For Osteoporosis, Are Two Antiresorptive Drugs Better Than One?

Bruce Ettinger and John P. Bilezikian

Division of Research, Kaiser Permanente Medical Care Program, Division of Research (B.E.), Oakland, California 94661; and Departments of Medicine and Pharmacology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032

Antiresorptive drugs have had an enormous impact on the therapy of osteoporosis. By inhibiting osteoclast-mediated bone resorption but via different mechanisms, drugs like alendronate and raloxifene reduce bone dynamics that are typically elevated in postmenopausal women. Accelerated bone resorption is believed to be a major pathogenetic mechanism in postmenopausal bone loss, and antiresorptive drugs can return to the premenopausal range the somewhat elevated levels of bone turnover found in such women. However, none of the available antiresorptive drugs restores bone density from osteoporotic to normal levels, nor is fracture incidence reduced to premenopausal levels. Clearly, there are factors beyond bone turnover, like age, that are important in the interplay between drug efficacy and fracture. Nevertheless, it is tempting to consider the possibility that combination therapy with antiresorptive drugs, either through additive effects on suppression of bone turnover or through other as yet unknown mechanisms, might provide benefits over and above what could be achieved with either one alone. There have been and will be more clinical trials to test this hypothesis.

In this issue of JCEM, Johnell et al. (1) report on their study of combination therapy with alendronate and raloxifene in postmenopausal women with osteoporosis. The results of this well-designed clinical trial indicate that the combined use of these two drugs is associated with increased bone density and lower bone turnover markers than one can achieve with either drug alone. For most parameters, the difference between single therapy and combination therapy was significant when raloxifene was the comparative single agent but not so when alendronate was the comparative single agent. These results suggest that one can achieve greater changes in two surrogate markers of therapeutic efficacy, reduced bone turnover, and increased bone density when alendronate is used in combination with raloxifene, but not when raloxifene is used in combination with alendronate. One of the major drawbacks of this and all other combination therapy protocols to date is that there are no data on fracture incidence. It remains to be seen whether any of the combination antiresorptive approaches (2, 3) will be associated with reductions in fracture incidence that are greater than what can be achieved with monotherapy. Based on the bone marker data, there is reason to expect that greater fracture efficacy might be the case, at least when alendronate is "added" to a raloxifene regimen. Furthermore, the analysis by Johnnell et al. (1) indicate that in most, but not all, respects, the additivity of gains in bone density or reductions in bone turnover with combination therapy were noninteracting, suggesting that effects of alendronate and raloxifene were independent of each other.

What are the practical implications of this important study? First, the data suggest that in selected patients for whom there is an urgency to deal with fracture risk in a manner that is of the highest order, perhaps combination antiresorptive therapy would be more efficacious than treatment with either agent alone. The study by Johnell et al. (1) did not consider these agents in any sequence, so inference regarding the addition of one antiresorptive after another one has been started is speculative. Nevertheless, the results do suggest that greater effects might be achieved in certain settings if alendronate were added to a regimen of raloxifene. The converse, namely adding raloxifene to a patient who is receiving monotherapy with alendronate, would be more problematical because changes in bone density and bone turnover with combination therapy in most respects were not different from the results with alendronate alone. Without any information on the key endpoint of fracture, one cannot be sure that combination therapy would be better even if the surrogate markers suggest this to be the case.

What are the potential disadvantages to combination therapy with antiresorptive drugs? First, combination therapy is more expensive than monotherapy. One always has to bear in mind additional costs in relation to potential benefit. A second potential disadvantage to combination antiresorptive therapy is that bone turnover could be reduced to levels that adversely affect skeletal mineralization. Under usual therapeutic circumstances, the percentage of bone that is mineralized (subsequently referred to as mineralization) is increased when bone turnover is reduced. The magnitude of this effect was demonstrated by Boivin et al. (4) finding that most of the increase in osteoporotic women’s bone mineral density observed with alendronate treatment over 3 yr could be accounted for by augmented mineralization.

Although some increase in mineralization should increase bone strength, an excessive degree of mineralization seems to alter the quality of bone (5). The scenario is a simple one. Bone turnover is reduced to such an extent that the material properties of bone are affected because progressively greater mineralization causes bones to become more and more brittle. Such hypermature bone that is not being renewed by remodeling mechanisms could be more likely to fracture. To date, there is no hard evidence that fracture risk is affected in human subjects, although animal data support the idea (6). With the advent of technologies to measure mineralization density directly, compared with bone density, we may be able to monitor this important parameter directly (7, 8). Only then will it be possible to measure the relationships between changes in mineralization density, bone mineral density, bone markers, and fracture incidence.

There are counterarguments to those who worry about oversuppression of bone turnover. For example, Johnell et al. (1) showed that with only one parameter of bone turnover, C-telopeptide of collagen, could these antiresorptive drugs in combination be shown to lower the value to below premenopausal levels in about half the subjects receiving alendronate alone or in combination with raloxifene. In all other respects, either singly or together, these drugs reduced levels of other turnover markers to within the premenopausal range. On the other hand, those who would rely on mid-range suppression of bone turnover markers as a safety indicator should be aware of the disparity between suppression of bone activation frequency and reduction in biochemical markers. For example, iliac crest bone biopsies of women exposed to 10 mg alendronate a day for 2 and 3 yr showed marked suppression of turnover, on average, 88% and 93% suppression of activation frequency (5). In contrast, the study by Johnell et al. (1) is consistent with many other studies in finding that 10 mg alendronate a day suppresses N- and C-telepeptides, on average, 58% and 74%, respectively (1).

How do these studies help us in the practical care of our patients with osteoporosis? Without guidelines that have been substantiated by definitive data, one can envision a number of different uses of the antiresorptives. Admittedly such thinking is fanciful at this point. In patients who are at great risk, namely those with osteoporotic fractures and very low bone density, one could start with combination antiresorptive therapy to be followed by maintenance regimen with a single agent. When PTH becomes available, as the first approved anabolic therapy for osteoporosis, it is likely to be prescribed alone, but would probably be followed with an antiresorptive drug after 1 or 2 yr.

It is evident that we do not yet have a clear sense of how to use the available efficacious therapies for osteoporosis so as to optimize patient benefit and minimize the potential for deleterious effects. As we learn more about antiresorptive approaches to osteoporosis, as illustrated by Johnell et al. (1), it is going to be possible to develop more rational algorithms and, therefore, take full advantage of what drugs are and will become available.

Acknowledgments

Footnotes

Address all correspondence and requests for reprints to: Bruce Ettinger, M.D., Division of Research, Kaiser Permanente Medical Care Program, 3505 Broadway, Oakland, California 94661. E-mail: .

Received January 10, 2002.

Accepted January 10, 2002.

References

  1. Johnell O, Scheele WH, Lu Y, Reginster J-Y, Need AG, Seeman E 2002 Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 87:985–992[Abstract/Free Full Text]
  2. Bone HG, Greenspan SL, McKeever C, Bell N, Davidson M, Downs RW, Emkey R, Meunier PJ, Miller SS, Mulloy AL, Recker RR, Weiss SR, Heyden N, Musliner T, Suryawanshi S, Yates AJ, Lombardi A 2000 Alendronate and estrogen effects in postmenopausal women with low bone density. J Clin Endocrinol Metab 85:720–726[Abstract/Free Full Text]
  3. Harris S, Eriksen EF, Davidson M, Ettinger MP, Moffett Jr AH Jr, Baylink DJ, Crusan CE, Chines AA 2001 Effect of combined risedronate and hormone replacement therapy on bone mineral density in postmenopausal women. J Clin Endocrinol Metab 86:1890–1897[Abstract/Free Full Text]
  4. Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ 2000 Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 27:687–694[CrossRef][Medline]
  5. Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ 2001 Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 100:1475–1480[Abstract/Free Full Text]
  6. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB 2001 Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 28:524–531[CrossRef][Medline]
  7. Roschger P, Fratzl P, Eschberger J, Klaushofer K 1998 Validation of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies. Bone 23:319–326[CrossRef][Medline]
  8. Roschger P, Grabner BM, Messmer P, Dempster DW, Cosman F, Nieves J, Lindsay R, Bilezikian JP, Kurland ES, Shane E, Fratzl P, Klaushofer K 2001 Influence of intermittent PTH on mineral distribution in the human ilium: a paired biopsy study before and after treatment (Abstract). J Bone Miner Res 16(Suppl 1):S179




This Article
Full Text (PDF)
Submit a related Letter to the Editor
Purchase Article
View Shopping Cart
Alert me when this article is cited
Alert me when eLetters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Request Copyright Permission
Google Scholar
Articles by Ettinger, B.
Articles by Bilezikian, J. P.
Articles citing this Article
PubMed
PubMed Citation
Articles by Ettinger, B.
Articles by Bilezikian, J. P.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals