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Effects of Teriparatide Versus Alendronate for TreatingGlucocorticoid-Induced Osteoporosis

Thirty-Six–Month Results of a Randomized, Double-Blind, Controlled Trial

Kenneth G. Saag,

Jose R. Zanchetta,

Jean-Pierre Devogelaer,

Robert A. Adler,

Richard Eastell,

Kyoungah See,

John H. Krege,

Kelly Krohn,

and Margaret R. Warner

Objective.

To compare the bone anabolic drugteriparatide (20



g/day) with the antiresorptive drugalendronate (10 mg/day) for treating glucocorticoid-induced 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 screen-ing. Measures included changes in lumbar spine andhip bone mineral density (BMD), changes in bonebiomarkers, fracture incidence, and safety.

Results.

Increases in BMD from baseline weresignificantly greater in the teriparatide group than inthe alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for totalhip, and 6.3% versus 3.4% for femoral neck (

< 0.001for all). In the teriparatide group, median percentincreases from baseline in N-terminal type I procolla-gen propeptide (PINP) and osteocalcin (OC) levels weresignificant from 1 to 36 months (

< 0.01), and in-creases in levels of C-terminal telopeptide of type Icollagen (CTX) were significant from 1 to 6 months (

< 0.01). In the alendronate group, median percentdecreases in PINP, OC, and CTX were significant by 6months and remained below baseline through 36months (

< 0.001). Fewer subjects had vertebralfractures in the teriparatide group than in the alendro-nate group (3 [1.7%] of 173 versus 13 [7.7%] of 169;



0.007), with most occurring during the first 18months. There was no significant difference betweengroups in the incidence of nonvertebral fractures (16[7.5%] of 214 subjects taking teriparatide versus 15[7.0%] of 214 subjects taking alendronate;



0.843).More subjects in the teriparatide group (21%) versusthe alendronate group (7%) had elevated predose serumcalcium concentrations (

< 0.001).

Conclusion.

Our findings indicate that subjects with glucocorticoid-induced OP treated with teripa-ratide for 36 months had greater increases in BMD andfewer new vertebral fractures than subjects treated withalendronate.

Glucocorticoids are beneficial for treatingchronic inflammatory conditions, such as rheumatoid

ClinicalTrials.gov identifier: NCT00051558.Supported by Eli Lilly and Company.

Kenneth G. Saag, MD: University of Alabama at Birming-ham;

Jose R. Zanchetta, MD: Universidad del Salvador, Buenos Aires, Argentina;

Jean-Pierre Devogelaer, MD: Universite´ Catho-lique de Louvain, Brussels, Belgium;

Robert A. Adler, MD: McGuireVAMC, Richmond, Virginia;

Richard Eastell, MD: University of Sheffield, Sheffield, UK;

Kyoungah See, PhD, John H. Krege, MD,Kelly Krohn, MD, Margaret R. Warner, PhD, DVM: Lilly ResearchLaboratories, Eli Lilly and Company, Indianapolis, Indiana.Dr. Saag has received consulting and speaking fees fromNovartis (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, EliLilly, Pfizer, and Servier (less than $10,000 each). Dr. Devogelaerreceives research support from Amgen, Eli Lilly, Merck, NordicBioscience, Novartis, Pfizer, Procter & Gamble, Sanofi-Aventis, Ser- vier, and Wyeth and speaking fees from Eli Lilly, Novartis, Procter &Gamble, and Servier (less than $10,000 each). Dr. Adler has receivedspeaking and consulting fees from Eli Lilly, Novartis, and Merck (lessthan $10,000 each), and research support from Eli Lilly, Novartis, andProcter & Gamble. Dr. Eastell has received consulting or advisoryboard fees from Amgen, Novartis, Procter & Gamble, Servier, Ono,and GlaxoSmithKline (less than $10,000 each), lecture fees from EliLilly (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, 1530Third Avenue South, Birmingham, AL 35294-3408. E-mail: ksaag@uab.edu.Submitted for publication December 12, 2008; accepted inrevised form July 11, 2009.3346

arthritis (RA), asthma, and systemic lupus erythemato-sus (SLE), but bone loss is a common side effect andfracture risk is increased (1–7). The finding that patientstaking glucocorticoids have an increased risk of fractureat any level of bone mineral density (BMD) compared with patients not taking glucocorticoids suggests thatglucocorticoid-induced osteoporosis (OP) is character-ized at least in part by impaired bone quality. Currentlyrecommended therapies for the prevention and treatmentof glucocorticoid-induced OP include the antiresorptivebisphosphonates alendronate and risedronate together with supplemental calcium and vitamin D (1,8,9).Teriparatide (recombinant human parathyroidhormone [rhPTH(1–34)]), a bone anabolic drug, in-creased BMD and reduced the risk of vertebral andnonvertebral fracture in postmenopausal women withOP (10) and increased BMD in men with hypogonadalor idiopathic OP (11). Analyses of paired iliac crestbiopsy samples from postmenopausal women with OPshowed that teriparatide increased cancellous bone vol-ume and connectivity, improved cancellous bone plate-like structure, and increased cortical thickness (12).Teriparatide induces differentiation of bone lin-ing cells and preosteoblasts into osteoblasts, stimulatespreexisting osteoblasts to form new bone, and decreasesosteoblast and osteocyte apoptosis (13–15). Because aprimary action of glucocorticoids is to decrease boneformation, the bone anabolic effects of teriparatide maydirectly target key pathogenic mechanisms associated with long-term glucocorticoid therapy. This hypothesis issupported by a study which showed that areal lumbarspine BMD, vertebral cross-sectional area, and esti-mated vertebral compressive strength increased signifi-cantly more in postmenopausal women withglucocorticoid-induced OP treated with synthetichPTH(1–34) plus estrogen compared with those treated with estrogen alone (16,17). Similarly, the results of the18-month primary phase of our study showed thatlumbar spine and hip BMD increased significantly morein subjects with glucocorticoid-induced OP treated withteriparatide compared with those receiving alendronate(18). This report extends the findings of this trial insubjects with glucocorticoid-induced OP to 36 monthsand includes changes in lumbar spine and hip BMD,changes in bone turnover markers, and fracture inci-dence.

SUBJECTS AND METHODS

Study design and participants.

This was a randomized,double-blind, double-dummy, active comparator–controlledstudy conducted in 13 countries at 76 centers. There was ascreening phase of



1.5 months, an 18-month primary phase(18), and an 18-month continuation phase. Investigators andsubjects remained blinded with regard to treatment through 36months. Each subject gave informed written consent, and localinstitutional review committees approved the protocol. Thestudy was conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. Thefirst subject was randomized in December 2002, and the trial was completed in January 2008.The primary objective was the change from baseline to18 months in lumbar spine BMD in the teriparatide versusalendronate group (18). Prespecified secondary objectives at36 months included lumbar spine and hip BMD, levels of boneturnover markers, vertebral and nonvertebral fractures, andadverse events. Ambulatory men and women were eligible for enroll-ment if they were at least 21 years of age and had takenprednisone or its equivalent at a dosage of



5 mg/day for



3months prior to screening. Subjects were required to have alumbar spine, femoral neck, or total hip BMD T score of



2or of



1 plus a prevalent low trauma or atraumatic fracture,as assessed by the investigator. Additional inclusion and exclu-sion criteria have been described previously (18).Subjects were randomly assigned to receive injectableteriparatide (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 torecord their glucocorticoid use. Glucocorticoid use at baseline was determined using the duration and dosage of only thoseglucocorticoids that a subject was taking at study entry. Infor-mation on previous usage was not obtained. The averageglucocorticoid dose at each visit was determined by averagingthe prednisone equivalent dose taken since the preceding visit.

BMD.

Areal BMD (gm/cm

) was measured by dual x-ray absorptiometry using Hologic (Hologic, Bedford, MA) orLunar (General Electric Medical Systems, Madison, WI) den-sitometers. Reading of BMD scans, quality assurance, cross-calibration adjustment, and data processing were performed byBio-Imaging Technologies (Newtown, PA). Lumbar vertebraethat became fractured during the trial were excluded from thecalculation of baseline and postbaseline lumbar spine BMD.

Biochemical markers of bone turnover.

Markers of bone turnover were measured in serum obtained at approxi-mately the same time each morning from a subset of subjects who had fasted overnight (n



98 subjects in the teriparatidegroup and 101 subjects in the alendronate group). The boneformation 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 procollagenpropeptide (PINP) (Intact UniQ assay; Orion Diagnostica,Espoo, Finland) (CV 3.2–5.2%), and osteocalcin (OC) (ELSA-OSTEO; CIS BioInternational, Bedford, MA) (CV 4.5–5.2%).The resorption marker was C-terminal telopeptide of type Icollagen (CTX) (Serum CrossLaps; Osteometer Biotech, Her-lev, Denmark) (CV 11.1–13.5%). Biomarkers were measuredat a central laboratory (Covance, Indianapolis, IN).

Radiographs.

Spinal radiographs were obtained atbaseline, 18 months, and 36 months, and at unscheduled times

TERIPARATIDE VERSUS ALENDRONATE IN GLUCOCORTICOID-INDUCED OP 3347

if subjects had symptoms suggestive of clinical vertebral frac-ture. Each vertebra was graded for compression deformity,using a visual semiquantitative method, by a Bio-ImagingTechnologies radiologist who was blinded with regard totreatment, but not to sequence of radiographs (19). An inci-dent vertebral fracture was defined as a vertebra not fracturedat baseline and subsequently graded as deformed (19).For incident nonvertebral fractures, radiographs orradiologist reports were assessed by a radiologist who wasblinded with regard to treatment. A fragility fracture wasdefined as a fracture associated with trauma equivalent to a fallfrom standing height or less, as assessed by the investigator.

Adverse events.

Data on adverse events were collectedthroughout 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 eventthat resulted in death, hospitalization, or significant disability/incapacitation, or was life threatening.

Serum calcium and urate measurements.

The numberof subjects with elevated serum urate levels (



9.0 mg/dl[535



moles/liter]) or elevated total serum calcium concentra-tions (



10.5 mg/dl [2.62 mmoles/liter] and



11.0 mg/dl[2.75 mmoles/liter]) was determined from serum collected



16hours after administration of study drugs.

Statistical analysis.

Analyses were conducted on datafrom all randomized and treated subjects. The study had apower of 90% to detect a between-treatment difference of 0.015 gm/cm

in the absolute change from baseline to lastmeasurement in lumbar spine BMD during the first 18 months,assuming a standard deviation of 0.04 and a 2-sided

-test withan alpha level of 0.05. Block randomization, stratified accord-ing to sex, investigative site, and previous use of bisphospho-nates, was used to assign subjects to treatment in an approxi-mate 1:1 ratio. Analysis of variance (ANOVA) was used forcontinuous variables except for markers of bone turnover, for which a nonparametric method (Wilcoxon’s rank sum test) wasrequired. Categorical variables were compared between treat-ment groups using region-stratified Cochran-Mantel-Haenszelor Fisher’s exact tests.For analyses of percent change in BMD from baseline,a treatment group comparison was made at end point, usingthe last observation carried forward method (defined as 36-month or last postbaseline measurement) using ANOVA withstratification variables as covariates. If the end point reachedstatistical significance, then the effect of treatments at eachtime point was assessed with mixed model repeated measures. A predefined gate-keeping strategy controlled the overallType I error at an alpha level of 0.05 for determining theearliest time at which the increase in BMD differed signifi-cantly between groups (20). If the 36-month comparison wassignificant at the 5% level then the 24-month comparison wastested, and so on. This approach ensured that the overall TypeI error was not increased above the 0.05 level by testing atmultiple time points. Testing of the remaining secondaryoutcomes was not adjusted for multiple comparisons. A within–treatment group post hoc analysis was per-formed to determine if the percent change in BMD wassignificantly different at successive time points using the mixedmodel with contrast. Covariates included were treatment,stratification variables, baseline lumbar spine BMD, time of visit, and interaction between visit and treatment. Additionalsubgroup analyses were performed using glucocorticoid dosageat baseline and 36 months (3 categories:



5, 5–



10, and



10 mg/day prednisone equivalent), and underlying conditionrequiring glucocorticoid use at baseline (4 categories: jointdisorders [e.g., RA, osteoarthritis], other musculoskeletal dis-ease [e.g., SLE], respiratory disorders, and other conditions)using ANOVA. All tests were 2-sided with the nominal significancelevel set at 0.05 and were performed using SAS statisticalsoftware, version 8.2 (SAS Institute, Cary, NC).

RESULTSSubject disposition and baseline characteristics.

Of the 712 subjects who were screened, 428 wererandomized and received treatment (Figure 1). A totalof 150 (70%) of the subjects receiving teriparatide and144 (67%) of the subjects receiving alendronate enteredthe 18-month continuation phase, and 123 (57%) of thesubjects receiving teriparatide and 118 (55%) of thesubjects receiving alendronate completed the 36-monthtrial. The most common reasons for study discontinua-tion were subject decision and adverse event, with nosignificant difference between treatment groups. Signif-icantly more teriparatide-treated subjects discontinued

Figure 1.

Disposition of the subjects. ‡





0.05 versus alendro-nate.3348 SAAG ET AL