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Bisphosphonates in bone diseases other than osteoporosis
Joint Bone Spine 2002 ; 69 : 19-27 © 2002 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S1297319X01003360/REV
REVIEW
Bisphosphonates in bone diseases other than osteoporosis Philippe Orcel*, Johann Beaudreuil Fédération de rhumatologie, centre Viggo-Petersen, hôpital Lariboisière, 2, rue Ambroise-Paré, 75475 Paris cedex 10, France (Submitted for publication June 20, 2001; accepted in revised form August 13, 2001)
Summary – The range of bone diseases in which bisphosphonates are used has extended far beyond osteoporosis during the last few years. Bisphosphonate therapy is now so well validated as to be the reference standard in Paget’s disease and in the prevention of bone complications related to malignant osteolysis. Promising preliminary findings warrant the use of bisphosphonates in conditions that are either rare (fibrous dysplasia) or severe (pediatric osteogenesis imperfecta). The third category of indications encompasses many conditions in which the limited available data do not warrant widespread use: examples include reflex sympathetic dystrophy syndrome, acute back pain after a vertebral crush fracture, and chronic inflammatory joint disease not treated by glucocorticoids. Joint Bone Spine 2002 ; 69 : 19-27. © 2002 Éditions scientifiques et médicales Elsevier SAS bisphosphonates / bone resorption / fibrous dysplasia / malignant osteolysis / osteogenesis imperfecta / Paget’s disease
INTRODUCTION Bisphosphonates are potent antiosteoclastic agents, whose chemical structure is derived from the pyrophosphate nucleus (figure 1). Various molecular mechanisms lead to inactivation and increased apoptosis of mature osteoclasts [1]. These effects decrease bone resorption, making bisphosphonates a treatment of choice in many bone diseases characterized by an increase in osteoclastic resorption. Over the last decade, several bisphosphonates have been introduced on the market for the treatment of osteoporosis, Paget’s disease, and the clinical manifestations of malignant osteolysis (table I).
* Correspondence and reprints. E-mail address: [email protected] (P. Orcel).
Postmenopausal osteoporosis and glucocorticoidinduced osteoporosis are well-validated indications discussed in recent review articles [2, 3]. Male osteoporosis has generated considerable controversy despite convincing evidence that alendronate is effective [4]; however, this drug has recently been licensed for use in men with osteoporotic fractures. Clearly, bisphosphonates are valuable in bone diseases other than osteoporosis [5]. In some of these diseases, bisphosphonates have been approved by regulatory authorities (table I), whereas in others they are being increasingly used in clinical practice (table II). The present review of scientific evidence supporting bisphosphonate therapy in conditions other than osteoporosis is designed to help practicing rheumatologists make treatment decisions.
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Figure 1. Diagram of the chemical formulas of the phosphate and phosphonate rings and of the main bisphosphonates used in clinical practice. Note the theoretical formula of the ‘diphosphonate’ ring, a name often used inappropriately instead of bisphosphonate.
In many of the indications discussed here, bisphosphonates are used parenterally. Several arguments suggest that injection may be better than oral administration. Because the intestinal absorption of bisphosphonates is poor, these agents are more powerful when given parenterally. Furthermore, orallyadministered aminobisphosphonates can produce gastrointestinal side effects. Parenteral administration is useful or indispensable in patients who have difficulty taking medications by mouth. Finally, parenteral administration ensures good long-term compliance. BISPHOSPHONATES IN PATIENTS WITH MALIGNANT OSTEOLYSIS The pivotal role played by osteoclasts in the genesis of the clinical symptoms of malignant osteolysis provides
the pathophysiological rationale for using bisphosphonates in this indication [6, 7]. When present in the bone, tumor cells from multiple myeloma or solid tumor metastases stimulate the recruitment and activation of osteoclasts and increase their survival time (figure 2). Increased osteoclastic resorption is among the central mechanisms underlying hypercalcemia of malignancy [8]. In addition, by decreasing the mechanical strength of bone, excessive osteoclastic resorption causes pain and increases the risk of fracture. Bone resorption results in local release of growth factors that stimulate tumor cell proliferation, generating a vicious circle that magnifies the above-described phenomena. Bisphosphonates put an end to this vicious circle by potently inhibiting resorption (figure 2). Finally, recent evidence suggests that some bisphosphonates may have direct antitumoral effects by inducing apoptosis of malignant plasma cells [9, 10]. Three bisphosphonates are available. Table III recapitulates their indications, dosages, and modalities of administration. In hypercalcemia, bisphosphonate therapy is usually started intravenously as a series of slow intravenous infusions in isotonic saline [8]. In a direct comparison of intravenous pamidronate and clodronate, efficacy was similar, but escape phenomenon occurred after only 14 days of clodronate as compared to 28 days of pamidronate [11]. In practice, it is important to bear in mind that rehydration must be achieved before intravenous bisphosphonate therapy is started and that serum calcium levels take several days to return to normal [8]. Two new bisphosphonates, ibandronate and zoledronate, have been proved effective in this indication [12, 13] and will probably be added soon to our therapeutic armamentarium. Bisphosphonates have shown efficacy in controlling the symptoms related to bone fragility in patients with malignant osteolytic lesions [14]. During the last few years, placebo-controlled studies of intravenous and oral bisphosphonate therapy in myeloma [15-20] (table IV) and metastatic breast cancer [21-27] (table V) have been published. Monthly infusions of pamidronate, 90 mg, significantly decreased fractures and other bone complications, as well as use of analgesic radiation therapy, in patients with myeloma [20] or metastatic breast cancer [22, 23, 28]. Overall, bone complication rates fell by 35 to 50% in these trials. No factors predictive of this bone response were identified; in particular, bone turnover markers were not helpful in identifying future responders. This evidence of major benefits provided by intravenous pamidronate has
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Bisphosphonates in bone diseases Table I. Bone disease indications of bisphosphonate therapy approved by French regulatory authorities as of May 2001. Osteoporosis Treatment Etidronate Didronelt Clodronate Clastobant, Lytost Pamidronate Arediat Tiludronate Skelidt Alendronate Fosamaxt Risedronate Actonelt Ibandronate Bondronatt Zolendronate Zometat
Prevention
Males
✚
Paget’s disease Glucocorticoidinduced ✚
Malignant osteolysis Hypercalcemia
Bone complications
✚
✚
✚
✚
✚
✚ ✚ ✚
✚
✚
✚
* ✚
✚ ✚ ✚
* Alendronate is not approved for the treatment of male osteoporosis but has been granted a 1-year period of reimbursement by the French national health insurance system when used in males with a history of osteoporotic fractures.
recently led the American Society of Clinical Oncology [29] to recommend this treatment in patients with metastatic breast cancer and symptomatic bone lesions (table VI). Clodronate can be used also by the oral route. The level of proof of efficacy in myeloma patients is far lower than for pamidronate, and this indication is not approved in France. Clodronate seems more promising Table II. Indications in which injectable pamidronate is used despite absence of approval from regulatory authorities. The bold type shows indications for which open-label studies suggest clinical efficacy and the italic type indications for which only anecdotal case reports or small series are available, the results being inconclusive or conflicting. Osteogenesis imperfecta (40, 42) Glucocorticoid-induced osteoporosis, osteoporosis in transplant recipients Fibrous dysplasia (38, 39, 65) Reflex sympathetic dystrophy syndrome (43, 44, 45, 46 [injectable alendronate]) Back pain after vertebral crush fractures (47) Rheumatoid arthritis, spondyloarthropathies (52, 53, 55) Gaucher’s disease (59, 60, 61) Cystic fibrosis (57) Mastocytosis (58) Myositis ossificans progressiva (62 [injectable etidronate]) Neuropathic arthropathies (Charcot’s foot) (56) Periarticular ossifications (63)
as a treatment of metastatic breast cancer (table V). In a study of patients with marrow micrometastases, oral clodronate therapy significantly reduced the rates of occurrence of bone metastases and soft tissue metastases and significantly increased survival [26]. This finding is controversial, however, as it has not been reported by other investigators. Consequently, clodronate should be used only as an adjunct to specific therapy. Furthermore, in another study, clodronate therapy was associated with decreased survival in women with breast cancer and positive nodes at diagnosis [27]. Ibandronate and zoledronate have been evaluated recently in this indication, with promising results [30]. BISPHOSPHONATES IN PATIENTS WITH PAGET’S DISEASE The considerable increase in bone turnover that characterizes Paget’s disease is a strong invitation to use bisphosphonates [31]. The goals are to alleviate bone pain in the short term and to prevent delayed bone, joint, and neurological complications in the long term [32]. Oral bisphosphonates (etidronate, tiludronate, or risedronate) are generally used first. Etidronate was less effective than the other two agents in direct comparisons [33, 34]. Thus, etidronate should be reserved for patients with little evidence of disease progression. Rates
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Figure 2. Diagram of interactions between bone and tumor cells. Mediators (cytokines, etc.) released into the bone environment by the tumor cells activate the osteoclasts and increase bone resorption. This produces a constellation of symptoms related to bone frailty and results in local release of matrix growth factors that stimulate tumor cell proliferation, perpetuating a vicious circle. There is incontrovertible proof that bisphosphonates inhibit osteoclast activity, thereby decreasing bone resorprtion. Bisphosphonates may also act directly on tumor cells to shorten their survival.
of partial remission (defined as a 50% or greater fall in serum alkaline phosphatase levels) decreased by 60–70% with tiludronate and by 85% with risedronate [33, 35]. Complete remission (return to normal of Table III. Indications and dosage of injectable bisphosphonates in malignant osteolysis related to myeloma and metastatic cancer. Indication Clodronate (Clastobant, Lytost) Pamidronate (Arediat) Ibandronate (Bondronatt)
hypercalcemia osteolysis hypercalcemia osteolysis hypercalcemia
Dosage IV/ 300 mg/d × 2–5 d PO/ 1600 mg/d IV/ 60-90 mg/d IV/ 90 mg/month IV/ 2-4 mg (single infusion)
alkaline phosphatase levels) occurred in about 25% of patients given tiludronate for 3 months and in 85% of patients given risedronate for 2 months. Unresponsiveness has been reported with etidronate but not tiludronate or risedronate; in patients who failed to respond to etidronate, switching to one of the other agents was followed by clinical and laboratory test improvements [36]. Pamidronate is used intravenously 2 or 3 consecutive days. Response rates and complete remission rates were high in all published studies, and the time to clinical improvement was very short [37]. Pamidronate is useful in patients with very extensive lesions, rapid lesion
Table IV. Controlled studies of the efficacy of bisphosphonates in preventing bone complications in patients with multiple myeloma. The gray areas indicate the study of the treatment regimen that is available in France. Study
N
BP
Belch 1991 [15] Lahtinen 1992 [16] Heim 1995 [17] McCloskey 1998 [18] Brincker 1998 [19] Berenson 1998 [20]
166 336 157 536 300 377
eti clo clo clo pami pami
Dose
Route
Duration
Osteolysis
Pain
Pathologic fractures
Radiation therapy/surgery
5 mg/kg/d 2400 mg/d 1600 mg/d 1600 mg/d 300 mg/d 90 mg/mo
PO PO PO PO PO IV
→ death 24 mo 12 mo 48 mo 18 mo 21 mo
0 + 0 ? 0 0
0 0 + 0 + +
0 0 0 + 0 +
? ? ? 0 0 +
BP: bisphosphonate; eti: etidronate; clo: clodronate; pami: pamidronate; PO: treatment given per os; IV: treatment given intravenously. 0: no proof of efficacy; +: significant efficacy; ?: inconclusive data.
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Bisphosphonates in bone diseases
Table V. Controlled studies of the efficacy of bisphosphonates in preventing bone complications in women with metastatic breast cancer. Cells with any level of gray indicate studies of treatment regimens that are available in France. Dark gray cells indicate studies of clodronate for preventing bone metastases in patients with nonmetastatic breast cancer at clodronate initiation. Study
N
BP
Dosage
Route
Duration Anti-E
Time to Complication Patients with Survival Time to 1st rate metastases radiological complication progression
Paterson 1993 [21] Hortobagyi 1996 [22] Theriault 1999 [23] Conte 1996 [24] Kanis 1997 [25]
173 380 372 295 133
clo pami pami pami clo
1600 mg/d 90 mg/mo 90 mg/mo 45 mg/3 wk 1600 mg/d
PO IV IV IV PO
12 mo 24 mo 12 mo 36 mo
– – – – +
Diel 1999 [26]
302
clo
1600 mg/d
PO
24 mo
+
Saarto 2001 [27]
299
clo
1600 mg/d
PO
36 mo
+
idem ↑ ↑
↓ 33% ↓ 14% ↓
↑ 11.3% vs. 14.3% (NS) 6.9% vs. 13.9% P < 0.001 21% vs. 24% (NS)
= ↑ ↓
BP: bisphosphonate; clo: clodronate; pami: pamidronate; PO: treatment given per os; IV: treatment given intravenously. Anti-E: adjuvant antiestrogen therapy.
progression, or incipient evidence of neurological compromise that does not require emergency surgical treatment. BISPHOSPHONATES IN PATIENTS WITH FIBROUS DYSPLASIA Fibrous dysplasia manifests as tumor-like osteolytic lesions. One or more bones can be affected; in polyostotic forms, the lesions are often confined to the limbs on one side of the body. The long bones and skull are predominantly affected. Clinical manifestations include pain, fractures of long bones related to decreased mechanical strength, deformities, and compression of neurological structures. An open-label study by Chapurlat et al. found that intravenous pamidronate given daily for 3 consecutive Table VI. Recommendations issued by the American Society of Clinical Oncology (ASCO) about intravenous bisphosphonates in patients with metastatic breast cancer [29]. 1. Monthly infusion (3–4 weeks) of 90 mg pamidronate – Metastatic cancer with radiographic lesions and concomitant chemotherapy/hormonal therapy (high level of proof) – Painful lesion not seen on radiographs but visible by another imaging technique (low level of proof) 2. Biochemical markers for bone turnover not helpful 3. Duration not well defined → until the terminal stage 4. Concomitant use of other analgesic treatments 5. Do not use in patients with nonskeletal metastases 6. Oral bisphosphonate therapy recommended to prevent chemotherapy-induced osteoporosis
days in a cumulative dosage of 180 mg on four occasions 6 months apart relieved the pain related to the dysplastic lesions and increased the density of longbone lytic lesions in some patients [38, 39]. The fracture risk was not evaluated because of the small size and marked heterogeneity of the study population. A controlled study would be of considerable interest to evaluate the efficacy of parenteral bisphosphonate therapy in patients with fibrous dysplasia. However, the low prevalence and marked heterogeneity of the disease are major obstacles to such a study. BISPHOSPHONATES IN PATIENTS WITH OSTEOGENESIS IMPERFECTA Osteogenesis imperfecta is a particularly severe variant of juvenile osteoporosis caused by mutations in genes encoding type 1 collagen chains. In the most severe forms of osteogenesis imperfecta, namely, types III and IV, severe osteoporosis develops in early infancy, causing multiple fractures, growth disorders, spinal deformities, and major disability. Until the recent introduction of bisphosphonates, treatment options were extremely limited. Pamidronate given as intermittent intravenous infusions was recently evaluated in an open-label study in about 30 children aged 3 to 16 years [40]. The results showed an increase in adjusted bone mineral density; there was some evidence of reductions in fractures, pain, and disability. No growth delay or other major side effects were noted, in keeping with a review of case reports of young
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children given bisphosphonates to treat juvenile osteoporosis [41]. The group that conducted the first open-label study [40] has recently reported a second open-label study [42] comparing pamidronate-treated patients to untreated age-matched controls. All patients and controls were younger than 3 years of age. The results confirmed the favorable effects of pamidronate found in the earlier study. There are major, perhaps insurmountable, ethical obstacles to a placebo-controlled trial of bisphosphonates in patients with osteogenesis imperfecta. Available data are more than encouraging and establish the beneficial effects of pamidronate infusions in children with severe forms of the disease. Alendronate is under evaluation in patients with less severe disease (particularly type I). BISPHOSPHONATES IN PATIENTS WITH REFLEX SYMPATHETIC DYSTROPHY SYNDROME Reflex sympathetic dystrophy syndrome (RSDS) is characterized by bone demineralization, usually triggered by an injury. Severe pain is the main symptom. Local and regional trophic disorders are common. RSDS can become chronic, and none of the treatments that are used empirically have been found effective in controlled clinical trials. The marked heterogeneity of RSDS is a major stumbling block for therapeutic trials. Nevertheless, bisphosphonates have been evaluated recently in this condition. A few open-label studies suggested beneficial effects, particularly on the time-course of the pain [43, 44]. This criterion, however, is of limited value in open-label studies of RSDS, a condition in which the placebo effect is probably large and spontaneous resolution of the pain a common outcome. A single multicenter, randomized placebo-controlled study of pamidronate infusions has been published. Pamidronate was used in a dosage of 75 mg or 150 mg. No significant differences were found among the groups for clinical criteria (spontaneous pain and skin hypesthesia) or radiological criteria [45]. A single published study found that a bisphosphonate was more effective than a placebo [46]; however, the bisphosphonate was intravenous alendronate, which is not available in France; pain was evaluated only 2 weeks after the treatment; and the study included only 20 patients. Thus, there is no proof to date that intravenous bisphosphonate therapy is effective in patients with RSDS. Use of bisphosphonates in this condition indi-
cation has not been approved by regulatory authorities and cannot be recommended based on available data. BISPHOSPHONATES IN PATIENTS WITH ACUTE PAIN AFTER A VERTEBRAL CRUSH FRACTURE Osteoporotic vertebral fractures are a major source of morbidity with severe pain that often fails to respond to major analgesics and causes functional impairment. Hospitalization is often required and is associated with immobility-related complications in elderly patients [47]. Several studies have investigated the effects of antiosteoclastic agents, chiefly calcitonin, on the time-course of postfracture pain. Their results are conflicting [47]. Some studies suggest a specific analgesic effect of calcitonin. A few anecdotal reports describe the effects of bisphosphonate therapy (usually with pamidronate) as intravenous infusions. A retrospective study evaluated the analgesic effects of pamidronate infusions in 26 patients with chronic low back pain caused by vertebral fractures related to idiopathic or glucocorticoid-induced osteoporosis [48]. Three months after one infusion of 30 mg pamidronate per day on two consecutive days, the pain and disability scores were lower and the patients had stopped their analgesic treatment. Although encouraging, these findings are not sufficiently compelling to recommend widespread use of intravenous pamidronate therapy in patients with recent osteoporotic vertebral fractures. Only a placebocontrolled study with analgesic therapy as needed in both groups could prove the value of intravenous pamidronate in this indication. BISPHOSPHONATES IN PATIENTS WITH INFLAMMATORY JOINT DISEASE Few studies of bisphosphonates have been conducted in patients with rheumatoid arthritis or spondyloarthropathies. The only approved indication in these conditions is prevention and management of glucocorticoidinduced osteoporosis, particularly in patients with rheumatoid arthritis [49]. Yet, bisphosphonates have been reported to decrease juxta-articular bone loss in adjuvant arthritis in rats [50]. In patients with rheumatoid arthritis, bone loss at the lumbar spine, femur, and radius is associated with increases in bone resorption markers, which in turn are correlated with C-reactive protein levels, suggesting that the severity of the bone loss is determined in part by the severity of the inflammation [51]. Two studies evaluated the efficacy of
Bisphosphonates in bone diseases
pamidronate. In one of these studies, a single intravenous infusion of pamidronate was rapidly followed by a drop in markers for bone resorption; an effect on inflammatory disease activity was suggested by reductions in the swollen joint count, Ritchie’s index, and laboratory tests for inflammation [52]. The other study, which had a longer follow-up, found no effect on inflammation, although bone resorption markers decreased and bone mineral density increased at all three measurement sites [53]. Axial demineralization is common in patients with spondyloarthropathies [54]. Beneficial effects of pamidronate infusions on clinical manifestations of inflammation have been reported in this group of conditions [55]. However, these results are of limited value given the small size and open-label design of the study [55]. CONCLUSIONS Strong evidence indicates that bisphosphonates are useful in conditions associated with demineralization, including the short-term treatment of acute hypercalcemia, Paget’s disease of bone, and prevention of the bone complications of malignant osteolytic lesions. The additional cost related to bisphosphonate therapy is acceptable given the reduction in morbidity and the favorable risk/benefit ratio. Conversely, extending the use of bisphosphonates to a broad range of bone and joint diseases is not supported by available data [56-63]. Reason dictates that controlled studies be conducted first to determine whether bisphosphonates are effective and safe in these indications. There is an intermediate category of conditions, however, in which bisphosphonate use may be warranted despite the absence of compelling data, either because the prognosis is extremely severe, as in some forms of osteogenesis imperfecta [64], or because the condition is extremely rare, an example being fibrous dysplasia [65]. In these indications, open-label studies have produced promising results. Bisphosphonate therapy may deserve discussion in some forms of hypercalcemia not associated with malignant disease. Promising results have been obtained in open-label studies. In hypercalcemia related to hyperparathyroidism, a few case reports [66] and a small case series [67] suggest that intravenous bisphosphonates may be effective. Bisphosphonates are being increasingly used in this indication. A recent study indicates that alendronate may improve the bone status of
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patients who have primary hyperparathyroidism but cannot undergo radical surgery [68]. In all these indications, further clinical research is needed to determine whether bisphosphonates provide substantial benefits. REFERENCES 1 Breuil V. Mechanisms of action of bisphosphonates. Rev Rhum [Engl Ed] 1999 ; 66 : 339-43. 2 Orcel P, Beaudreuil J. Bisphosphonates et traitement de l’ostéoporose. Méd Thérap Endocrinol 2000 ; 2 : 129-35. 3 Orcel P, Roux C. Ostéoporose cortisonique. Rev Rhum 2001 (in press). 4 Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000 ; 343 : 604-10. 5 Devogelaer JP. Treatment of bone diseases with bisphosphonates, excluding osteoporosis. Curr Opin Rheumatol 2000 ; 12 : 331-5. 6 Beaudreuil J, Orcel P. L’hyperrésorption osseuse au cours du myélome multiple. Presse Med. 2000 ; 29 : 492-7. 7 Paule B, Clerc D, Brion N. Bisphosphonates en cancérologie. Presse Med 2000 ; 29 : 723-9. 8 Orcel P. Hypercalcémies des affections malignes. In: Kuntz D, Ed. Maladies métaboliques osseuses. Paris: Flammarion Médecine Sciences; 1996. p. 391-412. 9 Shipman CM, Rogers MJ, Apperley JF, Russell RG, Croucher PI. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997 ; 98 : 665-72. 10 Hiraga T, Williams PJ, Mundy GR, Yoneda T. The bisphosphonate ibandronate promotes apoptosis in MDA-MB-231 human breast cancer cells in bone metastases. Cancer Res 2001 ; 61 : 4418-24. 11 Purohit OP, Radstone CR, Anthony C, Kanis JA, Coleman RE. A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. Br J Cancer 1995 ; 72 : 1289-93. 12 Pecherstorfer M, Herrmann Z, Body JJ, Manegold C, Degardin M, Clemens MR, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996 ; 14 : 268-76. 13 Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001 ; 19 : 558-67. 14 Berenson JR, Lipton A. Bisphosphonates in the treatment of malignant bone disease. Annu Rev Med 1999 ; 50 : 237-48. 15 Belch AR, Bergsagel DE, Wilson K, O’Reilly S, Wilson J, Sutton D, et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol 1991 ; 9 : 1397-402. 16 Lahtinen R, Laakso M, Palva I, Virkkunen P, Elomaa I. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet 1992 ; 340 : 1049-52. 17 Heim ME, Clemens MR, Queisser W. Prospective randomized trial of dichloromethylene bisphosphonate (clodronate) in patients with multiple myeloma requiring treatment: a multicenter study. Onkologie 1995 ; 18 : 439-48. 18 McCloskey EV, MacLennan IC, Drayson MT, Chapman C, Dunn J, Kanis JA. A randomized trial of the effect of clodronate
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35
36
37 38 39 40
41
42
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44 45
46 47
48 49
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Kruse HP, et al. Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget’s disease of bone. Arthritis Rheum 1995 ; 38 : 851-8. Miller PD, Brown JP, Siris ES, Hoseyni MS, Axelrod DW, Bekker PJ. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget’s disease of bone. Paget’s Risedronate/Etidronate Study Group. Am J Med 1999 ; 106 : 513-20. Siris ES, Chines AA, Altman RD, Brown JP, Johnston CC, Lang R, et al. Risedronate in the treatment of Paget’s disease of bone: an open label, multicenter study. J Bone Miner Res 1998 ; 13 : 1032-8. Gutteridge DH, Ward LC, Stewart GO, Retallack RW, Will RK, Prince RL, et al. Paget’s disease: acquired resistance to one aminobisphosphonate with retained response to another. J Bone Miner Res 1999 ; 14 (Suppl 2) : 79-84. Selby PL. Pamidronate in the treatment of Paget’s disease. Bone 1999 ; 24 (Suppl 5) : 57-8. Chapurlat RD, Delmas PD, Liens D, Meunier PJ. Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. J Bone Miner Res 1997 ; 12 : 1746-52. Weinstein RS. Long-term aminobisphosphonate treatment of fibrous dysplasia: spectacular increase in bone density. J Bone Miner Res 1997 ; 12 : 1314-5. Glorieux FH, Bishop NJ, Plotkin H, Chabot G, Lanoue G, Travers R. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998 ; 339 : 947-52. Brumsen C, Hamdy NA, Papapoulos SE. Long-term effects of bisphosphonates on the growing skeleton. Studies of young patients with severe osteoporosis. Medicine (Baltimore) 1997 ; 76 : 266-83. Plotkin H, Rauch F, Bishop NJ, Montpetit K, Ruck-Gibis J, Travers R, et al. Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab 2000 ; 85 : 1846-50. Cortet B, Flipo RM, Coquerelle P, Duquesnoy B, Delcambre B. Treatment of severe, recalcitrant reflex sympathetic dystrophy: assessment of efficacy and safety of the second generation bisphosphonate pamidronate. Clin Rheumatol 1997 ; 16 : 51-6. Maillefert JF, Cortet B, Aho S. Pooled results from 2 trials evaluating biphosphonates in reflex sympathetic dystrophy. J Rheumatol 1999 ; 26 : 1856-7. Liens D, Lavoignat D, Meunier PJ, Delmas PD. Bisphosphonate et algodystrophie réflexe. In: Simon L, Pélissier J, Hérisson C, Eds. Actualités en rééducation fonctionnelle et réadaptation, 20th series. Paris: Masson; 1995. p. 380-2. Adami S, Fossaluzza V, Gatti D, Fracassi E, Braga V. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 1997 ; 56 : 201-4. Dubourg G, Orcel P. Traitement d’une fracture vertébrale ostéoporotique récente. In: Kahn MF, Kuntz D, Meyer O, Bardin T, Orcel P, Guérin C, Eds. l’Actualité rhumatologique 1999. Paris: Expansion Scientifique Publications; 1999. p. 40621. Gangji V, Appelboom T. Analgesic of intravenous pamidronate on chronic back pain due to osteoporotic vertebral fractures. Clin Rheumatol 1999 ; 18 : 266-7. Eastell R, Devogelaer JP, Peel NF, Chines AA, Bax DE, SaccoGibson N, et al. Prevention of bone loss with risedronate in glucocorticoid-treated rheumatoid arthritis patients. Osteoporos Int 2000 ; 11 : 331-7. Muller K, Wiesenberg I, Jaeggi K, Green JR. Effects of the
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52
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56 57 58
bisphosphonate zoledronate on bone loss in the ovariectomized and in the adjuvant arthritic rat. Arzneimittelforschung 1998 ; 48 : 81-6. Gough A, Sambrook P, Devlin J, Huissoon A, Njeh C, Robbins S, et al. Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis. J Rheumatol 1998 ; 25 : 1282-9. Eggelmeijer F, Papapoulos SE, Van Paassen HC, Dijkmans BA, Breedveld FC. Clinical and biochemical response to single infusion of pamidronate in patients with active rheumatoid arthritis: a double blind placebo controlled study. J Rheumatol 1994 ; 21 : 2016-20. Eggelmeijer F, Papapoulos SE, Van Paassen HC, Dijkmans BA, Valkema R, Westedt ML, et al. Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three-year randomized, double-blind trial. Arthritis Rheum 1996 ; 39 : 396-402. Toussirot E, Ricard-Blum S, Dumoulin G, Cedoz JP, Wendling D. Relationship between urinary pyridinium cross-links, disease activity and disease subsets of ankylosing spondylitis. Rheumatology (Oxford) 1999 ; 38 : 21-7. Maksymowych WP, Lambert R, Jhangri GS, Leclercq S, Chiu P, Wong B, et al. Clinical and radiological amelioration of refractory peripheral spondyloarthritis by pulse intravenous pamidronate therapy. J Rheumatol 2001 ; 28 : 144-55. Guis S, Pellissier JF, Arniaud D, Turck F, Witjas T, Roux H, et al. Healing of Charcot’s joint by pamidronate infusion. J Rheumatol 1999 ; 26 : 1843-5. Haworth CS, Selby PL, Adams JE, Mawer EB, Horrocks AW, Webb AK. Effect of intravenous pamidronate on bone mineral density in adults with cystic fibrosis. Thorax 2001 ; 56 : 314-6. Marshall A, Kavanagh RT, Crisp AJ. The effect of pamidronate on lumbar spine bone density and pain in osteoporosis secondary to systemic mastocytosis. Br J Rheumatol 1997 ; 36 : 393-6.
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59 Ciana G, Cuttini M, Bembi B. Short-term effects of pamidronate in patients with Gaucher’s disease and severe skeletal involvement. N Engl J Med 1997 ; 337 : 712. 60 Samuel R, Katz K, Papapoulos SE, Yosipovitch Z, Zaizov R, Liberman UA. Aminohydroxy propylidene bisphosphonate (APD) treatment improves the clinical skeletal manifestations of Gaucher’s disease. Pediatrics 1994 ; 94 : 385-9. 61 Ostlere L, Warner T, Meunier PJ, Hulme P, Hesp R, Watts RW, et al. Treatment of type 1 Gaucher’s disease affecting bone with aminohydroxypropylidene bisphosphonate (pamidronate). Q J Med 1991 ; 79 : 503-15. 62 Brantus JF, Meunier PJ. Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clin Orthop 1998 ; 346 : 117-20. 63 Need AG, Angel KA, Cornish BL, Phillips PJ. Diphosphonates for periarticular ossification. Lancet 1982 ; 1 : 1130. 64 Chevrel G, Meunier PJ. Osteogenesis imperfecta: lifelong management is imperative and feasible. Rev Rhum [Engl Ed] 2001 ; 68 : 125-9. 65 Lane JM, Khan SN, O’Connor WJ, Nydick M, Hommen JP, Schneider R, et al. Bisphosphonate therapy in fibrous dysplasia. Clin Orthop 2001 ; 382 : 6-12. 66 Tal A, Graves L. Intravenous pamidronate for hypercalcemia of primary hyperparathyroidism. South Med J 1996 ; 89 : 637-40. 67 Jansson S, Tisell LE, Lindstedt G, Lundberg PA. Disodium pamidronate in the preoperative treatment of hypercalcemia in patients with primary hyperparathyroidism. Surgery 1991 ; 110 : 480-6. 68 Rossini M, Gatti D, Isaia G, Sartori L, Braga V, Adami S. Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism. J Bone Miner Res 2001 ; 16 : 113-9.
REVIEW
Bisphosphonates in bone diseases other than osteoporosis Philippe Orcel*, Johann Beaudreuil Fédération de rhumatologie, centre Viggo-Petersen, hôpital Lariboisière, 2, rue Ambroise-Paré, 75475 Paris cedex 10, France (Submitted for publication June 20, 2001; accepted in revised form August 13, 2001)
Summary – The range of bone diseases in which bisphosphonates are used has extended far beyond osteoporosis during the last few years. Bisphosphonate therapy is now so well validated as to be the reference standard in Paget’s disease and in the prevention of bone complications related to malignant osteolysis. Promising preliminary findings warrant the use of bisphosphonates in conditions that are either rare (fibrous dysplasia) or severe (pediatric osteogenesis imperfecta). The third category of indications encompasses many conditions in which the limited available data do not warrant widespread use: examples include reflex sympathetic dystrophy syndrome, acute back pain after a vertebral crush fracture, and chronic inflammatory joint disease not treated by glucocorticoids. Joint Bone Spine 2002 ; 69 : 19-27. © 2002 Éditions scientifiques et médicales Elsevier SAS bisphosphonates / bone resorption / fibrous dysplasia / malignant osteolysis / osteogenesis imperfecta / Paget’s disease
INTRODUCTION Bisphosphonates are potent antiosteoclastic agents, whose chemical structure is derived from the pyrophosphate nucleus (figure 1). Various molecular mechanisms lead to inactivation and increased apoptosis of mature osteoclasts [1]. These effects decrease bone resorption, making bisphosphonates a treatment of choice in many bone diseases characterized by an increase in osteoclastic resorption. Over the last decade, several bisphosphonates have been introduced on the market for the treatment of osteoporosis, Paget’s disease, and the clinical manifestations of malignant osteolysis (table I).
* Correspondence and reprints. E-mail address: [email protected] (P. Orcel).
Postmenopausal osteoporosis and glucocorticoidinduced osteoporosis are well-validated indications discussed in recent review articles [2, 3]. Male osteoporosis has generated considerable controversy despite convincing evidence that alendronate is effective [4]; however, this drug has recently been licensed for use in men with osteoporotic fractures. Clearly, bisphosphonates are valuable in bone diseases other than osteoporosis [5]. In some of these diseases, bisphosphonates have been approved by regulatory authorities (table I), whereas in others they are being increasingly used in clinical practice (table II). The present review of scientific evidence supporting bisphosphonate therapy in conditions other than osteoporosis is designed to help practicing rheumatologists make treatment decisions.
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Figure 1. Diagram of the chemical formulas of the phosphate and phosphonate rings and of the main bisphosphonates used in clinical practice. Note the theoretical formula of the ‘diphosphonate’ ring, a name often used inappropriately instead of bisphosphonate.
In many of the indications discussed here, bisphosphonates are used parenterally. Several arguments suggest that injection may be better than oral administration. Because the intestinal absorption of bisphosphonates is poor, these agents are more powerful when given parenterally. Furthermore, orallyadministered aminobisphosphonates can produce gastrointestinal side effects. Parenteral administration is useful or indispensable in patients who have difficulty taking medications by mouth. Finally, parenteral administration ensures good long-term compliance. BISPHOSPHONATES IN PATIENTS WITH MALIGNANT OSTEOLYSIS The pivotal role played by osteoclasts in the genesis of the clinical symptoms of malignant osteolysis provides
the pathophysiological rationale for using bisphosphonates in this indication [6, 7]. When present in the bone, tumor cells from multiple myeloma or solid tumor metastases stimulate the recruitment and activation of osteoclasts and increase their survival time (figure 2). Increased osteoclastic resorption is among the central mechanisms underlying hypercalcemia of malignancy [8]. In addition, by decreasing the mechanical strength of bone, excessive osteoclastic resorption causes pain and increases the risk of fracture. Bone resorption results in local release of growth factors that stimulate tumor cell proliferation, generating a vicious circle that magnifies the above-described phenomena. Bisphosphonates put an end to this vicious circle by potently inhibiting resorption (figure 2). Finally, recent evidence suggests that some bisphosphonates may have direct antitumoral effects by inducing apoptosis of malignant plasma cells [9, 10]. Three bisphosphonates are available. Table III recapitulates their indications, dosages, and modalities of administration. In hypercalcemia, bisphosphonate therapy is usually started intravenously as a series of slow intravenous infusions in isotonic saline [8]. In a direct comparison of intravenous pamidronate and clodronate, efficacy was similar, but escape phenomenon occurred after only 14 days of clodronate as compared to 28 days of pamidronate [11]. In practice, it is important to bear in mind that rehydration must be achieved before intravenous bisphosphonate therapy is started and that serum calcium levels take several days to return to normal [8]. Two new bisphosphonates, ibandronate and zoledronate, have been proved effective in this indication [12, 13] and will probably be added soon to our therapeutic armamentarium. Bisphosphonates have shown efficacy in controlling the symptoms related to bone fragility in patients with malignant osteolytic lesions [14]. During the last few years, placebo-controlled studies of intravenous and oral bisphosphonate therapy in myeloma [15-20] (table IV) and metastatic breast cancer [21-27] (table V) have been published. Monthly infusions of pamidronate, 90 mg, significantly decreased fractures and other bone complications, as well as use of analgesic radiation therapy, in patients with myeloma [20] or metastatic breast cancer [22, 23, 28]. Overall, bone complication rates fell by 35 to 50% in these trials. No factors predictive of this bone response were identified; in particular, bone turnover markers were not helpful in identifying future responders. This evidence of major benefits provided by intravenous pamidronate has
21
Bisphosphonates in bone diseases Table I. Bone disease indications of bisphosphonate therapy approved by French regulatory authorities as of May 2001. Osteoporosis Treatment Etidronate Didronelt Clodronate Clastobant, Lytost Pamidronate Arediat Tiludronate Skelidt Alendronate Fosamaxt Risedronate Actonelt Ibandronate Bondronatt Zolendronate Zometat
Prevention
Males
✚
Paget’s disease Glucocorticoidinduced ✚
Malignant osteolysis Hypercalcemia
Bone complications
✚
✚
✚
✚
✚
✚ ✚ ✚
✚
✚
✚
* ✚
✚ ✚ ✚
* Alendronate is not approved for the treatment of male osteoporosis but has been granted a 1-year period of reimbursement by the French national health insurance system when used in males with a history of osteoporotic fractures.
recently led the American Society of Clinical Oncology [29] to recommend this treatment in patients with metastatic breast cancer and symptomatic bone lesions (table VI). Clodronate can be used also by the oral route. The level of proof of efficacy in myeloma patients is far lower than for pamidronate, and this indication is not approved in France. Clodronate seems more promising Table II. Indications in which injectable pamidronate is used despite absence of approval from regulatory authorities. The bold type shows indications for which open-label studies suggest clinical efficacy and the italic type indications for which only anecdotal case reports or small series are available, the results being inconclusive or conflicting. Osteogenesis imperfecta (40, 42) Glucocorticoid-induced osteoporosis, osteoporosis in transplant recipients Fibrous dysplasia (38, 39, 65) Reflex sympathetic dystrophy syndrome (43, 44, 45, 46 [injectable alendronate]) Back pain after vertebral crush fractures (47) Rheumatoid arthritis, spondyloarthropathies (52, 53, 55) Gaucher’s disease (59, 60, 61) Cystic fibrosis (57) Mastocytosis (58) Myositis ossificans progressiva (62 [injectable etidronate]) Neuropathic arthropathies (Charcot’s foot) (56) Periarticular ossifications (63)
as a treatment of metastatic breast cancer (table V). In a study of patients with marrow micrometastases, oral clodronate therapy significantly reduced the rates of occurrence of bone metastases and soft tissue metastases and significantly increased survival [26]. This finding is controversial, however, as it has not been reported by other investigators. Consequently, clodronate should be used only as an adjunct to specific therapy. Furthermore, in another study, clodronate therapy was associated with decreased survival in women with breast cancer and positive nodes at diagnosis [27]. Ibandronate and zoledronate have been evaluated recently in this indication, with promising results [30]. BISPHOSPHONATES IN PATIENTS WITH PAGET’S DISEASE The considerable increase in bone turnover that characterizes Paget’s disease is a strong invitation to use bisphosphonates [31]. The goals are to alleviate bone pain in the short term and to prevent delayed bone, joint, and neurological complications in the long term [32]. Oral bisphosphonates (etidronate, tiludronate, or risedronate) are generally used first. Etidronate was less effective than the other two agents in direct comparisons [33, 34]. Thus, etidronate should be reserved for patients with little evidence of disease progression. Rates
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Figure 2. Diagram of interactions between bone and tumor cells. Mediators (cytokines, etc.) released into the bone environment by the tumor cells activate the osteoclasts and increase bone resorption. This produces a constellation of symptoms related to bone frailty and results in local release of matrix growth factors that stimulate tumor cell proliferation, perpetuating a vicious circle. There is incontrovertible proof that bisphosphonates inhibit osteoclast activity, thereby decreasing bone resorprtion. Bisphosphonates may also act directly on tumor cells to shorten their survival.
of partial remission (defined as a 50% or greater fall in serum alkaline phosphatase levels) decreased by 60–70% with tiludronate and by 85% with risedronate [33, 35]. Complete remission (return to normal of Table III. Indications and dosage of injectable bisphosphonates in malignant osteolysis related to myeloma and metastatic cancer. Indication Clodronate (Clastobant, Lytost) Pamidronate (Arediat) Ibandronate (Bondronatt)
hypercalcemia osteolysis hypercalcemia osteolysis hypercalcemia
Dosage IV/ 300 mg/d × 2–5 d PO/ 1600 mg/d IV/ 60-90 mg/d IV/ 90 mg/month IV/ 2-4 mg (single infusion)
alkaline phosphatase levels) occurred in about 25% of patients given tiludronate for 3 months and in 85% of patients given risedronate for 2 months. Unresponsiveness has been reported with etidronate but not tiludronate or risedronate; in patients who failed to respond to etidronate, switching to one of the other agents was followed by clinical and laboratory test improvements [36]. Pamidronate is used intravenously 2 or 3 consecutive days. Response rates and complete remission rates were high in all published studies, and the time to clinical improvement was very short [37]. Pamidronate is useful in patients with very extensive lesions, rapid lesion
Table IV. Controlled studies of the efficacy of bisphosphonates in preventing bone complications in patients with multiple myeloma. The gray areas indicate the study of the treatment regimen that is available in France. Study
N
BP
Belch 1991 [15] Lahtinen 1992 [16] Heim 1995 [17] McCloskey 1998 [18] Brincker 1998 [19] Berenson 1998 [20]
166 336 157 536 300 377
eti clo clo clo pami pami
Dose
Route
Duration
Osteolysis
Pain
Pathologic fractures
Radiation therapy/surgery
5 mg/kg/d 2400 mg/d 1600 mg/d 1600 mg/d 300 mg/d 90 mg/mo
PO PO PO PO PO IV
→ death 24 mo 12 mo 48 mo 18 mo 21 mo
0 + 0 ? 0 0
0 0 + 0 + +
0 0 0 + 0 +
? ? ? 0 0 +
BP: bisphosphonate; eti: etidronate; clo: clodronate; pami: pamidronate; PO: treatment given per os; IV: treatment given intravenously. 0: no proof of efficacy; +: significant efficacy; ?: inconclusive data.
23
Bisphosphonates in bone diseases
Table V. Controlled studies of the efficacy of bisphosphonates in preventing bone complications in women with metastatic breast cancer. Cells with any level of gray indicate studies of treatment regimens that are available in France. Dark gray cells indicate studies of clodronate for preventing bone metastases in patients with nonmetastatic breast cancer at clodronate initiation. Study
N
BP
Dosage
Route
Duration Anti-E
Time to Complication Patients with Survival Time to 1st rate metastases radiological complication progression
Paterson 1993 [21] Hortobagyi 1996 [22] Theriault 1999 [23] Conte 1996 [24] Kanis 1997 [25]
173 380 372 295 133
clo pami pami pami clo
1600 mg/d 90 mg/mo 90 mg/mo 45 mg/3 wk 1600 mg/d
PO IV IV IV PO
12 mo 24 mo 12 mo 36 mo
– – – – +
Diel 1999 [26]
302
clo
1600 mg/d
PO
24 mo
+
Saarto 2001 [27]
299
clo
1600 mg/d
PO
36 mo
+
idem ↑ ↑
↓ 33% ↓ 14% ↓
↑ 11.3% vs. 14.3% (NS) 6.9% vs. 13.9% P < 0.001 21% vs. 24% (NS)
= ↑ ↓
BP: bisphosphonate; clo: clodronate; pami: pamidronate; PO: treatment given per os; IV: treatment given intravenously. Anti-E: adjuvant antiestrogen therapy.
progression, or incipient evidence of neurological compromise that does not require emergency surgical treatment. BISPHOSPHONATES IN PATIENTS WITH FIBROUS DYSPLASIA Fibrous dysplasia manifests as tumor-like osteolytic lesions. One or more bones can be affected; in polyostotic forms, the lesions are often confined to the limbs on one side of the body. The long bones and skull are predominantly affected. Clinical manifestations include pain, fractures of long bones related to decreased mechanical strength, deformities, and compression of neurological structures. An open-label study by Chapurlat et al. found that intravenous pamidronate given daily for 3 consecutive Table VI. Recommendations issued by the American Society of Clinical Oncology (ASCO) about intravenous bisphosphonates in patients with metastatic breast cancer [29]. 1. Monthly infusion (3–4 weeks) of 90 mg pamidronate – Metastatic cancer with radiographic lesions and concomitant chemotherapy/hormonal therapy (high level of proof) – Painful lesion not seen on radiographs but visible by another imaging technique (low level of proof) 2. Biochemical markers for bone turnover not helpful 3. Duration not well defined → until the terminal stage 4. Concomitant use of other analgesic treatments 5. Do not use in patients with nonskeletal metastases 6. Oral bisphosphonate therapy recommended to prevent chemotherapy-induced osteoporosis
days in a cumulative dosage of 180 mg on four occasions 6 months apart relieved the pain related to the dysplastic lesions and increased the density of longbone lytic lesions in some patients [38, 39]. The fracture risk was not evaluated because of the small size and marked heterogeneity of the study population. A controlled study would be of considerable interest to evaluate the efficacy of parenteral bisphosphonate therapy in patients with fibrous dysplasia. However, the low prevalence and marked heterogeneity of the disease are major obstacles to such a study. BISPHOSPHONATES IN PATIENTS WITH OSTEOGENESIS IMPERFECTA Osteogenesis imperfecta is a particularly severe variant of juvenile osteoporosis caused by mutations in genes encoding type 1 collagen chains. In the most severe forms of osteogenesis imperfecta, namely, types III and IV, severe osteoporosis develops in early infancy, causing multiple fractures, growth disorders, spinal deformities, and major disability. Until the recent introduction of bisphosphonates, treatment options were extremely limited. Pamidronate given as intermittent intravenous infusions was recently evaluated in an open-label study in about 30 children aged 3 to 16 years [40]. The results showed an increase in adjusted bone mineral density; there was some evidence of reductions in fractures, pain, and disability. No growth delay or other major side effects were noted, in keeping with a review of case reports of young
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children given bisphosphonates to treat juvenile osteoporosis [41]. The group that conducted the first open-label study [40] has recently reported a second open-label study [42] comparing pamidronate-treated patients to untreated age-matched controls. All patients and controls were younger than 3 years of age. The results confirmed the favorable effects of pamidronate found in the earlier study. There are major, perhaps insurmountable, ethical obstacles to a placebo-controlled trial of bisphosphonates in patients with osteogenesis imperfecta. Available data are more than encouraging and establish the beneficial effects of pamidronate infusions in children with severe forms of the disease. Alendronate is under evaluation in patients with less severe disease (particularly type I). BISPHOSPHONATES IN PATIENTS WITH REFLEX SYMPATHETIC DYSTROPHY SYNDROME Reflex sympathetic dystrophy syndrome (RSDS) is characterized by bone demineralization, usually triggered by an injury. Severe pain is the main symptom. Local and regional trophic disorders are common. RSDS can become chronic, and none of the treatments that are used empirically have been found effective in controlled clinical trials. The marked heterogeneity of RSDS is a major stumbling block for therapeutic trials. Nevertheless, bisphosphonates have been evaluated recently in this condition. A few open-label studies suggested beneficial effects, particularly on the time-course of the pain [43, 44]. This criterion, however, is of limited value in open-label studies of RSDS, a condition in which the placebo effect is probably large and spontaneous resolution of the pain a common outcome. A single multicenter, randomized placebo-controlled study of pamidronate infusions has been published. Pamidronate was used in a dosage of 75 mg or 150 mg. No significant differences were found among the groups for clinical criteria (spontaneous pain and skin hypesthesia) or radiological criteria [45]. A single published study found that a bisphosphonate was more effective than a placebo [46]; however, the bisphosphonate was intravenous alendronate, which is not available in France; pain was evaluated only 2 weeks after the treatment; and the study included only 20 patients. Thus, there is no proof to date that intravenous bisphosphonate therapy is effective in patients with RSDS. Use of bisphosphonates in this condition indi-
cation has not been approved by regulatory authorities and cannot be recommended based on available data. BISPHOSPHONATES IN PATIENTS WITH ACUTE PAIN AFTER A VERTEBRAL CRUSH FRACTURE Osteoporotic vertebral fractures are a major source of morbidity with severe pain that often fails to respond to major analgesics and causes functional impairment. Hospitalization is often required and is associated with immobility-related complications in elderly patients [47]. Several studies have investigated the effects of antiosteoclastic agents, chiefly calcitonin, on the time-course of postfracture pain. Their results are conflicting [47]. Some studies suggest a specific analgesic effect of calcitonin. A few anecdotal reports describe the effects of bisphosphonate therapy (usually with pamidronate) as intravenous infusions. A retrospective study evaluated the analgesic effects of pamidronate infusions in 26 patients with chronic low back pain caused by vertebral fractures related to idiopathic or glucocorticoid-induced osteoporosis [48]. Three months after one infusion of 30 mg pamidronate per day on two consecutive days, the pain and disability scores were lower and the patients had stopped their analgesic treatment. Although encouraging, these findings are not sufficiently compelling to recommend widespread use of intravenous pamidronate therapy in patients with recent osteoporotic vertebral fractures. Only a placebocontrolled study with analgesic therapy as needed in both groups could prove the value of intravenous pamidronate in this indication. BISPHOSPHONATES IN PATIENTS WITH INFLAMMATORY JOINT DISEASE Few studies of bisphosphonates have been conducted in patients with rheumatoid arthritis or spondyloarthropathies. The only approved indication in these conditions is prevention and management of glucocorticoidinduced osteoporosis, particularly in patients with rheumatoid arthritis [49]. Yet, bisphosphonates have been reported to decrease juxta-articular bone loss in adjuvant arthritis in rats [50]. In patients with rheumatoid arthritis, bone loss at the lumbar spine, femur, and radius is associated with increases in bone resorption markers, which in turn are correlated with C-reactive protein levels, suggesting that the severity of the bone loss is determined in part by the severity of the inflammation [51]. Two studies evaluated the efficacy of
Bisphosphonates in bone diseases
pamidronate. In one of these studies, a single intravenous infusion of pamidronate was rapidly followed by a drop in markers for bone resorption; an effect on inflammatory disease activity was suggested by reductions in the swollen joint count, Ritchie’s index, and laboratory tests for inflammation [52]. The other study, which had a longer follow-up, found no effect on inflammation, although bone resorption markers decreased and bone mineral density increased at all three measurement sites [53]. Axial demineralization is common in patients with spondyloarthropathies [54]. Beneficial effects of pamidronate infusions on clinical manifestations of inflammation have been reported in this group of conditions [55]. However, these results are of limited value given the small size and open-label design of the study [55]. CONCLUSIONS Strong evidence indicates that bisphosphonates are useful in conditions associated with demineralization, including the short-term treatment of acute hypercalcemia, Paget’s disease of bone, and prevention of the bone complications of malignant osteolytic lesions. The additional cost related to bisphosphonate therapy is acceptable given the reduction in morbidity and the favorable risk/benefit ratio. Conversely, extending the use of bisphosphonates to a broad range of bone and joint diseases is not supported by available data [56-63]. Reason dictates that controlled studies be conducted first to determine whether bisphosphonates are effective and safe in these indications. There is an intermediate category of conditions, however, in which bisphosphonate use may be warranted despite the absence of compelling data, either because the prognosis is extremely severe, as in some forms of osteogenesis imperfecta [64], or because the condition is extremely rare, an example being fibrous dysplasia [65]. In these indications, open-label studies have produced promising results. Bisphosphonate therapy may deserve discussion in some forms of hypercalcemia not associated with malignant disease. Promising results have been obtained in open-label studies. In hypercalcemia related to hyperparathyroidism, a few case reports [66] and a small case series [67] suggest that intravenous bisphosphonates may be effective. Bisphosphonates are being increasingly used in this indication. A recent study indicates that alendronate may improve the bone status of
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