
Long-lasting Suppression of Paget’s Disease Activity With Cyclical Tiludronate Treatment J. D. RINGE1 and O. WIEDEMANN2 Klinikum Leverkusen, University of Cologne, Cologne, Germany and 2 Sanofi Winthrop, Munich, Germany
1
According to an own epidemiological study, the prevalence of Paget’s disease of bone in the German population of age $40 amounts to 1.8%. This frequent, localized bone disease was treated in Germany over the last two decades, mainly with calcitonins, oral etidronate, or intravenous pamidronate. When tiludronate was
approved for this indication 3 years ago, we started a long-term clinical trial to evaluate the efficacy of this new oral bisphosphonate on the clinical and biochemical course of Paget’s disease. Up to now, 41 patients (24 men and 17 women) have been included in our prospective, single-center, open study. Eighteen cases suffered from monostotic disease and 23 from polyostotic disease. The mean age of all patients was 67.5 years. The diagnosis was based on radiologic lesions characteristic of Paget’s disease of bone and increased concentrations of serum alkaline phosphatase (AP). In some patients, the diagnosis had to be proven by bone biopsy. The treatment consisted of a 3 month cycle of daily 400 mg tiludronate. There were no significant side effects. In symptomatic patients we observed a significant decrease in pain and an amelioration of mobility. AP decreased by an average of 53% after month 3 (end of treatment), and showed further moderate decreases in most patients at months 6 and 9. At month 12, 40% of patients still showed a decreasing tendency of AP, whereas 60% reincreased. In four cases, a second tiludronate cycle had to be started. The first results of this ongoing study indicate that cyclical tiludronate is a safe, well-tolerated, and very effective treatment for Paget’s disease of bone. Address for correspondence and reprints: Prof. J. D. Ringe, Med. Klinik IV, Klinikum Leverkusen, 9-51375 Leverkusen, Germany. PII S8756-3282(99)00066-6
Biochemical Markers of Bone Turnover in Predicting Response to Clodronate Therapy in Paget’s Disease C. R. PARKER, P. J. BLACKWELL, N. LAWSON, and D. J. HOSKING Division of Mineral Metabolism, City Hospital, Nottingham, UK Total alkaline phosphatase (TALP) is widely used as a serum marker to monitor disease activity and response to treatment in Paget’s disease of bone. We examined the role of TALP, bone-specific alkaline phosphatase (BALP), osteocalcin (OC), hydroxyproline (Hypro), and deoxypyridinoline (DPD) in predicting extent and rate of response to bisphosphonate treatment. We studied 21 patients (10 male, 11 female; median age 74 years, range 49 – 86 years) with symptomatic Paget’s disease; all had a baseline TALP of .1.5 times the upper limit of normal. Subjects were randomized in a double-blind fashion to a single infusion of clodronate, 1500 mg or placebo. At 12 weeks, 13 patients who had not responded were treated with an infusion of 1500 mg clodronate. Subjects were followed-up for 12 months. At each visit all patients had measurements of TALP and BALP, OC, Hypro, DPD and alanine aminotransferase as an indicator of hepatic function. Baseline (pretreatment) and nadir (lowest posttreatment) values were determined once the investigators were unblinded to treatment allocation. In one case, nadir DPD could not be identified satisfactorily. Using linear regression analysis, we examined the relationship between baseline, nadir, and half life (T1/2) of the biochemical variables. Probability values are shown in Table 1.
Table 1. Probability results
Baseline nadir Baseline T1/2 Nadir T1/2
BALP
TALP
OC
Hypro
DPD
0.0001 0.1 0.0006
<0.0001 0.23 0.002
<0.0001 0.77 0.77
0.04 0.45 0.05
0.02 0.09 0.57
KEY: BALP, bone-specific alkaline phosphatase; DPD, deoxypyridinoline; Hypro, hydroxyproline; OC, osteocalcin; TALP, total alkaline phosphatase. Values in bold type indicate significance levels equal to or less than p 5 0.05. Baseline values of all the formation markers were strongly predictive of nadir values. Although pretreatment values did not directly predict rate of response (T1/2), nadir values of BALP and TALP were strongly predictive. The weaker performance of the resorption markers may be accounted for by the greater difficulty in accurately identifying nadir values. These findings, if reproducible with other bisphosphonates, suggest that, for a given treatment protocol, pretreatment values of either BALP or TALP may be used to predict degree and rate of response. This may be utilized when initiating therapy to adjust treatment dose and duration, particularly as normalization of bone turnover has been shown to prolong remission. Address for correspondence and reprints: Dr. C. R. Parker, Division of Mineral Metabolism, City Hospital, Nottingham, UK. PII S8756-3282(99)00067-8