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Keywords:

  • osteoporosis;
  • postmenopausal women;
  • teriparatide;
  • hormone replacement therapy;
  • BMD;
  • bone turnover markers;
  • adverse events

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

The effects of teriparatide when given in combination with HRT were studied in postmenopausal women with low bone mass or osteoporosis. The data provide evidence that the adverse event profile for combination therapy with teriparatide + HRT together is consistent with that expected for each treatment alone and that the BMD response is greater than for HRT alone.

Introduction: Teriparatide {rhPTH(1-34)}, given as a once-daily injection, activates new bone formation in patients with osteoporosis. Hormone replacement therapy (HRT) prevents osteoporosis by reducing bone resorption and formation. Combination therapy with these two compounds, in small clinical trials, increased BMD and reduced vertebral fracture burden. The purpose of this study was to determine whether teriparatide provided additional effect on BMD when given in combination with HRT.

Materials and Methods: A randomized, double-blind, placebo-controlled study was conducted in postmenopausal women with either low bone mass or osteoporosis. Patients were randomized to placebo subcutaneous plus HRT (n = 125) or teriparatide 40 μg/day (SC) plus HRT (TPTD40 + HRT; n = 122) for a median treatment exposure of 13.8 months. Approximately one-half of the patients in each group were pretreated with HRT for at least 12 months before randomization. Patients received 1000 mg calcium and 400–1200 IU of vitamin D daily as oral supplementation. BMD was measured by DXA.

Results: Compared with HRT alone, TPTD40 + HRT produced significant (p < 0.001) increases in spine BMD (14% versus 3%), total hip (5.2% versus 1.6%), and femoral neck (5.2% versus 2%) at study endpoint. BMD, in whole body and ultradistal radius, was higher, and in the one-third distal radius was lower, in the combination therapy but not in the HRT group. Serum bone-specific alkaline phosphatase and urinary N-telopeptide/Cr were increased significantly (p < 0.01) in the women receiving TPTD40 + HRT compared with HRT. A similar profile of BMD and bone markers was evident in both randomized patients as well as in subgroups of patients not pretreated or pretreated with HRT. Patients tolerated both the treatments well. Nausea and leg cramps were more frequently reported in the TPTD40 + HRT group.

Conclusions: Adding teriparatide, a bone formation agent, to HRT, an antiresorptive agent, provides additional increases in BMD beyond that provided by HRT alone. The adverse effects of teriparatide when added to HRT were similar to the adverse effects described for teriparatide administered alone. Whether teriparatide was initiated at the same time as HRT or after at least 1 year on HRT, the incremental increases over HRT alone were similar.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

OSTEOPOROSIS, A SKELETAL disorder characterized by compromised bone strength predisposing to an increased fracture risk, (1) is a major public health problem in the United States. Ten million individuals are affected with osteoporosis, and an additional 18 million with low bone mass are at risk. (1) Osteoporosis is more prevalent in postmenopausal white women, (1, 2) and it is a preventable disease of menopause. (3)

Bone resorption and formation is at equilibrium before menopause, and after menopause, resorption increases, resulting in bone loss. (4) Hormone replacement therapy (HRT) is currently approved in the United States for the prevention, but not the treatment, of postmenopausal osteoporosis. HRT maintains or improves BMD and seems to prevent vertebral and hip fractures. (5–8) In addition, many postmenopausal women with osteoporosis are still taking HRT for the treatment of hot flashes or vulvo-vaginal atrophy or may be reluctant to discontinue HRT for other reasons. Therefore, there is both a substantial population of patients with osteoporosis who are already on HRT and a population naïve to HRT, who may be initiating HRT for treatment of menopausal symptoms.

Among the available pharmacological therapies for the treatment of osteoporosis, teriparatide {rhPTH(1-34)} is a bone-forming drug that stimulates increased bone turnover, (9–12) with a positive bone balance resulting in increases in bone mass and improved micro- and macro-architecture. (11, 13–17) In the Fracture Prevention Trial, teriparatide at 20 μg/day, an approved dose, reduced the risk of vertebral and nonvertebral fragility fractures by 65% and 53% versus placebo treatment and 40 μg/day reduced the risk of vertebral and nonvertebral fragility fractures by 69% and 54%, respectively, (18) suggesting similar efficacy with both doses. Spine BMD, on the other hand, increased 14% in the 40 μg/day group compared with 10% in the 20 μg/day group. (18) Different forms of human PTH have been shown, in recent clinical trials, to increase BMD in postmenopausal women with osteoporosis when given concomitantly with HRT, (11, 17) and all studies, including this one, were initiated before the approval of teriparatide 20 μg/day (Fortéo; Eli Lilly and Company).

Estrogen reduces bone resorption through the regulation of osteoclast cell number by inhibition of cytokine synthesis, (19) and teriparatide stimulates bone formation. (20) Because these two agents with different mechanisms offer therapeutic benefits to patients with osteoporosis, it is possible that the combination of these two compounds might increase BMD.

The objective of this study was to determine whether teriparatide {rhPTH(1-34)}, increased BMD in postmenopausal women with low bone mass or osteoporosis when given in combination with HRT.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

Patients

A total of 247 postmenopausal women with low bone mass or osteoporosis, 30–85 years of age, were included in the study. Of 247 patients, 122 were previously treated and 125 were not treated with HRT for at least 12 months preceding the study. Patients taking HRT were allowed to continue the approved regimen during this study. To be eligible, women had to be postmenopausal for at least 5 years before randomization and free of any severe or chronically disabling conditions other than osteoporosis. The hip or lumbar spine BMD was at least 1.0 SD below the average bone mass for young, healthy women (T score), based on input from clinicians who would consider adding a bone formation agent if a patient was still osteopenic after treatment with HRT. The human studies review board at each investigational center approved the study, and each patient provided written consent to participate in the study.

Study design and treatment

This was a global multicenter, double-blind, placebo-controlled, parallel, randomized study. Patients were randomized to placebo daily injections plus HRT (n = 125) or teriparatide 40 μg/day injections (TPTD40) plus HRT (n = 122). Of 125 patients randomized to HRT, 48.8% were pretreated with HRT for at least 12 months and 51.2% were not pretreated with HRT. Of 122 patients randomized to TPTD40 + HRT, 50% were pretreated and the other 50% were not pretreated with HRT. HRT consisted of Premarin (conjugated estrogens; Wyeth-Ayerst Laboratories, Philadelphia, PA, USA) 0.625 mg/day plus Provera (medroxyprogesterone acetate; Upjohn, Kalamazoo, MI, USA) 2.5 mg/day. Patients were allowed to use the sponsor-provided HRT regimen or to use an alternative HRT regimen of their physician's choice. In all 247 randomized patients, 43.7% took oral Premarin and Provera, 35.6% took only oral Premarin, 2.4% took oral combination estradiol and estriol, 2.8% took transdermal estradiol, 2% took oral combination estradiol and norethisterone acetate, and the rest (13.5%) were not recorded or took other HRT regimens. The median duration of previous HRT use was 84.8 months. Compliance was assessed by accounting the returned medications. All patients received calcium (1000 mg) and vitamin D (400-1200 IU) as daily oral supplementation throughout the study period. The planned study duration was 24 months. The study was terminated early because of the unexpected finding of osteosarcoma in a long-term toxicology study in Fisher 344 rats. (21) The median duration of treatment exposure was 13.8 months, with an interquartile range (IQR) of 13.3-14.9 months.

Measurements

BMD was assessed using DXA (Hologic, Bedford, MA, USA, or Lunar Corp., Madison, WI, USA). The BMD measurements were reviewed and analyzed centrally (Synarc, Portland, OR, USA), and the values are expressed as grams per square centimeter. (22) Lumbar spine BMD was measured at baseline, 3, 6, and 12 months, and a study endpoint. Hip, whole body, and radial BMD was measured at baseline, 12 months, and a study endpoint.

Serum and urine samples were collected at approximately same time in the morning at baseline and 1, 3, 6, and 12 months for assessment of biochemical marker of bone formation, bone-specific alkaline phosphatase (BSALP; Tandem-R Ostase Immunoradiometric Assay; Beckman-Coulter, Brea, CA, USA) and resorption, urinary N-telopeptide/Cr (NTxCr; ELISA; OSTEX, Seattle, WA, USA). Biochemical assays were measured by Covance Laboratories (Indianapolis, IN, USA).

All adverse events were collected in an unsolicited manner at each visit. All adverse events that were new or worsened after randomization, regardless of the relationship to the study drug, were summarized as treatment-emergent adverse events (TEAEs).

Statistical analysis

Treatment group comparisons in baseline characteristics were done using ANOVA. The percent changes from baseline in BMD were analyzed using ANOVA with treatment and investigator in model. Endpoint BMD data were obtained using the last-observation-carried-forward (LOCF) data imputation method. The percent changes in bone markers were analyzed using ranked ANOVA. These analyses were done both in all randomized patients as well as in each subgroups (pretreated or not pretreated with HRT). ANOVA with treatment, investigator, pretreatment status, and pretreatment by therapy interaction in the model was used to test pretreatment status by therapy interaction on endpoint BMD and bone turnover marker data. The interaction test was performed to see whether the therapy effect was independent of the subgroups. For categorical measures including the analyses of adverse events, treatment groups were compared using a Fisher's exact test. All tests were two-sided, with a significance level of p < 0.05. The data were analyzed using SAS for MVS statistical software (SAS Institute, Cary, NC, USA).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

No statistically significant differences were found in baseline characteristics or BMD between the two treatment groups (Table 1). Compliance with teriparatide, as assessed by accounting the returned medications, was 91% and 89% in the HRT and HRT + TPTD40 groups, respectively. Compliance with HRT was not assessed.

Table Table 1.. Baseline Characteristics of All Randomized Patients (Mean ± SD)
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Percent changes in lumbar spine BMD from baseline as a function of time and at study endpoint after treatment with HRT or TPTD40 + HRT are presented in Fig. 1A. There was a steady increase of BMD in both treatment groups. However, the women receiving TPTD40 + HRT showed a greater gain in BMD from 4.8% at 3 months to 14.0% at study endpoint compared with modest increases of 1.2% at 3 months to 3.0% at study endpoint in women receiving HRT alone. The increases in BMD at all time-points were significantly (p < 0.001) higher in the TPTD40 + HRT group compared with the HRT group. The percent change in BMD from baseline to the study endpoint in both treatment groups were significant (p < 0.001). Percent changes in lumbar spine BMD from baseline as a function of time and at study endpoint in subgroups of patients pretreated or not pretreated with HRT after treatment with HRT or TPTD40 + HRT are presented in Fig. 1B and Tables 3 and 4. In the pretreated subgroup, women assigned to HRT alone maintained or only slightly increased lumbar spine BMD (1.5% at endpoint) during the study, as expected for a patient on chronic HRT with no treatment change at the time of randomization. On the other hand, in the patients assigned to HRT who had not been pretreated with HRT, lumbar spine BMD increased by 4.6% from baseline. In both the pretreated and nonpretreated subgroups, patients assigned to TPTD40 + HRT increased BMD significantly more than those on HRT alone at every time-point. At endpoint, spine BMD had increased by 11.2% and 16.9% from baseline in the pretreated and nonpretreated subgroups, respectively.

Table Table 3.. Percent Change in BMD From Baseline in Patients Not Pretreated With HRT at 12 Months and at Study Endpoint
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Table Table 4.. Percent Change in BMD From Baseline in Patients Pretreated With HRT at 12 Months and at Study Endpoint
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Figure FIG. 1.. (A) Percent change from baseline in lumbar spine BMD as a function of time in all randomized patients treated with HRT (•) or TPTD40 + HRT (○). *p < 0.001 between treatment groups. (B) Percent change from baseline in lumbar spine BMD as a function of time in patients either not pretreated or pretreated with HRT. HRT (•) or TPTD40 + HRT (○) not pretreated; HRT (▾) or TPTD40 + HRT (▿) pretreated. *p < 0.001 between the treatment groups in each subgroup.20

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Percent changes in total hip BMD from baseline, at 12 months, and at study endpoint, after treatment with HRT or TPTD40 + HRT, are presented in Fig. 2A. The total hip BMD significantly (p < 0.001) increased by 4.7% and 5.2% in the TPTD40 + HRT group at 12 months and at study endpoint, respectively, compared with modest increases of 1.7% and 1.6% for the same time-points in the HRT group. Percent changes in total hip BMD from baseline, at 12 months, and at study endpoint in subgroups of patients pretreated or nonpretreated with HRT after treatment with HRT or TPTD40 + HRT are presented in Fig. 2B and in Tables 3 and 4. As with spine BMD, TPTD40 + HRT significantly (p < 0.01) increased total hip BMD compared with HRT in both subgroups. In both the HRT and the TPTD40 + HRT treatment arms, patients not pretreated with HRT had greater change from baseline than those pretreated. However, the incremental effect of adding teriparatide to HRT compared with HRT alone was similar in both subgroups.

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Figure FIG. 2.. (A) Mean percent change ± SE in BMD of the total hip with HRT (▪) or TPTD40 + HRT (□) at 12 months of treatment and at study end in all randomized patients. *p < 0.001 between the treatment groups. (B) Mean percent change ± SE in BMD of the total hip in patients either not pretreated or pretreated with HRT. HRT (▪) or TPTD40 + HRT (□) not pretreated; HRT ({lined square}) or TPTD40 + HRT ({thatched square}) pretreated. *p < 0.001, p < 0.01 between the treatment groups in each subgroup.20

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The BMD changes from baseline for all other skeletal sites including whole body, femoral neck, ultradistal radius, and one-third distal radius after treatment with HRT or TPTD40 + HRT are presented in Table 2 for all randomized patients. The increase in BMD at the femoral neck was significantly (p < 0.001) greater in the TPTD40 + HRT group than in the HRT group at both 12 months and study endpoint, whereas whole body BMD change was significantly (p < 0.05) greater in the TPTD40 + HRT group at 12 months but not at study endpoint. The differences in BMD between the two treatment groups at the ultradistal radius and the one-third distal radius were not statistically significant. The BMD changes from baseline for all other skeletal sites including whole body, femoral neck, ultradistal radius, and one-third distal radius in the patients not pretreated and pretreated with HRT after treatment with HRT or TPTD40 + HRT are presented in Tables 3 and 4. Patients not pretreated with HRT and receiving TPTD40 + HRT showed significant increases of BMD in all skeletal sites except in the one-third distal radius at study endpoint compared with patients receiving HRT alone (Table 3). Patients pretreated with HRT and receiving TPTD40 + HRT showed significant increases of BMD in all skeletal sites except in whole body, ultradistal radius, and one-third distal radius at study endpoint compared with patients receiving HRT alone (Table 4).

Table Table 2.. Percent Change in BMD From Baseline in all Randomized Patients at 12 Months and at Study Endpoint
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Although there were differences in the BMD percent changes from baseline in the two subgroups (pretreatment with HRT or no pretreatment with HRT), there was not a significant treatment-by-subgroup interaction for BMD at study endpoint (for all skeletal sites, p > 0.10, except for ultradistal BMD, p > 0.05), which indicated that the incremental effects of adding teriparatide to HRT compared with HRT alone were independent of pretreatment status.

Results of bone turnover markers including serum BSALP and urinary N-telopeptide in all randomized patients are presented in Figs. 3A and 4A. In women receiving TPTD40 + HRT, serum BSALP, a marker for bone formation, increased rapidly to near-maximum increase of 61.6% at 1 month and then continued to increase more slowly until reaching its maximum of an 85.2% increase by 6 months of treatment (Fig. 3A). The women receiving HRT alone showed gradual decline in BSALP to a maximum of a 34.9% decrease from baseline at 12 months. The differences between the two treatment groups at all time-points were significant (p < 0.001), and the percent change in BSALP from baseline to the study endpoint in both treatment groups was significant (p < 0.001). N-telopeptide, a marker for resorption, was also increased from baseline as a function of time in women receiving TPTD40 + HRT (Fig. 4A). The levels of bone resorption marker increased by 12.5% in the first month and then rose more rapidly by 3 months of treatment, reaching a maximum of a 131.3% increase by 12 months. In the HRT group, the maximum of a 28% decrease of N-telopeptide from baseline in the HRT group occurred at 6 months after treatment and returned to baseline by 12 months of treatment. The differences between the two treatment groups, at all time-points, were significant (p < 0.01), and the percent change in N-telopeptide from baseline to the study endpoint was significant in the TPTD40 + HRT group (p < 0.001) but not in the HRT group.

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Figure FIG. 3.. (A) Median percent change from baseline in serum BSALP as a function of time. ▾, HRT group; ○, TPTD40 + HRT in all randomized patients. *p < 0.001 between the treatment groups. (B) Median percent change from baseline in serum BSALP as a function of time in patients either not pretreated or pretreated with HRT. HRT (•) or TPTD40 + HRT (○) not pretreated; HRT (▾) or TPTD40 + HRT (▿) pretreated. *p < 0.001 between the treatment groups in each subgroup.20

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Figure FIG. 4.. (A) Median percent change from baseline in urinary N-telopeptide as a function of time. ▾, HRT group; ○, TPTD40 + HRT in all randomized patients. *p < 0.001, p < 0.01 between the treatment groups. (B) Median percent change from baseline in urinary N-telopeptide as a function of time in patients either not pretreated or pretreated with HRT. HRT (•) or TPTD40 + HRT (○) not pretreated; HRT (▾) or TPTD40 + HRT (▿) pretreated. *p < 0.001, p < 0.01 between the treatment groups in each subgroup.20

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The bone turnover marker data including serum BSALP and urinary N-telopeptide in patients not pretreated or pretreated with HRT are presented in Figs. 3B and 4B. In patients not pretreated with HRT, initiating HRT showed the expected suppression of bone turnover, reaching maximum 57% decrease in BSALP at 12 months and 42% decrease in N-telopeptide at 6 months. Patients pretreated with HRT maintained relatively stable bone turnover with little change after randomization to continue HRT alone. Patients in the TPTD40 + HRT group showed significant increases in BSALP and N-telopeptide compared with HRT alone in both the pretreated and not pretreated subgroups, except at 1 month for N-telopeptide in not pretreated group. The BSALP rose quickly in both subgroups, reaching 54% and 79% at 1 month in the nonpretreated and pretreated subgroups, respectively. In the pretreated subgroup, BSALP continued to increase over time, reaching a maximum 185% increase at 12 months, whereas BSALP remained nearly unchanged in the nonpretreated subgroup after 1 month (Fig. 3B). Similarly, N-telopeptide decreased to a maximum of 42% at 6 months in the nonpretreated subgroup randomized to begin HRT, whereas it remained unchanged in the patients pretreated with HRT who continued their HRT-only regimen. Treatment with TPTD40 + HRT increased N-telopeptide, reaching maximum 74% increase at 3 months in patients not pretreated with HRT and 215% increase at 6 months in the pretreated subgroup. Despite the substantial differences in the bone marker responses to HRT in the two subgroups (pretreatment with HRT or no pretreatment with HRT), there was no significant interaction between pretreatment status and therapy groups in percent changes from baseline to endpoint for bone markers (p > 0.10), which indicated that the effects of adding teriparatide to HRT compared with HRT alone were independent of the subgroups.

A total of 61 TEAEs with >3% incidence were reported, and only two were significantly different between the treatment groups. There were no events significant between the treatment groups with <3% incidence rates. Of the 247 postmenopausal women with osteoporosis enrolled in this study, no deaths occurred during the study, and 214 (87%) reported at least one TEAE: 107 (86%) in the HRT group and 107 (88%) in the TPTD40 + HRT group; the differences were not significant (p = 0.710). A total of two TEAEs were reported with a statistically significant (p < 0.05) difference between the two treatment groups. Nausea (30/122) and leg cramps (9/122) were more frequently reported in women receiving TPTD40 + HRT compared with the HRT group (nausea, 12/125; leg cramps, 2/125). Hypercalcemia was defined as 2.64 mM. Elevated serum calcium occurred at least once in 0.8% (1/125) of the patients on HRT and 12.3% (15/122) in patients on TPTD40 + HRT. Patients on TPTD40 + HRT had elevated calcium in 4.9% (6/122), and 0% of patients in the HRT group had elevated calcium after two or more repeat tests. Of 16 patients with elevated calcium, 10 patients were pretreated with HRT and 6 were not pretreated.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

In this study, daily treatment of teriparatide in combination with HRT produced dramatic improvements of BMD at different skeletal sites and bone turnover marker profile compared with patients treated with HRT alone. The spine BMD was increased from baseline as a function of time, reaching a maximum at 12 months in the patients receiving combination therapy. The patients receiving HRT alone showed a modest increase of spinal BMD at 12 months. The differences between the two treatment groups were significant (p < 0.001) at all time-points. A significant (p < 0.001) increase of total hip and femoral neck BMD was also observed in the patients on combination therapy compared with the HRT group alone both at 12 months and at study end. Whole body and ultradistal radius BMD was also increased, and the one-third distal radius BMD was slightly decreased, in the combination therapy group compared with the HRT group alone, but the differences were not significant except for the change in whole body BMD at 12 months (p = 0.041). A subgroup analysis revealed that teriparatide + HRT significantly increased BMD at spine, total hip, and femoral neck compared with HRT alone in patients either pretreated or not pretreated with HRT. This study also showed that the combination of teriparatide and HRT had an adverse event profile similar to what is expected based on the known adverse events of both treatments alone.

The combined effect of teriparatide and HRT observed in this study is consistent with the results reported by earlier clinical trials with a small number of patients. (11, 23, 24) These studies were conducted for 3 years compared with 13.8 months of treatment exposure in this trial. Despite the short duration of treatment, the increases in BMD, at all skeletal sites in this study, were similar to the studies with a 3-year duration of treatment of teriparatide plus HRT, with the exception of the study reported by Roe et al. (24) In the study of Roe et al., a remarkably high increase of 29% BMD in the spine, 11% in the femoral neck, and 9.5% in the total hip was reported in patients receiving teriparatide plus HRT. (24) Consistent with other studies of teriparatide, total body BMD increased more slowly and to a lesser extent than several other regions of interest, such as the lumbar spine and the total hip. However, in clinical trials, statistically significant reductions in the incidence of nonvertebral fractures have been observed during treatment. (18, 25) Nonvertebral fragility fracture risk reduction persisted for at least 30 months after termination of treatment, even though BMD fell substantially. (26) Data from both human and nonhuman primates suggest that the mechanism by which teriparatide improves cortical bone strength involves improvements in macroarchitecture, resulting in a larger diameter, biomechanically stronger bone with little change in BMC and even a small decrease in BMD. (15, 27) The improved architecture may be the mechanism by which nonvertebral and vertebral fracture risk reduction is maintained even as BMD begins to diminish after cessation of treatment. Regardless of the mechanism, treatment with teriparatide has resulted in substantial decreases in nonvertebral fractures, and the differential effects on trabecular and cortical bone do not seem to cause any clinical consequences.

This study was limited by early termination, lack of a teriparatide-only control arm, the use of a 40 μg/day rather than the currently approved 20 μg/day, dose, and a sample size that precluded a fracture endpoint. The objective of this study and those reported earlier was to determine if adding teriparatide increased BMD in patients treated with HRT. Therefore, these studies did not include a teriparatide-only arm of treatment for better comparison between teriparatide plus HRT and teriparatide alone. Whereas it is clear that adding teriparatide to HRT increases BMD more than HRT alone, it is not known whether the combination provides greater benefits than teriparatide alone. This study also did not include fracture assessment, although one other small study did show a decrease in vertebral fracture incidence when teriparatide was administered to patients already on HRT. (23) This and the other studies were initiated before the publication of the results of the Women's Health Initiative (WHI), (8) approval of teriparatide 20 μg/day for the treatment of osteoporosis, or the publication of the teriparatide Fracture Prevention Trial, (18) and used teriparatide doses higher than the currently approved dose. However, in the teriparatide Fracture Prevention Trial, 20 and 40 μg/day both reduced the relative risk of fractures by nearly identical amounts, and 20 μg/day was associated with significantly fewer adverse effects than 40 μg/day. The effects on BMD and markers of bone formation and resorption were substantially greater in the 40 μg/day group than in the 20 μg/day group. The BMD data from this study using 40 μg/day indicate that combination therapy may be beneficial to the patients when teriparatide is superimposed on HRT therapy. However, it is now clear from the results of the Fracture Prevention Trial that doses >20 μg/day are not necessary to provide the maximal clinical benefit (i.e., fracture risk reduction) and are associated with more adverse effects. This study also did not examine the effects of continuing HRT after discontinuation of teriparatide treatment, as was done in several other studies that showed that the continued therapy with HRT after discontinuation of teriparatide maintained teriparatide-induced bone mass for a period of 1–2 years. (12, 23, 28)

BSALP, a marker of bone formation, rapidly increased as early as 1 month after treatment with TPTD40 plus HRT, with a continued increase up to 12 months. Patients receiving HRT alone showed a decrease in BSALP at all time-points. These data support that early bone formation after initiating treatment with teriparatide is not dependent on antecedent increases in bone resorption. (10, 16, 29) N-telopeptide, a marker for bone resorption, showed a delayed increase and peaked by 12 months after treatment with TPTD40 plus HRT. However, the patients receiving HRT alone showed a slight decrease up to 6 months and returned to baseline by 12 months of treatment. These data on bone turnover markers indicate that teriparatide is stimulating bone formation outside of the normal remodeling cycle, and HRT has an opposite effect. HRT treatment reduces bone resorption through the regulation of osteoclast cell number by inhibition of cytokine synthesis. (19) On the other hand, teriparatide can stimulate bone formation and increase BMD, even with the bone formation- and resorption-depressing effects of HRT. In contrast, bisphosphonates, but not raloxifene, seem to prevent teriparatide from maximally increasing bone formation and BMD in both animal(30, 31) and human studies. (32) Although this study did not include a teriparatide-only arm, the magnitude of the BMD response is similar to that observed with monotherapy, and neither estrogen nor raloxifene seem to reduce the maximal bone formation response to teriparatide.

This study evaluated the overall safety of combined TPTD40 plus HRT treatment compared with HRT alone. In general, both treatments were well tolerated, with few TEAEs, of which some were significantly different between the two treatment groups. Nausea and leg cramps were reported more frequently in the patients receiving combination therapy.

The BMD and bone marker results in the HRT-pretreated and HRT-naïve subgroups are interesting in two respects. First, regardless of pretreatment status, teriparatide plus HRT significantly increased bone formation and resorption and BMD compared with HRT alone. Second, the differential influence of pretreatment status on BMD and bone turnover markers provides some insights into the tight coupling of bone formation and resorption and the difficulties in trying to project the results of combination treatment on BMD based on bone markers. In patients pretreated with HRT, and at a new equilibrium of bone formation and resorption as shown by the stability of BSALP, N-telopeptide, and BMD in the HRT-only arm after randomization, the effects of adding teriparatide to HRT on bone markers and BMD are similar to those reported for teriparatide in placebo-controlled studies. (15, 16, 18, 32)

In conclusion, in postmenopausal women with low bone mass or osteoporosis, the data provide evidence that the adverse event profile for combination therapy with teriparatide + HRT together is consistent with that expected for each treatment alone and that the BMD response at lumbar spine, total hip, and femoral neck is greater than for HRT alone. Furthermore, teriparatide + HRT significantly increased BMD at these sites compared with HRT alone both in patients pretreated with HRT and those not pretreated with HRT.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References

This study was sponsored and supported by Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA. The authors thank the following investigators who participated in the study: Canada: Drs AB Cranney, R Kremer, WP Olszynski; Mexico: Drs S Jasqui-Romano, JE Santos; South Africa: Dr F Grobler; United States: Dr P Mease. We also thank Mary Ellen Perron for preparing the figures.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. References
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