Review. Combination Treatment of Osteoporosis: A Clinical Review CAROLYN CRANDALL, M.D., F.A.C.P.

JOURNAL OF WOMEN S HEALTH & GENDER-BASED MEDICINE Volume 11, Number 3, 2002 Mary Ann Liebert, Inc. Review Combination Treatment of Osteoporosis: A Clinical Review CAROLYN CRANDALL, M.D., F.A.C.P. ABSTRACT Objective: Because of the limited efficacy of available agents and to limit toxicity, there is considerable interest in combination pharmacotherapy for osteoporosis. Methods: A search was performed for randomized controlled trials in MEDLINE (1966 present) using the keywords osteoporosis treatment and combination. Results: Twenty-four randomized controlled trials evaluated osteoporosis medications in combination. Study duration ranged from 1 to 4 years. No serious adverse events were definitively attributable to study drugs. Fracture reduction outcome is not shown for any combination regimen. The literature was mixed regarding bone density augmentation. Combinations of nandrolone decanoate plus calcitonin, calcitonin plus growth hormone (GH), or pamidronate plus GH may be contradictory or detrimental to bone mineral density (BMD). For postmenopausal osteoporosis or osteopenia, four combinations appear to increase hip and lumbar BMD: 10 mg alendronate with 0.625 mg conjugated equine estrogens (CEE), cyclic etidronate with 0.625mg CEE, 10 mg alendronate with 2 mg estradiol (E 2 ), and tibolone with fluoride. For steroid-related osteoporosis, intermittent etidronate with fluoride increases lumbar BMD. Conclusions: The few trials including Food and Drug Administration (FDA)-approved medications suggest that 10 mg/day alendronate with estrogen (equivalent of 0.625 mg CEE daily) can increase BMD moreso than each medication given singly in postmenopausal osteoporotic women. Estrogen dose and type must be controlled in future trials. Long-term safety data are lacking. The utility of these combinations rests on whether bone density changes will translate into decreased fracture rates. INTRODUCTION TEN MILLION PEOPLE in the United States have osteoporosis, and 18 million more have low bone mass, placing them at increased risk for fracture. 1 Although osteoporosis occurs in men, between 13% and 18% of postmenopausal white women in the United States have osteoporosis, making it especially problematic in women. 2 Not only is the problem of osteoporosis common, but also its physical, emotional, and economic consequences are substantial. Nearly one third of patients with hip fractures require discharge to nursing homes within a year after frac- Department of Medicine, UCLA School of Medicine, UCLA National Center of Excellence in Women s Health (U.S. Dept. of Health & Human Services), Los Angeles, California. 211

ture, and 1 in 5 patients is no longer alive 1 year after hip fracture. 3 Vertebral fractures are a potential cause of marked pain and have been shown to interfere significantly with quality of life. 4 The United States spends $10 15 billion annually on direct costs for treatment of osteoporotic fractures. This figure is likely an underestimate because it does not include indirect costs. 3 In the setting of known osteoporosis, no current treatment is able to reduce the risk of fracture to zero; that is, there is no cure. Although no combinations are approved by the Food and Drug Administration (FDA) for use in treatment of osteoporosis, because of the limited efficacy of available agents and because of continuing efforts to limit toxicity, there is considerable interest in the potential for use of treatments in combination. Considerable focus has been placed on simultaneous use of medications with complementary but different mechanisms of action, for example, bone resorption inhibitors given together with bone formation inducers. 212 MATERIALS AND METHODS A search was performed for all randomized controlled trials in MEDLINE (1966 present) using keywords osteoporosis treatment and combination. A review of retrieved references did not reveal additional relevent references. RESULTS One hundred four references were retrieved using the predefined terms, but only 24 were randomized, controlled trials of medication combinations with either bone density or fracture outcomes. Of these, 18 studied combination pharmacotherapy of established osteoporosis or osteopenia (Table 1). Trials of nonosteoporotic women were not included, as they were not the focus of this review. Studies ranged from 1 year 5 to 4 years 6 in duration (Table 1). Subject numbers ranged from 14 7 to 428. 8 Fifteen trials involved subjects with baseline osteopenia or osteoporosis, and one trial involved patients with steroid-associated osteoporosis (Table 1). Treatment combinations studied involved various combinations of 13 medications: alendronate, conjugated equine estrogens (CEE), oral estradiol (E 2 ), fluoride, calcitonin (CT) injection, intranasal CT, growth hormone (GH) injection, nandrolone decanoate (ND) injection, pamidronate, etidronate, parathyroid hormone (PTH) injection, phosphate, and tibolone. As expected, not all the potential, different combinations of these 13 medications have yet been examined in published reports. In the 18 studies, the most common combination regimen studied was subcutaneous CT with GH 7,9,10 (Table 1). The next most common combinations were estradiol valerate with ND, 11,12 alendronate with CEE, 8,13 CT with ND, 14,15 and CT with phosphate. 15,16 Most often, treatment was via continuous combination. However, sometimes combination treatment was sequential 17 or, more often, cyclical. 6,7,10,16,18,19 The calcium and vitamin D supplementation varied tremendously across trials (Table 2). Although the emphasis of the discussion is on efficacy, adverse events of the treatment regimens are summarized in Table 3. No serious adverse events were definitively attributable to study drugs. Fractures were usually monitored as part of safety assessment rather than as primary outcomes (Table 3). There was generally a very low incidence of fractures regardless of the specific combination regimen. Notably, no trials had a proper design from which to glean statistically sound fracture outcome data with any combination regimen. Evidence regarding the use of these 13 medications in combination regimens is divided into sections based on specific treatment combinations employed in published randomized controlled trials. The putative mechanisms of action of the medications are described in Table 4. Antiresorptives in combination CRANDALL Alendronate and hormone replacement therapy (HRT). Postmenopausal HRT, consisting of the administration of estrogen alone or with progesterone to menopausal women, prevents bone resorption. Alendronate is a potent bisphosphonate. Bisphosphonates inhibit osteoclast activity, functioning as inhibitors of bone resorption. HRT has been combined with alendronate in three trials. 8,13,23 Subjects were either osteopenic hysterectomized women 13 or had established postmenopausal osteoporosis. 8,23 In all trials, the

COMBINATION TREATMENT OF OSTEOPOROSIS 213 alendronate dose was 10 mg/day. Whereas the dose of estrogen replacement therapy (ERT) was fixed at 0.625 mg/day CEE for 2 years in one trial, 13 a second trial employed micronized E 2 2 mg day with norethisterone acetate, 23 and the third trial used a heterogeneous group of estrogens, consisting mostly of CEE. 8 The last trial also differed in adding alendronate to previously in- TABLE 1. RANDOMIZED, CONTROLLED TRIALS TESTING COMBINATION TREATMENT REGIMENS FOR OSTEOPOROSIS Trial Subjects Regimen a Bone density b Aloia et al. 9 Aloia et al. 7 Birkenhager et al. 11 Bone et al. 13 Erdtsieck et al. 12 Erdtsieck et al. 5 25 postmenopausal women with radiographic spinal osteoporosis 14 women with postmenopausal osteoporosis with $1 vertebral crush fracture 36 women with postmenopausal osteoporosis $1 vertebral fracture or osteopenia t # 1 20 425 hysterectomized postmenopausal women with low bone mass 20 33 women with postmenopausal osteoporosis ($1 vertebral fracture or osteopenia) 21 postmenopausal osteoporotic women ($1 vertebral fracture) CT c 100 IU s.c. 4 3 week vs. CT alternating with GH 6 IU s.c. 33/week for 24 months Human GH s.c. for 2 months followed by salmon CT s.c. for 3 months, in cycles, vs. CT alone for 24 months d Cyclical HRT (estradiol valerate 2 mg days 1 25/month 1 MPA (10 mg/day days 16 25 each month) alone or with ND 50 mg i.m. q4 weeks for 2 years Alendronate 10 mg/day vs. CEE 0.625 mg/day vs. combination vs. placebo (calcium) for 2 years Cyclical HRT alone or with ND IM every 4 weeks for 3 years, followed for 1 year off treatment e Pamidronate 150 mg daily for 12 months 1 either placebo (calcium) or recombinant human GH 0.0675 IU/kg s.c. 33/week for 6 months, followed for 6 months on pamidronate alone Radius bone mineral content (BMC) decreased with combination vs. baseline, whereas BMC increased with CT alone Distal radius SPA did not change with combination or with CT; no difference between groups Forearm SPA (proximal and distal) and spine DEXA increased in both groups; no difference between groups in changes from baseline at any site Alendronate effects were equivalent to those of CEE at all sites, except they were greater than CEE at the trochanter; combination greater than alendronate or CEE at spine and femoral neck; combination equivalent to alendronate but better than CEE at trochanter and total hip; lumbar, total hip, femoral neck, and femoral trochanter changes on active treatment were all significant vs. baseline and vs. placebo Proximal and distal forearm SPA and lumbar DEXA increased similarly vs. baseline in both groups Lumbar and distal forearm BMD increased vs. baseline with pamidronate but not combination; femoral neck and proximal forearm BMD did not change in either group (continued)

214 CRANDALL TABLE 1. (CONT D) RANDOMIZED, CONTROLLED TRIALS TESTING COMBINATION TREATMENT REGIMENS FOR OSTEOPOROSIS Trial Subjects Regimen a Bone density b Flicker et al. 14 Gonnelli et al. 10,f Hodsman et al. 18 Kuntz et al. 16,f Lems et al. 19 123 women with prior osteoporotic fracture or osteopenia 30 women with established postmenopausal osteoporosis ($1 vertebral fracture) 30 osteoporotic women ($1 vertebral fracture) 47 postmenopausal women with vertebral osteoporosis and $1 atraumatic vertebral compression fracture 47 male and female patients getting corticosteroids with history of peripheral fracture and/or vertebral deformity Intranasal CT 400 IU/day vs. 2 courses of 10 i.m. injections ND 50 mg vs. combination vs. placebo (calcium) for 2 years Recombinant human GH s.c. followed by salmon CT s.c. vs. salmon CT alone vs. GH alone for 24 months (8 cycles) g Human PTH-(1-34) 800 U/day s.c. for 28 days, repeated every 3 months, followed by either placebo or sequential CT 75 U/day s.c. for 42 days, for 2 years CT 50 IU/day i.m. or s.c. for 5 days q3 weeks with phosphate 500 mg p.o. vs. CT alone vs. untreated controls for 1 year Cyclical etidronate (200 mg b.i.d. for 2 weeks, followed by 11 weeks without treatment) vs. etidronate 1 sodium fluoride 25 mg b.i.d. vs. placebo (calcium 1 vitamin D) for 2 years No effects of treatments on forearm BMD; lumbar BMD increased vs. baseline with CT alone and baseline with CT alone but did not change with placebo or combination; proximal femur BMD increased with ND but decreased with CT vs. baseline; possible antagonism between study medications at lumbar spine Lumbar BMD increased vs. baseline with combination but decreased with CT and GH alone; femoral shaft BMD did not change with CT but decreased vs. baseline with combination and with GH alone; distal radius did not change in any group, and there was no significant difference between groups at any region Lumbar BMD increase not different with PTH vs. combination; femoral neck increased with combination vs. decrease with PTH; no significant difference across time or between groups DEXA distal radius decreased with placebo vs. no significant change with combination; specific details not given Lumbar BMD increased with combination and did not change with etidronate; hip BMD did not change with combination therapy but decreased with etidronate; no difference between groups in lumbar or hip change

COMBINATION TREATMENT OF OSTEOPOROSIS 215 Lindsay et al. 8 Murphy et al. 21 Reginster et al. 22 Rittmaster et al. 17 Szues et al. 15 Tiras et al. 23 428 postmenopausal women with osteoporosis (BMD t score #2) already on HRT for $1 year 292 women with low femoral neck BMD 94 postmenopausal women with low BMD ("below fracture threshold" predefined BMD level) 66 postmenopausal osteoporotic women 20 45 women with postmenopausal osteoporosis ($1 vertebral crush fracture) 120 women with postmenopausal osteoporosis Continued HRT h with or without alendronate 10 mg/day for 12 months MK-677 25 mg vs. alendronate 10 mg vs. combination vs. placebo daily for 12 months Tibolone 2.5 mg/day 1 fluoride 26.4 mg/day vs. fluoride alone for 2 years Recombinant human PTH-(1-84) daily s.c. 50, 75, or 100 mg vs. placebo (calcium) for 1 year, followed by alendronate 10 mg/day alone for an additional year in open extension CT 50 U injection q.o.d. for 2 weeks/month 1 calcium 500 mg/day vs. CT 1 phosphate 750 mg/day 1 calcium vs. CT 1 ND injection 50 mg/ month 1 calcium for 3 years Micronized 17b-estradiol 1 NETA vs. alendronate 10 mg vs. combination daily for 12 months Increase with combination was greater than with HRT at both lumbar and hip trochanter, but no difference between groups in percent change at femoral neck Combination induced greater increase in femoral neck BMD than alendronate alone but had no advantage over alendronate alone at lumbar spine or total hip Lumbar BMD increased vs. baseline in combination group more than fluoride alone; total hip increased similarly vs. baseline with combination or with fluoride alone After 1st year (PTH alone), vertebral BMD increased in all groups vs. placebo, with higher increase with increasing PTH dose; same pattern of change after 2nd year (alendronate alone), after 1st year (PTH alone), no change in femoral BMD between groups or vs. baseline; after 2nd year (alendronate alone), femoral neck increased, but not significantly, for 100 mg dose Midshaft radius SPA decreased in all 3 groups compared to baseline (CT 1 phosphate group lost early at 18 months) i ; distal radius SPA did not change significantly with CT 1 ND vs. baseline, but decreased with CT Increase in lumbar and femoral neck BMD in all groups, but the increase in spine BMD was more pronounced with alendronate or combination than with HRT alone; no significant difference between groups in femoral neck BMD changes (continued)

216 TABLE 1. CRANDALL (CONT D) RANDOMIZED, CONTROLLED TRIALS TESTING COMBINATION TREATMENT REGIMENS FOR OSTEOPOROSIS Trial Subjects Regimen a Bone density b Wimalawansa et al. 6 n 72 postmenopausal women with established osteoporosis (1 4 atraumatic vertebral fractures and BMD t $ 2). Cyclical HRT (CEE 0.625 mg/day 1 norgestrel 150 mg/day for 12 days/month) vs. intermittent cyclical etidronate 400 mg/day for 14 days each 12 weeks vs. combination vs. placebo (calcium 1 vitamin D) for 4 years Lumbar and total hip increases with combination were greater than either agent alone; no difference between etidonate and HRT, but change in hip vs. baseline was greater with HRT than with etidronate a Regimens are oral unless otherwise stated. b Dual-energy x-ray absorptiometry (DEXA) unless otherwise stated. c BMD, bone mineral density; CEE, conjugated equine estrogens; CT, calcitonin; DEXA, dual-energy x-ray absorptiometry; GH, growth hormone; HRT, hormone replacement therapy; i.m., intramuscular injections; MPA, medroxyprogesterone acetate; ND, nandrolone decanoate; NETA, norethindrone acetate; PTH, parathyroid hormone; s.c., subcutaneous injection; SPA, single photon absorptiometry. d Human GH 7 IU/day s.c. for 2 months followed by salmon CT 100 IU s.c. qod for 3 months, followed by 3 months rest, cycle repeated twice vs. CT alone, for 24 months. e Cyclical HRT (estradiol valerate 2 mg days 1 25 with MPA 10 mg/day days 16 25) alone or with ND 50 mg i.m. every 4 weeks for 3 years, followed for 1 year off treatment. f Trial did not use calcium supplementation. g GH 12 IU/day s.c. for 7 days, followed by salmon CT 50 IU/day s.c. for 21 days, followed by 61 days without treatment vs. placebo for 7 days, followed by salmon CT for 21 days, followed by 61 days without treatment vs. GH for 7 days, followed by placebo 7 days, followed by 61 days without treatment. h HRT "approximately equivalent to at least 0.625 mg/d of conjugated equine estrogens." About 75% of the estrogen was CEE. i CT 1 phosphate group was stopped after 2 years because of unfavorable results. stituted ERT, as opposed to de novo. 8 It is possible that different estrogen regimens would have varying effects when given with, or compared with, alendronate. The trials confirmed the expected favorable increases in BMD induced by the individual medications at the lumbar spine 8,13,23 and forearm. 8 In two trials, combination treatment was synergistic at the spine and femoral neck, 8,13 but in the third trial, there was no difference in femoral neck BMD changes between groups. 23 There may be subtle differences between the regimens at different sites in the hip. 13,23 Etidronate with HRT. Etidronate is a bisphosphonate that reduces bone resorption via inhibition of osteoclastic activity. 14 Because of past concerns about possible impairment of bone mineralization by etidronate, 25 it has been combined with other medications (Table 1). Intermittent cyclical etidronate (400 mg/day for 14 days every 12 weeks) has been combined with HRT (CEE 0.625 mg/day with cyclical norgestrel) in treatment of postmenopausal osteoporosis. 6 The etidronate regimen worked as well as did HRT, and the medications in combination were additive at the lumbar and hip sites. There was a trend to lower rate of new radiographic vertebral fractures in the active treatment groups, and less height loss was experienced by the treatment groups, especially the combination therapy group, vs. placebo. Antiresorptives combined with inducers of bone formation Alendronate with PTH. PTH increases trabecular bone density via stimulation of bone formation. In one trial, after 1 year of s.c. PTH 50 100 mg/day, alendronate 10 mg/day given for 1 year, sequentially, to osteoporotic women increased spine density. 17 The increases in bone density are difficult to interpret because of absence of a comparison group. HRT with ND. ND is an anabolic steroid. 14 HRT was combined with ND in two studies, both of which employed estradiol valerate (2 mg/day with cyclical medroxyprogesterone acetate) alone or with ND (50 mg i.m. every 4 weeks) in sub-

COMBINATION TREATMENT OF OSTEOPOROSIS 217 TABLE 2. INCIDENCE OF CALCIUM AND VITAMIN D SUPPLEMEN TATION Trial Calcium supplementation Vitamin D Aloia et al., 1985 9 To ensure 1000 mg/day No Aloia et al., 1987 7 To ensure 1000 1200 mg/day No Birkenhager et al., 1992 11 To ensure 1000 mg/day No Bone et al., 2000 13 500 mg/day No Erdtsieck et al., 1994 12 To ensure 1000 mg/day No Erdtsieck et al., 1995 5 To ensure 1000 mg/day No Flicker et al., 1997 14 1000 mg/day No Gonnelli et al., 1997 10 No No Hodsman et al., 1997 18 500 mg/day No Kuntz et al., 1986 16 No No Lems et al., 1997 19 1000 mg/day if baseline 0.2 mg dihydrotachysterol 1 / 2 dietary intake,500 mg/day Lindsay et al., 1999 8 If baseline dietary intake 400 IU/day,1000 mg/day, supplement to ensure 1000 mg/day Murphy et al., 2001 21 500 mg/day No Reginster et al., 1999 22 500 mg/day No Rittmaster et al., 2000 17 500 mg/day 400 IU/day Szucs et al., 1992 15 500 mg/day No Tiras et al., 2000 23 1500 mg/day No Wimalawansa, 1998 6 1000 mg/day 400 IU/day jects with postmenopausal osteoporosis. 11,12 The trials suggested that increases in forearm and spine BMD were similar when treatments were used individually or in combination. CT and GH. CT is a hormone produced in the human parathyroid gland and is an inhibitor of osteoclastic bone resorption. GH activates bone remodeling via mechanisms not completely understood but likely involving stimulation of bone formation. At one point, work using GH for postmenopausal osteoporosis 7 was terminated secondary to the concern over transmission of Creutzfeldt-Jakob disease. When recombinant GH became available, work continued free of this concern. CT has been combined with GH in three trials. 7,9,10 They all were of 2 years duration in osteoporotic women, but the dose regimens varied. Administration of CT either alternated with GH every other day 9 or was given after 7 days of GH in repeated cycles. 7,10 The dose of CT was either 100 IU s.c. q.o.d. 7,9 or 50 IU/day s.c. 10 All three studies report no benefit of combination therapy over CT alone at the radius, spine, or hip, and two of the three reported detrimental effects of combination treatment at the radius 9 or femoral shaft. 10 tablet alternating days if serum 25-hydroxyvitamin D low CT and PTH. CT 75 U s.c. was combined in one trial with PTH 800 U s.c. on the theory that sequential CT would limit bone resorption induced by PTH. 18 The 2-year trial showed no particular benefit of combination treatment over PTH alone in osteoporotic women at the lumbar or femoral neck sites. CT and Phosphate. Phosphate has been postulated to induce secondary hyperparathyroidism to increase the numbers of bone metabolic units. 16 Phosphate has been tested with bone resorption inhibitors on the theory that sequential addition of an agent blocking bone destruction could yield transient uncoupling of bone formation and resorption, thereby enhancing gains in BMD. 16 One study of postmenopausal women with compression fractures found that the combination of CT (50 IU/day i.m. or s.c. for 5 days every 3 weeks) with phosphate (500 mg/day) augmented the response of distal radius BMD to CT alone, but the report does not give specific details. 16 Another trial compared CT alone 50 U injected q.o.d. 2 weeks per month with CT combined with phosphate (750 mg/day) or CT combined with ND (50 mg injected) in the treatment of postmenopausal osteoporosis. 15 The investigators found that the phosphate did not beneficially augment the ef-

218 CRANDALL TABLE 3. TOLERABILITY AND ADVERSE EFFECTS (AE) OF MEDICATIONS Fracture documented Trial Tolerability as safety outcome Aloia et al. 9 Aloia et al. 7 Birkenhager et al. 11 Bone et al. 13 Erdtsieck et al. 12 Erdtsieck et al. 5 Flicker et al. 14 Gonnelli et al. 10 Hodsman et al. 18 Kuntz et al. 16 Lems et al. 19 Lindsay et al. 8 Nausea and flushing with CT a CT caused transient nausea; no change in bone histomorphometric values in 4 patients from each group ND caused voice changes and decrease in high-density lipoprotein All treatments well-tolerated; upper gastrointestinal AE similar frequency across different groups; CEE associated with breast pain and complaint of weight gain, although no objective weight gain; histomorphometry showed no qualitative abnormalities Voice changes occurred with ND, but no hair growth or liver function changes GH caused fluid retention ("minor heart failure") in 1 patient; pamidronate caused gastric complaints ND caused increased systolic and diastolic blood pressure, leg edema, hoarseness, facial hair, and increase in creatinine, aspartate transaminase, and hemoglobin; there was a 13% per year dropout in ND group; hair growth and hoarseness were mild overall; some subjects could not tolerate ND injections secondary to anticoagulants; CT caused decreased diastolic blood pressure and nasal irritation Transient minor arthralgia, muscle pain, ankle swelling during GH administration; nausea and vomiting with CT Mild nausea and skin flushing with calcitonin No specific comments; bone histology showed no significant change in any parameter for CT but increase in trabecular bone volume and total osteoid surface with CT 1 phosphate Treatments were well tolerated All treatments well tolerated, including gastrointestinal events Vertebral x-rays only Vertebral x-rays only Vertebral x-rays only Clinical, number of events too small for antifracture analysis Vertebral x-rays only No No No Clinical and radiographic, number of events too small to report antifracture efficacy No Clinical and radiographic, small number of events Clinical, no patient had hip fracture or symptomatic vertebral fracture, fractures analyzed as AE

COMBINATION TREATMENT OF OSTEOPOROSIS 219 Murphy et al. 21 Reginster et al. 22 Rittmaster et al. 17 Szucs et al. 15 Tiras et al. 23 Wimalawansa 6 n a Abbreviations as in Table 1. fects of CT. It remains possible that ND could act as an augmentor of CT effects for preserving distal radius BMD. Growth hormone-mediated side effect" (fluid retention, weight gain, edema/swelling, abdominal distention (which generally did not result in discontinuation; increases in serum glucose, prolactin, and transaminases associated with GH Only 58.5% completed the study, gastrointestinal events being the main reason for discontinuation No specific comments Analgesic effect of CT was noted; AE were rare and minimal, including mild nausea and flushing; no laboratory test changes; the CT 1 phosphate group was stopped after 2 years because of unfavorable results Esophagitis, with severe epigastric pain associated with alendronate or alendronate 1 E 2 ; proliferative endometrium with uterine bleeding associated with HRT or HRT 1 alendronate No notable AE; estrogen-related side effects were noted but not described in detail; histomorphometry in subset showed no osteomalacia Clinical and radiologic No No Vertebral x-rays, small number of vertebral fractures; reduction in height halted by treatment No Clinical and radiographic, small number of fractures during trial; trend to lower rate of new radiographic vertebral fractures in active treatment groups; less height loss in treatment groups, especially combination therapy group, vs. placebo CT with ND. ND has been combined with HRT and with CT (Table 1) in efforts to increase BMD by two mechanisms concurrently, that is, inhibition of bone resorption (HRT or CT) and stimulation of bone formation (ND). In two studies of ND and CT combination therapy in osteoporotic or osteopenic postmenopausal women, results were conflicting. One study suggested possible antagonism of the medications at the lumbar spine, certainly with no advantage to the combination, 14 whereas the other study suggested that the combination was promising because it prevented a decrease in distal radius BMD seen with CT alone. 15 The disparate results may be partially because of different routes of CT administration, intranasal in the former vs. a cyclical schedule of injection in the latter, or to different schedules of ND injections. Etidronate with Fluoride. Fluoride is a bone formation inducer. At doses that impressively increase vertebral BMD, fluorosis has occurred, with its attendant harmful effects. 26 There has been a recent movement toward changing to a sustained release type of fluoride preparation. The addition of an antiresorptive to fluoride has been an especially attractive idea for preservation of cortical bone. Because of the narrow therapeutic window between beneficial therapeutic effects and toxic effects, fluoride has been studied in combination with three different medications to minimize the adverse effects on cortical bone and the gastrointestinal tract (Table 1). Intermittent cyclical etidronate (200 mg b.i.d.

220 CRANDALL TABLE 4. MECHANISMS OF ACTION SERVING AS A BASIS FOR OSTEOPOROSIS MEDICATION TRIALS FDA-approved Medication Class Mechanism for osteoporosis Alendronate Bisphosphonate Antiresorptive a Yes Calcitonin Polypeptide Antiresorptive Yes b hormone produced by thyroid gland Estrogen Ovarian steroid Antiresorptive Yes replacement hormone Etidronate Bisphosphonate Antiresorptive Yes Growth Hormone produced Bone formation No hormone/mk-677 by the anterior inducer (anabolic pituitary gland c agent) Fluoride Derived from the Bone formation No; has been halogen family inducer (anabolic considered but not agent) approved Nandrolone Anabolic steroid Bone formation No decanoate inducer (anabolic agent) Pamidronate Bisphosphonate Antiresorptive No Parathyroid Hormone produced Bone formation No, but currently hormone by parathyroid inducer (anabolic under review gland agent) Phosphate Mediator of Bone formation No parathyroid inducer (anabolic hormone agent) d Tibolone Partial estrogen, Antiresorptive No progesterone, and androgen agonist a The term "antiresorptive" is generally understood to mean inhibition of osteoclasts in one or more ways. b For treatment of osteoporosis in women more than 5 years menopausal if estrogen use is contraindicated. 32 c Current researchers use recombinant human GH to avoid possible risk of transmission of infectious agents with use of the human product. d Theory was to try to induce release of endogenous parathyroid hormone in order to increase number of bone metabolic units. 16 for 2 weeks) given with fluoride 25 mg b.i.d. may have an advantage over etidronate alone at the lumbar spine but not at the hip in corticosteroidrelated osteoporosis. 19 Pamidronate and GH. Pamidronate is a high-potency bisphosphonate that increases BMD by inhibiting bone resorption. Pamidronate has been combined thus far only with GH, an inducer of bone formation, and in the doses used, the addition of GH surprisingly blunted the lumbar and radius response to pamidronate in osteoporotic postmenopausal women 5 (Table 1). Tibolone and Fluoride. Tibolone has weak estrogenic, progestogenic, and androgenic effects. Tibolone 2.5 mg/day has been combined only with fluoride 26.4 mg/day in women with low bone density 22 (Table 1). The combination had an advantage over fluoride alone in increasing lumbar BMD, but its effects were equivalent to those of fluoride at the total hip. Alendronate and MK-677. MK-677 is a GH, analog. 21 GH, in turn, stimulates osteoblastic activity. One study compared alendronate 10 mg and MK-677 25 mg combination treatment or placebo in women with low femoral neck BMD. The combination regimen yielded higher increases in femoral neck BMD compared with alendronate alone but had no advantage at the lumbar spine or total hip sites over the 12 months of the trial. Histological analysis Bone histology was analyzed in subsets of patients in several of the studies (Table 3). Combinations for which data were reported included GH with calcitonin, 7 alendronate with CEE, 13 CT with phosphate, 16 and CEE/norgestrel with in-

COMBINATION TREATMENT OF OSTEOPOROSIS 221 termittent cyclical etidronate. 6 None of the trials found abnormal bone histology. Gastrointestinal complaints Gastrointestinal adverse effects (AE) of the bisphosphonates account for specific instructions on consumption with water and avoidance of the supine position immediately after consumption. Seven studies of combination regimens involved bisphosphonates (Table 3), and AE were similar with alendronate plus CEE and CEE alone, 8,13 or no AE were mentioned. 17 However, one trial reported esophagitis with severe epigastric pain associated with the use of alendronate or alendronate combined with E 2. 23 With pamidronate, 1 patient dropped out because of gastrointestinal effects. 5 With etidronate, one study found no gastrointestinal problems, 19 whereas the other study 6 reported nausea (7 of 15 patients). Other medications besides bisphosphonates were associated with gastrointestinal adverse events, including fluoride 22 and CT 7,9,10,15,1 8 (Table 3). In one study involving fluoride, the incidence of nausea was so high that it caused a substantial discontinuation rate; only 58.5% completed the study. 22 Other AE AE are summarized in Table 3. Not surprisingly, vaginal bleeding, breast tenderness, and weight gain were complaints reported with HRT, 6,13,23 but evidence of objective weight gain was not found in one study in which subjective weight gain was reported. 13 Flushing 9,15,18 and nasal irritation 14 were reported in association with CT use, and ND was associated with voice changes and lowering of high-density lipoprotein (HDL), 11,12 as well as mild increases in systolic and diastolic blood pressure, edema, hoarseness, facial hair, creatinine, and abnormal liver function tests. 14 MK-677 use was associated with elevations of serum glucose, prolactin, and serum transaminases, as well as edema/swelling and weight gain. 21 Suggestion of synergy vs. antagonism Evidence for synergism in increasing bone density was found with combinations of alendronate with CEE, HRT with etidronate, etidronate with fluoride, and tibolone with fluoride. Alendronate and CEE were synergistic at the spine and femoral neck, and alendronate and estradiol were synergistic at the lumbar spine in the setting of postmenopausal osteoporosis or osteopenia. There was synergy of cyclic etidronate plus CEE 0.625 mg at the lumbar spine and hip for postmenopausal osteoporosis 6 and of intermittent etidronate plus fluoride at the lumbar spine, but not hip, for corticosteroid-related osteoporosis. 19 Tibolone and fluoride were better at increasing lumbar (but not hip) BMD than was fluoride alone for postmenopausal osteoporosis. 22 In addition to bone density outcome, slowing of height loss may indicate evidence of synergy. Slowing of height loss was reported in one trial of CT with ND 15 and etidronate with HRT, 6 although evidence was not statistically strong. In the latter trial, the combination group did not have significant height loss, in contrast to the groups taking the same medications individually. 6 There was also a trend to a lower rate of new vertebral fractures in all the treatment groups. There was a suggestion of lower vertebral fracture incidence with the combination of PTH and CT compared to PTH alone. 18 Evidence for antagonism of two components of a combination regimen was reported with GH and CT, GH with pamidronate, and ND with CT (conflicting reports). Antagonism was seen at the lumbar spine with intranasal CT plus ND i.m., 14 at the radius or hip with GH injection plus CT s.c., 9,10 and at the radius with pamidronate plus GH in postmenopausal osteoporosis. 5 No benefit was seen in adding phosphate to PTH, CT, or etidronate, nor was combining ND with oral E 2 better than ND alone. No phosphate-containing combinations were useful. There was not support for ND combination regimens or for CT plus PTH. Success might have been obtained with a different dose, route, or schedule in some of the studies that did not report benefit of specific combination regimens. Examples are GH with CT, 7,10 pamidronate with GH, 5 and CT with ND. 14 DISCUSSION Overall, there have been 18 randomized controlled studies evaluating the use of osteoporosis medications in combination to treat osteopenia or osteoporosis. Studies ranged from 1 to 4 years in duration. Fracture reduction is not proven for any combination regimen, so that bone density has

222 CRANDALL been used as a surrogate for treatment efficacy in all trials discussed. The most common combination regimen was s.c. CT with GH. The next most common combinations, each investigated in two studies, were E 2 with ND, alendronate with CEE, CT with ND, and CT with phosphate, all studied in the treatment of postmenopausal osteoporosis. Whereas alendronate with CEE was promising for increasing lumbar and hip density in postmenopausal osteoporosis/osteopenia, results with the other regimens were either mixed (CT with ND, E 2 V with ND) or not beneficial (CT with phosphate) for postmenopausal osteoporosis. The small volume of literature about combination treatment of osteoporosis thus does not allow well-grounded conclusions. There is a potential role for the combination of HRT and alendronate in women who remain osteoporotic on HRT alone 8 or who were not taking HRT before institution of the combination. 13 It should be noted that these two studies involving CEE 0.625 mg/day cannot be compared with studies employing ethinyl estradiol or E 2. Future studies may show even greater benefit with more potent estrogens, such as ethinyl estradiol. Because all estrogens cannot be assumed to offer the same osteoporosis benefits, it will be imperative to control for the specific dose and type of estrogen in future trials, and more fracture outcome data and long-term safety data are necessary. Regimens may conflict with each other or cause detrimental bone effects, as may be the case with ND and CT, 14 CT with GH, 9 or pamidronate and GH. 5 However, although bone density is a convenient measurement outcome, unless the medication combinations were directly compared in the same trial, conclusions cannot be drawn across trials regarding which regimen caused the greater increase in bone density. The efficacy of combination regimens in increasing BMD can be classified according to baseline disease/characteristics, that is, postmenopausal osteoporosis, osteopenia, or steroidrelated osteoporosis. For patients with postmenopausal osteoporosis or osteopenia, three combinations increase hip and lumbar BMD: alendronate 10 mg with CEE 0.625 mg/day, cyclic etidronate with CEE 0.625 mg/day, and tibolone with fluoride. In the setting of steroid-related osteoporosis, intermittent etidronate with fluoride increases lumbar BMD. Bone density is the usual outcome in the clinical trials to date because it is convenient to measure and takes less time to manifest treatment effects than does fracture outcome, thus allowing shorter-term studies. In addition, BMD outcome is popular because fracture efficacy outcome requires larger numbers of subjects for adequate numbers of events to allow statistical significance. However, treatment-induced changes in bone density do not necessarily yield a decrease in fracture rates. For example, early work showed fluoride treatments to actually increase nonvertebral fractures, despite fluoride having been established as an inducer of impressive increases in bone density. 26 Future studies involving fluoride and other new osteoporosis medications must include histomorphometry and fracture outcome data. It is, therefore, worthy of emphasis that in the studies reviewed, fracture outcome was a component of the safety assessment for AE rather than a primary outcome. Sometimes, fractures were assessed only as part of safety assessment, or there were too few fracture events for adequate statistical analysis. Study duration and numbers of fracture events often are inadequate to offer fracture outcome, and long-term safety data have likewise been lacking. The fact that fracture outcome is of utmost importance should be remembered, in spite of the seemingly encouraging increases in BMD that are the most commonly presented outcome. No apparent harm resulted from any combination as related to fracture incidence in the randomized controlled trials published to date. Relevant to application of trial results to everyday practice, many components of the studied treatment combinations are not yet available for clinical use in the formulas and doses used in the clinical trials, nor are any of the medications approved by the FDA to be used in combination. Besides concerns about medication availability, extrapolation of trial results requires assessment of expected compliance. Knowledge of whether patients were compliant with study medications is important not only for deciding applicability of results to general practice but also because new treatments/regimens can be designed based on analysis of the reasons for medication noncompliance. 27 It is difficult to draw conclusions about efficacy in the setting of the high dropout rate seen in some of the reviewed studies of combination regimens. 22 Injection may not be widely accepted as a method for medication delivery in

COMBINATION TREATMENT OF OSTEOPOROSIS 223 the large number of treatment candidates suffering from osteoporosis. Quality of life and tolerability of injection regimens (e.g., CT s.c. or i.m., GH s.c., ND i.m., and PTH s.c.) will have to be further explored. Additionally, injections may be a problem for many potential recipients of osteoporosis treatment who may be using concurrent anticoagulants. It is not clear whether the bone density benefits seen with the various combinations are longlived. Equally important is to what extent AE (such as voice changes, adverse lipid changes, and hair growth) worsen with time, yield unexpected serious adverse changes (e.g., cardiac events) after long periods of use, and, if completely reversible, over what expected time period reversibility of AE may be anticipated. Ongoing research on combination therapy in healthy women who are not osteoporotic potentially may be extended to women with osteoporosis in the future. For example, ipriflavone is a synthetic isoflavone that has been combined with estrogen replacement in three trials. 27 29 Isoflavones are the principal phytoestrogens (plant estrogens) of soy and have weak estrogenic activity. 30 Combinations included ipriflavone 600 mg/day with either CEE 0.625 mg/day, 28 CEE 0.3 mg/day, 27,29 or CEE 0.15 mg/day. 29 Although the study populations varied (early postoopherectomy in one, healthy postmenopausal in another, and postmenopausal with osteoporosis risk factors in the third), all three trials suggested a benefit of the combination treatment over CEE 0.3 0.625 mg/day alone. Additionally, two other recent trials suggest a preventive benefit of CEE combined with either calcitriol or risedronate. 31,32 CONCLUSIONS Experimentation with combination therapy for treatment of osteoporosis or osteopenia is still in its rudimentary stages. The combination of alendronate 10 mg day in conjunction with estrogen replacement (equivalent of CEE 0.625 mg/day) in postmenopausal women is the only regimen in which both components are available in FDA-approved doses for treatment of osteoporosis. No combination regimens are FDA approved. Effects of any combination regimen on fracture reduction is unknown. However, alendronate 10 mg/day combined with CEE 0.625 mg/day may be more effective than either treatment alone in increasing lumbar and hip BMD for women with postmenopausal osteoporosis or osteopenia. The 11 tested combinations include alendronate with HRT, alendronate with PTH, etidronate with HRT, HRT with ND, CT with GH, CT with PTH, CT with phosphate, CE with ND, etidronate with fluoride, pamidronate with GH, and tibolone with fluoride. However, only one combination, alendronate plus CEE, has been tested in more than one trial and been found to increase BMD advantageously compared with the components given individually. No fracture outcome of this combination has yet been determined. Information regarding how many more fractures would be prevented by adding one medication to another is necessary and lacking. All combination regimens lack fracture outcome and long-term safety data. The basis on which we discuss the use of these combinations rests on whether the scanty early data regarding favorable changes in BMD increases will translate into decreased fracture rates in the individual patient. Still to be explored are many other combinations of medications already existing. Different doses and schedules of the medications already tested may also prove efficacious. REFERENCES 1. National Institutes of Health. Consensus development conference statement: Osteoporosis prevention, diagnosis, and therapy. National Institutes of Health, March 27 29, 2000. 2. National Osteoporosis Foundation. Physician s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation, 1998. 3. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, March 27 29, 2000: Highlights of the conference. JAMA 2001; 285(6):785. 4. Greendale GA, Barrett-Connor E, Ingles S, Haile R. Late physical and functional effects of osteoporotic fracture in women: The Rancho Bernardo Study. J Am Geriatr Soc 1995;43:955. 5. Erdtsieck RJ, Pols HA, Valk NK, et al. Treatment of post-menopausal osteoporosis with a combination of growth hormone and pamidronate: A placebo-controlled trial. Clin Endocrinol (Oxf) 1995;43:557. 6. Wimalawansa SJ. A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis. Am J Med 1998;104:219. 7. Aloia JF, Vaswani A, Meunier PJ, et al. Coherence treatment of postmenopausal osteoporosis with

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Combination treatment with estrogen and calcitriol in the prevention of age-related bone loss. J Clin Endocrinol Metab 2001;86:3618. 02 Address reprint requests to: Carolyn Crandall, M.D. F.A.C.P. Assistant Professor of Medicine UCLA School of Medicine & UCLA National Center of Excellence in Women s Health (US DHHS) Iris Cantor-UCLA Women s Health Center 100 UCLA Medical Plaza, Suite 250 Los Angeles, CA 90095-7023