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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2489
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4644-4649
Copyright © 2005 by The Endocrine Society

Bone Mineral and Collagen Quality in Iliac Crest Biopsies of Patients Given Teriparatide: New Results from the Fracture Prevention Trial

Eleftherios P. Paschalis, Emmett V. Glass, David W. Donley and Erik F. Eriksen

Mineralized Tissue Section (E.P.P.), Research Division, The Hospital for Special Surgery, New York, New York 10021; and Eli Lilly and Co. (E.V.G., D.W.D., E.F.E.), Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Dr. Emmett Glass, Eli Lilly and Co., Lilly Corporate Center, Drop code 6134, Indianapolis, Indiana 46285. E-mail: glassem{at}lilly.com.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Evidence suggests that both bone mineral density and bone quality should be taken into account when assessing bone strength and fracture risk. Bone quality is a multifactor entity, of which bone architecture and material properties are two important components. Matrix mineralization, hydroxyapatite characteristics, and collagen cross-link ratio are key determinants of material properties. Fourier transform infrared imaging (FTIRI) yields data on these characteristics from bone sections.

Objective: We sought to determine collagen cross-link ratios and matrix mineralization of bone from patients randomized to teriparatide [recombinant human PTH (1–34)] treatment using FTIRI.

Design: The Fracture Prevention Trial was randomized, double blind, and placebo-controlled.

Setting: The trial was conducted at global clinical research centers.

Patients: Patients consisted of postmenopausal women with osteoporosis.

Interventions: Patients were randomized to receive daily sc injections of placebo (n = 12) or 20 µg (n = 13) or 40 µg (n = 13) teriparatide. Biopsies were obtained after 12 months of treatment or at the end of treatment (range, 19–24 months for end of treatment paired biopsies).

Main Outcome Measures: Biopsies were analyzed by FTIRI to determine the matrix mineralization (mineral to matrix), mineral crystallinity, and collagen cross-link ratio (pyridinoline/dehydrodihydroxylysinonorleucine) with a spatial resolution of approximately 6.3 µm.

Results: Patients administered teriparatide 20 and 40 µg/d exhibited significantly lower matrix mineralization, mineral crystallinity, and collagen cross-link ratio when compared with placebo.

Conclusions: These findings indicate that the bone-forming effect of teriparatide results in bone with a molecular profile reminiscent of younger bone.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS IS AN increasing public health problem. Treatment therapies include estrogens, selective estrogen-receptor modulators, vitamin D, calcitonin, calcitriol, and bisphosphonates (1). The purpose of all these therapies is to restore bone mineral density (BMD) and diminish fracture risk associated with osteoporosis.

PTH stimulates bone formation and bone turnover, resulting in increased bone mass and strength. In a recent study, teriparatide [recombinant human PTH(1–34)] treatment of ovariectomized monkeys for up to 18 months significantly increased whole-body bone mineral content, bone mass of the spine, long bones, and femoral neck as well as structural (extrinsic) mechanical properties at the spine and hip (2, 3, 4). Fourier transform infrared imaging (FTIRI) analysis of thin tissue sections obtained from this study showed that PTH administration resulted in bone with a lower degree of mineralization, reduced mineral crystallinity, and collagen cross-link ratio [pyridinoline (pyr)/dehydrodihydroxylysinonorleucine (deH-DHLNL)], compared with control animals (5).

In a recent large clinical trial of postmenopausal women with prior vertebral fractures, daily sc injections of teriparatide, for a median of 18 months, decreased the risk of both vertebral and nonvertebral fractures and increased vertebral, femoral, and total-body BMD (1). The BMD increase was dose dependent, whereas the decrease in fracture risk was not (1). The purpose of the present study was to evaluate material properties of human bone treated with teriparatide by FTIRI. We used undecalcified thin tissue sections of iliac crest biopsies obtained as part of the previously reported clinical trial (1). For the purposes of this paper, material properties determined by FTIRI were defined as matrix mineralization, mineral crystallinity, crystallite size in the c-crystallographic axis, and the ratio of two of the major mineralizing tissue collagen cross-links (pyr/deH-DHLNL).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The protocol and procedures employed in the clinical trial were reported previously (1). Briefly, women were eligible for enrollment if they were ambulatory, at least 5 yr had passed since menopause, and they had at least one moderate or two mild atraumatic vertebral fractures of the thoracic and lumbar spine. If fewer than two moderate fractures were evident, hip or lumbar spine BMD had to be at least 1 SD below the mean value in normal premenopausal white women for enrollment. A total of 1637 participants were randomly assigned to receive daily sc injections of placebo, teriparatide 20 µg, or teriparatide 40 µg. Patients who consented to the biopsy investigation provided a transiliac crest bone biopsy at baseline and were randomly assigned to provide a follow-up biopsy from the contralateral iliac crest after either 12 months of treatment or at study end point. The study methods and procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. Institutional review board approval was obtained at all study sites, and written informed consent was obtained from each patient.

Specimens

A total of 102 patients consented to the biopsy investigation, and 61 patients provided paired transiliac crest bone specimens: 21 (eight placebo; seven teriparatide 20 µg; six teriparatide 40 µg) at 12 months and 40 (16 placebo; 14 teriparatide 20 µg; 10 teriparatide 40 µg) at study end point. From among these 61 patients, methyl methacrylate-embedded, undecalcified, thin tissue sections (~5 µm) were selected from 15 patients per treatment group for FTIRI analysis. Selection of tissue sections for FTIRI analysis was performed without the aid of a randomization technique, knowledge of the biopsy date, or knowledge of other biopsy parameters. Seven of the 45 specimens selected for FTIRI analysis were damaged during transport and were excluded from analyses. Hence, 38 patients were included in the analysis: 14 (four placebo; four teriparatide 20 µg; six teriparatide 40 µg) at 12 months (range, 11–14 months) and 24 (eight placebo; nine teriparatide 20 µg; seven teriparatide 40 µg) at study end point (range, 19–24 months). The tissue sections were placed between two BaF2 FTIRI windows.

FTIRI

Spectral images were acquired by a FTIR microspectroscopy system (Sting Ray, Bio-Rad Laboratories, Cambridge, MA.), consisting of a step-scan interferometer interfaced to a mercury-cadmium-telluride focal plane array detector imaged onto the focal plane of an infrared microscope. Interferograms were simultaneously collected from each element of the 64 x 64 array to provide 4096 spectra (~4 min scan time) at a spectral resolution of 8 cm–1. At each step of the interferometer, signals from each element were examined 81 times to provide signal averaging. The (square) sample size imaged (400 µm x 400 µm) correlated to an optimal spatial resolution of approximately 6.3 µm x 6.3 µm. Background imaging spectra were collected under identical conditions from the same BaF2 windows. The spectrometer was left continuously on to minimize warm-up instabilities and purged with dry air to minimize water vapor and CO2 interference employing a dry-air pump (Whatman Analytical Gas Systems, Scotch Plains, NJ) (6).

After acquisition, spectra were transferred off line and zero corrected for the baseline in the spectral areas of Amide I (~1590–1700 cm–1) and v1,v3 PO4 (~900–1200 cm–1) using Grams/32 (Thermo Galactic Software, Woburn, MA). Parameters calculated were: 1) mineral to matrix (ratio of integrated areas of Amide I and v1,v3 PO4 bands; 2) mineral crystal maturity (crystallite size in the c-crystallographic axis, stoichiometry), expressed as absorbance ratio at two specific wavelengths (1030 and 1020 cm–1) (6, 7); and 3) relative ratio of pyridinoline and deH-DHLNL collagen cross-links, expressed as the absorbance ratio at two specific wavelengths (1660 and 1690 cm–1) (8). Technical characteristics pertaining to parameters such as signal to noise ratio have been published elsewhere (9). Details for the spectral processing methods and reproducibility of measurements (correlation coefficient R2 = 0.973) have been published elsewhere (6, 8). We previously performed this type of analysis in iliac crest biopsies from early postmenopausal women treated with hormonal replacement therapy (10) and in an ovariectomized animal model that was treated with PTH (5) in bone areas devoid of resorption (as evidenced by the absence of resorption pits/perforations). So that the results of the present study may be comparable, similar areas were selected. Three areas in the cortical periosteal and endosteal regions and three trabeculae were surveyed for each biopsy, and resulting values were averaged. Each field of analysis was 400 x 400 µm2. Results were expressed as color-coded images (using the same scale for all data; Origin 6.0, Microcal Software, Northampton, MA). In the spectral images, pixels devoid of bone (no mineral and/or matrix spectral signature) were set equal to zero and excluded from calculations.

Statistical methods

To adjust for the timing of the biopsy, the mineral to matrix, mineral crystallinity, and collagen cross-linking ratio for the periosteal, endosteal, and trabecular regions were regressed separately on the months elapsed from randomization until biopsy collection. The residuals from the fitted model were then analyzed using Wilcoxon’s rank sum test to perform pairwise comparisons from among the three treatment groups. All analyses were performed using SAS statistical software (version 8; SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Baseline characteristics of patients included in FTIRI analyses are in Table 1Go. Patients included in the FTIRI analysis had similar baseline characteristics across study groups. Figure 1Go shows representative results of the FTIRI analysis in the areas of periosteal (Fig. 1AGo), endosteal (Fig. 1BGo), and trabecular bone (Fig. 1CGo). In each, the top row is from a section from the placebo group, whereas the bottom from the teriparatide 20 µg group. The first column in Fig. 1Go is a photomicrograph obtained from the digital camera attached to the FTIRI instrument, the second column the calculated spatial distribution of mineral crystallinity, and the third column the calculated spatial variation of the pyr/deH-DHLNL. In all calculated images, blue is minimum, and red is maximum. When interpreting the color images, it should be kept in mind that the spectroscopically determined change in both the mineral maturity/crystallinity and collagen cross-links ratio are not in a linear relationship with the actual physical change, but an exponential decay relationship (6, 7, 8). There were statistically significant differences in material properties between the teriparatide-treated patients and the patients that received placebo. The results are summarized in Table 2Go.


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  		TABLE 1. Baseline characteristics for patients included in FTIRI analyses

 


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  		FIG. 1. FTIRI of bone after treatment with teriparatide: periosteal (A), endosteal (B), and trabecular (C). The x- and y-axes are labeled with row and column numbers of the detector corresponding to a spatial resolution of 400 µm x 400 µm (~6.3 µm x 6.3 µm per pixel). The color coding used to generate the spectroscopic images is identical and indicated to the right of trabecular images. Blue is minimum, and red is maximum.

 


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  		FIG. 1C. Continued

 

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  		TABLE 2. Summary of comparisons of the mineral crystallinity, collagen cross-links ratio (pyr/deH-DHLNL), and matrix mineralization measures between the teriparatide-treated and placebo groups

 
Patients treated with teriparatide exhibited significantly lower values than patients treated with placebo in mineral crystallinity and matrix mineralization (mineral to matrix) at all anatomical locations analyzed (periosteal, endosteal, and trabecular). Collagen cross-linking properties as reflected in the collagen cross-link ratio (pyr to deH-DHLNL) showed a shift toward more divalent cross-links in bone matrix in teriparatide-treated patients.


   Discussion
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The critical factors contributing to the fragility of bone in osteoporosis are still being defined. Loss of BMD is an important feature related to osteoporotic fractures, accounting for a significant portion of osteoporotic fracture risk (11, 12, 13). Furthermore, BMD has been shown to correlate significantly with bone strength (14, 15). On the other hand, BMD alone does not determine whether an individual will sustain a fracture (16). This evidence supports the use of additional factors in assessing fracture risk. Therefore, in addition to BMD, factors such as geometry and bone mass distribution, trabecular bone microarchitecture, microdamage, and/or increased remodeling activity, genetics, body size, environmental factors, and changes in bone matrix properties should also be taken into account (17) when assessing fracture risk.

Two key components of bone matrix properties are matrix mineralization and collagen properties. Extreme deviations in matrix mineralization have been shown to affect the material properties of bone (18). Both too small and too high mineral to matrix ratios exert negative effects on bone strength (19). Whether smaller deviations have any effects on bone still remains to be established.

Using techniques such as small-angle x-ray scattering, quantitative backscattered electron imaging, and Fourier transform infrared microspectroscopy and FTIRI, the analysis of bone mineral (poorly crystalline hydroxyapatite) at the microscopic level and the contribution of mineral crystallinity (crystallite size) and maturity (shape, volume) to bone strength is being actively pursued (5, 10, 20, 21, 22, 23, 24, 25, 26, 27). Based on such studies, models for the importance of mineral crystallite shape and size in determining bone strength have been put forth (28, 29). Moreover, studies involving fluoride-treated bone strongly suggest a prominent role in determining mechanical properties (21).

Considerably less attention has been directed at collagen, although there are several publications in the literature reporting altered collagen properties associated with fragile bone in both animals and humans (30, 31, 32, 33, 34). The collagen molecule is secreted by the cell as its precursor form, procollagen. The collagen molecule is generated outside the cell by enzymatic cleavages at both the C- and the N-terminal ends of the procollagen molecule (35, 36, 37). The important intracellular modifications of procollagen polypeptide chains include hydroxylation of specific lysyl and prolyl residues and the glycosylation of specific hydroxylysine residues. Outside the cell, the procollagen molecule is further processed by cleavages of both N- and C-terminal propeptide extensions to form a collagen molecule. Although type I collagen is the most ubiquitous protein in the body’s various connective tissues, the chemistry varies from tissue to tissue because of posttranslational modifications (38). The intermolecular cross-linking provides the fibrillar matrices with various mechanical properties such as tensile strength and viscoelasticity. All the known cross-links of type I collagen are condensation products between the prosthetic groups of juxtaposed specific peptidyl residues of lysine, hydroxylysine, and histidine. The process of cross-linking is initiated by the enzymatic oxidative deamination by lysyl oxidase of {epsilon}-amino groups on specific peptidyl lysine and hydroxylysine to aldehyde. The aldehydes formed then undergo a series of condensation reactions to form complex intra and intermolecular cross-links in the fibril. The minimum divalent intermolecular cross-links seem to be the first to form and then mature into more complex multivalent cross-links. Because cross-link condensation reactions, except for the initial oxidation step, are spontaneous, turnover rate is an important factor in regulating cross-link maturation (38).

In summary, there is an abundance of divalent cross-links in freshly synthesized collagen (young tissue age), whereas older bone tissue collagen contains an abundance of trivalent cross-links. It is widely accepted that collagen plays a significant role in determining bone fracture risk (39, 40). Although the precise relationship between collagen cross-links and bone biomechanical properties remains under investigation, increased amounts of reducible deH-DHLNL cross-links have been associated with decreased fracture load and offset yield load (33), whereas pyridinoline cross-links have been reported to enhance bone toughness (40).

The present study demonstrates that bone matrix from patients treated with teriparatide exhibits significantly different molecular properties, compared with patients who received placebo. Matrix mineralization, mineral crystallinity, and collagen cross-link ratio values were significantly lower in patients treated with teriparatide 20 µg or 40 µg, compared with placebo patients at periosteal and endosteal cortical surfaces as well as trabecular bone surfaces. These data are consistent with prior results in which PTH administration increased bone turnover, which in turn results in a reduction of mean tissue age (thus the observed decrease in all three outcomes monitored in the present study). They are also in agreement with our previously reported studies involving the FTIRI analysis of bone mineral and collagen quality in humeri of ovariectomized cynomolgus monkeys given recombinant human PTH(1–34) for 18 months (5) as well as published reports describing the teriparatide effect on bone quality (different outcomes) in human iliac crest biopsies (22). Although values for both teriparatide 20 µg and teriparatide 40 µg treatment groups were different, compared with placebo, they were generally not different among themselves. This correlates with the previously reported finding that the teriparatide 20 µg and teriparatide 40 µg groups had similar effects on the risk of fracture (1).

In conclusion, decreases in matrix mineralization, mineral crystallinity, and collagen cross-link ratio related to bone matrix and bone mineral exemplifies the bone-forming action of teriparatide. Therapeutically, teriparatide stimulates the deposition of new, not yet fully mineralized bone, with a cross-linking pattern consistent with that encountered in younger tissue (i.e. more divalent cross-links). Apart from the pronounced improvements in bone architecture previously demonstrated after treatment with teriparatide, the current study demonstrates that newly formed bone in response to teriparatide treatment displays mineral and collagen quality characteristics routinely encountered in younger bone (7, 38, 41, 42).


   Acknowledgments
 
The authors are grateful to Janelle Brentlinger for assistance in data handling.


   Footnotes
 
This work was supported by funding from Lilly Research Laboratories.

This work was presented in part at the first joint meeting of the International Bone and Mineral Society and Japanese Society for Bone and Mineral Research in Osaka, Japan, June 3–7, 2003.

Current address for E.P.P.: Ludwig Boltzmann Institute for Osteology, 4th Medical Department, Hanusch-KH and UKH-Meidling, Vienna, Austria.

First Published Online May 24, 2005

Abbreviations: BMD, Bone mineral density; deH-DHLNL, dehydrodihydroxylysinonorleucine; FTIRI, Fourier transform infrared imaging; pyr, pyridinoline.

Received December 17, 2004.

Accepted May 17, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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