Bisphosphonate Therapy ANGELO A. LICATA, MD, PHD, FACP
ABSTRACT: The bisphosphonates are longlived synthetic analogs of pyrophosphate, a natural, short-lived inhibitor of bone. Oral doses share similar qualities (ie, they inhibit bone resorption, poor absorption, and potential gastrointestinal irritants), but each one has a unique spectrum of potency and a probable mechanism of action. The parent compound, etidronate, was first used in multicentered trials for the treatment of primary osteoporosis and showed some success in increasing bone density and perhaps controlling fracture rates. The recently approved drug alendronate is a more potent agent than etidronate, produces a greater increase in bone density, and decreases fractures. Oral and intravenous pamidronate have similar positive effects on bone density. Studies with tiludronate, risedronate, and clodronate show similar promise as therapeutic agents. KEY INDEXING TERMS: Bisphosphonates; Osteoporosis; Antiresorption; Bone Density. [Am J Med Sci 1997;313(1):17 -22.]
T
he last two decades of this century will be known for the development of new drugs to treat primary osteoporosis. Moreover, the 1990s will be called the decade of the bisphosphonate drugs. Although this drug class was first developed more than a century ago, only recently have these drugs been used to treat calcium and bone disorders. It was purely serendipitous that this application ever occurred. 1 ,2 These agents are actually commercial demineralizing compounds for the detergent industry. Etidronate disodium, the mother compound, is the model for several related compounds and is the prototype for the treatment of osteoporosis. 3 ,4 This review describes the pharmacology of these drugs and their mechanisms of action, and it presents data From the Department of Endocrinology, The Cleveland Clinic Foundation, Cleveland,. Ohio. Submitted July 10, 1996; accepted September 5, 1996. Correspondence: Angelo A. Licata, MD, PhD, FACP, Department of Endocrinology, The Cleveland Clinic Foundation, Cleveland, OH 44195. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
on the efficacy of the different bisphosphonates in the treatment of osteoporosis. Pharmacology of Bisphosphonates
Bisphosphonates are chemical analogs of the endogenous substance known as pyrophosphate, a natural inhibitor of bone resorption (Figure 1). However, rapid enzymatic hydrolysis of pyrophosphate makes it an ineffective therapeutic agent. The bisphosphonates are synthetic analogs in which a carbon atom is substituted for the central oxygen atom (Figure 2). This modification makes the compound resistant to enzymic degradation and gives it a longer biologic half-life to influence the metabolism of the skeleton. Various constituents of this carbon atom provide the unique qualities of each drug (Figure 3).5 Mfinity for bone crystal resides in the Rl groups, whereas pharmacologic potency and activity arise from the R2 components. 6 ,7 The original notion about their mechanism of action was based on their high -binding affinity for skeletal calcium and their prevention of bone crystal dissolution. 8 It became quickly apparent that binding affinity alone was not sufficient to explain the effects of the drugs. Such a small quantity of drug was absorbed orally that crystal saturation alone in relation to surface mineral was insufficient to produce all the effects. Extensive research subsequently has shown that these agents have a more complicated biochemical function than originally thought. As a class, all these agents impair the resorptive function of osteoclasts. Both mature and immature osteoclasts are affected, but generally a lesser amount of the drug is needed to impair the immature forms.9 Shallower resorption cavities in bone mark the site of drug inhibition, an effect caused by altered cytoskeleton and cellular membrane functions. 1o ,11 In vitro, the drugs stimulate glycogen and collagen synthesis, fatty acid oxidation, impairment of lysosomal enzymes, prostaglandin synthesis, and interleukin-1 production. 12 Variable effects (ie, increases or decreases dependent on the cellular model) are seen in the production of alkaline phosphatase, lactic acid, proteoglycan synthesis, mitochondrial calcium release, and cell replication. 12 Some new concepts view bisphosphonate action on a more global scale. 13 These drugs impair the development of the immature osteoclase4 and the func17
Bisphosphonate Therapy
oII
0
II
(OH)2 - P - 0 - P - (OHh Figure 1. Structure of pyrophosphate.
tion of mature osteoclasts, they depress chemical signaling to adjacent cells, and they alter the osteoclast life cycle (apoptosis).15 The involvement of osteoblasts is also a probable mechanism of action. 16 - 18 Because the remodeling (repair) process of the skeleton is linked to osteoclastic function, there are concerns that these long-lived agents actually may be detrimental to the skeleton. The major worry is that these drugs might "freeze" the metabolism of the skeleton, stopping the normal repair process, and thereby increase the rates of fracture. Etidronate is the one drug of concern. High, long-term oral doses inhibit mineralization. 19 ,2o For example, with long-term use, even the recommended therapeutic dose to treat Paget's disease of the bone may cause this problem. However, pamidronate also has been shown to inhibit mineralization during acute (6 to 9 weeks) or long-term (1 year) treatment. 21 Therefore, the potential to hinder mineralization is present with these drugs. Whether it actually occurs and produces clinical problems probably are modified by the individual factors in each patient. Etidronate Disodium
The clinical trials with etidronate disodium were a "medical first." They were the initiation ofthe large multicenter studies in the field of osteoporosis and the paradigm for all present-day clinical trials. The original program in the United States was a doubleblind placebo-controlled study of women with osteoporosis who received cyclical etidronate, with or without phosphorus, a bone metabolism stimulator. 3,4 Etidronate treatment (400 mg/day) administered for a period of 14 days every 3 months increased skeletal density in the spine (average, 5% to 6%) more than in the hip (less than 3%).
Rl
01 0 ", I II
II
(OH)2 - P - C - P - (OH)2
R2 Figure 2. General structure of the bisphosphonate drug class.
18
compound
R j group
etidronate
-OH
-CH3
clodronate
-CI
-CI
pamidronate
-OH
-(CH2~NH2
100
alendronate
-OH
-(CH2f.J NH2
<1000
risedronate
-OH
-CHz-Q-
tiludronate
-H
-S-<
R2 group
potency
10
>CI
<10,000 10
Figure 3. Commonly used bisphoshponates. Data adapted from references 12 and 69.
The reduction of vertebral fracture rates was significant in the patients at high risk for fractures (eg, a subgroup with very low mineral density), regardless of the presence of phosphorus. 22 The original concern as to the safety of the drug was not supported by the histomorphometric and longitudinal studies. 23 ,24 Other less well-controlled studies also confirmed the basic observations of the original studies. 25 - 27 In the early years of the study, biochemical data showed an initial decline of 10% to 20% in alkaline phosphatase,3,4 but they later showed a restoration to the basal levels. 17 Therefore, one must assume that there was no "frozen state" of bone metabolism or impairment of the bone formation. Still, etidronate can cause osteomalacia if used on a daily basis as it is used in the treatment of Paget's disease of the bone. 18 However, this method of administration must be clearly distinguished from the cyclical treatment used in osteoporosis. Sodium Alendronate
Sodium alendronate was approved recently by the Food and Drug Administration for the treatment of osteoporosis. It is an aminobisphosphonate with a higher degree of potency than etidronate and has less potential for skeletal toxicity (osteomalacia) during long-term use. The therapeutic ratio is more than 1,000. 28 A 3-year multicenter trial of women with postmenopausal osteoporosis showed that the optimal dose of sodium alendronate (10 mg/day) produced a favorable response in the spinal mineral density of 96% ofthe women who participated in the study.29 The average spinal density increased 8.8%. The femoral neck and trochanter density increased 5.9% and 7.8%, respectively. The increase in hip density was a noteworthy difference from the effect of etidronate at this anatomic site. Although new vertebral fractures occurred less (P = 0.03) in the treated group (3.2%) than in the placebo group (6.2%), total nonvertebral fractures occurred at a similar rate (46 January 1997 Volume 313 Number 1
Licata
versus 47, respectively). Interestingly, 32.6% of these fractures were in the ankles, feet, or toes in the treated group, and 34% were in the wrists and the forearms of the placebo groUp.29 Recent data from the fracture intervention trial of almost 6500 women indicate approximately a 50% reduction in total vertebral, wrist, and hip fractures. 3o Pharmacologic studies attest to the uniqueness of alendronate. The drug localizes to the attachment site of the os teo clasts on the bone where it impairs osteoclastic function. The effect is reversible. 31 The free drug ultimately is incorporated into the bone without any subsequent effect. 28,32 Like other bisphosphonates, this drug is absorbed poorly. Under the best of conditions, only 0.75% of a dose is absorbed. 32 Therefore, adherence to a strict regimen of administration must be followed. Generally, the medication is taken in the morning while the patient is in a fasting state and consumed with water only because other liquids such as coffee, fruit juice, or milk impair further absorption. 32 Gastrointestinal side effects are a known complication. The original studies indicated a low incidence of these side effects. 28 General use of the drug has generated a number of reports of adverse events, especially esophagitis, which prompted the manufacturer to send out a notification to all physicians warning them of the anticipated problems if the drug was not used appropriately. Pamidronate
Pamidronate is an intravenous bisphosphonate approved in the United States for the treatment of hypercalcemia and Paget's disease of the bone; the oral preparation has been studied mainly for osteoporosis treatment. Early clinical studies of the drug in Paget's disease showed a favorable response on bone growth (the suppression of bone resorption but not offormation and a positive calcium balance) that prompted studies in osteoporosis. Initial studies showed an increase in the calcium balance, which represented a total skeletal gain of 2% to 3%.33 The suppression of resorption is not total or irreversible. Long-term use (5 years) did not impair skeletal resorption during hypocalcemic challenge. 34 A number of small, usually uncontrolled, studies showed the different, varying, positive effects on spinal density. A daily dose of 150 mg for approximately 2 years increased bone mineral content approximately 7% ± 1%.35 Cyclical administration of 200 mg to 300 mg every 2 months for an average period of 5 years increased bone density by approximately 2.5%.36 Doses of 4.8 mg/kg per day to 6.0 mg/kg per day for a period of 1.5 years increased spinal density 5.3%.37 The effect was more pronounced on trabecular bone rather than cortical bone; Larger effects on density seemed to occur with continued oral daily use rather than with intermittent use. Intestinal side effects from THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
the oral compound were more common with doses greater than 300 mg/day and occurred in 40% to 50% of the patients. Tablets were more tolerable than gelatin capsules. 38 A rare case of ototoxicity was reported39 with long-term intravenous use. After long-term treatment (5 to 9 years), there was continued suppression of new vertebral fractures for approximately 2 years after discontinuation of the pamidronate. 4o Within 6 months of the discontinuation of the therapy, serum alkaline phosphatase returned to basal levels, but urinary hydroxyproline was still suppressed by approximately 10% to 20%.40 Intravenous pamidronate (30 mg) every 3 months increased lumbar mineral density by approximately 10% and femoral neck density by approximately 5% after a 24-month period of treatment.41 Risedronate
Clinical trials are now under way to evaluate this drug in the treatment of osteoporosis. A I-year study to evaluate daily doses of 2.5 mg and 5.0 mg showed a dose-response increase in spinal density and hip density that ranged from 2% to 4%.42 Daily doses of 5 mg prevented postmenopausal bone loss better than 5 mg given 2 weeks of every 10 weeks. 43 ,44 The effect, however, was reversed 1 year after treatment was discontinued. 45 No adverse effects on the bone histology were seen with this dose leve1. 45 Although data are preliminary, a 2-year prevention study of women soon (6 to 60 months) after menopause showed various dose-dependent effects. Cyclical residronate (5 mg administered 2 of every 4 weeks) was better than daily residronate (2.5 mg/day) in the prevention of bone loss. A dose of only 5 mg/day increased bone mass. 46 Clodronate
There are limited data on the usefulness of clodronate to treat osteoporosis. In a 2-year study, after menopause, women who received 200 mg clodronate intravenously every month experienced a decrease in the loss of spinal density. Average density was approximately 7% better than the control data. 47 In another study, oral clodronate (400 mg/day), which was administered every third month, with or without calcitriol (2 p,g for 5 days), significantly reduced bone loss during a 12-month period. 47 A 5-year study indicated that 200 mg administered every 3 weeks decreased the vertebral fracture rate from 77 per 1,000 patient years to 23 per 1,000 patient years, concurrent with a 7% to 8% rise in spinal density.48,49 Tiludronate
Tiludronate is a third-generation cyclic bisphosphonate under evaluation worldwide for the treatment of osteoporosis. 50 An early study of 76 healthy women, after menopause, showed the efficacy of a daily 100 mg dose in the prevention of postmeno19
Bisphosphonate Therapy
pausal bone 10ss.51 Experimental studies that used rats and monkeys corroborated the antiresorptive effects of the drug in bone loss from immobilization 52 and showed a parallel increase in bone density and biomechanical strength. 53
6. 7.
Secondary Osteoporosis
The unique bioactivity of these drugs makes them theoretically useful in the treatment of many forms of secondary osteoporosis. Etidronate partially reverses or prevents bone loss caused by glucocorticoids,53-57 pregnancy, 58 organ transplantation,59 congenital neuropenia treated with granulocyte colony stimulating factor,60 homocystinuria,61 and suppressive doses of thyroxine (experimental animals).62 Pamidronate shows promise in the treatment of glucocorticoid-induced osteoporosis 63 and Gaucher's disease. 64 Tiludronate decreases the osteoclastic activity in osteoporosis of immobilization (paraplegia) and preserves bone mass and biochemical coupling. 65 Clodronate controls bone loss caused by myeloma,66,67 multifocal eosinophilic granu10ma,68 vitamin D intoxication,69 and systemic mastocytosis. 70
8. 9.
10. 11.
12. 13.
14.
Summary
By virtue of their effect on osteoclasts, the pivotal cell in bone metabolism, this class of drugs has wide applicability to all high-turnover skeletal states. Some of these disease states are alluded to above. Although these reports are generally uncontrolled anecdotal studies, they indicate the usefulness of these agents within a diverse number of conditions that heretofore had at best dismal therapeutic options. With the advent of several new second- and third-generation drugs, clinicians will face a new challenge similar to that posed by the numerous types of antihypertensives and nonsteroidal, antiinflammatory drugs. That challenge will be to decide the appropriate match of drug and patient. This is certainly a more pleasant challenge, and less daunting than when little was available to treat patients.
15.
16. 17. 18.
19. 20.
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43. Johnston Jr CC, Bekker PJ, Ouweland FVD, Horowitz ZD, Rupich R, Digennaro J, et al. Risedronate prevention of bone loss in early postmenopausal women (abstract). Calcif Tiss Int. 229:479. 44. Mortensen L, Bekker P, Digennaro J, Axelrod D, Charles P, Johnston CC. Prevention of early postmenopausal bone loss by risedronate: A one-year follow-up data (abstract). Bone. 1995;17:607. 45. Langdahl B, Eriksen EF, Mortensen L, Charles CC, Bekker P, Axelrod D. Histomorphometry from a three-year risedronate bone loss prevention study (abstract). Bone. 1995; 17:607. 46. Bekker P, Licata A, Harris S, Genant H, et al. Residronate dose response in prevention of early postmenopausal bone loss. American Journal of Bone Mineral Research. 1996; l1(suppl 1):S346. 47. Filipponi P, Pedetti M, Fedeli L, Cini L, Palumbo R, et al. Cyclical clondronate is effective in preventing postmenopausal bone loss: A comparative study with transcutaneous hormone replacement therapy. J Bone Miner Res. 1995; 10: 697-703. 48. Giannini S, D'Angelo A, Malvasi L, Castrignano R, Pati T, Tronca R, et al. Effects of one-year cyclical treatment with clodronate on postmenopausal bone loss. Bone. 1993; 14:137-41. 49. Filipponi P, Cristallini S, Rizzello E, Policani G, Fedeli L, et al. Five-year cyclical clodronate increases bone mineral density in postmenopausal osteoporosis. Effect on new vertebral fractures (abstract). Calcif Tiss Int. 1995; 56:479. 50. Chesnut CH, Reginster J-Y; eds. Proceedings of an official satellite symposium held at the XIITH international conference on calcium regulating hormones. Bone. 17;5S:471-519. 51. Reginster J-Y, Deroisy R, Dennis D, Collette J, Lecart MP, et al. Prevention of postmenopausal bone loss by tiludronate. Lancet. 1989;2:1469-71. 52. Murakami H, Nakamura T, Tsurukami B, Abe M, Barbier A, Suzuki K. Effects oftiludronate on bone mass, structure and turnover at the epihyseal, primary, and secondary spongiosa in the proximal tibia of ruined rats after sciatic neurectomy. J Bone Miner Res. 1994;9:1355-64. 53. Geusens P, Nijs J, Vanderperre G, Vanaudekercke R, Lowet G, Goovaerts S, et al. Longitudinal effect oftiludronate on bone mineral density, resident frequency on strength in monkeys. J Bone Miner Res. 1992; 7:599-609. 54. Struys A, SneIder AA, Mulder H. Cyclical etidronate reverses bone loss of the spine and proximal femur in patients with established corticosteroid-induced osteoporosis. Am J Med. 1995;99:235-42. 55. Worth H, Stammen D, Keck E. Therapy of steroid-induced bone loss in adult asthmatics with calcium, vitamin D and a diphosphonate. Am J Resp Crit Care Med. 1994; 150:394-97. 56. Diamond T, McGuij NL, Barbagallo S, Bryant C. Cyclical etidronate plus ergocalciferol prevents glucocorticoid-induced bone loss in postmenopausal women. Am J Med. 1995; 98:459-63. 57. Molder H, Struys A. Intermittent cyclical etidronate in the prevention of corticosteroid-induced bone loss. Br J Rheumatol. 1994;33:348-50. 58. Blanch J, Pacifici R, Chines A. Pregnancy-associated osteoporosis. Report of two cases oflong-term bone density follow-up. Br J Rheumatol. 1994;33:269-72. 59. Valero MA, Loinez C, Larrodera L, Leon M, Moreno E, Hawkins F. Calcitonin and bisphosphonates treatment in bone loss after liver transplantation. Calcif Tiss Int. 1995;57:15-19. 60. Bishop NJ, Williams DM, Compton JC, Stirling DM, Prentice A. Osteoporosis in severe congenital neutropenia treated with granulocyte colony-stimulating factor. Br J Haematol. 1995; 89:927 - 28. 61. Licata AA. Treatment of osteoporosis in a patient with homo-
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22
cysteinemia (uria) using etidronate disodium and pyridoxine. J Bone Miner Res. 1995; 10(suppl 1):8509. Kung AWC, Ng F. Cyclical etidronate prevents bone loss induced by thyroxine treatment in rats (abstract). Endocrine 80c Meeting. 1993:307. Reid IR, Schooler BA, Stewart AW. Prevention of glucocorticoid-induced osteoporosis. J Bone Miner Res. 1990; 5:619-23. Ostlere L, Warner T, Maunier PJ, Hulme P, Hesp R, et al. Treatment of type I Gaucher's disease affecting bone with aminohydroxypropylidene bisphosphonate (pamidronate). QJM. 1991; 79:503-15. Chappard D, Minaire P, Privat C, Berard E, MendozaSarmiento J, Taurnebis CH, et al. Effects of tiludronate on bone loss in paraplegic patients. J Bone Miner Res. 1995; 10:112-18.
66. Clemens MR, Fessle K, Heim ME. Multiple myeloma: Effect of daily dichloroethylene bisphosphonate on skeletal complications. Ann Hematol. 1993;66:141-46. 67. Jantunen E, Lahtinen R, Laakso M. Use of clodronate in multiple myeloma. Leuk Lymphoma. 1995;19:207-11. 68. Elomaa I, Blomqvist C, Porkka L, Holmstrom T. Experiences of clodronate treatment of multi focal eosinophilic granuloma of bone. J Int Med. 1989;225:59-61. 69. Rizzoli R, Stoermann C, Ammann P, Bonjour JP. Hypercalcemia and hyperosteolysis in vitamin D intoxication: Effects of clodronate therapy. Bone. 1994; 15:193-8. 70. Cundy T, Beneton MN, Darby AJ, et al. Osteopenia in systemic mastocytosis: Natural history and responses to treatment with inhibitors of bone resorption. Bone. 1987; 8:149-55.
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