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Potential benefits of intermittent bisphosphonate therapy in osteoporosis
Joint Bone Spine 71 (2004) 2–3 www.elsevier.com/locate/bonsoi
Editorial
Potential benefits of intermittent bisphosphonate therapy in osteoporosis Keywords: Osteoporosis; Bisphosphonates
The introduction of etidronate on the French market in 1990 marked the advent of a new class of drugs, called bisphosphonates, which now constitute the main therapeutic weapon for osteoporosis. Bisphosphonates are useful in all categories of osteoporosis (postmenopausal, age-related, male, and glucocorticoid-induced). The new bisphosphonates alendronate and risedronate have proved capable of decreasing the fracture risk in patients with osteoporosis. On the other hand, fluoride and calcitonin are now recognized as ineffective in osteoporosis. Although bisphosphonates are not the only drugs capable of inhibiting bone resorption, they play a major role in the management of osteoporosis, together with estrogens and raloxifen. However, in the treatment of osteoporosis, bisphosphonates are used only by the oral route, whereas intravenous forms are available for other conditions such as hypercalcemia of malignancy, bone metastases, myeloma, and Paget’s disease. Furthermore, the newer more potent drugs can be given as a slow intravenous injection instead of the 2–3–h infusion needed for their predecessors. Intravenous bisphosphonate therapy for osteoporosis may be preferable to oral administration, for several reasons. • Since the fraction of bisphosphonates absorbed by the intestinal tract is tiny, about 0.7% for alendronate and risedronate, very large doses must be used to produce a pharmacological effect. These large doses can cause gastrointestinal side effects, which are occasionally severe [1]. • Bisphosphonates taken with food are not absorbed at all. The daily dose must be taken on an empty stomach, either before breakfast or during the day but at a distance from meals. This is a major inconvenience that promotes poor compliance and therefore decreases overall treatment effectiveness. Adding to the risk of poor compliance is the fact that the patients do not readily perceive the main long-term benefit (absence of fractures) and experience no short-term benefits (in contrast to estrogens given to relieve hot flushes). Furthermore, patients on glucocorticoids and other medications for organ transplantation, rheumatoid arthritis, or polymyalgia rheumatica may be unwilling to add yet another drug to their regimen. However, recently introduced galenic © 2003 Published by Elsevier SAS. doi:10.1016/S1297-319X(03)00156-8
forms that can be taken once a week seem to have comparable efficacy and safety profiles to those of oncedaily forms [2,3]. • After taking a dose of alendronate or risedronate, the patient must remain in an upright position to minimize the risk of esophagitis due to gastroesophageal reflux of the drug [1]. Consequently, oral bisphosphonates cannot be used in bed bound patients, who are at high risk for osteoporosis. • The effect on bone is small initially, because of the small dose absorbed. Thus, in patients with rapidly progressive osteoporosis and multiple sequential vertebral fractures, oral bisphosphonate therapy is inadequate. These problems raised by oral bisphosphonate administration suggest that intravenous administration may deserve consideration, should prove effective and devoid of major side effects. Several studies of the efficacy of intravenous bisphosphonates have been published during the last 10 years. Some of these studies evaluated bisphosphonates whose clinical development program does not include osteoporosis. Overall, the results are consistent with a beneficial effect of intravenous bisphosphonate therapy on bone mineral density and bone resorption markers. Few data are available on clodronate and alendronate [4,5], but pamidronate has been more extensively evaluated. In most studies, pamidronate was used in a dosage of 30–60 mg once every 3 months [6–8]. However, sample sizes were usually small, and no data were collected on potential changes in fracture risk in response to pamidronate therapy. Studies of last-generation intravenous bisphosphonates were more carefully designed and included larger number of patients; they will soon be available. Among these drugs, zoledronate in a dosage of 4 mg injected intravenously only once a year may be useful in the treatment of osteoporosis [9]; however, data on the fracture risk with this regimen are not yet available. Ibandronate is another promising agent that seems to improve bone mineral density [10]. However, ibandronate failed to decrease the fracture risk [11], perhaps because the dosage used was low (1 mg/3 months). For each bisphosphonate, studies are needed to determine whether beneficial effects on surrogate variables such as bone mineral density and bone turnover
Editorial / Joint Bone Spine 71 (2004) 2–3
markers translate into a reduction in the fracture risk. Bisphosphonates act by decreasing bone turnover. When given intravenously, their effectiveness varies with the dose and dosing interval. The treatment objective is to return the bone turnover rate to normal values (i.e., to premenopausal values). Assaying a bone resorption marker immediately before the next bisphosphonate injection may be useful for checking that the rate of bone turnover is still low. Intravenous bisphosphonate administration can cause side effects, which will have to be compared to those seen with the oral route. A flu-like syndrome is the most common injection-related event with pamidronate (25–50% of injections). Although lower doses can be used with the more potent last-generation bisphosphonates, flu-like syndrome remains common (25–40% with zoledronate [9] and 5–20% with ibandronate [10]). However, these medications are given as a slow intravenous injection instead of a 2–3–h infusion. In practice, flu-like syndrome rarely leads to treatment discontinuation. Calcium levels decline, but in too modest measure to induce symptoms, and no renal toxicity has been reported. The main concern is a potential deleterious effect on bone tissue. Conceivably, the dose and dosing interval may lead to a cumulative effect with a profound decrease in bone remodeling. Consistent with this hypothesis, about 80% decrease in the activity of bone remodeling units has been shown with zoledronate [9]. Although the long-lasting effect of bisphosphonates justifies intermittent administration by the oral or intravenous route, the dose and dosing interval associated with maximum efficacy and minimum toxicity must be determined for each agent. Intravenous bisphosphonates hold considerable promise for the treatment of osteoporosis and can be expected to be available soon. Patients who cannot or will not use the oral route will be particularly likely to benefit from this new route of administration. Furthermore, should combined parathyroid hormone and bone resorption-inhibiting treatment prove optimal [12], the added inconvenience of an intravenous bisphosphonate injection every 3 months, or perhaps even once a year, will probably seem negligible to patients who are used to a daily subcutaneous injection of parathyroid hormone. References [1]
[2]
de Groen PC, Lubbe DF, Hirsch LJ, Daifotis A, Stepenson W, Freedholm D, et al. Esophagitis associated with use of alendronate. N Engl J Med 1996;335:1016–21. Greenspan SL, Bone HG, Schnitzer TJ, Watts NB, Adami S, Foldes AJ, et al. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 2002;17:1988–96.
3
[3]
Brown JP, Kendler DL, McKlung MR, Emkey RD, Adachi JD, Bolognese MA, et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002;71:103–11. [4] Filipponi P, Pedetti M, Fedeli L, Cini L, Palumbo R, Boldrini S, et al. Cyclical clodronate is effective in preventing postmenopausal bone loss: a comparative study with transcutaneous hormone replacement therapy. J Bone Miner Res 1995;10:697–703. [5] Vasikaran SD, Khan S, McCloskey EV, Kanis JA. Sustained response to intravenous alendronate in postmenopausal osteoporosis. Bone 1995;17:517–20. [6] Thiébaud D, Burckhardt P, Melchior J, Eckert P, Jacquet AF, Schnyder P, et al. Two years’effectiveness of intravenous pamidronate (APD) versus oral fluoride for osteoporosis occurring in the postmenopause. Osteoporosis Int 1994;4:76–83. [7] Noord RM, Minkowitz R, Maid P, Lane JM. Effect of pamidronate and alendronate on bone mineral density in osteoporotic patients. A control matched study [abstract]. J Bone Miner Res 2002;17(Suppl 1):S473. [8] Lamy O, Pache I, Fatio S, Sandini L, Krieg MA, Burckhardt P. Effect of various doses of pamidronate with constant yearly dose in women with osteoporosis: a 2–year pilot study [abstract]. Osteoporosis Int 2002;13(Suppl 1):S32. [9] Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653–61. [10] Thiébaud D, Burckhardt P, Kriegbaum H, Huss H, Mulder H, Juttmann JR, et al. Three monthly intravenous injections of ibandronate in the treatment of postmenopausal osteoporosis. Am J Med 1997;103: 298–307. [11] Recker RR, Stakkestad JA, Felsenberg D, Chesnut CH, Christiansen C, Ettinger MP, et al. A new treatment paradigm: quarterly injections of ibandronate reduce the risk of fractures in women with postmenopausal osteoporosis: results of a 3–year trial [abstract]. Osteoporosis Int 2000;11(Suppl 2):S209. [12] Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001;16:925–31.
Alain Daragon * Rheumatology Department, Rouen Teaching Hospital, Rouen, France Inserm U 519, IFR 23, School of Medicine and Pharmacy, Rouen, France E-mail address: [email protected] (A. Daragon) Sophie Pouplin Rheumatology Department, Rouen Teaching Hospital, Rouen, France Received 18 March 2003; accepted 16 May 2003 * Corresponding author. Rheumatology Department, Hôpital de Boisguillaume, CHU de Rouen, 76031 Rouen cedex, France.
Editorial
Potential benefits of intermittent bisphosphonate therapy in osteoporosis Keywords: Osteoporosis; Bisphosphonates
The introduction of etidronate on the French market in 1990 marked the advent of a new class of drugs, called bisphosphonates, which now constitute the main therapeutic weapon for osteoporosis. Bisphosphonates are useful in all categories of osteoporosis (postmenopausal, age-related, male, and glucocorticoid-induced). The new bisphosphonates alendronate and risedronate have proved capable of decreasing the fracture risk in patients with osteoporosis. On the other hand, fluoride and calcitonin are now recognized as ineffective in osteoporosis. Although bisphosphonates are not the only drugs capable of inhibiting bone resorption, they play a major role in the management of osteoporosis, together with estrogens and raloxifen. However, in the treatment of osteoporosis, bisphosphonates are used only by the oral route, whereas intravenous forms are available for other conditions such as hypercalcemia of malignancy, bone metastases, myeloma, and Paget’s disease. Furthermore, the newer more potent drugs can be given as a slow intravenous injection instead of the 2–3–h infusion needed for their predecessors. Intravenous bisphosphonate therapy for osteoporosis may be preferable to oral administration, for several reasons. • Since the fraction of bisphosphonates absorbed by the intestinal tract is tiny, about 0.7% for alendronate and risedronate, very large doses must be used to produce a pharmacological effect. These large doses can cause gastrointestinal side effects, which are occasionally severe [1]. • Bisphosphonates taken with food are not absorbed at all. The daily dose must be taken on an empty stomach, either before breakfast or during the day but at a distance from meals. This is a major inconvenience that promotes poor compliance and therefore decreases overall treatment effectiveness. Adding to the risk of poor compliance is the fact that the patients do not readily perceive the main long-term benefit (absence of fractures) and experience no short-term benefits (in contrast to estrogens given to relieve hot flushes). Furthermore, patients on glucocorticoids and other medications for organ transplantation, rheumatoid arthritis, or polymyalgia rheumatica may be unwilling to add yet another drug to their regimen. However, recently introduced galenic © 2003 Published by Elsevier SAS. doi:10.1016/S1297-319X(03)00156-8
forms that can be taken once a week seem to have comparable efficacy and safety profiles to those of oncedaily forms [2,3]. • After taking a dose of alendronate or risedronate, the patient must remain in an upright position to minimize the risk of esophagitis due to gastroesophageal reflux of the drug [1]. Consequently, oral bisphosphonates cannot be used in bed bound patients, who are at high risk for osteoporosis. • The effect on bone is small initially, because of the small dose absorbed. Thus, in patients with rapidly progressive osteoporosis and multiple sequential vertebral fractures, oral bisphosphonate therapy is inadequate. These problems raised by oral bisphosphonate administration suggest that intravenous administration may deserve consideration, should prove effective and devoid of major side effects. Several studies of the efficacy of intravenous bisphosphonates have been published during the last 10 years. Some of these studies evaluated bisphosphonates whose clinical development program does not include osteoporosis. Overall, the results are consistent with a beneficial effect of intravenous bisphosphonate therapy on bone mineral density and bone resorption markers. Few data are available on clodronate and alendronate [4,5], but pamidronate has been more extensively evaluated. In most studies, pamidronate was used in a dosage of 30–60 mg once every 3 months [6–8]. However, sample sizes were usually small, and no data were collected on potential changes in fracture risk in response to pamidronate therapy. Studies of last-generation intravenous bisphosphonates were more carefully designed and included larger number of patients; they will soon be available. Among these drugs, zoledronate in a dosage of 4 mg injected intravenously only once a year may be useful in the treatment of osteoporosis [9]; however, data on the fracture risk with this regimen are not yet available. Ibandronate is another promising agent that seems to improve bone mineral density [10]. However, ibandronate failed to decrease the fracture risk [11], perhaps because the dosage used was low (1 mg/3 months). For each bisphosphonate, studies are needed to determine whether beneficial effects on surrogate variables such as bone mineral density and bone turnover
Editorial / Joint Bone Spine 71 (2004) 2–3
markers translate into a reduction in the fracture risk. Bisphosphonates act by decreasing bone turnover. When given intravenously, their effectiveness varies with the dose and dosing interval. The treatment objective is to return the bone turnover rate to normal values (i.e., to premenopausal values). Assaying a bone resorption marker immediately before the next bisphosphonate injection may be useful for checking that the rate of bone turnover is still low. Intravenous bisphosphonate administration can cause side effects, which will have to be compared to those seen with the oral route. A flu-like syndrome is the most common injection-related event with pamidronate (25–50% of injections). Although lower doses can be used with the more potent last-generation bisphosphonates, flu-like syndrome remains common (25–40% with zoledronate [9] and 5–20% with ibandronate [10]). However, these medications are given as a slow intravenous injection instead of a 2–3–h infusion. In practice, flu-like syndrome rarely leads to treatment discontinuation. Calcium levels decline, but in too modest measure to induce symptoms, and no renal toxicity has been reported. The main concern is a potential deleterious effect on bone tissue. Conceivably, the dose and dosing interval may lead to a cumulative effect with a profound decrease in bone remodeling. Consistent with this hypothesis, about 80% decrease in the activity of bone remodeling units has been shown with zoledronate [9]. Although the long-lasting effect of bisphosphonates justifies intermittent administration by the oral or intravenous route, the dose and dosing interval associated with maximum efficacy and minimum toxicity must be determined for each agent. Intravenous bisphosphonates hold considerable promise for the treatment of osteoporosis and can be expected to be available soon. Patients who cannot or will not use the oral route will be particularly likely to benefit from this new route of administration. Furthermore, should combined parathyroid hormone and bone resorption-inhibiting treatment prove optimal [12], the added inconvenience of an intravenous bisphosphonate injection every 3 months, or perhaps even once a year, will probably seem negligible to patients who are used to a daily subcutaneous injection of parathyroid hormone. References [1]
[2]
de Groen PC, Lubbe DF, Hirsch LJ, Daifotis A, Stepenson W, Freedholm D, et al. Esophagitis associated with use of alendronate. N Engl J Med 1996;335:1016–21. Greenspan SL, Bone HG, Schnitzer TJ, Watts NB, Adami S, Foldes AJ, et al. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 2002;17:1988–96.
3
[3]
Brown JP, Kendler DL, McKlung MR, Emkey RD, Adachi JD, Bolognese MA, et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002;71:103–11. [4] Filipponi P, Pedetti M, Fedeli L, Cini L, Palumbo R, Boldrini S, et al. Cyclical clodronate is effective in preventing postmenopausal bone loss: a comparative study with transcutaneous hormone replacement therapy. J Bone Miner Res 1995;10:697–703. [5] Vasikaran SD, Khan S, McCloskey EV, Kanis JA. Sustained response to intravenous alendronate in postmenopausal osteoporosis. Bone 1995;17:517–20. [6] Thiébaud D, Burckhardt P, Melchior J, Eckert P, Jacquet AF, Schnyder P, et al. Two years’effectiveness of intravenous pamidronate (APD) versus oral fluoride for osteoporosis occurring in the postmenopause. Osteoporosis Int 1994;4:76–83. [7] Noord RM, Minkowitz R, Maid P, Lane JM. Effect of pamidronate and alendronate on bone mineral density in osteoporotic patients. A control matched study [abstract]. J Bone Miner Res 2002;17(Suppl 1):S473. [8] Lamy O, Pache I, Fatio S, Sandini L, Krieg MA, Burckhardt P. Effect of various doses of pamidronate with constant yearly dose in women with osteoporosis: a 2–year pilot study [abstract]. Osteoporosis Int 2002;13(Suppl 1):S32. [9] Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653–61. [10] Thiébaud D, Burckhardt P, Kriegbaum H, Huss H, Mulder H, Juttmann JR, et al. Three monthly intravenous injections of ibandronate in the treatment of postmenopausal osteoporosis. Am J Med 1997;103: 298–307. [11] Recker RR, Stakkestad JA, Felsenberg D, Chesnut CH, Christiansen C, Ettinger MP, et al. A new treatment paradigm: quarterly injections of ibandronate reduce the risk of fractures in women with postmenopausal osteoporosis: results of a 3–year trial [abstract]. Osteoporosis Int 2000;11(Suppl 2):S209. [12] Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, et al. Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. J Bone Miner Res 2001;16:925–31.
Alain Daragon * Rheumatology Department, Rouen Teaching Hospital, Rouen, France Inserm U 519, IFR 23, School of Medicine and Pharmacy, Rouen, France E-mail address: [email protected] (A. Daragon) Sophie Pouplin Rheumatology Department, Rouen Teaching Hospital, Rouen, France Received 18 March 2003; accepted 16 May 2003 * Corresponding author. Rheumatology Department, Hôpital de Boisguillaume, CHU de Rouen, 76031 Rouen cedex, France.