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The Long and the Short of Bone Therapy
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     In 2004, the Surgeon General's report on bone health highlighted osteoporosis as an important and growing national medical problem.1 The authors of this report recognized that identification and treatment of this condition in women and men alike has lagged behind the increasing availability of instruments with which to detect low bone mass and the advancing pharmacologic approaches for prevention and therapy.

    Lack of compliance with approved drug regimens can hinder progress in the treatment of osteoporosis.2 In this issue of the Journal, from a study that was sponsored, designed, and analyzed by Amgen, McClung et al.3 report on the safety and efficacy of various doses of denosumab (formerly known as AMG 162), a humanized monoclonal antibody to the receptor activator of nuclear factor-B (RANK) ligand (RANKL). The antibody was administered subcutaneously either every three months or every six months for one year to a relatively small number of postmenopausal women selected because they had low bone mineral density on the basis of dual-energy x-ray absorptiometry results.

    RANKL, a member of the tumor necrosis factor superfamily of ligands and receptors, is essential for the differentiation, activation, and survival of bone-resorbing osteoclasts.4 It is expressed on the surface of marrow stromal cells, activated T cells, and precursors of bone-forming osteoblasts (Figure 1). 4 RANKL accelerates osteoclastogenesis when it binds to its receptor, RANK, on osteoclast precursor cells to enhance nuclear factor-B and other signaling pathways.4 Osteoprotegerin that is produced by osteoblasts, the key modulator of RANKL, acts as a soluble decoy receptor for RANKL and blocks its effects.4 McClung et al. report that denosumab, mimicking the function of osteoprotegerin, caused especially rapid, potent, dose-dependent decreases in biochemical markers of bone resorption, as determined by levels of serum and urine telopeptide products of bone-collagen degradation. Subsequent decrements in serum bone-specific alkaline phosphatase, a marker of osseous tissue formation, indicated an overall reduction in skeletal remodeling. Ideally, an inhibitor of RANKL would not suppress bone formation, but compensatory decreases in bone accretion can follow potent antiresorptive therapy.5

    Figure 1. The Skeletal Action of Denosumab.

    RANKL, a member of the tumor necrosis factor superfamily of ligands and receptors, promotes the differentiation, activation, and survival of bone-resorbing osteoclasts. Osteoprotegerin (OPG) that is produced by osteoblasts, the key modulator of RANKL, acts as a natural soluble decoy receptor for RANKL and blocks its effects. Denosumab functions like OPG and has the effect of decreasing osteoclastogenesis, as revealed by diminished biochemical markers of bone resorption.

    Denosumab increased bone mineral density at one year, especially in the lumbar spine, and there were slight gains in the total hip and distal radius that seemed somewhat greater than were the responses to standard weekly 70-mg doses of alendronate taken orally in a parallel study group. The 30-mg and 60-mg doses of denosumab administered at intervals of every three or six months, respectively, appear to be most appropriate for further clinical trials, on the basis of the present report. McClung et al. emphasize the appeal of denosumab because of its prolonged bone antiresorptive action.3

    Targeting RANKL for deactivation makes sense as a way to prevent or to treat many types of bone loss.6 Conditions that may potentially benefit from RANKL inhibition include not only various types of osteoporosis but also multiple myeloma, metastatic bone disease, humoral hypercalcemia of malignancy, hyperparathyroidism, and other conditions, particularly those featuring RANKL–osteoprotegerin dyssynergy. Testing of recombinant osteoprotegerin preceded the evaluation of denosumab, but osteoprotegerin seems to have fallen by the wayside, partly because neutralizing antibodies to it could develop in patients.6

    Long-acting doses of denosumab should enhance our pharmaceutical arsenal for the treatment of osteoporosis by improving convenience and compliance for some patients.2 However, this issue is also being addressed by the availability of increasingly potent antiresorptive bisphosphonates. Alendronate, risedronate, and ibandronate were marketed with administration schedules that increasingly simplified oral therapy from once daily, to weekly, to monthly. Another advanced-generation bisphosphonate, zoledronic acid, is being tested in the form of a brief intravenous infusion administered yearly.5

    Anti-RANKL treatment represents a novel antiresorptive therapy. However, one concern with this approach is that denosumab could globally disrupt the signaling pathway that involves RANKL, osteoprotegerin, RANK, and nuclear factor-B. RANK is expressed on cells other than osteoclast precursors, including dendritic cells and T and B cells.4 RANKL not only regulates osteoclastogenesis but also functions within the immune system.7 The effects of denosumab could differ from those of the bisphosphonates, the selective estrogen-receptor modulator raloxifene, and salmon calcitonin (all three of which are approved for the treatment of some forms of osteoporosis). In the study by McClung et al., there was a 1.9 percent incidence of neoplasm and a 1.0 percent incidence of unspecified infection in the denosumab groups, although these occurrences were not statistically significant. Neither of these problems developed in subjects in the placebo group or the alendronate group after 12 months, but both of these groups were smaller than the group that received denosumab. Although tumor necrosis factors and differ structurally from RANKL, pharmaceutical agents that inhibit these molecules engender concern about the potential development of infections, tumors, and hematologic and immune dysfunction.7 Accordingly, larger and longer clinical trials of denosumab for the prevention of osteoporotic fracture must search for these potential complications.

    Because inhibition of RANKL blocks osteoclastogenesis and osteoclast action, the increases in bone mineral density after treatment that are reported by McClung et al. would reflect a filling of bone-resorption spaces by osteoblasts. As bone mass is then preserved, further increments in bone mineral density might not occur with continued treatment.8 Recently, bone antiresorptive bisphosphonates, especially pamidronate and zoledronic acid, have been associated with osteonecrosis of the maxilla and mandible,9 particularly after tooth extraction and in persons who have been treated with corticosteroids or chemotherapy. Thus, there is concern that adynamic bone disease ("frozen bone") could result from excessive suppression of bone remodeling and lead to fracture.8

    McClung et al. demonstrate that denosumab can cause rapid and potent suppression of bone resorption and that this suppression seems to be reversible. Perhaps short-acting bone antiresorptive agents (e.g., lower doses of denosumab), coordinated with anabolic agents for bone, might best augment skeletal mass and improve bone quality while preventing depressed skeletal turnover.10 Denosumab, at doses that are relatively short-acting, may be a promising match for some anabolic agents, such as human recombinant parathyroid hormone (1-34) (teriparatide) and the parathyroid hormone (1-84) molecule presently undergoing clinical evaluation.11 Bone anabolic and antiresorptive agents together in optimal doses and sequences might further uncouple bone turnover in favor of progressive and greater bone accretion, but the complexity of such regimens would increase the risk of poor compliance in some patients.

    Therapy for osteoporosis is increasingly being tailored to treat specific clinical situations and to enhance compliance with medical therapy. Denosumab is a promising antiresorptive treatment that may play a role in both the long and the short of bone therapy.

    No potential conflict of interest relevant to this article was reported.

    Source Information

    From the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis.

    References

    Office of the Surgeon General. Bone health and osteoporosis: a report of the Surgeon General. Rockville, Md.: Department of Health and Human Services, 2004.

    Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medications. Arch Intern Med 2005;165:2414-2419.

    McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821-831.

    Martin TJ. Paracrine regulation of osteoclast formation and activity: milestones in discovery. J Musculoskelet Neuronal Interact 2004;4:243-253.

    Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653-661.

    Kostenuik PJ. Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Curr Opin Pharmacol 2005;5:618-625.

    Walsh MC, Kim N, Kadono Y, et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol (in press).

    Ott SM. Long-term safety of bisphosphonates. J Clin Endocrinol Metab 2005;90:1897-1899.

    Woo S-B, Hande K, Richardson PG. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005;353:100-100.

    Heaney RP, Recker RR. Combination and sequential therapy for osteoporosis. N Engl J Med 2005;353:624-625.

    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.(Michael P. Whyte, M.D.)