increased bone resorption in patients with crohn’s disease

Increased bone resorption in patients with Crohn's disease

R. J. ROBINSON*, S. J . IQBAL , K. ABRAMSà , F. AL-AZZAWI§ & J. F. MAYBERRY*

*Gastrointestinal Research Unit, Leicester General Hospital; Department of Clinical Chemistry, Leicester Royal In®rmary;

àDepartment of Epidemiology and Public Health, University of Leicester; and §Department of Obstetrics & Gynaecology,

Leicester Royal In®rmary, Leicester, UK

Accepted for publication 7 April 1998

INTRODUCTION

Osteoporosis is a common complication of in¯ammatory

bowel disease, and people with Crohn's disease are at

particular risk.1, 2 Many factors contribute to low bone

mineral density,3 however the pathophysiology and

mechanisms of bone loss have yet to be established.

Histomorphometric analysis of iliac crest biopsy speci-

mens in patients with in¯ammatory bowel disease

suggests osteoporosis is the result of reduced bone

formation and negative remodelling imbalance.4, 5

However, the severity of osteoporosis and the rapid

rates of bone loss suggest increased bone turnover is

also likely to contribute to the development of osteopo-

rosis.3 Biochemical markers of osteoblast and osteoclast

function re¯ect bone turnover6 and can be used to

investigate mechanisms of bone loss in in¯ammatory

bowel disease. Osteoblast markers re¯ecting the rate of

bone formation include osteocalcin (BGP), pro-collagen

carboxy-terminal peptide (PICP) and bone speci®c

alkaline phosphatase (BALP). Markers of bone resorp-

tion include urinary deoxypyridinoline (DPD) and

serum type 1 collagen carboxy-terminal telopeptide

SUMMARY

Background: Patients with Crohn's disease are at risk of

osteoporosis and premature fracture. However, the

pathophysiology underlying bone loss remains poorly

understood and the optimum treatment has not been

established.

Aim: To investigate mechanisms of bone loss in Crohn's

disease using biochemical markers of bone turnover.

Methods: Bone mineral density was measured at the hip

and spine using dual-energy X-ray absorptiometry in

117 patients (48 male) with Crohn's disease. Bone

turnover was assessed by measuring serum osteocalcin

(BGP), pro-collagen carboxy-terminal propeptide (PICP),

bone speci®c alkaline phosphatase (BALP) and urinary

deoxypyridinoline (DPD); and compared to age-matched

healthy controls (n � 28).

Results: Bone mineral density was reduced (z-score < )1)

in 48 (41%) patients with Crohn's disease. Mean values

for bone formation markers in patients with Crohn's

disease were all within the normal reference range (BGP

8.92 (� 3.23) ng/mL (normal range 3.4±10.0), BALP

17.6 (� 12.6) U/L (normal range 11.6±43.3), PICP 95.1

(� 46.5) ng/mL (normal range 69±163)) and were not

signi®cantly different to the control population. However,

mean urinary DPD was signi®cantly higher in patients

with Crohn's disease compared to healthy controls

(10.97 (� 9.22) nM DPD/mM creatinine vs. 5.02

(� 1.03) nM DPD/mM creatinine, difference in means

� 5.95, 95% CI: )9.6 to )2.3, P � 0.00001) and

compared to the UK reference range DPD levels were

increased in 74 (63%) patients.

Conclusions: Bone resorption as evidenced by urinary

DPD was frequently increased in patients with Crohn's

disease and was signi®cantly higher than in an age-

matched control population. The high levels of urinary

DPD suggest increased bone collagen degradation may

contribute to osteoporosis in patients with Crohn's

disease. These results suggest anti-resorptive agents

such as the bisphosphonates may be effective treatment

for osteoporosis in Crohn's disease.

Correspondence to: Dr R. Robinson, Gastrointestinal Research Unit,Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK.

Aliment Pharmacol Ther 1998; 12: 699±705.

Ó 1998 Blackwell Science Ltd 699

(ICTP). Published studies using biochemical markers in

patients with in¯ammatory bowel disease have shown

con¯icting results.7±10 However, these studies have

included cases of both ulcerative colitis and Crohn's

disease, although bone metabolism in the two condi-

tions is likely to be very different.2, 11 The treatment of

osteoporosis in patients with in¯ammatory bowel

disease remains to be established, and mechanisms

underlying bone loss are an important factor in

determining optimum therapy. Antiresorptive agents

such as the bisphosphonates should be effective therapy

if increased bone resorption is the major pathogenic

process, wheras a formation stimulating agent such as

¯uoride would be more appropriate if bone loss is

secondary to reduced bone formation.

The aims of this cross-sectional study were to use

biochemical markers of bone turnover to investigate the

possible mechanisms of bone loss in patients with

Crohn's disease.

PATIENTS AND METHODS

One hundred and seventeen Caucasian patients (48

male) with Crohn's disease were recruited from a

database of in¯ammatory bowel disease cases held in

Leicestershire. The following were considered exclusion

criteria: pregnancy, ankylosing spondylitis, taking HRT/

bisphosphonates, or a concurrent medical condition

leading to osteoporosis (e.g. liver disease, chronic renal

failure, hypogonadism, thyrotoxicosis). Mean age was

40.6 years (� 13.3), with disease duration of 9.6 years

(� 8.0). Fifty-eight (84%) of the women were pre-

menopausal, 11 (16%) post-menopausal. Thirty-one

(27%) patients had colonic disease only, 19 (16%) ileal

only, 59 (50%) ileocolonic, seven (6%) jejunal and one

had gastroduodenal disease. Seventy-six (65%) had

previous bowel resection. Twenty-six (22%) patients

were taking oral steroids, with a mean daily dose of

12.3 (� 15.1) mg (range 1±60 mg). One hundred

patients (86%) had previously used oral steroids.

Current disease activity was assessed using the `Simple

Disease Activity Score'.12 This is a clinical scoring

system based on symptoms during the previous day and

correlates well with the more complex Crohn's Disease

Activity Index.12 Mean disease activity was 1.52

(� 1.86).

Biochemical markers of bone formation were measured

in 28 healthy controls (14 males, mean age 36.6

(� 10.5) years, range 23±65). The bone resorption

marker deoxypyridinoline (DPD) was measured in 25

healthy controls (12 males, mean age 41.0 (� 10.1)

years, range 23±65). The control groups were matched

for age, and included only healthy men and women

taking no medication known to affect bone turnover

(e.g. hormone replacement therapy, bisphosphonates,

calcium, vitamin D, ¯uoride, calcitonin) and who had

no metabolic bone disease or recent fracture.

The study was approved by the Leicestershire Health

Authority ethics committee. Patients and controls gave

informed consent to these studies.

Biochemical assessment

After an overnight fast, `second morning void' urine

samples were collected and uncuffed venesection per-

formed. Samples were frozen within 30 min. Bone

turnover markers were analysed `en bloc' using com-

mercially-available immunoassays (Metra Biosystems

Incorporated, CA, USA). Osteocalcin (BGP), pro-colla-

gen carboxy-terminal propeptide (PICP) and bone

speci®c alkaline phosphatase (BALP) were measured to

assess bone formation. Urinary deoxypyridinoline (DPD)

and urinary calcium corrected for creatinine were

measured to assess bone resorption. All assays were

calibrated using four parameter calibration curves as

recommended by the manufacturer, and quality control

samples were within accepted limits. BGP (normal

range for adults: male 3.4±9.1 ng/mL, female 3.7±

10.0 ng/mL) was measured by competitive enzyme-

linked immunoassay (ELISA) with a within-run preci-

sion of 10%. BALP (normal range for adults: male:

15.0±41.3 U/L, female 11.6±43.4 U/L) (within-run

precision 3.9%) and PICP (normal range for adults:

male 76±163 ng/mL, female 69±147 ng/mL) (within-

run precision 6.8%) were measured by non-competitive

immunoassay and DPD (normal range for adults: male

2.1±6.4 nM DPD/mM creatinine, female 3.3±9.3 nM

DPD/mM creatinine) was measured by a competitive

enzyme assay on a microtitre plate (within-run preci-

sion 6.2%). The sex and age-adjusted reference ranges

for bone formation markers in healthy adults were

supplied by Metra Biosystems Incorporated and are

based on healthy American Caucasians. Normal refer-

ence ranges for these assays have not been established

for the UK population. The reference range for DPD was

provided by the University of Shef®eld. This is based on

the healthy UK population (126 males aged 20±

65 years, and 70 pre-menopausal females aged

700 R. J. ROBINSON et al.

Ó 1998 Blackwell Science Ltd, Aliment Pharmacol Ther 12, 699±705

20±47 years) (R. Hannon, personal communication).

Serum concentrations of calcium (normal range 2.1±

2.6 mmol/L), phosphate (normal range 0.8±1.4 mmol/

L), total alkaline phosphatase (normal range 65±130 U/

L) and albumin (normal range 35±65 g/L) were

measured by standard methods (Kodak Ecktachem

700XR; Orthodiagnostics, Amersham, UK). Plasma 25

(OH)-D levels (normal range 5±40 ng/L) were measured

on patients with low bone mineral density (Incstar

Corporation, Stillwater, MN).

Bone density measurement

Bone mineral density (g/cm2) of the lumbar spine (L2±

L4) and hip (femoral neck, greater trochanter and

Ward's triangle) was measured by dual-energy X-ray

absorptiometry (Lunar DPX, Lunar software version

3.1; Lunar Radiation, Madison, WI). Reproducibilty of

DXA in our hands determined on 10 healthy individuals

was 0.5% at the lumbar spine, 0.49% at the femoral

neck, 1.7% at the greater trochanter and 2.14% at

Ward's triangle. To avoid the confounding effect of age,

bone mineral density (BMD) was de®ned using z-scores.

Osteoporosis was de®ned as BMD more than 2 standard

deviations below age- and sex-matched normal values

(z-score < )2), and osteopenia as BMD between 1 and 2

standard deviations below age- and sex-matched nor-

mals (z-score < )1, > )2). Normative data for the UK

were supplied by Lunar Radiation and were based on

ambulatory subjects from the general population of the

UK who were not on medication or suffering from

conditions affecting bone density.

Statistical analysis

Continuous data which were normally distributed were

presented as means (� standard deviation) and the

statistical signi®cance of differences between groups of

patients was assessed using 95% con®dence intervals

for the differences and Student's unpaired t-test. The

Mann±Whitney U-test was used where the data were

not normally distributed. Correlations between contin-

uous variables were assessed using Pearson's correla-

tion coef®cients together with 95% con®dence intervals.

Two-tailed values for signi®cance were used in all the

statistical analyses and P < 0.05 was considered statis-

tically signi®cant. The Statistical Package for Social

Sciences (SPSS) was used for the analysis.

RESULTS

Mean adjusted calcium in patients with Crohn's disease

was 2.29 (� 0.07) mmol/L, phosphate 1.09 (� 0.4)

mmol/L, albumin 40.2 (� 3.12) g/L and total alkaline

phosphatase 79.11 (� 22.05) U/L. Five patients had

total alkaline phosphatase values above the normal

reference range. However, in all cases the elevation was

minimal, with other biochemical parameters including

25 (OD) vitamin D within the normal reference range.

Two patients had 25 (OH) vitamin D levels below the

reference range but in both cases other biochemical

parameters were normal, with no evidence of osteom-

alacia.

Mean BMD (z-score) of the 117 patients was )0.09

(� 1.42) at the lumbar spine, )0.20 (� 1.11) at the

femoral neck, )0.30 (� 1.2) at the trochanter and

)0.09 (� 1.12) at Ward's triangle.

Bone formation markers

The results of osteocalcin (BGP), bone speci®c alkaline

phosphatase (BALP), pro-collagen carboxy-terminal

propeptide (PICP) and deoxypyridinoline (DPD) in 117

patients with Crohn's disease are shown in Figure 1.

Mean values for bone formation markers in patients

with Crohn's disease were all within the normal

reference range (BGP 8.92 (� 3.23) ng/mL (normal

range 3.4±10.0), BALP 17.6 (� 12.6) U/L

(normal range 11.6±43.3), PICP 95.1 (� 46.5) ng/mL

(normal range 69±163)). Mean values for all bone

formation markers in healthy controls were within the

normal reference range (BGP 8.23 (� 1.83) ng/mL

(normal range 3.4±10.0), BALP 17.7 (� 5.8) U/L

(normal range 11.6±43.3), PICP 97.0 (� 46.9) ng/

mL, (normal range 69±163)) and were not signi®cantly

different to patients with Crohn's disease (Table 1).

PICP was lower in patients with osteoporosis (n � 14)

or osteopenia (n � 34) compared to those with normal

bone mineral density (Table 2), but other bone forma-

tion markers were not signi®cantly different.

Bone resorption markers

Mean DPD in healthy controls was 5.02 (� 1.03)

nM DPD/mM creatinine (normal range 2.1±9.3).

The distribution of DPD in patients with Crohn's

disease is shown in Figure 1. Mean urinary DPD was

increased compared to the UK reference range at 10.97

(� 9.22) nM DPD/mM creatinine (normal range

BONE RESORPTION IN CROHN'S DISEASE 701


2.1±9.3), and was signi®cantly higher than the control

population (Table 1). Compared to the UK reference

range, DPD levels were increased in 74 (63%) patients

(32 (67%) men and 42 (61%) women). In 40 (34%)

patients with increased levels of DPD, all markers of

bone formation remained within the normal reference

range. Mean urinary calcium in patients with Crohn's

disease was 0.22 (� 0.25) mmol/mM creatinine (range

0.1±2.2) (normal range < 0.59).

DPD was not signi®cantly associated with markers of

bone formation, but the correlation with urinary

calcium excretion was statistically signi®cant

(r � 0.53, 95% CI: 0.38±0.65, P < 0.0001). Bone

resorption markers were not signi®cantly different in

patients with osteoporosis or osteopenia (Table 2).

FACTORS AFFECTING BONE TURNOVER

IN CROHN'S DISEASE

Corticosteroids

BGP (8.48 (� 2.8) vs. 9.05 (� 3.3), difference in means

� 0.57 ng/mL, 95% CI: )1.9 to 0.85, P � 0.43),

PICP (97.8 (� 49.8) vs. 94.3 (� 45.8), difference in

means � 3.5 ng/mL, 95% CI: )17.1 to 24.0,

P � 0.74) and BALP (16.3 (� 4.3) vs. 18.0 (� 1.7),

Figure 1. Osteocalcin (BGP), bone speci®c alkaline phosphatase (BALP), pro-collagen carboxy-terminal propeptide (PICP) and

deoxypyridinoline (DPD) in 117 patients with Crohn's disease.

Table 1. Bone turnover markers in patients with Crohn's disease compared to controls

Controls Patients

Difference in means

(95% CI) P-value

Deoxypyridinoline (DPD) 5.02 (� 1.03) 10.97 (� 9.22) 5.95 ()9.6 to )2.3) 0.00001

(nM DPD/mM creatinine)

Osteocalcin (BGP) (ng/mL) 8.23 (� 1.83) 8.92 (� 3.23) 0.69 ()1.9 to 0.56) 0.28

Bone speci®c alkaline

phosphatase (BALP) (U/L)

17.7 (� 5.8) 17.6 (� 12.6) 0.1 ()2.3 to 2.7) 0.87

Pro-collagen

carboxy-terminal

propeptide (PICP) (ng/mL)

97.0 (� 46.9) 95.1 (� 46.5) 1.9 ()21.3 to 17.5) 0.88

Urinary DPD was signi®cantly increased in Crohn's disease compared to age-matched healthy controls. Results are expressed as mean (� s.d.).



difference in means � 1.7 U/L, 95% CI: )7.3 to 3.9,

P � 0.55) were not signi®cantly different in patients

taking oral corticosteroids at the time of study (n � 26)

compared to patients off steroids. There was a negative

correlation between current prednisolone dose and

markers of bone formation in patients on steroids; this

was signi®cant only for PICP (r � )0.40, 95% CI:

)0.68 to )0.01, P � 0.04). BALP was signi®cantly

associated with lifetime steroid dose estimated from

hospital records (r � 0.19, 95% CI: )0.007 to 0.37,

P � 0.04), but there was no signi®cant correlation

between cumulative dose and other markers of forma-

tion or resorption.

Urinary DPD (8.0 (� 3.6) vs. 11.8 (� 10.1), difference

in means � 3.8 nM DPD/mM creatinine, 95% CI: )7.8

to 0.23, P � 0.06), and urinary calcium (0.25

(� 0.19) vs. 0.21 (� 0.26), difference in means

� 0.04 mmol/mM creatinine, 95% CI: )0.08 to 0.14,

P � 0.53) were not signi®cantly different in patients

on oral steroids compared to patients off steroids.

Biochemical markers of bone turnover were not signif-

icantly different in patients receiving rectal steroids

(n � 5) at the time of study.

Disease site and activity

Current disease activity was not signi®cantly related to

biochemical markers of bone formation (BGP,

r � 0.07, 95% CI: )0.11 to 0.25, P � )0.47; BALP,

r � )0.08, 95% CI: )0.26 to 0.10, P � 0.4; PICP,

r � )0.09, 95% CI: )0.27 to 0.09, P � 0.31).

Similarly bone resorption markers were not signi®cantly

associated with current disease activity (DPD,

r � )0.03, 95% CI: )0.21 to 0.15, P � 0.73; urinary

calcium, r � )0.01, 95% CI: )0.19 to 0.17,

P � 0.89).

There was no signi®cant variation in BGP (P � 0.85),

BALP (P � 0.66) or PICP (P � 0.39) with site of the

Crohn's disease. Urinary DPD (P � 0.14) and urinary

calcium (P � 0.72) did not vary signi®cantly with

disease site.

Sex and menstrual status

Urinary DPD was signi®cantly higher in post-meno-

pausal women (17.1 (� 21.8) nM DPD/mM creatinine)

compared to men (8.4 (� 6.0) nM DPD/mM creatinine)

and pre-menopausal women (11.9 (� 6.7) nM DPD/

mM creatinine, P � 0.007). BGP and BALP did not

vary signi®cantly according to sex or menstrual status,

but PICP was signi®cantly lower in post-menopausal

women (65.3 (� 13.2) ng/mL) compared to men

(109.2 (� 59.1) ng/mL) and pre-menopausal women

(89.1 (� 33.4) ng/mL, P � 0.04).

DISCUSSION

In this study urinary deoxypyridinoline (DPD) was

frequently increased in patients with Crohn's disease

and was signi®cantly higher than in an age-matched

control population. Although levels of osteocalcin

(BGP), pro-collagen carboxy-terminal propeptide (PICP)

and bone speci®c alkaline phosphatase (BALP) varied

considerably, they were not signi®cantly different to

healthy controls. These results suggest bone resorption

is commonly increased in patients with in¯ammatory

bowel disease, with no consistent increase in bone

formation.

Table 2. Bone metabolism in patients with Crohn's disease with osteoporosis, osteopenia and with normal bone mineral density (BMD)

Osteoporosis Osteopenia Normal BMD

(n�14) (n�34) (n�69) P-value

Osteocalcin (BGP) (ng/mL) 9.52 (� 4.1) 9.69 (� 4.1) 8.42 (� 2.4) 0.13

Pro-collagen carboxy-terminal

propeptide (PICP) (ng/mL)

117.0 (� 74.0) 102.9 (� 50.3) 86.8 (� 34.9) 0.04

Bone speci®c alkaline

phosphatase (BALP) (U/L)

19.5 (� 6.8) 16.7 (� 6.4) 17.6 (� 15.5) 0.79

Deoxypyridinoline (DPD) 8.9 (� 4.9) 11.4 (� 5.9) 11.4 (� 5.9) 0.68

(nM DPD/mM creatinine)

Urinary calcium 0.17 (� 0.14) 0.23 (� 0.18) 0.23 (� 0.18) 0.75

(mmol/mM creatinine)

Biochemical markers of bone turnover were not signi®cantly different in patients with osteoporosis or osteopenia compared to those with normalbone mineral density. Results are expressed as mean (� s.d.).



Previous studies using biochemical markers of bone

turnover to investigate the mechanisms of bone loss in

in¯ammatory bowel disease have produced con¯icting

results.7±10 However, comparison of studies is compli-

cated by the measurement of different turnover markers

and considerable variability in the clinical characteris-

tics of the patients studied. In a recent UK study,

Bjarnason et al. measured DPD, PICP and BGP in

patients with in¯ammatory bowel disease.10 Although

they included cases of both ulcerative colitis and

Crohn's disease, in an attempt to study a homogeneous

group of patients, they excluded patients at high risk for

metabolic bone disease. Therefore individuals receiving

treatment for osteoporosis, patients with small intestinal

resection, malnutrition or receiving high doses of oral

corticosteroids were excluded. Post-menopausal women

and patients with active disease were also excluded. In

their selected patient population they also found

markedly increased DPD but no consistent increase in

any marker of bone formation. Silvennoinen et al.

randomly studied patients from a community register

of patients with in¯ammatory bowel disease.9 They

found increased bone resorption as evidenced by

elevated carboxy-terminal telopeptide of type 1 collagen

(ICTP) in patients with in¯ammatory bowel disease

compared to a control population. The bone formation

markers PICP and BGP were not signi®cantly different

to controls. Both studies concluded that osteoporosis in

in¯ammatory bowel disease is due to an increase in bone

resorption without a compensatory increase in bone

formation. Results of these studies are similar to our

own, but con¯ict with ®ndings of bone biopsy and other

bone turnover studies where reduced bone formation

was the major underlying process.4, 5, 8 These con¯ict-

ing results cannot be adequately explained by differen-

ces in patients or methodology between the studies, and

suggest that more than one process must contribute to

bone loss in in¯ammatory bowel disease. Low bone

formation and increased bone resorption could contrib-

ute at different phases of the disease.

Corticosteroids are considered an important factor

contributing to bone loss in patients with in¯ammatory

bowel disease.13 However, in this study, biochemical

markers of bone turnover did not vary signi®cantly with

current or previous use of oral corticosteroids. This is

consistent with other studies investigating bone turn-

over in in¯ammatory bowel disease,8, 10 and is surpris-

ing given the direct inhibitory effects of steroids on

osteoblast function.14 There are a number of possible

reasons for these ®ndings. Corticosteroids depress bone

formation in a dose-dependent fashion,15 and the mean

daily dose of prednisolone in this study was only 12

(� 15) mg, with 15 patients taking less than 7.5 mg

daily. Furthermore, some patients had been taking oral

steroids for many months, when the suppression of bone

formation is less pronounced.

It has been suggested that bone loss in in¯ammatory

bowel disease is the result of cytokines (e.g. interleukin

6, interleukin 1, tumour necrosis factor) released from

the in¯amed intestine directly in¯uencing osteoblast

and osteoclast function.2, 16 In this study there was no

signi®cant association between disease activity and

markers of bone formation or resorption; although at

the time of study most patients had clinically quiescent

Crohn's disease. Similarly, disease extent and site did

not signi®cantly affect bone turnover. This contrasts

with the ®ndings of Silvennoinen et al. who reported

increased bone resorption, as evidenced by raised ICTP,

in patients with active, extensive ulcerative colitis.9

There are a number of limitations which need to be

considered before drawing ®rm conclusions from this

cross-sectional study. Although only patients with

Crohn's disease were studied, the population was

heterogeneous in terms of age, sex, menstrual status

and use of corticosteroids. Urinary DPD was signi®cant-

ly increased in post-menopausal women with Crohn's

disease. No women included in the study were within

5 years of the menopause, when bone turnover is

particularly high, however, the increased DPD is

consistent with the accelerated bone loss recognized in

post-menopausal women.17 Although meaningful anal-

ysis of the various subgroups was limited by the small

number of patients, DPD levels were higher in post-

menopausal women with Crohn's disease than previ-

ously reported in healthy post-menopausal women.18

Excluding post-menopausal women from the analysis

did not alter the signi®cance of the results. The reference

ranges for bone formation markers used in this study

are based on the healthy American population, because

UK normal ranges have not been established. Although

the number of healthy controls we studied was small, it

was age-matched to the study population, and mean

values of all bone turnover markers were within the

quoted reference ranges.

Markers of bone formation and resorption varied

considerably in this study, which is likely to re¯ect the

heterogeneous nature of bone loss in patients with

Crohn's disease. However, bone resorption, as evidenced



by urinary deoxypyridinoline (DPD), was frequently

increased and was signi®cantly higher than in age-

matched healthy controls. This suggests that in patients

with established Crohn's disease, increased bone colla-

gen degradation may contribute to bone loss and

osteoporosis. Although Vitamin D,19 hormone replace-

ment therapy20 and exercise21 can reduce the rate of

bone loss in Crohn's disease, the optimum prevention

and treatment of osteoporosis in these patients remains

to be established. The high levels of bone resorption seen

in this study suggest anti-resorptive agents such as the

bisphosphonates would be effective therapy. However,

gastrointestinal side-effects are common with

bisphosphonates,22 and they should be used only in

patients with established osteoporosis until their safety

and ef®cacy in this high-risk population has been

evaluated.

ACKNOWLEDGEMENTS

Dr R. J. Robinson was supported by a grant from the

National Association for Colitis and Crohn's. The

authors are grateful to Dr B. Rathbone, Dr J. Nightin-

gale, Dr A. C. B. Wicks and Dr J. de Caestecker for

allowing their patients to be studied.

REFERENCES

1 Jahnsen J, Falch J, Aadland E, Mowinckel P. Bone mineral

density is reduced in patients with Crohn's disease but not in

patients with ulcerative colitis: a population based study. Gut

1997; 40: 313±19.

2 Ghosh S, Cowen S, Hannan W, Ferguson A. Low bone mineral

density in Crohn's disease, but not in ulcerative colitis, at

diagnosis. Gastroenterology 1994; 107: 1031±9.

3 Compston J. Review article: osteoporosis, corticosteroids and

in¯ammatory bowel disease. Aliment Pharmacol Ther 1995;

9(3): 237±50.

4 Hessov I, Mosekilde L, Melsen F. Osteopenia with normal vit-

amin D metabolites after small bowel resection for Crohn's

disease. Scand J Gastroenterol 1984; 19: 691±6.

5 Croucher P, Vedi S, Motley R, Garrahan N, Stanton M,

Compston J. Reduced bone formation in patients with osteo-

porosis associated with in¯ammatory bowel disease. Osteo-

porosis Int 1993; 3(5): 236±41.

6 Blumsohn A, Eastell R. The performance and utility of bio-

chemical markers of bone turnover: do we know enough to

use them in clinical practice? Ann Clin Chem 1997; 34(5):

449±59.

7 Kjeldsen J, Junker P, Schaffalitzky de Muckadell O. Evidence

that collagen 1 turnover is increased in active Crohn's disease.

Gastroenterology 1994; 104(Suppl. 4): A712(Abstract).

8 Abitbol V, Roux C, Chaussade S, et al. Metabolic bone as-

sessment in patients with in¯ammatory bowel disease. Gas-

troenterology 1995; 108: 417±22.

9 Silvennoinen J, Ristelli L, Karttunen T, Risteli J. Increased

degradation of type 1 collagen in patients with in¯ammatory

bowel disease. Gut 1996; 38: 223±8.

10 Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas

M, Forgacs I, Moniz C. Reduced bone density in patients with

in¯ammatory bowel disease. Gut 1997; 40: 228±33.

11 Hyams J, Wyzga N, Kreutzer D, Justinich C, Gronowicz G.

Alterations in bone metabolism in children with in¯ammatory

bowel disease: an in vitro study. J Pediatr Gastroenterol Nutr

1997; 24(3): 289±95.

12 Harvey R, Bradshaw J. A simple index of Crohn's disease ac-

tivity. Lancet 1980; March 8th: 514.

13 Bernstein C, Seeger L, Sayre J, Anton P, Artinian L, Shanahan

F. Decreased bone density in in¯ammatory bowel disease is

related to corticosteroid use and not disease diagnosis. J Bone

Min Res 1995; 10(2): 250±5.

14 Lukert B, Raisz L. Glucocorticoid-induced osteoporosis:

pathogenesis and management. Ann Intern Med 1990;

112(5): 352±64.

15 Godschalk M, Downs R. Effect of short-term glucocorticoids on

serum osteocalcin in healthy young men. J Bone Min Res

1988; 3: 113±15.

16 Lin C, Moniz C, Chambers T, Chow J. Colitis causes bone loss

in rats through suppression of bone formation. Gastroenter-

ology 1996; 111: 1263±71.

17 Uebelhart D, Schlemmer A, Johansen J, Gineyts E, Christian-

sen C, Delmas P. Effect of menopause and hormone replace-

ment on the urinary excretion of pyridinum crosslinks. J Clin

Endocrinol Metab 1991; 72: 367±73.

18 van Daele PLA, Siebel MJ, Burger H, et al. Case-control anal-

ysis of bone resorption markers, disability, and hip fracture

risk: the Rotterdam study. Br Med J 1997; 312: 482±3.

19 Vogelsang H, Ferenci P, Resch H, Kiss A, Gangl A. Prevention

of bone mineral loss in patients with Crohn's disease by long-

term oral vitamin D supplementation. Eur J Gastroenterol

Hepatol 1995; 7(7): 609±14.

20 Clements D, Compston J, Evans W, Rhodes J. Hormone re-

placement therapy prevents bone loss in patients with in-

¯ammatory bowel disease. Gut 1993; 34: 1543±6.

21 Robinson R, Krwyzicki T, Almond L, et al. The effect of low

impact exercise on bone mineral density in patients with

Crohn's disease. A randomised controlled study. Gut 1997;

41(Suppl. 3): A17(Abstract).

22 Adami S, Zamberlan N. Adverse effects of bisphosphonates.

Drug Safety 1996; 14: 158±70.



increased bone resorption in patients with crohn’s disease

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