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The Journal of Clinical Endocrinology & Metabolism 92(4):1305–1310 Copyright 2007 by The Endocrine Society The Peroxisome Proliferator-Activated Receptor-␥
Agonist Rosiglitazone Decreases Bone Formation and
Bone Mineral Density in Healthy Postmenopausal
Women: A Randomized, Controlled Trial
Andrew Grey, Mark Bolland, Greg Gamble, Diana Wattie, Anne Horne, James Davidson, and Ian R. Reid Department of Medicine (A.G., M.B., G.G., D.W., A.H., I.R.R.), University of Auckland, and LabPlus (J.D.), Auckland CityHospital, 1020 Auckland, New Zealand Context: Thiazolidinediones, which are peroxisome proliferator-ac-
Results: The osteoblast markers procollagen type I N-terminal
tivated receptor-␥ agonists, are widely prescribed to patients with propeptide and osteocalcin declined by 13% (P Ͻ 0.005 vs. placebo) disorders characterized by insulin resistance. Preclinical studies sug- and 10% (P ϭ 0.04 vs. placebo), respectively, in the rosiglita- gest that peroxisome proliferator-activated receptor-␥ signaling neg- zone group. These changes were evident by 4 wk and persisted for atively regulates bone formation and bone density. Human data on the duration of the study. There was no change in the serum the skeletal effects of thiazolidinediones are currently available only ␤-C-terminal telopeptide of type I collagen, a marker of bone re- sorption (P ϭ 0.9 vs. placebo). Total hip bone density fell in therosiglitazone group (mean change from baseline rosiglitazone Objective: The objective of the study was to determine whether
Ϫ1.9%, placebo Ϫ0.2%; between-group difference 1.7%, 95% con- rosiglitazone, a thiazolidinedione, inhibits bone formation.
fidence interval 0.6 –2.7, P Ͻ 0.01); lumbar spine bone density fellsignificantly from baseline values in the rosiglitazone group (P ϭ Design: The study was a 14-wk randomized, double-blind, placebo-
0.02 vs. baseline) but was not significantly different between groups (mean change from baseline rosiglitazone Ϫ1.2%, placebo Ϫ0.2%; between-group difference 1.0%, 95% confidence interval Setting: The study was conducted in the general community.
Patients: Fifty healthy, postmenopausal women participated in the study.
Conclusions: Short-term therapy with rosiglitazone exerts
detrimental skeletal effects by inhibiting bone formation. Skeletal
Intervention: Intervention was rosiglitazone 8 mg/d.
end points should be included in future long-term studies of thia-
zolidinedione use. (J Clin Endocrinol Metab 92: 1305–1310,
Main Outcome Measures: The primary end point was biochemical
markers of bone formation, and secondary end points were a boneresorption marker and bone mineral density.
THIAZOLIDINEDIONESAREinsulin-sensitizingagents PPAR-␥isexpressedinanumberoftissues(1),raisingthe that are widely prescribed in the management of a possibility that drugs that interact with it may induce clinical variety of clinical conditions characterized by insulin resis- effects other than insulin sensitization. Prominent among the tance (1, 2). They are agonists of the peroxisome proliferator- tissues in which PPAR-␥ is expressed is bone. In skeletal activated receptor (PPAR) family of nuclear transcription tissue, PPAR-␥ acts as a molecular switch that regulates the factors, in particular the PPAR-␥ isoform (1). In patients with fate of pluripotent mesenchymal stem cells, which have the type 2 diabetes mellitus, their use is associated with signif- ability to differentiate into adipocytes or osteoblasts. In vitro, icant improvements in glycemic control and serum lipopro- PPAR-␥ agonists promote adipocyte differentiation in pref- tein profile, although their ability to reduce the incidence of erence to osteoblast differentiation (5– 8). There are conflict- vascular events is uncertain (3). At present, thiazolidinedio- ing reports of the effects of PPAR-␥ activation on osteoclas- nes account for 21% of oral antihyperglycemic drugs used in togenesis (9, 10). Haploinsufficiency of the PPAR-␥ gene in the United States and 5% in Europe (4). It is estimated that mice induces a high bone density phenotype characterized 2 million Americans were prescribed rosiglitazone last year by increased rates of osteoblastic bone formation (11, 12), (personal communication, Westun, C., GlaxoSmithKline, whereas treatment of rodents with PPAR-␥ agonists induces bone loss characterized by deficient osteoblast function (12–14). Data from human studies of the skeletal actions of thia- First Published Online January 30, 2007
zolidinediones are currently available only from an obser- Abbreviations: BMD, Bone mineral density; ␤CTX, ␤-C-terminal te- vational study, which reported that female, but not male, lopeptide of type I collagen; P1NP, procollagen type-I N-terminal diabetic thiazolidinedione users experience accelerated bone propeptide; PPAR, peroxisome proliferator-activated receptor.
loss, compared with nonthiazolidinedione users (15).
JCEM is published monthly by The Endocrine Society (http://www.
Patients with type 2 diabetes may be at increased risk of endo-society.org), the foremost professional society serving the en-
docrine community.
fragility fractures (16 –22). Because PPAR-␥ agonists are in- J Clin Endocrinol Metab, April 2007, 92(4):1305–1310 Grey et al. • Rosiglitazone and Bone Formation creasingly frequently used to treat this disease, it is important tablet was similar, but not identical with, the active tablet. Tablets were to determine whether these drugs have adverse effects on the dispensed into identical opaque containers by a staff member who was human skeleton. We undertook a randomized, placebo-con- not involved in giving study medication to participants. Each containerwas labeled with the subject’s study number and distributed to the trolled trial to test the hypothesis that treatment with ros- participant by another staff member. Subjects took one study tablet daily iglitazone would cause adverse skeletal effects in healthy for the first 2 wk and then two tablets daily for the remainder of the postmenopausal women. The primary objective was to de- study. Blood samples were collected fasting between 0800 and 1000 h at termine the effect of rosiglitazone 8 mg daily on biochemical baseline and 2, 4, 8, and 14 wk. Treatment allocations were randomizedby the study statistician, using a variable block size schedule, based on markers of bone formation over a 14-wk period. Secondary computer-generated random numbers. To ensure masking, only the end points were change in markers of bone resorption and statistician had access to treatment allocation. All the other study per- sonnel and subjects were blinded to treatment allocation throughout.
Only the study statistician saw unblinded data, but he had no contact Subjects and Methods
with study participants. The study was approved by the AucklandEthics Committee, and written informed consent was provided by each participant. The trial is registered at the Australian Clinical Trials Reg-ister (ACTRN 012605000218695; www.actr.org.au).
Participants were normal postmenopausal women who were more than 5 yr postmenopausal and aged older than 55 yr. They were re-cruited between January and October 2005. Women with illnesses or receiving therapies likely to affect bone were ineligible, as were thosewith osteoporosis [bone mineral density (BMD) T score at lumbar spine Serum calcium, phosphate, albumin, and total alkaline phosphatase or total hip Յ Ϫ2.5] and those with any other major systemic disease or activity were measured on a modular autoanalyzer (Roche, Stockholm, contraindications to the use of thiazolidinediones. Subjects were re- Sweden). 25-Hydroxyvitamin D was measured using a chemilumines- cruited by advertisements seeking healthy postmenopausal women to cent assay (Nichols, San Juan Capistrano, CA). Intact PTH was measured participate in clinical bone research. Of the 183 women who received using an electrochemiluminescence immunoassay (E170; Roche). Serum study information sheets, 75 attended a screening visit (Fig. 1). Six osteocalcin, serum ␤-C-terminal telopeptide of type I collagen (␤CTX) women met exclusion criteria (one taking estrogen, one taking a bisphos- and serum procollagen type-I N-terminal propeptide (P1NP) were mea- phonate, one taking glucocorticoids, one taking an anticonvulsant, one sured using commercially available kits, as previously described (23, 24).
with cancer, one with primary hyperparathyroidism), and 19 women Coefficients of variation of these markers are as follows: osteocalcin, elected for personal reasons (10 concerned about possible weight gain, 5.5%; ␤CTX, 5.1%; PINP, 1.9%. Each turnover marker was assayed at the two unwilling to undergo blood tests, four with nonexclusionary inter- end of the study period in a single batch. Samples were stored at Ϫ70 current illnesses, three for unstated reasons) not to proceed to Bone mineral density of the lumbar spine and proximal femur was Among the 50 women randomized, four (two placebo, two rosigli- measured by dual-energy x-ray absorptiometry using a Lunar Prodigy tazone) withdrew during the study. One woman in each group never instrument (GE-Lunar, Madison, WI; software version 7.51.008) at base- started study medication (withdrew for personal reasons). One partic- line and 14 wk. Bone density measurements were performed by two ipant in the rosiglitazone group withdrew at 4 wk because of meno- experienced technicians, both of whom are certified by Synarc, the pausal symptoms, and one participant in the placebo group withdrew international company that provides bone density oversight for most after 16 d because of limb paresthesiae. Five women in the rosiglitazone international osteoporosis drug registration trials. The coefficients of group reported ankle swelling during the study, one of whom took 4 mg variation for measurement of total hip and lumbar spine bone mineral densities in our laboratory are 1.1 and 1.4%, respectively.
A randomized trial, comparing rosiglitazone 8 mg daily (2 ϫ 4 mg The primary end points of the study were the two specific markers tablets) with placebo over a period of 14 wk was performed. The placebo of bone formation, osteocalcin and P1NP. The study was therefore de- FIG. 1. Flow of subjects through the study.
Grey et al. • Rosiglitazone and Bone Formation J Clin Endocrinol Metab, April 2007, 92(4):1305–1310 signed to detect a 1 sd difference between the treatment groups in thechange in either of these markers. Because recruitment made allowancefor dropouts, the number of completing subjects provides 80% power atthe 5% significance level to detect differences of at least 90% of 1 sdbetween the placebo and rosiglitazone arms. Sample-size calculationswere performed using PASS (NCSS and PASS number cruncher statis-tical systems, Kaysville, UT). Procedures of the statistical analysis systemSAS (version 9.2; SAS Institute Inc., Cary, NC) were used for all analyses.
All statistical tests were two tailed, and a 5% significance level wasmaintained throughout. All treatment evaluations were performed onthe principle of intention to treat. A mixed-models approach to repeatedmeasures was used to examine the time course of response in treatmentand control arms at baseline and at 2, 4, 8 and 14 wk. The correctcovariance structure was determined by likelihood ratio test (i.e. thefirst-order autoregression matrix was compared against an unstructuredcovariance matrix). Maximum likelihood imputation was used to ensureall the randomized patients could be included in the model (25). Theassumptions of normality of the dependent variable and residuals weretested by inspection and goodness of fit assessed by maximizing theAkaike information criterion. P values for significant main and inter-action (treatment by time) effects were constructed using the method ofTukey.
The baseline characteristics of the study subjects are shown in Table 1. At baseline, the only significant differencebetween the study groups was in serum osteocalcin, whichwas lower in the rosiglitazone group. Five of 25 subjects inthe placebo group and four of 25 subjects in the rosiglitazonegroup were taking calcium supplements at study inception;in each case the dose was unchanged during the study. Nosubjects took vitamin D supplements during the study. Com-pliance with study medication, as assessed by tablet counts,was 97% in the placebo group and 99% in the rosiglitazonegroup.
The effects of rosiglitazone on markers of bone turnover are shown in Fig. 2. Figure 2, A and B, shows the osteoblast-specific markers P1NP and osteocalcin. Each of these mark-ers of bone formation was stable in the placebo group anddeclined significantly in the rosiglitazone group. Overall,P1NP declined by 13% in the rosiglitazone group by 4 wk,and this effect was maintained for the remainder of the study(P for time ϫ treatment interaction ϭ 0.004). Osteocalcin fellby 8% from baseline values in the rosiglitazone group, and FIG. 2. The effects of rosiglitazone or placebo on markers of bone the between-groups difference in this bone formation marker turnover in normal postmenopausal women. A, Serum P1NP. B, Se- was 10% at the study conclusion (P for time ϫ treatment rum osteocalcin. C, ␤CTX P (group ϫ time) is the P value for thetime-treatment interaction. Data are mean Ϯ SEM percent changefrom baseline.
TABLE 1. Baseline characteristics of study subjects
interaction ϭ 0.04). Total serum alkaline phosphatase alsodeclined, by 17%, in the rosiglitazone group and remained stable in the placebo group (mean change ϩ0.01%) (P for time ϫ treatment interaction Ͻ 0.001). ␥-Glutamyl trans- ferase did not change during the study (P for time ϫ treat- In contrast to the bone formation markers, levels of serum ␤CTX, a marker of bone resorption, did not change in re- sponse to rosiglitazone (P for time ϫ treatment interaction ϭ There were no differences between the groups in the levels of serum calcium, phosphate, and PTH (Table 2). Mean val- Data are mean (SD) or number of subjects. Biochemical analytes are ues of each of these variables were within the normal range measured in serum. To convert 25-hydroxyvitamin D values to nano-moles per liter, multiply by 2.5.
a P Ͻ 0.05 vs. placebo.
The changes in bone density are shown in Fig. 3. Total hip J Clin Endocrinol Metab, April 2007, 92(4):1305–1310 Grey et al. • Rosiglitazone and Bone Formation TABLE 2. Serum biochemistry in study subjects
Data are mean (SD). There were no differences between the groups in the change from baseline values in any of the variables shown. To convert serum calcium to millimoles per liter, multiply by 0.25; to convert serum phosphate to millimoles per liter, multiply by 0.32; to convert PTHto picomoles per liter, multiply by 0.11.
the therapies commonly used to treat the disease may beincreasing that risk is a cause for concern. The increasing useof thiazolidinediones in other clinical conditions character-ized by insulin resistance (28, 29), including impaired glu-cose tolerance (30), is a further reason to fully characterizetheir long-term skeletal effects. We therefore suggest thatskeletal safety end points should be added to existing andplanned randomized trials of PPAR-␥ agonists so that theskeletal effects of thiazolidinediones can be studied over alonger period.
FIG. 3. The effect of rosiglitazone or placebo on BMD in normal post- Although preclinical studies have consistently reported menopausal women. P values refer to comparisons between groups in that rosiglitazone impairs osteoblast function (13, 14, 31, 32), the percent change from baseline at each indicated skeletal site. Data conflicting in vitro data exist as to whether PPAR-␥ signaling are mean Ϯ SEM percent change from baseline.
affects osteoclastogenesis (7, 9, 10). Our data suggest that bone density declined by a greater amount in the rosiglita- PPAR-␥ agonists do not influence bone resorption in vivo, a zone group than the placebo group [mean (sd) change ros- finding consistent with those of in vivo studies in rodents (11, iglitazone Ϫ1.9 (2.0)%, placebo Ϫ0.2 (1.6)%, between-groups 13, 14). The limited preclinical data that are available on the difference 1.7%, 95% confidence interval 0.6 –2.7, P ϭ 0.003].
skeletal effects of pioglitazone, the other commonly pre- Lumbar spine bone density fell significantly from baseline scribed thiazolidinedione, suggest that it has comparable values in the rosiglitazone group (P ϭ 0.02 vs. baseline) and actions with those of rosiglitazone (33, 34). Whether there is remained stable in the placebo group (P ϭ 0.7 vs. baseline) a class effect of thiazolidinediones on skeletal homeostasis is but was not different between groups [mean (sd) change uncertain, with recent preclinical studies of new compounds rosiglitazone Ϫ1.2 (2.1)%, placebo Ϫ0.2 (2.1)%, between- reporting both adverse (35) and neutral (36) effects in rodent groups difference 1.0%, 95% confidence interval Ϫ0.2–2.3, P ϭ 0.13]. As expected, body weight tended to increase in the Currently there are few data available on the skeletal ac- rosiglitazone group (mean change rosiglitazone ϩ0.7 kg; pla- tions of thiazolidinediones in humans. Uncontrolled studies cebo Ϫ0.8 kg, P for between-groups comparison in change of Japanese subjects with type 2 diabetes treated with tro- from baseline ϭ 0.07). Adjusting the bone density data for glitazone, a PPAR-␥ agonist no longer in clinical use, re- change in body weight, the baseline osteocalcin level, or both ported significant reductions in markers of both bone for- variables did not change the results.
mation and resorption after 1 month, but values returned tobaseline by 1 yr (37, 38). More recently an analysis of the Discussion
small number (n ϭ 69) of diabetic subjects taking thiazo- This study demonstrates that short-term therapy with ros- lidinediones (pioglitazone, troglitazone, and rosiglitazone) iglitazone, a commonly prescribed PPAR-␥ agonist, inhibits in the Health, Aging, and Body Composition observational bone formation and accelerates bone loss in healthy post- study reported accelerated bone loss in over 4 yr in women menopausal women. These data are consistent with those but not men (15). After our manuscript was submitted, Kahn from in vitro and animal studies demonstrating that PPAR-␥ et al. (39) reported a higher incidence of fractures, detected signaling negatively regulates osteoblast function (bone for- as adverse events, in female diabetic subjects randomized to mation) and bone mass (7, 8, 11, 13, 14). The pattern of receive rosiglitazone, compared with those randomized to alteration of bone remodeling that we observed in response receive either metformin or glyburide, during a 4 yr study of to rosiglitazone is similar to that seen after the initiation of glycemic durability of oral monotherapies. Our findings pro- glucocorticoid therapy (26). The uncoupling of bone forma- vide rigorous evidence for a detrimental effect of PPAR-␥ tion from resorption by glucocorticoids is accompanied by agonists on the postmenopausal female skeleton. Whether early and rapid bone loss and an increased risk of fragility there is a gender difference in the skeletal response to thia- fractures (27). Our data suggest that rosiglitazone may also zolidinediones can be determined only by a randomized, promote rapid bone loss; longer-term studies are needed to determine whether the rate of loss we observed is sustained.
The mechanism(s) by which rosiglitazone alters bone re- Because patients with type 2 diabetes may have an increased modeling likely involves direct effects on osteoblast devel- risk of fragility fractures (16 –20), the possibility that one of opment and function, but the possibility of indirect skeletal Grey et al. • Rosiglitazone and Bone Formation J Clin Endocrinol Metab, April 2007, 92(4):1305–1310 actions also exists. Adipose tissue is a target for PPAR-␥ PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular agonists, and some adipokines influence bone cell function.
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Acknowledgments
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