Effects of alendronate and risedronate on bone material properties in actively forming trabecular bone surfaces

We used Raman and Fourier transform infrared microspectroscopy (FTIRM) analysis to examine the intrinsic bone material properties at actively bone-forming trabecular surfaces in iliac crest biopsies from women with postmenopausal osteoporosis (PMO) who were treated with either alendronate (ALN) or risedronate (RIS). At eight study sites, women were identified who had postmenopausal osteoporosis (PMO), were at least 5 years postmenopause, and had been on long-term therapy (either 3-5 years or >5 years) with daily or weekly ALN or RIS. Following standard tetracycline labeling, biopsies were collected from 102 women (33 treated with ALN for 3-5 years [ALN-3], 35 with ALN for >5 years [ALN-5], 26 with RIS for 3-5 years [RIS-3], and 8 with RIS for >5 years [RIS-5]) and were analyzed at anatomical areas of similar tissue age in bone-forming areas (within the fluorescent double labels). The following outcomes were monitored and reported: mineral to matrix ratio (corresponding to ash weight), relative proteoglycan content (regulating mineralization commencement), mineral maturity (indicative of the mineral crystallite chemistry and stoichiometry, and having a direct bearing on crystallite shape and size), and the ratio of two of the major enzymatic collagen cross-links (pyridinoline/divalent). In RIS-5 there was a significant decrease in the relative proteoglycan content (-5.83% compared to ALN-5), while in both RIS-3 and RIS-5 there was significantly lower mineral maturity/crystallinity (-6.78% and -13.68% versus ALN-3 and ALN-5, respectively), and pyridinoline/divalent collagen cross-link ratio (-23.09% and -41.85% versus ALN-3 and ALN-5, respectively). The results of the present study indicate that ALN and RIS exert differential effects on the intrinsic bone material properties at actively bone-forming trabecular surfaces.     

Bone quality of the newest bone formed after two years of teriparatide therapy in patients who were previously treatment-naïve or on long-term alendronate therapy

Summary

The results of the present study, involving analysis of biopsies from patients who received teriparatide for 2 years and were previously either treatment-naïve or on long-term alendronate therapy, suggest that prior alendronate use does not blunt the favorable effects of teriparatide on bone quality.

Introduction

Examine the effect of 2 years of teriparatide (TPTD) treatment on mineral and organic matrix properties of the newest formed bone in patients who were previously treatment-naïve (TN) or on long-term alendronate (ALN) therapy.

Methods

Raman and Fourier transform infrared microspectroscopic analyses were used to determine the mineral/matrix (M/M) ratio, the relative proteoglycan (PG) content, and the mineral maturity/crystallinity (MMC; determined by three methods: carbonate content, full width at half height of the v ₁ PO₄ band [FWHH], and wavelength at maxima of the v ₁ PO₄ band), as well as collagen maturity (ratio of pyridinoline/divalent cross-links), in paired iliac crest biopsies at trabecular, endosteal, and osteonal surfaces of newly formed bone in postmenopausal osteoporotic women who were previously either TN (n?=?16) or receiving long-term ALN treatment (n?=?24).

Results

Trabecular M/M ratio increased and matrix content decreased significantly in the ALN pretreated group. Collagen maturity decreased in both patient groups. Endosteal M/M ratio increased significantly in the TN group. Trabecular M/M ratio was higher at endpoint in the ALN pretreated group than in the TN group. Overall, no changes from baseline were observed in PG content, except that PG content was higher in the ALN pretreated group than in the TN group at endosteal surfaces at endpoint. The ability of TPTD treatment to reduce MMC in both patient groups and at the different bone surfaces depended on the measurement tool (relative carbonate content or wavelength at maxima of the v ₁ PO₄ band). None of the changes in MMC were different between the two patient groups.

Conclusions

The results suggest some favorable impact of TPTD on bone mineral and organic matrix properties of in situ forming bone in terms of increased initial mineralization and decreased MMC and collagen maturity. Moreover, prior long-term ALN administration may have only limited influence on these properties in bone newly formed after 2 years of TPTD treatment.     

Bone material properties in trabecular bone from human iliac crest biopsies after 3- and 5-year treatment with risedronate.

Long-term effects of risedronate on bone mineral maturity/crystallinity and collagen cross-link ratio in triple iliac crest biopsies of osteoporotic women were evaluated. In this double-blinded study, 3- and 5-year treatment with risedronate arrested the tissue aging encountered in untreated osteoporosis and in osteoporosis treated with other antiresorptives. This effect may be contributing to risedronate's antifracture efficacy. INTRODUCTION: Risedronate is widely used in the treatment of osteoporosis. It reduces bone turnover, increases BMD, and decreases fracture risk. To date, there are no data available on the long-term effects of risedronate on bone material properties in humans. MATERIALS AND METHODS: Osteoporotic women enrolled in the VERT-NA trial received either risedronate (5 mg/day, orally) or placebo for up to 5 years. All subjects received calcium. They also received vitamin D supplementation if deficient at baseline. Triple iliac crest biopsies were collected from a subset of these subjects at baseline, 3 years, and 5 years. Mineral maturity/crystallinity and collagen cross-link ratio was measured in these biopsies using Fourier transform infrared imaging. RESULTS: Patients that received placebo exhibited increased mineral maturity/crystallinity and collagen cross-link ratio after 3 and 5 years compared with baseline values. On the contrary, patients that received risedronate retained baseline values in both bone material indices throughout. A more spatially detailed analysis revealed that this was achieved mainly through beneficial effects on active bone-forming areas. Surprisingly, patients that received risedronate achieved premenopausal values at bone-forming areas in both indices after 5 years of treatment. CONCLUSION: Long-term treatment with risedronate affects bone material properties (mineral maturity/crystallinity and collagen cross-link ratio) and arrests the tissue aging apparent in untreated osteoporosis. These changes at the material level of the bone matrix may contribute to risedronate's rapid and sustained antifracture efficacy in osteoporotic patients.     

Tissue mineralization is increased following 1-year treatment with high doses of bisphosphonates in dogs

Suppression of bone turnover using anti-resorptive agents such as bisphosphonates prevents bone loss but also may increase tissue mineralization. This may make the bone more prone to initiate microcracks. The objective of this study was to determine whether suppression of remodeling caused by treatment of dogs for 1 year with five times the clinical dose of either alendronate or risedronate is associated with increased tissue mineralization and whether it changes the nature of the mineral crystal. Thirty-five dogs were divided into three weight-matched groups and treated daily for 1 year with a subcutaneous injection of saline (CON, n = 12), oral risedronate (RIS, 0.5 mg/kg/day, n = 11), or oral alendronate (ALN, 1.0 mg/kg/day, n = 12). Density fractionation, peripheral quantitative computerized tomography (pQCT), and quantitative backscattered electron microscopy (qBSE) were used to evaluate changes in mineral content of bone tissue from the vertebrae or ribs. Infrared microspectroscopy (IR) and X-ray diffraction were used to assess the quality of the mineral and some aspects of collagen structure in the thoracic vertebrae and iliac crest. Following 12 months of treatment, there was a significant shift toward higher density bone in both ALN (P = 0.04) and RIS (P = 0.002) by density fractionation methods. IR, pQCT, and qBSE did not detect any significant differences in mineralization, probably because of their lower sensitivity and/or because of the smaller region of interest they sample. No significant differences were found in the maturity of the mineral crystals or in their length or size. We conclude that treatment for 1 year with high doses of bisphosphonates which suppress bone remodeling up to 90% increases tissue mineralization, but does not change the nature of the mineral crystal.     

Effects of teriparatide on serum calcium in postmenopausal women with osteoporosis previously treated with raloxifene or alendronate

SUMMARY: The effect of teriparatide (20 microg/day) on serum calcium was examined in postmenopausal women previously treated with alendronate or raloxifene. Women previously treated with alendronate or raloxifene who added teriparatide or switched to teriparatide did not have clinically meaningful increases in mean predose serum calcium. INTRODUCTION: The effects of a 6-month treatment with teriparatide (20 microg/day; rhPTH(1-34), TPTD) on serum calcium (Ca) was examined in a prospective study of postmenopausal women previously treated with alendronate (70 mg/week or 10 mg/day [ALN] or raloxifene 60 mg/d [RLX]) for > or =18 months. METHODS: Women continued their usual ALN or RLX during a 2-month antiresorptive phase. Women previously treated with ALN were randomized to add TPTD (n = 52) or switch to TPTD (n = 50) and women previously treated with RLX were randomized to add TPTD (n = 47) or switch to TPTD (n = 49). All were to take at least 500 mg/day of elemental Ca and 400-800 IU/day of vitamin D. RESULTS: Predose mean serum Ca did not significantly change in groups adding TPTD to either RLX or ALN treatment. In patients who switched from RLX or ALN to TPTD, mean serum Ca increased by 0.05 mmol/L and 0.04 mmol/L respectively. Only 1 patient had the predefined calcium endpoint of serum calcium > 2.76 mmol/L (11 mg/dL) at more than one visit. CONCLUSIONS: Women previously treated with ALN or RLX who added TPTD or switched to TPTD did not have clinically meaningful increases in mean predose serum Ca.     

Effects of Daily or Cyclic Teriparatide on Bone Formation in the Iliac Crest in Women on No Prior Therapy and in Women on Alendronate

There is little information on the effects of combination therapy for osteoporosis at the tissue level. Using quadruple tetracycline‐labeled bone biopsies, we have compared the bone formation response to teriparatide (TPTD) in treatment‐naïve subjects (Rx‐Naïve) and in subjects on prior and ongoing alendronate (ALN) treatment (ALN‐Rx). Three bone envelopes were analyzed: cancellous, endocortical, and intracortical. TPTD was given as a standard, continuous daily injection or as a cyclic regimen (3 months on daily TPTD, 3 months off, 3 months on daily TPTD). Subjects were biopsied at 7 weeks and at 7 months to allow comparison of the bone formation response to the first and second cycles of TPTD. Baseline values for dynamic bone formation indices were lower in ALN‐Rx than Rx‐Naïve subjects. Both Rx‐Naïve and ALN‐RX subjects responded to TPTD with significant increases in bone formation indices at both time points. With cyclic TPTD treatment, the first and second cycles of TPTD stimulated bone formation rate in the cancellous and endocortical envelopes to a similar extent in ALN‐Rx and Rx‐Naïve subjects. However, in Rx‐Naïve patients, bone formation rate (BFR/BS) was higher in patients receiving daily treatment compared with those receiving cyclic TPTD treatment in all three envelopes in the 7‐month biopsies. This suggests that the cyclic approach does not provide a skeletal benefit in treatment‐naive patients. In the 7‐month biopsies, cortical porosity was higher in the Rx‐Naïve group receiving daily TPTD than in all other groups. These data provide supporting evidence at the tissue level for previous biochemical and densitometric data suggesting that addition of either cyclic or daily TPTD to ongoing ALN treatment may be an effective approach for patients with severe osteoporosis already treated with ALN who remain at high risk of fracture. © 2016 American Society for Bone and Mineral Research.     

Bone mineral and collagen quality in humeri of ovariectomized cynomolgus monkeys given rhPTH(1-34) for 18 months.

A recent study of ovariectomized monkeys, treated with recombinant human parathyroid hormone (rhPTH)(1-34) at 1 or 5 mg/kg/day for 18 months or for 12 months followed by 6 months withdrawal from treatment, showed significant differences in the geometry and histomorphometry of cortical bone of the midshaft humerus. To determine the extent to which the rapid bone turnover and cortical porosity induced by rhPTH(1-34) in ovariectomized monkeys modified mineral content, mineral crystal maturity and collagen maturity (cross-link distribution) in the cortical periosteal and endosteal regions, cross-sections of the cortical bone of the mid-humerus, were examined using Fourier transform infrared imaging (FTIRI). FTIRI analyses demonstrated that rhPTH(1-34) altered bone mineral and collagen properties in a dose-dependent manner. Mineral crystal maturity and collagen cross-link ratio (pyridinoline/dehydro-dihydroxylysinonorleucine) on both endosteal and periosteal surfaces decreased relative to ovariectomized animals, consistent with new bone formation. These changes were partially sustained after withdrawal of the higher dose of rhPTH(1-34), suggesting a prolonged after-effect on bone properties for at least two bone remodeling cycles. In conclusion, treatment of ovariectomized monkeys with rhPTH(1-34) had significant effects on cortical bone mineral-to-matrix ratio, mineral crystal maturity, and collagen cross-link ratio. These were fully reversible when the 1-microg rhPTH(1-34) treatment was withdrawn, but only partially reversed when the 5-microg rhPTH(1-34) dose was withdrawn.     

Treatment of osteoporosis after alendronate or risedronate

Alendronate (ALN) and risedronate (RIS) are ideal as first-choice therapy options in the treatment of postmenopausal osteoporosis. What to do for patients who do not respond adequately to bisphosphonates has not been conclusively determined, but transitioning to other therapies should be considered. The aim of this article is to describe potential alternatives for patients switching from ALN or RIS to other therapies for osteoporosis. A systematic search of PubMed was conducted to find papers that evaluate the effects of switching therapies on fractures, bone mineral density (BMD), or bone turnover markers. Results from 11 studies that prospectively assessed treatment after ALN or RIS in women with postmenopausal osteoporosis were reviewed. All studies are of short duration (all 24 months or less) and assess the topic of transitioning therapy from ALN or RIS. None of the studies had the statistical power to assess fracture-reduction efficacy. Transitioning from ALN to zoledronic acid maintains therapeutic effects for 12 months. Switching to strontium ranelate, denosumab, or teriparatide causes further increases in BMD. Specifically, transitioning to teriparatide could be used for a limited time for select patients but needs to be followed up with anti-resorptive treatment to prevent a loss of the bone gained. There are only few studies—of short duration—that assess the topic of transitioning therapy from ALN or RIS, although this is a very frequent occurrence in clinical practice. This is especially true if the patient has not reached his/her therapy goal. Further long-term studies are needed.     

Bisphosphonates alter trabecular bone collagen cross-linking and isomerization in beagle dog vertebra

Summary Changes in organic matrix may contribute to the anti-fracture efficacy of anti-remodeling agents. Following one year of treatment in beagle dogs, bisphosphonates alter the organic matrix of vertebral trabecular bone, while raloxifene had no effect. These results show that pharmacological suppression of turnover alters the organic matrix component of bone. Introduction The collagen matrix contributes significantly to a bone’s fracture resistance yet the effects of anti-remodeling agents on collagen properties are unclear. The goal of this study was to assess changes in collagen cross-linking and isomerization following anti-remodeling treatment. Methods Skeletally mature female beagles were treated for one year with oral doses of vehicle (VEH), risedronate (RIS; 3 doses), alendronate (ALN; 3 doses), or raloxifene (RAL; 2 doses). The middle dose of RIS and ALN and the lower dose of RAL approximate doses used for treatment of post menopausal osteoporosis. Vertebral trabecular bone matrix was assessed for collagen isomerization (ratio of α/β C-telopeptide [CTX]), enzymatic (pyridinoline [PYD] and deoxypyridinoline [DPD]), and non-enzymatic (pentosidine [PEN]) cross-links. Results All doses of both RIS and ALN increased PEN (+34–58%) and the ratio of PYD/DPD (+14–26%), and decreased the ratio of α/β CTX (−29–56%) compared to VEH. RAL did not alter any collagen parameters. Bone turnover rate was significantly correlated to PEN (R = −0.664), α/β CTX (R = 0.586), and PYD/DPD (R = −0.470). Conclusions Bisphosphonate treatment significantly alters properties of bone collagen suggesting a contribution of the organic matrix to the anti-fracture efficacy of this drug class.     

Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density

During teriparatide (TPTD) treatment, high levels of bone formation are accompanied by an increase in bone resorption. The aim of this work was to test if coadministration of raloxifene (RAL) or alendronate (ALN) following 9 months of ongoing TPTD therapy would reopen the anabolic window, thereby exerting additional benefit on bone mineral density (BMD). Postmenopausal women (n = 125) with severe osteoporosis on TPTD treatment for 9 months were randomized into three open‐label groups for a further 9 months: ALN (70 mg/week) in addition to TPTD; RAL (60 mg/d) in addition to TPTD; or no medication in addition to TPTD. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), and areal and volumetric BMD at the lumbar spine and hip were assessed. During the combination period, P1NP concentrations did not change on TPTD monotherapy (693% ± 371%, p < 0.0001) and decreased in the ALN (360% ± 153%, p < 0.0001) and RAL (482% ± 243%, p < 0.0001) combination groups; whereas CTX did not change on TPTD monotherapy (283% ± 215%, p < 0.0001), decreased to the starting level in the ALN combination group (17% ± 72%, p = 0.39), and remained elevated in the RAL combination group (179% ± 341%, p < 0.0001). The increase in lumbar spine BMD was 5% ± 6.3% in the ALN and 6% ± 5.2% in the RAL combination groups compared with 2.8% ± 9.3% in the TPTD monotherapy group (p = 0.085 and p = 0.033, respectively). The increase of trabecular lumbar spine BMD for both the ALN and RAL combination groups was superior to TPTD monotherapy. Total hip BMD changes were 4% ± 5.3% for the ALN combination group and 1.4% ± 5.1% for the TPTD monotherapy (p = 0.032), and 1.4% ± 3.4% (p = 0.02) for the RAL combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the ALN combination group for all other comparisons were significantly superior to the two other groups. Our data suggest that ALN when added to TPTD 9 months after initiation of TPTD monotherapy results in a more robust increase in BMD, probably due to a reopening of the anabolic window. The clinical relevance of the BMD increase is unknown. © 2013 American Society for Bone and Mineral Research     

Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women

Introduction: We evaluated effects of teriparatide (rDNA origin) injection [teriparatide, rhPTH (1–34), TPTD] on hip structure among a subset 558 postmenopausal women enrolled in the Fracture Prevention Trial. Methods: Patients were randomized to once-daily, self-administered subcutaneous injections of placebo (N = 189), teriparatide 20 μg (TPTD20; N = 186), or 40 μg (TPTD40; N = 183) for a median of 20 months. Repeated dual energy X-ray absorptiometry (DXA) hip scans were analyzed with the Hip Structure Analysis (HSA) program to derive structural geometry. Results and conclusions: There were no significant differences in age or body size between groups at baseline, 1 year, or study termination. At the femoral neck, teriparatide increased bone mass and improved bone geometric strength in both treatment groups compared to the placebo group, with the response being dose-related. The mean difference (95% CI) in bone cross-sectional area (CSA) in the TPTD20 was 3.5% (1.8% to 5.3%), and 6.3% (4.5% to 8.2%) in TPTD40 at study termination, compared to placebo controls. Teriparatide treatment increased bending strength, with the mean difference in section modulus being 3.6% (1.4% to 5.8%) and 6.8% (4.6% to 9.1%) greater in the TPTD20 and TPTD40 groups, respectively. Compared to placebo, local cortical instability characterized by the buckling ratio decreased by 5.5% (3.5% to 7.5%) and 8.6% (6.6% to 10.5%) in the TPTD20 and TPTD40 groups, respectively, during the study period. The changes at the intertrochanteric region were comparable to those at the narrow neck although between-group differences were slightly smaller. Except for an inconsequential (1%) improvement in section modulus in TPTD20, teriparatide effects did not reach significance at the femoral shaft. In conclusion, teriparatide treatment improved axial and bending strength, and increased cortical thickness and stability at the femoral neck and intertrochanteric region. Teriparatide treatment effects were not apparent at the purely cortical femoral shaft.     

Weekly teriparatide injections successfully treated advanced bisphosphonate-related osteonecrosis of the jaws

This study investigated whether weekly teriparatide (TPTD) injections are as effective as daily teriparatide injections for the treatment of stage 3 bisphosphonate-related osteonecrosis of the jaws (BRONJ) and compared serum markers of bone turnover between the two treatment regimens. Daily TPTD treatment has recently been reported to be effective for BRONJ, but there are no reports describing the effectiveness of weekly TPTD injections. We report two patients with stage 3 BRONJ. One patient was successfully treated with weekly TPTD injections and the other with daily TPTD injections. Changes in the levels of serum N-telopeptide of type I collagen (s-NTX) and serum N-terminal propeptide of type I collagen (P1NP) were studied. Two patients with stage 3 BRONJ that was refractory to conservative treatment were treated with TPTD. Their medical records were reviewed and the patients were interviewed. There was complete mucosal coverage of the intraoral defects after 3 months of TPTD treatment in both patients. Progressive bone regeneration in an area of mandibular fracture was identified after 4 months of treatment. The s-NTX level increased slightly in both patients. This is the first report of successful treatment of stage 3 BRONJ with weekly TPTD injections. Either daily or weekly TPTD injections may effectively treat stage 3 BRONJ and should be considered before or perhaps even in lieu of undertaking major resection and reconstruction.     

Mapping Bone Changes at the Proximal Femoral Cortex of Postmenopausal Women in Response to Alendronate and Teriparatide Alone,Combined or Sequentially

Combining antiresorptive and anabolic drugs for osteoporosis may be a useful strategy to prevent hip fractures. Previous studies comparing the effects of alendronate (ALN) and teriparatide (TPTD) alone, combined or sequentially using quantitative computed tomography (QCT) in postmenopausal women have not distinguished cortical bone mineral density (CBMD) from cortical thickness (CTh) effects, nor assessed the distribution and extent of more localized changes. In this study a validated bone mapping technique was used to examine the cortical and endocortical trabecular changes in the proximal femur resulting from an 18‐month course of ALN or TPTD. Using QCT data from a different clinical trial, the global and localized changes seen following a switch to TPTD after an 18‐month ALN treatment or adding TPTD to the ALN treatment were compared. Ct.Th increased (4.8%, p < 0.01) and CBMD decreased (?4.5%, p < 0.01) in the TPTD group compared to no significant change in the ALN group. A large Ct.Th increase could be seen for the switch group (2.8%, p < 0.01) compared to a significantly smaller increase for the add group (1.5%, p < 0.01). CBMD decreased significantly for the switch group (–3.9%, p < 0.01) and was significantly different from no significant change in the add group. Ct.Th increases were shown to be significantly greater for the switch group compared to the add group at the load bearing regions. This study provides new insights into the effects of ALN and TPTD combination therapies on the cortex of the proximal femur and supports the hypothesis of an increased bone remodeling by TPTD being mitigated by ALN. © 2014 American Society for Bone and Mineral Research.     

Lathyrism-induced alterations in collagen cross-links influence the mechanical properties of bone material without affecting the mineral

In the present study a rat animal model of lathyrism was employed to decipher whether anatomically confined alterations in collagen cross-links are sufficient to influence the mechanical properties of whole bone. Animal experiments were performed under an ethics committee approved protocol. Sixty-four female (47 day old) rats of equivalent weights were divided into four groups (16 per group): Controls were fed a semi-synthetic diet containing 0.6% calcium and 0.6% phosphorus for 2 or 4 weeks and β-APN treated animals were fed additionally with β-aminopropionitrile (0.1% dry weight). At the end of this period the rats in the four groups were sacrificed, and L2-L6 vertebra were collected. Collagen cross-links were determined by both biochemical and spectroscopic (Fourier transform infrared imaging (FTIRI)) analyses. Mineral content and distribution (BMDD) were determined by quantitative backscattered electron imaging (qBEI), and mineral maturity/crystallinity by FTIRI techniques. Micro-CT was used to describe the architectural properties. Mechanical performance of whole bone as well as of bone matrix material was tested by vertebral compression tests and by nano-indentation, respectively. The data of the present study indicate that β-APN treatment changed whole vertebra properties compared to non-treated rats, including collagen cross-links pattern, trabecular bone volume to tissue ratio and trabecular thickness, which were all decreased (p<0.05). Further, compression tests revealed a significant negative impact of β-APN treatment on maximal force to failure and energy to failure, while stiffness was not influenced. Bone mineral density distribution (BMDD) was not altered either. At the material level, β-APN treated rats exhibited increased Pyd/Divalent cross-link ratios in areas confined to a newly formed bone. Moreover, nano-indentation experiments showed that the E-modulus and hardness were reduced only in newly formed bone areas under the influence of β-APN, despite a similar mineral content. In conclusion the results emphasize the pivotal role of collagen cross-links in the determination of bone quality and mechanical integrity. However, in this rat animal model of lathyrism, the coupled alterations of tissue structural properties make it difficult to weigh the contribution of the anatomically confined material changes to the overall mechanical performance of whole bone. Interestingly, the collagen cross-link ratio in bone forming areas had the same profile as seen in actively bone forming trabecular surfaces in human iliac crest biopsies of osteoporotic patients.     

Overlapping and Continued Alendronate or Raloxifene Administration in Patients on Teriparatide: Effects on Areal and Volumetric Bone Mineral Density—The CONFORS Study

Nine month teriparatide (TPTD) monotherapy followed by co‐administration of raloxifene (RAL) or alendronate (ALN) for another nine 9 months resulted in incremental bone mineral density (BMD) increase. The aim of this study was to investigate the effects of continued antiresorptive treatments for 12 months in the extension phase. Postmenopausal women (n = 125) with severe osteoporosis on ongoing TPTD treatment for 9 months were randomized into three open‐label groups for another 9 months: ALN (70 mg/week, n = 41), RAL (60 mg/d, n = 37) in addition to TPTD or no additional medication (n = 47) except Ca and vitamin D. After discontinuation of TPTD the respective antiresorptives were continued for a further 12 months, while patients in the TPTD monotherapy group received Ca and vitamin D. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), areal and volumetric BMD at the lumbar spine (LS) and hip were assessed. ALN resulted in continued BMD increase in LS (4.3 ± 1.5%; mean ± SD), femoral neck (4.2 ± 1.6%) and total hip (4 ± 1.6%; p < 0.001 for all), while RAL was only effective at the LS (2.4 ± 1.7%, p < 0.001) but no changes at the femoral neck (0.4 ± 1.4%) or total hip (?0.8 ± 1.5%) were observed. Cortical bone only increased in the ALN group (femoral neck 6.7 ± 2.7% and ?1.3 ± 2.5%; total hip 13.8 ± 2.9% and ?2.3 ± 2.5% for ALN and RAL, p < 0.001 for all; respectively). Analyzing the entire 30 months of therapy, the ALN group revealed the largest BMD increase in all regions. Our results suggest that the addition of ALN to ongoing TPTD and continuing ALN after TPTD was stopped may be beneficial for patients in terms of areal and volumetric BMD increase. Further research is warranted to determine the optimal timing of the initiation of the combination treatment, the respective antiresorptive medication and the potential benefit of this BMD increase regarding fracture prevention. © 2014 American Society for Bone and Mineral Research     

Fourier Transform Infrared Imaging Microspectroscopy and Tissue-Level Mechanical Testing Reveal Intraspecies Variation in Mouse Bone Mineral and Matrix Composition

Fracture susceptibility is heritable and dependent upon bone morphology and quality. However, studies of bone quality are typically overshadowed by emphasis on bone geometry and bone mineral density. Given that differences in mineral and matrix composition exist in a variety of species, we hypothesized that genetic variation in bone quality and tissue-level mechanical properties would also exist within species. Sixteen-week-old female A/J, C57BL/6J (B6), and C3H/HeJ (C3H) inbred mouse femora were analyzed using Fourier transform infrared imaging and tissue-level mechanical testing for variation in mineral composition, mineral maturity, collagen cross-link ratio, and tissue-level mechanical properties. A/J femora had an increased mineral-to-matrix ratio compared to B6. The C3H mineral-to-matrix ratio was intermediate of A/J and B6. C3H femora had reduced acid phosphate and carbonate levels and an increased collagen cross-link ratio compared to A/J and B6. Modulus values paralleled mineral-to-matrix values, with A/J femora being the most stiff, B6 being the least stiff, and C3H having intermediate stiffness. In addition, work-to-failure varied among the strains, with the highly mineralized and brittle A/J femora performing the least amount of work-to-failure. Inbred mice are therefore able to differentially modulate the composition of their bone mineral and the maturity of their bone matrix in conjunction with tissue-level mechanical properties. These results suggest that specific combinations of bone quality and morphological traits are genetically regulated such that mechanically functional bones can be constructed in different ways.     

Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization

In the treatment of postmenopausal osteoporosis (PMOP), the use of alendronate (ALN) leads to a decrease in the risk of vertebral and nonvertebral fractures. To explore the possible adverse effects of prolonged ALN therapy, we studied the effects of 8 ± 2 years (6–10 years) of ALN treatment on the iliac cortical bone mineral and collagen quality and micromechanical properties; by design, our study examined these parameters, independent of the degree of mineralization. From six ALN‐treated and five age‐matched untreated PMOP women, 153 bone structural units have been chosen according their degree of mineralization to obtain the same distribution in each group. In those bone structural units, Fourier transform infrared spectroscopy, quantitative microradiography, and nanoindentation were used to assess bone quality. Irrespective of the degree of mineralization, ALN treatment was associated with higher collagen maturity (+7%, p < 0.001, c.v. = 13% and 16% in treated and untreated women, respectively) and lower mineral crystallinity than that observed in the untreated PMOP group (?2%, p < 0.0001, c.v. = 3% in both groups). Bone matrix from ALN‐treated women also had lower elastic modulus (?12%, p < 0.0001, c.v. = 14% in both groups) and, contact hardness (?6%, p < 0.05, c.v. = 14% in both groups) than that of untreated women. Crystallinity (which reflects the size and perfection of crystals) was associated with both elastic modulus and contact hardness in treated women exclusively (r = 0.43 and r = 0.54, p < 0.0001, respectively), even after adjustment for the amount of mineral. We infer that long‐term ALN treatment compromises micromechanical properties of the bone matrix as assessed ex vivo. The strength deficits are in part related to difference in crystallinity, irrespective of the mineral amount and mineral maturity. These novel findings at local levels of bone structure will have to be taken into account in the study of the pathophysiology of bone fragilities associated with prolonged ALN treatment. © 2012 American Society for Bone and Mineral Research.     

Bisphosphonates do not alter the rate of secondary mineralization

Bisphosphonates function to reduce bone turnover, which consequently increases the mean degree of tissue mineralization at an organ level. However, it is not clear if bisphosphonates alter the length of time required for an individual bone-modeling unit (BMU) to fully mineralize. We have recently demonstrated that it takes ~ 350 days (d) for normal, untreated cortical bone to fully mineralize. The aim of this study was to determine the rate at which newly formed trabecular BMUs become fully mineralized in rabbits treated for up to 414 d with clinical doses of either risedronate (RIS) or alendronate (ALN). Thirty-six, 4-month old virgin female New Zealand white rabbits were allocated to RIS (n = 12; 2.4 μg/kg body weight), ALN (n = 12; 2.4 μg/kg body weight), or volume-matched saline controls (CON; n = 12). Fluorochrome labels were administered at specific time intervals to quantify the rate and level of mineralization of trabecular bone from the femoral neck (FN) by Fourier transform infrared microspectroscopy (FTIRM). The organic (collagen) and inorganic (phosphate and carbonate) IR spectral characteristics of trabecular bone from undecalcified 4 micron thick tissue sections were quantified from fluorescently labels regions that had mineralized for 1, 8, 18, 35, 70, 105, 140, 210, 280, and 385 d (4 rabbits per time point and treatment group). All groups exhibited a rapid increase in mineralization over the first 18 days, the period of primary mineralization, with no significant differences between treatments. Mineralization continued to increase, at a slower rate up, to 385 days (secondary mineralization), and was not different among treatments. There were no significant differences between treatments for the rate of mineralization within an individual BMU; however, ALN and RIS both increased global tissue mineralization as demonstrated by areal bone mineral density from DXA. We conclude that increases in tissue mineralization that occur following a period of bisphosphonate treatment is a function of the suppressed rate of remodeling that allows for a greater number of BMUs to obtain a greater degree of mineralization.     

Spectroscopic markers of bone quality in alendronate-treated postmenopausal women

Summary  Comparison of infrared spectroscopic images of sections from biopsies of placebo-treated post-menopausal women and women treated for 3 years with 10 mg/day alendronate demonstrated significant increases in cortical bone mineral content, no alterations in other spectroscopic markers of “bone quality,” but a decrease in tissue heterogeneity. Methods  The material properties of thick sections from iliac crest biopsies of seven alendronate-treated women were compared to those from ten comparably aged post-menopausal women without bone disease, using infrared spectroscopic imaging at ∼7 μm spatial resolution. Parameters evaluated were mineral/matrix ratio, crystallinity, carbonate/amide I ratio, and collagen maturity. The line widths at half maximum of the pixel histograms for each parameter were used as measures of heterogeneity. Results  The mineral content (mineral/matrix ratio) in the cortical bone of the treated women’s biopsies was higher than that in the untreated control women. Crystallinity, carbonate/protein, and collagen maturity indices were not significantly altered; however, the pixel distribution was significantly narrowed for all cortical and trabecular parameters with the exception of collagen maturity in the alendronate treatment group. Conclusions  The increases in mineral density and decreased fracture risk associated with bisphosphonate treatment may be counterbalanced by a decrease in tissue heterogeneity, which could impair tissue mechanical properties. These consistent data suggest that alendronate treatment, while increasing the bone mass, decreases the tissue heterogeneity.     

Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis.

FE modeling was used to estimate the biomechanical effects of teriparatide and alendronate on lumbar vertebrae. Both treatments enhanced predicted vertebral strength by increasing average density. This effect was more pronounced for teriparatide, which further increased predicted vertebral strength by altering the distribution of density within the vertebra, preferentially increasing the strength of the trabecular compartment. INTRODUCTION: Teriparatide 20 microg/day (TPTD) and alendronate 10 mg/day (ALN) increase areal, measured by DXA, and volumetric, measured by QCT, lumbar spine BMD through opposite effects on bone remodeling. Using finite element (FE) modeling of QCT scans, we sought to compare the vertebral strength characteristics in TPTD- and ALN-treated patients. MATERIALS AND METHODS: A subset of patients (N = 28 TPTD; N = 25 ALN) from the Forteo Alendronate Comparator Trial who had QCT scans of the spine at baseline and postbaseline were analyzed. The QCT scans were analyzed for compressive strength of the L(3) vertebra using FE modeling. In addition, using controlled parameter studies of the FE models, the effects of changes in density, density distribution, and geometry on strength were calculated, a strength:density ratio was determined, and a response to bending was also quantified. RESULTS: Both treatments had positive effects on predicted vertebral strength characteristics. At least 75% of the patients in each treatment group had increased strength of the vertebra at 6 months compared with baseline. Patients in both treatment groups had increased average volumetric density and increased strength in the trabecular bone, but the median percentage increases for these parameters were 5- to 12-fold greater for TPTD. Larger increases in the strength:density ratio were also observed for TPTD, and these were primarily attributed to preferential increases in trabecular strength. CONCLUSIONS: These results provide new insight into the effects of these treatments on estimated biomechanical properties of the vertebra. Both treatments positively affected predicted vertebral strength through their effects on average BMD, but the magnitudes of the effects were quite different. Teriparatide also affected vertebral strength by altering the distribution of density within the vertebra, so that overall, teriparatide had a 5-fold greater percentage increase in the strength:density ratio.