CRD summary

The authors found that calcitriol and alfacalcidol may reduce the risk of non-vertebral fractures and falls, but that the impact on vertebral fracture rates may depend on the type of active vitamin D used. Hypercalcaemia and hypercalciuria were potential adverse effects. The review was well conducted and the cautious conclusions appear reliable.

Authors' objectives

To evaluate the benefits and harms of calcitriol and alfacalcidol for reducing the risk of fractures and falls.

Searching

MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials were searched from inception to March 2006. Search terms were reported. Grey literature and the reference lists of relevant systematic reviews were handsearched. Authors were contacted for additional information. The search was restricted to published studies in English.

Study selection

Randomised controlled trials (RCTs) comparing calcitriol or alfacalcidol with placebo or calcium were eligible for inclusion provided they investigated fracture and/or fall risk and were conducted among postmenopausal women or older men. The primary outcomes were the number of participants with one or more fractures (vertebral or non-vertebral) or falls. Other outcomes of interest were withdrawals (total and harm-related) deaths and other harms (hypercalcaemia, hypercalciuria, renal stones and gastrointestinal side effects). Studies in which both groups also received native vitamin D were eligible. RCTs including participants with secondary causes of bone loss or with neurological disorders likely to affect fall risk were excluded, as were studies in which the effects of calcitriol and alfacalcidol could not be separated out.

Most studies in the review included solely postmenopausal women (two studies included men). All participants were community-dwelling. The mean age ranged from 51 to 72 years. Some studies excluded participants with renal disease, hyperparathyroidism and/or hypercalcaemia. Most studies were conducted in Japan or the USA and most addressed treatment rather than prevention. Calcitriol or alfacalcidol were administered with or without calcium supplements and with or without advice on dietary calcium. Controls received calcium, placebo or no treatment. Native vitamin D was used in both groups in some studies. Threshold values for hypercalcaemia and hypercalciuria differed across studies. Some studies used an incremental dosing schedule until hypercalcaemia occurred. The duration of intervention or follow-up ranged from 36 weeks to three years.

Two reviewers independently selected studies for inclusion.

Assessment of study quality

Study quality was evaluated using the Jadad scale, which measures adequacy of randomisation, blinding and management of withdrawals and dropouts. Each study was awarded up to 5 points; those with 3 or more points were designated high quality. Adequacy of allocation concealment was also assessed. Two reviewers independently conducted the assessment.

Data extraction

Odds ratios (ORs) were calculated from the numbers of events in the control and intervention groups of each study, with 95% confidence intervals (CIs). Denominators were calculated using an intention to treat approach, where possible. Studies reporting fractures were categorised as prevention or treatment studies (using a hierarchy of criteria detailed in the review). Fractures were excluded from analysis if they were unlikely to be osteoporotic (for example, fractures of the ankle, heel, toe, finger or face). Three reviewers independently extracted the data; differences were resolved by consensus.

Methods of synthesis

Studies were combined using a random-effects model to obtain a pooled OR and 95% CI. Heterogeneity was assessed with the I² statistic (a value of over 50 per cent indicated high heterogeneity). Publication bias was evaluated by funnel plots using the methods of Sterne and Egger. A priori subgroup analyses were conducted to investigate clinical and methodological differences between the studies (for example, the type of active vitamin D, duration of follow up, calcium treatment and whether a treatment or prevention study). Sensitivity analyses were conducted to investigate the effects of study quality.

Results of the review

Sixteen RCTs (23 publications) were included (n=2,139, range 14 to 622). Twelve studies had a Jadad score of three or more. Four studies reported adequate allocation concealment. Seven studies had losses to follow up of less than 20 per cent (range six per cent to 30 per cent, where stated).

Primary outcomes

Calcitriol or alfacalcidol (with or without calcium) versus placebo or calcium: There was no statistically significant difference between the groups in the risk of new vertebral fractures (OR 0.89, 95% CI: 0.57, 1.39, 13 RCTs, n=1,396). The funnel plot for this outcome suggested significant publication bias (p=0.10). There were significantly fewer non-vertebral fractures (OR 0.51, 95% CI: 0.30, 0.88, six RCTs, n=1,014) and falls (OR 0.66, 95% CI: 0.44, 0.98, two RCTs, n=624) in the intervention group.

Withdrawals and harms

Calcitriol or alfacalcidol (with or without calcium) versus placebo or calcium: The intervention group had a significantly higher risk of hypercalcaemia (OR 3.63, 95% CI: 1.51, 8.73, 10 RCTs) and a trend to increased risk of hypercalciuria (five RCTs, unsuitable for meta-analysis). There was no statistically significant difference between the groups in the risk of total or harm-related withdrawal, death, renal stones or gastrointestinal side effects.

Calcitriol or alfacalcidol with calcium versus calcium alone: There was a significantly higher risk of hypercalcaemia in the intervention group (OR 2.85, 95% CI: 1.21, 6.70, five RCTs, n=536).

Subgroup and sensitivity analyses

Alfacalcidol (with or without calcium) was associated with a significantly lower rate of vertebral fractures than placebo or calcium (OR 0.50, 95% CI: 0.25, 0.98, five RCTs, n=410), although calcitriol was not (eight RCTs, n=986). Other analyses did not change the statistical significance of the overall results.

Statistical heterogeneity was generally low for all analyses.

Authors' conclusions

The risk of non-vertebral fractures and falls may be reduced by calcitriol and alfacalcidol. The impact on vertebral fracture rates may depend on the type of active vitamin D used. Hypercalcaemia and hypercalciuria are potential adverse effects.

CRD commentary

The objectives and inclusion criteria of the review were clear. Relevant sources were searched for studies, but the restriction to published studies in English meant that the review was prone to language and publication biases. Steps were taken to minimise the risk of reviewer bias and error by having more than one reviewer independently select studies, assess validity and extract the data. Relevant criteria were used for the validity assessment. Suitable statistical techniques were used to combine studies and to assess for heterogeneity and publication bias. Potential sources of bias were acknowledged in the discussion section and taken into account in the interpretation. The review was well conducted and the authors’ cautious conclusions appear reliable.

Implications of the review for practice and research

Practice: The authors stated that patients taking active vitamin D should be monitored closely for hypercalcaemia and hypercalciuria, and the dose (or calcium intake) should be adjusted accordingly.

Research: The authors stated that future studies of vitamin D analogues should use standardised and validated methods to ascertain and report fractures, falls and harms.

Funding

No external funding.

Bibliographic details

O'Donnell S, Moher D, Thomas K, Hanley D A, Cranney A. Systematic review of the benefits and harms of calcitriol and alfacalcidol for fractures and falls. Journal of Bone and Mineral Metabolism 2008; 26(6): 531-542. [PubMed: 18979152]

Indexing Status

Subject indexing assigned by NLM

MeSH

Accidental Falls /prevention & control; Bone Density Conservation Agents /therapeutic use; Calcitriol /therapeutic use; Calcium /metabolism; Fractures, Bone /drug therapy /prevention & control; Humans; Hydroxycholecalciferols /therapeutic use; MEDLINE; Placebos; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

AccessionNumber

12009102714

Database entry date

08/07/2009

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.