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Keywords:

  • osteoporosis;
  • pamidronate;
  • glucocorticoids;
  • bone mineral density;
  • bone remodeling

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The aim of this study was to compare the action of two regimens of intravenous (iv) pamidronate in the primary prevention of glucocorticoid-induced osteoporosis (GC-OP). The primary purpose of the study was to determine whether any differences in bone mineral density (BMD) appeared after 1 year. A secondary endpoint aimed at assessing the remodeling parameters in order to better understand the mechanisms of action of the various regimens. Thirty-two patients, who required first-time, long-term glucocorticoid therapy at a daily dose of at least 10 mg of prednisolone, were studied. Simultaneously with the initiation of their glucocorticoid treatment, patients also were randomly allocated to receive a single iv infusion of 90 mg of pamidronate at the start (group A); a first infusion of 90 mg of pamidronate followed, subsequently, by an iv infusion of 30 mg pamidronate every 3 months (group B); and a daily 800-mg elemental calcium supplement given as calcium carbonate (group C), which also was taken by patients in groups A and B. Patients were matched for starting glucocorticoid doses, sex, menopausal status, and hormonal replacement therapy. Lumbar spine and hip (total and subregions) BMDs were measured at the outset and repeated at 6-month intervals by dual-energy X-ray absorptiometry (DXA; Hologic QDR-2000). Bone turnover was assessed by measurement of total and bone-specific serum alkaline phosphatase activity (B-ALP), serum osteocalcin (OC), and serum C-telopeptide cross-links of type I collagen (CTX). After 1 year, the mean BMD changes for groups A, B, and C were, respectively, 1.7, 2.3, and −4.6% at the lumbar spine; 1.2, 1.2, and −3.1% at the femoral neck; 1.0, 2.6, and −2.2% for the total hip region. No difference was observed between pamidronate regimens but a highly significant difference was observed between both pamidronate regimens and the control group at the lumbar spine (p < 0.001), at the femoral neck (p < 0.01), and for the total hip (p < 0.05). A significant decrease of serum C-telopeptide was observed, after 3 months, in groups A and B (p = 0.029), but a sustained decrease of bone resorption over time was observed only in group B. As far as BMD evolution over 1 year was concerned, iv pamidronate, given either as a single infusion or once every 3 months, effectively achieved primary prevention of GC-OP.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

OSTEOPOROSIS IS a major complication in patients who require chronic glucocorticoid treatment. The glucocorticoid-induced bone loss mainly results from depressed osteoblastic activity and differentiation, but many pathways contribute to the skeletal morbidity: enhanced osteoclastic activity, reduced intestinal calcium absorption, increased renal calcium excretion, disturbances in vitamin D and gonadal hormones metabolism, and increased apoptosis of osteoblasts and osteocytes.(1–5) Glucocorticoid-induced osteoporosis (GC-OP) is a severe condition, resulting in an overall fracture rate higher than 40% in patients on long-term glucocorticoid therapy.(6) The relative fracture risk is not only increased at the sites rich in trabecular bone such as the vertebrae and the ribs but also is increased at the hip.(7,8) Bone fractures occur after long-term use of glucocorticoid therapy but the accelerated bone loss occurs very early.(9–11) Therefore, to achieve an effective primary prevention, it seems mandatory to initiate GC-OP treatment as soon as glucocorticoid therapy begins.

Over the last few years, several controlled studies have reported bisphosphonates to be efficacious at preventing or treating GC-OP, as far as bone mineral density (BMD) was concerned.(12–30) A meta-analysis, ranking drug treatments for GC-OP by efficacy, found bisphosphonates substantially better than calcium, vitamin D, calcitonin, or fluoride.(31) However, etidronate most often failed to provide a statistically significant effect at the hip(2,23,25) whereas more potent bisphosphonates such as pamidronate, alendronate, or risedronate appeared to be efficacious at the hip.(24,26,30) Although not powered to definitely show fracture efficacy, some studies with etidronate, alendronate, and risedronate reported fracture reduction in patients receiving glucocorticoids.(23,27,30)

Previous studies have reported intravenous (iv) pamidronate given once every 3 months as a simple, safe, and effective means to achieve primary prevention(24) or treatment of GC-OP.(14,28) The present study was undertaken to compare the efficacy of iv pamidronate given either as a single initial infusion or on a regimen of once every 3 months, as primary prevention of GC-OP, over 1 year, and to assess the different effects of the various regimens on bone remodeling.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

During a 2-year period, in- or out-patients, older than 18 years and who were expected to require glucocorticoid therapy at a daily dose of at least 10 mg of prednisolone for at least 3 months, were selected. Most of the patients suffered from various inflammatory rheumatic diseases (Table 1). Patients previously treated with either glucocorticoids, fluoride, or bisphosphonates were not eligible, nor were those with renal disease, urolithiasis, hyperparathyroidism, malignancy, or liver or thyroid disease. Patients with prevalent vertebral fracture also were excluded.

Table Table 1.. Baseline Characteristics of the 27 Patients Available for BMD Analysis
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To receive a single infusion (group A), an iv pamidronate infusion given once every 3 months (group B), or oral calcium alone (group C), patients were randomly matched, 3 by 3, taking into account the starting dose of steroid (daily prednisolone dosage, 10–20 mg; >20-40 mg, or >40 mg), sex, and pre- or postmenopausal status, with or without estrogen-replacement therapy (ERT+ or ERT−, respectively). In practice, for every combination of these four parameters that was not yet observed, the new patient was randomly assigned to group A, B, or C. If this combination was already present in one subject, the new patient was randomly assigned to one of the two other groups. If the combination was present in two subjects, the new patient received the treatment that was not given to both previously enrolled subjects.

Simultaneously with the initiation of glucocorticoid therapy, group A patients received a single iv infusion of pamidronate (Aredia; Novartis, Basle, Switzerland), 90 mg in 500 ml of NaCl, 0.9%, over 2 h. Patients in group B received a first infusion of 90 mg of pamidronate and, subsequently, iv infusions of 30 mg of pamidronate every 3 months for 1 year. Control patients (group C) only received a daily 800-mg elemental calcium supplement given as calcium carbonate, which also was taken by patients in groups A and B. This intermittent iv regimen was used according to our former experience with iv pamidronate.(24)

Lumbar spine, hip, and hip subregions (total hip, neck, trochanter, intertrochanter, and Ward's triangle) bone mineral densities (BMDs) were measured at the outset and at 6-month intervals thereafter. BMDs were measured by dual-energy X-ray absorptiometry (DXA) on a QDR-2000 (Hologic, Inc., Waltham, MA, USA). The first BMD measurement was always carried out immediately before the start of the glucocorticoid therapy or, at the latest, within the first week. In our hands, the CV of the technique amounts to 0.82% at the spine, 0.75% at the total hip, and 0.79% at the femoral neck.(32)

One of the authors (Y.B.) took the medical history and made a clinical examination every 3 months. As well as routine laboratory tests, 24-h urine calcium, creatinine, and sodium measurements were performed at entry to the study. This was repeated every 3 months.

Bone turnover was assessed by measurement of total serum alkaline phosphatase (T-ALP) and bone-specific ALP (B-ALP) activity and serum osteocalcin (OC) as biochemical markers of bone formation, and serum C-telopeptide cross-links of type I collagen (CTXs) as a marker of bone resorption. T-ALP activity was measured by a colorimetric method (ALP; Boehringer Mannheim, Mannheim, Germany; normal values, 90–265 IU/liter). B-ALP was measured with an immunoradiometric assay (IRMA; Tandem-R Ostase; Hybritech, San Diego, CA, USA; normal values: postmenopausal women, 13.2 ± 4.7 μg/liter; premenopausal women, 8.7 ± 2.9 μg/liter; males, 12.3 ± 4.3 μg/liter) and OC was measured using the N-midfragment one-step ELISA (Osteometer Biotech A/S, Herlev, Denmark; normal values: postmenopausal women, 28.9 ± 9.7 ng/ml; premenopausal women, 17.7 ± 6.4 ng/ml; males, 23.2 ± 7.2 ng/ml). CTXs were measured using a one-step ELISA (CrossLaps; Osteometer Biotech A/S; normal values: postmenopausal women, 3634 ± 1833 pM; premenopausal women, 2304 ± 1110 pM; males, 2382 ± 1364 pM). OC and CTX analyses were kindly performed by Claus Christiansen's group (Ballerup, Denmark).

T-ALP was routinely measured in all patients at entry to the study and then every 3 months, together with routine laboratory tests, serum cortisol, parathyroid hormone [PTH(1–84)], 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D. B-ALP, OC, and CTXs were measured blindly, at the end of the study, in the same series on the frozen specimens available from 20 patients. Blood samples were always drawn before pamidronate infusions (groups A and B).

Lateral X-rays of the thoracic and lumbar spine were obtained at entry and at 12 months in order to detect any asymptomatic vertebral fracture and to measure the spine deformity index according to Minne's method.(33) When appropriate, additional X-rays were performed in patients with acute thoracic or lumbar spine symptoms in order to detect vertebral fractures.

The study protocol was approved by the Ethics Committee of the Louvain University Hospital in Mont Godinne. All patients gave their written informed consent.

Statistics

Numerical parameters were compared between the three groups by a one-way analysis of variance (ANOVA) for repeated measures when the matched patients were concerned, followed by 2-by-2 comparisons with the method of least significant difference in the case of a significant heterogeneity. The effect of pamidronate and glucocorticoid treatments on B-ALP, OC, and CTX measurements was studied by regression analysis of repeated measures using generalized estimating equations(34) with the RMGEE program(35) because the number of available results at various times was different. Pooled (groups A and B) biochemical results at 3 months, expressed as a percentage of initial values, were compared by the Wilcoxon rank sum test. Numerical results are expressed as means ± SD and by medians unless otherwise specified.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Thirty-two patients were enrolled at the end of the 2-year recruitment period. Thirty were matched and 2 more patients were assigned to the group in which pamidronate was given once every 3 months. Of the 30 matched patients, 1 patient (group B) dropped out because, unexpectedly, she no longer required glucocorticoids after 2 months. Therefore, only 27 patients remained available for BMD analysis on matched groups. Baseline characteristics of these 27 patients are shown in Table 1. Patient groups did not differ with respect to clinical data or baseline BMD measurements. All the patients received at least 10 mg of prednisolone daily during the first 3 months. The initial and cumulative steroid doses, shown in Table 2, were not different over the entire study period in either group.

Table Table 2.. Initial and Cumulative Glucocorticoid Dosages at Study Completion, Expressed as Milligrams of Prednisolone
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Changes in BMD

Table 3 shows lumbar spine and hip (total and subregions) BMD measurements, expressed as absolute values and percentage of initial values, after 6 months and 12 months.

Table Table 3.. BMD of the Lumbar Spine, Femoral Neck, Total Hip, and Trochanter Expressed as Absolute Values and Percentage of Change From Baseline, After 6 Months and 12 Months (Mean ± SD)
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BMD of the lumbar spine increased in both pamidronate groups whereas a BMD reduction was registered in the control group. No significant difference in BMD changes was observed between both pamidronate regimens but a highly significant difference was observed between either pamidronate regimen group and the calcium group, after 12 months (p < 0.001; Fig. 1). Individual changes of lumbar spine BMD, displayed in Fig. 2, showed that bone mass increased in 15 out of the 18 patients in the pamidronate groups whereas it decreased in 8 of 9 patients in the control group, after 12 months. Thus, the individual rate of response to pamidronate (i.e., the percentage of patients with a lumbar BMD increase at 1 year) reaches 83%.

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Figure FIG. 1. Mean BMD of the lumbar spine, femoral neck, and total hip expressed as a percentage of the baseline values, after 1 year, in patients receiving a single infusion of pamidronate (striped bar), pamidronate given once every 3 months (dotted bar), or calcium (white bar). The vertical bars represent the SEM. *p < 0.001 versus calcium group; **p < 0.01 versus calcium group; ***p < 0.05 versus calcium group.

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Figure FIG. 2. Individual values of lumbar spine BMD expressed as a percentage of baseline values, after 1 year in patients receiving a single infusion of pamidronate (▪), pamidronate given once every 3 months (▴), or calcium (○).

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BMD of the hip, (femoral neck, total hip, and trochanter) increased in both pamidronate groups and decreased in the control group. No difference was observed between pamidronate groups. At 12 months, a significant difference was observed between both pamidronate regimens and the calcium group at the femoral neck (p < 0.01); and for the total hip, p < 0.05 between groups A and C and p < 0.01 between groups B and C (Fig. 1). The difference also reached statistical significance between groups B and C at the trochanter. BMD differences between groups A and C were not significant for the trochanter.

At 6 months, a significant difference was already observed between either pamidronate regimens and the calcium group for the lumbar spine and femoral neck subregion (Table 3).

Biochemical results

Bone turnover biochemical markers are displayed in Table 4 and shown in Fig. 3 for pamidronate regimens.

Table Table 4.. T-ALP, B-ALP, OC, and CTX in Serum
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Figure FIG. 3. Evolution of serum B-ALP, OC, and CTX levels in patients receiving a single infusion of pamidronate (▪) or pamidronate given once every 3 months (▴). Results are expressed as mean ± SEM. Multivariate analysis disclosed a significant reduction over time for B-ALP (p < 0.001), OC (p = 0.029), and CTX (p = 0.021) on the regimen of once every 3 months.

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Before starting any glucocorticoid therapy, T-ALP levels were at the upper limit of normal values, OC levels were below the lower limit of normal values, and B-ALP and CTXs were within the normal range. There was no difference between the three groups in any baseline biochemical marker. All these decreased at 12 months in the three groups. The reduction of the serum levels was significant (ANOVA) for T-ALP (p = 0.002), B-ALP (p = 0.011), OC (p = 0.027), and CTXs (p < 0.001) as compared with initial values.

At 3 months, biochemical results were pooled for groups A and B because pamidronate regimens were identical over the first 3 months (i.e., these patients received an identical 90-mg pamidronate infusion at baseline). Results expressed as a percentage of initial values at 3 months were as follows: T-ALP, 60 ± 21% (pamidronate groups) and 79 ± 31% (calcium group), NS; B-ALP, 55 ± 20% (pamidronate groups) and 78 ± 27% (calcium group), NS; OC, 30 ± 26% (pamidronate groups) and 80 ± 18% (calcium group), p = 0.011; CTX, 44 ± 54% (pamidronate groups) and 103 ± 59% (calcium group), p = 0.029.

The multivariate analysis, using glucocorticoid dosage and baseline values of biochemical markers as covariates, disclosed a significant reduction over time for B-ALP (p < 0.001), OC (p = 0.029), and CTX (p = 0.021), on the pamidronate regimen of once every 3 months only. Thus, the reduction of bone turnover appeared more sustained on this regimen.

Analysis of serum calcium, phosphorus, creatinine, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D was within the normal range at baseline and showed no relationship with pamidronate regimens or glucocorticoid therapy, over time. As expected, a significant reduction of serum cortisol levels was observed in the three groups (data not shown).

X-rays

During the 1-year follow-up, we did not record any vertebral or peripheral fracture. Spine deformity indices measured at 1 year according to Minne's method(33) showed no significant changes in either study group.

Adverse effects

Pamidronate infusions were well tolerated. No case of thrombophlebitis at the infusion site was observed. No patient suffered from fever, myalgias, or uveitis. No other relevant symptoms or biological changes were recorded in the examinations and routine laboratory measurements performed every 3 months.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In the present study, we observed that iv pamidronate given as a single infusion or as a regimen of once every 3 months induced a marked decrease in bone resorption and prevented glucocorticoid-induced bone loss, as far as BMD changes over 1 year were concerned. BMD increase was observed at both the hip (total hip, femoral neck, and trochanter) and the lumbar spine despite high-dose glucocorticoid therapy, as patients initially received more than 25 mg prednisolone daily and, later on, a mean daily dose higher than 10 mg of prednisolone over 1 year.

BMD results observed in the regimen of once every 3 months are consistent with earlier observations using intermittent iv pamidronate as primary(24) or secondary(14) prevention of GC-OP. In both pamidronate groups, BMD changes over 1 year were similar. This may be related to both the glucocorticoid regimen and the design of our study, as patients received a higher steroid dosage during the first 3–6 months. The well-described “rapid bone loss,” occurring during the first 6 months of glucocorticoid therapy,(9–11) thus is averted in a similar way, in both groups, by the first “loading” pamidronate infusion.

At 6 months, BMD increase was similar with both pamidronate regimens. Between 6 and 12 months, we observed a nonsignificant trend to BMD decrease in the pamidronate single infusion group, concomitant with the increase in bone turnover in the second 6 months.

In our study, the magnitude of lumbar BMD gain at 12 months was comparable with the results of the various regimens used in other bisphosphonate trials conducted in the setting of GC-OP.(2) The lumbar BMD increase in the present study reaches the 2.1% and 2.9% levels observed, after 1 year, in a recent trial with 5 mg or 10 mg daily alendronate(26) and is markedly higher than the 0.6% BMD increase reported after 1 year with intermittent etidronate.(23) Furthermore, the individual rate of response in this trial with etidronate was only 59%. However, the latter two studies were not really designed as primary prevention because nearly 50% of the patients had already been on glucocorticoid treatment for more than 1 year in the first one and patients were included even if they had been on glucocorticoids for up to 100 days in the second one. Also, in these two studies, patients with vertebral fractures at baseline were not excluded. Both these differences have to be stressed because they might explain why a larger BMD decrease was observed in our control group and why no vertebral fracture occurred during the 1-year follow-up in our trial.

At the femoral neck, the BMD increase is quite similar to the 1.2% and 1.0% observed after 1 year on 5 mg and 10 mg daily alendronate.(26) In contrast, most of the trials using intermittent etidronate as prevention of GC-OP failed to find any significant difference at the femoral neck between etidronate and control groups.(2,23,25) The lack of any beneficial effect of etidronate at the femoral neck is even reported after 3 years of therapy.(29) In a double-blind placebo-controlled trial with risedronate, given for 96 weeks, either continuously (2.5 mg/day) or cyclically (15 mg/day for 2 out of 12 weeks), to postmenopausal women with glucocorticoid-treated rheumatoid arthritis, bone loss from the lumbar spine and from the proximal femur appeared to be prevented.(22) This suggests the need of potent bisphosphonates, like pamidronate, alendronate, or risedronate, in order to counteract entirely the glucocorticoid-induced bone loss at the spine and at the hip.

The baseline increase in T-ALP probably can be ascribed to the inflammatory nature of our patients' conditions, mainly polymyalgia rheumatica and temporal arteritis. Liver involvement in polymyalgia and temporal arteritis has been described for many years, with complete recovery within 1–3 months on glucocorticoid therapy.(36) The decrease in serum T-ALP is more likely to be related to the healing of the inflammatory diseases and cannot be used as a specific marker of bone formation.

Baseline OC levels were decreased in our study whereas B-ALP remained in the normal range. A similar biochemical pattern was reported in a large group of rheumatoid arthritis patients, with or without glucocorticoid therapy,(37) suggesting that the inflammatory disease itself may depress OC. The marked decrease in serum OC and B-ALP observed later in our three groups is likely to reflect the well-described, glucocorticoid-induced reduction of bone formation.(38–40) The more important decrease occurred during the first 3 months (Fig. 3), when patients received their higher glucocorticoid dosage and the less dramatic changes, over the last 9 months, may be related to a tapering of glucocorticoids. The more pronounced reduction of serum OC levels, at 3 months, in groups A and B, as compared with group C, furthermore suggests that the initial pamidronate infusion provokes an additional reduction in bone formation because of the well-known coupling between bone resorption and formation. An early discrepancy between bone formation and bone resorption was not observed, probably because no biochemical measurement was performed during the first days or weeks after the pamidronate infusions.

As to the inhibition of osteoclast-mediated bone resorption with pamidronate infusions, this was clearly shown by the significant serum CTX decrease observed, after 3 months, in groups A and B. Not surprisingly, the more sustained decrease was observed in the pamidronate regimen of once every 3 months. On the contrary, the supplemental oral 800-mg elemental calcium did not give rise to any significant reduction of bone resorption after 3 months of glucocorticoid therapy. In the absence of a placebo control group, we cannot discern whether the physiological doses of calcium, given to all patients, provoked some reduction in the biochemical markers of bone turnover or whether it was merely related to the progressive decrease in glucocorticoid doses.

Many studies reported a significant correlation between the decrease in serum or urinary cross-linked collagen and the BMD changes in patients treated with various bisphosphonates for postmenopausal osteoporosis.(41–43) Similarly, prevention of GC-OP probably is achieved through this inhibition of bone resorption. Our data suggest that repeated courses of iv pamidronate should be recommended, in patients requiring glucocorticoids for more than 1 year, in order to maintain a long-term inhibition of bone resorption.

Additional long-term studies are required to determine which of the infusion schedules would be the most appropriate. Once every 3 months, once every 6 months, or once a year. Complementary studies also are needed to determine the usefulness of biochemical bone turnover monitoring to optimize the prevention of GC-OP in various glucocorticoid treatment modalities.

We selected pamidronate because it is the most potent bisphosphonate commonly available for iv use and because of its high activity-to-toxicity ratio, especially as to the risk of impaired mineralization, at the currently used dose.(44) Although given intravenously, the treatment was well tolerated, better than usually reported when treating other conditions.(45) No acute phaselike response (fever or skeletal pain) was observed in our patients, probably because glucocorticoids oppose the well-known cytokine production associated with iv pamidronate.(46)

Low intestinal absorption, further decreased in relation with food or calcium intake, and upper gastrointestinal side effects, common to all oral aminobisphosphonates, may reduce compliance with oral bisphosphonates. On the contrary, the iv route not only ensures optimal compliance, but also is convenient, safe, and brings appreciated relief to sick patients already receiving large amounts of oral drugs.

The iv pamidronate, given as a single infusion or on a regimen of once every 3 months, induced a dramatic decrease in bone resorption and prevented bone loss at the hip and the lumbar spine in patients receiving long-term high doses of glucocorticoids. As far as BMD evolution over 1 year was concerned, both modalities of treatment proved to be an efficacious means to achieve primary prevention of GC-OP. Results observed with the single pamidronate infusion show, for the first time, that a sustained prevention of GC-OP, lasting at least for 1 year, can be obtained by using a very simple, safe, and convenient regimen. However, the reincrease of bone resorption markers suggests that the time interval between two pamidronate infusions should not last longer than 1 year.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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