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Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. Effect of adding hormone replacement therapy
ORIGINAL ARTICLE
Joint Bone Spine 2001 ; 68 : 410-5 © 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S1297319X01002974/FLA
Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. Effect of adding hormone replacement therapy Bernard Cortet1*, Anne Béra-Louville1, Patrick Gauthier1, Alain Gauthier2, Xavier Marchandise3, Bernard Delcambre1 1 Rheumatology department, hôpital Roger-Salengro, CHRU Lille, 59037 Lille cedex, France; 2Gynecology department, hôpital Roger-Salengro, CHRU Lille, 59037 Lille cedex, France; 3Central nuclear medicine department, hôpital Roger-Salengro, CHRU Lille, 59037 Lille cedex, France
(Submitted for publication February 13, 2001; accepted in revised form June 6, 2001)
Summary – Objectives. To compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis and to assess the efficacy of either bisphosphonate in combination with hormone replacement therapy (HRT). Patients and methods. In this pragmatic study, the main efficacy criterion was the mean annual change in bone mineral density (BMD). Patients who had a past or current history of etidronate or alendronate treatment for postmenopausal osteoporosis with at least 18 months follow-up and an evaluation in 1999 were eligible. Recruitment was in an outpatient clinic with a special focus on metabolic bone diseases. Osteoporosis was defined as at least one low-energy fracture or as a lumbar spine or femoral neck BMD decrease to at least 2.5 SD below the mean in young women. HRT was not an exclusion criterion provided treatment duration was longer than 1 year. Etidronate was given cyclically (14-day courses in a dosage of 400 mg/d separated by 76-day intervals with calcium and vitamin D supplementation) and alendronate was given daily in a dosage of 10 mg/d. Results. Of the 99 patients who met our inclusion criteria, 53 received etidronate (including 23 on HRT) and 46 alendronate (18 on HRT). Repeat BMD measurements were obtained in 88 patients, including 11 who stopped their bisphosphonate therapy within the first year of use because of adverse events. Lumbar spine BMD (mean ± SD) increased significantly both in the etidronate group (+2.1% ± 0.7%/year) and in the alendronate group (+5.3% ± 0.9%/year). The increase was significantly greater with alendronate (P < 0.01). The lumbar spine BMD increase was largest in the patients on alendronate and HRT (+6.5% ± 1.4%/year) and was smallest (and nonsignificant) in the patients on etidronate without HRT (+1.2% ± 0.8%). Femoral neck BMD showed no significant changes in any group. In the intention-to-treat analysis, fractures occurred in 12 etidronate patients (22.6%) and six (13.0%) alendronate patients (nonsignificant). Adverse events requiring bisphosphonate discontinuation before the scheduled date of the follow-up BMD measurement occurred in one patient (1.9%) in the etidronate group (generalized osteomalacia) and in ten patients (21.7%) in the alendronate group (upper or lower gastrointestinal tract symptoms in six and four patients, respectively; P < 0.01). Conclusion. Both etidronate and alendronate significantly increased lumbar BMD, but the effect
* Correspondence and reprints:. E-mail address: [email protected] (B. Cortet).
Etidronate vs alendronate in osteoporosis
411
was significantly more marked with alendronate. Conversely, adverse effects, most notably gastrointestinal symptoms, were more common with alendronate, so that premature treatment discontinuation because of adverse events were more common in the alendronate group. Both differences should be taken into account when selecting the best drug for a patient with postmenopausal osteoporosis. Joint Bone Spine 2001 ; 68 : 410-5. © 2001 Éditions scientifiques et médicales Elsevier SAS alendronate / bisphosphonate / bone mineral density / etidronate / postmenopausal osteoporosis
INTRODUCTION
PATIENTS AND METHODS
The curative treatment of postmenopausal osteoporosis can, in theory, rely on drugs capable of stimulating bone formation or inhibiting bone resorption. Fluoride, which increases bone formation, is no longer used because the fluoride treatment schedule recommended in France significantly increases bone mineral density (BMD) but fails to reduce the risk of fractures, most notably at the spine [1]. Bisphosphonates inhibit bone resorption and have a place of choice in the treatment of postmenopausal osteoporosis. Two bisphosphonates are licensed for use in France in this indication, etidronate and alendronate. Etidronate has been on the market for 10 years and is used in 3-month cycles of which each includes 2 weeks of etidronate therapy in a daily dosage of one 400 mg tablet. Efficacy data are conflicting [2-4]. The safety profile is outstanding. Alendronate is given daily (10 mg/d) and decreases the fracture rates at the spine, wrist, and hip [5, 6]. In therapeutic trials, the safety profile was satisfactory, with no significant difference as compared to the placebo [5, 6]. It is important to bear in mind, however, that patients with a history of upper gastrointestinal disease were excluded from all therapeutic trials [5, 6]. Few data are available on the comparative efficacy and safety of these two bisphosphonates [7]. Although the effects on bone of bisphosphonates and hormone replacement therapy (HRT) involve the same mechanism of action, namely, inhibition of bone resorption, a few studies suggest that taking a bisphosphonate and HRT in combination may increase the beneficial effects on bone as compared to use of either treatment alone [8-10]. The main objective of this pragmatic study was to compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis. The primary efficacy criterion was the mean BMD change during 1 year. The second objective of the study was to evaluate the influence of concomitant HRT.
Patients The study patients were recruited in an outpatient clinic with a special focus on metabolic bone diseases. Patients with postmenopausal osteoporosis who were examined during 1999 and had a past or current history of etidronate or alendronate therapy were eligible. HRT was an exclusion criterion only if treatment duration was shorter than 1 year. All study patients were examined by the same physician (B.C.) and received standardized outpatient follow-up with 6-monthly visits. Osteoporosis was defined as at least one low-energy fracture or a greater than 2.5 decrease in the BMD T-score (World Health Organization definition, [11]). Dual-energy X-ray absorptiometry was performed in all patients at study inclusion using either a Sophos L-XRAt (N = 44) or a Hologic QDR-2000t (N = 55) device. Measurements were obtained at the lumbar spine (L2, L3, and L4) on an anteroposterior view and at the femoral neck (site common to the two devices). Of the 99 patients who met our study inclusion criteria, 77 (77.7%) had experienced one or more bone insufficiency fractures. The fracture or fractures were at the spine (N = 45, 58.4%), wrist (N = 14, 18.2%), hip (N = 5, 6.5%), or other sites (N = 13, 16.9%). Table I shows the distribution of fracture sites in each of the two treatment groups. Methods Treatment regimens Of the 99 study patients, 53 received etidronate and 46 alendronate. Forty-one patients overall were on HRT, 23 in the etidronate group and 18 in the alendronate group. HRT was given orally in 11 patients (26.8%), transdermally in 11 patients (26.8%), and percutaneously in 19 patients (46.4%). The daily estradiol dosage was 1.2 ± 0.1 mg in the patients treated orally and
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Table I. Main patient characteristics at baseline in each of the treatment groups. Treatment
Etidronate
Alendronate
Number of patients Age (years) Body weight (kg) Height (cm) Years since menopause Lumbar spine T-score Femoral neck T-score History of fractures (%) Vertebral fractures Wrist fractures Hip fractures Other fractures
53 63 ± 1 60 ± 2 159 ± 1 17 ± 1 –2.8 ± 0.1 –2.5 ± 0.1 39 (73%) 24 (45%) 6 (11%) 2 (4%) 7 (13%)
46 60 ± 2 62 ± 2 160 ± 1 16 ± 2 –2.9 ± 0.2 –2.7 ± 0.1 38 (83%) 21 (46%) 8 (17%) 3 (7%) 6 (13%)
42.3 ± 6 g in the patients treated transdermally or percutaneously. Five of the HRT patients had a history of hysterectomy; the remaining 36 patients received a progestogen (nomegestrol, N = 8; promegestone, N = 9; dydrogestone, N = 10; or natural progesterone, N = 9). Apart from HRT, none of the patients had a history of treatment with agents known to influence bone metabolism or BMD. The calendar year of bisphosphonate treatment initiation influenced the likelihood of receiving etidronate or alendronate; although all study patients were evaluated in 1999, their bisphosphonate therapy was started earlier. Other factors that influenced the choice between the two bisphosphonates were a history of gastrointestinal disorders contraindicating alendronate therapy and poor compliance compromising full exposure to the prescribed alendronate dosage. All study patients received detailed explanations on how to take the bisphosphonate and on the possible adverse events of the drug. Etidronate was given cyclically according to the standard regimen, i.e., consecutive 3-month cycles, each with 14 days of etidronate in a dosage of one 400 mg tablet per day 2 hours before breakfast with a glass of water, followed by 76 days of supplemental calcium supplementation (1 g/ d) alone (N = 9) or with supplemental vitamin D3 (800 IU/d (N = 44). This cyclical treatment was continued until the follow-up absorptiometry. Alendronate was given continuously as one 10 mg tablet in the morning at least 30 minutes before breakfast, with a large glass of water. Patients were instructed to refrain from lying down during the interval between dosing and breakfast. Of the 46 patients in the alendronate group, 38 received supplemental calcium (1 g/d) alone (N = 6) or with supplemental vitamin D (N = 32). The
decision to use calcium and vitamin D (alendronate group) or vitamin D alone (etidronate group) was based on the baseline calcium and vitamin D status evaluated by history taking and by routine assays of calcium, phosphate, and serum 25-dihydroxyvitamin D3. The two absorptiometry studies were done 18 months apart. This interval was chosen based on reproducibility of dual-energy x-ray absorptiometry measurements from anteroposterior views of the lumbar spine and on mean BMD gains reported during earlier studies of bisphosphonate therapy. To facilitate comparisons, the mean annual BMD change was calculated as the BMD change found during the 18-month follow-up divided by 1.5. Statistical methods Results are reported as means ± standard error (SEM). BMD values at baseline and at study completion were compared using Student’s t-test for paired data or Wilcoxon’s rank sum test. Analysis of variance or the Kruskal-Wallis test were used to compare the percentage change in BMD among the treatment groups. Main patient characteristics at baseline and during follow-up were compared using analysis of variance or the KruskalWallis test for quantitative variables and the χ2 test with Yates’s correction if appropriate for qualitative variables (prevalent and incidence fractures). Fracture incidence during the 18-month study period was evaluated in the intention-to-treat population. All statistical tests were run using the Statview 5 program (SAS Institute, Cary, NC, USA). RESULTS Table I reports the main patient characteristics at baseline. Although the treatments were not allocated at random, no significant differences were found for age, body weight, height, time since menopause, lumbar spine or femoral neck BMD, or fracture status. Although a history of bone insufficiency fracture was more common in the alendronate group, the difference with the etidronate group was not statistically significant. Efficacy Eighty-eight patients underwent a follow-up absorptiometry scan; the remaining 11 patients experienced adverse effects requiring discontinuation of their bisphosphonate therapy before the scheduled follow-up absorptiometry (see below). Figure 1 shows BMD
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Etidronate vs alendronate in osteoporosis
Table III. Incident fractures during the 18-month follow-up in the two treatment groups. Fracture site
Vertebra
Wrist
Other
Etidronate Alendronate
6 (11.3%) 3 (6.5%)
2 (3.8%) 0 (0%)
6 (11.3%) 4 (8.7%)
fractures in six alendronate patients (13%) (P nonsignificant). Table III provides details on the fractures that occurred during the 18-month study period. Safety Figure 1. Change in bone mineral density (percent per year) in the etidronate and alendronate groups.
changes over time in the two treatment groups. Lumbar spine BMD increased significantly in the etidronate group (+2.1% ± 0.7%/year, P < 0.05) and in the alendronate group (+5.3% ± 0.9%/year, P < 0.01). The increase was significantly greater in the alendronate group (P < 0.01). Table II shows BMD changes in HRT users and nonusers. Bone gain at the lumbar spine was greatest in the group taking alendronate and HRT (+6.5% ± 1.4%, P < 0.01) and smallest in the group given etidronate without HRT (+1.2% ± 0.8%, P nonsignificant). Femoral neck BMD showed no change in the etidronate group (–0.1% ± 0.7) and a nonsignificant increase in the alendronate group (+1.8% ± 0.9%). Table II shows femoral neck BMD changes in HRT users and nonusers. No significant femoral neck BMD changes were seen in any of the four groups, although a nonsignificant increase was recorded in the alendronate group (+1.6% ± 1.7%) and in the alendronate-HRT group (+1.9% ± 1%). During the 18-month follow-up, 14 fractures occurred in 12 etidronate patients (22.6%) and seven Table II. Mean percent change in bone mineral density (BMD) per year at the lumbar spine (LS) and femoral neck (FN) in the various treatment groups. HRT: hormone replacement therapy. *P < 0.05 and **P < 0.01 for the BMD at the end of follow-up versus BMD at baseline. Treatment
LS BMD change FN BMD change
Etidronate (N = 29) Etidronate + HRT (N = 23) Alendronate (N = 22) Alendronate + HRT (N = 14)
+1.2% ± 0.8 +3.8% ± 1.2* +4.2% ± 1.0** +6.5% ± 1.4**
+0.0% ± 0.5 -0.3% ± 1.9 +1.6% ± 1.7 +1.9% ± 1.0
Adverse effects requiring bisphosphonate discontinuation before the scheduled follow-up absorptiometry occurred in one etidronate patient (1.9%) and ten alendronate patients (21.7%). Premature treatment discontinuations were significantly more common in the alendronate group (P < 0.01). The etidronate patient had osteomalacia suggested by clinical and radiographic findings and confirmed by histomorphometric studies. In the alendronate group, all premature treatment discontinuations were ascribable to epigastric pain (N = 6) or abdominal distension (N = 4). Premature alendronate discontinuation occurred within the first 6 months in all ten patients and within the first 2 months in four patients. Adverse events that did not require treatment discontinuation occurred in both groups. In the etidronate group, they consisted of a sensation of difficult digestion during the first two treatment weeks. Seven patients in the alendronate group experienced mild gastrointestinal symptoms consisting of epigastric pain (N = 4), abdominal distension (N = 2), or diarrhea (N = 1). DISCUSSION Our data suggest that both etidronate and alendronate produce significant increases in lumbar BMD in patients with postmenopausal osteoporosis. With etidronate, the gain was 2.1%/year, which is similar to the result reported by Storm et al. (about 2%/year) [2]. Slightly lower gains were obtained by Watts et al. (about 3.5% per year) [3] and Sahota et al. (4.9%/year) [7]. These earlier data were obtained during therapeutic trials, whereas our work was a pragmatic study conducted under the conditions of everyday clinical practice. With alendronate, the gain in our study was 5.4% per year, in keeping with the findings by Liberman et al. (about 4% per year) [12] and by Sahota et al. (5.7% per
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year) [7]. Similar to Watts et al. [3], Sahota et al. [7] reported a significant BMD increase at the hip (+1.6%); they did not report findings at the femoral neck. With alendronate, we recorded a nonsignificant increase at the hip (+1.8% per year) similar to reports by Liberman et al. and Black et al. of an about 2% gain per year [5, 12]. We found evidence that lumbar BMD increases more with alendronate than with etidronate. Few data comparing these two drugs are available. Sahota et al. [7] recently reported a slightly greater bone gain at the lumbar spine with alendronate than with etidronate, although the difference was not statistically significant. Furthermore, our results are in line with the main published data on the efficacy of each of these drugs [2-6]. Although treatments were not randomly allocated in our study, the patient population was homogeneous (with all patients recruited by the same physician), and the main patient characteristics were similar at baseline in the two treatment groups. That we found no statistically significant difference in the fracture rate between the two groups may be ascribable to the small sample size (the percentage of patients with a history of fracture was higher in the alendronate group than in the etidronate group). Furthermore, the efficacy of bisphosphonates in preventing fractures increases with the severity of osteoporosis evaluated based on the BMD decrease or on the number of prevalent vertebral fractures [4]. However, our primary efficacy criterion was the lumbar spine BMD change, and at baseline lumbar spine BMD was similar in the two groups. These considerations strongly suggest that our findings are valid. Similar to others [8-10], we found that combining a bisphosphonate with HRT produced a larger lumbar spine BMD gain than a bisphosphonate alone. This was true of both etidronate and alendronate. In a study of osteoporotic women, Wimalawansa [8] reported a mean lumbar spine BMD increase of about 7% after 2 years of therapy with etidronate and HRT, a figure similar to our 3.8% per year rate of BMD gain. However, in their study [8], BMD increased significantly at the femoral neck (about 4% after 2 years), a site where we found no significant change. Wimalawansa [8] started bisphosphonate therapy and HRT at the same time, whereas in our study the patients had already received HRT for at least 1 year at study inclusion. Lindsay et al. [10] also found that concomitant alendronate and HRT for 1 year produced a larger BMD increase than HRT alone (3.6 vs 1%) in women with osteoporosis. However,
they did not include any patients on alendronate only. The findings by Greenspan et al. in osteopenic women [9] are similar to ours: after 2 years of alendronate and HRT, the BMD gain was 8.3% (6.5%/year in the relevant group in our study). At the femoral neck, the gain was 4.2% with alendronate and HRT (1.6%/year in our study) and 2.9% with alendronate alone (1.9% in our study). The above-mentioned studies were prospective and controlled, whereas ours was retrospective and pragmatic. Etidronate had a favorable gastrointestinal safety profile in our study, in keeping with earlier reports [2-4, 7]. Osteomalacia developed in one of our patients during treatment. However, the contribution of etidronate therapy to this complication is unclear because bone biopsy was not performed prior to initiation of the drug. Wimalawansa [8] and Thomas et al. [13] reported four cases of osteomalacia in patients on etidronate therapy; one patient had generalized disease (as in our patient), two had focal disease, and one had atypical disease. Alendronate was associated with gastrointestinal symptoms in 37% of our patients, in line with earlier data [5]. Conversely, in contrast to previous reports, the rate of treatment discontinuations ascribable to gastrointestinal symptoms was 24% in our study. Liberman et al. [12] reported that only 1 to 3.5% of patients had to stop alendronate therapy because of gastrointestinal symptoms (vs 59% in our patients). However, a recent study [7] found a prevalence of 27%. In this controlled study [7], another group received cyclical etidronate therapy, which had an excellent gastrointestinal safety profile with no treatment discontinuations after 1 year. The number of patients in our study is too small to allow conclusions about the efficacy of bisphosphonate therapy in preventing fractures. However, incident fractures occurred in 22.6% of etidronate patients versus 13% of alendronate patients; thus, incident fractures were 42.5% less common with alendronate than with etidronate. We are not aware of any randomized studies comparing the efficacy of etidronate and alendronate in preventing fractures. Nevertheless, our data are in good agreement with the results of published randomized studies. For instance, alendronate has been found effective in reducing the incidence of osteoporotic fractures [5, 6]. Data about etidronate are conflicting [2-4]. Our work has several limitations: the treatments were not randomly allocated, the number of patients was small, and HRT was not standardized. Despite these shortcomings, it provides numerical data on the safety
Etidronate vs alendronate in osteoporosis
of the two bisphosphonates currently approved in France for the treatment of osteoporosis. Furthermore, the absorptiometry findings are in agreement with the main data in the literature [2-7, 12]. In conclusion, both etidronate and alendronate significantly increase lumbar spine BMD, with alendronate being the more effective agent. Conversely, alendronate has a less favorable safety profile, most notably with regard to gastrointestinal symptoms, and is consequently associated with a higher treatment discontinuation rate. These two facts should be weighed against each other when deciding which bisphosphonate to use in a patient with osteoporosis. REFERENCES 1 Meunier PJ, Sebert JL, Reginster JY, Briançon D, Appelboom T, Netter P, et al. Fluoride salts are no better at preventing new vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis: the FAVOS study. Osteoporos Int 1998 ; 8 : 4-12. 2 Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990 ; 322 : 1265-71. 3 Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990 ; 323 : 73-9. 4 Harris ST, Watts NB, Jackson RD, Genant HK, Wasnich RD, Ross P, et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med 1993 ; 95 : 557-67.
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5 Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996 ; 348 : 1535-41. 6 Cummings SR, Black DM, Thompson DE, Appelgate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998 ; 280 : 2777-82. 7 Sahota O, Fowler I, Blackwell PJ, Lawson N, Cawte A, San P, et al. A comparison of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in the treatment of postmenopausal vertebral osteoporosis: a randomized controlled trial. Osteoporosos Int 2000 ; 11 : 959-66. 8 Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenoapusal osteoporosis. Am J Med 1998 ; 104 : 219-26. 9 Greenspan S, Bankhurst N, Bell N, Bolognese M, Bone H, Davidson M, et al. Effects of alendronate, alone or in combination on bone mass and turn-over in postmenopausal osteoporosis [abstract]. Bone 1998 ; 23 (Suppl 1) : 174. 10 Lindsay R, Cosman F, Obo RA, Walsh BW, Harris ST, Reagan JE, et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial. J Clin Endocrinol Metab 1999 ; 84 : 3076-81. 11 Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994 ; 9 : 1137-41. 12 Liberman UA, Weiss R, Bröll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995 ; 333 : 1437-43. 13 Thomas T, Lafage MH, Alexandre C. Atypical osteomalacia after 2 year etidronate intermittent cyclic administration in osteoporosis. J Rheumatol 1995 ; 22 : 2183-5.
Joint Bone Spine 2001 ; 68 : 410-5 © 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S1297319X01002974/FLA
Comparative efficacy and safety study of etidronate and alendronate in postmenopausal osteoporosis. Effect of adding hormone replacement therapy Bernard Cortet1*, Anne Béra-Louville1, Patrick Gauthier1, Alain Gauthier2, Xavier Marchandise3, Bernard Delcambre1 1 Rheumatology department, hôpital Roger-Salengro, CHRU Lille, 59037 Lille cedex, France; 2Gynecology department, hôpital Roger-Salengro, CHRU Lille, 59037 Lille cedex, France; 3Central nuclear medicine department, hôpital Roger-Salengro, CHRU Lille, 59037 Lille cedex, France
(Submitted for publication February 13, 2001; accepted in revised form June 6, 2001)
Summary – Objectives. To compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis and to assess the efficacy of either bisphosphonate in combination with hormone replacement therapy (HRT). Patients and methods. In this pragmatic study, the main efficacy criterion was the mean annual change in bone mineral density (BMD). Patients who had a past or current history of etidronate or alendronate treatment for postmenopausal osteoporosis with at least 18 months follow-up and an evaluation in 1999 were eligible. Recruitment was in an outpatient clinic with a special focus on metabolic bone diseases. Osteoporosis was defined as at least one low-energy fracture or as a lumbar spine or femoral neck BMD decrease to at least 2.5 SD below the mean in young women. HRT was not an exclusion criterion provided treatment duration was longer than 1 year. Etidronate was given cyclically (14-day courses in a dosage of 400 mg/d separated by 76-day intervals with calcium and vitamin D supplementation) and alendronate was given daily in a dosage of 10 mg/d. Results. Of the 99 patients who met our inclusion criteria, 53 received etidronate (including 23 on HRT) and 46 alendronate (18 on HRT). Repeat BMD measurements were obtained in 88 patients, including 11 who stopped their bisphosphonate therapy within the first year of use because of adverse events. Lumbar spine BMD (mean ± SD) increased significantly both in the etidronate group (+2.1% ± 0.7%/year) and in the alendronate group (+5.3% ± 0.9%/year). The increase was significantly greater with alendronate (P < 0.01). The lumbar spine BMD increase was largest in the patients on alendronate and HRT (+6.5% ± 1.4%/year) and was smallest (and nonsignificant) in the patients on etidronate without HRT (+1.2% ± 0.8%). Femoral neck BMD showed no significant changes in any group. In the intention-to-treat analysis, fractures occurred in 12 etidronate patients (22.6%) and six (13.0%) alendronate patients (nonsignificant). Adverse events requiring bisphosphonate discontinuation before the scheduled date of the follow-up BMD measurement occurred in one patient (1.9%) in the etidronate group (generalized osteomalacia) and in ten patients (21.7%) in the alendronate group (upper or lower gastrointestinal tract symptoms in six and four patients, respectively; P < 0.01). Conclusion. Both etidronate and alendronate significantly increased lumbar BMD, but the effect
* Correspondence and reprints:. E-mail address: [email protected] (B. Cortet).
Etidronate vs alendronate in osteoporosis
411
was significantly more marked with alendronate. Conversely, adverse effects, most notably gastrointestinal symptoms, were more common with alendronate, so that premature treatment discontinuation because of adverse events were more common in the alendronate group. Both differences should be taken into account when selecting the best drug for a patient with postmenopausal osteoporosis. Joint Bone Spine 2001 ; 68 : 410-5. © 2001 Éditions scientifiques et médicales Elsevier SAS alendronate / bisphosphonate / bone mineral density / etidronate / postmenopausal osteoporosis
INTRODUCTION
PATIENTS AND METHODS
The curative treatment of postmenopausal osteoporosis can, in theory, rely on drugs capable of stimulating bone formation or inhibiting bone resorption. Fluoride, which increases bone formation, is no longer used because the fluoride treatment schedule recommended in France significantly increases bone mineral density (BMD) but fails to reduce the risk of fractures, most notably at the spine [1]. Bisphosphonates inhibit bone resorption and have a place of choice in the treatment of postmenopausal osteoporosis. Two bisphosphonates are licensed for use in France in this indication, etidronate and alendronate. Etidronate has been on the market for 10 years and is used in 3-month cycles of which each includes 2 weeks of etidronate therapy in a daily dosage of one 400 mg tablet. Efficacy data are conflicting [2-4]. The safety profile is outstanding. Alendronate is given daily (10 mg/d) and decreases the fracture rates at the spine, wrist, and hip [5, 6]. In therapeutic trials, the safety profile was satisfactory, with no significant difference as compared to the placebo [5, 6]. It is important to bear in mind, however, that patients with a history of upper gastrointestinal disease were excluded from all therapeutic trials [5, 6]. Few data are available on the comparative efficacy and safety of these two bisphosphonates [7]. Although the effects on bone of bisphosphonates and hormone replacement therapy (HRT) involve the same mechanism of action, namely, inhibition of bone resorption, a few studies suggest that taking a bisphosphonate and HRT in combination may increase the beneficial effects on bone as compared to use of either treatment alone [8-10]. The main objective of this pragmatic study was to compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis. The primary efficacy criterion was the mean BMD change during 1 year. The second objective of the study was to evaluate the influence of concomitant HRT.
Patients The study patients were recruited in an outpatient clinic with a special focus on metabolic bone diseases. Patients with postmenopausal osteoporosis who were examined during 1999 and had a past or current history of etidronate or alendronate therapy were eligible. HRT was an exclusion criterion only if treatment duration was shorter than 1 year. All study patients were examined by the same physician (B.C.) and received standardized outpatient follow-up with 6-monthly visits. Osteoporosis was defined as at least one low-energy fracture or a greater than 2.5 decrease in the BMD T-score (World Health Organization definition, [11]). Dual-energy X-ray absorptiometry was performed in all patients at study inclusion using either a Sophos L-XRAt (N = 44) or a Hologic QDR-2000t (N = 55) device. Measurements were obtained at the lumbar spine (L2, L3, and L4) on an anteroposterior view and at the femoral neck (site common to the two devices). Of the 99 patients who met our study inclusion criteria, 77 (77.7%) had experienced one or more bone insufficiency fractures. The fracture or fractures were at the spine (N = 45, 58.4%), wrist (N = 14, 18.2%), hip (N = 5, 6.5%), or other sites (N = 13, 16.9%). Table I shows the distribution of fracture sites in each of the two treatment groups. Methods Treatment regimens Of the 99 study patients, 53 received etidronate and 46 alendronate. Forty-one patients overall were on HRT, 23 in the etidronate group and 18 in the alendronate group. HRT was given orally in 11 patients (26.8%), transdermally in 11 patients (26.8%), and percutaneously in 19 patients (46.4%). The daily estradiol dosage was 1.2 ± 0.1 mg in the patients treated orally and
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Table I. Main patient characteristics at baseline in each of the treatment groups. Treatment
Etidronate
Alendronate
Number of patients Age (years) Body weight (kg) Height (cm) Years since menopause Lumbar spine T-score Femoral neck T-score History of fractures (%) Vertebral fractures Wrist fractures Hip fractures Other fractures
53 63 ± 1 60 ± 2 159 ± 1 17 ± 1 –2.8 ± 0.1 –2.5 ± 0.1 39 (73%) 24 (45%) 6 (11%) 2 (4%) 7 (13%)
46 60 ± 2 62 ± 2 160 ± 1 16 ± 2 –2.9 ± 0.2 –2.7 ± 0.1 38 (83%) 21 (46%) 8 (17%) 3 (7%) 6 (13%)
42.3 ± 6 g in the patients treated transdermally or percutaneously. Five of the HRT patients had a history of hysterectomy; the remaining 36 patients received a progestogen (nomegestrol, N = 8; promegestone, N = 9; dydrogestone, N = 10; or natural progesterone, N = 9). Apart from HRT, none of the patients had a history of treatment with agents known to influence bone metabolism or BMD. The calendar year of bisphosphonate treatment initiation influenced the likelihood of receiving etidronate or alendronate; although all study patients were evaluated in 1999, their bisphosphonate therapy was started earlier. Other factors that influenced the choice between the two bisphosphonates were a history of gastrointestinal disorders contraindicating alendronate therapy and poor compliance compromising full exposure to the prescribed alendronate dosage. All study patients received detailed explanations on how to take the bisphosphonate and on the possible adverse events of the drug. Etidronate was given cyclically according to the standard regimen, i.e., consecutive 3-month cycles, each with 14 days of etidronate in a dosage of one 400 mg tablet per day 2 hours before breakfast with a glass of water, followed by 76 days of supplemental calcium supplementation (1 g/ d) alone (N = 9) or with supplemental vitamin D3 (800 IU/d (N = 44). This cyclical treatment was continued until the follow-up absorptiometry. Alendronate was given continuously as one 10 mg tablet in the morning at least 30 minutes before breakfast, with a large glass of water. Patients were instructed to refrain from lying down during the interval between dosing and breakfast. Of the 46 patients in the alendronate group, 38 received supplemental calcium (1 g/d) alone (N = 6) or with supplemental vitamin D (N = 32). The
decision to use calcium and vitamin D (alendronate group) or vitamin D alone (etidronate group) was based on the baseline calcium and vitamin D status evaluated by history taking and by routine assays of calcium, phosphate, and serum 25-dihydroxyvitamin D3. The two absorptiometry studies were done 18 months apart. This interval was chosen based on reproducibility of dual-energy x-ray absorptiometry measurements from anteroposterior views of the lumbar spine and on mean BMD gains reported during earlier studies of bisphosphonate therapy. To facilitate comparisons, the mean annual BMD change was calculated as the BMD change found during the 18-month follow-up divided by 1.5. Statistical methods Results are reported as means ± standard error (SEM). BMD values at baseline and at study completion were compared using Student’s t-test for paired data or Wilcoxon’s rank sum test. Analysis of variance or the Kruskal-Wallis test were used to compare the percentage change in BMD among the treatment groups. Main patient characteristics at baseline and during follow-up were compared using analysis of variance or the KruskalWallis test for quantitative variables and the χ2 test with Yates’s correction if appropriate for qualitative variables (prevalent and incidence fractures). Fracture incidence during the 18-month study period was evaluated in the intention-to-treat population. All statistical tests were run using the Statview 5 program (SAS Institute, Cary, NC, USA). RESULTS Table I reports the main patient characteristics at baseline. Although the treatments were not allocated at random, no significant differences were found for age, body weight, height, time since menopause, lumbar spine or femoral neck BMD, or fracture status. Although a history of bone insufficiency fracture was more common in the alendronate group, the difference with the etidronate group was not statistically significant. Efficacy Eighty-eight patients underwent a follow-up absorptiometry scan; the remaining 11 patients experienced adverse effects requiring discontinuation of their bisphosphonate therapy before the scheduled follow-up absorptiometry (see below). Figure 1 shows BMD
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Etidronate vs alendronate in osteoporosis
Table III. Incident fractures during the 18-month follow-up in the two treatment groups. Fracture site
Vertebra
Wrist
Other
Etidronate Alendronate
6 (11.3%) 3 (6.5%)
2 (3.8%) 0 (0%)
6 (11.3%) 4 (8.7%)
fractures in six alendronate patients (13%) (P nonsignificant). Table III provides details on the fractures that occurred during the 18-month study period. Safety Figure 1. Change in bone mineral density (percent per year) in the etidronate and alendronate groups.
changes over time in the two treatment groups. Lumbar spine BMD increased significantly in the etidronate group (+2.1% ± 0.7%/year, P < 0.05) and in the alendronate group (+5.3% ± 0.9%/year, P < 0.01). The increase was significantly greater in the alendronate group (P < 0.01). Table II shows BMD changes in HRT users and nonusers. Bone gain at the lumbar spine was greatest in the group taking alendronate and HRT (+6.5% ± 1.4%, P < 0.01) and smallest in the group given etidronate without HRT (+1.2% ± 0.8%, P nonsignificant). Femoral neck BMD showed no change in the etidronate group (–0.1% ± 0.7) and a nonsignificant increase in the alendronate group (+1.8% ± 0.9%). Table II shows femoral neck BMD changes in HRT users and nonusers. No significant femoral neck BMD changes were seen in any of the four groups, although a nonsignificant increase was recorded in the alendronate group (+1.6% ± 1.7%) and in the alendronate-HRT group (+1.9% ± 1%). During the 18-month follow-up, 14 fractures occurred in 12 etidronate patients (22.6%) and seven Table II. Mean percent change in bone mineral density (BMD) per year at the lumbar spine (LS) and femoral neck (FN) in the various treatment groups. HRT: hormone replacement therapy. *P < 0.05 and **P < 0.01 for the BMD at the end of follow-up versus BMD at baseline. Treatment
LS BMD change FN BMD change
Etidronate (N = 29) Etidronate + HRT (N = 23) Alendronate (N = 22) Alendronate + HRT (N = 14)
+1.2% ± 0.8 +3.8% ± 1.2* +4.2% ± 1.0** +6.5% ± 1.4**
+0.0% ± 0.5 -0.3% ± 1.9 +1.6% ± 1.7 +1.9% ± 1.0
Adverse effects requiring bisphosphonate discontinuation before the scheduled follow-up absorptiometry occurred in one etidronate patient (1.9%) and ten alendronate patients (21.7%). Premature treatment discontinuations were significantly more common in the alendronate group (P < 0.01). The etidronate patient had osteomalacia suggested by clinical and radiographic findings and confirmed by histomorphometric studies. In the alendronate group, all premature treatment discontinuations were ascribable to epigastric pain (N = 6) or abdominal distension (N = 4). Premature alendronate discontinuation occurred within the first 6 months in all ten patients and within the first 2 months in four patients. Adverse events that did not require treatment discontinuation occurred in both groups. In the etidronate group, they consisted of a sensation of difficult digestion during the first two treatment weeks. Seven patients in the alendronate group experienced mild gastrointestinal symptoms consisting of epigastric pain (N = 4), abdominal distension (N = 2), or diarrhea (N = 1). DISCUSSION Our data suggest that both etidronate and alendronate produce significant increases in lumbar BMD in patients with postmenopausal osteoporosis. With etidronate, the gain was 2.1%/year, which is similar to the result reported by Storm et al. (about 2%/year) [2]. Slightly lower gains were obtained by Watts et al. (about 3.5% per year) [3] and Sahota et al. (4.9%/year) [7]. These earlier data were obtained during therapeutic trials, whereas our work was a pragmatic study conducted under the conditions of everyday clinical practice. With alendronate, the gain in our study was 5.4% per year, in keeping with the findings by Liberman et al. (about 4% per year) [12] and by Sahota et al. (5.7% per
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year) [7]. Similar to Watts et al. [3], Sahota et al. [7] reported a significant BMD increase at the hip (+1.6%); they did not report findings at the femoral neck. With alendronate, we recorded a nonsignificant increase at the hip (+1.8% per year) similar to reports by Liberman et al. and Black et al. of an about 2% gain per year [5, 12]. We found evidence that lumbar BMD increases more with alendronate than with etidronate. Few data comparing these two drugs are available. Sahota et al. [7] recently reported a slightly greater bone gain at the lumbar spine with alendronate than with etidronate, although the difference was not statistically significant. Furthermore, our results are in line with the main published data on the efficacy of each of these drugs [2-6]. Although treatments were not randomly allocated in our study, the patient population was homogeneous (with all patients recruited by the same physician), and the main patient characteristics were similar at baseline in the two treatment groups. That we found no statistically significant difference in the fracture rate between the two groups may be ascribable to the small sample size (the percentage of patients with a history of fracture was higher in the alendronate group than in the etidronate group). Furthermore, the efficacy of bisphosphonates in preventing fractures increases with the severity of osteoporosis evaluated based on the BMD decrease or on the number of prevalent vertebral fractures [4]. However, our primary efficacy criterion was the lumbar spine BMD change, and at baseline lumbar spine BMD was similar in the two groups. These considerations strongly suggest that our findings are valid. Similar to others [8-10], we found that combining a bisphosphonate with HRT produced a larger lumbar spine BMD gain than a bisphosphonate alone. This was true of both etidronate and alendronate. In a study of osteoporotic women, Wimalawansa [8] reported a mean lumbar spine BMD increase of about 7% after 2 years of therapy with etidronate and HRT, a figure similar to our 3.8% per year rate of BMD gain. However, in their study [8], BMD increased significantly at the femoral neck (about 4% after 2 years), a site where we found no significant change. Wimalawansa [8] started bisphosphonate therapy and HRT at the same time, whereas in our study the patients had already received HRT for at least 1 year at study inclusion. Lindsay et al. [10] also found that concomitant alendronate and HRT for 1 year produced a larger BMD increase than HRT alone (3.6 vs 1%) in women with osteoporosis. However,
they did not include any patients on alendronate only. The findings by Greenspan et al. in osteopenic women [9] are similar to ours: after 2 years of alendronate and HRT, the BMD gain was 8.3% (6.5%/year in the relevant group in our study). At the femoral neck, the gain was 4.2% with alendronate and HRT (1.6%/year in our study) and 2.9% with alendronate alone (1.9% in our study). The above-mentioned studies were prospective and controlled, whereas ours was retrospective and pragmatic. Etidronate had a favorable gastrointestinal safety profile in our study, in keeping with earlier reports [2-4, 7]. Osteomalacia developed in one of our patients during treatment. However, the contribution of etidronate therapy to this complication is unclear because bone biopsy was not performed prior to initiation of the drug. Wimalawansa [8] and Thomas et al. [13] reported four cases of osteomalacia in patients on etidronate therapy; one patient had generalized disease (as in our patient), two had focal disease, and one had atypical disease. Alendronate was associated with gastrointestinal symptoms in 37% of our patients, in line with earlier data [5]. Conversely, in contrast to previous reports, the rate of treatment discontinuations ascribable to gastrointestinal symptoms was 24% in our study. Liberman et al. [12] reported that only 1 to 3.5% of patients had to stop alendronate therapy because of gastrointestinal symptoms (vs 59% in our patients). However, a recent study [7] found a prevalence of 27%. In this controlled study [7], another group received cyclical etidronate therapy, which had an excellent gastrointestinal safety profile with no treatment discontinuations after 1 year. The number of patients in our study is too small to allow conclusions about the efficacy of bisphosphonate therapy in preventing fractures. However, incident fractures occurred in 22.6% of etidronate patients versus 13% of alendronate patients; thus, incident fractures were 42.5% less common with alendronate than with etidronate. We are not aware of any randomized studies comparing the efficacy of etidronate and alendronate in preventing fractures. Nevertheless, our data are in good agreement with the results of published randomized studies. For instance, alendronate has been found effective in reducing the incidence of osteoporotic fractures [5, 6]. Data about etidronate are conflicting [2-4]. Our work has several limitations: the treatments were not randomly allocated, the number of patients was small, and HRT was not standardized. Despite these shortcomings, it provides numerical data on the safety
Etidronate vs alendronate in osteoporosis
of the two bisphosphonates currently approved in France for the treatment of osteoporosis. Furthermore, the absorptiometry findings are in agreement with the main data in the literature [2-7, 12]. In conclusion, both etidronate and alendronate significantly increase lumbar spine BMD, with alendronate being the more effective agent. Conversely, alendronate has a less favorable safety profile, most notably with regard to gastrointestinal symptoms, and is consequently associated with a higher treatment discontinuation rate. These two facts should be weighed against each other when deciding which bisphosphonate to use in a patient with osteoporosis. REFERENCES 1 Meunier PJ, Sebert JL, Reginster JY, Briançon D, Appelboom T, Netter P, et al. Fluoride salts are no better at preventing new vertebral fractures than calcium-vitamin D in postmenopausal osteoporosis: the FAVOS study. Osteoporos Int 1998 ; 8 : 4-12. 2 Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990 ; 322 : 1265-71. 3 Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990 ; 323 : 73-9. 4 Harris ST, Watts NB, Jackson RD, Genant HK, Wasnich RD, Ross P, et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med 1993 ; 95 : 557-67.
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5 Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996 ; 348 : 1535-41. 6 Cummings SR, Black DM, Thompson DE, Appelgate WB, Barrett-Connor E, Musliner TA, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures. JAMA 1998 ; 280 : 2777-82. 7 Sahota O, Fowler I, Blackwell PJ, Lawson N, Cawte A, San P, et al. A comparison of continuous alendronate, cyclical alendronate and cyclical etidronate with calcitriol in the treatment of postmenopausal vertebral osteoporosis: a randomized controlled trial. Osteoporosos Int 2000 ; 11 : 959-66. 8 Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenoapusal osteoporosis. Am J Med 1998 ; 104 : 219-26. 9 Greenspan S, Bankhurst N, Bell N, Bolognese M, Bone H, Davidson M, et al. Effects of alendronate, alone or in combination on bone mass and turn-over in postmenopausal osteoporosis [abstract]. Bone 1998 ; 23 (Suppl 1) : 174. 10 Lindsay R, Cosman F, Obo RA, Walsh BW, Harris ST, Reagan JE, et al. Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial. J Clin Endocrinol Metab 1999 ; 84 : 3076-81. 11 Kanis JA, Melton LJ, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994 ; 9 : 1137-41. 12 Liberman UA, Weiss R, Bröll J, Minne HW, Quan H, Bell NH, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995 ; 333 : 1437-43. 13 Thomas T, Lafage MH, Alexandre C. Atypical osteomalacia after 2 year etidronate intermittent cyclic administration in osteoporosis. J Rheumatol 1995 ; 22 : 2183-5.