Treatment of Paget's Disease — Taming the Wild Osteoclast
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《新英格兰医药杂志》
Fifty years of steady clinical progress and five years of accelerated basic research in understanding the cellular and molecular biology of the osteoclast have led to the development of two drugs for the treatment of Paget's disease of bone, as reported in this issue of the Journal by Reid and colleagues (pages 898–908) and Cundy and colleagues (pages 918–923). In Paget's disease, as in many other skeletal disorders, the osteoclast is the cellular villain; it literally chews up and spits out the skeleton (see diagram). In the normal adult skeleton, this large, multinucleated cell helps to maintain skeletal homeostasis by resorbing bone in a balance with the bone-forming activity of its smaller skeletal partner, the osteoblast. In Paget's disease, the bone-resorbing function of the osteoclast is greatly magnified, owing to an increase in its number, size, and resorbing activity. The osteoblast attempts to compensate for the increased bone resorption by forming more bone, but it can do so only in a deficient and disorganized fashion. The resultant untamed skeleton is structurally weak and deformed and subject to fracture and to impinging on adjacent organs. The causes of this feral phenotype and function of the osteoclast in Paget's disease have not been fully elucidated, but both genetic factors (e.g., mutations of the sequestosome 1 gene) and environmental factors (e.g., infection with a paramyxovirus) seem to be important. Treatments for Paget's disease have been aimed at taming the osteoclast at each stage of its cell cycle: birth by osteoclastogenesis; the functions of migration, adhesion, and resorption; and death by apoptosis (see diagram).
Biology of the Osteoclast in Bone Metabolism as a Model for Drug Discovery.
When bone is resorbed, growth factors in the bone matrix are released, often stimulating osteoclasts, which secrete resorption products into the circulation. Osteoblastic stromal (mesenchymal) cells and maturing osteoclasts express a soluble version of the osteokine-receptor activator of the nuclear factor-B ligand (sRANKL), its cell-bound receptor RANK, and osteoprotegerin (OPG), which sustain osteoclastogenesis. The stimulatory activity of RANKL and the inhibitory effects of OPG regulate osteolysis. Bisphosphonates concentrated under the osteoclasts inhibit resorptive function and promote osteoclast apoptosis. The incorporation of bisphosphonates into bone may increase resistance to resorption. Current therapies for hyperresorptive states can be accommodated by this model; the pathways outlined here suggest additional targets, for which therapies are under development: bone growth factor antagonists; guanine nucleotide exchange factors (GEFs), which inhibit cell migration; arginine–glycine–aspartic acid peptides, which act on integrins; carbonic anhydrase inhibitors, which block the generation of hydrochloric acid; cathepsin K and matrix metalloproteinase 9 (MMP-9) inhibitors; and antibodies to parathyroid hormone-related protein (PTHrP) and RANKL.
Osteoclasts have the unique molecular machinery needed to resorb bone. Formed by the fusion of mononuclear precursors under the influence of local regulatory factors, mature osteoclasts attach to the bone matrix by way of an integrin seal, primarily v3. In Paget's disease, osteoclasts voraciously dissolve skeletal minerals with acid and dissolve bone matrix with enzymes and then release the resorption products into the circulation through transcytosis. Osteoclasts then detach and migrate to other resorption sites or undergo apoptosis. Because the osteoclast is involved in many, if not most, of the common skeletal diseases — including bone metastases, humoral hypercalcemia of malignant disease, osteoporosis, and renal osteodystrophy — Paget's disease has become a clinical proving ground for drugs with potentially wider application to many bone diseases.
The two new drugs for the treatment of Paget's disease, zoledronic acid and osteoprotegerin, that are the subject of studies reported in this issue of the Journal both act by inhibiting osteoclast function, but they do so by different mechanisms of action. Zoledronic acid acts primarily by impairing key metabolic pathways of the mature osteoclast and, perhaps, by stabilizing bone against resorption, and osteoprotegerin acts primarily by inhibiting osteoclastogenesis. The contrasting clinical journeys of these two drugs span the modern era of the treatment of Paget's disease, from analogues of industrial chemicals (zoledronic acid) to a recombinant-protein product of modern technology (osteoprotegerin). The reports by Reid and colleagues and Cundy and colleagues represent the culmination of two different roads toward drug development — a somewhat serendipitous route for zoledronic acid but one based on careful clinical observation, and a more directed route for osteoprotegerin, grounded in basic studies. The development of zoledronic acid required many decades; that of osteoprotegerin, less than a decade. The development of both was informed by research into the clinical, cellular, and molecular biology of the skeleton.1
The modern era of bone-specific drugs for the treatment of Paget's disease over the past 50 years was preceded by the era of non–skeletal-specific agents that addressed a presumed inflammatory component of the disease. Such an inflammatory component was implicated in the original description of the disease, in 1887, by Sir James Paget, who named it osteitis deformans. The "osteitis" was presumably targeted, beginning in the 1950s, by a variety of antiinflammatory agents including salicylates, nonsteroidal antiinflammatory drugs (in particular, indomethacin), corticotropin, and glucocorticoids. Low-dose mithramycin (now known as plicamycin) also found some use in the treatment of this disease. Although these drugs had some beneficial effects on the disease, the high doses required had unacceptable side effects. These agents yielded to calcitonin, which was approved by the Food and Drug Administration as a treatment for Paget's disease in the 1960s, a few years before the bisphosphonates were approved for the same purpose. Although this osteoclast-inhibiting peptide hormone was widely applied in the treatment of Paget's disease and other skeletal disorders, its use has been largely superseded by that of the bisphosphonates.2
Bisphosphonates were first chemically synthesized in the mid-19th century and used primarily in industrial plants because of their properties of preventing scaling by the inhibition of calcium-carbonate precipitation. Because the skeletal effects of early bisphosphonates were limited by the agents' rapid inactivation, longer-acting analogues were developed that led to wide clinical use. Their common characteristic remains a tropism to mineral, a property that directs bisphosphonates to deposition in the skeleton. In the 1960s, etidronate became the first bisphosphonate used in the treatment of Paget's disease. Since then, the progressive development of more effective bisphosphonates led to zoledronic acid, which is orders of magnitude more potent than the earlier analogues. Bisphosphonates act by becoming metabolized in the cell to toxic analogues of ATP or by inhibiting farnesyl diphosphate synthase; zoledronic acid acts through the latter mechanism. Because bisphosphonates are selectively deposited under osteoclasts in the skeleton, their effects are localized by a relatively short skeletal pathway to these cells (see diagram). The chemical characteristics of zoledronic acid prolong its biologic half-life in bone and allow it to exert its skeletal effects for at least months and perhaps years after administration.3
Osteoprotegerin was discovered through the basic studies that led to the elucidation of the long-sought pathway that coupled bone formation to bone resorption — a pathway regulated by marrow mesenchymal cells and osteoblasts. The molecular participants in this pathway are the membrane-associated protein that is the receptor activator of the nuclear factor-B (RANK) ligand (RANKL), the ligand's cognate receptor, RANK, and their soluble versions (sRANKL) and osteoprotegerin. In the physiology of bone metabolism, RANKL is expressed on the surface of osteoblastic stromal cells, and by binding to RANK on osteoclast precursors, it enhances osteoclastogenesis. Osteoprotegerin can inhibit osteoclastogenesis by binding RANKL.4 In the pathophysiology of Paget's disease, this osteoclastogenic cascade is ramped up to overstimulate osteoclasts (see diagram). The administration of osteoprotegerin can bind RANKL and thus inhibit osteoclastogenesis. Juvenile Paget's disease can be characterized by osteoprotegerin deficiency, so osteoprotegerin may be a form of replacement therapy in this form of Paget's disease. Fusing this recombinant protein to a larger molecule confers a surprisingly long duration of action for osteoprotegerin, and antigenicity is surprisingly absent.
The two studies reported in this issue of the Journal use bone markers that reflect the collagen-derived products of bone resorption and the cellular products of bone cells to evaluate treatment (see diagram). Although research studies warrant the wide array of bone markers used, the standard measurement of total serum alkaline phosphatase stands up well to the new bone markers used in both of these and many other studies of Paget's disease. The measurement of this osteoblast product thus provides an inexpensive, convenient, and readily available test that the physician can use to evaluate the clinical response to treatments, both old and new, for Paget's disease, and serial measurement of serum alkaline phosphatase may also be useful in defining and monitoring treatment schedules for long-acting drugs.
The efficacy of osteoprotegerin and zoledronic acid in the treatment of Paget's disease bodes well for their application to other hyperresorptive bone diseases. The sophisticated clinical and basic research that led to the development of these therapies culminates on a practical note. Both agents have convenient dose regimens because of their long durations of action, a feature that should facilitate acceptance of these drugs among patients. On the basis of the data in the two reports in this issue of the Journal and other reports, treatment intervals that vary from months to years may be anticipated for these new agents, particularly for zoledronic acid. However, their prolonged biologic effects, especially in the case of zoledronic acid, also raise a caution flag. Oversuppression of bone resorption and its deleterious consequences, such as the inhibition of skeletal metabolic activity ("frozen bone") and osteonecrosis, loom as even larger concerns with regard to these two agents than to shorter-acting drugs.5 However, the prudent and informed physician should anticipate these potential complications with the use of all potent antiresorptive agents, especially bisphosphonates.
Continued and careful studies should define the benefits and risks involved in treatment with these two agents and assign both of them their proper place in the growing repertoire of bone-active drugs. Progress toward further elucidation of the basic pathways of bone metabolism continues to identify other therapeutic approaches to Paget's disease and the many skeletal disorders characterized by increased bone resorption and caused by an osteoclast untamed by its environment.
Source Information
Dr. Deftos is a professor of medicine and a physician at the University of California at San Diego and the San Diego Veterans Affairs Medical Center, respectively, and a professor of law at the California Western School of Law, San Diego.
References
Vaananen K. Mechanisms of osteoclast mediated bone resorption -- rationale for the design of new therapeutics. Adv Drug Deliv Rev 2005;57:959-971.
Potts JT Jr, Deftos LJ. Parathyroid hormone, calcitonin, vitamin D, bone and bone mineral metabolism. In: Bondy PK, Rosenberg LE, eds. Duncan's diseases of metabolism. 7th ed. Philadelphia: W.B. Saunders, 1974:904-1082.
Fleisch H, Reszka A, Rodan G, Rogers M. Bisphosphonates: mechanisms of action. In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of bone biology. 2nd ed. Vol. 2. San Diego, Calif.: Academic Press, 2002:1361-86.
Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-176.
Odvina CV, Zerwekh JE, Rao DS, Maaloof N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301.(L.J. Deftos, M.D., J.D.)
Biology of the Osteoclast in Bone Metabolism as a Model for Drug Discovery.
When bone is resorbed, growth factors in the bone matrix are released, often stimulating osteoclasts, which secrete resorption products into the circulation. Osteoblastic stromal (mesenchymal) cells and maturing osteoclasts express a soluble version of the osteokine-receptor activator of the nuclear factor-B ligand (sRANKL), its cell-bound receptor RANK, and osteoprotegerin (OPG), which sustain osteoclastogenesis. The stimulatory activity of RANKL and the inhibitory effects of OPG regulate osteolysis. Bisphosphonates concentrated under the osteoclasts inhibit resorptive function and promote osteoclast apoptosis. The incorporation of bisphosphonates into bone may increase resistance to resorption. Current therapies for hyperresorptive states can be accommodated by this model; the pathways outlined here suggest additional targets, for which therapies are under development: bone growth factor antagonists; guanine nucleotide exchange factors (GEFs), which inhibit cell migration; arginine–glycine–aspartic acid peptides, which act on integrins; carbonic anhydrase inhibitors, which block the generation of hydrochloric acid; cathepsin K and matrix metalloproteinase 9 (MMP-9) inhibitors; and antibodies to parathyroid hormone-related protein (PTHrP) and RANKL.
Osteoclasts have the unique molecular machinery needed to resorb bone. Formed by the fusion of mononuclear precursors under the influence of local regulatory factors, mature osteoclasts attach to the bone matrix by way of an integrin seal, primarily v3. In Paget's disease, osteoclasts voraciously dissolve skeletal minerals with acid and dissolve bone matrix with enzymes and then release the resorption products into the circulation through transcytosis. Osteoclasts then detach and migrate to other resorption sites or undergo apoptosis. Because the osteoclast is involved in many, if not most, of the common skeletal diseases — including bone metastases, humoral hypercalcemia of malignant disease, osteoporosis, and renal osteodystrophy — Paget's disease has become a clinical proving ground for drugs with potentially wider application to many bone diseases.
The two new drugs for the treatment of Paget's disease, zoledronic acid and osteoprotegerin, that are the subject of studies reported in this issue of the Journal both act by inhibiting osteoclast function, but they do so by different mechanisms of action. Zoledronic acid acts primarily by impairing key metabolic pathways of the mature osteoclast and, perhaps, by stabilizing bone against resorption, and osteoprotegerin acts primarily by inhibiting osteoclastogenesis. The contrasting clinical journeys of these two drugs span the modern era of the treatment of Paget's disease, from analogues of industrial chemicals (zoledronic acid) to a recombinant-protein product of modern technology (osteoprotegerin). The reports by Reid and colleagues and Cundy and colleagues represent the culmination of two different roads toward drug development — a somewhat serendipitous route for zoledronic acid but one based on careful clinical observation, and a more directed route for osteoprotegerin, grounded in basic studies. The development of zoledronic acid required many decades; that of osteoprotegerin, less than a decade. The development of both was informed by research into the clinical, cellular, and molecular biology of the skeleton.1
The modern era of bone-specific drugs for the treatment of Paget's disease over the past 50 years was preceded by the era of non–skeletal-specific agents that addressed a presumed inflammatory component of the disease. Such an inflammatory component was implicated in the original description of the disease, in 1887, by Sir James Paget, who named it osteitis deformans. The "osteitis" was presumably targeted, beginning in the 1950s, by a variety of antiinflammatory agents including salicylates, nonsteroidal antiinflammatory drugs (in particular, indomethacin), corticotropin, and glucocorticoids. Low-dose mithramycin (now known as plicamycin) also found some use in the treatment of this disease. Although these drugs had some beneficial effects on the disease, the high doses required had unacceptable side effects. These agents yielded to calcitonin, which was approved by the Food and Drug Administration as a treatment for Paget's disease in the 1960s, a few years before the bisphosphonates were approved for the same purpose. Although this osteoclast-inhibiting peptide hormone was widely applied in the treatment of Paget's disease and other skeletal disorders, its use has been largely superseded by that of the bisphosphonates.2
Bisphosphonates were first chemically synthesized in the mid-19th century and used primarily in industrial plants because of their properties of preventing scaling by the inhibition of calcium-carbonate precipitation. Because the skeletal effects of early bisphosphonates were limited by the agents' rapid inactivation, longer-acting analogues were developed that led to wide clinical use. Their common characteristic remains a tropism to mineral, a property that directs bisphosphonates to deposition in the skeleton. In the 1960s, etidronate became the first bisphosphonate used in the treatment of Paget's disease. Since then, the progressive development of more effective bisphosphonates led to zoledronic acid, which is orders of magnitude more potent than the earlier analogues. Bisphosphonates act by becoming metabolized in the cell to toxic analogues of ATP or by inhibiting farnesyl diphosphate synthase; zoledronic acid acts through the latter mechanism. Because bisphosphonates are selectively deposited under osteoclasts in the skeleton, their effects are localized by a relatively short skeletal pathway to these cells (see diagram). The chemical characteristics of zoledronic acid prolong its biologic half-life in bone and allow it to exert its skeletal effects for at least months and perhaps years after administration.3
Osteoprotegerin was discovered through the basic studies that led to the elucidation of the long-sought pathway that coupled bone formation to bone resorption — a pathway regulated by marrow mesenchymal cells and osteoblasts. The molecular participants in this pathway are the membrane-associated protein that is the receptor activator of the nuclear factor-B (RANK) ligand (RANKL), the ligand's cognate receptor, RANK, and their soluble versions (sRANKL) and osteoprotegerin. In the physiology of bone metabolism, RANKL is expressed on the surface of osteoblastic stromal cells, and by binding to RANK on osteoclast precursors, it enhances osteoclastogenesis. Osteoprotegerin can inhibit osteoclastogenesis by binding RANKL.4 In the pathophysiology of Paget's disease, this osteoclastogenic cascade is ramped up to overstimulate osteoclasts (see diagram). The administration of osteoprotegerin can bind RANKL and thus inhibit osteoclastogenesis. Juvenile Paget's disease can be characterized by osteoprotegerin deficiency, so osteoprotegerin may be a form of replacement therapy in this form of Paget's disease. Fusing this recombinant protein to a larger molecule confers a surprisingly long duration of action for osteoprotegerin, and antigenicity is surprisingly absent.
The two studies reported in this issue of the Journal use bone markers that reflect the collagen-derived products of bone resorption and the cellular products of bone cells to evaluate treatment (see diagram). Although research studies warrant the wide array of bone markers used, the standard measurement of total serum alkaline phosphatase stands up well to the new bone markers used in both of these and many other studies of Paget's disease. The measurement of this osteoblast product thus provides an inexpensive, convenient, and readily available test that the physician can use to evaluate the clinical response to treatments, both old and new, for Paget's disease, and serial measurement of serum alkaline phosphatase may also be useful in defining and monitoring treatment schedules for long-acting drugs.
The efficacy of osteoprotegerin and zoledronic acid in the treatment of Paget's disease bodes well for their application to other hyperresorptive bone diseases. The sophisticated clinical and basic research that led to the development of these therapies culminates on a practical note. Both agents have convenient dose regimens because of their long durations of action, a feature that should facilitate acceptance of these drugs among patients. On the basis of the data in the two reports in this issue of the Journal and other reports, treatment intervals that vary from months to years may be anticipated for these new agents, particularly for zoledronic acid. However, their prolonged biologic effects, especially in the case of zoledronic acid, also raise a caution flag. Oversuppression of bone resorption and its deleterious consequences, such as the inhibition of skeletal metabolic activity ("frozen bone") and osteonecrosis, loom as even larger concerns with regard to these two agents than to shorter-acting drugs.5 However, the prudent and informed physician should anticipate these potential complications with the use of all potent antiresorptive agents, especially bisphosphonates.
Continued and careful studies should define the benefits and risks involved in treatment with these two agents and assign both of them their proper place in the growing repertoire of bone-active drugs. Progress toward further elucidation of the basic pathways of bone metabolism continues to identify other therapeutic approaches to Paget's disease and the many skeletal disorders characterized by increased bone resorption and caused by an osteoclast untamed by its environment.
Source Information
Dr. Deftos is a professor of medicine and a physician at the University of California at San Diego and the San Diego Veterans Affairs Medical Center, respectively, and a professor of law at the California Western School of Law, San Diego.
References
Vaananen K. Mechanisms of osteoclast mediated bone resorption -- rationale for the design of new therapeutics. Adv Drug Deliv Rev 2005;57:959-971.
Potts JT Jr, Deftos LJ. Parathyroid hormone, calcitonin, vitamin D, bone and bone mineral metabolism. In: Bondy PK, Rosenberg LE, eds. Duncan's diseases of metabolism. 7th ed. Philadelphia: W.B. Saunders, 1974:904-1082.
Fleisch H, Reszka A, Rodan G, Rogers M. Bisphosphonates: mechanisms of action. In: Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of bone biology. 2nd ed. Vol. 2. San Diego, Calif.: Academic Press, 2002:1361-86.
Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998;93:165-176.
Odvina CV, Zerwekh JE, Rao DS, Maaloof N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005;90:1294-1301.(L.J. Deftos, M.D., J.D.)