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ARTHRITIS & RHEUMATISM Vol. 60, No. 11, November 2009, pp 3346–3355 DOI 10.1002/art.

24879 © 2009, American College of Rheumatology

Effects of Teriparatide Versus Alendronate for Treating Glucocorticoid-Induced Osteoporosis
Thirty-Six–Month Results of a Randomized, Double-Blind, Controlled Trial
Kenneth G. Saag,1 Jose R. Zanchetta,2 Jean-Pierre Devogelaer,3 Robert A. Adler,4 Richard Eastell,5 Kyoungah See,6 John H. Krege,6 Kelly Krohn,6 and Margaret R. Warner6
Objective. To compare the bone anabolic drug teriparatide (20 g/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoidinduced osteoporosis (OP). Methods. This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22–89 years) who had received >5 mg/day of prednisone equivalent for >3 months preceding screening. Measures included changes in lumbar spine and
ClinicalTrials.gov identifier: NCT00051558. Supported by Eli Lilly and Company. 1 Kenneth G. Saag, MD: University of Alabama at Birming2 ham; Jose R. Zanchetta, MD: Universidad del Salvador, Buenos Aires, Argentina; 3Jean-Pierre Devogelaer, MD: Universite Catho´ lique de Louvain, Brussels, Belgium; 4Robert A. Adler, MD: McGuire 5 VAMC, Richmond, Virginia; Richard Eastell, MD: University of Sheffield, Sheffield, UK; 6Kyoungah See, PhD, John H. Krege, MD, Kelly Krohn, MD, Margaret R. Warner, PhD, DVM: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. Dr. Saag has received consulting and speaking fees from Novartis (more than $10,000) and from Eli Lilly, Merck, Amgen, Procter & Gamble, and Aventis (less than $10,000 each). Dr. Zanchetta has received consulting and speaking fees from Amgen, Eli Lilly, Pfizer, and Servier (less than $10,000 each). Dr. Devogelaer receives research support from Amgen, Eli Lilly, Merck, Nordic Bioscience, Novartis, Pfizer, Procter & Gamble, Sanofi-Aventis, Servier, and Wyeth and speaking fees from Eli Lilly, Novartis, Procter & Gamble, and Servier (less than $10,000 each). Dr. Adler has received speaking and consulting fees from Eli Lilly, Novartis, and Merck (less than $10,000 each), and research support from Eli Lilly, Novartis, and Procter & Gamble. Dr. Eastell has received consulting or advisory board fees from Amgen, Novartis, Procter & Gamble, Servier, Ono, and GlaxoSmithKline (less than $10,000 each), lecture fees from Eli Lilly (less than $10,000), and grant support from AstraZeneca, Procter & Gamble, and Novartis (less than $10,000 each). Drs. See, Krege, Krohn, and Warner own stock or stock options in Eli Lilly. Address correspondence and reprint requests to Kenneth G. Saag, MD, University of Alabama at Birmingham, FOT 820, 1530 Third Avenue South, Birmingham, AL 35294-3408. E-mail: ksaag@ uab.edu. Submitted for publication December 12, 2008; accepted in revised form July 11, 2009. 3346

hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety. Results. Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001). Conclusion. Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate. Glucocorticoids are beneficial for treating chronic inflammatory conditions, such as rheumatoid

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arthritis (RA), asthma, and systemic lupus erythematosus (SLE), but bone loss is a common side effect and fracture risk is increased (1–7). The finding that patients taking glucocorticoids have an increased risk of fracture at any level of bone mineral density (BMD) compared with patients not taking glucocorticoids suggests that glucocorticoid-induced osteoporosis (OP) is characterized at least in part by impaired bone quality. Currently recommended therapies for the prevention and treatment of glucocorticoid-induced OP include the antiresorptive bisphosphonates alendronate and risedronate together with supplemental calcium and vitamin D (1,8,9). Teriparatide (recombinant human parathyroid hormone [rhPTH(1–34)]), a bone anabolic drug, increased BMD and reduced the risk of vertebral and nonvertebral fracture in postmenopausal women with OP (10) and increased BMD in men with hypogonadal or idiopathic OP (11). Analyses of paired iliac crest biopsy samples from postmenopausal women with OP showed that teriparatide increased cancellous bone volume and connectivity, improved cancellous bone platelike structure, and increased cortical thickness (12). Teriparatide induces differentiation of bone lining cells and preosteoblasts into osteoblasts, stimulates preexisting osteoblasts to form new bone, and decreases osteoblast and osteocyte apoptosis (13–15). Because a primary action of glucocorticoids is to decrease bone formation, the bone anabolic effects of teriparatide may directly target key pathogenic mechanisms associated with long-term glucocorticoid therapy. This hypothesis is supported by a study which showed that areal lumbar spine BMD, vertebral cross-sectional area, and estimated vertebral compressive strength increased significantly more in postmenopausal women with glucocorticoid-induced OP treated with synthetic hPTH(1–34) plus estrogen compared with those treated with estrogen alone (16,17). Similarly, the results of the 18-month primary phase of our study showed that lumbar spine and hip BMD increased significantly more in subjects with glucocorticoid-induced OP treated with teriparatide compared with those receiving alendronate (18). This report extends the findings of this trial in subjects with glucocorticoid-induced OP to 36 months and includes changes in lumbar spine and hip BMD, changes in bone turnover markers, and fracture incidence. SUBJECTS AND METHODS
Study design and participants. This was a randomized, double-blind, double-dummy, active comparator–controlled study conducted in 13 countries at 76 centers. There was a

screening phase of 1.5 months, an 18-month primary phase (18), and an 18-month continuation phase. Investigators and subjects remained blinded with regard to treatment through 36 months. Each subject gave informed written consent, and local institutional review committees approved the protocol. The study was conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. The first subject was randomized in December 2002, and the trial was completed in January 2008. The primary objective was the change from baseline to 18 months in lumbar spine BMD in the teriparatide versus alendronate group (18). Prespecified secondary objectives at 36 months included lumbar spine and hip BMD, levels of bone turnover markers, vertebral and nonvertebral fractures, and adverse events. Ambulatory men and women were eligible for enrollment if they were at least 21 years of age and had taken prednisone or its equivalent at a dosage of 5 mg/day for 3 months prior to screening. Subjects were required to have a lumbar spine, femoral neck, or total hip BMD T score of 2 or of 1 plus a prevalent low trauma or atraumatic fracture, as assessed by the investigator. Additional inclusion and exclusion criteria have been described previously (18). Subjects were randomly assigned to receive injectable teriparatide (20 g/day) plus oral placebo or oral alendronate (10 mg/day) plus injectable placebo. Supplements of calcium (1,000 mg/day) and vitamin D (800 IU/day) were provided. Glucocorticoid use. Subjects kept a daily diary to record their glucocorticoid use. Glucocorticoid use at baseline was determined using the duration and dosage of only those glucocorticoids that a subject was taking at study entry. Information on previous usage was not obtained. The average glucocorticoid dose at each visit was determined by averaging the prednisone equivalent dose taken since the preceding visit. BMD. Areal BMD (gm/cm2) was measured by dual x-ray absorptiometry using Hologic (Hologic, Bedford, MA) or Lunar (General Electric Medical Systems, Madison, WI) densitometers. Reading of BMD scans, quality assurance, crosscalibration adjustment, and data processing were performed by Bio-Imaging Technologies (Newtown, PA). Lumbar vertebrae that became fractured during the trial were excluded from the calculation of baseline and postbaseline lumbar spine BMD. Biochemical markers of bone turnover. Markers of bone turnover were measured in serum obtained at approximately the same time each morning from a subset of subjects who had fasted overnight (n 98 subjects in the teriparatide group and 101 subjects in the alendronate group). The bone formation markers were bone alkaline phosphatase (bone ALP) (Hybritech Tandem-R Ostase; Beckman Coulter, Brea, CA) (interassay coefficient of variation [CV] 7.4–7.9%), C-terminal type I procollagen propeptide (PICP; DiaSorin, Stillwater, MN) (CV 5.4–8.5%), N-terminal type I procollagen propeptide (PINP) (Intact UniQ assay; Orion Diagnostica, Espoo, Finland) (CV 3.2–5.2%), and osteocalcin (OC) (ELSAOSTEO; CIS BioInternational, Bedford, MA) (CV 4.5–5.2%). The resorption marker was C-terminal telopeptide of type I collagen (CTX) (Serum CrossLaps; Osteometer Biotech, Herlev, Denmark) (CV 11.1–13.5%). Biomarkers were measured at a central laboratory (Covance, Indianapolis, IN). Radiographs. Spinal radiographs were obtained at baseline, 18 months, and 36 months, and at unscheduled times

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if subjects had symptoms suggestive of clinical vertebral fracture. Each vertebra was graded for compression deformity, using a visual semiquantitative method, by a Bio-Imaging Technologies radiologist who was blinded with regard to treatment, but not to sequence of radiographs (19). An incident vertebral fracture was defined as a vertebra not fractured at baseline and subsequently graded as deformed (19). For incident nonvertebral fractures, radiographs or radiologist reports were assessed by a radiologist who was blinded with regard to treatment. A fragility fracture was defined as a fracture associated with trauma equivalent to a fall from standing height or less, as assessed by the investigator. Adverse events. Data on adverse events were collected throughout the study. A treatment-emergent adverse event was defined as any untoward medical event that occurred or worsened after baseline. A serious adverse event was an event that resulted in death, hospitalization, or significant disability/ incapacitation, or was life threatening. Serum calcium and urate measurements. The number of subjects with elevated serum urate levels ( 9.0 mg/dl [535 moles/liter]) or elevated total serum calcium concentrations ( 10.5 mg/dl [2.62 mmoles/liter] and 11.0 mg/dl [2.75 mmoles/liter]) was determined from serum collected 16 hours after administration of study drugs. Statistical analysis. Analyses were conducted on data from all randomized and treated subjects. The study had a power of 90% to detect a between-treatment difference of 0.015 gm/cm2 in the absolute change from baseline to last measurement in lumbar spine BMD during the first 18 months, assuming a standard deviation of 0.04 and a 2-sided t-test with an alpha level of 0.05. Block randomization, stratified according to sex, investigative site, and previous use of bisphosphonates, was used to assign subjects to treatment in an approximate 1:1 ratio. Analysis of variance (ANOVA) was used for continuous variables except for markers of bone turnover, for which a nonparametric method (Wilcoxon’s rank sum test) was required. Categorical variables were compared between treatment groups using region-stratified Cochran-Mantel-Haenszel or Fisher’s exact tests. For analyses of percent change in BMD from baseline, a treatment group comparison was made at end point, using the last observation carried forward method (defined as 36month or last postbaseline measurement) using ANOVA with stratification variables as covariates. If the end point reached statistical significance, then the effect of treatments at each time point was assessed with mixed model repeated measures. A predefined gate-keeping strategy controlled the overall Type I error at an alpha level of 0.05 for determining the earliest time at which the increase in BMD differed significantly between groups (20). If the 36-month comparison was significant at the 5% level then the 24-month comparison was tested, and so on. This approach ensured that the overall Type I error was not increased above the 0.05 level by testing at multiple time points. Testing of the remaining secondary outcomes was not adjusted for multiple comparisons. A within–treatment group post hoc analysis was performed to determine if the percent change in BMD was significantly different at successive time points using the mixed model with contrast. Covariates included were treatment, stratification variables, baseline lumbar spine BMD, time of visit, and interaction between visit and treatment. Additional

Figure 1. Disposition of the subjects. ‡ nate.

P

0.05 versus alendro-

subgroup analyses were performed using glucocorticoid dosage at baseline and 36 months (3 categories: 5, 5– 10, and 10 mg/day prednisone equivalent), and underlying condition requiring glucocorticoid use at baseline (4 categories: joint disorders [e.g., RA, osteoarthritis], other musculoskeletal disease [e.g., SLE], respiratory disorders, and other conditions) using ANOVA. All tests were 2-sided with the nominal significance level set at 0.05 and were performed using SAS statistical software, version 8.2 (SAS Institute, Cary, NC).

RESULTS Subject disposition and baseline characteristics. Of the 712 subjects who were screened, 428 were randomized and received treatment (Figure 1). A total of 150 (70%) of the subjects receiving teriparatide and 144 (67%) of the subjects receiving alendronate entered the 18-month continuation phase, and 123 (57%) of the subjects receiving teriparatide and 118 (55%) of the subjects receiving alendronate completed the 36-month trial. The most common reasons for study discontinuation were subject decision and adverse event, with no significant difference between treatment groups. Significantly more teriparatide-treated subjects discontinued

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Table 1. Baseline characteristics of the subjects with glucocorticoid-induced osteoporosis* Subjects taking alendronate (n 214) Age, mean SD years White Women Postmenopausal women Treatment† Glucocorticoid use, median (25th, 75th percentiles) years‡ Prednisone equivalent, median (25th, 75th percentiles) 5 mg/day 5 mg/day to 10 mg/day 10 mg/day Prior bisphosphonate use§ Fractures Prevalent radiographic vertebral fracture(s)¶ Prior nonvertebral fracture(s) Prior nonvertebral fragility fracture(s) BMD, least squares mean SEM# Lumbar spine BMD, gm/cm2 Lumbar spine BMD T score Total hip BMD, gm/cm2 Total hip BMD T score Femoral neck BMD, gm/cm2 Femoral neck BMD T score Biomechanical markers of bone turnover, median (25th, 75th percentiles)** Bone ALP, g/liter OC, g/liter PICP, g/liter PINP, g/liter CTX, pmoles/liter Disorders requiring glucocorticoid treatment Rheumatic disorders Rheumatoid arthritis Systemic lupus erythematosus Polymyalgia rheumatica Vasculitis Other rheumatic disorders Respiratory disorders Inflammatory bowel disease Other conditions 57.3 14.0 148 (69) 173 (81) 143 (67) 2.0 (0.4, 6.5) 7.5 (5.0, 10.0) 20 (9) 98 (46) 93 (44) 20 (9) 53 (25) 89 (42) 43 (20) 0.864 2.5 0.776 2.0 0.721 2.1 0.014 0.12 0.013 0.11 0.013 0.10 Subjects taking teriparatide (n 214) 56.1 13.4 153 (71) 172 (80) 134 (63) 2.3 (0.5, 5.8) 7.5 (5.0, 10.0) 9 (4) 111 (53) 91 (43) 20 (9) 63 (30) 93 (43) 42 (20) 0.863 2.4 0.763 2.1 0.705 2.2 0.014 0.12 0.013 0.10 0.013 0.10

9 (7, 12) 14 (10, 19) 140 (111, 177) 39 (29, 51) 3,331 (2,388, 5,366) 161 (75) 111 (52) 21 (10) 8 (4) 3 (1) 18 (8) 31 (14) 4 (2) 18 (8)

9 (6, 11) 14 (9, 19) 148 (122, 183) 39 (29, 57) 3,378 (2,050, 4,732) 161 (76) 98 (46) 28 (13) 10 (5) 5 (2) 20 (9) 29 (14) 3 (1) 21 (10)

* Except where indicated otherwise, values are the number (%). There were no significant differences between groups. † Glucocorticoid use was assessed in 212 subjects in the alendronate group and 213 subjects in the teriparatide group, and prednisone equivalent was assessed in 211 subjects in each group. ‡ The duration of glucocorticoid therapy was determined based on the time that the subject was taking current glucocorticoids; information on previous usage was not obtained. § Received a bisphosphonate for 2 weeks within 6 months before randomization or for 2 years within the previous 3 years. ¶ Prevalent radiographic vertebral fractures were assessed in 212 subjects in the alendronate group and 209 subjects in the teriparatide group. # Lumbar spine bone mineral density (BMD) was assessed in 207 subjects in the alendronate group and 208 subjects in the teriparatide group, and lumbar spine BMD T score was assessed in 162 subjects in the alendronate group and 167 subjects in the teriparatide group. Total hip BMD and femoral neck BMD were assessed in 209 subjects in each group. Total hip BMD T score and femoral neck BMD T score were assessed in 199 subjects in each group. ** Bone alkaline phosphatase (bone ALP) was assessed in 91 subjects in the alendronate group and 81 subjects in the teriparatide group, osteocalcin (OC) was assessed in 101 subjects in the alendronate group and 97 subjects in the teriparatide group, C-terminal type I procollagen propeptide (PICP) was assessed in 92 subjects in the alendronate group and 82 subjects in the teriparatide group, N-terminal type I procollagen propeptide (PINP) was assessed in 100 subjects in the alendronate group and 98 subjects in the teriparatide group, and C-terminal telopeptide of type I collagen (CTX) was assessed in 96 subjects in the alendronate group and 87 subjects in the teriparatide group.

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due to physician decision (P 0.028), and significantly more alendronate-treated subjects were lost to followup (P 0.026). There were no significant differences between groups in baseline characteristics (Table 1). The age range of the subjects was 22–89 years. In addition, there were no significant differences in the baseline characteristics of subjects who discontinued the study during the first 18 months (n 134) compared with those who continued after 18 months (n 294), except in the proportion of subjects taking 5 mg/day of prednisone equivalent (4 [3.0%] of the 132 subjects who discontinued and 25 [8.6%] of the 290 subjects who continued; P 0.037) (other data not shown). Glucocorticoid dosage. There was no significant difference between groups in the median glucocorticoid dosage at baseline (Table 1) or at 36 months (6.9 mg/day in the teriparatide group versus 7.5 mg/day in the alendronate group; P 0.326). The proportion of subjects taking 5, 5– 10, or 10 mg/day of prednisone equivalent did not differ significantly between groups at baseline (Table 1) or at 36 months ( 5 mg/day in 17 [15%] of 117 subjects in the teriparatide group and 24 [22%] of 107 subjects in the alendronate group [P 0.166]; 5– 10 mg/day in 59 [50%] of 117 subjects in the teriparatide group and 49 [46%] of 107 subjects in the alendronate group [P 0.506]; 10 mg/day in 41 [35%] of 117 subjects in the teriparatide group and 34 [32%] of 107 subjects in the alendronate group [P 0.671]). The median cumulative prednisone equivalent dose was not significantly different between groups during the first 18 months (3,444 mg in the teriparatide group versus 3,315 mg in the alendronate group; P 0.566) or during the final 18 months of the study (3,554 mg in the teriparatide group versus 3,010 mg in the alendronate group; P 0.084). Changes in BMD. The mean percent changes from baseline in lumbar spine, total hip, and femoral neck BMD were significantly greater in the teriparatide group than in the alendronate group at each time point and end point (Figure 2). At 36 months the mean percent increases from baseline were 11.0% versus 5.3% for lumbar spine BMD (P 0.001), 5.2% versus 2.7% for total hip BMD (P 0.001), and 6.3% versus 3.4% for femoral neck BMD (P 0.001) in the teriparatide group and alendronate group, respectively. Within the teriparatide group, the mean percent changes in BMD were significantly greater between successive time points from 3 through 36 months at the lumbar spine, between 12 and 18 months and between 18 and 24 months at the total hip, and between 24 and 36 months at the femoral neck. Within the alendronate group, the

Figure 2. Mean percent changes from baseline in lumbar spine (A), total hip (B), and femoral neck (C) bone mineral density (BMD) in the alendronate (ALN) group and teriparatide (TPTD) group. Numbers below the graph are the numbers of subjects assessed at each time point and for the last observation carried forward (LOCF) analysis and were identical for the total hip and femoral neck. Values are the least squares (LS) mean SEM. P 0.001; † P 0.01; ‡ P 0.05 for the mean percent change from baseline in the teriparatide versus alendronate group. § P 0.001; P 0.01, # P 0.05 for the mean percent change from baseline within each treatment group for 6 versus 3 months, 12 versus 6 months, 18 versus 12 months, 24 versus 18 months, and 36 versus 24 months.

mean percent changes in BMD were significantly greater between 3 and 6 months, 6 and 12 months, and 18 and 24

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Figure 3. Median percent changes from baseline in markers of bone formation, N-terminal type I procollagen propeptide (PINP) (A), osteocalcin (OC) (B), bone alkaline phosphatase (bone ALP) (C), and C-terminal type I procollagen propeptide (PICP) (D), and in a marker of bone resorption, C-terminal telopeptide of type I collagen (CTX) (E). Numbers below the graphs are the numbers of subjects assessed at each time point. Values are the median and 25th to 75th percentiles. LOCF values are not included, as they would overestimate the effect of teriparatide. P 0.001; † P 0.01, ‡ P 0.05 for the median percent change from baseline in the teriparatide versus alendronate group. § P 0.001, P 0.01 for the median percent change from baseline at each time point versus baseline within each treatment group. See Figure 2 for other definitions.

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Table 2. Incident vertebral and nonvertebral fractures in subjects with glucocorticoid-induced osteoporosis* Subjects taking Subjects taking alendronate teriparatide (n 214) (n 214) 13 (7.7) 4 (2.4) 15 (7.0) 5 (2.3) 3 (1.7) 0 16 (7.5) 9 (4.2)

Fracture type 1 1 1 1 radiographic vertebral† clinical vertebral‡ nonvertebral nonvertebral fragility

P 0.007 0.037 0.843 0.256

* Values are the number (%). † Subjects with baseline and postbaseline spinal radiographs (n 169 subjects in the alendronate group and 173 subjects in the teriparatide group). ‡ A clinical vertebral fracture (assessed in 169 subjects in the alendronate group and 173 subjects in the teriparatide group) was a new radiographically confirmed fracture that was associated with symptoms such as back pain.

months at the lumbar spine, between 12 and 18 months at the total hip, and between 12 and 18 months and 24

and 36 months at the femoral neck. For both treatments, the mean percent increases in BMD were significant compared with baseline at each measured time point (P 0.001 for teriparatide and P 0.002 for alendronate, at all time points and sites). The differences between teriparatide and alendronate with regard to the percent change in lumbar spine BMD from baseline to end point were not significantly different across 4 underlying disease subgroups or across 3 glucocorticoid dose ranges at baseline or 36 months. These results suggest that the treatment difference between teriparatide and alendronate for percent change in lumbar spine BMD was not affected by the underlying disease requiring glucocorticoid therapy or by the dose of glucocorticoid at baseline or at 36 months. Changes in levels of biochemical markers of bone turnover. In the teriparatide group, there were significant median percent increases from baseline in all

Table 3. Summary of treatment-emergent adverse events and predose serum calcium and urate concentrations* Subjects taking alendronate (n 214) Overall adverse events 1 adverse event 1 serious adverse event 1 possibly treatment-related adverse event Adverse events that occurred with a 2% difference between groups Higher proportion in the teriparatide group Nausea Headache Gastritis Dyspnea Insomnia Fatigue Viral infection Higher proportion in the alendronate group Urinary tract infection Influenza Anemia Dyspepsia Nasopharyngitis Rash Joint injury Weight loss Predose total calcium and urate† 1 serum calcium 10.5 mg/dl‡ 2 serum calcium 10.5 mg/dl§ 1 serum calcium 11.0 mg/dl‡ 2 serum calcium 11.0 mg/dl§ 1 serum urate 9.0 mg/dl¶ 184 (86) 64 (30) 42 (20) Subjects taking teriparatide (n 214) 194 (91) 70 (33) 58 (27) P 0.116 0.518 0.074

18 (8) 14 (7) 8 (4) 6 (3) 3 (1) 4 (2) 0 29 (14) 24 (11) 17 (8) 15 (7) 13 (6) 10 (5) 6 (3) 9 (4) 14 (7) 6 (3) 3 (1) 0 11 (5)

36 (17) 19 (9) 17 (8) 16 (7) 12 (6) 9 (4) 5 (2) 22 (10) 18 (8) 11 (5) 9 (4) 7 (3) 4 (2) 1 (0.5) 0 44 (21) 16 (8) 9 (4) 1 (0.5) 20 (9)

0.007 NS NS 0.028 0.017 NS 0.023 NS NS NS NS NS NS NS 0.002 0.001 0.046 0.140 1.000 0.135

* Predose was defined as 16 hours after administration of study drugs. Values are the number (%). NS not significant (P 0.05). † To convert serum calcium concentrations to mmoles/liter multiply by 0.25, and to convert serum urate concentrations to moles/liter multiply by 59.5. ‡ Baseline and 1 postbaseline serum calcium measurements were available for 209 subjects in the alendronate group and for 211 subjects in the teriparatide group. § Baseline and 2 postbaseline serum calcium measurements were available for 196 subjects in each group. ¶ Baseline and 1 postbaseline serum urate measurements were available for 208 subjects in the alendronate group and 212 subjects in the teriparatide group.

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markers after 1 month, and the changes were maximal at 1 month for OC and PICP, and at 6 months for bone ALP, PINP, and CTX (Figure 3). The median percent changes in bone ALP, OC, and PINP levels remained significantly increased compared with baseline at 6, 18, and 36 months, while the median percent changes in PICP and CTX were not significantly different from baseline at 6 (PICP only), 18, or 36 months (Figure 3). In the alendronate group, there were significant median percent decreases from baseline after 1 month for PICP, PINP, and CTX levels, and after 6 months for bone ALP and OC levels (Figure 3). The decreases from baseline were maximal at 6 months for PINP, at 18 months for bone ALP, PICP, and CTX, and at 36 months for OC; however, for PINP, OC, PICP, and CTX the median percent decreases were significantly different from baseline from 6 through 36 months (Figure 3). There were significant differences between the teriparatide and alendronate groups in the median percent change from baseline for all biomarkers at 1, 6, 18, and 36 months (P 0.05). Incident vertebral and nonvertebral fractures. A total of 3 (1.7%) of 173 subjects receiving teriparatide compared with 13 (7.7%) of 169 subjects receiving alendronate had 1 new radiographic vertebral fracture over 36 months (P 0.007) (Table 2). Most of the vertebral fractures occurred during the first 18 months (in 1 subject receiving teriparatide and 10 subjects receiving alendronate). There were no significant differences between groups in the number of subjects with new nonvertebral fractures or with new nonvertebral fragility fractures (Table 2). Comparison of adverse events. There were no significant differences between groups in the number of subjects reporting 1 adverse event, in the incidence of serious adverse events, or in the incidence of adverse events considered to be possibly related to study drugs as assessed by investigators (Table 3). There was no significant difference between groups in the number of subjects who died during the study (n 9 in the teriparatide group and n 15 in the alendronate group; P 0.219). Table 3 lists the adverse events that occurred with 2% difference between groups. Comparison of serum calcium and urate concentrations. Significantly more subjects in the teriparatide group than in the alendronate group had 1 or 2 predose serum calcium concentrations of 10.5 mg/dl, with no significant difference between groups in the number of subjects with 1 or 2 predose serum calcium concentrations of 11.0 mg/dl (Table 3). There was no significant difference between groups in the

number of subjects with 1 serum urate concentration 9.0 mg/dl (Table 3). Adverse events related to serum calcium or urate included hypercalcemia in 1 subject receiving teriparatide, nephrolithiasis in 3 subjects receiving teriparatide and 2 subjects receiving alendronate, and gout in 1 subject receiving teriparatide. DISCUSSION Among subjects with glucocorticoid-induced OP, increases in spine and hip BMD were significantly greater in those receiving teriparatide than in those receiving alendronate through 36 months. New radiographic vertebral fractures occurred in significantly fewer subjects in the teriparatide group than in the alendronate group, with no significant difference between groups in the number of subjects with new nonvertebral fractures. In the teriparatide group, levels of bone formation markers were significantly above baseline at 1 month through 36 months, and in the alendronate group, markers of bone formation and resorption were significantly decreased from baseline by 1–6 months through 36 months. In previous placebo-controlled trials, antiresorptive therapy significantly increased spine and hip BMD in subjects beginning glucocorticoid therapy (21) or in subjects with established glucocorticoid-induced OP (22–25). For example, in subjects taking glucocorticoids, there was a 3.9% increase in lumbar spine BMD after 24 months in the alendronate 10 mg/day group versus a 0.8% decrease in the placebo group (23). In our study, subjects with glucocorticoid-induced OP receiving 10 mg/day of alendronate had an increase in lumbar spine BMD of 5.2% at 24 months and 5.3% at 36 months. In comparison, subjects receiving teriparatide had an increase in lumbar spine BMD of 9.8% at 24 months and 11.0% at 36 months. Thus, in subjects taking glucocorticoids, the bone anabolic drug, teriparatide, was more efficacious than alendronate for increasing BMD and resulted in further significant increases in BMD beyond the initial 18-month primary study end point. The changes from baseline in bone turnover markers in subjects taking teriparatide or alendronate were directionally similar to those reported in subjects not taking glucocorticoids (26,27), reflecting the bone anabolic effects of teriparatide and the antiresorptive effects of alendronate in subjects with glucocorticoidinduced OP. It has been suggested that optimal gains in BMD with daily teriparatide treatment may be limited over time due to the return toward baseline in bone forma-

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tion markers after 9–12 months of therapy (28). Similar to previous findings with teriparatide (27,28), in our study the bone turnover markers in subjects with glucocorticoid-induced OP receiving teriparatide returned toward baseline by 18 months. However, levels of the bone formation markers, OC, PINP, and bone ALP, each remained significantly increased above baseline through 36 months, whereas the bone resorption marker, CTX, was not significantly different from baseline at 18 or 36 months. These changes in bone formation markers were associated with significant increases in lumbar spine BMD between successive time points through 36 months, indicating that gains in BMD with daily administration of teriparatide continued even though there was a decline in the levels of bone turnover markers. This result may be explained by the balance in bone turnover favoring formation over resorption. However, the precise relationship between the serum concentration of bone biomarkers and relative gain or loss in BMD is unknown. Sustained anabolic effects on cortical and cancellous bone have also been shown during treatment with once-daily PTH(1–34) for 18–36 months in subjects with OP (29). With the antiresorptive drug alendronate, the sustained decrease in CTX, OC, PICP, and PINP levels through 36 months was associated with a significant increase in lumbar spine BMD between successive time points from 3 to 12 months and between 18 and 24 months, but with no significant increase in lumbar spine BMD between 24 and 36 months. Over 36 months, 16 subjects (3 receiving teriparatide and 13 receiving alendronate) experienced 1 new radiographic vertebral fracture. Most of these new vertebral fractures occurred during the first 18 months of the study (1 in the teriparatide group and 10 in the alendronate group) (18). There was no significant difference between groups in the number of subjects with 1 new nonvertebral fracture over 18 months (12 in the teriparatide group versus 8 in the alendronate group) or 36 months (16 in the teriparatide group versus 15 in the alendronate group) (18). This trial was not designed to determine the effects of teriparatide or alendronate on the risks of vertebral or nonvertebral fracture. In placebo-controlled trials, both teriparatide and alendronate have been shown to decrease vertebral and nonvertebral fracture incidence in postmenopausal women not taking glucocorticoids (10,30,31). Strengths of our study include the controlled, randomized, double-blind design, the finding that changes in lumbar spine BMD observed with alendronate 10 mg/day were similar to those reported in previ-

ous studies of alendronate in glucocorticoid-induced OP (22,23), and the first clinical trial experience with teriparatide and alendronate for up to 36 months in glucocorticoid-induced OP. Limitations include the subject discontinuation rate of 44% at 36 months which, in part, reflects the severity of underlying disease in subjects with glucocorticoid-induced OP and the propensity for these subjects to have multiple comorbid conditions (32). There was no significant difference between groups in the subject discontinuation rate, and in placebocontrolled studies of bisphosphonate treatment in glucocorticoid-induced OP, similar discontinuation rates have been reported (21,22,24). Although 86 subjects with missing or unreadable spinal radiographs were excluded from the vertebral fracture analysis, there was no significant difference between groups in the baseline characteristics of the excluded subjects. Because predose serum calcium was measured, transient hypercalcemia after the administration of study drugs would not have been detected (10). In summary, subjects at high risk of fracture associated with sustained glucocorticoid use who received teriparatide had significantly greater increases in spine and hip BMD compared with subjects receiving alendronate during 36 months of therapy. Patients with glucocorticoid-induced OP treated with teriparatide also experienced significantly fewer new vertebral fractures, most occurring during the first 18 months, with no significant difference between groups in the incidence of nonvertebral fractures. Additional key findings included significant increases in lumbar spine BMD between 24 and 36 months in the teriparatide group, and sustained increases in biomarkers of bone formation through 36 months in the teriparatide group with sustained decreases in biomarkers of bone formation and resorption in the alendronate group. There remains an unmet need for therapies that can substantially improve the skeletal status of subjects with glucocorticoid-induced OP (1,33). Our data indicate that teriparatide is efficacious and generally well tolerated for treating subjects with glucocorticoid-induced OP and should be considered as a therapeutic option for subjects at high risk of fracture. ACKNOWLEDGMENT
The authors acknowledge the clinical trial investigators (18). AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved

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the final version to be published. Dr. Saag had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Saag. Acquisition of data. Saag, Zanchetta, Devogelaer, Adler. Analysis and interpretation of data. Saag, Zanchetta, Devogelaer, Adler, Eastell, See, Krege, Krohn, Warner.

17.

18. 19. 20. 21.

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