The Role of Combination Treatment for Osteoporosis
Robert R. Recker and
Robert P. Heaney
Osteoporosis Research Center
Creighton University
Omaha, Nebraska 68131-5149
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Introduction
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Combination treatments, pharmaceutical or
otherwise, have been common in medical practice dating from ancient
Greek physicians to the modern day. Modern examples include rifampin
and isoniazid for mycobacterium infections, or combination drug therapy
for heart failure, angina, asthma, hypertension, cancer, and many more.
In this issue of The Journal of Clinical Endocrinology &
Metabolism, Harris et al. (1) describe the
results of combination therapy for preservation of bone mass in
postmenopausal women. The results show that when a bisphosphonate
(BIS), risedronate, is added to conventional hormone replacement
therapy (HRT) in postmenopausal women, the increases in bone density at
nearly every skeletal site are at least marginally enhanced compared
with HRT alone. The report adds to three others (2, 3, 4) and
one abstract (5) describing results of this approach using
several regimens. Further, there are at least three ongoing studies
looking at this issue.
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Why consider combination therapy?
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Added efficacy. Available evidence indicates that there is
additive efficacy for the combination of HRT and BIS
(2, 3, 4, 5). Further, there is evidence that both BIS and HRT,
though remodeling suppressors, nevertheless have net anabolic effects.
That they might be expected to be additive is suggested by the fact
that each acts through a different cellular mechanism. The major bone
effect of BIS at the tissue level is to reduce markedly the activation
frequency of new remodeling sites (6). However, Heaney
et al. (7) demonstrated that the time course of
the increase in spine bone density in patients on BIS (alendronate)
therapy could not be fully explained on the basis of a skeletal
transient due to the resultant reduction in the remodeling space. The
same was true for HRT (Ref. 8 and Heaney R. P.,
unpublished data). This is important in understanding the effect of the
combination. If both HRT and BIS act solely through reduction in
activation frequency, then one could expect that a higher dose of one
or the other would have the same effect on bone mass as using lower
doses of the combination. This does not seem to be the case, although
the absence of a BIS-only-treated group in this study leaves uncertain
whether the sum of the effects of the combination would be equal to or
greater than the effect of BIS alone. The anabolic effects of both BIS
and HRT need further documentation in adults.
Added safety. In some instances, optimal efficacy of a
pharmaceutical agent is not achieved without dose levels high enough to
cause unacceptable side effects. Thus combination therapies may give
desired efficacy at doses low enough to avoid the unacceptable side
effects of single drug therapy, such as in treatment of hypertension or
malignancy. In the case of HRT and BIS, the safety profiles are
distinctly different. In the study by Harris et al. (Ref.
1 , and the others) the safety profile was essentially that
of HRT, given that risedronate was very well tolerated. Reduced doses
of either agent were not tested; hence, the potential safety benefit is
not applicable. Because the safety profile of the combination of BIS
and HRT for most patients is dominated by HRT, the use of low-dose HRT
should be considered in this context.
Another safety question concerns the risk of long-term reduction
in the remodeling rates that might result in the inability to repair
skeletal microdamage resulting in loss of antifracture efficacy despite
maintaining bone mass (9). Long-term HRT does not seem to
carry that risk. However, if the mechanism behind the additive increase
in bone mass of the combination is simply reduction in remodeling rates
greater than occurs with either alone, the question becomes relevant.
Long-term observation is needed.
Antifracture efficacy. Since the fluoride experience
(10) there has been a conviction that efficacy in
osteoporosis is tantamount to antifracture efficacy, and that
change in bone mineral density (BMD) was not enough. The fluoride study
of Riggs et al. (10), often cited as evidence
to that effect, did actually demonstrate antifracture efficacy for the
spine in yr 2 through 4 of the trial, a fact that seems largely
ignored.
The primary endpoints in the combination treatment studies have
been BMD changes as measured by dual energy x-ray absorptiometry.
Because of both the fluoride experience and difficulty in demonstrating
a correlation between the antifracture effect and the change in BMD in
recent BIS trials, doubt has been expressed as to whether BMD changes
are a reliable surrogate for antifracture efficacy. This remains an
open question, although many investigators hold that there is a
connection between increases in BMD and fracture protection. To the
best of the authors knowledge, there has never been a study
demonstrating antifracture efficacy in osteoporosis in the absence of
an increase in bone mass, or at least stabilization of bone mass.
Cost considerations. The addition of HRT to a BIS in a
combination regimen brings added cost. However, conventional HRT
regimens are relatively inexpensive, and the added nonskeletal benefits
of HRT may make the cost to benefit ratio attractive to many patients.
The real question is whether the added bone mass benefit of the
combination is worth the sum of the side effects and the additional
cost. The answer must include consideration of the nonskeletal risks
and benefits of HRT.
Long-term effects. The 1-yr length of observation in the study
by Harris et al. (1) was relatively short as
osteoporosis trials go. It allows only for expression of the remodeling
transient (11) and provides no data on the steady-state
effects of the combination. Thus, the question about long-term utility
remains unanswered. The combination was marginally better at 1 yr,
consistent with the greater remodeling suppression (both by biomarker
and histology); hence, one would expect a larger remodeling transient
with the combination than with HRT alone.
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Conclusion
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Although the results of the study by Harris et al.
(1) are promising, the jury is still out on the efficacy
of combination therapy in osteoporosis even if the primary endpoint is
BMD. Heaney has pointed out (11) that evaluation of
steady-state effects of skeletal treatment trials must be undertaken
from 12 months onwards. Thus, we need at least 3-yr and, preferably,
longer studies.
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Footnotes
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Robert Recker, M.D., Osteoporosis Research Center, 601 North 30th
Street, No. 4820, Creighton University, Omaha, Nebraska 68131-5149.
Received March 21, 2001.
Accepted March 21, 2001.
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References
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Harris S, Ericksen E, Davidson M, et
al. 2001 Effect of combined risedronate and hormone
replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab. 86:18901897.[Abstract/Free Full Text]
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Bone HG, Greenspan SL, McKeever C, et al. 2000 Alendronate and estrogen effects in postmenopausal women with low bone
mineral density. J Clin Endocrinol Metab. 85:720726.[Abstract/Free Full Text]
-
Wimalawansa SJ. 1998 A four-year randomized
controlled trial of hormone replacement and bisphosphonate, alone or in
combination, in women with postmenopausal osteoporosis. Excerpta
Medica. 104:219226.
-
Wimalawansa SJ. 1997 Combined therapies with
calcitonin and corticosteroids, or bisphosphonate, for treatment of
hypercalcemia of malignancy. J Bone Miner Metab. 15:160164.
-
Johnell O, Scheele WH, Lu Y, Lakshmanan M. 1999 Effects of raloxifene (RLX), alendronate (ALN) and RLX+ALN on bone
mineral density (BMD) and biochemical markers of bone turnover in
postmenopausal women with osteoporosis. J Bone Miner Res.
14:S157S157 (Abstract).
-
Arlot MC, Meunier PJ, Chavassieux P, et al. 1995 Effects of long-term alendronate treatment for post-menopausal
osteoporosis on bone histomorphometry. J Bone Miner Res.
10:S199S199. (Abstract).
-
Heaney RP, Yates AJ, Santora II AC. 1997 Bisphosphonate effects and the bone remodeling transient. J Bone
Min Res. 12:11431151.[Medline]
-
Recker RR, Davies KM, Dowd RM, Heaney RP. 1999 The
effect of low dose continuous estrogen and progesterone therapy with
calcium and vitamin D on bone in elderly women: a randomized,
controlled trial. Ann Intern Med. 130:897904.[Abstract/Free Full Text]
-
Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston
CC, Burr DB. 2000 Suppressed bone turnover by bisphosphonates
increases microdamage accumulation and reduces some biomechanical
properties in dog rib. J Bone Miner Res. 15:613620.[Medline]
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Riggs BL, Hodgson SF, OFallon WM, et al. 1990 Effect of fluoride treatment on the fracture rate in postmenopausal
women with osteoporosis. New Engl J Med. 322:802809.[Abstract]
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Heaney RP. 1996 Design considerations for
osteoporosis trials. In: Marcus R, Feldman D, Kelsey J, eds.
Osteoporosis. San Diego: Academic Press; 11251143.