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Tolerability of oral pamidronate in elderly patients with osteoporosis and other metabolic bone diseases
CURRENT THERAPEUTIC RESEARCH@ VOL. 57, NO. 2, FEBRUARY 1996
TOLERABILITY OF ORAL PAMIDRONATE IN ELDERLY PATIENTS WITH OSTEOPOROSIS AND OTHER METABOLIC BONE DISEASES FRANCISCO R. SPIVACOW,’ JO& R. ZANCHE’ITA,’ EDUARDO M. KERZBERG,’ ADRIANA FRIGERI,3 ROXANA FIASCHI?,3 AND EMIL10 J. A. ROLDAN4 ‘Znstituto de Znvestigaciones Metabblicas, ‘Department of Rheumatology, Ramos Mejla Hospital, 3Department of Endocrinology, Alvarez Hospital, and 4Department of Clinical Pharmacology, Gador SA, Buenos Aires, Argentina
ABSTRACT
Oral pamidronate (APD) is being used increasingly in the treatment of a variety of bone diseases. In a retrospective chart review of patients at three research centers (a 558.3 patient-year sample), the side effects of treatment with oral, low-dose APD administered in enteric-coated, soft gelatin capsules were analyzed in a group composed primarily of elderly women with osteoporosis. Although 21.8% of the patients experienced various gastrointestinal side effects, 89.1% complied with the treatment schedule. Among patients who discontinued therapy, two had duodenal ulcerations and one had hemorrhagic gastritis. There was a statistically significant negative correlation (r < -.90) between duration of treatment and rate of side effects; this correlation was influenced by patients who discontinued treatment early because of side effects. No clear dose-effect relationship could be demonstrated. No differences were detected when patients concomitantly received calcium, vitamin D, or any other nonosteotrophic drug, such as vasodilators or antiarrhythmic drugs. Hematologic abnormalities, including a reversible decrease in leukocyte count, were noted in 9.4% of the 635 patient charts that contained this type of data. This phenomenon is gradual and appears to be different from the sudden hematologic manifestation of the acute reaction phase described with intravenous administration of APD. Thus it may be concluded that oral APD administered to elderly patients for approximately 1 year would be expected to cause gastrointestinal side effects in about 21.8% of patients and the gradual progression of hematologic side effects in about 9.4%. INTRODUCTION
Pamidronate (APD) ([3-amino-l-hydroxypropylidenel-l,l-bisphosphonate), a second-generation bisphosphonate, is being used increasingly in the treatment of a variety of bone disorders. APD has demonstrated efficacy in Paget’s bone disease,’ tumor-induced hypercalcemia,2 bone metastases,3 Address correspondence to: Dr. Francisco Spivacow, IDIM, Libertad 836, 1012 Buenos Aires, Argentina. Received for publication on October 16, 1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. 123
0011-393x.96/$3.50
TOLERABILITY
OF ORAL PAhfIDRONATE
and osteoporosis.4 Once the efficacy of a drug has been established, tolerability becomes a concern, particularly for drugs administered over an extended period for the treatment of silent diseases such as osteoporosis.5 Compliance with the treatment regimen is another concern. Only a few studies have dealt with the side effects of APD administered orally. In the most extensive study of this drug, which was conducted by Mautalen et a1,6 the most frequently encountered side effects were gastrointestinal; even higher rates of gastrointestinal adverse events were seen in other studies.‘s7 The frequency and severity of abdominal symptoms appear to depend on the particular formulation of APD being studied. Consequently, it is difficult to draw conclusions about APD from the current medical literature. For example, in one study’ two oral formulations of pamidronate-a tablet and an effervescent powder-induced moderateto-severe esophageal and gastric intolerance. Bisphosphonates are poorly soluble compounds. Gastric media may predispose the aggregation and precipitation of these compounds and the consequent irritation of the gastric wall. Thus a formulation that eludes gastric media appears to be advantageous. The purpose of this study was to determine the tolerability of oral APD (an enteric-coated, soft gelatin capsule formulation) in a group of patients treated for 558.3 patient years. (This formulation is currently available in some countries.) PATIENTS AND METHODS
The medical charts of patients with metabolic bone diseases were retrospectively reviewed in three different medical centers in Buenos Aires, using the same methods in all centers. From this population, the records of patients who had been treated with daily oral APD alone or in combination with calcium salts and/or vitamin D derivatives, at the doses recommended for their bone conditions, were studied. Compliance was regularly assessed, as in routine practice, by simply questioning the patients whenever they went for their clinical visit. If no interruption of daily oral APD treatment was recorded, patients were considered to have undergone therapy. The records of selected patients who discontinued therapy, because of side effects or for other reasons, were also evaluated. The sample did not include patients who had incomplete clinical files (mainly due to lack of follow-up), who were undergoing concomitant therapy with other drugs affecting bone metabolism or with more than one drug of any other type, or patients who had a previous history of peptic ulcer, kidney, or liver disease, or hematologic abnormalities. APD was prescribed in enteric-coated, soft gelatin capsules, each containing 100mg of the anhydrous disodium salt of the drug micronized and 124
F. R. SPIVACOW
ET AL
suspended in an oil medium (IG-7913, Gador SA, Buenos Aires, Argentina). According to manufacturer instructions, APD was to be taken 1 hour before dinner with one glass of water; fasting was recommended during that hour. When twice daily dosing was required (only in the few patients who received the higher doses), the second dose was to be given 1 hour before breakfast using the same fasting conditions described above. Records for analysis were maintained from 1989 to 1993 and were crosssectionally collected in the last quarter of 1993 by experienced investigators who had previously participated in clinical trials of bisphosphonates. A specially designed electronic form common to the three participating research centers was used. When available, pre- and posttreatment hematologic and biochemical data were also obtained. In this paper we report only biochemical data not related to metabolic bone function. To facilitate evaluation of the data, the entire sample was clustered in subgroups (blocks) for analysis according to sex, dose size, number of days of uninterrupted daily administration, and concomitant therapy. Data were collected and analyzed using a computerized statistical program (Tadpole PC, Version III, Elsevier Biosoft, Cambridge, Massachusetts). The chi-square test or Student’s t test with a two-sided P value < 0.05 was used to determine significance. Trend analysis was done through the Spear-man correlation test. The study was approved by the review board of the participating institutions. RESULTS A sample of 779 clinical records was selected; the patients represented in these records were receiving oral APD for established osteoporosis (685 patients; 88%), for unclassified osteopenia (47 patients; 6%), for Paget’s bone disease (31 patients; 4%), and for other disturbances of bone metabolism (16 patients; 2%). Most (94%) of the patients whose records were analyzed were women. The daily oral dose of APD ranged from 1 to 5 capsules, with 79% of patients receiving two capsules daily. The mean (* SEM) duration of treatment was 8.6 + 0.3 months (range, 1 week to 60 months), with a total of 558.3 patient years accounted for in the study. The mean age of the patients was 64.0 ? 8.0 years at the beginning of therapy. Undesirable side effects were reported in 181 (23.2%) of 779 patients (Table I). Gastrointestinal disturbances, the most frequently experienced side effects, were reported in 170 (21.8%) patients. Among the gastrointestinal side effects, but not included in the table due to low frequency, were endoscopically diagnosed duodenal ulcerations (2 patients) and hemorrhagic gastritis (1patient). Of these 170 patients, each experienced one of the following: regurgitation, constipation, low abdominal pain, and anorexia. There were 10 other patients who reported non-drug-related symptoms that were not gastrointestinal (overall 1.3%): fatigue, insomnia, 125
TOLERABILITY
OF ORAL PAMIDRONATE
Table I. Most frequently recorded side effects and abnormal laboratory values in the clinical records of 779 patients with osteoporosis and other metabolic bone diseases treated continuously with an enteric-coated, soft gelatin capsule of pamidronate. No. of Patients WI Gastrointestinal side effects ;;;Mu-ral parn Heartburn Dyspepsia Vomiting Diarrhea flatulence Other side effects Total side effects* Total abnormal hematologic values4 Decreased leukocyte count Other abnormal hematologic values Treatment discontinued due to drug intolerance or abnormal laboratory values * Some patients experienced more than one side effect. T Hematologic data were available in the records of only 635 patients
drowsiness, itching, headache, and rash. One patient experienced transient fever (38 “Cl 36 hours after taking the drug. One patient developed Sjogren syndrome associated with leukopenia and thrombocytopenia. Another patient had episodes of bronchospasm that required therapy with bronchodilators and corticosteroids. Tendinitis was observed in 2 patients. In the small subgroup of men, the global incidence of side effects was lower (13.3%) than that seen in the total patient population. When the sample was clustered according to the number of capsules administered daily, there was a slight, nonsignificant trend toward a higher rate of side effects varying according to the number of capsules (data not shown). In 169 of the patient records, the daily dose was calculated on the basis of mg/kg body weight. The dose ranged from 1.44 to 9.09 mg/kg in 85 patients who tolerated the drug; it ranged from 1.31 to 7.01 mg/kg in 84 patients matched for age, sex, and body weight who experienced gastrointestinal side effects (t test; P = not significant). When the sample was clustered according to the length of treatment (Table II), there was a significant (P < 0.02) negative correlation (r < - .90) between treatment length and rate of side effects. These findings were influenced by patients who discontinued treatment early because of drug sensitivity. No differences were detected when patients concomitantly received calcium (side-effect rate, 22.9%), vitamin D (24.5%), or other nonosteotrophic drugs (eg, vasodilators or antiarrhythmic drugs [17.1%1) (chisquare = 0.19; P = not significant). Abnormal variations in hematologic values were observed in 60 (9.4%) of the 635 charts containing hematologic data. The total number of leuko126
F. R. SPIVACOW
ET AL
Table II. Absolute and relative relationship between the rate of side effects and the treatment length observed in the 181 patients whose clinical records indicated undesirable side effects among the 779 patients using daily oral pamidronate. Cumulative Periods
Individual Periods Treatment Duration (months)
No. of Patients’
%
No. of Patients*
%
E2
;I-‘3
&:” 211117
2:: 17.9
1631632 1141324
% 35:2
>12 and ~60
z::;
1:::
1811779
E:!
%:
* Patients with side effects/evaluated patients
cytes decreased in 47 patients (Table I), while maintaining the relative proportions of the different types of leukocytes. Of these 47 patients, 9 discontinued APD therapy because their leukocyte count had decreased to less than 3000 leukocytes/mm3; the cell count returned to normal after treatment was discontinued. A mild decrease in platelet count was seen in 13 patients, but none of these patients discontinued therapy. Four reports of changes in erythrocyte counts and hematocrit levels were not considered to be drug related. Increased liver transaminase and alkaline phosphatase activities were seen in 2 patients; these changes were not considered related to the use of APD and disappeared despite continuation of the medication. The drug was discontinued in 85 patients due to adverse events, although compliance was achieved in 89.1% of the population. In 77 of these patients, withdrawal was due to clinical symptoms-abdominal pain, vomiting, and heartburn. Of the 18 patients who experienced diarrhea, 15 discontinued treatment. The withdrawal of 10 other patients was based on abnormal laboratory values. Another 95 patients discontinued treatment for reasons not related to intolerance; 9 had previously experienced clinically undesirable symptoms and 15 experienced reversible or constant hematologic abnormalities. No evidence of kidney or liver toxicity nor manifestations of hypersensitivity were found. DISCUSSION AND CONCLUSIONS
The efficacy of the present formulation and administration schedules of APD has been previously published,4*6with demonstrated efficacy in patients with Paget’s disease or osteoporosis. On the basis of our finding of 89.1% compliance with the treatment regimen, the risk:benelit ratio of this APD formulation appears to be favorable. No matched control group was available, mainly because our available historical groups had received different concomitant therapy or doses and 127
TOLERABILITY
OF ORAL
PAhlIDRONATE
because there were not enough records of long-term untreated patients. Therefore, at least two facts may bias our findings with regard to the rate of side effects: current concomitant therapy and the placebo effect. Thus this open report should be considered a statistical description of the undesirable effects commonly observed in patients treated with oral APD in regular practice, and these undesirable effects must not be definitely attributed to the bisphosphonate. APD-treated patients initially excluded from the statistical analysis due to incomplete records may be suspected of having experienced drug-related side effects. However, the rate of incomplete records was the same for the sample treated with oral APD as for the entire patient population in the three medical centers we studied (data not shown). As a result, our selected sample is considered representative of patients treated with APD in our area. This series provides useful evidence for the tolerability of oral APD, particularly because it was carried out in an elderly population with Paget’s bone disease and postmenopausal osteoporosis. A compilation of side effects in elderly people, most of them women, is not common in the medical literature. Adverse effects have been associated with the majority of bisphosphonates; however, it must be stressed that results obtained with one bisphosphonate cannot be extrapolated to another bisphosphonate or necessarily to another formulation of the same compound.g The two most frequent types of adverse effects described here-gastrointestinal disturbances and hematologic abnormalities-both resulted in discontinuation of treatment. In the present study 23.2% of the patients were identified as having experienced clinically undesirable events, a lower rate than the 50% obtained by Harinck et al’ using oral doses of 600 mg/d of APD in patients with Paget’s disease, and the series of Nagant de Deuxchaisnes et al7 that describes 38% intolerance in patients treated with the same doses. Both studies were performed with noncoated tablets of APD. Fromm et allo recently reported results similar to ours, with 28% gastrointestinal side effects in an open-label sample of 228 patients treated with the same enteric-coated, soft gelatin capsules, and a daily dose ranging from 4.8 to 6 mg/kg, which was slightly higher than the dose range in our study. Several studie&s have shown that the side effects of oral APD are dose related, being less frequent with doses lower than 300 mg/d. In the present study, no clear dose-effect relationship could be demonstrated. Since the appearance of the enteric-coated, soft gelatin capsule, gastrointestinal manifestations of treatment with APD have been considerably reduced.4 When compared with independent studies, few cases of moderate-to-severe intolerance have been reported: with an effervescent powder or an enteric-coated tablet of oral APD reported rates of side effects were 40% and 21% at low doses and 73% and 55% at high doses, respectively.’ Lufkin et al” reported esophagitis in 4 (8.2%) of 49 patients 128
F. Ft. SPNACOW
ET AL.
treated at bedtime with two APD 75mg capsules containing enteric-coated pellets. Thus tolerance may be related to the pharmaceutical formulation used. The complete avoidance of gastric media appears to be a key factor in achieving an acceptable rate of tolerability. Parenthetically, because an endoscopic examination is not routinely performed, the occurrence rate of some asymptomatic gastroesophageal lesions could be understated. In a review by Francis,12 the side effects of pamidronate occurred in a limited number of patients treated with either an effervescent powder that spilled pamidronate on the gastric wall, or an apparently unsuitable enteric-coated tablet or a gelatin capsule with coated granules that stuck to the gastric or esophageal walls. al1 Our data were gathered from patients treated with a different formulation that is resistant to gastric media; this may explain the disparity in results among the studies. A recent prospective study of alendronate tablets 20 or 40 mg/d reveals good tolerability with the former dose and gastroesophageal side effects with the latter.13 These dosages were equivalent in potency to those used in our study of oral APD. The observed transient decrease in leukocyte count seen in this study may be ascribed to a direct or indirect effect of APD on the mononuclear phagocytic system; the phenomenon is gradual and appears to be different from the sudden blood-cell manifestations of the acute reaction phase seen when intravenous formulations are used.i4 This event may be easily monitored by routine methods. In the nine patients in our study whose leukocyte count decreased to less than 3000 leukocytes/mm3, APD was discontinued despite the fact that no medical complications were reported; hematologic values then returned to normal. Thus it may be concluded that oral APD, in the enteric-coated, soft gelatin capsule formulation, administered to elderly patients for approximately 1 year would be expected to cause gastrointestinal side effects in about 21.8% of treated patients and gradually developing hematologic side effects in about 9.4% of patients. A total of 89.1% of the study patients continued the APD therapy for the entire year. Acknowledgments work was partially supported by a grant from FIM (Fundacion de Investigaciones Metabolicas), Buenos Aires, Argentina.
This
References:
1. Harinck HIJ, Papapoulos SE, Blankama HJ, et al. Paget’s disease of bone: Early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD). BMJ. 1987;295:1301-1305. 2. van Breukelen FJM, Bijvoet OLM, Frijlink WB, et al. Efficacy of amino-hydroxypropyl129
TOLERABILITY
OF ORAL PAMIDRONATE
idene bisphosphonate in hypercalcemia: Observations on regulation of serum calcium. Calcif Tissue Znt. 1982;34:321-327.
3. van Holten-Verzantvoort AT, Bijvoet OLM, Cleton FJ, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet. 1987;2:983-985. 4. Fromm GA, Vega E, Plantalech L, et al. Differential action of pamidronate on trabecular and cortical bone in women with involutional osteoporosis. Osteoporosis Znt. 1991;1:129133. 5. Foti R, Martorana U, Broggini M. Long-term tolerability of nasal spray formulation of salmon calcitonin. Curr Ther Res. 1995;56:429-435. 6. Mautalen CA, Casco CA, Gonzalez D, et al. Side effects of disodium aminohydroxypropylidene diphosphonate (APD) during treatment of bone diseases. BMJ. 1984;288:828-
829. 7. Nagant de Deuxchaisnes C, Rombouts-Lindesmans C, Huaux JP, et al. Treatment of
Paget’s disease with the bisphosphonate APD. A biological and radiological study. In: Donath A, Curvoisier B, eds. Diphosphonates and Bone. Geneva: Medicine et Hygiene; 1982:303-327. 8. Coleman RE, Dirix LY, Dodwell D, et al. Phase I/II evaluation of effervescent and enteric coated oral pamidronate for bone metastases. Eur J Cancer. 1991;27:945-946. 9. Fleisch H. Bisphosphonate in Bone Disease. From the Laboratory Berne: Stampfli Co; 1993.
to the Patient.
1st ed.
10. Fromm GA, Vega E, Galich AM, et al. Side effects verified during the treatment of 228 cases of involutional osteoporosis with pamidronate. Bone Miner. 1992;17(Suppl):S17. Abstract. 11. LuIkin EG, Argueta R, Whitaker MD, et al. Pamidronate: An unrecognized problem in gastrointestinal tolerability. Osteoporosis Znt. 1994;4:320-322. 12. Francis RM. Oral bisphosphonates in the treatment of osteoporosis: A review. Curr Ther Res. 1995;56:831-851. 13. Adami A, Mian M, Gatti P, et al. Effects of two oral doses of alendronate in the treatment of Paget’s disease of bone. Bone. 1994;15:415-417. 14. Adami S, Bhalla AK, Dorizzi R, et al. The acute phase response after bisphosphonate administration. Calcif Tissue Znt. 1987;41:326-331.
130
TOLERABILITY OF ORAL PAMIDRONATE IN ELDERLY PATIENTS WITH OSTEOPOROSIS AND OTHER METABOLIC BONE DISEASES FRANCISCO R. SPIVACOW,’ JO& R. ZANCHE’ITA,’ EDUARDO M. KERZBERG,’ ADRIANA FRIGERI,3 ROXANA FIASCHI?,3 AND EMIL10 J. A. ROLDAN4 ‘Znstituto de Znvestigaciones Metabblicas, ‘Department of Rheumatology, Ramos Mejla Hospital, 3Department of Endocrinology, Alvarez Hospital, and 4Department of Clinical Pharmacology, Gador SA, Buenos Aires, Argentina
ABSTRACT
Oral pamidronate (APD) is being used increasingly in the treatment of a variety of bone diseases. In a retrospective chart review of patients at three research centers (a 558.3 patient-year sample), the side effects of treatment with oral, low-dose APD administered in enteric-coated, soft gelatin capsules were analyzed in a group composed primarily of elderly women with osteoporosis. Although 21.8% of the patients experienced various gastrointestinal side effects, 89.1% complied with the treatment schedule. Among patients who discontinued therapy, two had duodenal ulcerations and one had hemorrhagic gastritis. There was a statistically significant negative correlation (r < -.90) between duration of treatment and rate of side effects; this correlation was influenced by patients who discontinued treatment early because of side effects. No clear dose-effect relationship could be demonstrated. No differences were detected when patients concomitantly received calcium, vitamin D, or any other nonosteotrophic drug, such as vasodilators or antiarrhythmic drugs. Hematologic abnormalities, including a reversible decrease in leukocyte count, were noted in 9.4% of the 635 patient charts that contained this type of data. This phenomenon is gradual and appears to be different from the sudden hematologic manifestation of the acute reaction phase described with intravenous administration of APD. Thus it may be concluded that oral APD administered to elderly patients for approximately 1 year would be expected to cause gastrointestinal side effects in about 21.8% of patients and the gradual progression of hematologic side effects in about 9.4%. INTRODUCTION
Pamidronate (APD) ([3-amino-l-hydroxypropylidenel-l,l-bisphosphonate), a second-generation bisphosphonate, is being used increasingly in the treatment of a variety of bone disorders. APD has demonstrated efficacy in Paget’s bone disease,’ tumor-induced hypercalcemia,2 bone metastases,3 Address correspondence to: Dr. Francisco Spivacow, IDIM, Libertad 836, 1012 Buenos Aires, Argentina. Received for publication on October 16, 1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. 123
0011-393x.96/$3.50
TOLERABILITY
OF ORAL PAhfIDRONATE
and osteoporosis.4 Once the efficacy of a drug has been established, tolerability becomes a concern, particularly for drugs administered over an extended period for the treatment of silent diseases such as osteoporosis.5 Compliance with the treatment regimen is another concern. Only a few studies have dealt with the side effects of APD administered orally. In the most extensive study of this drug, which was conducted by Mautalen et a1,6 the most frequently encountered side effects were gastrointestinal; even higher rates of gastrointestinal adverse events were seen in other studies.‘s7 The frequency and severity of abdominal symptoms appear to depend on the particular formulation of APD being studied. Consequently, it is difficult to draw conclusions about APD from the current medical literature. For example, in one study’ two oral formulations of pamidronate-a tablet and an effervescent powder-induced moderateto-severe esophageal and gastric intolerance. Bisphosphonates are poorly soluble compounds. Gastric media may predispose the aggregation and precipitation of these compounds and the consequent irritation of the gastric wall. Thus a formulation that eludes gastric media appears to be advantageous. The purpose of this study was to determine the tolerability of oral APD (an enteric-coated, soft gelatin capsule formulation) in a group of patients treated for 558.3 patient years. (This formulation is currently available in some countries.) PATIENTS AND METHODS
The medical charts of patients with metabolic bone diseases were retrospectively reviewed in three different medical centers in Buenos Aires, using the same methods in all centers. From this population, the records of patients who had been treated with daily oral APD alone or in combination with calcium salts and/or vitamin D derivatives, at the doses recommended for their bone conditions, were studied. Compliance was regularly assessed, as in routine practice, by simply questioning the patients whenever they went for their clinical visit. If no interruption of daily oral APD treatment was recorded, patients were considered to have undergone therapy. The records of selected patients who discontinued therapy, because of side effects or for other reasons, were also evaluated. The sample did not include patients who had incomplete clinical files (mainly due to lack of follow-up), who were undergoing concomitant therapy with other drugs affecting bone metabolism or with more than one drug of any other type, or patients who had a previous history of peptic ulcer, kidney, or liver disease, or hematologic abnormalities. APD was prescribed in enteric-coated, soft gelatin capsules, each containing 100mg of the anhydrous disodium salt of the drug micronized and 124
F. R. SPIVACOW
ET AL
suspended in an oil medium (IG-7913, Gador SA, Buenos Aires, Argentina). According to manufacturer instructions, APD was to be taken 1 hour before dinner with one glass of water; fasting was recommended during that hour. When twice daily dosing was required (only in the few patients who received the higher doses), the second dose was to be given 1 hour before breakfast using the same fasting conditions described above. Records for analysis were maintained from 1989 to 1993 and were crosssectionally collected in the last quarter of 1993 by experienced investigators who had previously participated in clinical trials of bisphosphonates. A specially designed electronic form common to the three participating research centers was used. When available, pre- and posttreatment hematologic and biochemical data were also obtained. In this paper we report only biochemical data not related to metabolic bone function. To facilitate evaluation of the data, the entire sample was clustered in subgroups (blocks) for analysis according to sex, dose size, number of days of uninterrupted daily administration, and concomitant therapy. Data were collected and analyzed using a computerized statistical program (Tadpole PC, Version III, Elsevier Biosoft, Cambridge, Massachusetts). The chi-square test or Student’s t test with a two-sided P value < 0.05 was used to determine significance. Trend analysis was done through the Spear-man correlation test. The study was approved by the review board of the participating institutions. RESULTS A sample of 779 clinical records was selected; the patients represented in these records were receiving oral APD for established osteoporosis (685 patients; 88%), for unclassified osteopenia (47 patients; 6%), for Paget’s bone disease (31 patients; 4%), and for other disturbances of bone metabolism (16 patients; 2%). Most (94%) of the patients whose records were analyzed were women. The daily oral dose of APD ranged from 1 to 5 capsules, with 79% of patients receiving two capsules daily. The mean (* SEM) duration of treatment was 8.6 + 0.3 months (range, 1 week to 60 months), with a total of 558.3 patient years accounted for in the study. The mean age of the patients was 64.0 ? 8.0 years at the beginning of therapy. Undesirable side effects were reported in 181 (23.2%) of 779 patients (Table I). Gastrointestinal disturbances, the most frequently experienced side effects, were reported in 170 (21.8%) patients. Among the gastrointestinal side effects, but not included in the table due to low frequency, were endoscopically diagnosed duodenal ulcerations (2 patients) and hemorrhagic gastritis (1patient). Of these 170 patients, each experienced one of the following: regurgitation, constipation, low abdominal pain, and anorexia. There were 10 other patients who reported non-drug-related symptoms that were not gastrointestinal (overall 1.3%): fatigue, insomnia, 125
TOLERABILITY
OF ORAL PAMIDRONATE
Table I. Most frequently recorded side effects and abnormal laboratory values in the clinical records of 779 patients with osteoporosis and other metabolic bone diseases treated continuously with an enteric-coated, soft gelatin capsule of pamidronate. No. of Patients WI Gastrointestinal side effects ;;;Mu-ral parn Heartburn Dyspepsia Vomiting Diarrhea flatulence Other side effects Total side effects* Total abnormal hematologic values4 Decreased leukocyte count Other abnormal hematologic values Treatment discontinued due to drug intolerance or abnormal laboratory values * Some patients experienced more than one side effect. T Hematologic data were available in the records of only 635 patients
drowsiness, itching, headache, and rash. One patient experienced transient fever (38 “Cl 36 hours after taking the drug. One patient developed Sjogren syndrome associated with leukopenia and thrombocytopenia. Another patient had episodes of bronchospasm that required therapy with bronchodilators and corticosteroids. Tendinitis was observed in 2 patients. In the small subgroup of men, the global incidence of side effects was lower (13.3%) than that seen in the total patient population. When the sample was clustered according to the number of capsules administered daily, there was a slight, nonsignificant trend toward a higher rate of side effects varying according to the number of capsules (data not shown). In 169 of the patient records, the daily dose was calculated on the basis of mg/kg body weight. The dose ranged from 1.44 to 9.09 mg/kg in 85 patients who tolerated the drug; it ranged from 1.31 to 7.01 mg/kg in 84 patients matched for age, sex, and body weight who experienced gastrointestinal side effects (t test; P = not significant). When the sample was clustered according to the length of treatment (Table II), there was a significant (P < 0.02) negative correlation (r < - .90) between treatment length and rate of side effects. These findings were influenced by patients who discontinued treatment early because of drug sensitivity. No differences were detected when patients concomitantly received calcium (side-effect rate, 22.9%), vitamin D (24.5%), or other nonosteotrophic drugs (eg, vasodilators or antiarrhythmic drugs [17.1%1) (chisquare = 0.19; P = not significant). Abnormal variations in hematologic values were observed in 60 (9.4%) of the 635 charts containing hematologic data. The total number of leuko126
F. R. SPIVACOW
ET AL
Table II. Absolute and relative relationship between the rate of side effects and the treatment length observed in the 181 patients whose clinical records indicated undesirable side effects among the 779 patients using daily oral pamidronate. Cumulative Periods
Individual Periods Treatment Duration (months)
No. of Patients’
%
No. of Patients*
%
E2
;I-‘3
&:” 211117
2:: 17.9
1631632 1141324
% 35:2
>12 and ~60
z::;
1:::
1811779
E:!
%:
* Patients with side effects/evaluated patients
cytes decreased in 47 patients (Table I), while maintaining the relative proportions of the different types of leukocytes. Of these 47 patients, 9 discontinued APD therapy because their leukocyte count had decreased to less than 3000 leukocytes/mm3; the cell count returned to normal after treatment was discontinued. A mild decrease in platelet count was seen in 13 patients, but none of these patients discontinued therapy. Four reports of changes in erythrocyte counts and hematocrit levels were not considered to be drug related. Increased liver transaminase and alkaline phosphatase activities were seen in 2 patients; these changes were not considered related to the use of APD and disappeared despite continuation of the medication. The drug was discontinued in 85 patients due to adverse events, although compliance was achieved in 89.1% of the population. In 77 of these patients, withdrawal was due to clinical symptoms-abdominal pain, vomiting, and heartburn. Of the 18 patients who experienced diarrhea, 15 discontinued treatment. The withdrawal of 10 other patients was based on abnormal laboratory values. Another 95 patients discontinued treatment for reasons not related to intolerance; 9 had previously experienced clinically undesirable symptoms and 15 experienced reversible or constant hematologic abnormalities. No evidence of kidney or liver toxicity nor manifestations of hypersensitivity were found. DISCUSSION AND CONCLUSIONS
The efficacy of the present formulation and administration schedules of APD has been previously published,4*6with demonstrated efficacy in patients with Paget’s disease or osteoporosis. On the basis of our finding of 89.1% compliance with the treatment regimen, the risk:benelit ratio of this APD formulation appears to be favorable. No matched control group was available, mainly because our available historical groups had received different concomitant therapy or doses and 127
TOLERABILITY
OF ORAL
PAhlIDRONATE
because there were not enough records of long-term untreated patients. Therefore, at least two facts may bias our findings with regard to the rate of side effects: current concomitant therapy and the placebo effect. Thus this open report should be considered a statistical description of the undesirable effects commonly observed in patients treated with oral APD in regular practice, and these undesirable effects must not be definitely attributed to the bisphosphonate. APD-treated patients initially excluded from the statistical analysis due to incomplete records may be suspected of having experienced drug-related side effects. However, the rate of incomplete records was the same for the sample treated with oral APD as for the entire patient population in the three medical centers we studied (data not shown). As a result, our selected sample is considered representative of patients treated with APD in our area. This series provides useful evidence for the tolerability of oral APD, particularly because it was carried out in an elderly population with Paget’s bone disease and postmenopausal osteoporosis. A compilation of side effects in elderly people, most of them women, is not common in the medical literature. Adverse effects have been associated with the majority of bisphosphonates; however, it must be stressed that results obtained with one bisphosphonate cannot be extrapolated to another bisphosphonate or necessarily to another formulation of the same compound.g The two most frequent types of adverse effects described here-gastrointestinal disturbances and hematologic abnormalities-both resulted in discontinuation of treatment. In the present study 23.2% of the patients were identified as having experienced clinically undesirable events, a lower rate than the 50% obtained by Harinck et al’ using oral doses of 600 mg/d of APD in patients with Paget’s disease, and the series of Nagant de Deuxchaisnes et al7 that describes 38% intolerance in patients treated with the same doses. Both studies were performed with noncoated tablets of APD. Fromm et allo recently reported results similar to ours, with 28% gastrointestinal side effects in an open-label sample of 228 patients treated with the same enteric-coated, soft gelatin capsules, and a daily dose ranging from 4.8 to 6 mg/kg, which was slightly higher than the dose range in our study. Several studie&s have shown that the side effects of oral APD are dose related, being less frequent with doses lower than 300 mg/d. In the present study, no clear dose-effect relationship could be demonstrated. Since the appearance of the enteric-coated, soft gelatin capsule, gastrointestinal manifestations of treatment with APD have been considerably reduced.4 When compared with independent studies, few cases of moderate-to-severe intolerance have been reported: with an effervescent powder or an enteric-coated tablet of oral APD reported rates of side effects were 40% and 21% at low doses and 73% and 55% at high doses, respectively.’ Lufkin et al” reported esophagitis in 4 (8.2%) of 49 patients 128
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treated at bedtime with two APD 75mg capsules containing enteric-coated pellets. Thus tolerance may be related to the pharmaceutical formulation used. The complete avoidance of gastric media appears to be a key factor in achieving an acceptable rate of tolerability. Parenthetically, because an endoscopic examination is not routinely performed, the occurrence rate of some asymptomatic gastroesophageal lesions could be understated. In a review by Francis,12 the side effects of pamidronate occurred in a limited number of patients treated with either an effervescent powder that spilled pamidronate on the gastric wall, or an apparently unsuitable enteric-coated tablet or a gelatin capsule with coated granules that stuck to the gastric or esophageal walls. al1 Our data were gathered from patients treated with a different formulation that is resistant to gastric media; this may explain the disparity in results among the studies. A recent prospective study of alendronate tablets 20 or 40 mg/d reveals good tolerability with the former dose and gastroesophageal side effects with the latter.13 These dosages were equivalent in potency to those used in our study of oral APD. The observed transient decrease in leukocyte count seen in this study may be ascribed to a direct or indirect effect of APD on the mononuclear phagocytic system; the phenomenon is gradual and appears to be different from the sudden blood-cell manifestations of the acute reaction phase seen when intravenous formulations are used.i4 This event may be easily monitored by routine methods. In the nine patients in our study whose leukocyte count decreased to less than 3000 leukocytes/mm3, APD was discontinued despite the fact that no medical complications were reported; hematologic values then returned to normal. Thus it may be concluded that oral APD, in the enteric-coated, soft gelatin capsule formulation, administered to elderly patients for approximately 1 year would be expected to cause gastrointestinal side effects in about 21.8% of treated patients and gradually developing hematologic side effects in about 9.4% of patients. A total of 89.1% of the study patients continued the APD therapy for the entire year. Acknowledgments work was partially supported by a grant from FIM (Fundacion de Investigaciones Metabolicas), Buenos Aires, Argentina.
This
References:
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3. van Holten-Verzantvoort AT, Bijvoet OLM, Cleton FJ, et al. Reduced morbidity from skeletal metastases in breast cancer patients during long-term bisphosphonate (APD) treatment. Lancet. 1987;2:983-985. 4. Fromm GA, Vega E, Plantalech L, et al. Differential action of pamidronate on trabecular and cortical bone in women with involutional osteoporosis. Osteoporosis Znt. 1991;1:129133. 5. Foti R, Martorana U, Broggini M. Long-term tolerability of nasal spray formulation of salmon calcitonin. Curr Ther Res. 1995;56:429-435. 6. Mautalen CA, Casco CA, Gonzalez D, et al. Side effects of disodium aminohydroxypropylidene diphosphonate (APD) during treatment of bone diseases. BMJ. 1984;288:828-
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Paget’s disease with the bisphosphonate APD. A biological and radiological study. In: Donath A, Curvoisier B, eds. Diphosphonates and Bone. Geneva: Medicine et Hygiene; 1982:303-327. 8. Coleman RE, Dirix LY, Dodwell D, et al. Phase I/II evaluation of effervescent and enteric coated oral pamidronate for bone metastases. Eur J Cancer. 1991;27:945-946. 9. Fleisch H. Bisphosphonate in Bone Disease. From the Laboratory Berne: Stampfli Co; 1993.
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