Management of corticosteroid-induced osteoporosis

Management of Corticosteroid-Induced Osteoporosis Jonathan D. Adachi, Wojciech P. Olszynski, David A. Hanley, Anthony B, Hodsman, David L. Kendler, Kerry G. Siminoski, Jacques Brown, Elizabeth A. Cowden, David Goltzman, George Ioannidis, Robert G. Josse, Louis-Georges Ste,Marie, Alan M, Tenenhouse, K. Shawn Davison, Ken L.N. Blocka, A. Patrice Pollock, and John Sibley

Objectives: To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. Methods: This review summarizes the pathophysiology of corticosteroidinduced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. Results: Despite our lack of understanding about the biological mechanisms From the Department of Medicine, St Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada; the Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; the Department of Medicine, Foothills Hospital, University of Calgary, Calgary, Alberta, Canada; the Department of Medicine, St Joseph's Hospital, University of Western Ontario, London, Ontario, Canada; the Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada; the Endocrine Center of Edmonton and Medical Imaging Consultants, Edmonton, Alberta, Canada; the Department of Rheumatology, Centre Hospitalier de l'Universite Laval, Ste-Foy Quebec, Canada; the Department of Medicine, Dalhousie University, Halifax Nova Scotia, Canada; the Department of Medicine, Royal V~ctoria Hospital, McGill University, Montreal Quebec, Canada; the Department of Medicine, St Joseph's Hospital McMaster University, Hamilton, Ontario, Canada; the Department of Medicine, St Michael's Hospital University of Toronto, Toronto, Ontario, Canada; the Department of Medicine, Centre Hospitaller de l'Universite Montreal Montreal Quebec, Canada; the Department of Medicine, Montreal General Hospital McGill University, Montreal, Quebec, Canada; and the college of Kinesiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Jonathan D. Adachi, MD: Professor, Department of Medicine, St Joseph's Hospital McMaster University, Hamilton, Ontario, Canada; Wojciech P. Olszynski, MD: Professor, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; David A. Hanley, MD: Professor, Department of Medicine, Foothills Hospital, University of Calgary, Calgat~y, Alberta, Canada; Anthony B. Hodsman, MD: Professor, Department of Medicine, St Joseph's Hospital University of Western Ontario, London, Ontario, Canada; David L. Kendler, MD: Department of Medicine, Vancouver General Hospital University of British Columbia, Vancouver British Columbia, Canada; Kerry G. Siminoski, MD: Endocrine Center of Edmonton and Medical Imaging Consultants, Edmonton, Alberta, Canada; Jacques Brown, MD: Professor, Department of Rheumatology, Centre Hospitalier de l'Universite Laval, Ste-Foy Quebec, 228

Canada; Elizabeth A. Cowden, MD: Professor, Department of Medicine, Dalhousie University, Halifax Nova Scotia, Canada; David Goltzman, MD: Professor, Department of Medicine, Royal ~ctoria Hospital, McGill University, Montreal, Quebec, Canada; George Ioatmidis, MSc: Research Associate, Department of Medicine, St Joseph's Hospital, MeMaster University, Hamilton, Ontario, Canada; Robert G. Josse, MD: Professor, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; Louis-Georges Ste-Marie, MD: Associate Professor, Department of Medicine, Centre Hospitalier de l'Universite Montreal, Montreal, Quebec, Canada; Alan M. Tenenhouse, MD: Professor, Department of Medicine, Montreal General Hospital McGill University, Montreal, Quebec, Canada; K. Shawn Davison, MSc: PhD Candidate, College of Kinesiology, University of Saskatchewan, Saskatoon Saskatchewan, Canada; Ken L.N. Blocka, MD: Professor, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; A. Patrice Pollock, MD: Professor, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; John Sibley, MD: Professor, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Supported by a grant-in-aid from Procter & Gamble Pharmaceuticals Canada, Inc. This report was prepared in collaboration with Hoechst Marion RousseL Drs Adachi, Brown, Cowden, Goltzman, Hanley, Hodsman, Jose, Kendler, Olszynski, Ste-Marie, Siminoski, and Tenenhouse are consultants to Procter & Gamble Pharmaceuticals Canada, Inc, and are involved in clinical trials in which a grant-in-aM has been provided by Procter & Gamble Pharmaceuticals Canada, Inc. Drs Pollock, Blocka, and Sibley, G. Ioannidis and K.S. Davison do not have any other financial arrangement with Procter & Gamble Pharmaceuticals Canada, Inc. Address reprint requests to Jonathan D. Adachi, MD, 501-25 Charlton Ave E, Suite 501, Hamilton Ontario, Canada LSN 1 }72. Copyright © 2000 by W.B. Saunders Company 0049-0172/00/2904-0004510.00/0

Seminars in Arthritis and Rheumatism, Vo129, No 4 (February), 2000: pp 228-251

CORTICOSTEROID-INDUCED OSTEOPOROSIS

229

leading to corticosteroid-induced bone loss, effective therapy has been devei= oped. Bisphosphonate therapy is beneficial in both the prevention and treat= ment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroidinduced bone loss and should be administered in combination with other agents. Conclusions: Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroidinduced osteoporosis. Semin Arthritis Rheum 29:228.251. Copyright © 2000 by W.B. Saunders Company INDEX WORDS: Corticosteroid-induced osteoporosis; bisphosphonates; drug trials; treatment options. INCE HARVEY CUSHING'S original observation of the coexistence of hypercortisolism and loss of skeletal mass more than 5 decades ago (1), it has been understood that supraphysiologic doses of corticosteroids cause clinically significant bone loss. Because of the rarity of Cushing's syndrome, corticosteroid-induced bone loss did not become a serious concern until these agents began to be used therapeutically. Currently, high dose oral corticosteroids are used to treat a variety of medical conditions. Corticosteroid use is associated with fractures at sites such as the spine and hip (2-4). It is estimated that between 30% and 50% of patients taking long-term corticosteroids experience fractures (5-6). In comparison with postmenopausal osteoporosis, little is known about corticosteroid-induced osteoporosis. Data regarding corticosteroid-induced osteoporosls are very difficult to interpret, and the pathophysiology of this condition remains unclear. Moreover, most clinical trials that have examined corticosteroid-induced osteoporosis have involved patients with complicated systemic disorders of varying severity. These disorders are characterized by dysregulated immune or hematopoietic cell function. Often, as with rheumatoid arthritis, it is not possible to separate the effects of the primary disease from the corticosteroids with respect to bone loss (7, 8). In addition, the risk of developing osteoporosis appears to be variable and depends on a number of factors, including the dose of corticosteroid prescribed and the duration of exposure. patient gender, and menopausal status (6).

S

This review attempts to summarize a very complex field. The pathophysiology of corticosteroidinduced osteoporosis is explored and the assessment methods used to evaluate this condition described. Finally, the resuks of clinical drug trials and a practical approach to the management of this condition are provided. PATHOPHYSIOLOGY The cause of corficosteroid-induced osteoporosis is multifactorial and occurs in addition to normal age- and menopause-associated bone loss. There are 2 purported abnormalities in bone metabolism that develop in patients with this condition: the first is a reduction in bone formation and the second is an increase in bone resorption (Fig 1). Reduced bone formation is caused by the direct inhibitory effects of corticosteroids on osteoblast function. Modest doses of corticosteroids prevent the synthesis of bone collagen by preexisting osteoblasts and the transformation of precursor cells into functioning osteoblasts (9-12). Furthermore. corucosteroids substantially reduce protein synthesis (13). Histomorphometrically, this is represented by a decrease in osteoid seams, a low mineral apposition rate as measured by tetracycline labeling, and a reduced mean wall thickness. The reduction in trabecular mean wall thickness is thought to be due to a shortened osteoblast life span (11). Also observed with the use of corticosteroids is a decrease in bone formation as seen by changes in bone turnover markers, such as osteocalcin. However. osteocalcin decrease may overestimate

230

ADACHI ET AL

Corticosteroids

I Altered Osteoblastic

/-

Altered Gonadal

Function

$ number of fxmcticnit g osteoblasts

\

Function

.__....-~per°ste°bes~gT:~ last 2 ~

$bone ~ul~t l~n t

~"Parathyroid

Altered Calcium

Secretion

Metabolism

absorption

Zo.io excretion

res

Fig 1. Pathophysiology of corticosteroid-induced osteoporosis.

the effects of corticosteroids on collagen synthesis (14-19). Moreover, corticosteroids may affect osteoblasts by modulating their responses to parathyroid hormone, prostaglandins, cytokines, growth factors, and 1,25-dihydroxy vitamin D. In addition, the synthesis and activity of many local paracrine factors can be altered (20). In comparison with normal aging, bone loss in corticosteroid-induced osteoporosis is greater because of an increased activation frequency (increased resorption and formation surfaces) and a more pronounced imbalance of remodeling (11, 21). As compared with bone formation, the effects of corticosteroids on bone resorption have not been extensively studied, and the results have been contradictory. It has been postulated that the influence of these agents on bone resorption is parathyroid hormone mediated (22-26). For example, investigators have shown that, after a parathyroidectomy, the osteoclastic response to corticosteroids in animals is completely abolished, suggesting that increased bone resorption is, in large part, controlled by parathyroid hormone (22). Others have suggested that an increase in bone resorption may result from secondary hyperparathyroidism and that this occurs as a consequence of decreased intestinal calcium absorption (27-31) and increased urinary excretion of calcium, leading to relative hypocalcemia (32-34). However, most studies have

not found any increases in parathyroid hormone levels in patients receiving corticosteroid therapy. Furthermore, the role of parathyroid hormone also has been challenged on the basis of the assay used to measure its serum concentration (20). Elevated parathyroid hormone levels were fotmd when using assays that measured hormone fragments (23-25, 32), whereas no change was seen with assays that measured intact parathyroid hormone (17) or midregion fragments (16, 35-57). The effect of corticosteroids on net intestinal calcium absorption also is controversial. Results from radioisotope studies indicate that calcium absorption may decrease (38, 39), increase (40), or remain unchanged (41) in response to corticosteroids. These contradictory results may be explained by the fact that corticosteroids act differently on individual intestinal segments. For instance, it has been reported that although duodenal absorption is depressed (30, 31, 42-44), these agents may stimulate colonic absorption (45, 46). Furthermore, corticosteroids may alter calcium absorption in a dosedependent manner (47), so that conflicting results may be caused by differences in corticosteroid dosages. In addition to decreased calcium absorption, corticosteroids may increase urinary excretion of calcium. In patients on long-term corticosteroids, hypercalciuria is most likely attributable to in-

CORTICOSTEROID-INDUCED OSTEO,POROSIS

creased skeletal calcium mobilization and decreased renal tubular reabsorption and results from a parathyroid hormone-independent mechanism (16). Corticosteroids may alter vitamin D metabolism, although the evidence is not convincing. Normal 25-hydroxyvitamin D concentrations have been found in patients receiving corticosteroid therapy. Prednisone depresses calcium absorption from the gastrointestinal tract in normal individuals without depressing serum 25-hydroxyvitanfin D levels (26, 48). Corticosteroids may act by reducing the serum levels of !,25-dihydroxyvitamin D (49); nonetheless, they do not alter the conversion of 25hydroxyvitamin D to 1,25'dihydroxyvitamin D (30, 3!). Seeman et al (27) confirmed the absence of significant abnormalities in vitamin D metabolism. Godschalk et al (50) found that corticosteroids reduced the number of vitamin D receptors, suggesting that this might be the mechanism by which these drugs antagonize vitamin D action. Corticosteroids alter gonadal function by inhibiting p i t u i t ~ gonadotrophin secretionl This, combined with their direct effect on the ovaries and testes, may lead to a reduction in the production of estrogen and testosterone. Co~Costeroids blunt the secretion of luteinizing hormone in response to luteinizing hormone-releasing hormone in both men and women (51, 52). They inhibit folliclestimulating-hormone-induced estrogen production in women and decrease testosterone production in men (53-56). Corticosteroids also reduced the secretion of adrenal sex hormones, Circulating levels of androstenedione and estrone are suppressed as a result :of the reduced adrenal produc, tion of androstenedione, caused by the suppression of adrenocorticotr0phie hormone and the subsequent adrenal atrophy (57). In fact, estrogen deficiency and corticosteroids may have an additive effect in accelerating the rate of bone los s (58), Data suggest that; when bone Ioss occurs, trabecular rather than cortical bone i s affected sooner and more severely by corticosteroids (4, 59). As a consequence, fractures affecting the ribs vertebrae, and pelvis are particuI~ty prevalent (60). In one study, patients who were not t ~ n g eorticosteroid therapy had a similar reduction in bone mass at: the metaphyseal (trabecular bone) and the diaphyseal (cortical bone) sites (59); In :Comparison, patients who were t a i n g more ihan i0 mg/d of prednis°ne had a greater degree of bone loss at the metaphyseal

231

site. as compared with the diaphyseal site. Other investigators have confirmed these findings (4). CORTtCOSTEROIDS AND BONE LOSS There is evidence that after corticosteroid initiation, hypercalciuria develops and bone loss occurs quickly within the first 6 to 12 months of beginning therapy; thereafter, the rate of bone loss slows to 2 to 3 times that of normal (61-63). The risk of corticosteroid-induced osteoporosis increases as the dose of the drug increases (63), but the shape of the dose-risk curve is unknown. It is unclear what the risk of corticosteroid-induced osteoporosis is in relation to either high-dose (prednisone >7.5 rag/d) short duration (<6 months), or low-dose (prednisone <7.5 mg/d) long duration (>6 months) corticosteroid therapy. However, the risk of corticosteroid-induced osteoporosis increases as the cumulative corticosteroid dose increases (35, 64. 65 }. Significant trabecular bone loss develops with prednisone doses greater than 7.5 mg/d in most patients (6, 63). Yet. in one study, bone loss rates increased with doses between 5 and 10 mg daily and with inhaled steroids (61). Thus, although lower doses of corticosteroids may be safer than higher doses, there is still no maly safe dose (61). As a general rule. all patients receiving any dose of corticosteroids for prolonged periods should have their bone mineral density momtored. ASSESSMENT Risk Assessment

Risk factors that should be examined in patients receiving corticosteroids include family history, hormonal status, fracture history, age, other medications that may interfere with normal bone metabolism. and lifestyle habits (51, 67-76). A family history should be completed to determine the existence of bone pathology in the patient's biological ancestry and should include history of osteoporosis, early menopause, longevity, and fractures. All medications that interfere with normal bone metabolism should be noted and avoided if possible (eg, cyclosporine, phenytoin, etc.I. If suitable, other drags with less detrimental bone effects should be substituted. Lifestyle risk factors, such as diet, physical activity, alcohol use. and smoking should be identified and treated appropriately. Assessing risk factors allows the clinician to form a

232

mosaic of the individual's unique susceptibility to bone loss during and after corticosteroid usage. If there is evidence of clinical hypogonadism, men should have their serum testosterone and hiteinizing hormone concentrations measured, and in oligomenorrheic or amenorrheic premenopausal women, levels of serum estradiol, follicle-stimulating hormone, and luteinizing hormone should be determined, ff an individual is deficient, attempts should be made to correct the imbalance, because this deficiency will negatively affect bone mass. With oligomenorrheic or amenorrheic premenopausal women, the cause of the menstrual dysfunction should be determined. For hypoestrogenemic women, birth control pills with adequate levels of estrogen (at least 50 gg estradiol) or hormone replacement therapy should be prescribed. For hypogonadal men, testosterone replacement should be considered. To aid with the diagnosis of secondary causes of osteopenia or osteoporosis, standard laboratory investigations should include a complete blood count, and measurement of serum creatinine, alkaline phosphatase, calcium, and phosphorus. In patients older than 65 years, serum protein electrophoresis and lipids and a urinary calcium-tocreatinine ratio determination also may be justified. Laboratory tests may be used later to assess treatment efficacy or identify complications of therapy, such as hypercalcemia.

Biochemical Assessment A number of clinical biochemistry parameters are altered in corticosteroid-induced osteoporosis. With corticosteroid use, urine calcium excretion is initially high, then falls over time. Measurement of urinary calcium concentrations are helpful in assessing calcium balance, susceptibility to secondary hyperparathyroidism, and possible treatment options for corticosteroid-treated patients (15, 16, 32). Bone turnover makers also have been studied. Bone-specific alkaline phosphatase and osteocalcin levels are low in most patients on corticosteroids. Daily doses of prednisone as low as 2.5 mg will suppress osteocalcin levels (77). Urinary hydroxyproline, pyridinoline, deoxypyridinoline, and carboxy- and amino-telopeptide excretions are good indicators of bone resorption, and, along with urinary calcium, may help predict those who will develop corticosteroid-induced osteoporosis (78, 79). Unfortunately, the usefulness of biochemical

ADACHI ET AL

markers is limited, because none can reliably predict those who will lose bone mass and the degree to which it might be lost as a result of corticosteroid treatment.

Radiologic Assessment Distinctive characteristics of corticosteroidinduced osteoporosis may be observed on radiographs (60). In postmenopausal osteoporosis, horizontal trabeculae are absorbed to a greater extent as compared with vertical trabeculae, which leads to a "corduroy stripe" appearance (5). However, in corticosteroid-induced osteoporosis, vertical and horizontal trabeculae are similarly thinned, yielding a uniformly translucent image of the vertebrae. Abundant pseudocallus formation at the site of stress fractures is a hallmark of corticosteroidinduced osteoporosis (5). This formation is encountered, for the most part, at the end plates of collapsed vertebrae or around stress fractures in the ribs or pelvis. The basis for this is a reduction in osteoblastic activity and increased production of cartilaginous callus that becomes highly mineralized in an amorphous fashion.

Bone Density Assessment Trabecular bone loss occurs initially in the course of corticosteroid therapy, although both trabecular and cortical loss occur over time. Early changes in bone mineral density can be observed in the lumbar spine and femoral neck using dual x-ray energy absorptiometry or quantitative computed tomography (80). Bone loss is distinguishable by 6 months with dual-energy x-ray absorptiometry, and, on average, 5% of bone mass is lost within the first year of therapy. During the second and third year of treatment, bone loss persists, but at a slower rate (63). Bone mineral density measurements have been used to assess the risk of osteoporosis and fractures in corticosteroid-treated patients. Although these measurements are accurate and precise, they may underestimate the fracture risk in patients receiving corticosteroids. With the use of these drugs, bone strength may not be related to bone mass as directly as it is in primary osteoporosis. For instance, in postmenopausal women, a decrease in bone mineral density of one standard deviation is associated with a 2-fold increase in fracture risk (81). This increase in fracture risk may be greater in patients who are treated with corticosteroids (82).

CORTICOSTEROID-INDUCED OSTEOPOROSIS

PREVENTION AND TREATMENT

Therapeutically, the use of alternative therapy or the early discontinuation of corticosteroids is the best means of preventing corticosteroid-induced osteoporosis. Thus, care must be taken to ensure that corticosteroid therapy is truly indicated and initiated only when potential benefits outweigh potential risks. Once corticosteroid therapy is initiated, repeated follow-up is needed to ensure that the dose, duration, treatment intervals, and corticosteroid preparation and route of administration are optimized to allow for the greatest benefit-to-risk ratio. Patients who have discontinued corticosteroid therapy exhibit a rebound increase in osteoblastic function and new bone formation (9, 51, 83, 84). Unfortunately, even with this increase in bone formation, bone resorption rates are usually greater than formation rates for some time after corticosteroid cessation. Consequently, bone loss still occurs. Alternate-day corticosteroid therapy may be less toxic than daily administration (85); nonetheless, bone loss has been detected in individuals receiving alternate-day treatment (86). THERAPEUTIC EFFICACY

When interpreting the efficacy of drug therapy in preventing corticosteroid-induced osteoporosis, it is important to assess the results in light of when drug therapy was initiated in the course of steroid use. Primary prevention studies are trials in which patients begin drug treatment at the same time or shortly after corticosteroid use is initiated. Treatment studies are trials in which patients begin drug treatment after chronic corticosteroid use. Prevention studies examine the efficacy of drug therapy in patients before rapid corticosteroid-induced bone loss, whereas treatment studies determine the efficacy of drug therapy in patients in whom bone loss has already occurred. The main goal inthe prevention and treatment of corticosteroid-induced bone loss is to stabilize bone mass and reduce fracture risk. However, studies that evaluate corticosteroid-induced bone loss tend to enroll study populations that include premenopausal women and men who are not at particularly high risk for fracture. Furthermore, it is common that inclusion criteria do not have preexisting fracture or bone mineral density target (Tscore < -2.5) requirements. Accordingly, by their very nature, these studies have low power to detect

233

a treatment effect for fracture occurrence. A number of interventions have been proposed in the management of corticosteroid-induced bone loss, but the effectiveness of only a few have been proved in randomized controlled trials. AVAILABLE THERAPIES

Bisphosphonates Bisphosphonates are potent inhibitors of bone resorption. Clinical trials in postmenopausal women with established osteoporosis have provided conclusive evidence that therapy with this class of drug leads to significant improvement in bone mass (87-89), and reduction in subsequent fractures (90-92). Although differences exist between the pathogenesis of postmenopausal osteoporosis and corticostetold-induced osteoporosis, both show increased bone resorption. Therefore, bisphosphonates might be expected to have an important role in preventing bone loss and treating established bone loss in patients on chronic corticosteroid therapy, and substantial data support such usage. Indeed, in a recent meta-analysis that examined calcitonin, vitamin D, fluoride, and bisphosphonates in corticosteroid-treated patients, bisphosphonate therapy had a larger bone density treatment effect at the lumbar spine as compared with either calcitonin or vitamin D, whereas fluoride had an intermediate effect (93). Seventeen randomized controlled clinical trials (94-110), 10 prevention and 7 treatment, have been identified in which the efficacy of bisphasphonates has been evaluated in corticosteroid-treated patients (Table 1). In general, patients suffered from a variety of underlying diseases that required corticosteroid therapy, and for the most part, patients were given calcium or vitamin D supplements throughout the study. Of the l0 prevention studies (94-103), 6 examined etidronate, and 1 study each examined risedronate, alendronate, clodronate, and intravenous pamidronate. Bisphosphonate therapy resulted in slight increases in lumbar spine bone mineral density, whereas treatment with placebo resulted in bone loss. Five studies report data on the femoral neck (94-96, 100, 101). Bisphosphonate-treated patients maintained femoral neck bone mineral density, whereas decreases were observed in placebotreated patients. Among these, the risedronate study found a significant difference between treatment groups (100). Two studies evaluated radial bone

Table 1: Bisphosphonate Therapies in the Prevention and Treatment of Corticosteroid-lnduced Bone Loss

Authors

Year Published

Study Design and Duration

Patients N (M/F)

CS Duration* TreatlPla All patients <90 days

Roux et al (94)

1998

RCT; 1 year

117 (42/75)

Adachi et at (95)

1997

RCT;1 year

141 (54/87)

Wolfhagen et al (96)

1997

RCT;1 year

t2 (3/9)

Started CS 1 month post-BL

Jenkins et al (97)

1997

RCT;1 year

28 (NA)

Started CS at BL

Skingle and Crisp (98)

1994

RCT;2 years

55 (11/44)

Started CS at BL

Mulder and Struys (99)

1994

Cohen et al¶ (100)

1998

8outsen et al (101)

1997

Prospective alternate patient 20 (0/20) controlled; I year RCT;3 arms: 2.5 mg risedro228 (NA) hate, 5.0 mg risedronate, placebo; 1 year M{nimized RCT; 1 year 27 (5/22)

Started CS at BL

Gonnelli et al (102) Nordborg et al (103)

1997 1997

RCT;1 year RCT;1 year

30 (10/20) 27 (6/21)

Started CS at BL Started CS at BL

Pitt et al (104)

1998

RCT;2 years

49 (19/30)

Ranged from (6 months to 35 years)

Guesens et al (105)

1997

RCT;2 years

37 (0/37)

All patients >3 months

Worth et al (106)

1994

RCT; 6 months

33 (12/21)

All patients >9 months

Saag et al# (t07)

1998

Saag et al** (108)

1998

Reid et a l t t (109)

1998

Reid et a155 (110)

1998

RCT; 3 arms: 5 mg alendronate, 477 (141/336) Stratified 10 mg alendronate, placebo; <4 months 48 weeks 4-12 months > 12 months RCT;4 arms: 5 mg alendronate, 208 (NA) NA 10 mg alendronate, 2.5/10 mg alendronate; placebo; 2 years RCT;3 arms: 2.5 mg risedro~ 290 (NA) All patients >6 months nate, 5.0 mg risedronate, placebo; 1 year RCT;1 year 35 (19/16) 5.0/6.5 years

Started CS at BL

Abbreviations:N, total number of patienta enrolled; M/F, number of men enrolled/number of women enrolled; CS, corticosteroid; Treat,treatment group; Pia, placebo group; BMD, bone mineral density; Dill, percent difference between groups after therapy in bone mineral density; RCT,randomized controlled trial; NA, not available; BL, baseline; LS, lumbar spine; FN, femoral neck;TR, trochanter; WB, whole body; FA, forearm; DR, distal radius; MR, midshaft radius; DXA, duaFenergy x-ray absorptiometry; DPA, dual photon absorptiometry; QCT, quantitative computer tomography. *Mean corticosteroid duration before baseline assessment. tMean baseline corticosteroid dose (mg/d). ~:Mean percent change from baseline to the end of therapy in bone mineral density. §Significant change from baseline (P < .05). liSignificant difference between groups (P < .05). ¶Cohen et at: Comparisons are made for the placebo and the risedronate 5 mg/d groups. #Snag et al: Comparisons are made for placebo and the atendronate 10 mg/d groups collapsed across CS duration. **Snag et al: Comparisons are made for placebo and the alendronate 10 mg/d groups~ t~Reid et al: Comparisons are made for the placebo and the risedronate 5 mg/d groups. ¢$Reid et al: The change in forearm bone content is between 3 and 12 months of therapy.

Table 1: Bisphosphonate Therapies in the Prevention and Treatment of Corticosteroid-lnduced Bone Loss (Cont'd) % BMD Changes

CS Doset Treat/Pla

Treatment

All patients >7.5

Etidronate, 400 mg/d for 2 weeks; followed by elemental calcium, 500 mg/d for 11 weeks; 4 cycles Etidronate, 400 mg/d for 2 weeks; followed by elemental calcium, 500 mg/d for 11 weeks; 4 cycles

21.0/23.0

All patients = 30

NA

All patients >5.0 All patients = 60 NA

31.2/28.1

32.6/35.4 10.3/10.9 8.2/7.2

6.3/6.4

27.0/28.0 10.0/11.0

NA

NA

15.1/12.6

Etidronate, 400 mg/d for 2 weeks; followed by elemental calcium, 500 mg/d for 11 weeks; 4 cycles Etidronate, 400 mg/d for 2 weeks; followed by elemental calcium, 500 mg/d for 11 weeks; 4 cycles Etidronate, 400 mg/d for 2 weeks out of 15; calcium, 1000 mg/d Etidronate, 400 mg/d for 2 weeks; followed by 11 weeks off therapy; 4 cycles Risedronate, 2.5 or 5 rag/d; elemental calcium, 500 mg/d Intravenous pamidronate, 90 mg (first infusion); followed by intravenous pamidronate, 30 mg every 3 months; elemental calcium, 800 mg/d Alendronate, 5 rng/d Clodronate, 800 mg/d in alternate months; elemental calcium, 500-750 mg/d Etidronate, 400 mg/d for 2 weeks; followed by elemental calcium and vitamin D, 97 rag/d, and 400 IU for 11 weeks; 8 cycles Etidronate, 400 mg/d for 2 weeks; followed by elemental calcium, 500 rag/d, for 11 weeks; 8 cycles Etidronate, 7.5 mg/kg/d; vitamin D, 1,000 IU; calcium, 1,000 mg/d Alendronate, 5 or 10 rag/d; elemental calcium, 800 to 1,000 rag/d; vitamin D, 250 to 500 IU/d Alendronate, 5 or 10 mg/d; elemental calcium, 800 to 1000 rag/d; vitamin D, 250 to 500 IU/d Risedronate, 2.5 or 5 mg/d; elemental calcium, 1,000 mg/d; vitamin D, 400 mg/d Oral pamidronate, 150 mg/d; elemental calcium, 1,000 mg/d

Site/instrument

Treat

Pla

LS/DXA FN/DXA TR/DXA LS/DXA FN/DXA TR/DXA DR/DXA MR/DXA LS/DXA FN/DXA

0.3 - 1~3§ -1.4§ 0.6 0.2 1,5 0,5 0.1 0.4 -0.1

2.8§ -2.6§ 1.7§ -3.2 - 1.7 2.7 0.3 -0.1 -&0§ 1.5

3.1 [ 1.3 0.3 3.8II 1.9 4.2 0.2 0.2 3.4 1.4

LS/DXA

1.8

-3.7

5.5

LS/DXA

4.8§

-0.7

5.5H

LS/DXA

1.4§

-5.0§

6.4r]

LS/NA FN/NA TR/NA LS/DXA FN/DXA

0.6 0.8 1.4§ 3.9 3.0

-2.8§ -3.1§ -3.1§ -6.0 -4.1

3.4ff 3.911 4.5fl 9.9 7.t

DR/DPA WB/DXA

0.8 1.0

-4.5§ 2.0

5.311 - 1.0

LS/DXA FN/DXA

5.1§ 2.5

LS/DPA FN/DPA TR/DPA LS/DPA

4.9§ 3.6§ 9.0 5.0§

-2.4 -2.4 0.5 -4.3§

7.31r 6,0 8.5 9.311

LS/DXA FN/DXA TR/DXA WB/DXA LS/DXA FN/DXA TR/DXA LS/NA FN/NA TR/NA LS/QCT FA/QCT

2.9§ 1.0§ 2.7§ 0.7§ 3.£§ 0.6 3.9§ 2.9§ 1.8§ 2.4§ 19.6§ -1.1

-0.4 -I.2§ -0.7 0.0 -0.8 -2.9§ - 1.2 0.4 -0.3 1.0 -8.8 -2.6§

3.3tl 2.21] 3.411 0.711 4.7tl 3.511 5.1Ji 2.611 2.111 ! .4 28.4/I 1.5

1.0 3.6§

Diff

4.11l -1.1

236

mineral density (95, 102). In one, the placebotreated patients lost significantly more bone mass than the alendronate-treated group (102). In the etidronate study, bone mineral density was maintained in both groups (95). Of the 7 treatment studies (104-110), 3 examined etidronate, 2 alendronate, 1 risedronate, and 1 pamidronate. Lumbar spine bone mineral density increased from baseline in the bisphosphonate groups, whereas it decreased, for the most part, in the placebo groups. In all 7 trials, differences between bisphosphonate and placebo groups were statistically significant. Five studies report data on the femoral neck (104, 105, 107-109). Of these, the 3 largest studies found significant differences between the treatment groups, in favor of bisphosphohate therapy (107-109). Furthermore, pooled results from the alendronate trials showed significant differences between groups in trochanter bone mineral density in favor of alendronate-treated patients after 1 (107) and 2 (108) years of treatment. Ideally, bisphosphonates should protect patients from skeletal fractures. Nine studies identified incident fractures (94, 95, 101, 104-109). Four trials found a reduced vertebral fracture incidence with bisphosphonate therapy. In the cyclical etidronate study of Adachi et al (95, 111) etidronatetreated postmenopausal women experienced an 85% reduction in the proportion of patients with vertebral fractures, compared with the placebo group. The relative risk for fracture in all patients within the etidronate group as compared with the placebo was 0.6 (CI, 0.2 to 1.6). In the study by Saag et al (108), new vertebral fractures were uncommon, most occurring among postmenopausal women. Overall, there was a trend to fewer vertebral fractures in the pooled alendronatetreated group (incidence in new vertebral fractures, 2.3% versus 3.7% in the placebo group; relative risk, 0.6; CI, 0.1 to 4.4) (107). In the extension study, reported as an abstract, after an additional year of blinded therapy with alendronate, a significant decrease in the incidence of vertebral fractures was found in the pooled treatment group (108). In another trial, also in abstract form, pooled results from separate prevention and treatment studies indicated that therapy with risedronate for 1 year was associated with a significant reduction in the incidence of vertebral fractures as compared with placebo (109). In summary, bisphosphouate treatment consistently improves axial bone mineral density in

ADACHI ET AL

corticosteroid-treated patients, with a smaller detectable benefit to the appendicular skeleton. The patient populations studied to date, of practical necessity, have been heterogeneous as to morbidity, corticosteroid dose and duration, and initial skeletal status. For the most part, with the use of bisphosphonates, larger increases in lumbar spine bone mineral density are observed in the treatment of established corticosteroid-induced osteoporosis as compared with the primary prevention of this condition. Cyclical etidronate, alendronate, and risedronate therapies reduce incident vertebral fractures in patients treated with corticosteroids. Clodronate and pamidronate have been studied less frequently, and thus it is difficult to weigh their efficacy against either cyclical etidronate or alendronate. In the future, the results of comparison trials may help determine the role of specific bisphosphonates in the prevention and treatment of corticosteroidinduced osteoporosis.

Hormone Replacement Therapy Two intervention studies evaluated hormone replacement therapy in the treatment of corticosteroid-induced osteoporosis (112, 113) (Table 2). Of these, one was retrospectively controlled and was not included in Table 2 (112). In these studies, the patients were postmenopausal women suffering from either rheumatoid arthritis or asthma. In one study, calcium supplements were given, to bring the total intake to 1,500 mg/d (112), whereas in the other, calcium (400 rag/d) was given to all patients (113). The average age of the patients ranged from 56 to 68 years. No primary prevention studies have been completed. Mean bone mineral density of the lumbar spine increased in the hormone replacement treatment groups, whereas it decreased in the placebo groups after therapy. The differences between treatment groups were significant. One study described data for femoral neck bone mineral density (113); a nonsignificant difference was found between treatment groups. In summary, hormone replacement therapy showed a positive effect on bone mineral density in the treatment of corticosteroid-induced osteoporosis. Although selective estrogen receptor modulator therapy, such as raloxifene, was effective in the treatment of postmenopausal osteoporosis (114), research is needed to elucidate its role in the management of corticosteroid-induced osteoporosis.

CORTICOSTEROID-INDUCED OSTEOPOROSIS

237

Table 2: Hormone Replacement Therapy in the Treatment of Corticosteroid-lnduced Bone Loss

Study Hall et al¶ (113)

Year Published 1994

Study Design & Duration

CS Patients Duration* CS Doset N (M/F) Treat/Plac Treat/Pla

RCT;2year 42 (0/42) only CS

NA

patients

7.5/6,2

Treatment Transdermal estradiol,

Site/ % BMD Changer Instrument Treat Pla Diff LS/DXA FN/DXA

3,8~ 1.6

-0.9 1.1

4.7]1 0.5

50 mg/d with oral norethisteroine, I mg for 12 d/too; elemental

calcium, 400 mg/d

Abbreviations: N, total number of patients enrolled; M/F, number of men enrolled/number of women enrolled; CS, corticosteroid Treat, treatment group; Pla, placebo group; BMD, bone mineral density; Diff, percent difference between groups after therapy in bone mineral density; F1CT,randomized controlled trial; NA, not available; LS, lumbar spine; FN, femoral neck; DXA, dual-energy x-ray abso rptio met ry. *Mean corticosteroid duration before baseline assessment. tMean baseline corticosteroid dose (rag/d). $Mean percent change from baseline to the end of therapy in bone mineral density. §Significant change from baseline (P < .05). IISignificant difference between groups (P < .05). ¶Hall et el: Comparisons are made for a subgroup of patients who were receiving corticosteroids,

Calcitonin

Seven randomized, placebo-controlled trials have assessed the efficacy of calcitonin in corticosteroidinduced osteoporosis (115-121) (Table 3). Calcitonin was administered intranasally or subcutaneously to relatively small numbers of middle-aged to elderly (mean age ranged from 49 to 72 years) patients. Pulmonary disease, rheumatologic disorders, or vasculitis, and a few patients with various other underlying conditions were studied. Three prevention trials were performed (115117). Lumbar spine bone mineral density decreased from baseline in both treatment groups, but to a lesser extent in the calcitonin-treated as compared with the placebo groups. In one study, the difference between groups was significant after therapy (115). In the other two studies (116, 117), calcitonin did not provide statistically greater bone preservation than the placebo group. Bone mineral density data of the femoral neck, trochanter, Ward's triangle, distal radius, and whole body also have been described. No significant differences were found between treatment groups at these sites after therapy. Four treatment trials have been conducted (118121). Three of the 4 studies measured lumbar spine bone mineral density (118-120). After therapy,

lumbar spine bone mineral density increased from baseline in the active treatment groups, and decreased in the placebo groups. In two. differences between treatment groups after therapy were significant (119, 120). Data on the femoral neck (118) and distal radius (121) also have been reported. Bone mineral density increased in the calcitonin groups and decreased in the placebo groups after therapy; at both sites, the differences between groups were significant. Five studies evaluated fracture rates (116-119, 121). No significant differences in fracture rates were found between treatment groups. This may reflect the small sample sizes of the studies, and thus the lack of power to detect differences between treatment groups. Side effects were common in corticosteroidtreated patients given subcutaneous calcitonin (120, 121). One study found that 23% of calcitonintreated subjects withdrew because of side effects (120). It also was difficult to recruit subjects to these studies because of the need to inject medication (116 ~. Intranasal calcitonin has greater patient acceptance, and the side effects are less severe and much less common (115, 117-119). One of the potential additional benefits of calci-

238

ADACHI ET AL

Table 3: Calcitonin Therapy in the Prevention and Treatment of Corticosteroid-lnduced Bone Loss

Study

Year Published

Study Design & Duration

Patients N (M/F)

CS Duration ~ Treat/Pla

Adachi et al (115)

1997

Minimized RCT; 1 year

31 (13/18)

All patients <1 month

Healy et al (116)

1996

RCT; 2 years

48 (12/36)

All patients < 3 m o n t h s

S a m b r o o k et alll (117)

1993

All patients < 4 weeks

Kotaniemi et al¶ (118)

1996

RCT; 3 arms: calcitonin, cal- 63 (13/50) Patients citriol, calcium; 1 year in the calcitonin and calcitriol arms RCT; 1 year 63 (0/63)

Luengo et al (119)

1994

RCT; 2 years

44 (6/38)

All patients >1 year

Luengo et al (120)

1990

RCT; 1 year

40 (16/24)

9.6/11.3 years

Ringe and Welzel (121)

1987

RCT; 6 months

36 (7/29)

67.3/75.4 m o n t h s

All patients = 2.5 years

Abbreviations: N, total number of patients enrolled; M/F, number of men enrolled/number of women enrolled; CS, corticosteroid; Treat, treatment group; Pla, placebo group; BMD, bone mineral density; RCT, randomized controlled trial; Diff, percent difference between groups after therapy in bone mineral density; NA, not available; LS, lumbar spine; DR, distal radius; FN, femoral neck; TR, trochanter; WT, Ward's triangle; WB, whole body; DPA, dual-photon absorptiometry; SPA, single-photon absorptiometry; DXA, dual-energy x-ray absorptiometry. *Mean corticosteroid duration before baseline assessment. tMean baseline corticosteroid dose (mg/d). CMean percent change from baseline to the end of therapy in bone mineral density. §Significant difference between groups (P < .05). IISambrook et ah Comparisons are made for the calcitonin plus calcitriol plus calcium group vthe calcitriol plus calcium group. ¶Kotaniemi et ah Absolute changes in LS and FN BMD were converted to % changes. In the study, a significant absolute difference between groups was found in FN BMD. #Significant change from baseline (P < .05}.

tonin beyond improving bone mass is that it may relieve pain associated with vertebral fracture. Ringe and Welzel (121) found that the amount of pain experienced by those treated with calcitonin (100 IU subcutaneously every 2 days) was significantly less than the placebo group, and the difference persisted for the duration of the study ( 121). No attempt was made to delineate the underlying origins of pain or to correlate the pain with new vertebral fractures. In summary, studies of calcitonin efficacy in corticosteroid-induced osteoporosis suggest that this drug, whether subcutaneous or intranasal, produces a beneficial effect on bone density. This appears to be true in both the treatment and the prevention of corticosteroid-induced osteoporosis. The benefit may be evident at 6 months but is most

readily seen at l year. The most consistent positive changes are seen in the spine. Studies with greater patient populations will be necessary to prove a reduction in fracture risk. Fluoride Because corticosteroids suppress osteoblastic activity, drugs that reverse this action should be useful. Four intervention studies have been performed assessing fluoride therapy in the treatment of corticosteroid-induced osteoporosis, using either sodium fluoride or monofluorophosphate (122-125) (Table 4). One trial compared the advantage of adding sodium fluoride to cyclical etidronate therapy (123). Patients in these studies had various underlying conditions that required corticosteroid therapy, and for the most part, were middle aged (mean age ranged from 45

CORTICOSTEROID-INDUCED OSTEOPOROSIS

239

Table 3: Calcitonin Therapy in the Prevention and Treatment of Corticosteroid-lnduced Bone Loss (Confd} CS Doset Treat/Pin

Site/ Instrument

Treatment

17.2/18.7

Intranasal calcitonin, 200 IU/d

NA

Subcutaneous calcitonin, 100 IU 3 time/week; vitamin D, 400 IU/d; calcium carbonate, 1,500 mg/d Intranasal calcitonin, 400 IU/d; calcitriol, 0.5 to 1.0 #g/d; elemental calcium, 1,000 mg/d

NA

8.5/8.6 NA 10,5/10.9 22.6/17.2

Intranasal calcitonin, 100 IU/d; elemental calcium, 500 mg/d Intranasal calcitonin, 200 IU; elemental calcium, 1,000 mg/d Subcutaneous calcitonin, 100 IU/3 times/week; elemental calcium, 1,000 mg/d Subcutaneous calcitonin, 100 IU every other day

to 60 years). In general, similar effects are seen with either sodium fuoride or monofluorophosphate. No primary prevention studies have been completed. On average, vertebral bone mineral density substantially increased in fluoride-treated patients after 18 to 24 months of therapy, whereas it remained stable or slightly increased from baseline in placebotreated patients. Differences between treatment groups were significant after therapy. Three studies report data for femoral neck (122, 123, 125), and found that femoral neck bone mineral density decreased from baseline in both treatment and placebo groups. Except for the study by Lems et al (123), the loss of femoral neck bone mineral density was greater in fluoride-treated patients as compared with patients in the placebo groups (123). All trials assessed vertebral fracture rates,

% BNIDChanges Treat Pin Diff

LS/DXA FN/DXA TR/DXA WT/DXA WB/DXA LS/DXA FN/DXA

-1.3 -3.6 - 1.3 - 1,6 1,0 -0.1 -3.6

-5.0 -2.4 1.4 0,0 1.0 -0.2 -6.8

3.7§ -1.2 -2.7 - 1,6 0.0 0.1 3,2

LS/DPA FN/DPA DR/DPA LS/DXA FN/DXA LS/DPA

-0.2 -2.8 1.3 0.5 0.3 2.8

-1,3 -2,8 0.8 -0,6 -2,7 -7.8#

1.! 0.0 0.5 1.1 3.0 10.6§

LS/DPA

4.0#

-2.5#

6.5§

DR/SPA

2.7

-3.5

6.2§

but none had enough power to show an effect on vertebral fracture rates. In summary, fluoride seems to increase bone mineral density at the spine without protecting the hip from the effects of corticosteroids. There may be an added benefit for the spine in using fluoride in combination with an antiresorptive agent, but no benefit has been seen in the appendicular skeleton. Fluoride therapy has not been shown to prevent fractures in corticosteroid-induced osteoporosis. Anabolic Hormones

Three randomized controlled studies have used anabolic hormones in the treatment of corticosteroid-induced osteoporosls (126-128) (Table 5~° One study each examined human parathyroid hormone, testosterone, and nandrolone decanoate. The aver-

ADACHI ET AL

240

Table 4: Fluoride Therapy in the Treatment of Cortieosteroid-lnduced Bone Loss

Study

Year Published

Study Design & Duration

Patients N (M/F)

CS Duration* Treat/Pla

Lems et al§ (122)

1997

RCT; 2 years

44 (17/27)

NA

Lems et al (123)

1997

RCT; 2 years

47 (14/33)

NA

Guaydier et al (124)

1996

RCT; 2 years

28 (21/7)

4.7/7.4 years

Rizzoli et al (125)

1995

RCT; 1.5 years

48 (23/25) 33 patients

7.5/9.3 years

were double-masked

Abbreviations: N, total number of patients enrolled; M/F, number of men enrolled/number of women enrolled; CS, corticosteroid; Treat, treatment group; Pla, placebo group; BMD, bone mineral density; RCT, randomized controlled trial; Diff, percent difference between groups after therapy in bone mineral density; NA, not available; LS, lumbar spine; FN, femoral neck; MR, midshaft radius; DPA, dual-photon absorptiometry; DXA, dual-energy x-ray absorptiometry. *Mean corticosteroid duration before baseline assessment. tMean baseline corticosteroid dose (mg/d). :~Mean percent change from baseline to the end of therapy in bone mineral density. §Lems et al: 14 of the 44 patients initiated CS at study entry. IISignificant change from baseline (P < .05). ¶Significant difference between groups (P < .05).

age age of the patients ranged from 54 to 65 years. The testosterone trial examined men, whereas the other 2 enrolled postmenopausal women. All men had asthma, whereas postmenopansal women suffered predominately from rheumatoid arthritis. Hypogonadal men were given calcium supplements (1,000 mg/d), whereas postmenopausal women received 1,200 to 1,500 mg/d calcium and 600 to 800 IU/d of vitamin D as part of their diet or supplement. No primary prevention studies have been completed. The bone mineral density of the lumbar spine (126, 127) and forearm (128) increased in the treatment groups, and decreased in the placebo groups after therapy. The differences between groups were significant. Human parathyroid hormone was found to have no effect on femoral neck, trochanter, total hip, and distal radius bone mineral density (126). Fm'thermore, testosterone therapy was found to have no effect on whole body bone mineral density after therapy (127). In conclusion, anabolic hormones may have some benefit in the treatment of corticosteroid-induced bone loss. The prevention of corticosteroid-induced osteoporosis with these agents still needs to be determined.

Calcium and Vitamin D and Its Analogs There are no randomized controlled trials of calcium alone in the prevention or treatment of corticosteroid-induced osteoporosis. Six controlled studies have been identified that examine the effects of vitamin D or its analogues in corticosteroid-treated patients (117, 129-133) (Table 6). Patients in the active treatment groups received calcium supplements ranging from 500 to 1,000 rag/d; in contrast, calcium supplements were administeredto patients in the placebo groups in 3 studies (117, 132, 133). Patients required corticosteroid therapy predominately because of rheumatologic disorders. Generally, middle-aged patients were studied (mean age ranging from 36 to 55 years), although, in one study, elderly patients were investigated (mean age older than 63 years) (129). Two prevention trials have been performed (117, 129). One study evaluated calcitriol (117); the other vitamin D (129). The 2 trials indicated that lumbar spine bone mineral density decreased from baseline in both treatment groups, but to a lesser extent in the active treatment groups as compared with the placebo groups. In the vitamin D trial, the differences between groups were not significant after therapy,

CORTiCOSTEROID-]NDUCED OSTEOPOROSIS

241

Table 4: Fluoride Therapy in the Treatment of Corticosteroid-lnduced Bone Loss (Cont'd) CS Doset Treat/Pla 14.6/21,2

! 0.6/16.9

15.9/20.4 18.2/12.1

Treatment Sodium fluoride, 50 mg/d; elemental calcium, 500-1,000 mg/d; vitamin D, in patients with subnormal levels Sodium fluoride, 50 mg/d; etidronate, 400 mg/d for 2 weeks followed by 11 weeks off; elemental calcium, 500-1,000 mg/d Sodium monofluorophosphate, 200 rag/d; elemental calcium, 1,000 mg/d Sodium monofluorophosphate, 200 mg/d; elemental calcium, 1,000 mg/d

whereas in the calcitriol trial, significant differences between groups were noted. The calcitriol study also assessed data on the femoral neck and distal radius; no significant differences were found between the treatment groups and placebo (calcium alone). Four relatively small treatment trials have been conducted (130-133). Of these, 3 examined vitamin D, and 1 calcitriol. Lumbar spine bone mineral density increased from baseline in the active treatment groups in all 3 studies, whereas it decreased in the placebo group in one trial after therapy. One study showed a significant difference between the treatment groups (130) in lumbar spine and in trochanter bone mineral density, in favor of vitamin D therapy. One treatment and both prevention studies evaluated fracture rates (117, 129, 133). All patients had spinal radiographs performed, but no significant differences in fracture rates were found between groups after therapy. In fact, in the study conducted by Dykman et al (133), fractures were frequently reported in both treatment groups. Although most studies investigating vitamin D treatment did not report side effects associated with therapy, the few that did frequently reported hypercalciuria. Therefore, urinary calcium levels should be checked before instituting therapy and should be

Site/ Instrument

Treat

% BNID Change~; Pla Diff

LS/DPA FN/DPA

2.2 -3.811

-3~0[[

5.2¶

-3.0[[

-0.8~

LS/DXA FN/DXA

9.3H -2.5

0.3 -4.o[I

9.0¶ 1.5

LS/DPA

11.0J]

1.2

9.8¶

LS/DPA FN/DPA MR/DPA

7.8 -1.5 -1.1

3.6 0.9 -0.5

4.2~[ -2.4 -0.6

monitored every 3 months while taking vitamin D. Patients taking calcitriol also should be monitored for the occurrence of hypercalcemia. Serum calcium should be checked regularly for all patients, but supplementation in the range of 400 to 1,000 IU is not likely to cause hypercalcemia, If hypercalcemia develops, the calcium or vatamin D metabolite dose should be reduced appropriately. In conclusion, although it is likely that vitamin D and its analogs have some benefit in the prevention of corticosteroid-induced osteoporosis, it is quite clear that these agents cannot completely prevent corticosteroid-induced bone loss. In the treatment of established corticosteroid-induced osteoporosis, therapy with calcium and vitamin D maintains spine and hip bone mineral density. A comparison study of vitamin D supplementation versus calcitriol should be considered. Thiazide Diuretics Thiazides or other calcium-retaining diuretics have not been subjected to prospective randomized, controlled trials using bone mineral density or fracture rates as a primary outcome measure in corticosteroid-induced osteoporosis. However, one

242

ADACHI ET AL

Table 5: Anabolie Hormone Therapies in the Treatment of Corticosteroid-lnduced Bone Loss

Study Authors

Year Published

Study Design & Duration

Patients N (M/F)

Lane et al (126)

1998

RCT; 1 year

51 (0/51)

12.4/14.9 years

Reid et al (127)

1996

RCT crossover; 1 year

15 (15/0)

All patients = 8 years

A d a m i et al (128)

1992

RCT; with an additional ret-

35 (0/35) patients in

24/18 months

rospective control group; 1.5 years

CS Duration* Treat/Pla

the RCT

Abbreviations: N, total number of patients enrolled; M/F, number of men enrolled/number of women enrolled; CS, corticosteroid; Treat, treatment group; Pla, placebo group; BMD, bone mineral density; RCT, randomized controlled trial; Diff, percent difference between groups after therapy in bone mineral density; LS, lumbar spine; FN, femoral neck; TR, trochanter; TH, total hip; DR, distal radius; WB, whole body; DXA, dual-energy x-ray absorptiometry; DPA, dual-photon absorptiometry. *Mean corticosteroid duration before baseline assessment. tMean baseline corticosteroid dose (mg/d). :#Mean percent change from baseline to the end of therapy in bone mineral density. §Significant change from baseline (P < .05). llSignificant difference between groups (P < .05). ¶Median values are expressed.

randomized controlled trial of a thiazide-like diuretic (chlorthalidone) in the treatment of hypertension showed a beneficial effect on bone density in postmenopausal osteoporosis (134). The major effect of thiazide diuretic administration is to reduce calcium excretion through increased tubular calcium reabsorption in the distal tubule. One study showed that 50 mg hydrochlorothiazide given twice daily also increased intestinal calcium absorption in corticosteroid-treated patients (43). However, thiazide diuretics are not without risk and may aggravate hypokalemia in corticosteroid-treated patients (135). In addition, there is a risk of hypercalcemia developing in those patients treated with a combination of vitamin D and thiazides (136); therefore, serum calcium levels should be carefully monitored. Despite their apparent widespread use, clinical data with appropriate long-term outcome measures supporting the use of thiazide diuretics in corticosteroid-induced osteoporosis are lacking. PRACTICAL APPROACH TO THE MANAGEMENT OF CORTICOSTEROID-INDUCED OSTEOPOROSIS

The practical approach outlined later serves to help direct clinicians to appropriate treatment for

their patients. The algorithm for the management of corticosteroid-induced osteoporosis is shown in Figure 2. Management should begin with an assessment of patient risk factors. Appropriate steps should be taken to modify lifestyle risk factors, including diet, physical activity, alcohol use, and smoking. If possible, bone mineral density measurements (at all sites if feasible) and a lateral thoracic and lumbar spinal radiograph should be completed. A bone density measurement should be performed as an intervention efficacy tool for the follow-up clinical assessment of bone mass. Because the World Health Organization classification for osteoporosis/osteopenia only apply to postmenopausal osteoporosis, there is no evidence that a bone scan is a useful diagnostic tool or that a t-score value for bone mineral density can be used to determine the relative risk of fracture in corticosteroid-treated patients. Furthermore, although Health Care Financing Administration regulations exist that describe possible intervals for the evaluation of bone mineral density during the course of treatment, they refer primarily to postmenopausal osteoporosis, and as such they may not be relevant for corticosteroid-induced osteoporosis (137). A lateral spine radiograph should be obtained as an instrument for the evaluation of fracture status. The presence of

CORTICOSTEROID-INDUCED OSTEOPOROSIS

243

Table 5: Anabolic Hormone Therapies in the Treatment of Corticosteroid-lnduced Bone Loss (Cont'd) CS Doset Treat/Pla

Site/

% BMD Change$

Treatment

Instrument

Treat

Pla

Diff

8.9/9.4

Parathyroid hormone (1-34), 25 IJg/d; Premarin, 0.625 mg/d; vitamin D, 800 IU/d; total calcium intake, 1,500 mg/d

9.2/11.6

intramuscular testosterone, esters, 250 mg/mo; calcium, 1,000 mg/d Intramuscular nandrolone decanoate, 50 mg every 3 weeks

LS/DXA FNIDXA TR/DXA TH/DXA DR/DXA LS/DXA WB/DXA DR/DPA

11.1 § 2,9 1.3 1.9 -0.9 5.0§ 0.7 6.1§

1.3 1.2 0.9 0.4 -0.6 -0.1 -0.4 -11.3§

91811 1.7 0,4 1.5 -0.3 5.111 1.1 16,4jl

10/10¶

secondary causes of osteopenia or osteoporosis also should be determined and treated (eg, multiple myeloma, hypercalciuria, hyperparathyroidism, etc). Although urine markers of bone turnover have been useful in clinical trials evaluating treatment for postmenopausal osteoporosis, none of these tests have an impact on the clinical management of corticosteroidinduced osteoporosis. Thus, their role remains unclear. The authors suggest that in patients initiating or on short courses of corticosteroids (<3 months), total calcium intake, diet and supplement, should be approximately 1,500 mg/d. To ensure proper calcium absorption, vitamin D also should be concurrently prescribed at a dose of 400 to 500 IU/d in younger individuals (<65 years) and 800 to 1,000 IU/d in older patients (>65 years). Patients should be advised on exercises to maintain or increase their muscle mass and strength. This is especially important in the elderly, in whom the risk of falling is greatly increased by weakened musculature (138, 139). A number of investigations have shown that exercise assists in counteracting the muscle-wasting effects of corticosteroids (140142). Physical therapy should include postural training and back extension exercises to strengthen the low-back musculature, and thus potentially reduce the risk of fracture.

Treatment beyond calcium and vitamin D supplements and exercise is needed if corticosteroid therapy goes beyond 3 months, or if it is anticipated that the duration of corticosteroid therapy will be longer than 3 months, or in the treatment of long-term corticosteroid use. For courses of corticosteroid therapy greater than 3 months, evidence supports the use of bisphosphonates as effective therapy for corticosteroid-induced bone loss (93). In the case of postmenopausal women, hormone replacement therapy also may be effective based on an individual's desire or contraindications. Currently, there is no evidence for the efficacy of adding estrogen to bisphosphonate therapy in corticosteroid-induced osteoporosis. Indeed, in a large randomized, placebo-controlled trial of alendronate in patients receiving corticosteroids, alendronatetreated postmenopausal women had slightly larger increases in lumbar spine bone density as compared with those receiving alendronate plus estrogen (107). In this trial, all patients received 800 to 1,000 mg elemental calcium and 250 to 500 IU vitamin D daily. Bisphosphonates also may be prescribed for premenopansal women who do not plan to conceive. For premenopausal women with future plans for childbirth, other agents should be used first. It is important that patients are aware that there are

244

ADACHt ET AL

Table 6: Calcium and Vitamin D and its Analogs in the Prevention and Treatment of Corticosteroid-lnduced Bone Loss Year Published

Study Design & Duration

Patients N (M/F)

CS Duration* Treat/Pla

Sambrook et al§ (117)

1993

1996

63 (14/49) Patients in the calcitriol and calcium arms 62 (20/42)

All patients <4 weeks

Adachi et al (129)

RCT; 3 arms: calcitonin, calcitriol, calcium; t year Minimized RCT; 3 years

Buckiey et al¶ (130)

1996

RCT; 2 years

NA

Bernstein et al (131)

1996

RCT; 1 year

66 (19/47) only CS patients 17 (14/3)

Bijsma et al (132)

1988

RCT; 2 years

21 (5/16)

38.0/44.2 months

Dykman et al (133)

1984

RCT; 1.5 years

23 (4/19)

4.8/7.3 years

Study

All patients <4 weeks

5.4/2.5 years

Abbreviations: N, total number of patients enrolled; M/F, number of men enrolled/number of women enrolled; CS, corticosteroid; Treat, treatment group; Pla, placebo group; BMD, bone mineral density; RCT, randomized controlled trial; Diff, percent difference between groups after therapy in bone mineral density; NA, not available; LS, lumbar spine; TR, trochanter; FN, femoral neck; PR, proximal radius; DR, distal radius; TH, total hip; WT, Ward's triangle; DXA, dual-energy x-ray absorptiometry; DPA, dual-photon absorptiometry; SPA, single-photon absorptiometry. *Mean corticosteroid duration before baseline assessment. 1Mean baseline corticosteroid dose (rag/d). SMean percent change from baseline to the end of therapy in bone mineral density. §Sambrook etal: Comparisons are made for the calcitriol plus calcium group vthe calcium-alone group. IlSignificant difference between groups (P < .05). ¶Buckley et al: % BMD change are express as rates of change per year.

theoretical risks to the developing fetus with bisphosphonate therapy, even years after drug termination. This is because of the drug's extremely long half-life in bone tissue. After 1 year of therapy, a follow-up bone density assessment should be performed. The measurement precision for dual-energy x-ray absorptiometry (DEXA) instruments is typically _+1.5% for the lumbar spine; thus, changes of greater than 3% are likely of clinical significance beyond the measurement en'ors of the instruments. If bone loss (assessed by DEXA measurement at the lumbar spine) has occurred at a rate greater than 3%/year, the intervention should be changed or another added. If bone loss has been less than 3%/year, treatment should continue for the duration of corficosteroid therapy plus 3 years afterward in those with low bone mass. Bone mineral density should then be reassessed every 2 years until corticosteroid therapy is terminated, ff at any time, bone loss is greater than 3%, therapy should be adjusted accordingly. DEXA

measurements at the femoral sites are less precise than at the lumbar spine; moreover, skeletal sites with higher proportions of cortical bone have lower metabolic turnover and thus result in lower rates of absolute change. For these reasons, it is considerably more difficult to assess clinical deterioration or therapeutic efficacy when bone mineral density measurements are made at sites other than the lumbar spine. However, if changes greater than 6%/year (2× the precision error) are observed in the hip, therapy should be modified. Once corticosteroid therapy is discontinued, the patient should be assessed and managed in the manner appropriate for a patient not using corticosteroids. SPECIAL CIRCUMSTANCES

Pulse Corticosteroid Therapy The effect of repeated high-dose administration of corticosteroids on bone remains controversial. Trials that have examined pulse therapy have been

CORTICOSTEROID-INDUCED OSTEOPOROSIS

245

Table 6: Calcium and Vitamin D and its Analogs in the Prevention and Treatment of Corticosteroid-lnduced Bone Loss (Cont'd) CS Doset Treat/Pla

Treatment

NA

Calcitriol, 0.5 to 1.0 pg/d; elemental calcium, 1,000 mg/d

21.2/16.6

Vitamin D, 50,000 IU/week; elemental calcium, 1,000 mg/d Vitamin D, 500 IU/d; calcium carbonate, 1,000 mg/d Vitamin D, 250 IU/d, elemental calcium, 1,000 mg/d

5.9/5.0 NA

NA 12.2/11.3

Vitamin D, 4,000 IU every 2 days; elemental calcium, 500 mg/d Calcitriol, 0.25 pg/d; elemental calcium, 500 mg/d; vitamin D, 400 IU/d

Site/ instrument

% BMD Changes Treat Pla Diff

LS/DPA FN/DPA DR/DPA LS/DPA,DXA

- 1.3 -2.8 0.8 -4.2

-4.3 "2.9 -3.0 -9:0

3.011 0.1 3.8 4.8

0.7 0.9 3.4 3.1 2.4 1.7 2,3 1.0 8.0

-2.0 -0.9 0.6 - 1.6 0.5 3,7 -0.5 2.0 5.0

2,711 1.8ll 2.8 4.7 1.8 -2.0 2.8 -1.0 3.0

LS/DXA TR/DXA LS/DXA TH/DXA WT/DXA LS/DPA FN/DPA PR/SPA DR/SPA

limited to only one or two pulses of high-dose corticosteroids (143-146). Because patients receiving pulse therapy may be exposed to high cumulative corticosteroid doses, prophylactic measures beyond that of calcium, vitamin D, and regular physical activity may be necessary. However, there is no information in the literature to suggest either thresholds for treatment or the proper prophylactic agents.

and phannacokinetics of bisphosphonate use in children is required. Calcium (at the daily recommended allowance for the appropriate age-group) and vitamin D (4 times the daily recommended allowance for the appropriate age-group) should be considered. Deficient sex hormone levels also should be corrected if possible and appropriate.

Children and Corticosteroid-Induced Osteoporosis

Based on currently available data, bisphosphonares appear to be the drugs of choice for the prevention or treatment of corticosteroi&induced osteoporosis. In fact, the data for the bisphosphohates are more compelling than for any other agent. Although hormone replacement therapy is extensively used in the treatment of primary osteoporosis, data for its effectiveness when used alone in corticosteroid-induced osteoporosis are limited. If bisphosphonate therapy is contraindi-

S U M M A R Y OF THERAPEUTIC OPTIONS

Corticosteroids have the same bone-resorbing effect in children as they do in adults, but they also interfere with normal bone growth. Furthermore, the high rates of bone turnover observed in childhood make children more sensitive to the effects of corticosteroids. The use of bisphosphonates has not been assessed in this population, and thus any use should be approached with caution. Further information regarding the safety

Prevention and Treatment of Corticosteroid-lnduced Osteoporosis

]

÷

/

Family history

/

Hormone status: estrogen, androgen, PTH*, vitamin D

J

/

///¢

Perform risk

/

assessment

I

f

M~U~ao~

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Fraoture history Lifestylefaetot~:diet, physical ' activity,alcohol, smoking

BMD* assessment at all sites if possiblel

o

Se°°n

causes ° f

k___.._~ /

I., steoporosis2?/ ~

steopemao r

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"/ /

ostaop~ni~ or osteoporosis ~ /

v i t a m i n D 8 0 0 - 1 0 0 0 I U / d 4,

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eight-bearing physical activity, and lifestyle education. /

Men: clinicalevidence of ehroine testosterone deficiency? Establish sex hormone level if necessary and correct if required and possible.

\

P . . . . . pausal women: oligo-or amenorrhea? Establish sex hormone vst if necessary and correct if required d possible. Post-menopausal women: offer HRT* if not contraindicated. ~

Legend: l= No evidence that a t-scorn value for BMD can be used to determinethe relative risk of fraetttre in CS-indueed osteoporosis. 2= Laboratory measures to include serum ealeinm, phosphorus, alkaline phosphatase; protein elcctrophoresis;and lipids and mina~ calcium/creatlnine. 3= i.e. Multiple myeloma, hyperparathyroidism, etc. 4 = Hi~her doses of vitaminD may be more beneficialin the elderly population. 5= In high-risk individualslower doses of CS may be harmful. *= PTH= parathyroid hormone; BMD bone mineral density, HRT= hormone replacement therapy; CS= anrtieosteroids; DEXA= dual energy x-ray absorptiomstty, yr.= year; J

Pre-menopausal women

\

Caution should be taken as bisphosphonste prescriptioncould possiblyinterferewith the normal developmentof the fetus during or after administration. Bi~phosphonateusage for women planning future childbirthshould be avoided if possible.

BMD assessment (DEXA*), if [

available at baseline& 1 yr,* I V . . follow-up. I ~

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f

I

1

one loss > 3%yr. at the lumbars p i n e . ] Bone loss > 6%/yr. /

CS[therapy •

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BMD assessment every 2 years until CS therapy [ is discontinued. {j I

Fig 2.

completion

%

,

#

Management algorithm for the prevention and treatment of corticosteroid-induced osteoporosis.

CORTICOSTEROID-INDUCED OSTEOPOROSIS

247

cated, calcitonin may be an effective alternative, particularly in those with acute back pain secondary to vertebral fractures. For patients who continue to lose bone, fluoride and anabolic hormones should be considered. Although calcium and vitamin D and its analogs appear to have weak positive effects on bone in those receiving corticosteroids,

they may not be potent enough to be used alone. As such, these agents should be administered in combination with other medications. Presently, little evidence is available to support the use of thiazide diuretics. In the future, the results of long-term clinical and comparison trials may provide us with more definitive treatment strategies.

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