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First- and second-year effects in trials of calcium supplementation on the loss of bone density in postmenopausal women |
Mackerras D, Lumley T |
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Authors' objectives To determine if the effect of calcium on the loss of bone or bone density differs in the first and second years after randomisation to calcium or control therapy.
Searching MEDLINE was searched from 1990 to July 1996 for trials reported in the English language. The searches were conducted using the MeSH terms 'osteoporosis', 'hip fracture' or 'bone density', each combined with the following: 'calcium', 'calcium carbonate', 'calcium phosphate', 'calcium, dietary', 'diet', 'dairy products [administration & dosage]' or 'dairy products [therapeutic use]'. Studies were also identified from the reference lists of review articles, editorials and known studies.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs), which reported the effect of calcium supplements or dairy products on bone mass or density, were included if they fulfilled the following criteria: the outcome was change in bone density; the trial lasted at least two years; they contained at least one group receiving calcium supplements or dairy products; an intention to treat analysis was either reported or could be reconstructed from the data given. Combination therapy arms involving calcium plus vitamin D or exercises were included. Studies were excluded on the basis of the following: they were obviously non-randomised trials; the combination therapy arms involved calcium and another drug known to have strong effects on bone, such as oestrogen or fluoride; and annual data were not provided.
Specific interventions included in the reviewParticipants received calcium in doses ranging from 500 to 2,000 mg, with or without exercise. The following forms of calcium were included: lactogluconate, carbonate, citrate-malate, milk powder (including a low-fat variety), and combinations of formulations. The control groups received placebo, with or without exercise.
Participants included in the reviewPostmenopausal women were studied. The number of years since the menopause ranged from 1 to 13 years, and the age of the women ranged from 51 to 66 years.
Outcomes assessed in the reviewThe outcome was change in bone density. The bone sites measured included the following: spine (L2 to L4); distal, medial and proximal forearm; humerus; distal and proximal radius; proximal ulna; femoral neck; Wards triangle; intertrochanter; trochanter; midtibia; and ultratibia.
How were decisions on the relevance of primary studies made?Abstracts were perused and articles describing trials lasting at least two years, measuring bone density, and containing at least one group receiving calcium supplements and a possible control group, were obtained and scrutinised.
Assessment of study quality The authors do not state that they assessed validity.
Data extraction Data on first- and second-year results were obtained where possible then converted to a percentage change in bone density from the baseline. Otherwise, this percentage change was estimated from graphs by one investigator. The percentage change of baseline lost in the first- and second-year treatment groups, and the rates of loss, were calculated.
Methods of synthesis How were the studies combined?Regression, both crude analysis and weighted by the inverse of the variance, with the bone sites entered as dummy predictor variables, was used to investigate the effect of calcium on bone density. The regression models explored were both unadjusted and adjusted for years since the menopause.
How were differences between studies investigated?The analysis was repeated after excluding groups in which women received vitamin D or exercise programmes in addition to calcium.
Results of the review Nine RCTS (999 women) were included.
The differences in the weighted and adjusted rate of bone density change (second-year rate minus first-year rate) were presented by site for the treatment and control groups.
Calcium groups: proximal forearm, -0.6 (95% confidence interval, CI: -1.9, 0.7, P=0.3); median forearm, -0.6 (95% CI: -7.3, 6.0, P=0.8); distal forearm, 0.4 (95% CI: -2.0, 2.7, P=0.8); spine, -1.4 (95% CI: -2.3, -0.5, P=0.004); femoral neck, -2.1 (95% CI: -3.3, -0.8, P=0.002); trochanter, -1.7 (95% CI: -3.1, -0.4, P=0.01); intertrochanter, -2.4 (95% CI: -4.1, -0.7, P=0.007); Wards triangle, -0.9 (95% CI: -3.4, 1.6, P=0.5); midtibia, -2.6 (95% CI: -4.2, -1.1, P=0.002); ultratibia, -3.0 (95% CI: -4.7,-1.4, P=0.001).
Control groups: proximal forearm, 1.6 (95% CI: -1.0, 4.2, P=0.2); median forearm, 1.8 (95% CI: -7.3, 10.9, P=0.7); distal forearm, 0.2 (95% CI: -3.3, 3.7, P=0.9); spine, 1.1 (95% CI: -1.1, 3.3, P=0.3); femoral neck, 0.9 (95% CI: -1.6, 3.3, P=0.5); trochanter, 2.0 (95% CI: -0.8, 4.8, P=0.2); intertrochanter, 1.3 (95% CI: -3.0, 5.6, P=0.5); Wards triangle 1.2 (95% CI: -2.7, 5.0, P=0.5); midtibia, 1.2 (95% CI: -2.4, 4.9, P=0.5); ultratibia, 1.8 (95% CI: -2.1, 5.6, P=0.3).
The findings were unaltered when conducting the following analyses: testing the positive and negative assumptions; crude analysis; and after excluding groups receiving vitamin D or exercise.
Authors' conclusions The rate of bone loss was significantly less in the first year after randomisation than in the second year. By contrast, the rate of loss in the control group was less in the second year than in the first, although this was not significant. Compared with the control, the effect of calcium in reducing bone loss was statistically significant at the spine, femoral neck, trochanter, intertrochanteric, midtibia and ultratibia, but only in the first year after randomisation; there was no difference in the rates between groups in the second year. It is recommended that an analysis and meta-analysis of trials should always consider the effects on a year-by-year basis, and should not be based on the average annual rates.
CRD commentary This clearly written review included defined inclusion criteria, and an analysis of the data using different assumptions and several factors into account. Sensitivity analyses investigated different assumptions regarding the covariance of the bone density between years, the use of adjusted and unadjusted regression, and analysis after excluding groups receiving vitamin D or exercise programmes. Limitations, such as the small sample sizes and large losses to follow-up (ranging from 0 to 38%), were mentioned. The need for a more thorough meta-analysis was acknowledged by the authors.
This was a review on a rather complex subject with many factors to consider. The data reported in the original studies appear to have been incomplete, thus limiting the review. By restricting the literature search to English language studies and searching only one database, some other relevant studies may have been omitted. Details of the methods used to select the studies for inclusion were incomplete. Only one investigator extracted the data, with much of the data being estimated from graphs in the original studies. The likely accuracy of this method of determining estimates was not discussed. Contacting the original authors may have provided individual patient data or have avoided the need to estimate from graphs. The validity of the included studies was not assessed. The first- and second-year losses in bone density were compared graphically by treatment group and by site, but only a limited investigation of heterogeneity among studies was undertaken. It may have been helpful to have included a comparison of results from individual studies. Several of the confidence intervals of the weighted adjusted differences between years were rather wide, presumably reflecting the small sample size.
It is not possible to unequivocally support the authors' conclusion given the uncertainties in the accuracy of the data used, incomplete exploration of heterogeneity among studies, and the lack of a validity assessment. Further investigation is required.
Implications of the review for practice and research The authors consider that a more thorough meta-analysis would need to include a blinded review of the methods and consider the adequacy of randomisation. Access to the original data may enable the within-person correlation in measurements to be adjusted properly for a more detailed examination of other important effects, such as the dose of calcium used.
The authors question the use of bone density in young middle-aged persons as an intermediate end point for evaluating potential agents to reduce osteoporotic fracture in the elderly.
Bibliographic details Mackerras D, Lumley T. First- and second-year effects in trials of calcium supplementation on the loss of bone density in postmenopausal women. Bone 1997; 21(6): 527-533 Indexing Status Subject indexing assigned by NLM MeSH Bone Density /drug effects; Calcium, Dietary /therapeutic use; Evaluation Studies as Topic; Female; Humans; Osteoporosis, Postmenopausal /therapy; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome AccessionNumber 11998000076 Date bibliographic record published 30/06/1999 Date abstract record published 30/06/1999 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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