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Departments of Medicine (D.C.B.) and Epidemiology and Biostatistics (D.C.B., D.M.B., L.P.), University of California, San Francisco, San Francisco, California 94107; Synarc and Institut National de la Santé de la Recherche Médicale Unit 403 (P.G.), Lyon, France; Department of Medicine (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10027; University of Pittsburgh (S.L.G.), Pittsburgh, Pennsylvania 15213; Departments of Medicine and Epidemiology (K.E.E.), Minneapolis Veterans Affairs Medical Center and University of Minnesota, Minneapolis, Minnesota 55417; and the Maine Center for Osteoporosis Research (C.J.R.), St. Joseph Hospital, Bangor, Maine 04401
Address all correspondence and requests for reprints to: Dr. D.C. Bauer, University of California, San Francisco Coordinating Center, 185 Berry 5700, San Francisco, California 94107. E-mail: DBauer{at}psg.ucsf.edu.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Objective: Our objective was to determine the relationship between levels of baseline turnover before PTH therapy and short-term changes in turnover during PTH therapy and subsequent changes in areal and volumetric BMD.
Design and Setting: We conducted a randomized, placebo-controlled trial at four academic centers.
Patients: Patients included 238 postmenopausal women with low hip or spine BMD.
Intervention: Subjects were randomized to sc PTH (1–84), 100 µg/d (119 women), for 1 yr.
Main Outcome Measure: Bone turnover markers were measured in fasting blood samples collected before therapy and after 1 and 3 months. Areal and volumetric BMD at the spine and hip were assessed by dual-energy x-ray absorptiometry and quantitative computed tomography (QCT) after 1 yr of therapy.
Results: Among women treated with PTH alone, the relationships between baseline turnover and 1-yr changes in dual-energy x-ray absorptiometry and QCT BMD were inconsistent. Greater 1- and 3-month increases in turnover, particularly the formation marker N-propeptide of type I collagen, were associated with greater increases in areal BMD. When volumetric hip and spine BMD were assessed by QCT, greater short-term increases in turnover were even more positively associated with 1-yr increases in BMD. Each SD increase in the 3-month change of N-propeptide of type I collagen was associated with an a 21% greater increase in QCT spine trabecular BMD.
Conclusions: Greater short-term changes in turnover with PTH therapy are associated with greater 1-yr increases in spine and hip BMD among postmenopausal osteoporotic women.
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Introduction |
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Unlike bisphosphonates and other antiresorptive agents, therapy with teriparatide or PTH is accompanied by increases first in biochemical markers of bone formation and subsequently in bone resorption markers (6, 8, 9). Previous studies among bisphosphonate-treated women demonstrated that higher pretreatment levels of turnover and greater on-therapy reductions in bone turnover are weakly associated with greater increases in bone mass (10, 11, 12). We and others have recently reported that among bisphosphonate-treated women, greater short-term reductions in bone turnover are associated with a greater reduction in the clinically relevant endpoints of spine and nonspine fractures (13, 14). Given the presumed mechanisms of action, some have hypothesized that antiresorptive agents will be most useful for individuals with elevated bone turnover, whereas anabolic agents will be most useful for those with normal or low turnover.
Little is known about how either the baseline levels of bone turnover markers or their initial response to therapy relate to the densitometric response to anabolic therapy in postmenopausal women. A recently reported analysis (15) found that among teriparatide-treated women, both higher baseline levels and greater short-term increases in turnover markers were associated with greater 1-yr increases in dual-energy x-ray absorptiometry (DXA) of the hip and spine. To address these questions among PTH-treated women, we assessed baseline and short-term changes in bone turnover markers and compared them to serial measurements of areal and volumetric BMD among PTH-treated women from the PTH and alendronate (PaTH) study.
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Subjects and Methods |
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Study design
After a 2-wk run-in period, 238 women were randomized into one of three treatment regimens: PTH plus alendronate placebo (PTH, n = 119), PTH plus alendronate (PTH/ALN, n = 59), or PTH placebo plus alendronate (n = 60). All participants received daily calcium and vitamin D. Although not germane to this analysis, in the second year of the study, group 1 received either alendronate or its placebo (randomized) whereas groups 2 and 3 received alendronate. This analysis covers only the first 12 months of the trial, the only period in which PTH was administered, and includes only the 119 women in group 1 (PTH plus placebo alendronate).
Except for a clinician responsible for reports to the Data and Safety Monitoring Board, all other participants, clinicians, and investigators remained blinded to study treatments.
Subjects
We recruited participants from four U.S. clinical centers: Bangor, ME; Minneapolis, MN; New York, NY; and Pittsburgh, PA. Postmenopausal women aged 55–85 yr were enrolled if they had a femoral neck, total hip, or spine BMD T-score below –2.5 or below –2 with at least one of the following risk factors: age at least 65, history of postmenopausal fracture (vertebral or nonvertebral), or maternal history of hip fracture. We excluded women with a history of more than 12 months of bisphosphonate use (ever) or more than 4 wk of bisphosphonate use in the last 12 months or if they had diseases or took medications known to affect bone metabolism. The Institutional Review Board at each clinical center approved the study protocol, and all women provided written informed consent before enrollment.
PTH treatment
The treatment in this study was full-length PTH (1–84), 100 µg daily (NPS Pharmaceuticals Corp., Salt Lake City, UT). All subjects received calcium carbonate (elemental calcium 500 mg, Tums; GlaxoSmithKline, Pittsburgh, PA) and a multivitamin containing 400 IU vitamin D (Rugby Laboratories, Inc., Norcross, GA). Participants injected PTH (1–84) sc in the morning using a cartridge-loaded pen. Cartridges were changed every 2 wk.
Measurements
Subjects were seen and evaluated 1, 3, and 12 months after randomization. After an overnight fast, serum was drawn at each visit and stored (–70 C) until assayed in a central laboratory (Synarc, Lyon, France). Serum C-terminal telopeptide of type I collagen (sCTX), a marker of bone resorption, and N-propeptide of type I collagen (PINP), a marker of bone formation, were measured with two-site immunoassays on an automatic analyzer (Elecsys; Roche Diagnostics, Mannheim, Germany). Intra- and interassay coefficients of variability for serum PINP and sCTX are approximately 4 and 6%, respectively. Bone-specific alkaline phosphatase (bone ALP) was measured by the Ostase assay (Beckman, San Diego, CA).
Areal BMD (g/cm2) was assessed by DXA (Hologic QDR-4500A or Delphi densitometers). BMD was measured at the hip (femoral neck and total hip regions) and the posteroanterior lumbar spine (L1–L4). The coefficient of variability for areal BMD at each of the sites was established to be 1–2% (17).
Volumetric BMD (g/cm3) in trabecular and cortical compartments were assessed by quantitative computed tomography (QCT) at the spine (L1 and L2) and hip (femoral neck and total hip regions). QCT was performed at three clinical centers at baseline and 12 months and was evaluated by a central imaging facility at the University of California, San Francisco, using methods described previously (18, 19). The coefficient of variability is 2–4% for volumetric BMD and 5–6% for cortical volume (17).
Statistical analysis
We attempted to follow randomized participants for all study visits and procedures regardless of adherence to treatment regimens; analyses are therefore intention-to-treat unless otherwise stated. Group means and 95% confidence intervals (CI) for percentage changes from baseline in DXA, QCT, and turnover parameters are presented. Marker levels that were not normally distributed were log transformed before analysis and then back transformed. We used age-adjusted linear regression models to determine the effect of baseline turnover and short-term absolute changes in turnover on 1-yr percent changes in DXA and QCT measurements of BMD. For ease of comparison, results from these linear relationships are reported as change in BMD per 1 SD increase in baseline marker value or per 1 SD increase in 1- and 3-month change in marker. We also calculated an uncoupling index, as proposed by Eastell et al. (20), defined as the ZPINP – ZCTX, where ZPINP = (observed PINP – mean PINP at baseline)/SD at baseline and ZCTX = (observed CTX – mean CTX at baseline)/SD at baseline. Our primary analyses were among all women randomized to PTH, but key analyses were repeated among compliant subjects, defined as those using more than 80% of study medication.
All analyses presented are limited to subjects randomized to PTH alone during the first year of the PaTH study.
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Results |
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At baseline, the mean (±SD) age of women who received PTH alone was 69.4 (±7.3) yr, and the mean body mass index was 25.6 (±4.6) kg/m2. Baseline levels of bone turnover (Table 1
) were similar to those reported in other studies of similar age and bone density (21). Among PTH-treated women, the mean (SD) femoral neck BMD T-score was –2.3 (0.8), with 45 (37.8%) women below –2.5.
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PTH-induced changes in bone turnover and BMD
As previously reported (16), bone turnover increased promptly with PTH therapy (Table 1
). After 1, 3, and 12 months of PTH therapy, levels of PINP increased by 80, 148, and 157%, respectively; levels of bone ALP increased by 22, 46, and 63%, respectively; and levels of sCTX increased by 5, 64, and 109%, respectively. The relative timing of these changes in bone markers is consistent with the hypothesis that the initial anabolic activity of PTH affects processes associated with bone formation. Change in sCTX, on the other hand, are delayed for several months, reflecting the subsequent involvement of the bone remodeling system by osteoclast activation.
As previously reported, PTH therapy also increased areal BMD of the spine and maintained BMD of the hip (16) (Table 2). After 1 yr, areal BMD by DXA of the spine had increased by 6.3% without any significant increase in hip bone density (+0.4%). By QCT, measurements of volumetric bone density were increased by PTH to an even greater degree. Spine QCT after 1 yr of PTH therapy showed a 29.5% increase in trabecular BMD and a 7.4% increase in cortical BMD. At the hip, QCT measurements revealed an 8.6% increase in trabecular BMD. There were small, nonsignificant declines in cortical BMD (–2.1%).
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Among PTH-treated women, higher baseline PINP levels were associated with greater increases in areal BMD (Table 3). Each SD increase in baseline PINP was associated with an additional 1.7% increase (95% CI, 0.5, 3.0) in spine DXA and a 1.2% increase (95% CI, 0.4, 2.0) in hip DXA BMD. Higher baseline bone ALP and sCTX levels were also associated with greater 1-yr increases in hip and spine DXA BMD, respectively. Neither baseline PINP nor bone ALP levels were significantly associated with 1-yr changes in BMD by QCT, but higher baseline sCTX levels were associated with greater 1-yr increases in trabecular spine QCT and cortical hip BMD by QCT.
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Although there were moderate associations between baseline turnover levels and subsequent DXA BMD changes among PTH-treated women, stronger associations were observed between short-term changes in bone formation markers and 1-yr changes in spine DXA BMD. Subjects who were in the upper tertile of PINP change over 3 months showed the greatest changes in spine BMD by DXA (Fig. 1). Each SD increase in 3-month change in PINP was associated with a 4.0% increase (95% CI, 2.9, 5.0) in spine DXA BMD and a 1.3% increase (95% CI, 0.4, 2.1) in hip DXA BMD. These relationships held also for 1-month changes in PINP and for short-term changes in bone ALP. For example, each SD increase in PINP after 1 month was associated with a 3.8% increase (95% CI, 2.6, 4.9) in spine DXA BMD and a 1.2% increase (95% CI, 0.4, 2.0) in hip DXA BMD (Table 4). The 1-month change in sCTX was not associated with 1-yr change in hip DXA BMD. However, the 3-month increase in sCTX was associated with greater 1-yr increases in spine DXA BMD.
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and 2). Each SD increase in the 3-month change in PINP was associated with a 21.2% increase (95% CI, 16.3, 26.0) in spine QCT trabecular BMD and a 7.0% increase (95% CI, 3.7, 10.3) in hip QCT trabecular BMD. The associations between short-term change in bone ALP, sCTX, and 1-yr change in QCT trabecular BMD were similar to those observed with PINP. One-month increases in PINP and 3-month increases in all turnover markers were also associated with greater 1-yr reductions in hip QCT cortical BMD (Figs. 1 and 2 and Table 4), but the effects were much smaller than those observed with QCT trabecular BMD.
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We found no relationship between baseline levels or short-term changes in bone turnover and several other QCT parameters, including hip volume, hip cortical volume, and hip cortical BMC (data not shown). The uncoupling index, as described by Eastell et al. (20) was calculated after 1 and 3 months of PTH therapy. Associations between 1- and 3-month uncoupling index with 1-yr change in DXA and QCT BMD were similar to those observed with PINP alone. For example, each SD increase in the uncoupling index calculated after 1 month of PTH therapy was associated with an additional 1.6% increase (95% CI, 0.7, 2.4) in hip DXA BMD and a 4.5% increase (95% CI, 3.4, 5.7) in spine DXA BMD, and each SD increase in the uncoupling index at 3 months was associated with a 1.5% increase (95% CI, 0.8, 2.3) in hip DXA BMD and a 3.5% increase (95% CI, 2.5, 4.6) in spine DXA BMD.
Last, as would be expected, our results were strengthened when we limited the analyses to compliant subjects. For example, among compliant subjects (>80% use of study medication), each 1 SD increase in baseline PINP was associated with a 3.4% increase (95% CI, 1.6, 5.3) in spine DXA BMD. Among compliant subjects, each 1 SD increase in the 1-month change in PINP was associated with a 4.3% increase (95% CI, 3.4, 5.2) in spine DXA BMD.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As reported previously (16), we found that women randomized to daily PTH demonstrated marked increases in both areal and volumetric BMD. The effects of daily PTH on bone were highly variable, however, both in terms of observed increases in bone turnover and subsequent increases in BMD. Our data suggest that baseline levels of bone turnover may account for at least some of this variability. Other baseline factors, such as pretreatment BMD, previous fracture history, and recent exposure to antiresorptive agents, may also influence PTH-induced changes in BMD. These possibilities are the subject of other analyses in the PaTH cohort (22).
As an anabolic agent, early interest in PTH focused on those with lower levels of bone turnover for whom it was viewed as a particularly attractive therapeutic agent (2). However, our data indicate that PTH therapy increases BMD whether or not bone turnover is suppressed. Moreover, and in keeping with the report of Kurland et al. (6) in male osteoporosis, we observed that increases in DXA BMD are, in fact, greater among those with higher baseline PINP levels. Similar trends were observed in this study with 1-yr changes in spine QCT trabecular BMD, although only sCTX reached statistical significance. Our results are also consistent with the recent teriparatide study of Chen et al. (15). In those analyses of a subset of the phase III cohort that made up the pivotal clinical trial of teriparatide, higher baseline and 1- and 3-month changes in bone formation markers correlated positively with changes in BMD by DXA after 18 months. Baseline levels of bone ALP were somewhat higher in our study (mean, 18.1 ± 75 ng/ml) compared with the Chen study (12.1 ± 7.2).
The strongest and most consistent associations in our study were observed between the 1- and 3-month changes in bone formation markers, particularly PINP, and 1-yr changes of spine BMD. The relationship among bone turnover markers and the change in bone density is greatest and earliest for the bone formation marker PINP, where greater 1-month changes were strongly associated with greater 1-yr changes in BMD. Conversely, the associations between changes in bone resorption, as measured by sCTX, were most apparent after 3 months of PTH treatment. These observations support the hypothesis that PTH increases bone mass initially by directly augmenting osteoblast function. This could occur initially at quiescent sites or, alternatively, at the sites of ongoing remodeling (23). Our findings also agree with an earlier study of PTH treatment among 28 postmenopausal women with glucocorticoid-induced osteoporosis (24), although that study did not measure serum PINP.
There was site specificity to our observations, with the strongest associations between BMD and bone turnover markers occurring at the spine, particularly trabecular areas. Only modest relationships were observed for cortical BMD at the hip. These findings are likely to be attributable to the faster rate of bone remodeling and greater response to PTH of trabecular sites. The association between 1-month changes in markers and the 1-yr change in BMD tend also to be stronger with bone formation markers, especially PINP, than with sCTX, a sensitive bone resorption marker. Thus, because of its rapid and marked increased after PTH administration, serum PINP may be the single most sensitive biochemical marker to monitor PTH efficacy.
Our study is short-term and therefore, by design, does not have fracture outcome data. Additional studies are needed to determine whether the 1-yr changes in DXA or QCT BMD relate to long-term fracture outcomes. Because we studied postmenopausal women at high risk of fracture, our results may not apply to other populations. Our study, however, is likely to be applicable to teriparatide and to men because they are in agreement with the work of Lane et al. (24), Kurland et al. (6), and Chen et al. (15). Our results are not corrected for multiple comparisons, and therefore individual associations should be interpreted in that context.
In summary, in this study of bone turnover markers and changes in BMD among postmenopausal women treated with PTH, we found that baseline turnover was associated with subsequent changes in BMD. Short-term treatment-related changes in bone turnover markers, especially bone formation, were strongly associated with subsequent changes in BMD. Although longer and larger studies with fracture endpoints are needed, our results suggest that serial measurement of bone turnover shortly after initiation of PTH therapy may be helpful in assessing an ultimate therapeutic response to PTH.
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Footnotes |
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D.C.B. has received research support from NPS Pharmaceuticals, Novartis, Aventis, and Amgen and has received lecture fees from Merck. P.G. has received lecture fees from Merck. J.P.B. has consulted for Eli-Lilly, NPS, Merck, Aventis, and Amgen and has received lecture fees from Eli-Lilly, Merck, and Procter and Gamble. S.L.G. has received research support from NPS and Merck. C.J.R. has received research support from Wyeth-Ayerst, Novartis, and Eli-Lilly. D.M.B. has received research support from Novartis, consulted for Roche, NPS, and GlaxoSmithKline, and received lecture fees from Merck.
First Published Online January 31, 2006
Abbreviations: ALP, Alkaline phosphatase; BMD, bone mineral density; CI, confidence interval; DXA, dual-energy x-ray absorptiometry; PaTH, PTH and alendronate; PINP, N-propeptide of type I collagen; QCT, quantitative computed tomography; sCTX, serum C-terminal telopeptide of type I collagen.
Received August 1, 2005.
Accepted January 20, 2006.
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