Alen 1

CURRENT THERAPEUTIC RESEARCH” VOL. 56, NO. 9, SEPTEMBER 1995

ORAL BISPHOSPHONATES IN THE TREATMENT OF OSTEOPOROSIS: A REVIEW ROGER M. FRANCIS

Freeman Hospital, Newcastle upon Tyne, United Kingdom

ABSTRACT Osteoporosis is characterized by decreased bone mass and disrupted bone architecture, which reduce bone strength and increase the risk of fracture. Bisphosphonates, although poorly absorbed from the gut when given orally, are preferentially localized to the skeleton where they inhibit bone resorption. This provides the rationale for their use in the treatment of diseases of high bone turnover, such as Paget’s disease and hypercalcemia of malignancy. The antiresorptive action of bisphosphonates is also useful in the management of osteoporosis, in which the rate of bone resorption exceeds that of bone formation. Cyclical etidronate and alendronate are the most extensively studied bisphosphonates in the management of osteoporosis, but limited data are also available for pamidronate, clodronate, tiludronate, and risedronate. All bisphosphonates have a similar rate of action, and their efficacy in increasing spinal bone mass in women with postmenopausal osteoporosis is broadly comparable over 2 to 3 years. The increase in spinal bone mass achieved with cyclical etidronate is associated with at least a 50% decrease in vertebral fracture rate, which is comparable to that seen with hormone replacement therapy, calcitonin, and, in preliminary data, for alendronate. Both cyclical etidronate and alendronate increase hip bone mass in patients with osteoporosis. The long-term safety data available for cyclical etidronate are generally favorable; clinical osteomalacia has not been experienced with the cyclical regimen during 7 years of treatment. Comparable long-term safety data are not yet available for the other bisphosphonates. The most common adverse events with oral bisphosphonate treatment are mild gastrointestinal disturbances, with an incidence rate generally similar to that with placebo and/or calcium. There have been reports, however, of erosive esophagitis during treatment with oral pamidronate and a higher incidence of abdominal pain during treatment with alendronate than with placebo and/or calcium; both of these compounds are amino bisphosphonates. Extensive experience with cyclical etidronate has established its long-term efficacy and safety. Long-term data are needed for the newer bisphosphonates, in order to position them correctly alongside the various other therapeutic options available for the successful management of osteoporosis. INTRODUCTION Osteoporosis is a common skeletal disease characterized by decreased bone mass and disrupted bone architecture, which together reduce bone Address conwpondence to: Dr. Roger M. Francis, Consultant Physician, Musculo-Skeletal Department, Freeman Hospital, High Heaton, Newcastle upon Tyne NE7 7DN, UK. Received forpublication on July 12,1995. Printed in the U.S.A. Reproduction in whole or part is not permitted. 831

0011~3931[/96/$3.60

strength and increase the risk of fracture.’ Fractures that occur as a resul of osteoporosis constitute a major health problem in the developed work and cause considerable morbidity and mortality among the elderly. It ha, been estimated that 60,000 hip fractures, 40,000 symptomatic vertebra fractures, and 50,000 radial fractures occur each year in the United King dom, and that osteoporotic fractures in England and Wales result in JZ74: million per year in health care costs, most of which are the direct hospita costs of treatment for hip fractures.’ Osteoporosis can be treated with either anabolic agents that stimulat bone formation or antiresorptive agents that decrease bone resorption Anabolic agents include fluoride, parathyroid hormone, and anabolic ste roids. Although fluoride produces a large increase in trabecular bone den sity, several studies show no reduction in the risk of fracture (reviewed ii Reginster3). The androgenic side effects of anabolic steroids make then unacceptable to most women, and the use of parathyroid hormone is stil experimental. Antiresorptive agents, which are more widely used thal anabolic agents in the management of osteoporosis, include hormone re placement therapy (HRT), calcitonin, calcium supplements with or with out vitamin D, and bisphosphonates. These agents all decrease bone loss and some produce a significant increase in bone mass, which is associates with a reduction in the rate of vertebral or hip fractures (see Reginster and Fleisch4 for general reviews of these agents and preclinical studies a the bisphosphonates). HRT is probably the therapy of choice for the prevention of osteopa rosis in most early postmenopausal women because it halts bone loss an reduces the risk of forearm, spinal, and hip fractures. HRT is effective il preventing bone loss and reducing the risk of further vertebral fractures il women with established spinal osteoporosis.6*6It also alleviates climac teric symptoms and reduces the risk of cardiovascular disease. Up to 509 of patients who begin HRT, however, discontinue therapy within ( months,7 and overall compliance with HRT may be as low as 30%.* Th main reasons cited are fear of cancer8’g and dislike of the return of month1 bleeding.7 Some women also complain of fluid retention and weight gait neither of which has been observed in clinical studies. In addition, man cases of osteoporosis are present in elderly women for whom the return a monthly bleeding is unacceptable. Such elderly patients, in addition t younger ones who refuse HRT, may benefit from other nonhormonal treat ments to reduce the incidence of subsequent osteoporosis-related fracturer The use of HRT in the management of osteoporosis in a large proportion c women, therefore, may be compromised by poor compliance. This is eve] more important in the prevention of osteoporosis, because HRT must b used for periods of 5 to 10 years to establish a fracture benefit. The mechanism by which the bisphosphonates inhibit bone resorption is still not completely clear. It is generally agreed that after deposition i 332

R. hf. FTtANcls

bone these agents inhibit osteoclastic activity; however, recent findings indicate that this may be the result of a decrease in the secretion of osteoclast-stimulating factors by osteoblasts4 Whether both mechanisms operate simultaneously in vivo and which mechanism is more important have not yet been determined. Bisphosphonates decrease bone resorption, but because of the coupling of bone resorption and formation, there is a subsequent decrease in bone formation, resulting in an overall decrease in bone turnover. This provides the rationale for the use of bisphosphonates in diseases characterized by high rates of bone turnover, such as Paget’s disease and hypercalcemia of malignancy. The antiresorptive action of bisphosphonates is also useful in the management of osteoporosis, where the rate of bone resorption exceeds that of bone formation. Clinical data are available for the use of etidronate, alendronate, pamidronate, clodronate, tiludronate, and risedronate in the treatment of osteoporosis. This paper reviews the evidence that bisphosphonates increase bone mass with no deleterious effects on the biomechanical properties of the bone, thus decreasing the rate of vertebral fracture in patients with osteoporosis. CLASSIFICATION

OF THE BISPHOSPHONATES

Bisphosphonates, analogues of pyrophosphate, contain a carbon instead of an oxygen atom, which allows many structural variations (Figure 1). Etidronate and clodronate have simple alkyl or halide side chains, alendronate and pamidronate both have amino side chains, and tiludronate and risedronate have cyclic side chains. Bisphosphonates possess both class and individual properties. As a class, they are not metabolized, but are absorbed, stored, and excreted unchanged by the body. A relatively small amount of any bisphosphonate is absorbed from the gut; for example, only 3.5% of etidronate” and 0.75% of alendronate” are absorbed when administered orally. Because absorption is further reduced by food and minerals” (such as iron, magnesium, and calcium), oral bisphosphonates should be taken on an empty stomach. The manufacturers recommend that oral etidronate be taken with water in the middle of a 4-hour fast and that alendronate be taken with water after an overnight fast, at least 30 minutes before the first food or medication intake of the day. Of the absorbed drug, however, 20% to 50% binds to bone within 12 to 24 hours due to the strong affinity of bisphosphonates for calcium phosphate. Subsequently, the bound drug remains inactive for many years.12 The presence of the different side chains confers diverse physicochemical and biological properties on the members of the bisphosphonate class. Thus, although all the bisphosphonates have a high affinity for bone and may inhibit calcification by physicochemical mechanisms,4 this inhibition 833

ORAL BISPHOSPHONAW

O=P-

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r O=P-C-P=0

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Etidronate (l-hydroxyethylidene)

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bisphosphonate

Alendronate (4-amino-1-hydroxybutylidene)

bisphosphonate

I O-

Pamidronate (3-amino-l -hydroxypropylidene)

I o-

I OH

I o-

r

T

7

c -

P=O

I Cl

I o-

I o-

OF OSTElOPOROSIS

I o-

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IN THE TFtEATMENT

bisphosphonate

Clodronate (dichloromethylene) bisphosphonate

$

iv7 O=PI 0-

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I H

I O-

Tiludronate ([(4chlorophenyl)

thio]-methylene) bisphosphonate

?

ir O=PI o-

Risedronate (1-hydroxy-2-[3-pyridinyll-ethylidene)

i”‘TC-P=0 I H

I o-

Figure 1. Chemical structures of the main bisphosphonates.

834

bisphosphonate

R. M. FRANCIS

varies considerably between them and is not related to antiresorptive potency.13 The differences in antiresorptive potency may be due to different biochemical effects at the cellular level resulting from the differences in structure of the various drugs. Although bisphosphonates are often classified according to their antiresorptive potency, their very different properties dictate that each should be considered individually. The accumulating clinical evidence presented in this paper suggests that the relationship of clinical benefit to potency in osteoporosis is questionable, and that greater potency may be related to a higher incidence of adverse events, such as those seen with amino bisphosphonates. Dose-related gastrointestinal side effects may occur in up to 50% of patients using oral pamidronate; drug-related erosive esophagitis has also been reported recently.14 END POINTS IN OSTROPOROSIS CLINICAL TRIALS

Before discussing the efficacy of bisphosphonates in osteoporosis, it is appropriate to consider the ways in which efficacy is measured. Evaluation of the efficacy of treatments for osteoporosis poses a major challenge, largely because postmenopausal osteoporosis results from progressive bone loss over a period of 10 to 40 years after menopause. As much as 30% to 50% of the peak bone mass may have been lost by the time osteoporosis is diagnosed. l6 The most stringent proof of therapeutic benefit is obtained from appropriately conducted studies in which determination of fracture rates is the primary end point.” In practice, however, several thousand patients must be studied to produce results of sufficient power to confirm a significant reduction in fracture rate, and treatment must be continued for several years. Thus, although fracture rate is the preferred clinical end point, in most studies it has been assessed as an efficacy variable, and significant effects for individual or optimal dose regimens often have not yet been demonstrated.16 The problem is further compounded by the difficulty of diagnosing vertebral fractures and the use of several different assessment or diagnostic criteria.16 The difficulties inherent in using fracture rate as the primary end point necessitate a more readily applicable method of measuring clinical efficacy. Several consensus conferences have defined osteoporosis as an increase in fracture risk due to decreased bone rnas8.l Several recent epidemiologic studies have shown that the risk of fracture increases exponentially as bone mass decreases: overall, each decrease in bone mass of 1 standard deviation (10% to 14%) compared with healthy premenopausal women is associated with an approximate doubling of fracture risk.17*18This association between bone mass and fracture risk is stronger 835

ORAL

BISPHOSPHONATEXJ

IN THR TREATMENT

OF OSTROPOROSIS

than several well-recognized risk factor associations in other disease states-blood pressure and risk of stroke, or serum cholesterol and risk of coronary eventslg- and justifies the use of bone mass as a surrogate effrcacy end point. The morbidity and mortality of osteoporosis derives mainly from fractures of the hip and spine. For a therapy to reduce this risk, the bone must not only be increased in mass but also be normal in structure. The potential problem in using bone mass as the sole criterion for treatment efficacy was illustrated by the earlier studies of fluoride, in which large increases in spinal bone mass of up to 8.2% per year (obtained with higher-thannormal dosages of 75 mg/d) were not associated with a reduction in the rate of new vertebral fractures.20p21However, beneficial effects on the rate of vertebral fractures (with lower dosages of 30 to 50 mgld of fluoride) have been observed with increases in spinal bone mass of up to 6% per year.22*23 Fluoride is known to preferentially increase trabecular bone mass, and in high doses it impairs mineralization and promotes the formation of disorganized, woven bone rather than maintaining normal bone structure.24 For this reason, normal bone structure must be demonstrated histologically if bone mass is to be accepted as a surrogate efficacy end point.15 EFFECTS

OF BISPHOSPHONATES

ON BONE MASS IN OSTEOPOROSIS

As might be anticipated, bone mass measurements at a given site are more predictive of fracture at that same site than measurements performed elsewhere.17318Typical sites of osteoporotic fracture are the spine, hip, and wrist, and clinical evidence is accumulating for the antiresorptive efficacy of bisphosphonates at these sites.

Spinal Bone Mass Two important studies published in 1990 showed the efficacy of cyclical dosing with etidronate and calcium in increasing spinal bone mass over at least 2 years in women with primary postmenopausal osteoporosis26y26; one of these26 was subsequently extended and the 4-year data published.27 Figure 2 summarizes all the published, placebo-controlled studies with at least 2 years of data in which cyclical etidronate was used to treat postmenopausal osteoporosis. 2sp27-32All but one of these studies consistently show a significant and progressive increase in spinal bone mass over pretreatment va1ues25,27-30p32 and significantly greater changes in bone mass with cyclical etidronate than with calcium supplementation a10ne.25~27-30~32 Pacifici et a131initially reported that cyclical etidronate did not prevent spinal bone loss; however, in this study it appears that twice-daily etidronate and calcium were taken at the same time, which would diminish the absorption and, hence, the efficacy of etidronate. Pacitici et a131have sub836

Reference 25 Reference 27 Reference 28 Reference 29 Reference 30 Reference 31 Reference 32

+ d + + + -O+I-

-controlled trials of at least Figure 2. Changes in spinal bone mass with cyclical etidronate, 400 mg/d for .__14_days each cycle, _. in place1 . 2 years’ duration in women with postmenopausal osteoporosis. All changes are relative to baseline and all are significant (Pc 0.05) except the year 1 data point from Storm et al% and the year 2 data point from Evans et al.” All meaaurementa were made using either dual-photon absorptiometry or dual-energy X-ray absorptiometry, except for those of Evans et aim and Pacifici et a1,31who used quantitative computerized tomography.

20 r

ORAL BISPHOSPHONAW

IN THE TRJSATMENT

OF OSTEOPOROSIS

sequently published another study in which cyclical etidronate increased bone mass in postmenopausal women significantly more than calcium alone at 12 and 18 months (P = 0.035 and P = 0.006, respectively). All five studies that have been extended for more than 2 years show that the significant initial beneficial increase in spinal bone mass with cyclical etidronate therapy is maintained.26*2’~2g*32*U This has been confirmed by a a-year, open-label extension of the study by Storm et a12’ (a total of 5 years of cyclical etidronate treatment), in which spinal bone mass was maintained at 7% above baseline.35 A 2-year study by Miller et a13’ showed that cyclical etidronate significantly (P < 0.001) increased axial bone mass by 15.7%. Long-term data covering 7 years of treatment have also been published by Miller and Ericksen34; they report that axial bone mass significantly increased to 12% over baseline and was significantly higher than with calcium alone. The authors suggested that these large increases in bone mass may be due to a proportion of patients with high bone turnover.30 The information currently available on the efficacy of the newer bisphosphonates in the treatment of postmenopausal osteoporosis is less extensive than that available for cyclical etidronate. In a double-blind, placebo-controlled study of women with postmenopausal osteoporosis, spinal bone mass significantly (P c 0.01) increased to 6% over baseline after 2 years of alendronate therapy, 10 mg/d (the optimal dosage)36; this increase was also significantly (P < 0.001) greater than with placebo and/or calcium. In a continuation of the study to 3 years, the increase in spinal bone mass was slightly higher (6.8%; P < 0.01).37 Other published reports show that after 3 years of treatment with alendronate, 10 mg/d, spinal bone mass in osteoporotic women significantly increased by 8.8% compared with placebo andfor calcium.38 Several studies of oral pamidronate therapy in the treatment of osteoporosis have reported results for a 2-year period. In an open-label study of pamidronate, 150 mgld for 2 years, the mean increase in spinal bone mass was 6.8% in osteoporotic patients (P < 0.001).3g In a double-blind, placebo-controlled study of women with postmenopausal osteoporosis, pamidronate, 150 mg/d, increased spinal bone mass significantly by about 5% over baseline after 1 year and by about 7% after 2 years (P c O.OOl), compared with no significant change in women treated with placebo and/or calcium.40 Similar results have been obtained with intravenous pamidronate41 To date, results with oral clodronate and tiludronate in the prevention and treatment of postmenopausal osteoporosis have been reported only in studies lasting 6 to 12 months. After 6 months, bone mass of the distal radius was increased by 1.7% in patients treated with clodronate, 80 mg/d, while placebo-treated patients continued to lose bone mass.42 Cyclical clodronate in a dosage of 400 mgld for 30 days, followed by 60 days without

therapy for 1 year, produced an increase in spinal bone mass of about 4% compared with a loss of 2% in the control group (P < 0.001).43 In a doubleblind, placebo-controlled trial in healthy postmenopausal women, tiludronate, 100 mgld for 6 months, increased spinal bone mass by about 0.6% over baseline by the end of the treatment period; spinal bone mass further increased to 1.33% over baseline after an additional g-month placebo period.44 Bone mass after 12 months (6 months of tiludronate plus 6 months of placebo) was significantly (P < 0.01) greater than in the patients receiving placebo for the entire period, who progressively lost bone mass. Results of a a-year study of the use of risedronate to prevent postmenopausal bone loss have recently been published. In a double-blind, placebo-controlled study of early postmenopausal women with normal bone mass, spinal bone mass relative to baseline after 2 years of treatment was significantly (P = 0.0004 and P = 0.0001, respectively) increased by 1.4% to 2.9% with risedronate, 5 mgld, compared with a decrease of 1.7% to 1.8% with cyclical risedronate (5 mg/d for 2 weeks followed by placebo for 2 weeks) and a decrease of 4.1% to 4.3% with placebo alone.45*46 The table summarizes the data available on the efficacy of the bisphosphonates in increasing spinal bone mass in controlled studies in postmenopausal osteoporosis. Although alendronate has been used in doses of 5 to 40 mg/d, 5 mgld and 10 mg/d are the doses currently approved for clinical use; 10 mg/d appears to be the optimal dose. As a class, bisphosphonates appear to increase spinal bone mass to a similar extent, but this increase has only been studied for longer than 3 years with cyclical etidronate, for which data are available for up to 7 years of treatment.34 Thus, when the appropriate therapeutic doses are used in patients with osteoporosis, the greater antiresorptive potency of the newer bisphosphonates is not translated into Table. Effects of oral bisphosphonates on spinal bone mass in placebo-controlled studies in primary osteoporosis. Mean Percent Increase In Blsphosphonate Etidronate Alendronate Pamidronate Clodronate

Regimen

Sp’E?ne

Reference

400 mgld for 14 days each cycle

2-7 years

2.4-15.7

2530,

400 1:Om;;d mg/d for 30 days,

FjGam 1 year

k%.: 4.0

36-36 ii, 40

followed by 60 days without treatment Tiludronate

100 mg/d*

Risedronate

5 mg/d*

6 months, followed by 6 months of placebo 2 years

* Studies in healthy or early postmenopausal women. 839

.

1.33 1.4-2.9

44 45, 46

32, 33, 34

a measurable clinical benefit at the spine over cyclical etidronate; however, no direct comparative data are available. It is important to note that the increases in spinal bone mass produced by bisphosphonates as a class are not achieved at the expense of hip” or wrist2’ bone mass. This has been shown conclusively for cyclical etidronate by comparing the change in spinal bone mineral density (expressed as the slope of the regression of the percentage change plotted against time) with the change in bone mineral density at Ward’s triangle. No correlations were found between the changes in bone mass at these two skeletal sites.26 Bisphosphonates as a class appear to have similar rates of action. Significant increases in spinal bone density have been demonstrated for cyclical etidronate, alendronate, and pamidronate after 6 months of treatment 40*47-54and smaller, nonsignificant increases for clodronate and tilu&nat.e.42*44 Hip Bone Mass Hip fracture is the major contributor to the morbidity and mortality of patients with osteoporosis. The available data suggest that, as a class, bisphosphonates increase bone mass at the hip in patients with osteoporosis. Thus, after 1 and 2 years of treatment with cyclical etidronate, Harris et a12’ reported significant (P < 0.05) increases in bone mass of the femoral neck (1.32% and l.ll%, respectively) and greater trochanter (2.54% and 2.33%, respectively) compared with baseline, and after 3 years in bone mass of the femoral neck (1.44%), greater trochanter (2.65%), and Ward’s triangle (2.14%) (Figure 3). After 3 years the increases were also significantly (P < 0.05) different from placebo and/or calcium. These findings are supported by the results of several recent studies, which show significant increases in hip bone mass of up to 6.8% after 1 year of cyclical etidronate therapy, 55-58 which can be maintained for up to 2 years,“*57*5g and in one report for up to 7 years.34 Results with alendronate in postmenopausal osteoporotic women are broadly comparable. The reported significant increases in bone mass of the femoral neck with alendronate, 10 mg/d, range from 2.2% to 2.9% at 1 year47.60 to 3.5% and 4.8%, respectively, at 2 and 3 years.36*37As with cyclical etidronate, the increases in bone mass at the trochanter are slightly higher than at the femoral neck,36*37P47p60 with significant (P c 0.01) bone mass increases of 5.4% and 6.9%, respectively, at 2 and 3 years. 36*37Data on the effects of the other newer bisphosphonates are limited; however, oral pamidronate, 150 mg/d, has been reported to significantly (P < 0.001) increase femoral bone mass in postmenopausal osteoporotic women by 5.4% after 2 years of treatment. No significant changes were observed with placebo and/or calcium.40 Risedronate, 5 mg/d, has recently been reported to significantly (P = 0.001) increase trochan840

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FRANCIS

n

Etidronate No etidronate

3.0 2.5 2.0 g

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0.5

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5 -0.5 CL a, -1.0 $

-1.5

5

-2.0 -2.5 -3.0 t Femoral Neck

Greater Trochanter

Ward’s Triangle

Figure 3. Changes in hip bone mineral density in patients treated with cyclical etidronate for 3 years. Date from Harris et al.a7 *P < 0.05 compared with baseline; tP < 0.05 between groups; $2 < 0.01 compared with baseline; W < 0.01 between groups.

teric bone mass by 2.3% after 2 years over baseline in early postmenopausal women with normal bone mass, compared with an increase of 0.5% with cyclical risedronate (5 mg/d for 2 weeks followed by placebo for 2 weeks) and a decrease of 2.8% with placebo alone.45p46 EFFECTS OF BISPHOSPHONATES ON FRACTURE RATES IN OSTEOPOROSIS

The ultimate aim of therapy for osteoporosis is a reduction in fracture risk at key sites-the spine, hip, and wrist. Despite the large increase in trabecular bone mass that occurs with high doses of fluoride, no reduction in the rate of vertebral fractures has been reported.20*21Therapies that decrease bone resorption, however, have generally been reported to substantially decrease fracture rates. In a small study of women with postmenopausal osteoporosis, HRT has been shown to significantly reduce the vertebral fracture rate by more than 50% (relative risk, 0.39; P = 0.04) a&r 1 year of treatment.’ A retrospective follow-up of postmenopausal women showed that vertebral and wrist fracture rates were significantly (P c 0.05) reduced by about 40% in those who had used HRT as a preventive therapy for at least 5 years. 61In both retrospectives2 and prospectivess trials of osteoporosis prevention, HRT was also associated with a signiticant reduction in hip fracture risk, particularly in younger postmeno341

pausal women. In association with a dose-related increase in bone mineral content of 1.7% to 3.0% over 2 years in elderly women with moderate osteoporosis, intranasal calcitonin significantly reduced the overall incidence of vertebral fractures in the pooled dose groups to about one third of that with placebo and/or calcium (relative risk, 0.23).64 Intramuscular calcitonin also significantly (P < 0.025) reduced the incidence of new vertebral fractures in postmenopausal osteoporosis by 60% over 2 years compared with an increase of 35% with calcium alone.65 Cyclical etidronate is the only bisphosphonate shown in peer-reviewed literature to significantly reduce the incidence of vertebral fractures in osteoporosis. Ita effect is comparable to the benefit achieved with HRT or calcitonin. Two studies26,26of cyclical etidronate have confirmed its longterm fracture benefit. Storm et a12’ showed a 58% reduction in the incidence of vertebral fracture over 150 weeks with cyclical etidronate (18/100 patient-years) compared with placebo and/or calcium (43/100 patientyears), although the difference was only significant between weeks 60 and 150 (6/100 patient-years compared with 54/100 patient-years, respectively; P = 0.023). In the larger study of Watts et a1,26 the incidence of new vertebral fractures was significantly reduced by 53% after 2 years in patients treated with cyclical etidronate compared with those who received placebo and/or calcium combination (29.511000 patient-years compared with 62.9/1000 patient-years, respectively; P = 0.043). The effect of treatment was most striking in the subgroup of patients with the lowest spinal bone mineral density at baseline, in whom fracture rates were reduced by 63% (42.3/1000 patient-years compared with 132.7/1000 patient-years, respectively; P = 0.004). Although after 3 years the difference between new vertebral fracture rates in patients treated with cyclical etidronate and patients treated with placebo and/or calcium was not significant, there was a tendency toward a lower rate in the etidronate-treated patients. In the high-risk subgroup (with the lowest spinal bone density), patients treated with cyclical etidronate showed a significant (P < 0.05) reduction in the incidence of new vertebral fractures compared with patients treated with placebo and/or calcium (155/1000 patient-years compared with 229/1000 patient-years, respectively).27 After a fourth year of open-label treatment with cyclical etidronate, vertebral fracture rates were lower than in any other study period.27 It should be noted that in the study by Watts et a1,26 the overall population had a higher bone mass and fewer fractures at baseline than the study population of Storm et a1,26indicating that the fracture rate in the former study might be expected to be correspondingly lower. Relatively few data are available on the efficacy of the newer bisphosphonates in reducing the rate of fractures associated with osteoporosis. Preliminary data on the efficacy of alendronate in reducing vertebral fractures in postmenopausal women have recently been presented.38 Of 881 patients for whom radiographs were assessable after 3 years of treatment, 842

R. M. FRANCIS

3.2% who received alendronate and 6.2% who received placebo and/or calcium had new vertebral fractures; this 48% reduction was significant (P = 0.034). The value of the lo-mgld dose in reducing the vertebral fracture rate remains to be clarified, however, because although a large number of patients were evaluated, data for the treatment groups (5 mg/d or 10 mgld for 3 years, and 20 mgld for 2 years plus 5 mg/d for 1 year) were pooled. Data are also available for pamidronate; in a double-blind, placebocontrolled study of 61 women with postmenopausal osteoporosis, the vertebral fracture rate was decreased from 24/100 patient-years with placebo and/or calcium (30 patients) to 13/100 patient-years with pamidronate, 150 mg/d (31 patients). This 46% decrease approached significance (P = o.07).40 No data are available on the effects of the other bisphosphonates on fracture rates in osteoporosis. SAFETY AND TOLERARILITY IN OSTROPOROSIS

Although bisphosphonates as a class are relatively new agents in the treatment of osteoporosis, etidronate is well established and has been used for more than 15 years in Paget’s disease and for 7 years in osteoporosis, accumulating 1.6 million patient-years of use, with 1.4 million patientyears of exposure to cyclical etidronate.= As discussed earlier, for a treatment to be effective not only must bone mass be increased, but this bone must also have a normal architecture.

Bone Histologg All bisphosphonates have a tendency to inhibit mineralization at high doses; however, for most of these drugs, the dose is much higher than that required for antiresorptive activity. Axelrod and Teitelbaum‘j7 observed histomorphometric changes in postmenopausal women with osteoporosis treated with cyclical etidronate. They reported atypical and focal osteomalacia (using the criteria of Pa&t); however, there was no relationship between these findings and any clinical osteomalacic syndrome. Clinical data from patients with osteoporosis have shown that neither cyclical dosing with etidronate nor continuous dosing with alendronate induces clinical osteomalacia. In the case of etidronate use in osteoporosis, this compound is given for only 2 weeks every 3 months, a cyclical regimen that mimics natural bone remodeling and avoids adverse clinical effects on bone. Two long-term studies have confirmed that when administered in this recommended regimen, there is no evidence of clinical osteomalacia. s4*68In one of these studies,34 38 patients with established osteoporosis treated for 6 to 7 years with cyclical etidronate showed significant in343

ORALBISPHOSPHONATRSINTHETRBATMENTOFOSTEOPOROSIS

creases in axial and femoral neck bone mineral density of 12% and 5%, respectively, relative to baseline. Quantitative bone histomorphometry performed at variable intervals throughout therapy showed no evidence of osteomalacia. In the other study,68 23 postmenopausal women receiving cyclical etidronate were followed for up to 7 years with bone biopsies, which showed positive effects on bone remodeling (reduced resorption depth and activation frequency) without any evidence of impaired mineralization; these changes were accompanied by a decreased rate of vertebral fractures at 3 years. These findings support the data from other histomorphometric studies showing no mineralization defects over periods of cyclical etidronate therThe mechanism for increasing apy ranging from 2 to 7 years. 26~26,35*6s-71 bone mass appears to be a reduction in activation frequency6s*72with a concomitant reduction in resorption depth, which protects the trabecular network against perforations and hence increases bone strength.72 These positive effects on bone remodeling assessed histomorphometrically have been associated with decreases in vertebral fracture rates in several studies =-?7,3W5,71 Few long-term safety data are available concerning the effects of the use of other bisphosphonates on human bone mineralization in osteoporosis. In general, however, they appear to produce little or no inhibition of mineralization at doses that show antiresorptive efficacy. Bone mineralization was normal after 2 years in 102 women and after 3 years in nine other patients with osteoporosis treated with alendronate.36,37A recently published histomorphometric study with risedronate indicates that it restores the negative bone balance in early postmenopausal women with normal bone mass, without any evidence of histologic abnormalities.73

Tolerability The most common adverse events with oral bisphosphonates are gastrointestinal disturbances, such as abdominal discomfort and pain and diarrhea.4 The incidence of such events with cyclical et&mate administered in the approved oral dose for osteoporosis is comparable to placebo and/or calcium25-27,32~52,63,6~,56 with diarrhea reported in 7% to 9% of patients in all g~=oups.~~ In general, alendronate is also well tolerated, and the incidence of gastrointestinal adverse events is comparable to that with placebo andfor calcium36,37,47,54,6~74-76; h owever, it has been associated with a significantly higher incidence of abdominal pain in a number of trials.74 Gastrointestinal adverse events have also been reported with pamidronate in up to 50% of patients treated for postmenopausal osteoporosis.14 Erosive esophagitis during oral pamidronate therapy,14 which resolved after dis844

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M. FRANCIS

continuing the drug and giving appropriate treatment, has been reported. This may explain why some clinical trials of oral pamidronate in osteoporosis have been stopped. It has been suggested that the higher incidence of gastrointestinal adverse events is linked tothe amino side chain,77 although this has yet to be confirmed. In view of the close structural similarity between pamidronate and alendronate, which are both amino bisphosphonates, the latter needs careful monitoring to establish its gastrointestinal tolerability. The higher incidence of abdominal pain reported with alendronate may therefore require further investigation in controlled trials. In clinical trials in patients with osteoporosis, oral clodronate commonly causes mild nausea, dyspepsia, and diarrhea.78 No significant gastrointestinal adverse events have been reported for tiludronate or risedronate. Several other less common adverse events have been associated with the use of some bisphosphonates. 7s Acute-phase reactions (fever and lymphopenia) may occur with parenteral use of any of the bisphosphonates and with oral use of pamidronate. a’ Several cases of leukemia have been reported in patients treated with clodronate, although this bisphosphonate has not been shown to be the causative agent.s’ Acute renal failure has been seen with rapid intravenous infusion of etidronate and clodr~nate,~~ but this should not occur when slow infusion rates are used.4a83Nevertheless, renal impairment is regarded as a relative contraindication to the use of bisphosphonates. ss Transient hypocalcemia may occur after treatment with etidronate, pamidronate, and clodronate, although this effect is generally asymptomatic. Transient elevation of serum lactate dehydrogenase activity following clodronate therapy has also been reported. Hypersensitivity reactions to the bisphosphonates and rashes have very occasionally been repor%x17s It should be remembered in the context of tolerability that calcium supplementation (or at least an adequate calcium intake) is recommended with all bisphosphonates when used in the treatment of osteoporosis. Calcium supplements, however, may be poorly tolerated by some patients, and this may potentially impair compliance with any bisphosphonate treatment. Thus a low incidence of adverse events related to the use of any active ingredient is important with long-term therapy for a chronic condition, as with bisphosphonates for osteoporosis, when compliance has a major impact on clinical outcome. DISCUSSIONANDCONCLUSIONS

The aim of treating osteoporosis is to alleviate the patients’ symptoms and to reduce the risk of further fractures. Bisphosphonates are potent inhibitors of bone resorption. Etidronate has been used for many years in the

treatment of diseases characterized by an increase in bone turnover. This experience has provided long-term safety and efficacy data, showing that cyclical etidronate can significantly improve spinal bone mass over 2 to 3 years and that this increase is maintained in the long term. Hip bone mass is also significantly increased with cyclical etidronate. Furthermore, cyclical etidronate is the only bisphosphonate for which a decrease in vertebral fracture rate in association with the increase in bone mass has been clearly established. As with cyclical etidronate, the results available for oral alendronate and pamidronate indicate efficacy in significantly increasing spinal and hip bone mass. The new vertebral fracture results recently reported for alendronate are promising, but must await formal peer review as no significant fracture benefit for the individual or optimal dosage regimens have been published to date. The early results with oral clodronate, tiludronate, and risedronate look promising, although few long-term data are yet available from controlled trials to confirm the safety and effmacy of these drugs. Results to date show that all three drugs significantly increase spinal bone mass and that risedronate also increases hip bone mass. The long-term safety of cyclical etidronate has been established in studies of 5 and 7 years’ duration, which showed no clinical osteomalacia. Histomorphometric studies have also indicated that, as with cyclical etidronate, alendronate is unlikely to impair human bone mineralization. As a class, bisphosphonates tend to produce mild gastrointestinal adverse events; these are particularly common with oral pamidronate, which has also been reported to cause erosive esophagitis. In view of the reports of significantly greater abdominal pain with other amino bisphosphonates, this area may warrant further investigation. Some consideration must also be given to the optimal dosage regimen for bisphosphonates. With these high-potency compounds, it should be noted that a much stronger inhibition of bone resorption is not necessarily advantageous. It may, on the contrary, reduce bone turnover to the point where bone fragility is increased. In conclusion, bisphosphonates, as a class, have been shown to have comparable efficacy in preventing postmenopausal bone loss in the spine and hip. This efficacy is maintained for at least 3 years, and for up to 5 to 7 years in two studies of cyclical etidronate. Data for cyclical etidronate over at least 4 years and preliminary data for alendronate over 3 years indicate that they both reduce vertebral fracture rate to an extent comparable with that achieved with HRT or calcitonin. Bisphosphonates are generally safe and well tolerated, although amino bisphosphonates can be associated with a higher incidence of potentially serious gastrointestinal adverse events. The usefulness of cyclical etidronate in osteoporosis is thus well established, and data on the other bisphosphonates appear promising for this 646

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