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Combination and Sequential Therapy for Osteoporosis
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     For an investment approaching $1 billion, a pharmaceutical manufacturer may obtain approval from regulatory agencies to market a specific dose of a given medication for the treatment or prevention of a particular disorder. Such approval emphasizes and is based largely on the demonstration of simple efficacy and safety. Often little is known, not just about unanticipated side effects of the drug, much in the news of late, but also about such fundamental and critically important issues as the optimal duration of treatment; the effects, if any, of interactions with other agents affecting the same organs or tissues; or optimal sequencing of the various available treatments. These questions are important to practitioners whose patients have the particular disease but who rarely have it in the pristine, often untreated form encountered in patients participating in clinical trials.1 Providing answers to these questions is often left to the less structured world of clinical practice and to formal testing of ad hoc combinations and sequences.

    Over the past 10 years, five agents have been approved for the treatment or prevention of osteoporosis in the United States. As a group, these drugs have revolutionized the management of osteoporosis. They fall into two broad categories — agents that reduce the often exaggerated bone remodeling in postmenopausal women (and patients with osteoporosis, generally)2 and those that stimulate bone formation. Agents exhibiting each mode of action have been shown to reduce the risk of fracture substantially (i.e., both classes of agents are efficacious). However, it has been uncertain whether such drugs enhance each other's effects if given together or in certain sequences or whether one agent alters responsiveness to the other.

    Two articles in this issue of the Journal, one by Black et al.3 and one by Cosman et al.,4 provide important, if still incomplete, information about the effects of sequences and combinations of so-called bone-active agents in current clinical practice. The conclusions one can draw are preliminary, in part because not all relevant questions have been addressed and in part because these newer studies, which involve small numbers of patients, are unable to assess the relative antifracture efficacy of the various combinations likely to be encountered in practice.

    Confining attention solely to effects on bone mass, one can state with reasonable certainty that the bisphosphonates produce a steady increase in bone mineral mass that, although not linear, averages about 1 percent per year for up to 8 to 10 years. Once-daily parathyroid hormone, administered as either the 1–34 or the 1–84 amino acid form of the molecule, increases central bone mass to a substantially greater extent (8 to 10 percent per year for up to two years of treatment, the period for which data are available). Using these figures as rough benchmarks, the findings from these two studies,3,4 together with those of other studies they cite, allow one to draw a number of conclusions.

    First, both classes of agents appear to be efficacious as monotherapy. Second, combination therapy with parathyroid hormone and a bisphosphonate appears to increase central bone mass, but to a lesser extent than does parathyroid hormone alone. Third, in the months and years after treatment with parathyroid hormone, some or all of the bone gained during treatment appears to be lost if no further therapy is implemented. Fourth, administering bisphosphonates after a course of parathyroid hormone appears to conserve the bone gained during therapy with parathyroid hormone and adds a further quantum of bone in its own right, roughly similar in magnitude to the short-term effect of bisphosphonates given to previously untreated patients. Finally, parathyroid hormone appears to retain its anabolic effect in patients previously treated with a bisphosphonate, although the effect is probably smaller than that seen in previously untreated patients.

    We would stress that these conclusions reflect the effects of the drug on bone mass alone. We note that there are strong reasons to conclude that the antifracture efficacy of both classes of agents derives, in part, from effects distinct from mass changes and that these effects may be at least as important in determining their antifracture efficacy as their effects on bone mass. For example, in addition to producing a small increase in bone mass, bisphosphonates and the other antiresorptive agents also promptly reduce the number of active remodeling loci on bone surfaces. These loci are believed to concentrate mechanical stress in adjacent bone when the structure bears weight, and a reduction in their number produces a prompt decrease in bone fragility, independent of any effect on bone mass.5 Furthermore, in addition to increasing trabecular bone volume, parathyroid hormone also increases the periosteal diameter at critical bony sites.6 Other things being equal, the latter effect increases the cross-sectional moment of inertia and improves bony resistance to bending.

    These features of osteoporosis and its response to treatment are not related to bone mass and are often grouped under the catchall phrase "bone quality." Defects in "quality" probably equal or even outweigh the mass defect in bone implied in the name for this condition, "osteoporosis." Thus, although the effect of combined treatment with a bisphosphonate and parathyroid hormone on bone mass seems to be less than that produced by treatment with parathyroid hormone alone, it could be that the antifracture efficacy of the combination is additive. This would be the case, for example, if it turns out that the bisphosphonate's effect on remodeling and the effect of parathyroid hormone on periosteal bone formation are each sufficiently expressed. Only time (and much larger studies) will provide answers to such questions.

    Given the heterogeneity of osteoporosis, it is unlikely that all patients will have an equally good response to all drugs in either class. "What is the treatment of choice for my patient?" remains an important question, particularly since treatment with parathyroid hormone (1–34) is limited by approved indications to a two-year period. Established efficacy data apply to groups of patients, not necessarily to individual patients, some of whom may appear to have no response to treatment with a particular regimen. Indeed, the delineation of such so-called treatment failure is a complicated and still unresolved issue. However, in the world of clinical practice, apparent failure often leads to a change in medication and is a major driver of the sequences discussed here. Although some of the issues involved in the sequential use of these drugs have been addressed by Black et al. and Cosman et al., other therapeutically important questions remain. For example, should patients with low initial rates of bone remodeling2 receive a suppressor of bone remodeling, or would they be better served by treatment with parathyroid hormone from the outset?

    We need the current and expanding variety of treatments for osteoporosis precisely because it is a multifactorial disorder, unlikely to be controlled in all patients by any single class of medication. The good news is that an expanding array of potent, generally well tolerated bone-active agents that operate through a variety of mechanisms have been developed and that more promising drugs are on the horizon.

    Dr. Heaney reports having received consulting fees from Merck and Lilly.

    Source Information

    From the Osteoporosis Research Center, Creighton University, Omaha, Nebr.

    References

    Dowd R, Recker RR, Heaney RP. Study subjects and ordinary patients. Osteoporos Int 2000;11:533-536.

    Recker RR, Lappe JM, Davies KM, Heaney RP. Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients. J Bone Miner Res 2004;19:1628-1633.

    Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 2005;353:555-565.

    Cosman F, Nieves J, Zion M, Woelfert L, Luckey M, Lindsay R. Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 2005;353:566-575.

    Heaney RP. Is the paradigm shifting? Bone 2003;33:457-465.

    Uusi-Rasi K, Semanick LM, Zanchetta JR, et al. Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women. Bone 2005;36:948-958.(Robert P. Heaney, M.D., a)