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Keywords:

  • parathyroid hormone;
  • cortical bone;
  • osteoporosis;
  • moment of inertia;
  • peripheral quantitative computed tomography

Abstract

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

Treatment with teriparatide (rDNA origin) injection {teriparatide, recombinant human parathyroid hormone (1–34) [rhPTH(1–34)]}reduces the risk of vertebral and nonvertebral fragility fractures and increases cancellous bone mineral density in postmenopausal women with osteoporosis, but its effects on cortical bone are less well established. This cross-sectional study assessed parameters of cortical bone quality by peripheral quantitative computed tomography (pQCT) in the nondominant distal radius of 101 postmenopausal women with osteoporosis who were randomly allocated to once-daily, self-administered subcutaneous injections of placebo (n = 35) or teriparatide 20 μg (n = 38) or 40 μg (n = 28). We obtained measurements of moments of inertia, bone circumferences, bone mineral content, and bone area after a median of 18 months of treatment. The results were adjusted for age, height, and weight. Compared with placebo, patients treated with teriparatide 40 μg had significantly higher total bone mineral content, total and cortical bone areas, periosteal and endocortical circumferences, and axial and polar cross-sectional moments of inertia. Total bone mineral content, total and cortical bone areas, periosteal circumference, and polar cross-sectional moment of inertia were also significantly higher in the patients treated with teriparatide 20 μg compared with placebo. There were no differences in total bone mineral density, cortical thickness, cortical bone mineral density, or cortical bone mineral content among groups. In summary, once-daily administration of teriparatide induced beneficial changes in the structural architecture of the distal radial diaphysis consistent with increased mechanical strength without adverse effects on total bone mineral density or cortical bone mineral content.


INTRODUCTION

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

THE SKELETAL EFFECTS of human parathyroid hormone (1-34) [hPTH(1-34)] have been studied for more than 25 years.(1) The results of early small observational and controlled clinical trials recently reviewed by Rubin et al.(2) confirmed the anabolic effects of hPTH(1-34) on cancellous bone, but the effects on cortical bone mass were variable. Clinical findings with hPTH(1-34) treatment have included a decrease in cortical bone mineral density (BMD), little change in the distal radius or femoral neck, or only small increments in BMD of the femoral neck or whole body.(2) Such results raised doubts that treatment with hPTH(1-34) could reduce the risk of nonvertebral fractures, a major source of morbidity and mortality in patients with osteoporosis.(3)

In an international fracture prevention trial, postmenopausal women with prevalent vertebral fracture(s) were randomized to once-daily treatment with teriparatide for up to 2 years.(4) Compared with placebo, teriparatide significantly reduced the risk of vertebral fractures by 65-69% and nonvertebral fragility fractures by 53-54%. These outcomes strongly suggested that women treated with teriparatide have improvement in both cancellous and cortical bone compartments.

In animals, beneficial effects of treatment with either hPTH(1-34) or teriparatide on geometric or structural properties of cortical bone have been found consistently by histomorphometry and biomechanical testing.(5,6) Peripheral quantitative computed tomography (pQCT), an alternative to invasive measures of bone quality, is capable of assessing bone structure in vivo and assessing cancellous and cortical bone effects separately.(7) Moreover, pQCT bypasses several significant limitations of more commonly used DXA measurements of BMD.

In the teriparatide fracture prevention trial, pQCT scans were obtained in a subgroup of patients to explore the effects of teriparatide treatment on bone properties relevant to bone strength. We present results that help to clarify the effects of teriparatide on the structural architecture of human cortical bone.

MATERIALS AND METHODS

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

Study subjects

This study was performed in a subgroup of 101 patients from a single clinical site who were enrolled in a multicenter international fracture prevention trial that included 1637 postmenopausal women with prior vertebral fractures to evaluate the effects of teriparatide on the risk of new vertebral and nonvertebral fragility fractures. The fracture incidence and DXA BMD results of this study have been published.(4) Briefly, ambulatory women, 5 years or more postmenopausal, with at least one moderate or two mild vertebral fractures were included. Women with fewer than two moderate fractures were required to also have hip or spine BMD at least 1 SD below the mean for healthy young women (T score ≤ −1.0). Dietary intake of calcium was determined by questionnaire. Patients received 1000 mg calcium and 400 IU vitamin D orally and were randomly allocated to once-daily, self-administered subcutaneous injections of placebo (n = 35) or of teriparatide 20 μg (TPTD20, n = 38) or 40 μg (TPTD40, n = 28). The study was approved by an independent Ethics Committee. All patients gave written informed consent to participate.

pQCT measurements

Measurements were performed at the nondominant forearm, after a median of 18 months exposure to treatment, using a Stratec XCT 960 pQCT machine (Stratec Medizintechnik GmbH, Pforzheim, Germany) with an X-ray tube (38.5 kV) radiation source. A single tomographic slice of 2.5 mm was taken at a site corresponding to 15% of the length of the ulna proximal to the radius distal end. Typically, this site contains less than 10% trabecular bone, and the bone mineral content (BMC) remains fairly constant along 10-90% of the radius length.(8) Furthermore, measures of cortical BMC and area at the 15% site (mid-distal radius) are the best predictors of the load needed to cause a fracture,(9) making this site preferable for measurement of cortical bone properties.

pQCT testing at the 15% site was conducted in a subset of the 144 patients (48 per group) randomized to treatment at the clinical site. Of the 118 women who consented to the pQCT testing, usable scans were obtained from 101 women, and the results are reported here. Movement artifact rendered 17 scans of unacceptable quality for data analysis. Scans were performed by an operator blinded to treatment assignment and sent to a blinded independent central reading facility for quality control and analysis. Image processing and the calculation of numerical values were performed using the Stratec software version 5.10. The cortical region was defined using an iterative contour-detection procedure wherein the threshold attenuation coefficient is set automatically by the algorithm. We obtained direct measurements of cortical thickness and inner and outer circumference. We then calculated the axial and polar second moments of inertia of the cross-sectional cortical bone area as the integral sum of products of voxel areas of cortical bone region and the square of the distance from each voxel to the reference axis. The short-term in vivo coefficients of variation calculated as root mean square CV (CVrms) of duplicate measurements were 2-3%, depending on the parameter measured.

Statistical analysis

We evaluated differences among groups by ANOVA and pairwise comparisons using Fisher's protected least significant difference. Adjusted data for the pooled teriparatide-treated groups were fitted to the log of the moments of inertia versus cortical BMC. Using the last nonmissing value for each patient, moments of inertia, circumferences, BMC, and bone area were adjusted for body height, weight, and age based on the work of Schneider et al.(10) All tests of hypotheses were conducted at a two-tailed α level of 0.05. Statistical analyses were performed using SAS (version 8.02; SAS Inc., Cary, NC, USA).

RESULTS

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

There were no significant differences among groups at baseline in demographic variables (Table 1). There were no differences among groups in the pQCT scans that were of unacceptable quality, all because of movement artifact (placebo, 9; TPTD20, 3; TPTD40, 5; p = 0.155). At the 15% distal radius site, there were significant increases in total BMC and total bone area for the TPTD20 and TPTD40 groups compared with placebo (Table 2), with no significant treatment effect for total bone density. Cortical bone area was 5% higher in the TPTD20 group (p = 0.005) and 7% higher in the TPTD40 group (p < 0.001) compared with placebo (Table 2). Cortical BMC was 6% and 4% higher in the TPTD20 and TPTD40 groups, respectively, compared with placebo, but the changes did not reach statistical significance (p = 0.054; Table 2). There was a trend toward lower cortical bone density in the TPTD40 group compared with placebo (Table 2). Notably, the thickness of the cortical bone was essentially the same in the teriparatide and placebo groups (Table 2).

Table Table 1.. Baseline Demographic Characteristics of Patients
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Table Table 2.. pQCT Parameters at the 15% Distal Radius Site After a Median 18 Months of Treatment
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Periosteal and endocortical circumferences were 5% and 9% higher, respectively, in the TPTD40 group when compared with placebo (Figs. 1A and 1B; p < 0.001). Periosteal circumference in the TPTD20 group was significantly higher than placebo (p = 0.005; Fig. 1A).

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Figure FIG. 1.. Cortical bone parameters assessed by pQCT at the 15% proximal radius site, adjusted for body height, weight, and age (mean and 95% confidence intervals). (A) Periosteal circumference. *TPTD20 vs. placebo, p = 0.005;TPTD40 vs. placebo, p < 0.001. (B) Endocortical circumference.TPTD40 vs. placebo, p < 0.001. (C) Axial moment of inertia.TPTD40 vs. placebo, p < 0.001. (D) Polar moment of inertia.TPTD20 and TPTD40 vs. placebo, p < 0.001.

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Both teriparatide-treated groups had significantly higher values of polar cross-sectional moment of inertia (9% and 21% for TPTD20 and TPTD40, respectively) compared with placebo (p < 0.001; Fig. 1D). The TPTD40 group also had 16% higher (p < 0.0001) axial cross-sectional moment of inertia compared with placebo (Fig. 1C). Because BMC has been considered a surrogate for biomechanical bone quality, we evaluated its relationship with polar moment of inertia. The pooled teriparatide-treated patients had a better distribution on average of cortical bone, represented by the adjusted mean polar moment of inertia, at any level of BMC compared with placebo (p < 0.001; Fig. 2).

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Figure FIG. 2.. Teriparatide effects on the relationship between the polar moment of inertia and the cortical bone mineral content. Bivariate fit of adjusted polar moment of inertia by adjusted cortical bone mineral content at the 15% distal radius site. Teriparatide-treated groups are pooled. TPTD vs. placebo, p < 0.001

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DISCUSSION

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

This cross-sectional study at a predominantly cortical bone site suggests that treatment with teriparatide induced periosteal mineral apposition and increased endocortical bone resorption. The net results were an improvement in bone geometry, reflected by higher axial and polar cross-sectional moments of inertia. From a biomechanical perspective, these changes in cortical bone geometry predict that treatment with teriparatide should be associated with an increase in bone strength and improved resistance to fracture.(11) This is consistent with the significant reduction in occurrence of nonvertebral fractures and a numerical decrease in frequency of wrist fractures observed in the fracture prevention trial.(4)

The axial and polar moments of inertia are architectural indicators of the bone's resistance to bending and torsional loading, respectively. Augat et al.(9) found that the geometric properties of the distal radius were highly correlated with the fracture load at the same site and were also correlated with fracture load of the femoral neck. The higher moments of inertia found in the teriparatide-treated groups should predict a reduced risk of fracture at both the distal radius and proximal femur, sites associated with osteoporotic fractures.

Schneider et al.(10) evaluated pQCT cortical bone parameters at a more distal (4%) radius site, and adjusted for body height, weight, and age to determine which measurements might best discriminate between women who have suffered Colles fractures while performing usual activities and women who have not suffered from fractures. Cortical bone content and area and axial and polar moments of inertia were significantly higher in women who had not suffered a Colles fracture compared with women who had. The investigators identified these parameters as relevant to fracture risk, whereas cortical bone density was not. We identified cross-sectional group differences or strong favorable trends in cortical bone architecture between the teriparatide and placebo treatment groups. Specifically, the improvements in cortical bone area, mineral content, periosteal and endocortical circumferences, and axial and polar moments of inertia parallel the discriminating factors found by Schneider et al.(10) Our findings suggest a positive effect on bone strength in the radial shaft of women treated with teriparatide, and contrast with the conclusions of a recent study that found no change in bone strength parameters at the radial shaft in patients with osteoporosis treated with alendronate.(12)

BMD by DXA is the accepted surrogate for the clinical estimation of bone mass, but this technique has several important shortcomings. For example, only a two-dimensional assessment of the skeleton is obtained, spatial resolution is low, the geometry of most bones cannot be evaluated with routine analysis, and an apparent or areal bone density is measured.(13) In the fracture prevention trial with teriparatide,(4) DXA BMD values at the one-third distal radius decreased in women treated with TPTD40. In contrast, there were significant increases in lumbar spine and hip bone density and in total body bone mineral observed in patients treated with TPTD20 or TPTD40.(4) The volumetric analysis of cancellous and cortical bone compartments at the slightly more distal radius site evaluated by pQCT in the present report suggests that treatment with teriparatide resulted in significant and potentially important increments in BMC and area. The discrepancy between these findings and the radius DXA measurements is most likely explained by methodological differences and the significant increases in periosteal circumference observed in patients treated with teriparatide, not by important anatomical differences between the adjacent sites.

A limitation of the present study is its cross-sectional design. Nevertheless, the cortical bone parameters in women treated with teriparatide are in agreement with cortical bone data from rabbit and monkey, species that also exhibit haversian remodeling.(5,6) Teriparatide increased periosteal and endocortical apposition, intracortical bone remodeling and porosity, which was accompanied by significant increases in the mechanical properties of ultimate force, stiffness, and work to failure.(6) Increased cortical porosity in rabbit and monkey does not adversely affect bone mechanical properties because the increases occur primarily along the endocortical surface and are offset by apposition onto endocortical and periosteal surfaces, resulting in larger moments of inertia and increased bone strength.(5,11)

Cortical bone quality is a function of material properties and structural architecture.(11) The favorable changes in the distribution or structural geometry of nonvertebral cortical bone produced by once-daily administration of teriparatide are consistent with theoretical improvements in skeletal mechanical strength and with the reductions in fracture incidence that were observed in the teriparatide fracture prevention trial.(4,11)

Acknowledgements

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

We thank Leonardo Muinios and Alejandro Mango for technical assistance in obtaining the pQCT measurements, and Mary E Perron for the preparation of the illustrations and editorial assistance with the manuscript. This work was supported by Eli Lilly and Company, Indianapolis, IN.

REFERENCES

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