Abstract
Background
Inhaled corticosteroids form the main therapy for asthma, but there is increasing concern about the potential systematic effects of long‐term inhaled corticosteroids including their effect on bone metabolism and bone loss.
Objectives
To determine the effect of inhaled corticosteroids use on biochemical markers of bone turnover, bone mineral density and the development of fractures.
Search methods
We searched the Cochrane Airways Group trials register, electronic reference databases, UK National Research Register, bibliographies of included studies, and contacted pharmaceutical companies.
Selection criteria
Randomised trials of the effect of inhaled steroid versus placebo on markers of bone function and metabolism, in adults with asthma or mild COPD.
Data collection and analysis
Trial quality was assessed and data extracted from the papers included (2 reviewers per paper) and from additional data supplied by the authors.
Main results
Of 438 references found, seven met the inclusion criteria. Three studies were in healthy subjects asthma or COPD. The patients were generally less than 60 years old and the male:female ratio was 2:1. There was no evidence of increased risk of loss of bone mineral density (BMD) or fractures. There was no significant change in osteocalcin at conventional doses of inhaled corticosteroids (Standardised Mean Difference [SMD] ‐0.34 (95% Confidence Interval [CI] ‐0.72, 0.04), although a statistically significant change was seen in those studies using experimental doses of inhaled steroid in excess of the doses recommended by the British Thoracic Society SMD 0.97 (95% CI ‐1.61, ‐0.34). A statistically significant change in parathyroid hormone seen in one small short trial (n=10, 6 weeks) may have been due to the trial design and outcome measurements used.
Authors' conclusions
In patients with asthma or mild COPD, there is no evidence of an effect of inhaled corticosteroid at conventional doses given for two or three years on BMD or vertebral fracture. Higher doses were associated with biochemical markers of increased bone turnover, but data on BMD and fractures at these doses are not available. There is a need for further, even longer term prospective studies of conventional and high doses of inhaled corticosteroids.
Plain language summary
Inhaled corticosteroid effects on bone metabolism in asthma and mild chronic obstructive pulmonary disease
Usual doses of corticosteroids for two or three years for asthma does not weaken bones in younger patients, although long term outcomes and after high doses need more research.
Background
Inhaled corticosteroids form the main therapy for asthma, but there is increasing concern about the potential systematic effects of long term inhaled corticosteroids including: bone loss, adrenal suppression, skin thinning, increased cataract formation, decreased linear growth in children, metabolic changes and behavioural abnormalities (Hanania 1995).
There is evidence that inhaled steroids affect bone metabolism (Agertoft 1994), reduces osteocalcin concentrations in health volunteers (Teelucksingh 1991) and reduce lumbar spine density (Anderson 1994). Evidence of the potential risk of bone fractures in patients receiving long‐term inhaled steroid therapy (Toogood 1995) could be greater than is suggested by the loss in bone mineral density (Luengo 1991).
Disturbances of bone metabolism are important because of their potential to cause fractures, but fractures are infrequent, requiring extended periods of follow up and long study periods. For this reason biochemical markers of bone metabolism have often been used as surrogate measurements of effects on the bones. Osteoporosis results from an imbalance between bone resorption (measured by, for example, parathyroid hormone and urinary hydroxyproline) and bone formation (measured by, for example, alkaline phosphatase and osteocalcin), with a relative excess of bone resorption causing bone loss in age related osteoporosis. The effect of corticosteroids on bone is primarily to reduce bone formation by a negative effect on osteoblastic function and life span. This is reflected by reductions in markers of bone formation, particularly in osteocalcin concentrations.
Several publications now confirm the validity of biochemical markers in predicting changes in bone turnover (Garnero 1998, Miller 1999). The bone turnover value of biochemical markers partly reflects the strong correlation with bone mineral density but evidence also exists for an effect independent and additive to bone density measurements. The best validated biochemical markers of bone formation include serum alkaline phosphatase (both total and bone specific), osteocalcin and carboxyterminal propeptide of type 1 procollagen (PICP). Whilst the best validated resorption markers encompass urinary pyridinoline cross links of type I collagen, hydroxyproline, C‐terminal and N‐terminal telopeptides of collagen. Although anti resorptive therapy reduces bone turnover, at present it is not certain whether biochemical markers are clinically useful for individual patients (Riggs 2000).
This review was planned as a review of inhaled corticosteroids in asthma supported by data from studies in healthy people. Since then, three large 3‐year studies of inhaled corticosteroids in COPD have been published. In one of these (EUROSCOP 1999), the patients had mild disease (FEV1 73% predicted) and were quite young (mean 52 years). The patients in the other two (Burge 2000b, Wise 2000b) were older (mean 56‐65 years) and with more severe airways obstruction (FEV1 50 ‐ 65% predicted). For this review, we have included just EUROSCOP 1999, the other trials will be considered in a revised version of this review.
Objectives
To determine whether use of inhaled corticosteroids has a harmful effect on bone, in terms of development of fractures, a reduction in bone mineral density (BMD), or changes in specified biochemical markers. A secondary objective was to explore the potential for biochemical markers to predict patients at increased risk of osteoporosis and fractures.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials
Types of participants
Adults with or without a clinical diagnosis of asthma or chronic obstructive pulmonary disease (COPD).
Types of interventions
Randomisation to an inhaled corticosteroid or matching placebo.
Types of outcome measures
Osteoporosis as suggested by:
Bone fracture (by type) Bone Mineral Density Bone Metabolism measures: total alkaline phosphatase bone‐specific alkaline phosphatase serum osteocalcin amino terminal propeptide of type I procollagen (PINP) carboxyterminal propeptide of type 1 procollagen (PICP) urinary hydroxyproline/creatinine urinary calcium:creatine ratio urinary galactosyl hydroxylysine pyridinium (cross‐links) pyridinoline (PYD) deoxypyridinoline (DPD) N‐terminal cross‐linked telopeptide (NTX) C‐terminal cross‐linked telopeptide (CTX) type I collagen C‐telopeptide (ICTP) tartrate resistant acid phosphatase (TRAP) plasma parathyroid hormone
Search methods for identification of studies
An advanced search was carried out on the following databases: MEDLINE, EMBASE, CINAHL, SCIENCE CITATION INDEX (BIDS ISI) and the COCHRANE TRIALS REGISTER (CCTR).
The studies were identified using the following search strategy:
1. STEROID$.tw. 2. CORTICOSTEROID$.tw. 3. CORTICO‐STEROID$.tw. 4. (BECLOMETHASONE or BECONASE or BECLOVENT or VANCENASE or VANCERIL OR AEROBEC or BECLAZONE or BECOTIDE or BECLOFORTE or BUDESONIDE or PULMICORT or RHINOCORT or FLUTICASONE or FLOVENT or FLONASE or CUTIVATE or FLIXOTIDE or FLIXONASWE or QVAR or ZONIVENT or FILAIR OR ASMABEC or BECODISK$).tw. 5. 1OR 2 OR 3 OR 4 6. INHAL$.tw. 7. 5 AND 6 8. (OSTEO$ or BONE$ or FRACTURE$ or BMD or CALCITONIN or CREATININE or CREATINE or CALCIUM or OSTEOCALCIN or HYDROXYPROLINE or PYRIDINIUM or PYRIDINOLINE or DEOXYPYRIDINOLINE or TELOPEPTIDE or (PROPEPTIDE$ OF TYPE I PROCOLLAGEN) OR (ALKALINE PHOSPHATASE) or (ACID PHOSPHATASE) or (GALACTOSYL HYDROXYLYSINE) OR (PARATHYROID HORMONE$)).tw. 9. 7 AND 8 10. LIMIT TO HUMAN
ALL TIME PERIODS UP To 1st November 1999 CONSIDERED initially. The search was updated in July 2001. ALL COUNTRIES AND LANGUAGES CONSIDERED.
Other potential studies were identified by:
Checking the bibliographies of the included studies
Searching key journals (electronically, and by hand)
Contacting key authors to locate other suitable data (unpublished or ongoing)
Contacting pharmaceutical companies (3M, Medeva, AstraZeneca, GlaxoWelcome) for RCT's (unpublished or ongoing)
Data collection and analysis
Data were extracted from the selected studies and entered into Review Manager. Trials were combined using the Review Manager software. For continuous variables, the results of the individual studies were calculated as fixed effects weighted mean difference (WMD) or standardised mean difference (SMD) and a 95% confidence interval (CI) was calculated for each study. The impact of different dosing regimes was assessed using subgroup analysis. Where two outcomes have been assessed in different units (e.g. nmol/L and mcg/L) these were combined using a SMD. For dichotomous variables (bone fractures), a random effects odds ratio (OR) with 95% confidence intervals (95% CI) was calculated for individual studies. Sub‐group analyses was planned categorising the participants into healthy subjects or those with asthma or chronic obstructive pulmonary disease. An additional analysis was planned when the primary trial data showed that some studies had used doses of inhaled corticosteroids above the currently recommended dosing regimes. These doses were termed 'conventional' and 'experimental'.
We were examining inhaled steroids for a harmful rather than a treatment effect. Falls in alkaline phosphatase and osteocalcin were harmful, as were rises in PTH or urinary hydroxyproline.
Results
Description of studies
The search of the Cochrane database provided 226 abstracts, and a further 189 came from running the search in MEDLINE CINAHL, EMBASE and BIDS ISI, giving a total of 415 references, which reduced to 288 on removal of duplicates. Two reviewers independently ascertained the relevance of each title and abstract (MB, KH, AJ, GR). Five relevant abstracts were found in the National Research Register and details of 18 studies were obtained from the pharmaceutical companies. From all of these, 18 full papers were considered in detail, each by 2 reviewers (MB, JF, KH, AJ, MS) and where there was discrepancy between reviewers, this was adjudicated at a team meeting. Seven studies were included in the final analysis. Contact was successfully made with the authors of all except Li 1999 (despite two mailings to the first author, and e‐mail correspondence to the second author), and AstraZeneca were able to provide additional data on the EUROSCOP study. The search was updated in July 2001, leading to the inclusion of the Tattersfield 2001study.
Seven studies met the inclusion criteria. Four (EUROSCOP 1999; Kerstjens 1994; Li 1999; Tattersfield 2001) recruited subjects with "mild" asthma or chronic obstructive pulmonary disease (total 1256 men and 614 women), and three (Hodsman 1991; Leech 1993; Toogood 1991) recruited healthy volunteers (total 41 men and 78 women), although in one of these (Leech 1993), 4 out of 21 subjects had mild asthma. Duration of follow‐up varied from 9 weeks to 3 years. In Hodsman 1991, Toogood 1991 and Leech 1993, follow‐up was up to 12 weeks, and the other studies, 104 weeks or more. In both Hodsman 1991 and Toogood 1991, data were extracted from the first half of the studies, in which inhaled steroid was compared with placebo.
The numbers of participants in the trials ranged from 21 to 1277, with a total of 1989 in the seven studies. EUROSCOP 1999 was the largest trial, and also had the highest average age (52 years); the other 6 studies all had average ages of 40 or below. One study recruited smokers (EUROSCOP 1999), one reported 20% of participants smoked (Tattersfield 2001), two recruited non‐smokers, and in 3 smoking status was not stated.
Only EUROSCOP 1999 and Tattersfield 2001 formally looked for bone fractures as an outcome measure. Li 1999, Tattersfield 2001and EUROSCOP 1999 considered bone mineral density. Data from Hodsman 1991, Toogood 1991 and Leech 1993 has been included for osteocalcin. Li 1999 reported that "Mean serum osteocalcin . . . did not differ significantly at any time point", but the actual figures were not reported, and we were unable to make contact with the first or second authors. Tattersfield 2001 also reported osteocalcin and urinary pyridinoline, but as % change from baseline of geometric mean values of the area under the curve. There was a significant change (p<0.05) in serum osteocalcin in the beclomethasone group, but not budesonide group, compared with the reference group. Kerstjens 1994 reported on procollagen type 1 carboxy terminal propeptide (PICP). Data from Hodsman 1991 on alkaline phosphatase, parathyroid hormone, and urinary hydroxyproline is included.
Beclomethasone, budesonide and fluticasone were the inhaled steroids used. "Conventional doses" were interpreted as those up to the maximum dose of beclomethasone or budesonide (22000 mmcg daily, or fluticasone (11000 mmcg daily recommended in the British Thoracic Society Asthma Guidelines (BTS 1997). Both Hodsman 1991 (budesonide 3.2 mg daily) and Toogood 1991 (budesonide 22.4 mmg daily used doses in excess of this in one arm of their studies, and these are referred to in the comparisons as "experimental dose".
A wide variety of outcome measures were reported; where these corresponded with the outcome measures detailed in our protocol, the figures were included for the meta‐analysis (except where raw data could not be obtained to facilitate this process).
Effect modifiers are detailed in the table of Characteristics of Included Studies and include the list below. We have included sub‐group analyses of; conventional maintenance dose vs high dose inhaled steroids; trials in asthma or COPD patients vs those in healthy volunteers, and those where duration of treatment was greater or less than 3 months. Asthma therapy (exposure to inhaled steroids) Strength of inhaled steroid drug(s) taken Duration of treatment Age Lifestyle data ‐ e.g. height, weight, BMI, smoking, alcohol, exercise Other asthma medication ‐ e.g. oral steroids and bronchodilators Non‐asthma medication ‐ e.g. HRT, calcium, Vitamin D Compliance Delivery system (e.g. clickhaler, turbohaler, spacer device) Duration of follow‐up
In terms of one important risk factor (age), the mean age of the study populations was quite low , in the range 20 ‐ 60 years, with a mean age of 30‐40 in most studies, but in EUROSCOP 1999 the mean age was 52 years. Sex is another important risk factor, summing the number of patients across the studies, the male:female ratio was 2:1.
Risk of bias in included studies
KH and JF independently assessed the methodological quality of the included RCTs using the Cochrane approach to quality assessment of allocation concealment. Trials were scored using the following principles:
Grade A: Adequate concealment. Grade B: Uncertain concealment. Grade C: Clearly Inadequate concealment.
Each study was also assessed for validity on a 0 ‐ 5 scale described by Jadad as follows:
1. Was the study described as randomised ? (1 = yes; 0 = no). 2. Was the study described as double‐blind? (1 = yes; 0= no). 3. Was there a description of withdrawals and drop‐out? ( 1 = yes; 0 = no) 4. Was the method of randomisation well described and appropriate? ( 1 = yes; 0 = no) 5. Was the method of double‐blinding well described and appropriate? ( 1 = yes; 0 = no) 6. Deduct 1 point if methods for randomisation or blinding were inappropriate.
Effects of interventions
Using the Cochrane concealment allocation criteria, there was on A grade trial (Hodsman 1991), four Grade B (EUROSCOP 1999, Kerstjens 1994, Li 1999, Toogood 1991) and two Grade C (Leech 1993, Tattersfield 2001). There was agreement between the two reviewers on all studies. Using the Jadad criteria, three studies were graded 3 ‐ 5 (EUROSCOP 1999, Hodsman 1991, Li 1999) and four were graded 0 ‐ 2 (Kerstjens 1994, Leech 1993, Tattersfield 2001, Toogood 1991). The reviewers disagreed over one paper only, and then by 1 only point.
BONE FRACTURES The two studies that collected fracture data prospectively (EUROSCOP 1999, Tattersfield 2001) showed no significant effect of inhaled steroids on vertebral fractures at conventional therapeutic doses (Peto OR 1.87, 95% CI 0.5, 7.03).
BONE MINERAL DENSITY The pooled results from three studies (EUROSCOP 1999, Li 1999, Tattersfield 2001) showed no significant effect of inhaled steroids in patients with asthma or COPD on bone mineral density measured by Dual Energy Xray Absorptiometry (DEXA) at lumber spine WMD 0.01(95%CI ‐0.08, 0.10), or femoral neck, (EUROSCOP 1999, Tattersfield 2001) WMD 0.61 (95% CI ‐0.34, 1.56).
BIOCHEMICAL MARKERS
1. Osteocalcin Overall, with all data at all doses of inhaled corticosteroids combined in meta‐analyses, there is no significant effect on osteocalcin SMD ‐0.34 (95%CI ‐0.72, 0.04). Li 1999 also considered osteocalcin after two years, but we were unable to obtain details of their results, the paper only reporting a graph. Indications from the graph would give an approximate effect size of ‐0.025, i.e. small effect favouring treatment. When considering the arms of those studies that used 'experimental' doses of inhaled corticosteroid (i.e. those in excess of those recommended in the BTS guidelines), there was a statistically significant lowering (i.e. worsening of osteocalcin SMD 0.97 (95%CI ‐1.61, ‐0.34).
2. Other biochemical markers A statistically significant fall (iDixie in parathyroid hormone WMD ‐10.0 (95%CI ‐17.7, ‐2.3) in favour of the treatment group, and alkaline phosphatase WMD ‐13.0 (95%CI ‐24.0, ‐2.0) in favour of the control group, was seen at conventional dosing only, in the Hodsman 1991 study, but this may be spurious for reasons explored below. The differences did not reach significance when the higher dosage regimens were included. There were no statistically significant results included from among the studies looking at patients with a history of asthma or COPD. These were also the papers with the longer follow‐up. No significant effect was shown on urinary hydroxyproline (p=0.7, WMD ‐0.08, 95%CI ‐0.5, 0.36) or C‐terminal propeptide of type one procollagen WMD 11.6, 95%CI ‐3.1, 26.3).
Discussion
This review has systematically evaluated seven papers which met our entry criteria aimed at determining whether inhaled corticosteroids have a harmful effect on bone in terms of fractures, bone mineral density or specific biochemical markers of bone turnover. At conventional doses of inhaled steroid there appears to be no significant effect on bone metabolism as measured by osteocalcin, bone mineral density, or clinical fracture rate. The effect on alkaline phosphatase and parathyroid hormone seen at conventional doses was not seen at the higher doses. The data for both sets of results comes from the very small study of Hodsman 1991. The alkaline phosphatase analyses is reported to have been "standard" suggesting that it was not bone specific, so would have varied with changes in serum alkaline phosphatase from muscular and hepatic sources, as well as bone. Hodsman 1991 has explained the parathyroid hormone result (which suggested that treatment with conventional doses of inhaled steroid was better than placebo) by pointing out that the recruits were placed on a calcium restricted diet for the study, and that this may have given rise to the slight rise in PTH seen in the control group.
Comparison of serum osteocalcin measured by different immunoassay kits is difficult in the absence of an internationally agreed standard (Swaminathan 1997). Additionally, samples should be collected on ice, stored at ‐70 degrees, and thawed only once. The effect of prolonged freezing on degradation and reliability is unclear. The studies included here used a variety of collecting and storage regimens.
The evidence available for this review suggest that inhaled steroids in currently recommended doses incur little risk of osteoporosis and fractures over the medium term (months to a few years), however there are important qualifications attached to this conclusion. First, asthma is life‐long so the period of these studies is small compared to the potential period of exposure to inhaled corticosteroids. Second, the studies have been carried out in relatively low‐risk patients (mainly under the age of 60 years and predominantly males). In the 3‐year studies in moderate‐severe COPD patients not yet included in this review (Burge 2000b, Wise 2000b), no increase in the risk of bone fractures was reported in either trial, although there was a small fall in bone mineral density in Wise 2000b after three years, but not before. The available trials provided no opportunity to assess the role of routine monitoring of biochemical markers of the bone turnover to identify patients potentially at greater risk of inhaled steroid‐induced fractures or osteoporosis.
Authors' conclusions
Implications for practice.
Treatment with inhaled corticosteroids at conventional doses over two or three years has not shown a significant effect on bone mineral density or increased risk of fracture in younger patients with asthma or mild COPD (i.e. at lower risk of osteoporosis and fractures). At present, current evidence also does not support the use of biochemical markers in the clinical setting.
Implications for research.
There is a need for further long term studies on both conventional and experimental doses of inhaled steroid, using fractures, bone mineral density and biochemical markers as outcomes. Such studies would ideally be prospective but could be supported by retrospective case control and cohort studies, looking particularly for fractures, comparing different steroids in different dosages. The role of biochemical markers in determining bone turnover in the clinical setting is at present uncertain. Our evidence suggests further research in this area may provide useful information in evaluating clinical outcomes and response to therapy. In studies using biochemical markers, careful attention needs to be paid to confounding factors (such as diet or time of specimen collection) and technical details (such as assay used, and specimen storage temperature) when planning further research in this area.
What's new
| Date | Event | Description |
|---|---|---|
| 30 July 2008 | Amended | Converted to new review format. |
History
Protocol first published: Issue 2, 1999 Review first published: Issue 2, 2002
| Date | Event | Description |
|---|---|---|
| 11 October 2001 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
We would like to thank the following authors for corresponding with us about their trials. Included trials:‐ Dr RA Pauwels, Dr AB Hodsman Dr HAM Kerstjens; Dr JA Leech; Dr JH Toogood.
Thank you also to:‐ DR M Roshan of 3M Health Care Limited; Ms Sophie Hadlow of AstraZeneca; Dr Gerry Hagan of GSK; Dr Francis Upchurch of Medeva for helping with the search for "grey literature".
Special thanks to Mrs Anne Powell, Library Services Manager and her team, The Post‐Graduate Library, Morriston Hospital, Swansea NHS Trust, Wales UK, for their help with searches and obtaining papers.
Data and analyses
Comparison 1. inhaled steroid vs placebo ‐ all outcomes.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 vertebral fractures | 2 | 892 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.87 [0.50, 7.03] |
| 2 Osteocalcin | 3 | 141 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.34 [‐0.72, 0.04] |
| 2.1 Parallel studies | 2 | 78 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.73 [‐1.28, ‐0.18] |
| 2.2 Cross‐over study | 1 | 63 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.51, 0.54] |
| 3 Bone mineral density | 3 | 792 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.08, 0.11] |
| 3.1 Change at lumbar spine (% fall) | 3 | 419 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.08, 0.10] |
| 3.2 Change at femoral neck (% fall) | 2 | 373 | Mean Difference (IV, Fixed, 95% CI) | 0.61 [‐0.34, 1.56] |
| 4 alkaline phosphatase IU/L | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐11.0 [‐25.30, 3.30] |
| 5 Parathyroid hormone (ng/l) | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐7.5 [‐15.73, 0.73] |
| 6 urinary hydroxyproline (umol/L GF) | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.08 [‐0.52, 0.36] |
| 7 PICP mcg/L | 1 | 105 | Mean Difference (IV, Fixed, 95% CI) | 11.57 [‐3.11, 26.25] |
1.1. Analysis.
Comparison 1 inhaled steroid vs placebo ‐ all outcomes, Outcome 1 vertebral fractures.
1.2. Analysis.
Comparison 1 inhaled steroid vs placebo ‐ all outcomes, Outcome 2 Osteocalcin.
1.3. Analysis.
Comparison 1 inhaled steroid vs placebo ‐ all outcomes, Outcome 3 Bone mineral density.
1.4. Analysis.
Comparison 1 inhaled steroid vs placebo ‐ all outcomes, Outcome 4 alkaline phosphatase IU/L.
1.5. Analysis.
Comparison 1 inhaled steroid vs placebo ‐ all outcomes, Outcome 5 Parathyroid hormone (ng/l).
1.6. Analysis.
Comparison 1 inhaled steroid vs placebo ‐ all outcomes, Outcome 6 urinary hydroxyproline (umol/L GF).
1.7. Analysis.
Comparison 1 inhaled steroid vs placebo ‐ all outcomes, Outcome 7 PICP mcg/L.
Comparison 2. inhaled steroid vs placebo ‐ Jadad scores 0‐2.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Osteocalcin | 2 | 111 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.19 [‐0.62, 0.25] |
| 1.1 Parallel study | 1 | 48 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.63 [‐1.40, 0.14] |
| 1.2 Cross‐over study | 1 | 63 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.51, 0.54] |
| 2 PICP mcg/L | 1 | 105 | Mean Difference (IV, Fixed, 95% CI) | 11.57 [‐3.11, 26.25] |
| 3 Vertebral fracture | 1 | 239 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 4.41 [0.07, 288.46] |
| 4 Bone Mineral Density | 1 | 444 | Mean Difference (IV, Fixed, 95% CI) | 0.07 [‐0.67, 0.81] |
| 4.1 lumber spine (% fall) | 1 | 220 | Mean Difference (IV, Fixed, 95% CI) | ‐0.25 [‐1.23, 0.73] |
| 4.2 neck of femur (% fall) | 1 | 224 | Mean Difference (IV, Fixed, 95% CI) | 0.5 [‐0.64, 1.64] |
2.1. Analysis.
Comparison 2 inhaled steroid vs placebo ‐ Jadad scores 0‐2, Outcome 1 Osteocalcin.
2.2. Analysis.
Comparison 2 inhaled steroid vs placebo ‐ Jadad scores 0‐2, Outcome 2 PICP mcg/L.
2.3. Analysis.
Comparison 2 inhaled steroid vs placebo ‐ Jadad scores 0‐2, Outcome 3 Vertebral fracture.
2.4. Analysis.
Comparison 2 inhaled steroid vs placebo ‐ Jadad scores 0‐2, Outcome 4 Bone Mineral Density.
Comparison 3. inhaled steroid vs placebo Jadad scores 3‐5.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 osteocalcin | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.44 [‐0.85, ‐0.03] |
| 2 urinary hydroxyproline (umol/L GF) | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.08 [‐0.52, 0.36] |
| 3 parathyroid hormone ng/L | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐7.5 [‐15.73, 0.73] |
| 4 alkaline phosphatase | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐11.0 [‐25.30, 3.30] |
| 5 Bone mineral density | 2 | 348 | Mean Difference (IV, Fixed, 95% CI) | 0.05 [‐0.21, 0.31] |
| 5.1 Change at femoral neck (% fall) | 1 | 149 | Mean Difference (IV, Fixed, 95% CI) | 0.86 [‐0.85, 2.57] |
| 5.2 Change at lumbar spine (% fall) | 2 | 199 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.24, 0.29] |
| 6 Vertebral fracture | 1 | 653 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.70 [0.42, 6.87] |
3.1. Analysis.
Comparison 3 inhaled steroid vs placebo Jadad scores 3‐5, Outcome 1 osteocalcin.
3.2. Analysis.
Comparison 3 inhaled steroid vs placebo Jadad scores 3‐5, Outcome 2 urinary hydroxyproline (umol/L GF).
3.3. Analysis.
Comparison 3 inhaled steroid vs placebo Jadad scores 3‐5, Outcome 3 parathyroid hormone ng/L.
3.4. Analysis.
Comparison 3 inhaled steroid vs placebo Jadad scores 3‐5, Outcome 4 alkaline phosphatase.
3.5. Analysis.
Comparison 3 inhaled steroid vs placebo Jadad scores 3‐5, Outcome 5 Bone mineral density.
3.6. Analysis.
Comparison 3 inhaled steroid vs placebo Jadad scores 3‐5, Outcome 6 Vertebral fracture.
Comparison 4. inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Vertebral fracture | 2 | 892 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.87 [0.50, 7.03] |
| 2 Bone mineral density | 3 | 792 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.08, 0.11] |
| 2.1 Change at lumbar spine (% fall) | 3 | 419 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.08, 0.10] |
| 2.2 Change at femoral neck (% fall) | 2 | 373 | Mean Difference (IV, Fixed, 95% CI) | 0.61 [‐0.34, 1.56] |
| 3 PICP mcg/L | 1 | 105 | Mean Difference (IV, Fixed, 95% CI) | 11.57 [‐3.11, 26.25] |
| 4 Alkaline phosphatase IU/L | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐13.0 [‐24.04, ‐1.96] |
| 5 Parathyroid hormone ng/L | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐10.0 [‐17.67, ‐2.33] |
| 6 urinary hydroxyproline | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 0.04 [‐0.48, 0.56] |
| 7 Osteocalcin | 3 | 111 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.18 [‐0.58, 0.21] |
| 7.1 Parallel studies | 2 | 48 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.45 [‐1.06, 0.16] |
| 7.2 Cross‐over study | 1 | 63 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.51, 0.54] |
4.1. Analysis.
Comparison 4 inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid, Outcome 1 Vertebral fracture.
4.2. Analysis.
Comparison 4 inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid, Outcome 2 Bone mineral density.
4.3. Analysis.
Comparison 4 inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid, Outcome 3 PICP mcg/L.
4.4. Analysis.
Comparison 4 inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid, Outcome 4 Alkaline phosphatase IU/L.
4.5. Analysis.
Comparison 4 inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid, Outcome 5 Parathyroid hormone ng/L.
4.6. Analysis.
Comparison 4 inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid, Outcome 6 urinary hydroxyproline.
4.7. Analysis.
Comparison 4 inhaled steroid vs placebo ‐ Conventional therapeutic dose of steroid, Outcome 7 Osteocalcin.
Comparison 5. inhaled steroid vs placebo ‐ experimental dose of steroid.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Osteocalcin ‐ parallel studies | 2 | 48 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.97 [‐1.61, ‐0.34] |
| 2 Alkaline phosphatase | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐9.0 [‐32.36, 14.36] |
| 3 Parathyroid hormone | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐5.0 [‐15.09, 5.09] |
| 4 Urinary hydroxyproline | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐0.65, 0.25] |
5.1. Analysis.
Comparison 5 inhaled steroid vs placebo ‐ experimental dose of steroid, Outcome 1 Osteocalcin ‐ parallel studies.
5.2. Analysis.
Comparison 5 inhaled steroid vs placebo ‐ experimental dose of steroid, Outcome 2 Alkaline phosphatase.
5.3. Analysis.
Comparison 5 inhaled steroid vs placebo ‐ experimental dose of steroid, Outcome 3 Parathyroid hormone.
5.4. Analysis.
Comparison 5 inhaled steroid vs placebo ‐ experimental dose of steroid, Outcome 4 Urinary hydroxyproline.
Comparison 6. inhaled steroid vs placebo ‐ healthy recruits.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Osteocalcin | 3 | 141 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.32 [‐0.70, 0.06] |
| 1.1 Parallel studies | 2 | 78 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.68 [‐1.23, ‐0.13] |
| 1.2 Cross‐over studies | 1 | 63 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.51, 0.54] |
| 2 Urinary hydroxyproline (umol/L GF) | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.08 [‐0.52, 0.36] |
| 3 Parathyroid hormone (ng/L) | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐7.5 [‐15.73, 0.73] |
| 4 Alkaline phosphatase | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐11.0 [‐25.30, 3.30] |
6.1. Analysis.
Comparison 6 inhaled steroid vs placebo ‐ healthy recruits, Outcome 1 Osteocalcin.
6.2. Analysis.
Comparison 6 inhaled steroid vs placebo ‐ healthy recruits, Outcome 2 Urinary hydroxyproline (umol/L GF).
6.3. Analysis.
Comparison 6 inhaled steroid vs placebo ‐ healthy recruits, Outcome 3 Parathyroid hormone (ng/L).
6.4. Analysis.
Comparison 6 inhaled steroid vs placebo ‐ healthy recruits, Outcome 4 Alkaline phosphatase.
Comparison 7. inhaled steroid vs placebo ‐ asthmatic or COPD recruits.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Vertebral fracture | 2 | 892 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.87 [0.50, 7.03] |
| 2 Bone MIneral Density | 3 | 792 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.08, 0.11] |
| 2.1 Change at lumbar spine (% fall) | 3 | 419 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.08, 0.10] |
| 2.2 Change at femoral neck (% fall) | 2 | 373 | Mean Difference (IV, Fixed, 95% CI) | 0.61 [‐0.34, 1.56] |
| 3 PICP (mcg/L) | 0 | 0 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
7.1. Analysis.
Comparison 7 inhaled steroid vs placebo ‐ asthmatic or COPD recruits, Outcome 1 Vertebral fracture.
7.2. Analysis.
Comparison 7 inhaled steroid vs placebo ‐ asthmatic or COPD recruits, Outcome 2 Bone MIneral Density.
Comparison 8. inhaled steroid vs placebo ‐ treatment & follow‐up </= 12 weeks.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Osteocalcin | 3 | 141 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.32 [‐0.70, 0.06] |
| 1.1 Parallel studies | 2 | 78 | Std. Mean Difference (IV, Fixed, 95% CI) | ‐0.68 [‐1.23, ‐0.13] |
| 1.2 Cross‐over studies | 1 | 63 | Std. Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.51, 0.54] |
| 2 urinary hydroxyproline umol/L GF | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.08 [‐0.52, 0.36] |
| 3 Parathyroid ng/L | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐7.5 [‐15.73, 0.73] |
| 4 Alkaline Phosphatase IU/L | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐11.0 [‐25.30, 3.30] |
8.1. Analysis.
Comparison 8 inhaled steroid vs placebo ‐ treatment & follow‐up </= 12 weeks, Outcome 1 Osteocalcin.
8.2. Analysis.
Comparison 8 inhaled steroid vs placebo ‐ treatment & follow‐up </= 12 weeks, Outcome 2 urinary hydroxyproline umol/L GF.
8.3. Analysis.
Comparison 8 inhaled steroid vs placebo ‐ treatment & follow‐up </= 12 weeks, Outcome 3 Parathyroid ng/L.
8.4. Analysis.
Comparison 8 inhaled steroid vs placebo ‐ treatment & follow‐up </= 12 weeks, Outcome 4 Alkaline Phosphatase IU/L.
Comparison 9. inhaled steroid vs placebo ‐ treatment & follow‐up > 12 weeks.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Vertebral fractures | 2 | 892 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.87 [0.50, 7.03] |
| 2 Bone mineral density | 3 | 792 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.08, 0.11] |
| 2.1 Change at femoral neck (% fall) | 2 | 373 | Mean Difference (IV, Fixed, 95% CI) | 0.61 [‐0.34, 1.56] |
| 2.2 Change at lumber spine (% fall) | 3 | 419 | Mean Difference (IV, Fixed, 95% CI) | 0.01 [‐0.08, 0.10] |
| 3 PICP mcg/l | 1 | 105 | Mean Difference (IV, Fixed, 95% CI) | 11.57 [‐3.11, 26.25] |
9.1. Analysis.
Comparison 9 inhaled steroid vs placebo ‐ treatment & follow‐up > 12 weeks, Outcome 1 Vertebral fractures.
9.2. Analysis.
Comparison 9 inhaled steroid vs placebo ‐ treatment & follow‐up > 12 weeks, Outcome 2 Bone mineral density.
9.3. Analysis.
Comparison 9 inhaled steroid vs placebo ‐ treatment & follow‐up > 12 weeks, Outcome 3 PICP mcg/l.
Comparison 10. inhaled steroid vs placebo ‐ Cochrane Concealment A.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Osteocalcin mcg/l | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.45 [‐0.86, ‐0.04] |
| 2 urinary hydroxyproline (umol/L GF) | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐0.08 [‐0.52, 0.36] |
| 3 Parathyroid hormone ng/l | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐7.5 [‐15.73, 0.73] |
| 4 Alkaline phosphatase IU/L | 1 | 30 | Mean Difference (IV, Fixed, 95% CI) | ‐11.0 [‐25.30, 3.30] |
10.1. Analysis.
Comparison 10 inhaled steroid vs placebo ‐ Cochrane Concealment A, Outcome 1 Osteocalcin mcg/l.
10.2. Analysis.
Comparison 10 inhaled steroid vs placebo ‐ Cochrane Concealment A, Outcome 2 urinary hydroxyproline (umol/L GF).
10.3. Analysis.
Comparison 10 inhaled steroid vs placebo ‐ Cochrane Concealment A, Outcome 3 Parathyroid hormone ng/l.
10.4. Analysis.
Comparison 10 inhaled steroid vs placebo ‐ Cochrane Concealment A, Outcome 4 Alkaline phosphatase IU/L.
Comparison 11. inhaled steroid vs placebo ‐ Cochrane Concealment B.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Vertebral fractures | 1 | 653 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.70 [0.42, 6.87] |
| 2 Bone mineral density | 2 | 348 | Mean Difference (IV, Fixed, 95% CI) | 0.05 [‐0.21, 0.31] |
| 2.1 Change at femoral neck (% fall) | 1 | 149 | Mean Difference (IV, Fixed, 95% CI) | 0.86 [‐0.85, 2.57] |
| 2.2 Change at lumbar spine (% fall) | 2 | 199 | Mean Difference (IV, Fixed, 95% CI) | 0.03 [‐0.24, 0.29] |
| 3 PICP mcg/L | 1 | 105 | Mean Difference (IV, Fixed, 95% CI) | 11.57 [‐3.11, 26.25] |
| 4 Osteocalcin nmol/l | 1 | 48 | Mean Difference (IV, Fixed, 95% CI) | ‐0.15 [‐0.27, ‐0.03] |
11.1. Analysis.
Comparison 11 inhaled steroid vs placebo ‐ Cochrane Concealment B, Outcome 1 Vertebral fractures.
11.2. Analysis.
Comparison 11 inhaled steroid vs placebo ‐ Cochrane Concealment B, Outcome 2 Bone mineral density.
11.3. Analysis.
Comparison 11 inhaled steroid vs placebo ‐ Cochrane Concealment B, Outcome 3 PICP mcg/L.
11.4. Analysis.
Comparison 11 inhaled steroid vs placebo ‐ Cochrane Concealment B, Outcome 4 Osteocalcin nmol/l.
Comparison 12. inhaled steroid vs placebo ‐ Cochrane Concealment C.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Osteocalcin mcg/l, cross‐over | 1 | 63 | Mean Difference (IV, Fixed, 95% CI) | 0.02 [‐0.61, 0.65] |
| 2 Vertebral fracture | 1 | 239 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 4.41 [0.07, 288.46] |
| 3 Bone mineral density | 1 | 444 | Mean Difference (IV, Fixed, 95% CI) | 0.07 [‐0.67, 0.81] |
| 3.1 lumbar spine (% fall) | 1 | 220 | Mean Difference (IV, Fixed, 95% CI) | ‐0.25 [‐1.23, 0.73] |
| 3.2 Neck of femur (% fall) | 1 | 224 | Mean Difference (IV, Fixed, 95% CI) | 0.5 [‐0.64, 1.64] |
12.1. Analysis.
Comparison 12 inhaled steroid vs placebo ‐ Cochrane Concealment C, Outcome 1 Osteocalcin mcg/l, cross‐over.
12.2. Analysis.
Comparison 12 inhaled steroid vs placebo ‐ Cochrane Concealment C, Outcome 2 Vertebral fracture.
12.3. Analysis.
Comparison 12 inhaled steroid vs placebo ‐ Cochrane Concealment C, Outcome 3 Bone mineral density.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
EUROSCOP 1999.
| Methods | randomised, double blind duration: 3 years follow‐up: 71% | |
| Participants | "mild COPD patients who continue to smoke" male / female: 932 / 345 Av age: 52.4yr +/‐ 7.7 (placebo) 52.5 +/‐ 7.5 (budesonide) | |
| Interventions | budesonide 400mcg or placebo twice daily. | |
| Outcomes | after 104 weeks: vertebral fracture; bone mineral density (BMD); adverse effects; spirometry; | |
| Notes | Jadad score 3. smoking education and inhaler compliance prior to randomisation. BMD data to be published soon. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Hodsman 1991.
| Methods | "random allocation" double blind double dummy Duration: 6 weeks Follow up: 100% | |
| Participants | healthy subjects male / female: 17 / 33 Av Age: 33, SD 9 Smoking status not stated. | |
| Interventions | 5 groups, each n=10; oral prednisolone 10mg or 40mg daily; inhaled budesonide 3.2mg or 0.8mg daily; or placebo; ethics committee stipulation that participants to be on a calcium restricted diet. | |
| Outcomes | measured at 1 week; serum osteocalcin; calcium, phosphate, creatinine, alk.phos.,24hr urinary Ca, Pi & creatinine; i‐PTH; 1,25‐(OH)2D3; cortisol; urinary hydroxyproline; urinary cAMP; | |
| Notes | Jadad score 4. pill counting + inhaler weights to assess compliance. Authors provided raw data from the end of week one before cross‐over for inclusion in meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Kerstjens 1994.
| Methods | double blind Duration: 2.5 yrs (retrospective) Follow‐up: 100% | |
| Participants | "airways obstruction" male / female: 101 / 54 Av Age: 40.0, SD 12 Smoking status not stated. | |
| Interventions | terbutaline 200mcg plus either beclomethasone 200mcg qds, n = 70, or ipratropium bromide 160mcg od, n = 44, or placebo, n = 41 (placebo & ipratropium pooled for analysis) | |
| Outcomes | PICP, ICTP; | |
| Notes | Jadad score 2. No measure of compliance. No samples taken within 1 month of oral steroids. Authors provided raw data, including separate figures for ipratropium group, and for placebo (pooled in original paper). From phase 2 of a study. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Leech 1993.
| Methods | randomised crossover. Unmarked inhalers not identical. duration: 9 weeks Follow up: 100% | |
| Participants | healthy non‐smoker volunteers (4 mild asthma) 21 women Age: 21 ‐ 41 | |
| Interventions | 3 cycles of 2 weeks inhaler use then 1 week no inhaler. 1st week of each cycle 2 puffs bd; 2nd week 4 puffs bd; inhalers were placebo or budesonide 200mcg/puff, or beclomethasone 250mcg/puff. | |
| Outcomes | serum osteocalcin; | |
| Notes | Jadad score 2. All original raw data destroyed in a flood. Therefore unable to take pre‐cross over data for the meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | High risk | C ‐ Inadequate |
Li 1999.
| Methods | randomised, double blind duration: 104 weeks Follow‐up: 66% fluticasone, 53% placebo | |
| Participants | "mild persistent asthma" male / female: 55 / 9 Av Age: 29.55, range 18‐49. Smoking status not stated. | |
| Interventions | fluticasone 500mcg or placebo twice daily. | |
| Outcomes | bone mineral density; serum osteocalcin; HPA‐axis function evaluations; urinary N‐telopeptide; ophthalmic exams. | |
| Notes | Jadad score 3. Less than 1 years total ever oral steroid use, + no oral steroids in month prior to recruitment; up to 2 x 10 day courses oral steroid use allowed during trial. Raw data for osteocalcin not obtained from authors. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Tattersfield 2001.
| Methods | randomised, open study. Duration 2 years. follow‐up 64% | |
| Participants | "mild asthma" (FEV1 86% predicted) male / female 168 / 206 Age 20 ‐ 60, Av 35 years Smokers 20% | |
| Interventions | beclomethasone 500mcg daily(rising to 2000mcg if required), budesonide 400mcg daily (rising to 1600mcg daily if required) or non‐corticosteroid asthma treatment alone. | |
| Outcomes | Fracture, bone mineral density; serum osteocalcin; urinary pyridinoline; urinary deoxypyridinoline | |
| Notes | Jadad score 2. Results presented on those completing follow‐up, rather than intention to treat, although it was commented that analysis on basis of intention to treat would not make significant difference to results. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | High risk | C ‐ Inadequate |
Toogood 1991.
| Methods | placebo controlled, double blind, cross‐over. duration: 4 weeks 1st intervention, 2 wks wash out, 4 wks 2nd intervention. follow‐up: 100% | |
| Participants | healthy, non‐smoking adults male / female: 24 / 24 Av age: 32.1, SD 8.8 | |
| Interventions | budesonide 1.2mg (n=20) or 2.4mg (n=20) or placebo(n=8) | |
| Outcomes | serum osteocalcin; 24hr urinary free cortisol; plasma cortisol; urinary calcium; urinary hydroxyproline; urinary phosphate; candida counts. | |
| Notes | Jadad score 2. further sub‐group analysis comparing 8am/8pm dosing with 8am/noon. Authors provided detailed raw data. Baseline data only available for ur. hydroxyproline placebo group, so not included in meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Unclear risk | B ‐ Unclear |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Barnes 1996 | trial abandoned as it was impossible to find enough patients in general practice in the UK with mild asthma who had not already been started on inhaled steroids. |
| Bootsma 1996 | cross‐over trial comparing two different steroids, with placebo in the run‐in and wash‐out periods only |
| Clark 1997 | different outcome measures ‐ plasma cortisol |
| Dempsey 1999 | different outcome measures (urinary cortisol:creatinine ratios) |
| Egan 1999 | randomisation to different inhaled steroid products, no placebo inhaler |
| Gross 1999 | compared inhaled steroid and placebo in their effect on the RECOVERY of osteocalcin levels after suppression by oral steroids |
| Harmanci 1998 | Comparison between two steroids, no placebo group |
| Herrala 1994 | No randomisation to a placebo group |
| Hughes 1999 | Two steroids; no placebo |
| Johnell 1999 | inhaled steroids compared with a reference group given theophylline, nedocromil and ipratropium, the effect of which on bone metabolism is not known |
| Kos‐Kudla 1997 | used oral steroid |
| Malo 1999 | Comparison of two steroids; no placebo group |
| Nikolaizik 1996 | different outcome measures ‐ cortisol and adreno‐corticotrophic hormone |
| Padfield 1993 | Not a RCT |
| Paggiaro 1998 | used cortisol as the out come measure |
| Pauwels 1998 | comparison between two steroids; no placebo group |
| Struijs 1997 | COPD patients who needed steroids were randomised to beclomethasone or budesonide. Patients not requiring corticosteroids were the comparison group. BMD, alkaline phosphatase, osteocalcin, PICP and ICTP were measured. |
| Suissa 2000 | Cohort study looking at inhaled steroid use and death rates. |
| Toogood 1988 | Not an RCT |
| Vickers 1999 | trial discontinued at the end of the feasibility phase because of the difficulties with recruitment ‐ the majority of patients were given steroids at time of diagnosis of asthma, making it difficult to recruit for randomisation. |
| Wilson 1997 | different outcomes ‐ plasma cortisol and urinary cortisol and creatinine excretion |
| Wilson 1997b | different outcome measures ‐ creatinine excretion |
| Wilson 1998 | randomisation to budesonide (via turbohaler) OR triamcinolone (via integrated actuator/spacer), but not to a placebo group |
| Wilson 1998c | randomisation to oral prednisolone OR nebulised budesonide no placebo group |
| Wilson 1999 | different outcomes ‐ plasma cortisol and urinary cortisol/creatinine excretion |
| Wilson1998b | different outcomes ‐ plasma cortisol and urinary cortisol creatinine ratios |
| Wood 1999 | no randomisation to placebo |
Contributions of authors
AJ and MB developed the original idea and protocol. All reviewers were involved in selecting abstracts and final papers for inclusion. GR searched alternative databases and JF contacted authors and pharmaceutical companies. MS advised on relevance of outcome measures. KH gave statistical advice and data extraction. JF did data extraction, all entry into Review Manager and analysis. All members contributed to the final document.
Sources of support
Internal sources
Department of General Practice, University of Wales College of Medicine, UK.
External sources
Wales Office of Research & Development for Health and Social Care, The National Assembly for Wales, UK.
Garfield Weston Foundation, UK.
Declarations of interest
None known.
Edited (no change to conclusions)
References
References to studies included in this review
EUROSCOP 1999 {published and unpublished data}
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Barnes 1996 {unpublished data only}
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Bootsma 1996 {published data only}
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Kos‐Kudla 1997 {published data only}
- Kos‐Kudla B, Pluskiewicz W. Quantitative ultrasound of the heel and serum and urinary cortisol values in assessment of long‐term corticotherapy side effects in female bronchial asthma patients. Ultrasound in Medicine and Biology 1997;23(9):1325‐30. [26] [DOI] [PubMed] [Google Scholar]
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Wilson 1997 {published data only}
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