Summary Objective Bone marrow lesions (BML), previously denoted bone marrow edema, are detected as water signals by magnetic resonance imaging (MRI). Previous histologic studies were unable to ...demonstrate any edematous changes at the tissue level. Therefore, our aim was to investigate the underlying biological mechanisms of the water signal in MRI scans of bone affected by BML. Methods Tetracycline labeling in addition to water sensitive MRI scans of 30 patients planned for total hip replacement surgery was undertaken. Twenty-one femoral heads revealed BML on MRI, while nine were negative and used as controls (CON). Guided by the MRI images cylindrical biopsies were extracted from areas with BML in the femoral heads. Tissue sections from the biopsies were subjected to histomorphometric image analyses of the cancellous bone envelope. Results patients with BML exhibited an average 40- and 18-fold increase of bone formation rate and mineralizing surfaces, respectively. Additionally, samples with BML demonstrated 2-fold reduction of marrow fat and 28 fold increase of woven bone Immunohistochemical analysis showed a 4 fold increase of angiogenesis markers CD31 and von Willebrand Factor in the BML-group compared to controls. Conclusion this study indicates that BML are characterized by increased bone turnover, vascularity and angiogenesis in keeping with it being a reparatory process. Thus, the water signal, which is the hallmark of BML on MRI, is most probably reflecting increased tissue vascularity accompanying increased remodeling activity.
Summary
Adherence to oral bisphosphonates is low. A screening strategy is proposed based on the response of biochemical markers of bone turnover after 3 months of therapy. If no change is observed, ...the clinician should reassess the adherence to the treatment and also other potential issues with the drug.
Introduction
Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients.
Methods
The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis.
Results
Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and 3 months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%.
Conclusions
If a significant decrease is observed, the treatment can continue, but if no decrease occurs, the clinician should reassess to identify problems with the treatment, mainly low adherence.
Abstract Prospective, controlled clinical trials in postmenopausal osteoporosis typically compare effects of an active drug with placebo in addition to vitamin D and calcium supplementation in both ...treatment arms. While clinical benefits are documented, the effect of this supplementation in the placebo arm and in clinical practice on bone material composition properties is unknown. The purpose of the present study was to evaluate these bone quality indices (specifically mineral/matrix, nanoporosity, glycosaminoglycan content, mineral maturity/crystallinity, and pyridinoline content) in patients that either received long-term vitamin D (400
–
1200 IU) and calcium (1.0
–
1.5 g) supplementation, or did not. We have analyzed by Raman microspectroscopy the bone forming trabecular surfaces of iliac crest in pre-treatment samples of a teriparatide study and the endpoint biopsies of the control arm obtained from the HORIZON trial. In general, the mineral/matrix ratio and the glycosaminoglycan (GAG) content was higher while nanoporosity, (a surrogate for tissue water content), the mineral maturity/crystallinity (MMC) and the pyridinoline (Pyd) content was lower in patients without long-term supplementation. Moreover, all indices were significantly dependent on tissue age. In conclusion, vitamin D and calcium supplementation is associated with altered mineral and organic matrix properties.
•Adaptation interventions may reinforce, redistribute or create new vulnerability.•Retrofitting adaptation into existing development agendas risks maladaptation.•Overcoming these challenges demands ...engaging more deeply with vulnerability contexts.•Real involvement of marginalised groups is required to improve use of climate finance.•Unless adaptation is rethought, transformation may also worsen vulnerability.
This paper critically reviews the outcomes of internationally-funded interventions aimed at climate change adaptation and vulnerability reduction. It highlights how some interventions inadvertently reinforce, redistribute or create new sources of vulnerability. Four mechanisms drive these maladaptive outcomes: (i) shallow understanding of the vulnerability context; (ii) inequitable stakeholder participation in both design and implementation; (iii) a retrofitting of adaptation into existing development agendas; and (iv) a lack of critical engagement with how ‘adaptation success’ is defined. Emerging literature shows potential avenues for overcoming the current failure of adaptation interventions to reduce vulnerability: first, shifting the terms of engagement between adaptation practitioners and the local populations participating in adaptation interventions; and second, expanding the understanding of ‘local’ vulnerability to encompass global contexts and drivers of vulnerability. An important lesson from past adaptation interventions is that within current adaptation cum development paradigms, inequitable terms of engagement with ‘vulnerable’ populations are reproduced and the multi-scalar processes driving vulnerability remain largely ignored. In particular, instead of designing projects to change the practices of marginalised populations, learning processes within organisations and with marginalised populations must be placed at the centre of adaptation objectives. We pose the question of whether scholarship and practice need to take a post-adaptation turn akin to post-development, by seeking a pluralism of ideas about adaptation while critically interrogating how these ideas form part of the politics of adaptation and potentially the processes (re)producing vulnerability. We caution that unless the politics of framing and of scale are explicitly tackled, transformational interventions risk having even more adverse effects on marginalised populations than current adaptation.
CONTEXT Risedronate, a potent bisphosphonate, has been shown to be effective
in the treatment of Paget disease of bone and other metabolic bone diseases
but, to our knowledge, it has not been ...evaluated in the treatment of established
postmenopausal osteoporosis. OBJECTIVE To test the efficacy and safety of daily treatment with risedronate
to reduce the risk of vertebral and other fractures in postmenopausal women
with established osteoporosis. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial of 2458 ambulatory
postmenopausal women younger than 85 years with at least 1 vertebral fracture
at baseline who were enrolled at 1 of 110 centers in North America conducted
between December 1993 and January 1998. INTERVENTIONS Subjects were randomly assigned to receive oral treatment for 3 years
with risedronate (2.5 or 5 mg/d) or placebo. All subjects received calcium,
1000 mg/d. Vitamin D (cholecalciferol, up to 500 IU/d) was provided if baseline
levels of 25-hydroxyvitamin D were low. MAIN OUTCOME MEASURES Incidence of new vertebral fractures as detected by quantitative and
semiquantitative assessments of radiographs; incidence of radiographically
confirmed nonvertebral fractures and change from baseline in bone mineral
density as determined by dual x-ray absorptiometry. RESULTS The 2.5 mg/d of risedronate arm was discontinued after 1 year; in the
placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively,
completed all 3 years of the trial. Treatment with 5 mg/d of risedronate,
compared with placebo, decreased the cumulative incidence of new vertebral
fractures by 41% (95% confidence interval CI, 18%-58%) over 3 years (11.3%
vs 16.3%;P=.003). A fracture reduction of 65% (95%
CI, 38%-81%) was observed after the first year (2.4% vs 6.4%; P<.001). The cumulative incidence of nonvertebral fractures over
3 years was reduced by 39% (95% CI, 6%-61%) (5.2% vs 8.4%; P=.02). Bone mineral density increased significantly compared with
placebo at the lumbar spine (5.4% vs 1.1%), femoral neck (1.6% vs −1.2%),
femoral trochanter (3.3% vs −0.7%), and midshaft of the radius (0.2%
vs −1.4%). Bone formed during risedronate treatment was histologically
normal. The overall safety profile of risedronate, including gastrointestinal
safety, was similar to that of placebo. CONCLUSIONS These data suggest that risedronate therapy is effective and well tolerated
in the treatment of women with established postmenopausal osteoporosis.
Treatments for postmenopausal women with osteoporosis include estrogens, selective estrogen-receptor modulators, bisphosphonates, calcitonin, vitamin D, and calcitriol. These treatments reduce bone ...resorption (and formation) and moderately increase bone density; some agents reduce the risk of fracture, but none routinely restore normal bone mass or strength. Treatments that stimulate bone formation may overcome these limitations.
Parathyroid hormone stimulates bone formation and resorption and can increase or decrease bone mass, depending on the mode of administration. Continuous infusions and daily subcutaneous injections of parathyroid hormone stimulate bone formation similarly but have different effects on bone resorption and bone mass.
1
,
2
Continuous infusions, . . .
Histomorphometry and μCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, ...cancellous bone plate‐like structure, and cortical thickness, and a reduction in marrow star volume.
Introduction: We studied the ability of teriparatide (rDNA origin) injection rhPTH(1–34), TPTD to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data.
Methods: Fifty‐one paired iliac crest bone biopsy specimens (placebo n = 19, 20 μg teriparatide n = 18, and 40 μg teriparatide n = 14) were analyzed using both two‐dimensional (2D) histomorphometry and three‐dimensional (3D) microcomputed tomography (μCT). Data for both teriparatide treatment groups were pooled for analysis.
Results and Conclusions: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, −24%; p = 0.001) and reduced marrow star volume (teriparatide, −16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, −12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, −14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate‐like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.
The effects of 3 years of oral risedronate treatment on bone quality and remodeling were assessed in women with postmenopausal osteoporosis. Transiliac bone biopsies were obtained at baseline and ...after treatment with placebo or risedronate 5 mg/day in 55 women (placebo, n = 27; risedronate 5 mg, n = 28); these pairs of samples allowed comparison of treatment effects vs. both baseline values and between treatment groups. A further 15 women (placebo, n = 6; risedronate 5 mg, n = 9) had measurements from a posttreatment biopsy, but not from a baseline biopsy. Samples were examined for qualitative changes (e.g., osteomalacia, peritrabecular fibrosis, and woven bone); no histological abnormalities were found to be associated with treatment. Among women with both baseline and posttreatment biopsies, risedronate-treated women experienced a moderate and expected reduction from baseline in bone turnover, which was reflected in mean decreases in mineralizing surface of 58% and in activation frequency of 47%. Histomorphometrical parameters indicated that bone formation rate decreased significantly from baseline with risedronate treatment, reflecting a decrease in bone turnover; bone mineralization was normal following treatment. Basic multicellular unit (BMU) balance tended to improve in the risedronate-treated women, whereas it tended to worsen in the placebo-treated women, although these changes were not statistically significant. There were no significant changes in structural parameters with treatment. The effects of 3 years of risedronate treatment on bone histology and histomorphometry reflect the antiresorptive mechanism of action, and are consistent with the antifracture efficacy and favorable bone safety profile demonstrated in large clinical trials.
We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6‐month double‐blind, placebo‐controlled trial that measured ...biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline.
Introduction: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide rhPTH(1–34) monotherapy with combination teriparatide and raloxifene therapy.
Materials and Methods: A 6‐month randomized, double‐blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis.
Results: Bone formation (N‐terminal propeptide of type 1 collagen PINP) increased similarly in both treatment groups. However, the increase in bone resorption (serum C‐terminal telopeptide of type I collagen CTx) in the combination group was significantly smaller than in the teriparatide‐alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 ± 0.67% from baseline in the teriparatide‐alone group. In the combination group, lumbar spine (6.19 ± 0.65%), femoral neck (2.23 ± 0.64%), and total hip (2.31 ± 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide‐alone group (p = 0.04). In the teriparatide‐alone group, mean serum calcium levels increased from baseline to endpoint (0.30 ± 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (−0.20 ± 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone.
Conclusions: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.
We describe a sinus, referred to as a bone remodeling compartment (BRC), which is intimately associated with cancellous bone remodeling. The compartment is lined on its marrow side by flattened cells ...and on its osseous side by the remodeling bone surface, resembling a roof of flattened cells covering the bone surface. The flat marrow lining cells are in continuity with the bone lining cells at the margins of the BRC. We examined a large number of diagnostic bone biopsy specimens received during recent years in the department. Furthermore, 10 patients (8 women and 2 men, median age 56 40–69 years) with the high turnover disease of primary hyperparathyroidism who were treated with parathyroidectomy and followed for 3 years were included in the histomorphometric study. Bone samples for the immuno‐enzyme staining were obtained from an amputated extremity of child. The total cancellous bone surface covered by BRC decreases by 50% (p < 0.05) following normalization of turnover and is paralleled by a similar 50% decrease in remodeling surface (p < 0.05). The entire eroded surface and two‐thirds of the osteoid surface are covered by a BRC. BRC‐covered uncompleted walls are 30% (p < 0.05) thinner than those without a BRC. This indicates that the BRC is invariably associated with the early phases of bone remodeling, that is, bone resorption, whereas it closes during the late part of bone formation. Immuno‐enzyme staining shows that the flat marrow lining cells are positive for alkaline phosphatase, osteocalcin, and osteonectin, suggesting that they are bone cells. The first step in cancellous bone remodeling is thought to be the lining cells digesting the unmineralized matrix membrane followed by their disappearance and the arrival of the bone multicellular unit (BMU). We suggest that the lining cell barrier persists during bone remodeling; that the old lining cells become the marrow lining cells, allowing bone resorption and bone formation to proceed under a common roof of lining cells; that, at the end of bone formation, new bone lining cells derived from the flattened osteoblasts replace the marrow lining cells thereby closing the BRC; and that the two layers of lining cells eventually becomes a single layer. The integrity of the osteocyte‐lining cell system is reestablished by the new generation of lining cells. The BRC most likely serves multiple purposes, including efficient exchange of matrix constituents and minerals, routing, monitoring, or modulating bone cell recruitment, and possibly the anatomical basis for the coupling of bone remodeling.
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