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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

Background : Osteoporosis is a common complication of Crohn's disease.

Aim : To study the effect on the bone mineral density of a bisphosphonate (pamidronate) given intravenously, in combination with oral calcium and vitamin D supplements, compared with oral calcium and vitamin D supplements alone.

Methods : Seventy-four patients with Crohn's disease and low bone mineral density at the lumbar spine and/or hip were randomized to receive either a daily dose of 500 mg of calcium with 400 IU of vitamin D alone or in combination with four three-monthly infusions of 30 mg of intravenous pamidronate over the course of 12 months. The main outcome measure was the change in bone mineral density at the lumbar spine and hip, measured by dual X-ray absorptiometry, at baseline and 12 months.

Results : Both groups gained bone mineral density at the lumbar spine and hip after 12 months. There were significant (P < 0.05) changes in the pamidronate group, with gains of + 2.6%[95% confidence interval (CI), 1.4–3.0] at the spine and + 1.6% (95% CI, 0.6–2.5) at the hip, compared with gains of + 1.6% (95% CI, − 0.1–3.2) and + 0.9% (95% CI, − 0.4–2.1) at the spine and hip, respectively, in the group taking vitamin D and calcium supplements alone.

Conclusions : In patients with Crohn's disease and low bone mineral density, intravenous pamidronate significantly increases the bone mineral density at the lumbar spine and hip.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

Previous studies have demonstrated that between 13 and 42% of patients with Crohn's disease have osteoporosis,1–3 and two recent epidemiological studies have suggested that patients are between 1.4 and 2.5 times more likely to fracture than the normal population.4, 5 A number of risk factors have been described, most prominently the use of corticosteroids.6–12 The mechanism responsible for the increased bone loss is unclear, but most studies describe an increase in serum or urine bone markers of resorption,1, 3, 13–15 suggesting that the introduction of bisphosphonates, which inhibit osteoclastic mediated bone resorption, would be a logical step in preventing further bone loss.

Guidelines for the prevention and treatment of osteoporosis associated with inflammatory bowel disease have been published in the UK.16 Amongst the general recommendations is the provision of daily calcium and vitamin D supplements (500–1000 mg daily and 400–800 IU daily, respectively). More specific measures include the addition of an oral bisphosphonate for postmenopausal women with osteoporosis, any patient with a fragility fracture and osteoporosis, and all patients taking systemic corticosteroids and whose bone mineral density (BMD) is more than 1.5 standard deviations below the mean value for a young adult (T score of less than − 1.5).

The use of bisphosphonates is well established in the treatment of postmenopausal osteoporosis, corticosteroid-induced bone loss and, more recently, in men with osteoporosis.17 Bisphosphonates, however, are poorly absorbed from the gut and, in patients with Crohn's disease in whom absorption may already be compromised, this is a potential problem. We have tried to overcome this problem by administering an intravenous preparation.

The aim of this 12-month randomized controlled trial was to investigate the effect on the BMD of an intravenous bisphosphonate (pamidronate), given in combination with calcium and vitamin D supplements, compared with calcium and vitamin D supplements alone, in patients with Crohn's disease and low BMD.

Our main outcome measure was the mean percentage change in BMD at the lumbar spine and hip.

To date, there has only been one published randomized controlled trial of oral bisphosphonates in patients with Crohn's disease.18 As far as we are aware, this is the first randomized controlled trial of intravenous bisphosphonates in patients with Crohn's disease and low BMD.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

We recruited subjects from the Inflammatory Bowel Disease Register at the Freeman Hospital and Royal Victoria Infirmary, Newcastle-upon-Tyne, UK, and, in addition, from the Queen Elizabeth Hospital, Gateshead, UK. All patients on the register with Crohn's disease who were aged between 25 and 70 years were invited, by letter, to attend for bone densitometry. All fulfilled the standard diagnostic criteria for Crohn's disease (histological, radiographic, endoscopic and surgical)19 and were under the care of either surgical or medical gastroenterologists. Only patients aged between 25 and 70 years were recruited as the effect of bisphosphonates on a growing skeleton is unclear and bone density measurement at the lumbar spine may be misleading over the age of 70 years. In addition, women who were pregnant were excluded because of the potential risk from exposure to ionizing radiation during bone density measurement.

Basic demographic data were obtained from all patients, as well as details of their Crohn's disease. All patients had a baseline full blood count, erythrocyte sedimentation rate and bone biochemistry assayed.

BMD was measured at the lumbar spine (L1–L4) and left hip (total hip) by dual X-ray absorptiometry (Hologic Inc. QDR 2000, Waltham, MA, USA). The coefficient of variation (CV) was 0.7% at the lumbar spine and 1.0% at the hip.20 BMD results were expressed as an area density in g/cm2, but were compared with the manufacturer's mean value for young adults to give T scores. The T score is the number of standard deviation units above or below the mean value for young adults of the same sex.

The World Health Organization has defined osteopenia as a T score of between − 1 and − 2.5, whilst osteoporosis is defined as a T score of − 2.5 or lower. Measurements were taken at baseline and, for those recruited to the randomized trial, after 12 months. Height and weight were measured immediately before bone densitometry and these figures were used to calculate the body mass index [weight/height2 (kg/m2)].

Patients with a BMD of − 1.5 or less at either the lumbar spine and/or hip were invited to take part in the study. There were a number of exclusion criteria: (i) women who were planning a pregnancy as bisphosphonates are contra-indicated; all premenopausal women were asked to use appropriate contraception; (ii) women within 10 years of the menopause who wished to use hormone replacement therapy; (iii) patients who had taken bone active agents within the preceding 2 years; (iv) patients with metabolic bone disease; (v) patients unable to give informed consent.

Those who were eligible and who consented to the trial were then randomized according to randomly generated numbers using sealed envelopes. All patients were prescribed one tablet containing 500 mg calcium and 10 µg (400 IU) vitamin D (Calichew D3 Forte, Shire) to be taken every day for 12 months, in line with general advice for patients with inflammatory bowel disease in the UK guidelines.16 In addition, half of the patients received 30 mg of disodium pamidronate (Novartis), given as an intravenous infusion over 1 h in 150 mL normal saline every 3 months, the same regimen as used in other studies to treat postmenopausal osteoporosis21 and to prevent steroid-induced osteoporosis.22 All patients were reviewed every 3 months when compliance and tolerance to the medication were evaluated and biochemical monitoring was performed.

Biochemical measurements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

Serum calcium, phosphate, 25-hydroxy-vitamin D and intact parathyroid hormone were measured once before inclusion in the study. Serum calcium and phosphate levels were measured using standard methods on an Olympus 600 automated system (inter-assay CVs for calcium and phosphate are < 1% and < 2%, respectively). Intact parathyroid hormone levels (reference range, 12–72 pg/mL) were measured by immunometric assay (Immulite Intact PTH, Diagnostics Products Corporation, Los Angeles, CA, USA) (inter-assay CV of < 5%). Vitamin D levels (25-hydroxy-colecalciferol and 25-hydroxy-ergocalciferol; normal range, 10–50 nmol/L) were assayed by high-performance liquid chromatography performed at the Department of Clinical Biochemistry, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK (inter-assay CV of < 12%).

Bone resorption was assessed by serial measurements of the urinary excretion of N-telopeptide. The urine samples were collected between 14.00 and 16.00 h at baseline, 3 months, 6 months, 9 months and 12 months. N-Telopeptide was measured by enzyme-linked immunoabsorbent assay (‘Osteomark’, Ostex International, Seattle, WA, USA), with results expressed as bone collagen equivalents per millimole of creatinine (inter-assay CV of < 9%). The reference ranges are 2–51 and 5–65 bone collagen equivalents per millimole of creatinine for men and women, respectively.

Statistical analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

It was calculated that a sample size of 40 patients in each group was required in order to have an 80% chance of detecting a significant difference of 10%, assuming a P value of < 0.05 to be statistically significant. Changes in BMD were analysed on an intention-to-treat basis. The results are expressed as the mean ± standard deviation (s.d.). Comparison between group means was analysed using Student's unpaired t-test and the paired t-test was used to compare changes within groups. Where possible, the 95% confidence intervals (CI) are quoted as a measure of significance.

Analyses were made with GraphPad Prism (GraphPad Software Inc., San Diego, CA, USA).

Ethical approval

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

The study received ethical approval from the Joint Ethics Committee of Newcastle-upon-Tyne & North Tyneside Health Authority and the University of Newcastle-upon-Tyne, and also from Gateshead Local Research Ethics Committee. Written consent was obtained from all patients participating in the study.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

Of the 258 patients who were screened, 112 had a T score of − 1.5 or less at the lumbar spine and/or hip (43%) (Figure 1). Of these, 19 had taken active treatment within the last 2 years, 11 were not able or did not wish to take part in the study and five were suitable for hormone replacement therapy. A further three patients either had biochemical evidence of osteomalacia (low serum calcium and 25-hydroxy-vitamin D, elevated parathyroid hormone and bone specific alkaline phosphatase [BSAP]) or were unable to give informed consent. The remaining 74 patients consented to participate in the study and were randomly allocated to receive either calcium with vitamin D alone (group C&D) or in combination with pamidronate (group C&D + P).

image

Figure 1. Flow diagram of the enrolment, randomization, follow-up and analysis of patients in our randomized controlled trial of calcium and vitamin D alone, or in combination with pamidronate, in the treatment of low bone density associated with Crohn's disease.

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The baseline disease characteristics and BMD of the 37 patients in each group are shown in Tables 1 and 2. The disease duration and number of months on corticosteroids were significantly longer in group C&D + P. Haematological and biochemical measurements reflecting disease activity, such as baseline haemoglobin, erythrocyte sedimentation rate and serum albumin, were not significantly different in the two groups (data not shown). The mean levels of serum calcium, phosphate, 25-hydroxy-vitamin D and parathyroid hormone and baseline levels of N-telopeptide were within the normal range and did not differ significantly between the two groups (Table 1).

Table 1.  Disease characteristics and baseline biochemical measurements of the two randomized groups (calcium and vitamin D only, group C&D: calcium and vitamin D with pamidronate, group, group C&D; calcium C&D + P)
 Group C&D (n = 37)Group C&D + P (n = 37)
  1. Values shown are means ± s.d.

  2. * Significant difference between the two groups .

Male : female14 : 2022 : 12
Postmenopausal89
Age (years)43.5 ± 12.345.1 ± 11.4
Disease duration* (months)14.2 ± 9.520.2 ± 9.9
Current or previous corticosteroid31 (84%)30 (81%)
Duration of corticosteroid* (months)39.7 ± 47.380.2 ± 99.1
Body mass index (kg/m2)23.5 ± 3.922.6 ± 3.0
25-Hydroxy-vitamin D (nmol/L)43.9 ± 20.947.3 ± 26.2
Parathyroid hormone (ng/L)36.1 ± 16.743.4 ± 37.5
N-Telopeptide (bone collagen equivalents/millimole of creatinine)56.8 ± 54.758.8 ± 59.4
Table 2.  Baseline bone mineral density (BMD) data in the two groups (calcium and vitamin D only, group C∓D; calcium and vitamin D with pamidronate, group C&D + P)
 Group C&D (n = 37)Group C&D + P (n = 37)
  1. * Significant difference between the two groups (unpaired t-test).

Lumbar spine BMD (g/cm2) 0.86 ± 0.08  0.87 ± 0.09
T score− 1.91 ± 0.72− 1.84 ± 0.82
Hip BMD (g/cm2) 0.78 ± 0.09 0.73 ± 0.01
T score*− 1.92 ± 0.77− 2.34 ± 0.79

Both the Calcichew D3 Forte and pamidronate were generally well tolerated. Three patients, all from group C&D, were unable to tolerate calcium and vitamin D because of nausea. Four patients from group C&D + P received only one pamidronate infusion: three because of flu-like symptoms 24 h after the infusion and one because of difficulty gaining venous access.

Changes in bone mineral density

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

Both groups gained density in the lumbar spine and hip at 12 months compared with baseline, but the gains were only statistically significant in group C&D + P (P < 0.05) (Figure 2). There was a mean gain of + 1.6% (± 4.7%; 95% CI, − 0.1–3.2) at the lumbar spine in group C&D and of + 2.6% (± 3.4%; 95% CI, 1.4–3.0) in group C&D + P. At the hip, there was a mean gain of + 0.9% (± 3.5%; 95% CI, − 0.4–2.1) in group C&D and of + 1.6% (± 2.9%; 95% CI, 0.6–2.5) in group C&D + P. There were no statistically significant differences when comparing the changes in BMD between the two groups. A sub-analysis of men, postmenopausal women and those currently taking corticosteroids revealed no statistically different changes compared with the group as a whole, although the numbers were small.

image

Figure 2. Percentage change in bone mineral density after 12 months for the group receiving calcium and vitamin D supplementation alone (group C&D) and that receiving calcium and vitamin D in combination with intravenous pamidronate (group C&D + P). Significant gains (P < 0.05) were seen at both the spine and hip in group C&D + P.

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A per protocol analysis was also carried out. Twenty-four patients in group C&D and 26 patients in group C&D + P attended all four follow-up visits and were included in this analysis. There were mean gains at the spine of + 1.2% (± 4.5%; 95% CI, − 0.69–3.13) in group C&D and + 2.9% (± 3.6%; 95% CI, 1.5–4.2) in group C&D + P. At the hip, the mean gains were + 0.9% (± 3.2%; 95% CI, − 0.5–2.3) and + 1.7% (± 2.7%; 95% CI, 0.7–2.7) in groups C&D and C&D + P, respectively.

Changes in urinary excretion of N-telopeptide

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

In both groups, there was huge variability in the levels of N-telopeptide over the course of the 12 months and none of the changes were significant (Figure 3). In group C&D, the levels fluctuated between a rise of 21.2% (95% CI, − 79.7–122.0) at 6 months and a drop of − 27.2% (95% CI, − 55.8–1.4) at 9 months. In group C&D + P, there was a sustained drop at 3 months (− 16.6%; 95% CI, − 54.8–21.6), 6 months (− 25.3%; 95% CI, − 56.3–5.7), 9 months (− 27.2%; 95% CI, − 55.8–1.4) and 12 months (− 34.4%; 95% CI, − 73.5–4.7).

image

Figure 3. Mean percentage change in the level of N-telopeptide from baseline at 3, 6, 9 and 12 months in the group receiving calcium and vitamin D supplementation alone (group C&D) (broken line, s.d. above) and that receiving calcium and vitamin D in combination with intravenous pamidronate (group C&D + P) (full line, s.d. below).

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

We have shown a significant gain in BMD over 12 months at both the spine and hip with a combination of intravenous pamidronate and calcium and vitamin D supplementation. Patients were not selected in terms of corticosteroid use or disease activity. The treatment groups were randomly allocated, but it should be noted that the group receiving pamidronate had a significantly lower BMD at the hip, a longer disease duration and had taken corticosteroids for longer.

The changes in BMD described in this study are comparable with those seen when pamidronate is used to prevent bone loss in postmenopausal women23 and during treatment with corticosteroids,22 or in other chronic inflammatory conditions, such as cystic fibrosis24 and rheumatoid arthritis.25

This study did not include a control group. There are few longitudinal data on the natural history of bone loss in patients with Crohn's disease. In one study comparing bone loss in patients with and without bowel resections, 108 patients, all with Crohn's disease, were observed for a mean of 5.5 years. The mean loss at the femoral neck was 2.2% in the group who had undergone a colectomy; there was no change at the lumbar spine and no significant effect from corticosteroids.26 Another study of 81 patients, 61 with Crohn's disease, who were followed up for a mean period of almost 18 months, reported mean gains of 0.46% at the lumbar spine and 0.06% at the hip.27 The patients who lost bone, mainly at the hip, were those taking corticosteroids. Much larger rates of bone loss have been described. In a randomized controlled trial of 75 patients with Crohn's disease, the median loss at the forearm was 7% over 12 months in the control group compared with − 0.2% in the treated group, in this case with 1000 IU vitamin D.28 Clearly, there is significant variability in the rate of bone loss, which cannot be predicted by corticosteroid use alone.

There have been few studies to date examining the management of osteoporosis complicating inflammatory bowel disease. Clements et al., in a 2-year prospective study of 47 postmenopausal women with inflammatory bowel disease, reported that hormone replacement therapy prevented bone loss at the wrist and spine irrespective of corticosteroid use.29 Two studies have investigated the efficacy of calcium and vitamin D supplementation. The first, a small randomized controlled trial of 17 patients with inflammatory bowel disease, all of whom were taking corticosteroids,30 found no effect of 1000 mg calcium and 250 IU vitamin D compared with placebo at 12 months, whilst a larger randomized controlled trial of 75 patients with Crohn's disease, comparing placebo with 1000 IU vitamin D, concluded that it was effective in preventing bone loss at the forearm at 12 months, particularly in patients with normal baseline measurements of vitamin D.28

More recently, Haderslev et al. described the effect of oral alendronate compared with placebo on bone density after 12 months in 32 patients with Crohn's disease.18 They reported a significant gain of 4.6% at the lumbar spine compared with a loss of 0.9% in the placebo group. There was a smaller, insignificant gain at the hip of 3.3% compared with a gain of 0.7% in those receiving placebo. In this study, patients were also encouraged to take calcium and vitamin D supplements and the study excluded patients taking corticosteroids. Oral sodium fluoride has been studied recently and was effective in a 12-month randomized controlled trial of 33 patients with Crohn's disease,31 but low-impact exercise did not confer any significant benefit compared with the control group.32

We were unable to demonstrate significant changes in bone resorption after 12 months in either treatment group. Whilst the routine measurement of markers of bone formation and resorption in the investigation and monitoring of osteoporosis has yet to be established, there have been a number of studies measuring bone markers in patients with inflammatory bowel disease. Most, including our own study of 248 patients,33 have demonstrated an increase in bone resorption, and one recent study has suggested that increased excretion of N-telopeptide may predict bone loss at the spine in patients with inflammatory bowel disease.34

We found that, in the pamidronate group, levels of N-telopeptide were suppressed throughout the study, although not significantly. Of all the markers of bone resorption, there is evidence that N-telopeptide shows the most decline after treatment with pamidronate, but also the largest long-term variability.35 The timing of urine collections may also explain why we were unable to demonstrate any significant sustained response. These were collected in the early afternoon, when there may be even greater variability in the levels of N-telopeptide than normal, rather than an early morning void, and were mostly collected just prior to the pamidronate infusions. Rosen et al.35 have shown that, following the administration of intravenous pamidronate, the levels of N-telopeptide drop by up to 85% at day 8 and levels remain suppressed up to day 58. We measured N-telopeptide levels up to 3 months after the pamidronate infusions when we might expect any suppression of bone resorption to be at its lowest.36

In summary, intravenous pamidronate significantly increased the bone density at the lumbar spine and hip in patients with Crohn's disease and low BMD. It was well tolerated with few side-effects and it is suggested that it may be a useful alternative to oral bisphosphonates.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References

This study was supported by grants from the National Association for Colitis and Crohn's Disease and the Special Trustees of the Freeman Hospital. Dr Bartram was working as a Research Fellow funded by the Dunhill Medical Trust and National Osteoporosis Society during this study.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Biochemical measurements
  6. Statistical analysis
  7. Ethical approval
  8. Results
  9. Changes in bone mineral density
  10. Changes in urinary excretion of N-telopeptide
  11. Discussion
  12. Acknowledgements
  13. References
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