The Role of Combination Treatment for Osteoporosis

Robert R. Recker and Robert P. Heaney

Osteoporosis Research Center Creighton University Omaha, Nebraska 68131-5149


    Introduction
 Top
 Introduction
 Why consider combination...
 Conclusion
 References
 
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.


    Why consider combination therapy?
 Top
 Introduction
 Why consider combination...
 Conclusion
 References
 
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 The same was true for HRT (Ref. 8 and Heaney R. P., unpublished data).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.


    Conclusion
 Top
 Introduction
 Why consider combination...
 Conclusion
 References
 
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.


    Footnotes
 
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.


    References
 Top
 Introduction
 Why consider combination...
 Conclusion
 References
 

  1. 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. 86:1890–1897.[Abstract/Free Full Text]
  2. 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. 85:720–726.[Abstract/Free Full Text]
  3. 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. 104:219–226.
  4. Wimalawansa SJ. 1997 Combined therapies with calcitonin and corticosteroids, or bisphosphonate, for treatment of hypercalcemia of malignancy. J Bone Miner Metab. 15:160–164.
  5. 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:S157–S157 (Abstract).
  6. 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:S199–S199. (Abstract).
  7. Heaney RP, Yates AJ, Santora II AC. 1997 Bisphosphonate effects and the bone remodeling transient. J Bone Min Res. 12:1143–1151.[Medline]
  8. 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. 130:897–904.[Abstract/Free Full Text]
  9. 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. 15:613–620.[Medline]
  10. Riggs BL, Hodgson SF, O’Fallon WM, et al. 1990 Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. New Engl J Med. 322:802–809.[Abstract]
  11. Heaney RP. 1996 Design considerations for osteoporosis trials. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego: Academic Press; 1125–1143.