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Centre d’Evaluation des Maladies Osseuses (C.R.), Hôpital Cochin, 75014 Paris; Clinique de Rhumatologie (B.C.), Hôpital B, 59037 Lille Cedex; Service d’Endocrinologie (J.M.P.), Hôpital Rangueil, 31054 Toulouse Cedex; Procter & Gamble Pharmaceuticals France (S.H.), 92201 Neuilly sur Seine Cedex, France; Istituto di Patologia Medica (O.D.M.), Università di Pisa, 56126 Pisa; Servizio di Rheumatologia (P.O.), Nuovo Policlinico, 80131 Napoli, Italy; Department of Rheumatology (R.A.H.), St. Peter Hospital, Guilford Hospital, Surrey KT 16 OPZ, United Kingdom; Department of Endocrinology and Rheumatology (S.G.), Unit of Osteoporosis and Metabolic Bone Diseases, Universiteits Ziekenhuis Gent, B-9000 Gent, Belgium; Department of Rheumatology (R.L.), Adademish Ziekenhuis St. Radboud, 6500 HB Nijmegen, The Netherlands; (J.I.) 86150 Augsburg, Germany
Address correspondence and requests for reprints to: Dr. Christian Roux, Centre d’Evaluation des Maladies Osseuses, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
Abstract
Osteoporosis is a well-recognized adverse effect of corticosteroid therapy. This study aimed to investigate the effect of etidronate, intermittent cyclical therapy, in the prevention of corticosteroid-induced bone loss.
Patients with various medical conditions starting high-dose corticosteroid therapy were enrolled in the study. The treatment had to be expected to continue for at least 12 months with the initial 90 days at a mean daily dose of at least 7.5 mg of prednisone, with subsequent treatment of at least 2.5 mg/day. One hundred seventeen patients were randomly assigned oral etidronate 400 mg/day, or placebo, for 14 days, followed by 76 days of oral calcium carbonate (500 mg elemental calcium), cycled over 12 months. The primary outcome measure was the difference in percent change from baseline in bone mineral density of the lumbar spine between the groups at the end of year 1. Secondary measures included changes in femur bone density and in biochemical markers of bone remodeling.
The mean (±SEM) lumbar spine bone density changed 0.30 ± 0.61% and -2.79 ± 0.63% in the etidronate and placebo groups, respectively. The mean difference between groups after 1 yr was 3.0 ± 0.84% (P = 0.004). The changes in the femoral neck and great trochanter were not different between the groups. There was a decrease in pyridinium crosslinks, significant from baseline at both 6 and 12 months, in the etidronate group. Osteocalcin increased in the placebo group, and difference between groups was -25.07 ± 14.89% (P = 0.032) and -34.68 ± 19.77% (P = 0.051), at 6 and 12 months respectively. There was no significant difference between the groups in number of adverse experiences, including gastrointestinal disorders.
Etidronate intermittent cyclical therapy prevents lumbar vertebral bone loss in patients starting high-dose corticosteroid therapy.
OSTEOPOROSIS is a well-recognized adverse effect of corticosteroid therapy (1, 2). As a consequence, the incidence of fractures of predominantly trabecular bones, as found in the vertebrae, increases in patients receiving corticosteroids (3, 4, 5, 6). The bone loss is most marked during the first 6 to 12 months of treatment (2). Despite the large number of people with a variety of medical conditions taking continuous oral steroids, preventive measures for osteoporosis are infrequently taken (7).
Corticosteroids affect both bone formation and bone resorption. A decrease in bone formation has been attributed to a decrease in osteoblast activity and life span (8). Corticosteroids alter gonadal sex steroid production through direct action and inhibition of gonadotrophin secretion and suppress adrenal function (9), resulting in decreased bone formation. The reported increase in bone resorption may be explained, in part, by parathyroid hormone (PTH)-mediated activation of osteoclasts (10, 11, 12). Corticosteroids may potentiate the effect of PTH on bone (13, 14). A direct effect of corticosteroids on bone resorption, related to an increase in osteoclast number and activity, has been reported (15, 16). On the other hand, the increase in bone resorption may be related to the underlying disease (17).
Bisphosphonates, structural analogs of inorganic pyrophosphate, are potent inhibitors of the osteoclastic activity both in vitro and in vivo. The first generation bisphosphonate, etidronate (1-hydroxyethylidene-1, 1 bisphosphonate) is widely used in various metabolic bone diseases, including Paget’s disease (18) and postmenopausal osteoporosis (19). In open studies in corticosteroid osteoporosis, a significant increase in bone mineral density has been reported in patients receiving intermittent cyclical therapy (ICT) with etidronate and calcium (20, 21, 22, 23).
We undertook a prospective, randomized, double-blind, multicenter study of the efficacy of etidronate ICT vs. placebo on lumbar spine bone mineral density changes in patients initiating high-dose corticosteroid therapy. The secondary end point was to evaluate the efficacy on femoral bone mineral density and bone remodeling.
Subjects and Methods
Patients
Patients who had recently initiated high-dose corticosteroid therapy were recruited for the study. High-dose corticosteroids had to have been initiated within 90 days of study entry. Low-dose prednisone in the year before the study was allowed, provided that the daily dose was less than 7.5 mg. The treatment had to be expected to continue for at least 12 months, with the initial 90 days (of being in the study) at a mean daily dose of at least 7.5 mg of prednisone or its equivalent, with subsequent ongoing treatment at a mean cumulative dose of at least 2.5 mg/day. Use of inhaled, topical, or intravenous steroids was allowed but not included in the calculation of mean cumulative oral corticosteroid dose.
At the entry visit, patients taking medications or presenting with diseases affecting bone or calcium metabolism were excluded. In particular, none had a history of treatment with any bisphosphonate, fluoride, estrogen, progestogen, or estrogen-like compounds within 1 yr, nor with calcitonin or supplemental vitamin D within the previous 6 months. In premenopausal patients, it was mandatory to check for a birth control method and to have a negative serum pregnancy test within 2 weeks before starting the study drug.
Study design and drug administration
The study was double-blind, randomized, multicenter, and parallel-group of 1 yr duration and was approved by the local ethics committee of each participating center. Written informed consent was obtained for all the participants. Patients were randomly allocated into one of two treatment groups: oral etidronate disodium 400 mg/day or placebo for 14 days, followed by 76 days of oral calcium carbonate (500 mg elemental calcium) cycled over 12 months. They were allowed to receive vitamin D up to 1000 UI per day.
Patients were instructed to take the study drug 2 h after breakfast with 150 mL of water. They were also instructed not to ingest any dairy products or antacids within 2 h after the intake of the study medication.
Patients were evaluated clinically every 3 months. Compliance with the study drug was assessed at each visit by regular pill counts and by review of patients’ medication diaries.
Patient evaluations
Bone mineral density (BMD in g/cm2) was measured at the lumbar spine, using a postero-anterior view on L2, L3, and L4 vertebrae, and on the upper extremity of the nondominant femur, where femoral neck and great trochanter were analyzed. Dual energy X-ray absorptiometry was performed using QDR (Hologic, Waltham, MA) (n = 85 patients), and DPX (Lunar, Madison, WI) (n = 32 patients) devices. Baseline mean values were considered separately for the 2 constructors. At the lumbar spine, patients were classified in T scores, i.e. the number of standard deviations below the peak bone mass in normal women (24). According to the World Health Organization, osteoporosis is defined by a T score of less than -2.5 (25). BMD was measured at baseline and after 12 months of treatment. An operator manual was sent to each center, with clear recommendations for standardization in acquisition. Daily quality assurance data from each center were collected to assess scanner performance. All the scans were reviewed by one investigator (J.M.P.) in a central facility. Only data from the central facility were included in the analysis.
Lateral radiographs of thoracic and lumbar spine were obtained at baseline. X-rays were repeated as necessary if there was clinical evidence of a new fracture during the course of the study (i.e. acute back pain, height reduction). Vertebral fractures were qualified by qualitative assessment.
Serum and urine samples were obtained at baseline and after 6 and 12 months of treatment. Blood and urine samples were taken after a 12-h overnight fast. The urine assessment was made on a 2-h fasting urine collection. In each center, standard laboratory methods were used to assess serum calcium, phosphate and creatinine, serum total alkaline phosphatase and, at baseline, plasma intact PTH (1–84) and 25 hydroxyvitamin D. Aliquots of serum, plasma, and urine were frozen for determinations of osteocalcin and pyridinium crosslinks at baseline, 6, and 12 months. The stored samples of each patient were assayed within the same batch. Osteocalcin was measured by immunoradiometric assay (26) (normal range: 1.5–8 ng/mL). Pyridinium crosslinks were measured by high-performance-liquid-chromatographies (27), and two ratios were calculated: pyridinoline/creatinine (Pyr/Creat) (normal range 15–28 nmol/mmol) and deoxypyridinoline/creatinine (DPyr/Creat) (normal range: 4–16 nmol/mmol).
Erythrocyte sedimentation rate (in mm/h), complete blood cell counts, liver and renal function tests, and determinations of urinary proteins, erythocytes, and leucocytes were also performed at baseline and every 3 months.
Statistical analysis
The principal criterion of the study was the percent change in lumbar spine BMD. The sample size was calculated assuming a 3% decrease in the placebo group and a 2% increase in the treatment group, with a 7% standard deviation. Thus 42 completed patients per treatment group were necessary to have a 90% power to detect such a difference. Assuming a drop-out rate of 20%, at least 53 patients had to be recruited in each treatment group.
Analyses were performed for the intent-to-treat population, comprising all patients randomized into the study. Supportive analyses were also conducted for the per-protocol subgroup, comprising patients who were compliant with the study medication and procedures. Comparisons between the two groups were made using analysis of covariance (ANCOVA), adjusting for the mean daily corticosteroid dose during the study, and the extent of prestudy corticosteroid use. All corticosteroid doses were converted to prednisone-equivalent values. Centers were modeled as random effects. The model assumptions were checked using standard statistical diagnostic tests.
We calculated the percentage of patients in each group, with a significant bone density change from baseline. Assuming a 1% precision error in lumbar BMD measurement, bone change in an individual can be demonstrated if it is greater than 2.8%, with a 95% 2-tailed confidence limit, or 1.8% with a 90% 2-tailed confidence limit (28). At the femoral neck, assuming a 2% precision error, this change is 5.6%, with a 95% 2-tailed confidence limit.
Results
Patients and study course
Between November 1994 and September 1995, 117 patients were
enrolled at 16 participating centers in 6 European countries: Belgium,
France, Great Britain, Germany, Italy, and The Netherlands. The study
population included 42 men aged 58.5 ± 15.6 yr (mean ±
SD) and 75 women aged 58.9 ± 14.1 yr; 57 of them were
postmenopausal. The major clinical characteristics of the 117 patients
are shown in Table 1
. There were no
statistically significant baseline differences between the two groups.
For the whole group, mean height was 163.8 ± 9.7 cms, and mean
weight was 67.7 ± 13.3 kg. The underlying diseases are reported
in Table 2.
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At baseline, 21 patients had a 25-OH vitamin D level below the lower limit of the normal range; they were randomly distributed among groups. Four patients had a slight increase in PTH(1–84) level. During the study, 6 patients took vitamin D supplements up to 800 UI per day: 2 patients in the etidronate group and 4 in the placebo group.
Osteocalcin and alkaline phosphatase levels were all within the normal range. Osteocalcin levels were similar in patients who were currently receiving corticosteroids and those who were not. In contrast, Pyr/Creat and DPyr/Creat ratios were on average 150 and 12.5% more than the upper limit of the normal ranges, respectively. This was not explained by either the gender or the menopausal status. DPyr/Creat was 16.77 ± 6.78 and 19.64 ± 9.69 nmol/mmol in patients who were receiving corticosteroids and in those who were not, respectively (P = 0.065). Pyr/creat was 63.11 ± 27.54 and 76.72 ± 44.55 nmol/mmol in these two populations respectively (P = 0.048). For the whole group, there was a correlation between these markers and erythrocyte sedimentation rate: r = 0.39 (P = 0.0001), and 0.29 (P = 0.0013) for Pyr/Creat and DPyr/Creat, respectively.
Ten patients (8%) discontinued treatment before completing the study. Three patients withdrew from the placebo group: one for personal reasons, one because of remission in condition and withdrawal of corticosteroid, and one for an adverse event. Seven patients withdrew from the etidronate group: one for personal reasons, one for protocol violation, and five for adverse events including two sudden deaths and one death due to myocardial infarction. One patient dropped out 13 weeks after inclusion, owing to carcinoma of the lung, which proved fatal. None of the events was attributed to the study drug, according to the investigator.
Over the first 6 months, mean cumulative corticosteroid dose was 2463.8 ± 1868.0 mg in the treated group and 2453.4 ± 1997.3 mg in the placebo group. During the whole study, the cumulative dose was 3949.0 ± 2317.0 mg and 4061.6 ± 2666.7 mg in these two groups respectively. Mean daily dose was 10.89 ± 6.34 and 11.19 ± 7.17 mg, respectively. None of these comparisons differed significantly.
The mean weight percent changes were +5.3 ± 1.2% and +4.7 ± 1.2% in the treated and the placebo groups respectively (P = 0.0001, for both). There was no significant difference between groups.
Efficacy assessment
Bone mineral density measurements. Mean percentage changes in
BMD from baseline are reported in Table 3
and Fig. 1. BMD results are from 103
(spine) and 106 (femur) patients. The other scans have been omitted by
the central reader because of artefacts.
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Exploratory regression analysis was performed to investigate the predictive effects of sex, corticosteroid use, and other baseline characteristics on 1-yr lumbar BMD percent change from baseline. The 1-yr lumbar spine BMD percent change from baseline was correlated with prestudy cumulative corticosteroid dose (r = -0.26), initial corticosteroid dose (r = -0.21), and mean corticosteroid dose over 1 yr (r = -0.30). Sex, menopausal status, and biochemical bone markers were not correlated with 1-yr BMD changes. No model achieved an R2 greater than 0.35, showing the weak predictive effects for this population.
Considering BMD changes of ± 2.8% (see Subjects and Methods), the number of patients who lost bone at the spine were 11 (22%) in the treated group and 21 (40%) in the placebo group (P = 0.059). Considering a 1.8% change, these numbers were 13 (26%), and 26 (49%) (P = 0.025), respectively. At the femoral neck, 12% and 24% of patients in the treated and the placebo groups respectively lost more that 5.6% of BMD (P = 0.13).
Biochemical markers. Mean percentage changes in biochemical
markers are reported in Table 3
. There was a statistically significant
difference between the etidronate and placebo groups in regard to
osteocalcin and pyridinium crosslinks changes, but not in alkaline
phosphatase changes.
There was no change in pyridinium crosslinks in the placebo group, except for DPyr/Creat at 12-month evaluation (-13.6 ± 6.2%). There was a decrease in the treated group, significant from baseline at both 6 and 12 months. The difference between the 2 groups was statistically significant at the 6-month evaluation only: -13.59 ± 6.27% (P = 0.028), and -22.10 ± 6.90% (P = 0.002) for Pyr/creat and DPyr/Creat, respectively. Among the etidronate patients completing the study, 88% had DPyr/creat values, which returned to normal range by 12 months.
In parallel, an increase in osteocalcin was observed in the placebo group. The difference between groups was -25.07 ± 14.89% (P = 0.032) and -34.68 ± 19.77% (P = 0.051) at 6 and 12 months respectively. There was no correlation between the osteocalcin changes and either the changes in mean daily corticosteroid dose, or the changes in ESR. Mean osteocalcin levels were still in the normal range at 6 and 12 months in both groups. There was a decrease in serum alkaline phosphatase in both groups, which was statistically significant from baseline.
Safety assessment
There was no statistically significant difference between etidronate and placebo groups in the incidence of adverse events. During the study as a whole, 88% and 86% of patients in the placebo group and the etidronate treated group respectively reported an adverse event, mainly related to the underlying diseases. Upper gastro-intestinal adverse events, all moderate in severity, were reported in 5.2% and 11.9% (P = 0.32) of patients in the placebo and treated group, respectively. The proportion of patients with abdominal pain, the most frequent adverse event, was 15.5 and 17% respectively.
Five patients in the placebo group (9%) experienced a total of 15 fractures, and 4 patients in the etidronate group (7%) experienced a total of 5 fractures. Fractures occured mainly at the vertebrae (11 and 3 in the placebo and etidronate groups respectively), in 6 menopausal women and 1 man (mean lumbar T score = -2.44 ± 1.23 (-3.86, -0.48). One wrist fracture and 3 rib fractures were observed in the placebo group. A phalangal fracture in a premenopausal woman and a metatarsal fracture in a man were observed in the treated group.
Discussion
This randomized, placebo-controlled study shows that intermittent cyclical etidronate prevents bone loss of the lumbar spine in patients starting high doses of corticosteroid therapy.
Noninvasive measurement of BMD, using dual energy X-ray absorptiometry, is safe and precise enough to be used for diagnosis and follow-up of bone effects of corticosteroids (29). In the placebo group, we observed a significant decrease of BMD in both lumbar spine and femoral neck. Bone loss was not observed at the lumbar spine in the etidronate group. There was no significant difference between groups in femoral neck or trochanteric bone density changes. It is well known that agents used to treat osteoporosis may have site-specific responses of different magnitude (19). Most of the previous open studies have been performed in patients taking corticosteroids for many years with established corticosteroid osteoporosis (20, 22, 23). The expected magnitude of bone loss during the first months of high-dose corticosteroid therapy might explain the lower effect of etidronate intermittent cyclical treatment observed in this study. The effect following 1 yr of treatment could represent a transient effect due to a "filling in" of osteoclast resorption cavities (30). Thus, we cannot speculate on a long-term effect. However, in a follow-up of patients receiving long-term corticosteroids, it has been shown that by 18–36 months the bone density is stable despite continuing low-dose corticosteroids (31). There is a well known heterogeneity in the individual bone response to corticosteroids (32, 33). Thus, the number of patients who benefitted from treatment must be considered. The proportion of patients who gained or maintained BMD was higher in the etidronate group than in the placebo group at the spine. The link between BMD and fracture may be different in corticosteroid osteoporosis compared with postmenopausal osteoporosis because of different changes in structure and other aspects of bone quality (34). However, prevention of bone loss at the lumbar spine is considered as a relevant criterion for the prevention of fractures (29, 35). This study was not powered to assess the effect of etidronate on fracture rate.
At baseline, we observed an uncoupling of bone remodeling with increased parameters of bone resorption and normal parameters of bone formation. Uncoupling appeared to be a consequence of the underlying disease activity (17). Interleukin 1 and other inflammatory cytokines are correlated with disease activity (36) and are able to stimulate bone resorption (37) as well as reduce osteocalcin synthesis (38). Disease activity itself, as well as functional impairment, may be determinants of bone loss in patients with recent onset rheumatoid arthritis not treated with corticosteroids (39). A significant increase in pyridinoline and deoxypyridinoline excretion has been reported in patients with active rheumatoid arthritis (40, 41). Pyridinoline is widely distributed in a number of tissues, including cartilage, and in smaller amounts in other connective tissues. Deoxypyridinoline is considered to be more bone specific. However, we postulate that in our study both are mainly related to bone because of the slower rate of turnover of other connective tissues. We observed a significant decrease in bone resorption markers in the etidronate group from the 6th month. In contrast, we did not observe any decrease in crosslinks, except for a slight decrease in urinary deoxypyridinoline/creatinine ratio at 12 months in the placebo group receiving calcium 500 mg daily.
During follow-up with corticosteroid therapy, a decrease in bone formation and osteocalcin levels has been described (42, 43, 44, 45, 46). In contrast, we observed a significant increase in osteocalcin in the control group. This may be explained by either the decrease in the corticosteroid dose or the decrease of the bone effect of the systemic inflammation. Such an increase has been previously reported in prospective studies of patients with rheumatic, immunologic, or respiratory diseases, receiving corticosteroids and calcium (35). In patients followed after cardiac transplantation, osteocalcin increased by 6 months, and an inverse relationship was observed between serum osteocalcin and the lumbar bone loss (47). Taken together, these data suggest that in the first year of corticosteroid therapy, osteocalcin may be a marker of bone remodeling. There is a discrepancy between osteocalcin and alkaline phosphatases changes, although both of these markers are related to bone formation. However, we measured total alkaline phosphatase and not bone-specific alkaline phosphatase. Furthermore, it is possible that these parameters represent different aspects of osteoblast function, which are not influenced in the same way by corticosteroids.
Intermittent cyclical etidronate therapy was well tolerated in this diverse corticosteroid-treated population. No subject withdrew because of gastro-intestinal side effects. Compliance was high, as shown by the low number of subjects who dropped out. Our results are parallel with those of a recent Canadian study (49). They show that lumbar vertebral bone loss can be prevented with etidronate and calcium treatment and that corticosteroid-induced osteoporosis may prove preventable.
Footnotes
1 The other investigators of the Ciblos study Group were E. Hachulla,
Lille, France; M. Passeri, Parma, Italy; T.H. Ittel, Aachen, Germany;
D. Reid, Aberdeen. A. Woolf, Truro, United Kingdom; B. Weschler, Paris,
France; R. Dreher, Bad Krenznach, Germany; F. Trotta, Ferrara, Italy;
C.L. Benhamou, Orléans, France; S. Pack, Staines, United
Kingdom. 
Received October 14, 1997.
Revised December 23, 1997.
Accepted January 7, 1998.
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