Recommandations pour la préventionet le traitement des nausées et vomissementsinduits par la chimiothérapieGuidelines for prophylaxis and treatment of chemotherapy-inducednausea and vomitingJ.-P. Durand1, I. Madelaine2, F. Scotté31Unité de cancérologie, hôpital Cochin, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France2Service de pharmacie, hôpital Saint-Louis, 75475 Paris, France3
- A |
J |K |
U |V |
33690 coeliac no14Guidelines for Osteoporosis in Coeliac disease and inflammatory bowel disease Guidelines for osteoporosis in coeliac disease andinﬂammatory bowel disease E M Scott, I Gaywood, B B Scott for the British Society of Gastroenterology 1.0 The problem
Osteoporotic fractures are a major public which these guidelinesare based was origi- health problem. It has been estimated that in There are several methods available for meas- the USA the remaining lifetime fracture risk at uring BMD.11 Dual energy x ray absorptio- the age of 50 years is 40% for white women and metry (DEXA) is currently most favoured, but 1998;10:689–98.
13% for white men,1 the major fracture sites is relatively costly and is not widely available; being spine, forearm and hip. This results in roughly 100 instruments have been installed in the UK. Broadband ultrasound attenuation of rising costs, including acute hospital care and long term care in the home or nursing home.
discriminates patients with and without osteo- The estimated total annual cost of osteoporotic porosis almost as well as actual measurements fractures in England and Wales is £742 million of bone density12 and is predictive of hip ($464 million).2 These costs are likely to fracture.6 It may also reﬂect bone architecture which contributes to overall bone strength,13 isrelatively cheap and the machine is portable.
However, its usefulness in monitoring responseto treatment has not been validated.
2.1 BONE MINERAL DENSITY
There are many risk factors for osteoporosis measurement of bone mineral density (BMD), including endocrine, metabolic and nutritional which can be expressed as the number of SDs disorders, and drugs. The value of screening groups in which the incidence of fracture is young adults (T score) or the mean BMD for increased is likely to be greater, and targeting age matched controls (Z score). A BMD more such patients should at least be considered than 2.5 SD below the mean for a young adult even in the absence of cost-beneﬁt studies.
is generally taken to indicate osteoporosis.3 Stratiﬁcation for fracture risk is possible using increased risk are already under medical super- BMD. The risk increases roughly twofold for each SD decline in BMD below the population treatment is likely to be high. Doctors respon- mean.4 5 This compares with a 1.5-fold in- sible for the management of such patients crease in the risk of death from coronary artery should seriously consider their role in detecting disease with each SD increase in cholesterol concentrations or diastolic pressure.
2.5 ROLE OF GASTROENTEROLOGISTSGastroenterologists care for a large proportion of patients at increased risk of osteoporosis.
It is important to recognise that osteoporosis is The two main groups are those with coeliac but one of a number of factors predisposing to disease and inﬂammatory bowel disease (IBD), fracture, just as a raised cholesterol and diasto- especially those on steroids. Alcoholism and lic pressure are each just one of many factors chronic liver disease are also important but are Department of
Awareness of surroundings, mobility, and eye- Endocrinology, St
sight collectively contribute to a tendency to 3.0 Coeliac disease
fall and all are likely to be important.6 Further- Hospital,
more, bone strength is largely related to Leeds LS9 7TF, UK
trabecular structure, certainly in the proximal The evidence for reduced BMD in coeliac dis- femur, whereas BMD is a composite measure- ease is good.14–22 One study19 showed that 47% Department of
ment of both cortical and trabecular bone.7 Gastroenterology,
Although the population can be stratiﬁed for diet had osteoporosis deﬁned as BMD more County Hospital,
fracture risk using BMD measurements, its Greetwell Road,
poor sensitivity for predicting actual fracture Lincoln LN2 5QY, UK
makes it unsuitable for screening the whole related to calcium intake, body mass index Department of
women—the diYculties and costs are great and Rheumatology, County
it would have only a small contribution to frac- Abbreviations used in these guidelines: BMD,
bone mineral density; IBD, inﬂammatory boweldisease; DEXA, dual energy x ray absorptiometry; whole.3 8–10 The alternative is to target certain BMI, body mass index; CT, computed tomography; high risk groups for screening or treatment, or HRT, hormone replacement therapy; IL, interleukin; APD, (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate.
(BMI) and menopausal age. Other studies have lumbar spine using CT scanning repeated at shown signiﬁcant improvement one year after one year in 54 patients with IBD and found a starting a gluten-free diet,23 normal BMD in rapid rate of trabecular bone loss in 20%. No patients who had been on a gluten-free diet signiﬁcant correlation with steroid use was since childhood,15 and improved bone miner- found. There was a negative correlation with alisation on a gluten-free diet in childhood and BMI. Clements and colleagues31 studied 50 adolescence.24 The incidence of fractures in patients with IBD at intervals over a mean of coeliac disease is not known but there is no eight years using single photon absorptiometry reason to suppose that the reduction in BMD is and found increased rates of cortical bone loss less predictive of fracture risk than in the gen- in some. Silvennoinen and colleagues,32 using eral population. The abstract of one study25 DEXA of the lumbar spine and femoral neck, reported a signiﬁcantly higher proportion of studied 67 patients with ulcerative colitis, 78 patients with a history of fracture than controls with Crohn’s disease, and seven with indeter- (21 v 3%). The mean age was 52 years and minate IBD. Of these, 30% had a Z score of −1 there was no relation between fracture and or below compared with 16% of controls. The BMD correlated negatively (slightly) with life-time steroid use. There was no signiﬁcant received steroids. A study published in abstract form33 of forearm CT scanning in 61 patients coeliac disease is likely to be related to calcium with Crohn’s disease, 22 with ulcerative colitis malabsorption leading to increased parathor- and seven with indeterminate IBD showed that mone secretion which, in turn, increases bone 19% had trabecular density more than 2 SD turnover and cortical bone loss.26 Vitamin D below the control mean. In another abstract34 malabsorption is probably of less importance.
of a study of 38 patients with ulcerative colitis, osteomalacia may co-exist, especially before BMD between patients and controls, but on treatment, and will require treatment with vita- repeat testing at one year there was a significant min D. Furthermore, osteomalacia may aVect fall in BMD in the group of six men who had the result of DEXA. In some men there may be loss of gonadal function27 which may, as in women, contribute to osteoporosis.28 Unfortu- patients with Crohn’s disease but not in 60 nately, serum testosterone concentrations are with ulcerative colitis, whereas a DEXA study unlikely to be helpful in planning testosterone from England,36 which found osteoporosis in replacement therapy because the concentra- 27% of 79 patients with IBD (44 with Crohn’s disease and 35 with ulcerative colitis) stated treatment, owing to androgen resistance.27 that there was no signiﬁcant diVerence between There seems to be impairment of peripheral Crohn’s disease and ulcerative colitis.
4.0 Inﬂammatory bowel disease
Only one36 of these studies used the generally accepted criterion for osteoporosis (i.e., BMD >2.5 SD below mean for young adults).
The results of studies of osteoporosis in Nevertheless, taken together they suggest that inﬂammatory bowel disease (IBD) are less osteoporosis is common in Crohn’s disease and consistent than in coeliac disease which is not less so in ulcerative colitis, and that there is a surprising given the great variation in site, positive correlation between BMD and BMI, extent and severity of disease between patients, and a negative correlation with steroid use.
variation of all these with time, and associated Furthermore, BMD may be reduced relatively drug treatment, especially steroids.
Compston and colleagues29 studied the fore- In men testosterone deﬁciency may contrib- arm with single photon absorptiometry and the ute to osteoporosis. Testicular function may be impaired in Crohn’s disease37 as well as in those tomography (CT) scanning in 17 patients with on steroids38 39 and although it is not known ulcerative colitis, 51 with Crohn’s disease (46 whether this is related to testosterone deﬁ- ciency, depressed blood testosterone concen- resections) and four with indeterminate IBD.
trations were found in three of 19 patients with They found osteoporosis (deﬁned as a BMD more than 2 SD below the age matched controlmean) in 14% of patients with ulcerative colitis 5.0 Steroid use
and 41% of those with Crohn’s disease. All except eight in each group had taken steroids.
Steroids have a number of adverse eVects on The BMD correlated negatively with lifetime bone. They suppress circulating oestrogen, steroid use and positively with BMI. A higher thus reducing its role in inhibiting the cytokine percentage of men than women had osteoporo- interleukin (IL) 6, which is a stimulator of sis, which might reﬂect the use of hormone osteoclastic activity.40 In men steroids reduce replacement therapy (HRT) in women whereas blood testosterone concentrations38 39 resulting the men were unlikely to have been oVered tes- in a similar eVect on bone.39 Steroids also tosterone. Motley and colleagues30 studied the inhibit osteoblast maturation, synthetic ability, Guidelines for Osteoporosis in Coeliac disease and inflammatory bowel disease Box 1—Summary strategy for prevention and treatment of
blacks and whites are equally susceptible.
osteoporosis in coeliac disease
6.0 Strategies for preventing and treating
+ Strict gluten-free diet **
+ Adequate dietary calcium; add calcium tablets if necessary to ensure daily intake of 1500 mg ***
+ Exercise ***
advice given about exercise (particularly weight + No smoking **
bearing), smoking, alcohol excess, and ad- + No alcohol excess **
equate dietary calcium. A total daily calcium intake of 1500 mg should be ensured—a pint of + Measure BMD at diagnosis; if low reinforce above advice skimmed milk provides 700 mg. If dietary cal-cium is inadequate 500–1000 mg supplemental calcium should be given (e.g., one or two Cal- + Measure BMD at menopause or when ﬁrst seen cichew (Shire, UK) tablets daily). In coeliac disease the importance of adhering strictly to a + HRT, preferably by skin patch, or ***
gluten-free diet should be stressed. Vitamin D + Bisphosphonate orally, or ***
deﬁciency should be sought and treated if + Calcitonin ***
found. Clinicians usually rely on serum cal- measurements. Osteomalacia may still exist + If osteoporotic† oVer bisphosphonate or calcitonin **
even if these tests are normal. When these tests are normal and osteomalacia is still suspected + If osteoporotic† oVer HRT (if post menopausal), bisphosphonate measured. However, this is expensive and the cheaper parathormone assay should be consid- + If already on HRT consider adding bisphosphonate or calcitonin *
ered. A low normal calcium and an elevated parathormone indicates secondary hyperpara- + For bisphosphonate and calcitonin measure BMD yearly thyroidism and treatment with calcium (800 + If BMD falls >4% per year in two successive years change to other mg daily) together with vitamin D (400–800 units daily) should be given. See boxes 1 and 2 + If no fall continue drug for at least three years — possibly long for summary strategies for the prevention of and treatment of osteoporosis in coeliac disease + Restart drug if, on stopping, yearly BMD falls >4% + For HRT check BMD after 10 years and continue HRT if osteoporosis persists *
6.2 TIMING OF DENSITOMETRYThe timing of densitometry presents a prob- †Osteoporosis deﬁned as BMD >2.5 SD below mean for young adult. ***, ** and lem. In women, postmenopausal densitometry * indicate the level of evidence for the recommendation (see text).
will be more sensitive at detecting osteoporosisbut the delay will give less scope for achieving ahigher bone density with treatment, despite and calcium absorption and increase urinary evidence that bisphosphonates may produce loss, thus causing secondary hyperparathy- some reversal of osteoporosis.44 45 Conversely, roidism which increases bone remodelling.
screening at presentation may reveal osteo- However, in Crohn’s disease the relation porosis at a young age when intervention would between steroids and reduced BMD could also theoretically have greater potential but for be partly explained by the associated increased which speciﬁc treatments such as bisphospho- activity of the disease necessitating the steroids.
nates and calcitonin have not been shown to be Preliminary data41 suggest that circulating IL-6 either eVective at preventing fractures (except is both increased in active disease and associ- patients have densitometry at diagnosis. This would allow reinforcement of general advice if BMD is low. However, we can appreciate that steroid use42 reports that although the associ- the burden on both the clinician and the densi- ation is real, the true incidence of osteoporosis tometry service might be counter-productive in steroid treated patients is unknown. Esti- and deter any screening. A simpler strategy, mates of the fraction of patients on long term steroids who will experience fractures vary patients and restricting BMD measurement to from one half42 to one quarter.43 Nevertheless, the older patients who are more likely to certain conclusions seem valid. Signiﬁcant beneﬁt, could therefore be more eVective in bone loss is caused by doses of prednisolone of IBD. In any case, patients with IBD at presen- 7.5 mg daily or greater in most patients. Bone tation are unlikely to have osteoporosis as a result of their disease. There is more reason for treatment. The usual risk factors for osteoporo- measuring BMD at diagnosis in patients with sis (age, race, sex, menopausal state, and coeliac disease because they will already have parity) do not apply to the same extent to ster- oid induced bone loss. In fact, one study women, if the diagnosis is made earlier the suggested that young people on steroids lose BMD should be measured at the menopause. It bone more rapidly than older patients, and is debateable whether a single measurement at sively with age, this might lead to treatment of Box 2—Summary strategy for prevention and treatment of
most very elderly patients. To ration the treat- osteoporosis in inﬂammatory bowel disease
the Z score below −1. For those on steroids a T + Adequate dietary calcium; add calcium tablets if necessary to score below −1.5 has been recommended as a ensure daily intake of 1500 mg ***
+ Exercise ***
+ No smoking **
+ No alcohol excess **
If osteoporosis is found (i.e., the BMD is more than 2.5 SD below the mean for a young adult) in postmenopausal women, they can be offeredtreatment with hormone replacement therapy + Measure BMD at menopause or when ﬁrst seen (HRT), a bisphosphonate, or calcitonin. There are no studies of comparability but all these are + HRT, preferably by skin patch, or ***
+ Bisphosphonate orally, or ***
Vective at reducing fracture risk in postmeno- pausal osteoporosis. The pros and cons will + Calcitonin ***
need to be discussed so patients can make an informed choice. None of these treatments has + Measure BMD in all patients with Crohn’s disease and in those been shown to reduce the fracture rate in with ulcerative colitis who have received systemic steroids patients with coeliac disease or IBD, but there + If osteoporotic†, measure serum testosterone and if low, give is no reason to suspect that such patients would replacement *
beneﬁt less than patients with osteoporosis + If testosterone normal or if BMD does not improve on testosterone oVer bisphosphonate or calcitonin **
+ Give lowest dose for as short as possible Hormone replacement therapy has been shown + Concurrently give 800 units vitamin D daily—for example two to reduce fracture risk in postmenopausal “calcium and vitamin D” or two Calcichew D3 Forte tablets daily women in general46 and those with osteoporotic fracture in particular,47 and to prevent bone + Measure BMD and repeat each year in which steroid treatment loss in patients with IBD.48 It is necessary to treat roughly only eight (95% conﬁdence inter- + If T score < −1.5* oVer bisphosphonate (in addition to vitamin D) val (CI) 3 to 17) postmenopausal women with osteoporotic fractures for one year to prevent one having a further vertebral fracture during that year.47 During HRT the rate of meno- + If osteoporotic† oVer HRT (if postmenopausal), bisphosphonate pausal loss of bone density falls and there may or calcitonin **
even be a small increase in bone density. With- + If already on HRT consider adding bisphosphonate or calcitonin *
drawal of HRT leads to a rise in the rate ofbone loss, but only to the same rate as normal postmenopausal bone loss.49 This randomised + For bisphosphonate and calcitonin measure BMD yearly controlled trial suggests that HRT buys time + If BMD falls >4% per year in two successive years change to for the skeleton, the beneﬁt being proportional to the duration of treatment. However, in a case + If no fall continue drug for at least three years — possibly long controlled study50 no substantial reduction in fracture risk was shown after HRT had been + Restart drug if, on stopping, yearly BMD falls >4% discontinued—even after more than 10 years’ + For HRT check BMD after 10 years and continue HRT if treatment. Maximal beneﬁt will clearly be osteoporosis† persists *
achieved by life-long HRT beginning at themenopause,50 but this will not be acceptable to †Osteoporosis deﬁned as BMD >2.5 SD below mean for young adult. ***, ** and* indicate the level of evidence for the recommendation (see text).
many women for a variety of reasons includingthe return of menstruation and the fear ofbreast cancer. Tibolone, which may be as the menopause is adequate because there is eVective as standard HRT, can be used to avoid considerable variation in the rate and duration menstruation. The risk of breast cancer may be of rapid perimenopausal bone loss. For this reason it would be sensible to repeat the BMD treatment51 or even after only ﬁve years.52 after perhaps two years in those whose BMD Although the overall beneﬁt of HRT, especially does not suggest osteoporosis. Similarly, in with regard to cardiovascular disease, may out- men the BMD should be measured at about 55 weigh the risks, the survival beneﬁt diminishes years of age if they presented at an earlier age.
with longer duration of use, particularly for BMD should be done at any age if there has women at low risk of coronary disease,53 and been a fragility fracture, namely one which is there are few data on the eVects of such long atraumatic or follows a simple fall.
term use which could amount to 30 years. Forthis reason the usual initial aim is 10 years’ this time, or sooner if the patient wishes to stop prematurely, would help in deciding whether or treatment threshold. Osteoporosis as deﬁned as not to continue. It is unlikely that the usual a T score below −2.5 would seem the obvious short term use of HRT at the menopause will threshold. However, as BMD falls progres- Guidelines for Osteoporosis in Coeliac disease and inflammatory bowel disease osteoporotic fracture. If there is doubt about continuing malabsorption, a skin patch prepa- No patient on HRT was included in the stud- ies of these drugs and so it is not knownwhether combined treatment is beneﬁcial.
Until such studies have been done, it would Bisphosphonates are synthetic analogues of seem reasonable to add one of these drugs to inorganic pyrophosphate that inhibit bone HRT or vice versa if an osteoporotic fracture alendronate,44 45 both given with 500 mgcalcium daily, can reduce postmenopausal fractures, although the beneﬁts should not be exaggerated. One study45 suggests it is neces- sary to treat about 14 (95% CI 10 to 16) and osteoporosis to women in coeliac disease and another44 about 33 (95% CI 17 to 1000) post- IBD. Furthermore, there are no conceptual menopausal osteoporotic women with alendro- measurements in devising a strategy for men as vertebral fracture44 45 and 83 (95% CI 43 to for women.60 There are no studies of the eVect of bisphosphonates or calcitonin on either fracture.45 These drugs are well tolerated BMD or fracture prevention in men. However, although nausea, diarrhoea and constipation have been reported. They are poorly absorbed treatments would not be as eVective in older men (e.g., over 55 years old) as in postmeno- some time before the next meal, and antacids pausal women,60 and so, until those studies should be avoided. Malabsorption may impair have been done it would seen reasonable to their eYcacy. Alendronate may cause oesopha- consider a bisphosphonate or calcitonin in men gitis and oesophageal ulceration and has to be taken with 200 ml water immediately after get- especially in those with a fragility fracture. In ting up in the morning and without lying down fact, given the seriousness of fragility fractures drug treatment should be considered at ayounger age in both men and women, acknowl-edging that its eVectiveness is unproved. BMD should be measured in all men with Crohn’s Calcitonin is a naturally occurring hormone disease and those men with ulcerative colitis which also inhibits bone resorption.56 It is usu- who have received steroids at age 55 years (or ally given with 500 mg calcium daily. One later if they present when older) and, if there is study57 of calcitonin given by nasal spray osteoporosis, serum testosterone should be suggested that treating seven (95% CI 4 to 38) measured and testosterone given if low.
women with postmenopausal osteoporosis fortwo years prevents one having a new fracture.
Conﬁrmation of this impressive result is awaited. It is safe and devoid of any serious or All patients requiring systemic steroids should long term side eVects and may also reduce have the lowest dose for as short a time as pos- osteoporotic bone pain. Unfortunately, the sible. There seems to be no advantage in terms nasal spray is not yet generally available and of preservation of BMD from alternate day treatment must be given by intramuscular or regimens. Oral controlled release budesonide subcutaneous injection, thus making it unat- should be considered instead of prednisolone tractive. Furthermore, calcitonin is much more patients.61 There have been no studies looking eight times more expensive than alendronate at BMD on budesonide but theoretically it is and sixteen times more expensive than etidro- less likely to cause osteoporosis and other sys- temic aVects. Deﬂazacort is a newer steroidwhich also may be associated with a lower risk of osteoporosis62 but there are no published bisphosphonates or calcitonin is not known nor It is usual to restrict intervention in patients is it known how reliably non-responders can be on steroids for those who are likely to receive the equivalent of 7.5 mg or more of pred- information is available it is suggested that nisolone for more than six months. It is difficult BMD is measured yearly while on treatment. If in IBD to predict requirements. That depends over two successive years there is deterioration on the frequency of relapse and, particularly in in the BMD (e.g., >4% per year58), treatment Crohn’s disease, whether there is likely to be should be changed to the other drug. If there is long term treatment. It would therefore seem no deterioration then treatment should be con- appropriate to intervene in all patients with tinued for at least three years, and possibly for as long as osteoporosis persists. Currently,experience of bisphosphonate treatment is conﬁned to ﬁve years and it seems to be safe.59 Prevention or treatment of steroid induced If there is deterioration at the yearly BMD bone loss by vitamin D has been the subject of measurement after cessation, the treatment several studies.63–71 Four63–66 of these nine studies appeared to show beneﬁt. However, it is difﬁcult to compare the results and to apply well as showing prevention of spinal and hip them because the investigators used diVerent bone loss, also demonstrated a reduction in ver- vitamin D preparations for diVerent lengths of tebral fractures in the subgroup of postmeno- pausal women. This study suggests that approxi- regimens, some were not randomised control- mately ﬁve post-menopausal women starting on led trials, the method of assessment of bone steroids need to be treated with a bisphospho- density varied, in some the number of patients nate for one year to prevent one having a verte- was small, and the patients had a variety of dif- bral fracture. Thus, a bisphosphonate could be ferent diseases. No reduction in fractures has recommended for those on steroids if vitamin D been demonstrated by any of these studies.
is either ineVective or cannot be tolerated. The Nevertheless, two of the largest randomised use of these drugs in combination for patients controlled trials65 66 did show a signiﬁcant with severe bone disease has been advised.80 reduction in bone loss—one66 used vitamin D3 Although this is logical, the combination has not (cholecalciferol) and the other65 calcitriol. The use of vitamin D is not without risk72 andhypercalcaemia occurred in a quarter of the 6.8.4 Bone mineral density threshold for patients on calcitriol.65 On the basis of these two studies we recommend the routine use of There is no direct evidence on which to base a vitamin D in patients with IBD while they threshold of BMD for giving a bisphosphonate.
receive steroids. Because of the risk of hyper- calcaemia with calcitriol we favour vitamin D2 treatment for a T score below −1.5.
or D3 depending on availability (they areequivalent). In the UK a convenient prepara- 6.8.5 Summary for patients on steroids tion is “calcium and ergocalciferol” (“calcium In summary, for those on steroids, we recom- and vitamin D”). Two tablets daily provide 800 mend 800 units of vitamin D daily for the units of vitamin D (and 200 mg calcium), as duration of steroid therapy. BMD should be measured, and repeated every year in which Rheumatology.43 This treatment seems to be steroids are given if the T score is <0. If the T safe without monitoring. These tablets are like score is >0 the BMD should be re-measured chalk and have to be chewed or crushed before every three to ﬁve years.81 If the T score is less swallowing. If they are not well tolerated two than −1.5 we would oVer a bisphosphonate, tablets of Calcichew D3 Forte (Shire, UK) could be used instead. This also provides 800units of vitamin D (cholecalciferol) but rather 7.0 Conclusion
more calcium (1000 mg). Additional dietary Although these suggested strategies are based calcium would therefore not be advised.
on published evidence as far as possible, they Although the above studies of vitamin D were are of necessity arbitrary to some extent mainly of patients with rheumatology disorders because there are many gaps in our knowledge.
and asthma rather than IBD, we are further An attempt has been made to indicate the areas where therapeutic research would be most use- because one study73 of 1000 units daily of vita- ful. Clearly, alternative strategies might be just min D3 in patients with Crohn’s disease (of as valid, and any strategy will require modiﬁca- whom one third received steroids) prevented tion in the light of new knowledge. In the bone loss. Furthermore, another study74 of 700 meantime it is hoped that these guidelines will units daily of vitamin D3 for three years in form a basis for rational management of two healthy people over 65 years caused a signiﬁ- cant reduction in non-vertebral fractures (ver-tebral fractures were not assessed). Thissuggests that roughly 14 (95% CI 8 to 34) peo-ple over 65 years of age need to be treated for 8.0 Search strategy
Medline was searched back to 1990 using the fracture. Nevertheless, this is indirect evidence subjects osteoporosis and bone density com- and a controlled study of vitamin D in patients with IBD receiving steroids would be appropri- Crohn’s disease, ulcerative colitis, and coeliac disease. All relevant papers were obtained andfurther papers obtained by scrutiny of the ref- Bisphosphonates have also been shown to beeVective at reducing steroid induced bone loss.
9.0 Levels of evidence for
There are ﬁve studies,75–79 all of which were for recommendations
one year and showed beneﬁt. One76 was not a The various recommendations in the summary randomised controlled trial. Two77 79 were on strategies are graded ***, ** and * according to patients embarking on steroids, and three75 76 78 the level of evidence: ***Evidence based upon were on patients on long term steroids, one of well designed randomised controlled trials which comprised patients with established osteoporosis.78 One study used the bisphosphon- (1) prospective non-randomised controlled ate APD ((3-amino-1-hydroxypropylidene)-1, 1-bisphosphonate)75 and the other four used cyclical etidronate. The largest study79 (141 (3) retrospective and cross sectional studies patients who had recently started steroids), as Guidelines for Osteoporosis in Coeliac disease and inflammatory bowel disease 17 Mazure R, Vasquez H, Gonzalez D, et al. Bone mineral aVection in asymptomatic adult patients with celiac disease. Am J Gastroenterol 1994;89:2130–4.
18 Valdimarsson T, Toss G, Ross I, et al. Bone mineral density in coeliac disease. Scand J Gastroenterol 1994;29:457–61.
19 McFarlane XA, Bhalla AK, Reeves DE, et al. Osteoporosis in treated adult coeliac disease. Gut 1995;36:710–14.
20 Walters JRF, Banks LM, Butcher GP, et al. Detection of low bone mineral density by dual energy absorptiometry inunsuspected suboptimally treated coeliac disease. Gut 10.0 Process of guideline formulation
21 Pistorius LR, Sweiden WH, Purdie DW, et al. Coeliac The guidelines were ﬁrst drafted by Dr Eleanor disease and bone mineral density in adult female patients.
M Scott (Registrar in Endocrinology at St Gut 1995;37:639–42.
22 Corazza GR, Sario AD, Cecchetti L, et al. Bone mass and James’s University Hospital, Leeds, UK) and Dr metabolism in patients with celiac disease. Gastroenterology Brian B Scott (Consultant Gastroenterologist at 1995;109:122–8.
23 Valdimarsson T, Lofman O, Toss G, et al. Reversal of osteo- Lincoln County Hospital, UK). These were then penia with diet in adult coeliac disease. Gut 1996;38:322–
sent to Dr Ian Gaywood (Consultant Rheuma- 24 Mora S, Weber G, Barera G, et al. EVect of gluten-free diet tologist at Lincoln County Hospital) for com- on bone mineral content in growing patients with celiac ments and suggestions. The guidelines were then disease. Am J Clin Nutr 1993;57:224–8.
sent to the European Journal of Gastroenterology 25 McFarlane XA, Dixey J, Dumfrey J, et al. Increased risk of bone fractures in coeliac disease [abstract]. Gastroenterology and Hepatology where they were modiﬁed consid- erably after detailed review by four experts 26 Walters JRF. Bone mineral density in coeliac disease. Gut 1994;35:150–1.
including Dr Juliet Compston (Cambridge, UK) 27 Farthing MJ, Rees LJ, Edwards CRW, et al. Male gonadal and Professor Richard Eastell (SheYeld, UK).
function in coeliac disease. 2. Sex hormones. Gut 1983;24:
They were then published (Scott EM, Scott BB.
28 Finkelstein JS, Klibanski A, Neer RM, et al. Osteoporosis in A strategy for osteoporosis in gastroenterology.
men with idiopathic hypogonadotropic hypogonadism.
Ann Intern Med 1987;106:354–61.
Eur J Gastroenterol Hepatol 1998;10:689–98).
29 Compston JE, Judd D, Crawley EO, et al. Osteoporosis in The guidelines were then redrafted in a form patients with inﬂammatory bowel disease. Gut 1987;28:
suitable for the British Society of Gastroenterol- 30 Motley RJ, Crawley EO, Evans C, et al. Increased rate of ogy and reviewed by all members of the Clinical spinal trabecular bone loss in patients with inﬂammatory
bowel disease. Gut 1988;29:1332–6.
Services & Standards Committee of the British 31 Clements D, Motley RJ, Evans WD, et al. Longitudinal Society of Gastroenterology. The guidelines study of cortical bone loss in patients with inﬂammatory were then again redrafted taking into account bowel disease. Scand J Gastroenterol 1992;27:1055–60.
32 Silvennoinen JA, Karttunen TJ, Niemela SE, et al. A controlled study of bone mineral density with inﬂamma-
tory bowel disease. Gut 1995;37:71–6.
33 BischoV SC, Herrman A, Evers J, et al. Bone density and bone metabolism in inﬂammatory bowel disorders (IBD).
A clinical study in 90 patients [abstract]. Gastroenterology1996;110:A865.
34 Lisciandrano D, Ranzi T, Ulivieri FM, et al. Bone mineral density in patients with ulcerative colitis [abstract]. Gastro- 1 Melton LJ, Chrischilles EA, Cooper C, et al. How many women have osteoporosis? J Bone Miner Res 1992;9:1005–
35 Jahnsen J, Falch JA, Aadland E, et al. Bone mineral density is reduced in patients with Crohn’s disease but not in 2 Department of Health. Report of the advisory group on patients with ulcerative colitis: a population based study.
osteoporosis. London: HMSO, 1994.
3 WHO Study Group on Assessment of Fracture Risk and its 36 Bjarnason I, Macpherson A, MacKintosh C, et al. Reduced Application to Screening for Post Menopausal Osteoporo- bone density in patients with inﬂammatory bowel disease.
sis. Assessment of fracture risk and its application to screening Gut 1997;40:228–33.
for post menopausal osteoporosis: report of a WHO study group.
37 Farthing MJG, Dawson AM. Impaired semen quality in (WHO technical series 843.) Geneva: WHO, 1994.
Crohn’s disease — drugs, ill health or undernutrition? 4 Melton LJ, Atkinson EJ, O’Fallon WM, et al. Long-term Scand J Gastroenterol 1983;18:57–60.
fracture risk prediction with bone mineral measurements 38 Schaison G, Durand F, Mowszowicz I. EVect of glucocorti- coids on plasma testosterone in men. Acta Endocrinol 1991;6(suppl 1):S136.
5 Cummings SR, Black DM, Nevitt MC, et al. Bone density at 39 MacAdams MR, White RH, Chipps BE. Reduction in various sites for prediction of hip fractures. Lancet serum testosterone levels during chronic glucocorticoid 1993;341:72–5.
therapy. Ann Intern Med 1968;104:648–51.
6 Porter RW, Miller CG, Grainger D, et al. Prediction of hip 40 Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone fracture in elderly women: a prospective study. BMJ 1990; remodelling — emerging insights into the pathophysiology 301:638–41.
of osteoporosis. N Engl J Med 1995;332:305–11.
7 Lotz JC, Gerhart TN, Hayes WC. Mechanical properties of 41 Tragone A, Mercuriali B, Vignola ML, et al. Bone mineral trabecular bone from the proximal femur: a quantitative density and serum interleukin-6 (IL-6) concentration in CT study. J Comput Assist Tomogr 1990;14:107–14.
patients with Crohn’s disease [abstract]. Gastroenterology 8 Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of 42 Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: osteoporotic fractures. BMJ 1996;312:1254–9.
pathogenesis and management. Ann Intern Med 1990;112:
9 Anonymous. Screening for osteoporosis to prevent fractures: bul- letin on the eVectiveness of health services intervention for deci- 43 American College of Rheumatology Task Force on Osteo- sion makers. Vol 1. London School of Public Health,University of Leeds, Centre for Health Economics, Univer- porosis Guidelines. Recommendations for the prevention sity of York, Research Unit of the Royal College of and treatment of glucocorticoid-induced osteoporosis.
Physicians, Department of Health, 1992.
Arthritis Rheum 1996;39:1791–801.
10 Sheldon TA, RaZe A, Watt I. Department of Health shoots 44 Liberman UA, Weiss SR, Broll J, et al. The eVect of oral itself in the hip. BMJ 1996;312:296–8.
alendronate on bone mineral density and the incidence of 11 Compston JE, Cooper C, Kanis JA. Bone densitometry in fractures in postmenopausal osteoporosis. N Engl J Med clinical practice. BMJ 1995;310:1507–10.
12 McCloskey EV, Murray SA, Miller C, et al. Broadband 45 Black DM, Cummings SR, Karpf DB, et al. Randomised ultrasound attenuation in the os calcis: relationship to bone trial of eVect of alendronate on risk of fracture in women mineral at other skeletal sites. Clin Sci 1990;78:227–33.
with existing vertebral fractures. Lancet 1996;348:1535–41.
13 McCloskey EV, Murray SA, Charlesworth D, et al.
46 Kiel DP, Felson DT, Anderson JJ, et al. Hip fracture and the Assessment of broadband ultrasound attenuation in the os use of estrogens in postmenopausal women — The Fram- calcis in vitro. Clin Sci 1990;78:221–5.
ingham study. N Engl J Med 1987;317:1169–74.
14 Caraceni MP, Molteni N, Bardella MT, et al. Bone and min- 47 Lufkin EG, Wahner HW, O’Fallon WM, et al. Treatment of eral metabolism in adult celiac disease. Am J Gastroenterol postmenopausal osteoporosis with transdermal estrogen.
Ann Intern Med 1992;117:1–9.
15 Molteni N, Caraceni MP, Bardella MT, et al. Bone mineral 48 Clements D, Compston JE, Evans WD, et al. Hormone density in adult celiac patients and the eVect of gluten-free replacement therapy prevents bone loss in patients with diet from childhood. Am J Gastroenterol 1990;85:51–3.
inﬂammatory bowel disease. Gut 1993;34:1543–60.
16 Bode S, Hassager C, Gudmand-Hoyer E, et al. Body 49 Christiansen C, Christiansen MS, Transbol I. Bone mass in composition and calcium metabolism in adult treated coe- postmenopausal women after withdrawal of oestrogen/ liac disease. Gut 1991;32:1342–5.
gestagen therapy. Lancet 1981;i:459–61.
50 Cauley JA, Seeley DG, Ensrud K, et al. Estrogen 67 Rickers H, Deding A, Christiansen C, et al. Corticosteroid- replacement therapy and fractures in older women. Ann induced osteopenia and vitamin D metabolism: eVect of Intern Med 1995;122:9–16.
vitamin D2, calcium phosphate and sodium ﬂuoride 51 Steinberg KK, Smith SJ, Thacker SB, et al. Breast cancer administration. Clin Endocrinol 1982;16:409–15.
risk and duration of estrogen use: the role of study design in 68 Braun JJ, Birkenhager-Frenkel DH, Rietveld JR, et al. Inﬂu- meta-analysis. Epidemiology 1994;5:415–21.
ence of 1 -(OH)D3 administration of bone and bone min- 52 Colditz GA, Hankinson SE, Hunter DJ, et al. The use of eral metabolism in patients on chronic glucocorticoid estrogens and progestins and the risk of breast cancer in treatment: a double blind controlled study. Clin Endocrinol postmenopausal women. N Engl J Med 1995;332:1589–93.
53 Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopau- sal hormone therapy and mortality. N Engl J Med 69 Dykman TR, Haralson KM, Gluck OS, et al. EVect of oral 1997;336:1769–75.
1,25-dihydroxyvitamin D and calcium on glucocorticoid- 54 Storm T, Thomsborg G, Steinche T, et al. EVect of induced osteopenia in patients with rheumatic diseases.
intermittent cyclical etidronate therapy on bone mass and Arthritis Rheum 1984;27:1336–43.
fracture rate in women with postmenopausal osteoporosis.
70 Bijlsma JWJ, Raymakers JA, Mosch C, et al. EVects of oral N Engl J Med 1990;322:1265–71.
calcium and vitamin D on glucocorticoid osteopenia. Clin 55 Watts NB, Harris ST, Genant HK, et al. Intermittent cycli- Exp Rheumatol 1988;6:113–19.
cal etidronate treatment of postmenopausal osteoporosis.
71 Adachi JD, Bensen WG, Bianchi F, et al. Vitamin D and cal- N Engl J Med 1990;323:73–9.
56 Reginster JY. Calcitonin for prevention and treatment of osteoporosis: a 3 year follow-up. J Rheumatol 1996;23:995–
osteoporosis. Am J Med 1993;95:44–75.
57 Overgaard K, Hansen MA, Jensen SB, et al. EVect of salca- 72 Marriott BM. Vitamin D supplementation: a word of tonin given intranasally on bone mass and fracture rates in caution. Ann Intern Med 1997;127:231–3.
established osteoporosis: a dose response study. BMJ 73 Vogelsang H, Ferenci P, Resch H, et al. Prevention of bone 1992;305:556–61.
mineral loss in patients with Crohn’s disease by long-term 58 Eastell R. Management of glucocorticoid-induced osteo- oral vitamin D supplementation. Eur J Gastroenterol Hepa- porosis. J Intern Med 1995;237:439–47.
59 Storm T, Kollerup G, Thomsborg G, et al. Five years of tol 1995;7:609–14.
clinical experience with intermittent cyclical etidronate for 74 Dawson-Hughes B, Harris S, Krall EA, et al. EVect of postmenopausal osteoporosis. J Rheumatol 1996;23:1560–
calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 60 Orwoll ES, Klein RF. Osteoporosis in men. Endocr Rev 1997;337:670–6.
75 Reid IR, King AR, Alexander CJ, et al. Prevention of steroid 61 Greenberg GR, Feagan BC, Martin F, et al. Oral budesonide as maintenance treatment for Crohn’s disease: A placebo- controlled, dose-ranging study. Gastroenterology 1996;110:
76 Adachi JD, Cranney A, Goldsmith CL, et al. Intermittent 62 Messina OD, Barreira JC, Zanchetta JR, et al. EVect of low cyclic therapy with etidronate in the prevention of doses of deﬂazacort vs prednisolone on bone mineral con- corticosteroid-induced bone loss. J Rheumatol 1994;21:
tent in premenopausal arthritis. J Rheumatol 1992;19:
77 Mulder H, Struys A. Intermittent cyclical etidronate in the 63 Hahn TJ, Halstead LR, Teitelbaum SL, et al. Altered prevention of corticosteroid-induced bone loss. Br J Rheu- mineral metabolism in glucocorticoid-induced osteopenia: matol 1994;33:348–50.
eVect of 25-hydroxyvitamin D administration. J Clin Invest 78 Struys A, Snelder AA, Mulder H. Cyclical etidronate 1979;64:655–65.
reverses bone loss of the spine and proximal femur in 64 DiMunno O, Boghe F, Favini P, et al. Prevention of patients with established corticosteroid-induced osteo- glucocorticoid osteopenia: eVect of oral 25-hydroxyvitamin D and calcium. Clin Rheumatol 1989;8:202–7.
porosis. Am J Med 1995;99:235–42.
65 Sambrook P, Birmingham J, Kelly P, et al. Prevention of 79 Adachi JD, Bensen WG, Brown J, et al. Intermittent etidron- corticosteroid osteoporosis - a comparison of calcium, cal- ate therapy to prevent corticosteroid-induced osteoporosis.
citriol and calcitonin. N Engl J Med 1993;328:1747–52.
N Engl J Med 1997;337:382–7.
66 Buckley LM, Leib ES, Cartularo KS, et al. Calcium and 80 Reid IR. Preventing glucocorticoid-induced osteoporosis. N vitamin D3 supplementation prevents bone loss in the Engl J Med 1997;337:420–1.
spine secondary to low-dose corticosteroids in patients 81 Eastell R, Reid DM, Compston, J, et al. A UK consensus with rheumatoid arthritis. Ann Intern Med 1996;125:961–
group of management of cortico-induced osteoporosis: an update. J Intern Med 1998;244:271–92.
Andria innocenza bongiorno ha conseguito la laurea in scienze biologiche presso l’università degli studi di pavia nell’anno accademico 2004/2005
Curriculum vitae Andria Innocenza Bongiorno Andria Innocenza Bongiorno Nata ad Alessandria il 20 ottobre 1980 Cellulare: 334 9010 511 e-mail: website:Andria Innocenza Bongiorno ha conseguito la laurea in Scienze Biologiche presso l’Università degli Studi di Pavia nell’anno accademico 2004/2005; argomento tesi di laurea : “ Disfunzione Mitocondriale nel morbo di Crohn: pos