Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis 

Authors Adachi J, Bensen W, Brown J, Hanley D, Hodsman A, Josse R, Kendler D, et al. 
Source New England Journal of Medicine. 337:382-7. August 7, 1997. 
Institutions Multi-institutional in Canada. 
Support Procter & Gamble Pharmaceuticals. 

 

Background

Long term, oral corticosteroid treatment is associated with a significantly increased risk for osteoporosis. This randomized trial was designed to investigate the potential for a bisphosphonate (etidronate) to decrease this risk. 

Methods

This was a 12-month, double-blind, randomized, placebo-controlled trial, conducted at multiple centers in Canada.

Patients

Eligibility: Age 18-90; started oral corticosteroid therapy within the previous 100 days; steroid dose: at least 7.5 mg/day prednisone (or equivalent) for 90 days, followed by at least 2.5 mg/day.

Exclusions: inability to assess bone density; other rx. affecting bone metabolism 

Intervention

Patients were stratified, for the purpose of randomization, into three groups: men, premenopausal women and postmenopausal women.

They were randomized to either 400 mg of etidronate or placebo daily, for 14 days, followed by 76 days of supplemental calcium (500 mg daily). This cycle was then repeated three times, for a total of 360 days. 

Analysis

Clinical parameters followed: rheumatologic disease activity; sedimentation rate in patients with polymyalgia rheumatica. At baseline and weeks 26 and 52: height and weight, serum for bone-specific alkaline phosphatase and urine for type I collagen N-telopeptide.

Bone density and fracture assessment:

  • Bone mass of lumbar spine by dual energy x-ray absorptiometry -- two scans at baseline (averaged), one at week 26 and two scans at week 52.
  • Bone mass of hip -- two scans at baseline, one at weeks 26 and 52.
  • Lateral and AP films of the spine at baseline; lateral films at week 52. A vertebral deformity score was evaluated (0 to 4) for each vertebra; a new fracture was any increase in this score between baseline and week 52; a spinal deformity index was also calculated (sum of scores divided by number of vertebrae evaluated) and compared, baseline to week 52.
Outcomes: The primary outcome was the difference between the two groups in the mean change, from baseline to week 52, in the lumbar spine bone density. Secondary outcomes were the change in density in the proximal femur and distal and midshaft radius [note: the protocol for radial bone densitometry was not mentioned in the methods section]. 

Results

Patients
  Etidronate Placebo
Randomized 67 randomized 74 randomized
Withdrawals 13 (1 death from pneumonia; 4 withdrawals for "adverse effects", only 1 felt to be drug related; 8 protocol violations) 11 (1 for "adverse effects"; 10 protocol violations)
Analyzed 54 analyzed 63 analyzed
Demographics Mean age 62
Men 39%; Premenopausal women 12%; Postmenopausal women 49%		 Mean age 60
Men 38%; Premenopausal women 12%; Postmenopausal women 50%
Prednisone dose 21 mg/day at baseline
3911 mg cumulative		 23 mg/day at baseline
4119 mg cumulative
LS bone density 0.94 g/cm2 0.90 g/cm2
Conditions requiring steroids Predominently polymyalgia rheumatica (53 patients total) and rheumatoid arthritis (34 patients total)

Treatment efficacy
 
  Etidronate Placebo
Bone density change baseline to 52 weeks
LS spine +0.61% -3.23% (p=0.02)
Femoral trochanter +1.46% -2.74% (p=0.02)
Femoral neck
Distal radius
Midshaft radius		 +0.19%
+0.51%
+0.10%		 -1.67% (p=NS)
+0.28% (p=NS)
-0.07% (p=NS)
Response rate
(positive slope of LS spine density curve)		 59% 23% (p<0.001)
Fractures
New vertebral fractures 9% of patients 15% of patients (p=NS)
Postmenopausal women 3.2% of patients 22% of patients (p=0.05)
Patients who lost height 28% of patients 51% of patients (p=0.01)
Other
Markers of bone turnover There was a significantly greater decrease in urinary N-telopeptide excretion in the etidronate group. The alkaline phosphatase response in the two groups was not significantly different.
Adverse effects Predominently GI, and not significantly different between the groups.

Author's discussion

The authors state that, although the reduction in vertebral fractures seen with etidronate did not achieve statistical significance in the whole group, it did in the subgroup of postmenopausal women, and they feel that "it is reasonable to conclude that etidronate therapy had a protective effect with respect to the fracture rate in corticosteroid-treated postmenopausal women." 

Editorial

In an accompanying editorial, Dr. Ian Reid from the University of Auckland discusses the problem of glucocorticoid-induced osteoporosis. He notes that treatment with vitamin D, calcium, calcitonin and hormone replacement therapy is effective in reducing or reversing bone loss, but results of some trials are conflicting, and an effect on fracture rate has not been demonstrated.

Prior trials of etidronate in corticosteroid treated patients have also demonstrated an effect on bone mineral density, but not on fracture rate. Dr. Reid feels the significance of this trial is in the demonstrated reduction in the vertebral fracture rate.

He recommends assessment of lumbar vertebral bone density and treatment of patients with densities at or below the lower end of normal for young adults. In the absence of bone densitometry, he recommends treatment for those at high risk, in particular older women and those who already have had minimal trauma fractures.

The treatment he recommends is calcium supplementation for all and hormone replacement where indicated. In those patients not taking HRT, he suggests treatment with a bisphosphonate or a vitamin D analog and calcitonin.

Comment

This trial investigated the use of a bisphosphonate, etidronate, in preventing osteoporosis among patients receiving long-term glucocorticoid treatment. The cyclic administration of etidronate for one year was associated with a significant improvement in vertebral and femoral trochanter bone mass. It was also associated with a significant decrease in the number of patients with new vertebral fractures, but only in the subgroup of post-menopausal women (from 22% to 3%).

This paper illustrates three topics that are recurring themes: the reporting of subgroup analysis, the reporting of results that do not reach statistical significance and the extrapolation of results to a class of drugs.

Subgroup analysis is a problem because the chance of finding a spurious effect increases with the number of subgroups that are analyzed a posteriori. Strictly speaking, the statistical significance of a result only applies to endpoints that are specified a priori. Of course, if a particular subgroup analysis yields a positive result that makes perfect sense from a pathophysiologic point of view, it is much more likely to be real than if no such explanation can be found. Nevertheless, subgroup analysis must be viewed with caution.

In this paper, the reduction in lumbar vertebral fracture rate was only significant in the subgroup of postmenopausal women. The significance in this subgroup was between p=0.03 and p=0.05. Since it certainly makes intuitive and pathophysiological sense that those patients at highest risk for fractures would be most likely to benefit, I believe that the results in this subgroup are likely to be valid. Nevertheless, it must be kept in mind that this was not a primary endpoint.

The problem of the reporting of results that are not "statistically significant" has been mentioned elsewhere in Journal Club (including a review of a paper on alendronate). I do not believe that one must ignore and not report all results which fail to strictly fit the criteria of p<0.05. I do believe, however, that such results should only be considered meaningful if they make sense in a wider context, if the p-value is reasonable and if the failure to meet the accepted test of significance is made very clear.

In this paper, a result that does not reach statistical significance (the reduction in vertebral fractures in the whole group) is reported. The authors state that "the relative risk of fractures in the etidronate group as compared with the placebo group was 0.6 (95% confidence interval 0.2 to 1.6)" and in the editorial, it is stated that "the proportion of patients with new vertebral fractures was halved in the etidronate group". Is this (statistically not significant) result plausible and meaningful, and should it have been reported this way? I do not believe so. Among men there were 4/19 patients with new fractures in the etidronate group and 3/25 in the placebo group. Among premenopausal women, there were no new fractures in either group. The decrease in vertebral fractures seen with etidronate was entirely the result of the decrease found among postmenopausal women, and should not be claimed for the group as a whole.

Finally, what about the extrapolation of the results using etidronate to the bisphosphonates as a whole? Etidronate has not been approved in the United States for the treatment of osteoporosis, although it has been used for this indication prior to the introduction of alendronate and is used for it in other countries. It is significantly cheaper when used cyclically than alendronate, but has one potential drawback: it inhibits bone mineralization as well as bone resorption and may cause osteomalacia. This is the rationale behind cyclical administration, which is meant to decrease the risk for osteomalacia.

Will etidronate now be approved in the U.S. for the treatment of steroid-induced osteoporosis, based on the results of this and prior trials? Or will the results be extrapolated to alendronate and other similar agents? The final thrust of the editorial is on the use of "bisphosphonates" rather than "etidronate", and Merck may well be more likely to benefit from this study than Procter & Gamble.

August 19, 1997

References

References related to this article from the NLM's PubMed database. 
 

Reader Comments

Date: Thu, 21 Aug 97
From: "Mark Leber" <besterdoc@classic.msn.com>

Were the racial composition and habits such as cigarette smoking and alcohol equal in both control and experimental groups? In the post hoc analysis, was the significant p-value adjusted downward based on multiple comparisons as is done in the Bonferroni test? How were outliers explained and adjusted for? What effect did outliers have on the data?
 
 

    The racial composition and habits (smoking and alcohol) are not specified in the article and not adjusted for. This is a good point, since these factors are known to affect osteoporosis.

    When multiple comparisons (subgroup analyses) are made, more stringent p values (i.e. smaller than 0.05) are usually required to meet the test of statistical significance. The subgroups looked at here (men, premenopausal women and postmenopausal women) were all specified a priori and randomization was stratified according to them. Thus, it is not clear to me that a Bonferroni correction or similar adjustment would be appropriate here. Nevertheless, the fact that these subgroups do not seem to have been specified as part of the primary endpoint analysis remains a bit troubling.

    No data is given concerning outliers (not unusual for this type of study). -- mj

Date: Tue, 26 Aug 1997
From: jfoxworth@pop.umkc.edu

An additional point in follow-up to the interesting discussion. Re proportion of vertebral fractures in postmenopausal women (1/31 treatment group vs 7/32 placebo group, P = 0.05), reported midway down the right column on p. 385 in the paper. A two by two table analysis of this data reveals an odds ratio of 0.12 with a 95% confidence interval of 0.01-1.09 (ie. not significant).

It's probably because the numbers are small, and I don't mean to try to remove any possibility that a benefit exists re fracture reduction, but it is an argument for providing confidence intervals whenever P values are presented, because they inform more about strength of evidence.

John Foxworth, PharmD
Clinical Pharmacology Section, Dept of Medicine, Truman Medical Center-West
Associate Professor, University of Missouri-Kansas City School of Medicine
 
 

    This is a very good point. When I plug the values (1 fracture among 31 women in the treatment group; 7 among 32 in the placebo group) into a 2x2 table and use Fisher's exact text, the P-value I get is 0.053 -- which the authors seem to have rounded down to 0.05 (not incorrect, strictly speaking, but a little misleading).

    The fact that the p-value is a bit greater than 0.05 explains why the 95% confidence interval for the odds ratio extends beyond 1.0 (my program gives me an odds ratio of 0.12 with a 95% confidence interval of 0.003 to 1.06). -- mj 

November 30, 1997

A recent editorial in the Lancet (November 8, 1997) addresses the issue of alendronate vs. etidronate (without coming to a clear conclusion). 

January 5, 1998

Letters to the editor about this article, from the December 28, 1997 New England Journal of Medicine. 
 

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