EAL

NSUP: Vitamin D (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To compare the efficacy and safety of alfacalcidol (vitamin D analog) to vitamin D plus calcium in osteoporotic post-menopausal women.

Inclusion Criteria:

Women between 55 and 75 years old
Post-menopausal for at least five years
History of at least one prior vertebral fracture confirmed by spinal radiography or a lumbar or femoral BMD T-score under 2.5.

Exclusion Criteria:

Secondary osteoporosis
Other bone disease
Significant concomitant diseases
Hypercalcemia
Hypercalcuria
Treated with drugs that influence bone metabolism (estrogens, progesterone), SERMS, calcitonins, vitamin D and calcium supplements taken for more than one month in the previous three months
Bisphosphonates, fluoride, ipriflavone, glucocorticoids, immunosuppressant agents, anticonvulsants or lithium taken for more than one month in the previous six months
Abnormal vitamin D status [25(OH)D3 in a serum less than 30nmol per L measured by HPLC].

Description of Study Protocol:

Recruitment

Of 170 osteoporotic post-menopausal recruited from 11 clinical centers all over Italy, 148 met the inclusion critieria.

Design

148 women were randomly allocated to received one of the following treatments once daily:

Alfacalcidol (one mcg)
Placebo of vitamin D₃ (880 IU) plus calcium carbonate (2,500mg)
Placebo of alfacalcidol (one mcg) plus vitamin D₃ (880 IU) plus calcium carbonate (2,500mg).

Blinding Used

Undisclosed.

Intervention

One mcg alfacalcidol
880 IU vitamin D plus calcium carbonate (2,500mg).

Statistical Analysis

Two-sided Student T-test was used to compare mean values of continuous data in the two groups at baseline
Chi-square test was used for categorical data
BMD values was performed using a linear model on the difference at each visit to the baseline, including baseline values as covariate (ANCOVA model)
Missing post-treatment values have been replaced using the last observation after randomization carried forward method (LOCF method)
For serum calcium, phosphorous and creatinine, a non-inferiority analysis was performed
The values obtained for LOCF were analyzed using a linear model on log-transformed values, including treatment and center as factors and log-transformed baseline values as covariates
The two-sided 95% confidence interval of the difference between the log-transformed adjusted means obtained from the two treatment groups were calculated and the values obtained for the point estimate and the bounds were transformed back to the original unit, leading to an estimation of the 95% CI of the ratio of the geometric means
Non-inferiority is assessed referring to the commonly used 80% to 124% equivalence range
ITT analysis.

Data Collection Summary:

Timing of Measurements

At screening:
- Medical history
- Physical exam
- Complete blood analysis
- Vital signs.
At three, six, 12 and 18 months:
- Serum calcium
- Phosphorous
- Creatitine.
At screening, 12 and 18 months: BMD measured at lumbar spine or femoral site by dual energy X-ray absorptiometry
At baseline and 18 months: Vertebral column X-ray.

Dependent Variables

Lumbar BMD
Femoral BMD.

Independent Variables

Alfacalcidol
Vitamin D plus calcium.

Description of Actual Data Sample:

Initial N: 148
Attrition (final N): 102
Age: 55 to 75 years old
Ethnicity: Caucasian.

Anthropometrics

A significant difference between the groups was found only in the measurement of the mean lumbar BMD
A remarkable difference was found between the number of patients who did have previous vertebral fractures (N.S., P=0.208)

Location

Italy.

Summary of Results:

Site	Treatment	BMD Mean (g/cm² ±SD)
		Absolute values
		N	Baseline	12 months	18 months
Lumbar	Alfacalcidol	50	0.731 (0.77)	0.748 (0.080)	0.752 (0.80)
	Vitamin D plus calcium	47	0.710 (0.076)	0.716 (0.070)	0.715 (0.077)
	P between treatments		0.190	0.039	0.024
Femoral	Alfacalcidol	44	0.607 (0.076)	0.615 (0.075)	0.610 (0.077)
	Vitamin D plus calcium	48	0.594 (0.074)	0.598 (0.074)	0.595 (0.085)
	P between treatments		0.390	0.287	0.375

Higher changes from baseline in the alfacalcidol group, as compared to the changes in the vitamin D plus calcium group at both 12 and 18 months, were found to be statistically significant (P=0.018, 0.0005)
In alfacalcidol group, mean BMD increased by 0.017g per cm² (2.33%) after 12 months and by 0.021g per cm² after 18 months vs. baseline (P<0.01)
In the vitamin D plus calcium group, mean BMD increased by 0.005g per cm²(0.70%) after 12 months and 18 months (NS)
A small increase in mean femoral BMD was achieved in both groups (NS)
No significant differences were noted between groups in serum calcium.

Other Findings

Adverse effects were similar in both groups.

Author Conclusion:

Our study shows alfacalcidol to be an efficient agent in the therapy of post-menopausal osteoporosis
Alfacalcidol was significantly superior to vitamin D in terms of bone mass gain and possibly in the reduction of vertebral fractures.

Funding Source:

University/Hospital:

University of Siena, Opital La Colleta, U of Florence, U of Bologna, U of La Spienza, U of Catania, U of Turin, U of Padua (all Italy)

Reviewer Comments:

Significant difference in the measurement of the mean lumbar BMD between groups
Study had limited power to evaluate the efficiacy on femoral BMD due to its short duration or to find differences in fracture rates due to the relatively low number of patients available for evaluation.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		No
	4.1.	Were follow-up methods described and the same for all groups?	N/A
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	No
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	???
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.6.	Were extra or unplanned treatments described?	No
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		???
	10.1.	Were sources of funding and investigators' affiliations described?	No
	10.2.	Was the study free from apparent conflict of interest?	???