Doi:10.1210/jc.2007-071

Effects of Previous Antiresorptive Therapy on the
Bone Mineral Density Response to Two Years of
Teriparatide Treatment in Postmenopausal Women
with Osteoporosis
Steven Boonen, Fernando Marin, Barbara Obermayer-Pietsch, Maria E. Simo˜es, Clare Barker,Emmett V. Glass, Peyman Hadji, George Lyritis, Heide Oertel, Thomas Nickelsen, andEugene V. McCloskey, for the EUROFORS Investigators Leuven University Center for Metabolic Bone Diseases and Division of Geriatric Medicine (S.B.), Universitaire Ziekenhuizen, B-3000Leuven, Belgium; Department of Medical Research (F.M., C.B., E.V.G., H.O., T.N.), Lilly Research Center, Windlesham GU20 6PH, UnitedKingdom; Universita¨tsklinik fu¨r Innere Medizin (B.O.-P.), Medizinische Universita¨t, A-8036 Graz, Austria; Instituto Portugues deReumatologia (M.E.S.), 1000-154 Lisboa, Portugal; Department of Endocrinology, Reproductive Medicine, and Osteoporosis (P.H.),Philipps University, D-35032 Marburg, Germany; Department of Orthopedics (G.L.), University of Athens, 10559 Kifissia, Greece; and TheWorld Health Organization Collaborating Centre for Metabolic Bone Diseases (E.V.M.), University of Sheffield, Sheffield S3 7HF, UnitedKingdom Introduction: EUROFORS was a 2-yr prospective, randomized trial of postmenopausal women with
established osteoporosis, designed to investigate various sequential treatments after teriparatide
20 ␮g/d for 1 yr. The present secondary analysis examined the effects of 2 yr of open-label teripa-
ratide in women previously treated with antiresorptive drugs for at least 1 yr.
Methods: A subgroup of 245 women with osteoporosis who had 2 yr of teriparatide treatment
were stratified by previous predominant antiresorptive treatment into four groups: alendronate
(n ϭ 107), risedronate (n ϭ 59), etidronate (n ϭ 30), and non-bisphosphonate (n ϭ 49). Bone mineral
density (BMD) at the lumbar spine and hip was determined after 6, 12, 18, and 24 months, and bone
formation markers were measured after 1 and 6 months.
Results: Significant increases in bone formation markers occurred in all groups after 1 month of
teriparatide treatment. Lumbar spine BMD increased at all visits, whereas a transient decrease in
hip BMD, which was subsequently reversed, was observed in all groups. BMD responses were similar
in all previous antiresorptive groups. Previous etidronate users showed a higher increase at the
spine but not at the hip BMD. Duration of previous antiresorptive therapy and lag time between
stopping previous therapy and starting teriparatide did not affect the BMD response at any skeletal
site. Treatment-emergent adverse events were similar to those reported in treatment-naive post-
menopausal women with osteoporosis treated with teriparatide.
Conclusions: Teriparatide induces positive effects on BMD and markers of bone formation in
postmenopausal women with established osteoporosis, regardless of previous long-term exposure
to antiresorptive therapies. (J Clin Endocrinol Metab 93: 852– 860, 2008)
Teriparatide,recombinanthumanPTH(1–34),isabone-an- anincreaseinmarkersofboneformationandresorption(2–4),
abolic agent indicated for the treatment of postmenopausal improvement in bone structure (5– 8), and an increase in bone women and men with osteoporosis. The anabolic effects of strength (9). These effects are achieved by preferentially stimu- teriparatide are manifested as an increase in skeletal mass (1–3), lating osteoblastic over osteoclastic activity (2).
Abbreviations: BMD, Bone mineral density; BMI, body mass index; BSAP, bone-specific alkaline phosphatase; ET/EPT, estrogen therapy/estrogen progestagens therapy; MMRM,mixed-model repeated measures; P1NP, N-terminal propeptide of type 1 collagen; TAP, Copyright 2008 by The Endocrine Society doi: 10.1210/jc.2007-0711 Received March 28, 2007. Accepted December 19, 2007.
J Clin Endocrinol Metab. March 2008, 93(3):852– 860 J Clin Endocrinol Metab, March 2008, 93(3):852– 860 Several osteoporosis treatment guidelines, mainly in Europe, Treatments and blinding
recommend the use of teriparatide for the treatment of severe All 245 patients received open-label teriparatide 20 ␮g/d and daily established osteoporosis as a second-line treatment (10). Thus, supplements of 500 mg elemental calcium and 400 – 800 IU vitamin D forup to 24 months. A screening visit was completed within 1 month of many patients initiating teriparatide therapy have often been obtaining written informed consent, and eligible women began teripa- previously treated with antiresorptives for long periods of time ratide treatment at a baseline enrollment visit. Additional visits were (11). An important clinical question is whether the response to conducted at 1, 6, 12, 18, and 24 months of treatment. Patient compli- teriparatide in these patients is similar to the response in patients ance was assessed by direct questioning of the patients and by quantifying who have never received treatment. Preclinical studies in ovari- the amount of study drug returned. The study protocol predefined non-compliance as missing more than 30% of study medication over two ectomized rats indicate that teriparatide significantly enhances bone mass and bone strength regardless of previous therapies(12). Clinical studies have shown that the sequential use of Baseline and follow-up assessments
teriparatide (20 ␮g/d) after long-term daily alendronate or ralox- Patient demographics, health history, and previous medication use ifene therapy stimulated bone turnover; however, previous treat- were obtained at baseline. Lumbar spine and hip BMD was assessed by ment with alendronate prevented early bone mineral density dual x-ray absorptiometry at baseline and 6, 12, 18, and 24 months.
Anteroposterior and lateral spine radiographs were obtained at baseline (BMD) responses to teriparatide (3). Other studies suggest that to determine whether at least two evaluable vertebrae in the lumbar concomitant use of alendronate with PTH therapy reduces the region (L2–L4) were present in each patient fulfilling BMD entry criteria.
ability of PTH to stimulate new bone formation (13–15).
All scans were sent to a reading center for analysis of areal BMD and Using data from the European Study of Forsteo (EURO- quality assurance (Bioimaging Technologies, Leiden, The Netherlands).
BMD results of the total hip obtained on Hologic, GE-Lunar, and Nor- FORS) (16), the effects of 2 yr of open-label teriparatide treat- land scanners were converted to standardized values, and BMD results ment on BMD and biochemical markers of bone formation was of the lumbar spine and femoral neck obtained on Lunar and Norland determined in women with established osteoporosis who were scanners were converted to Hologic values using published and validated previously treated with antiresorptive therapy for at least 1 yr.
formulae (17, 18). Quality control procedures for densitometric equip-ment were performed at each laboratory by validating scanners with astandard anthropomorphic spine phantom.
Biochemical markers of bone formation, including N-terminal propeptide of type 1 collagen (P1NP) (two-site immunoassay; Roche Subjects and Methods
Diagnostics, Indianapolis, IN), bone-specific alkaline phosphatase(BSAP) (enzyme-linked immunoassay, Alkphase-B; Metra Biosystems, Study design and participants
Mountain View, CA), and total alkaline phosphatase (TAP) (dry slide; EUROFORS was a prospective, open-label, randomized trial of 865 Ortho-Clinical Diagnostics, Bucks, UK) were measured in serum col- postmenopausal women with established osteoporosis designed to in- lected after an overnight fast at baseline and after 1 and 6 months of vestigate various sequential treatments of teriparatide over 2 yr. The teriparatide treatment. All samples were analyzed at the University ofSheffield (Sheffield, UK). Detailed assay methodology has been previ- study was conducted at 95 centers in 10 European countries. The present ously reported (19). Assay coefficients of variation were P1NP, 9.9%; analyses were conducted using data from 245 patients treated with open- label teriparatide therapy for more than 12 months and up to 24 months Serum calcium, albumin, and alkaline phosphatase levels were mea- and who had previously been treated with one predominant antiresorp- sured before the injection of teriparatide during clinic visits at month 6, tive drug for a minimum of 12 months. These patients were stratified by 12, 18, and 24. Serum calcium was corrected for serum albumin accord- type of previous antiresorptive therapy. Participants were women age 55 ing to the following formula: corrected calcium ϭ total calcium ϩ [ yr and above that were at least 2 yr postmenopausal at the time of study (40 Ϫ albumin ) ϫ 0.02] (20). Fasting clinical chemistry, hematology, entry. Patients were required to be ambulatory and free of severe chron- and urinalysis laboratory tests were performed at baseline and 24 months ically disabling conditions other than osteoporosis and to have normal at the local investigative site laboratory. Hypercalcemia was defined as laboratory values for serum calcium, alkaline phosphatase, and PTH, an albumin-corrected serum calcium level above the upper limit of nor- with a lumbar spine (L1–L4), femoral neck, or total hip BMD T-score mal serum calcium using the assay employed by the local investigative below Ϫ2.5 SD. At least two lumbar vertebrae were required to be with- site. Study site personnel were instructed to note the occurrence and out artifacts, fractures, and/or other abnormalities. Patients were re- nature of each patient’s medical condition before study entry and mon- quired to have at least one documented preexisting clinical vertebral or itor any changes in these conditions and the occurrence and nature of any nonvertebral fragility fracture within the last 3 yr before enrollment.
adverse events throughout the study.
Additional inclusion criteria for the present prespecified subgroup anal-ysis included patient self-reported use of alendronate, risedronate, or Statistical analysis
etidronate for more than 12 months with less than 3 months of any other The primary objective of the EUROFORS study was to compare bisphosphonate, or the use of any non-bisphosphonate (including cal- change in lumbar spine BMD after 24 months of teriparatide treatment citonin, raloxifene, estrogen therapy/estrogen progestagens therapy (ET/ with change in lumbar spine BMD after 12 months of teriparatide treat- EPT) and vitamin D metabolites) for more than 12 months with less than ment followed by 12 months of no active treatment. The aim of the 3 months bisphosphonate use. Women were excluded if they had other secondary analysis presented in this manuscript was to examine the diseases affecting bone metabolism; past radiation therapy involving the change in BMD after 24 months of teriparatide treatment stratified by skeleton, skeletal tumors, or metastases; nephrourolithiasis within the long-term previous antiresorptive treatment.
past 2 yr; carcinoma of the breast or estrogen-dependent neoplasia ever Mixed-model repeated measures (MMRM) was used to analyze or other malignancies in the past 5 yr; and abnormal thyroid, liver, or changes from BMD at baseline using changes in BMD as the response renal function. Each patient provided written informed consent, and variable and previous antiresorptive therapy, visit, and their interaction institutional review board approval was obtained at each study center.
as fixed effects using SAS Proc Mixed. Models were fitted with adjust- All study methods and procedures were conducted in accordance with ment for baseline BMD, duration of previous therapy, lag time between the ethical standards of the Declaration of Helsinki.
stopping previous therapy and starting teriparatide, age, time since Teriparatide Therapy after Antiresorptive Drugs J Clin Endocrinol Metab, March 2008, 93(3):852– 860 menopause, body mass index (BMI), and baseline P1NP. A sensitivity Analyses were performed using SAS software (SAS Institute, Cary, analyses was completed looking at absolute differences in changes in BMD without adjustment for baseline data. Pairwise differences betweenleast-square means gave estimates for between-group differences inchanges from baseline. The least-square means of change from baseline were divided by the mean baseline BMD, which gave a crude estimate ofpercent change for a patient with average baseline BMD.
Patient disposition
Biochemical markers were not normally distributed and were log Of the 865 women enrolled to EUROFORS and initiating transformed before modeling and analyzed using MMRM. The logged teriparatide treatment, 659 had been previously treated with actual endpoint was the explanatory variable in the model. Fixed effectsfor previous treatment, visit, and their interaction were used. Other ex- antiresorptive therapy (Fig. 1). Three hundred seventy-seven of planatory variables were age, BMI, lag time between the end of previous these pretreated patients had been treated with one antiresorp- antiresorptive treatment and the start of teriparatide, and duration of tive drug for at least 12 months. Of these, 315 (83.6%) com- previous treatment. Pairwise differences were exponentiated to give pleted the first year of teriparatide treatment, and 245 women within-group percent changes from baseline. The raw data were sum- were randomized to continue into a second year of teriparatide marized and medians and interquartile ranges plotted.
All models allowed for the correlations between repeated measure- therapy and constituted the population for analysis in this study ments on subjects, and these correlations were estimated by the data. The (Fig. 1). For the purpose of the analysis, the women were clas- models were fit using the restricted maximum likelihood method, with sified into subgroups according to previous predominant anti- Kenward Roger degrees of freedom (21). Assumptions of normality were resorptive treatment as follows: alendronate (n ϭ 107), risedr- checked. The MMRM methodology assumes data are missing at ran- onate (n ϭ 59), etidronate (n ϭ 30), and non-bisphosphonate dom. All nonmissing data contribute to the model, and no missing dataare imputed. All efficacy and safety analyses were conducted on a mod- antiresorptive (n ϭ 49). In total, 228 (93.1%) women completed ified intent-to-treat basis and included all data from patients starting a a second year of teriparatide treatment (Fig. 1). Among these second year of teriparatide therapy.
women, measurements of returned pens used for the sc admin- Differences in baseline characteristics were tested using ANOVA for istration of teriparatide revealed that 96.5% of them used at least parametric data and the Kruskal-Wallis test for nonparametric data.
70% of the expected amount of teriparatide.
All adverse events were categorized as treatment-emergent if first occurrence of the event was observed after initiating teriparatide therapy Baseline demographics
or the event worsened in severity on teriparatide treatment comparedwith the baseline period. No formal comparisons between groups were The baseline characteristics are shown in Table 1. There were no significant differences for age, BMI, or spine or hip BMD.
FIG. 1. Patient disposition.
J Clin Endocrinol Metab, March 2008, 93(3):852– 860 TABLE 1. Baseline characteristics of 245 women starting second year of teriparatide treatment stratified by previous
antiresorptive therapy
Baseline characteristics
Alendronate
Risedronate
Etidronate
bisphosphonatea
P value
Lag time was defined as the time between stopping antiresorptive therapy and starting teriparatide.
a Main therapy: raloxifene, 22 cases; ET/EPT, 20 cases; calcitonin, six cases; vitamin D metabolites, one case.
b Nonparametric data are presented as median (Q1, Q3) (Kruskal Wallis test). For other variables, data are presented as mean (SD) (ANOVA).
Time since menopause was lower in the non-bisphosphonate peared to differ between the subgroups, the differences were not group, probably reflecting postmenopausal ET/EPT use. Bio- significantly different at any time point in the study (Fig. 2B).
chemical markers of bone formation were significantly different Total hip BMD decreased at 6 months but was not significantly between study groups at baseline (Table 1). This result was ex- different from baseline in the previous etidronate (Ϫ0.006 Ϯ pected given the differences in the degree of bone turnover sup- 0.006 gm/cm2, Ϫ0.9%, P ϭ 0.32) and non-bisphosphonate pression induced by antiresorptive therapies with the lowest val- (Ϫ0.002 Ϯ 0.005 gm/cm2, Ϫ0.3%, P ϭ 0.71) subgroups, ues being observed in alendronate or risedronate users and the whereas total hip BMD decreased significantly in the previous highest values in the etidronate group. Lag time between stop- alendronate (Ϫ0.008 Ϯ 0.003 gm/cm2, Ϫ1.2%, P ϭ 0.004) and ping antiresorptive treatment and initiating teriparatide therapy risedronate (Ϫ0.011 Ϯ 0.004 gm/cm2, Ϫ1.6%, P ϭ 0.003) sub- and duration of previous predominant antiresorptive treatment groups. At 24 months, total hip BMD was significantly increased were both significantly different between subgroups (Table 1).
compared with baseline in all subgroups, and changes were not The majority of previous alendronate-, risedronate-, and non- significantly different among subgroups (Table 2).
bisphosphonate-treated women initiated teriparatide therapy Femoral neck BMD decreased in all subgroups at 6 months, within 1 month of stopping antiresorptive treatment, whereas although this decrease was significant only in the previous alen- the majority of previous etidronate-treated women initiated dronate subgroup (Ϫ0.011 Ϯ 0.003 gm/cm2, Ϫ2.0%, P Ͻ teriparatide treatment after 1 month of stopping etidronate ther- 0.001). No statistically significant differences between sub- apy due to the cyclic dosing scheme of this drug (Table 1).
groups at any time point in the study were found, except for thedifference at 18 months between the etidronate and alendronate subgroups (Fig. 2C). At 18 and 24 months of treatment, BMD at Lumbar spine BMD significantly increased relative to base- the femoral neck was statistically increased compared with base- line at all time points in each subgroup (Fig. 2A). Significant line in all subgroups, except the previous alendronate subgroup, increases compared with baseline were observed in all subgroups where the change at 18 months (0.006 Ϯ 0.003 gm/cm2, 1.1%) at 24 months, ranging between 0.062 Ϯ 0.004 gm/cm2 (mean Ϯ was not significant (P ϭ 0.06). Pairwise BMD differences be- SE) (9.3%) in the previous alendronate to 0.089 Ϯ 0.009 gm/cm2 tween previous predominant groups at 24 months are detailed in (13.3%) in the previous etidronate subgroup (Fig. 2A). Changes Table 2. The small symmetric confidence intervals around zero in lumbar spine BMD from baseline were similar at each time indicate similar results among the four previous treatment point among previous alendronate, risedronate, and non- groups. Our conclusions regarding the differences between pre- bisphosphonate subgroups. However, women previously vious treatment and changes from baseline were consistent treated with etidronate experienced significantly greater lumbar whether the analysis is adjusted for baseline values or spine BMD increases at all time points compared with women previously treated with alendronate and risedronate, and at 18 The MMRM models showed that baseline BMD and P1NP and 24 months compared with women previously treated with levels and either age or time since menopause were associated with the BMD changes at the three sites. Lower baseline BMD Although the pattern of early changes in total hip BMD ap- values, higher baseline P1NP values, and older age were associ- Teriparatide Therapy after Antiresorptive Drugs J Clin Endocrinol Metab, March 2008, 93(3):852– 860 ated with higher BMD increases. Type of previous antiresorptive was associated with spine, but not hip, BMD increase, with pre- vious etidronate users showing higher values (Fig. 2A). The du- ration of antiresorptive treatment, lag time between stopping antiresorptive medications and start of teriparatide, and either baseline BMI or its change over time were not associated with BMD increase at any of the three sites analyzed.
Biochemical markers of bone formation
After 1 month of teriparatide treatment, all subgroups showed statistically significant increases from baseline for P1NP and BSAP (Fig. 3, A and B). Comparisons of P1NP levels between treatment groups at baseline and month 1 showed P1NP levels in the previous alendronate group were significantly lower com- pared with all other previous treatment groups. TAP signifi- cantly increased after 1 month of teriparatide treatment in all subgroups except in the previous etidronate group (data not At month 6, P1NP levels in the previous risedronate group were significantly greater compared with the previous alendro- nate and non-bisphosphonate groups. A similar trend was ob- served for changes in BSAP levels, which were significantly lower at all time points in the previous alendronate treatment group compared with previous etidronate and risedronate groups and at baseline and month 1 compared with the previous non- Type of previous predominant antiresorptive medication, time since stopping previous antiresorptive therapy and starting teriparatide treatment, and visit were associated with bone turn- over marker levels after initiating teriparatide treatment in the MMRM models. Previous risedronate treatment was associatedwith a higher increase in P1NP and BSAP at 6 months. Each additional week of lag time between stopping antiresorptives and starting teriparatide was associated with a 0.9% increase in P1NP and 0.4% in BSAP. The duration of previous antiresorp- tive therapy, age, and BMI did not influence the bone marker A sensitivity analysis of the biochemical markers of bone for- mation was performed to exclude 29 women who sustained an incident fracture during the first 6 months of teriparatide. The absolute changes and the conclusions from the MMRM did notshow any substantial variation to the results of the overall cohort Treatment-emergent adverse events occurring in more than seven patients (Ն3%) during the 2-yr continuous teriparatide FIG. 2. Adjusted mean BMD changes from baseline after 2 yr of continuous
treatment are presented in Table 3. Hypercalcemia, defined as teriparatide treatment stratified by previous predominant treatment: A, lumbar greater than the upper limit of normal at the local laboratory spine; B, total hip; C, femoral neck. A, Within-group changes from baseline: P Ͻ0.001 in all treatment groups at all time points; between-group comparisons at level, developed in 15 women (6.1%) in the study: seven (6.5%) 6, 12, 18, and 24 months: P Ͻ 0.05 etidronate (ETI) vs. alendronate (ALN) and in previous alendronate, five (8.5%) in previous risedronate, and ETI vs. risedronate (RIS), and P Ͻ 0.05 ETI vs. non-bisphosphonate (NONBP) at 18 three (6.1%) in previous non-bisphosphonate study groups. The and 24 months. All other between-group comparisons were not statisticallysignificant. B, There were no significant between-group differences at any time incidence of hypercalcemia was not significantly different (P ϭ point. C, P Ͻ 0.05 ALN vs. ETI between-group comparisons at 18 months. All 0.38) among study groups. No adverse treatment effects were other between-group comparisons were not statistically significant. Numbers at observed in the other hematology or chemistry tests with the top vertical bars indicate percent change from baseline. Error bars indicate SE. *,P Ͻ 0.001 within-group change from baseline; †, P Ͻ 0.05 within-group change exception of hypercholesterolemia, which occurred in five pa- J Clin Endocrinol Metab, March 2008, 93(3):852– 860 TABLE 2. Pairwise BMD differences between previous predominant treatment groups at 24 months
Drug/comparator
Estimate
95% confidence interval
P value
ALN, Alendronate; BP, bisphosphonate; ETI, etidronate; RIS, risedronate.
Discussion
presence of long-term and continued alendronate and are con-sistent with the findings in alendronate-pretreated men who were The results of the BMD changes and biochemical markers of treated sequentially with teriparatide (14). In the Anabolic After bone formation in the EUROFORS trial support the concept that Antiresorptive trial (3), pretreatment with alendronate mitigated treatment with teriparatide induces positive effects on bone mass the early BMD and formation marker responses to teriparatide and osteoblast function regardless of previous long-term expo- compared with more robust changes in patients previously sure to antiresorptive therapies in postmenopausal women with established osteoporosis. Duration of antiresorptive therapy and BMD data in osteoporosis treatment-naive patients from the lag time between stopping previous therapy and starting teripa- EUROFORS trial have shown a more robust response to teripa- ratide did not affect the BMD response at any skeletal site. The ratide (19, 23). In 84 treatment-naive patients treated for 24 skeletal responses at the lumbar spine were similar among pre- months, BMD increases were 13.5, 3.9, and 4.6% at the lumbar vious antiresorptive therapy groups at each time point during the spine, total hip, and femoral neck, respectively (23). Overall, the study, although previous users of etidronate showed a higher BMD increase was higher in this group than in patients previ- increase, probably reflecting its weaker anti-remodeling activity.
ously treated with potent antiresorptive therapies, and similar to At month 6, total hip and femoral neck BMD significantly de- etidronate-pretreated patients. Although percent increase in creased in the previous alendronate subgroup, and total hipBMD significantly decreased in the previous risedronate sub- P1NP seems lower in treatment-naive patients (252% vs. base- group. Total hip and femoral neck BMD was numerically de- line) compared with antiresorptive-pretreated patients (approx- creased from baseline in all other subgroups at 6 months. How- imately 600%) (23), this is the result of the much lower baseline ever, this transitory decrease was reversed with longer bone turnover values of the pretreated patients. The increase in teriparatide treatment, with all subgroups showing a statistically the absolute values of bone markers was similar regardless of significant increase compared with baseline after 18 and 24 months of treatment, and without differences between the The early decrease in hip BMD after therapy with oral nitro- groups at any time point in the study.
gen-containing bisphosphonates and subsequent reversal with Previous studies have reported the effect of teriparatide ad- longer teriparatide treatment deserves further discussion. Previ- ministered cyclically or sequentially with antiresorptive therapy ous studies have reported that teriparatide-induced BMD on BMD. Cosman et al. (22) showed that giving teriparatide in changes at skeletal sites with a high proportion of cortical bone 3-month cycles (daily for 3 months, switch to alendronate for 3 are less than at sites with predominantly trabecular bone (3, 9, months) for 15 months gave a similar increase in spine BMD as 13, 24). This phenomenon has been postulated to be the result of daily teriparatide for 15 months in patients previously treated the mechanism of action of teriparatide in cortical bone (3). At with long-term alendronate therapy. These results indicate that cortical sites, teriparatide induces the simultaneous periosteal teriparatide stimulates bone formation and increases BMD in the apposition of young bone matrix and endosteal resorption of old Teriparatide Therapy after Antiresorptive Drugs J Clin Endocrinol Metab, March 2008, 93(3):852– 860 treatment, where it may be advisable to measure BMD at the end of the approved treatment duration, i.e. after 18 or 24 months The results of the biochemical markers of bone formation and TAP after short-term teriparatide treatment were similar to pre- vious findings by Ettinger et al. (3) in a smaller cohort of pre- treated patients and in a study of men with osteoporosis (15).
Statistically significant increases from baseline for P1NP and BSAP were observed in all groups after 1 month of teriparatide treatment, which provides additional evidence that teriparatide activates osteoblast function in women with severe osteoporosis after previous antiresorptive treatment use. Levels of bone for- mation markers varied according to the type of previous treat- ment and according to the time since stopping previous antire- sorptive therapy. Previous treatment with alendronate was associated with a consistent trend among all biochemical mark- ers of bone formation for lower values at 1 month compared with all other previous treatment groups. Interestingly, previous risedronate treatment was associated with a higher P1NP and BSAP at 6 months than the other groups, although the clinical significance of this is unclear. Additionally, time since stopping previous antiresorptive therapy and starting teriparatide treat- ment was associated with 6-month changes in these two markers.
These findings suggest that early treatment response to teripa- ratide is attenuated by previous use of potent nitrogen-contain- ing bisphosphonates but that these effects are overcome with longer treatment. These biochemical differences, although re- flecting a possible inhibitory effect on osteoblast function, are not paralleled by differences in BMD response and thus may not Treatment-emergent adverse events were similar to those re- ported in osteoporosis treatment-naive women in the Fracture Prevention Trial (1, 25) and in men (26). Hypercalcemia devel- FIG. 3. Median values of serum bone turnover markers over time stratified by
oped in 6.1% of women in the study and was not statistically previous predominant treatment: A, P1NP; B, BSAP. Error bars indicate 25–75% significant between study groups. The incidence of hypercalce- interquartile range. A, P Ͻ 0.001 within-group change from baseline at each mia observed in this study was comparable to the proportion time point for all subgroups; between-group comparisons at baseline: P Ͻ 0.001alendronate (ALN) vs. etidronate (ETI) and ALN vs. non-bisphosphonate (NONBP), reported by Cosman et al. (22) (3%) and Orwoll et al. (26) P Ͻ 0.01 risedronate (RIS) vs. ETI and RIS vs. NONBP, P Ͻ 0.05 ALN vs. RIS. At (6.2%) and was lower than the proportion reported by Ettinger month 1, P Ͻ 0.001 ALN vs. NONBP, P Ͻ 0.01 ALN vs. RIS, and P Ͻ 0.05 ALN vs. et al. (3) in women previously treated with alendronate (12.1%) ETI. At month 6, P Ͻ 0.01 ALN vs. RIS, and P Ͻ 0.05 NONBP vs. RIS. Unlessnoted above, all other comparisons were not statistically significant. B, P Ͻ 0.001 or raloxifene (9.1%). Importantly, no patient discontinued the within-group change from baseline at each time point for all subgroups, except P Ͻ 0.05 ETI at month 1; between-group comparisons at baseline: P Ͻ 0.001 Limitations of our analyses should be noted. First, the EU- ALN vs. ETI, P Ͻ 0.01 ALN vs. NONBP, P Ͻ 0.05 ALN vs. RIS. At month 1, P Ͻ0.05 ALN vs. ETI, ALN vs. NONBP, and ALN vs. RIS. At month 6, P Ͻ 0.01 ALN vs. ROFORS study was an open-label design, and during the first RIS, P Ͻ 0.05 ALN vs. ETI, and P Ͻ 0.05 NONBP vs. RIS. Unless noted above, all year, there was no control group. However, the main outcomes other comparisons were not statistically significant.
(BMD and biochemical markers of bone turnover) are unlikelyto be influenced by a lack of blinding. Second, the use of anti- bone matrix. Patients who have received more potent nitrogen- resorptive therapies before the study was not randomized, and containing bisphosphonates experienced more pronounced previous treatment duration was not uniform among the differ- early decreases in hip BMD after starting teriparatide. This find- ent groups, because each individual therapy has been available ing supports the hypothesis that in patients whose bone turnover for the treatment of osteoporosis for different lengths of time.
was more inhibited, the resorption of highly mineralized bone However, the protocol contained stringent requirements for a results in a transitory BMD decrease during the first few months standardized and detailed documentation of previous antire- of teriparatide therapy, which is then transformed into an in- sorptive treatment, which allowed statistical modeling to ac- crease during the further course of treatment as the new bone count for any imbalances. Furthermore, these heterogeneous co- fully mineralizes. These findings may have practical conse- horts reflect real-life clinical practice, enhancing the clinical quences in the interval assessment and interpretation of dual validity of these results. Bone resorption markers were not mea- x-ray absorptiometry results in patients receiving teriparatide sured in the study, which prevented a complete understanding of J Clin Endocrinol Metab, March 2008, 93(3):852– 860 TABLE 3. Summary of treatment-emergent adverse events with an incidence of seven cases (Ն3%) or greater in second-year
teriparatide-treated patients
Previous therapy
Alendronate
Risedronate
Etidronate
Non-bisphosphonate
All patients
Adverse event
(n ؍ 107)
(n ؍ 245)
the effects of previous antiresorptive treatment on bone turn- F. van den Bosch (Elisabethziekenhuis, Damme), Y. Boutson (Cliniques over, although this was done previously in a smaller study (3) Universitaires de Mont Godinne, Yvoir), J.-M. Kaufman (Universitair with a design that was similar to the EUROFORS study. Finally, Ziekenhuis Gent), and S. Boonen (Universitair Ziekenhuis GasthuisbergLeuven); Denmark: K. Brixen (Universitetshospital, Odense), B. Lang- the study lacked statistical power to assess the association of dahl (Aarhus Amtssygehus), and J.-E. B. Jensen (Hvidovre Hospital, fracture with changes in BMD and bone marker data. However, Hvidovre); France: M. Audran (CHU d’Angers), C. Alexandre (Hoˆpital recent data from the Fracture Prevention Trial shows that rela- Bellevue, Saint Etienne); C. Roux (Hoˆpital Cochin, Paris), C. L. Ben- tive fracture risk reduction seen with teriparatide was indepen- hamou (Hoˆpital Porte Madeleine, Orleans), C. Ribot (Hoˆpital Paule de dent of pretreatment bone turnover (27).
Viguier, Toulouse), C. Cormier (Hoˆpital Cochin, Paris), J.-L. Kuntz (Hoˆ- In conclusion, although teriparatide was effective in increas- pital de Hautepierre, Strasbourg), A. Daragon (CHU de Bois Guillaume,Rouen), B. Cortet (Hoˆpital Roger Salengro, Lille), M. Laroche (Hoˆpital ing bone formation markers and BMD after previous antiresorp- de Rangueil, Toulouse), M. C. de Vernejoul (Hoˆspital Lariboisiere, tive treatment use regardless of type or duration of therapy, the Paris), P. Fardellone (Hoˆpital Sud, Amiens), and G. Weryha (Chu de BMD increase was less robust for patients previously treated Nancy Hoˆpital D’Adultes de Brabois, Vandoeuvre Les Nancy); Ger- with alendronate and risedronate than in the treatment-naive many: H. W. Minne (Klinik-Der Fu¨rstenhof, Bad Pyrmont), H.-J. He- group. Adverse events and hypercalcemia rates were very similar berling (Robert-Koch-Klinik, Leipzig), K. Badenhoop (Klinikum der Jo-hann Wolfgang Goethe-Universita¨t Frankfurt), H. G. Fritz (Berlin), J.
to those reported in treatment-naive patients. These findings sup- Kekow (Krankenhaus Vogelsang, Vogelsang/Gommern), H. Moenig port the use of teriparatide as an effective treatment option in (Klinikum der Christian-Albrechts-Universita¨ts zu Kiel), T. Brabant women with severe osteoporosis after previous antiresorptive (Krankenhaus St. Josef Stift Bremen), H.-P. Kruse (Univerita¨ts-Kranken- treatment use, including long-term previous alendronate and haus Eppendorf, Hamburg), W. Spieler (Zefor, Zerbst), R. Mo¨ricke (Magdeburg), A. Wagenitz (Berlin), F. Flohr (Universita¨tsklinikumFreiburg), J. Semler (Immanuel Krankenhaus Rheuma Klinik BerlinWannsee), P. Hadji (Klinikum der Phillips-Universita¨t, Marburg), P.
Kaps (Braunfels), T. Hennigs (Osteoporose Studiengesellschaft bR, Acknowledgments
Frankfurt), R. R. Fritzen (Med.Klinik fu¨r Endokrinologie des Universi-ta¨tsklinikums Du¨sseldorf), J. Feldkamp (Sta¨dtische Kliniken, Bielefeld), We thank the following individuals for technical assistance: Petra Ochs G. Hein (Klinikum der Friedrich-Schiller-Universita¨t, Jena), U. Haschke (central study coordination); Ruth Alonso, David Lo´pez, and Laura Brio- (Osnabru¨ck), C. Kasperk (Universita¨tsklinkum Heidelberg), J. D. Ringe nes (data management); and Alain Frix (study drug coordination). We (Klinikum Leverkusen), H. Radspieler (Osteoporose-Diagnostik und are indebted to Melinda Rance for her assistance with graphs and figures.
Therapiezentrum Mu¨nchen), N. Vollmann (Mu¨nchen), E. Blind (Klini- Steve Boonen is senior clinical investigator of the Fund for Scientific kum der Universita¨t Wu¨rzburg), M. Runge (Aerpah-Klinik Esslingen- Research and is holder of the Leuven University Chair in Metabolic Bone Kennenburg), F. Jakob (Orthopa¨dische Klinik Ko¨nig-Ludwig-Haus, Wu¨rzburg), H.-G. Dammann (Klinikische Forschung Hamburg), and EUROFORS investigators from Austria: B. Obermayer-Pietsch (Lkh- S. S. Scharla (Bad Reichenhall); Greece: G. Lyritis (K.A.T. Hospital of Universita¨tsklinikum Graz), L. Erlacher (Krankenhaus der Elisabethi- Athens, Kifissia) and A. Avramides (Ippokratio Hospital, Thessaloniki); nen, Klagenfurt), and G. Finkenstedt (Landeskrankenhaus-Universita¨- Iceland: G. Sigurdsson (Landspitalinn Hasko´lasju´krahu´s, Reykjavik) tskliniken, Innsbruck); Belgium: P. Geusens (Limburgs Universitair and B. Gudbjo¨rnsson (Fjordungssjukrahusid Akureyri); Portugal: M. E.
Centrum, Diepenbeek), F. Raeman (Jan Palfijn Ziekenhuis, Merksem), Simo˜es (Instituto Portugues De Reumatologia, Lisboa), J. Melo-Gomes Teriparatide Therapy after Antiresorptive Drugs J Clin Endocrinol Metab, March 2008, 93(3):852– 860 (Servimed, Lisboa), J. C. Branco (Hospital Egas Moniz, Lisboa), and A.
Dempster DW 2006 A novel tetracycline labeling schedule for longitudinal
Malcata (Hospitais da Universidade, Coimbra); Spain: C. Dı´az-Lopez (J.
evaluation of the short-term effects of anabolic therapy with a single iliac crest Farrerons, Hospital Santa Creu i Sant Pau, Barcelona), J. Gonza´lez de la bone biopsy: early actions of teriparatide. J Bone Miner Res 21:366 –373 Vera (H. U. Virgen Macarena, Sevilla), J. A. Roma´n (H. U. Dr. Pesset, 9. Keaveny TM, Donley DW, Hoffmann PF, Mitlak BH, Glass EV, San Martin
JA 2007 The effects of teriparatide and alendronate on vertebral strength as
Valencia), X. Sans (Ciutat Sanitaria Vall D’Hebron, Barcelona), A. Laf- assessed by finite element modeling of QCT scans in women with osteoporosis.
fo´n (Hospital de la Princesa, Madrid), E. Rejo´n (H. U. Nuestra Sen˜ora de Valme, Sevilla), and J. del Pino (Hospital Clı´nico, Salamanca); United 10. NICE Guideline TA087 The clinical effectiveness and cost effectiveness of
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Trust), R. Eastell (University of Sheffield), W. Fraser (University of Liv- acteristics of the population in the European Forsteo Observational Study erpool), D. Hosking (Nottingham City Hospital NHS Trust), T. O’Neill (Salford Hospital NHS Trust), J. Compston (Addenbrookes NHS Trust), 12. Ma YL, Bryant HU, Zeng Q, Schmidt A, Hoover J, Cole HW, Yao W, Jee WS,
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13. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF,
Palferman (East Somerset NHS Trust), A. Woolf (Royal Cornwall Hos- Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ 2003 The effects of para-
pitals NHS Trust), T. Wheatley (Brighton and Sussex University Hos- thyroid hormone and alendronate alone or in combination in postmenopausal pitals NHS Trust), P. Thompson (Poole Hospital NHS Trust), R. Keen osteoporosis. N Engl J Med 349:1207–1215 (Royal National Orthopaedic Hospital NHS Trust), P. Ryan (The Med- 14. Finkelstein JS, Hayes A, Hunzelman JL, Wyland JJ, Lee H, Neer RM 2003 The
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Address all correspondence and requests for reprints to: Steven K, Neer RM 2006 Effects of teriparatide, alendronate, or both on bone turn-
over in osteoporotic men. J Clin Endocrinol Metab 91:2882–2887
Boonen, M.D., Ph.D., Leuven University Center for Metabolic Bone 16. Eastell R, Hadji P, Farrerons P, Audran M, Boonen S, Brixen K, Melo-Gomes
Diseases and Division of Geriatric Medicine, Universitaire Ziekenhui- J, Obermayer-Pietsch B, Avramidis A, Sigurdsson G, Glueer CG, Cleall S,
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of teriparatide: final results from the EUROFORS Study. J Bone Miner Res Funding was provided by Lilly Research Center, Europe.
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