Osteoporosis: Eastell R

Reid DM, Doughty J, Eastell R, Heys SD, Howell A, McCloskey EV, Powles T, Selby P, Coleman RE. · Department of Rheumatology, University of Aberdeen, United Kingdom. · Cancer Treat Rev. · Pubmed #18515009 No free full text.

Abstract: In postmenopausal women, the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1-3% per year leading to an increase in fracture incidence compared to that seen during tamoxifen use. The bone loss is much more marked in young women with treatment-induced ovarian suppression followed by aromatase inhibitor therapy (average 7-8% per annum). Pre-treatment with tamoxifen for 2-5 years may reduce the clinical significance of the adverse bone effects associated with aromatase inhibitors, particularly if this leads to a shortening in the duration of exposure to an aromatase inhibitor. However, skeletal status should still be assessed at the commencement of aromatase inhibitor therapy. The rate of bone loss in women who experience a premature menopause before the age of 45 or are receiving ovarian suppression therapy is accelerated by the concomitant use of aromatase inhibitors. These patients are considered to be at high risk of clinically important bone loss and should have a baseline dual energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD). Randomised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting. Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels. Bisphosphonates, along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss. Due to the rate of bone loss associated with breast cancer treatments, and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk, the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis. Management recommendations have been summarised in two algorithms, one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy.

Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J, Anonymous00109. · Inserm Research Unit 403 and Claude Bernard University of Lyon, France. · Osteoporos Int. · Pubmed #11193237 No free full text.

This publication has no abstract.

Meunier PJ, Delmas PD, Eastell R, McClung MR, Papapoulos S, Rizzoli R, Seeman E, Wasnich RD. · Hôpital Edouard Herriot, Lyon, France. · Clin Ther. · Pubmed #10440625 No free full text.

Abstract: The authors, all physicians involved in clinical research on bone and practicing clinicians, propose practical guidelines for identifying persons with osteoporosis or those at high risk of developing the disease and for managing patients who may benefit from therapy. These guidelines are based on an analysis of peer-reviewed articles published before November 1998. A flowchart of women who might benefit from treatment is provided, including clinical presentation (recent fracture of the spine, hip, or other bone or no fracture; risk factors for osteoporosis); relevant investigations (bone mineral density measurement and laboratory tests required for the differential diagnosis); and therapeutic management (general measures such as calcium and vitamin D supplementation and specific pharmacologic interventions such as estrogen, bisphosphonates, intranasal calcitonin, raloxifene, fluoride salts, and other compounds that have been assessed in randomized clinical trials). The strongest evidence for antifracture efficacy (reduction of vertebral and nonvertebral fracture risk) was observed with alendronate.

Eastell R. · No affiliation provided · J Clin Endocrinol Metab. · Pubmed #17209223 links to  free full text

This publication has no abstract.

Eastell R, Hannon RA. · Academic Unit of Bone Metabolism, University of Sheffield, Metabolic Bone Centre, Sorby Wing, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK. · Proc Nutr Soc. · Pubmed #18412989 No free full text.

Abstract: The assay features of biochemical markers of bone turnover have markedly improved in the past few years. The most sensitive and specific markers of bone formation include serum bone alkaline phosphatase, total osteocalcin (including the intact molecule and the large N-mid fragment) and the procollagen type I N-terminal propeptide assay. Among the various markers of bone resorption, measurements of the urinary excretion of N- and C-terminal cross-linked telopeptides) and of serum C-terminal cross-linked telopeptides are the most sensitive and specific. Markers of bone turnover can be used to predict the rate of bone loss in post-menopausal women and can also be used to assess the risk of fractures. In osteoporosis-treatment studies (with alendronate, risedronate, raloxifene) markers of bone turnover appear even more strongly associated with fracture risk reduction than bone mineral density (BMD). These observations support the use of markers of bone turnover as surrogates for fracture risk reduction, perhaps even more so than BMD. Bone markers can also be used to monitor the efficacy of antiresorptive therapy such as hormone-replacement therapy, raloxifene and bisphosphonates in individual patients. Furthermore, they have also proved to be helpful in monitoring the response to nutritional interventions and have the advantage over BMD in that they provide information about mechanism of effect and changes are often observed much more rapidly.

Rogers A, Eastell R. · Academic Unit of Bone Metabolism, University of Sheffield, Sheffield S5 7AU, United Kingdom. · J Clin Endocrinol Metab. · Pubmed #16105967 links to  free full text

Abstract: CONTEXT: The discovery of the receptor activator for nuclear factor kappaB (RANK) ligand (RANKL)/RANK signaling pathway has marked a major advance in our understanding of the mechanisms controlling osteoclastogenesis. RANKL, expressed by preosteoblasts and stromal cells, binds to RANK, expressed by cells of the osteoclast lineage, inducing a signaling cascade leading to the differentiation and fusion of osteoclast precursor cells and stimulating the activity of the mature osteoclast. The effects of RANKL are counteracted by osteoprotegerin (OPG), a soluble neutralizing decoy receptor. EVIDENCE: This paper reviews the literature surrounding the use of circulating OPG and soluble RANKL (sRANKL) measurements and assesses their potential as markers of bone disease. Original clinical and basic research articles and reviews were identified using a Pubmed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) and cover the time period up until January 2005. Search terms osteoprotegerin, OPG, RANK, RANKL, and RANK ligand were used alone and in combination with bone, osteoporosis, and disease. EVIDENCE SYNTHESIS: Assays for detecting OPG and sRANKL in the circulation in humans have been developed, and differences in the circulating concentrations of OPG and sRANKL have been observed in different disease states. There are, however, some inconsistencies in study outcome. These may relate to differences in study design, methodology, and other unknown factors influencing the variability of these measurements. CONCLUSIONS: The clinical utility of serum OPG and sRANKL measurements as markers of disease activity requires additional investigation. In particular, rigorous testing of assays and identification of the sources of measurement variability are required.

Eastell R, Hannon R. · Academic Unit of Bone Metabolism, University of Sheffield Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield, South Yorkshire, S5 7AU, UK. · J Steroid Biochem Mol Biol. · Pubmed #15970439 No free full text.

Abstract: The risk of fracture in the postmenopausal woman given aromatase inhibitors may be increased by up to 60%. This is likely to be true for all third generation drugs, but the clinical trials did not include sufficient fracture events for certainty on this issue. It would appear that most of the excess fracture risk relates to vertebral fracture and in future studies, more effort should be given to ascertaining these fractures. The likely mechanism for the increase in fracture risk is an increase in bone turnover (of about 20%) and an acceleration of bone loss. There is evidence to suggest that the residual levels of oestradiol present in the postmenopausal woman are important for bone health, and thus, the effect of these drugs is to remove this protective effect. Current clinical practice should include the measurement of bone mineral density in postmenopausal women taking these drugs and commencement of antiresorptive therapy if osteoporosis is already present.

Ferrar L, Jiang G, Adams J, Eastell R. · Bone Metabolism Group, Section of Human Metabolism, Division of Clinical Sciences, University of Sheffield, UK. · Osteoporos Int. · Pubmed #15868071 No free full text.

Abstract: Osteoporotic vertebral fracture is associated with increased morbidity and mortality. As a powerful predictor of future fracture risk, the identification of vertebral fracture helps target individuals who will benefit from anti-fracture therapy. The identification of vertebral fractures is problematic because (1) "normal" radiological appearances in the spine vary greatly both among and within individuals; (2) "normal" vertebrae may exhibit misleading radiological appearances due to radiographic projection error; and (3) "abnormal" appearances due to non-fracture deformities and normal variants are common, but can be difficult to differentiate from true vertebral fracture. Various methods of vertebral fracture definition have been proposed, but there is no agreed gold standard. Quantitative methods of vertebral fracture definition are objective and reproducible, but the major limitation of these methods is their inability to differentiate between vertebral deformity and vertebral fracture. The qualitative visual approach draws on the expertise of the reader, but it is a subjective method with poor interobserver agreement. Semiquantitative assessment of vertebral fracture is a standardized visual method, which is commonly applied in research studies as a surrogate gold standard. This method is more objective and reproducible than a purely qualitative approach, but can be difficult to apply. The established methods focus primarily on the identification of "reduced" or short vertebral height as an indication of vertebral fracture, but this is also a feature of some non-fracture deformities and normal variants. A modified visual approach known as algorithm-based qualitative assessment of vertebral fracture (ABQ) has recently been introduced, and this focuses on radiological evidence of change at the vertebral endplate as the primary indicator of fracture. Preliminary testing of the ABQ method has produced promising results, but the method requires further evaluation. Vertebral imaging by means of dual energy X-ray absorptiometry (DXA) scanner produces images of near-radiographic quality at a fraction of the radiation dose incurred by conventional radiography. There is growing interest in vertebral fracture assessment using this technique as a means of assessing a patient's fracture risk. Given the increasing availability of new technology and the importance of accurate diagnosis of vertebral fracture, there is an urgent need for better awareness of and training in the definition of vertebral fracture. Methods of vertebral fracture definition should be validated by testing the association with clinical outcomes of vertebral fracture, in particular the prediction of incident fractures.

Eastell R. · University of Sheffield, Sheffield, United Kingdom. · Med Pediatr Oncol. · Pubmed #12868123 No free full text.

Abstract: The management of oestrogen deficiency bone loss needs to include general measures to protect against osteoporosis, the identification and treatment of other reversible causes of bone loss, and the use of proven agents for the treatment of osteoporosis. The general measures include improved physical activity, adequate diet (paying particular attention to calcium and vitamin D), and avoidance of behaviours that promote bone loss, such as smoking and alcohol abuse. The diseases that should be identified, other than estrogen-deficiency, include primary hyperparathyroidism, thyrotoxicosis and celiac disease. The treatments that are proven to prevent fractures in women with estrogen deficiency, include hormone replacement therapy, raloxifene, nasal calcitonin, bisphosphonates, (alendronate and risedronate) and parathyroid hormone. The most appropriate therapy in the younger woman is HRT, although the trial-based evidence that HRT prevents fractures is not strong. There is a wide choice of preparations and the use of continuous combined preparations avoids regular menstrual periods, one of the limitations to the use of HRT. Raloxifene has less effect on bone mineral density than HRT, but a similar effect on vertebral fractures and does not result in menstrual bleeding or increased risk of breast cancer. There is recent evidence suggesting that the beneficial effects on lipids translate into reduced risk of cardiovascular disease. Bisphosphonates are the standard treatment for the older woman with osteoporosis. Alendronate has been found to reduce the risk of spine, hip, and wrist fractures and has approval for a once weekly regimen, an approach that appears to prevent GI side effects. Risedronate reduces the risk of spine and non-vertebral fractures within the first year of treatment and has been shown to reduce the risk of hip fracture. It has not been associated with an excess of GI side effects. Parathyroid hormone therapy results in increases in BMD that are even greater than estrogen and the bisphosphonates and to an even greater reduction in the risk of fractures, particularly non-vertebral fractures. It works by stimulation of bone formation rather than by inhibition of bone resorption. However, it has to be given by daily injection. Thus, we have a wide choice of therapies for the woman with osteoporosis due to ovarian failure.

Hannon RA, Eastell R. · Research Associate, Bone Metabolism Group, University of Sheffield, Sheffield, UK. · J Br Menopause Soc. · Pubmed #12804307 No free full text.

Abstract: Low bone mineral density is a strong risk factor for fractures in the older woman. Biochemical markers of bone turnover may predict fracture risk independently of bone mineral density. High levels of bone resorption markers are associated with increased risk of fracture in both retrospective and prospective studies, although the evidence for bone formation markers and fracture risk is equivocal. For example, the risk of fracture is increased up to two-fold in women with elevated levels of several markers of bone resorption. Prediction models have been developed to predict the 10-year risk of fracture using bone mineral density and biochemical markers of bone turnover and these could prove very useful in clinical practice.

Eastell R, Lambert H. · Division of Clinical Sciences, Northern General Hospital, Sheffield, England S5 7AU. · Calcif Tissue Int. · Pubmed #11960202 No free full text.

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Eastell R, Reid DM, Compston J, Cooper C, Fogelman I, Francis RM, Hay SM, Hosking DJ, Purdie DW, Ralston SH, Reeve J, Russell RG, Stevenson JC. · University of Sheffield Medical School, Sheffield, UK. · QJM. · Pubmed #11704688 links to  free full text

Abstract: The burden of non-vertebral fractures is enormous. Hip fractures account for nearly 10% of all fractures (and a much greater proportion in the elderly), while wrist fractures may account for up to 23% of all limb fractures. The best available predictors of non-vertebral fracture risk are low BMD and a tendency to fall. Hip, forearm, proximal humerus and rib fractures have all been associated with low BMD, though ankle fracture is not strongly related to osteoporosis. Although clinical risk factors identify only about one-third of postmenopausal women at increased risk of osteoporotic fracture, the occurrence of one fracture commonly predicts a second fracture. Guidelines are presented for identifying and treating patients at risk of non-vertebral osteoporotic fractures, especially those with a previous fracture, based on the algorithm recently published by the Royal College of Physicians and the Bone and Tooth Society. Prevention of falls and use of external hip protectors may reduce the occurrence of hip fracture. Treatment options for patients presenting with hip fracture include HRT, bisphosphonates, and calcium plus vitamin D, and for Colles' fracture include general measures, HRT, bisphosphonates, or calcitonin plus calcium.

Clowes JA, Peel N, Eastell R. · University of Sheffield, Division of Clinical Sciences (North), Northern General Hospital, Sheffield, United Kingdom. · Curr Opin Rheumatol. · Pubmed #11555737 No free full text.

Abstract: Glucocorticoids remain a key component in the management of many inflammatory disorders but the adverse consequences, especially on bone, can be devastating. The incidence of glucocorticoid-induced osteoporosis (GIO) may be as high as 50% after 6 months' treatment with steroids. This manifests itself as a 30 to 400% increase in the incidence of low trauma fractures. The incidence rates can be even greater in specific clinical settings such as following organ transplantation. The pathogenesis of glucocorticoid-induced osteoporosis remains complex and perplexing.The concomitant prescription of bone-active drugs for the prevention and treatment of GIO in the United Kingdom population remains low, despite the availability of effective therapies. In addition, there remain many unanswered questions about the pathogenesis of GIO and clinical management. These include identification of the optimum bone mineral density threshold at which to intervene with bone-active drugs, the dose or duration of exposure to steroid therapy that warrants intervention, and the demonstration of the efficacy of fracture prevention for different bone-active drugs or for a combination of these drugs.

Clowes JA, Eastell R. · University of Sheffield, Division of Clinical Sciences (NGHT), Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield, S5 7AU, England. · Baillieres Best Pract Res Clin Endocrinol Metab. · Pubmed #11035903 No free full text.

Abstract: The clinical evaluation of osteoporosis in individual patients involves confirmation of the diagnosis, the investigation of secondary causes of osteoporosis and the evaluation of subsequent fracture risk. Optimum clinical assessment involves bone mineral densitometry with the treatment thresholds modified by clinical risk factors for individual patients. Bone turnover markers and clinical risk factors can be used to identify patients at risk of osteoporotic fracture and those who have secondary osteoporosis. Risk assessment should involve the evaluation of absolute rather than relative risk. Further work is required to improve the integration of clinical risk factors, bone turnover markers and bone densitometry into appropriate models to enable the assessment of the absolute risk of fracture for individual patients.

Lee AJ, Hodges S, Eastell R. · Division of Clinical Sciences (NGHT), University of Sheffield, Northern General Hospital, UK. · Ann Clin Biochem. · Pubmed #10902858 No free full text.

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Hart SM, Eastell R. · University of Sheffield, Division of Clinical Sciences (NGHT), Northern General Hospital, Sheffield, UK. · Curr Opin Nephrol Hypertens. · Pubmed #10491736 No free full text.

Abstract: Biochemical markers of bone turnover that are specific to bone allow study of the subtle changes in bone turnover associated with osteoporosis. They have been evaluated in Paget's disease of the bone and chronic renal failure. This review focuses on the use of biochemical markers of bone turnover in osteoporosis. The data in this review period are numerous and varied due to the growing interest in the use of biochemical markers of bone turnover in clinical practice. The data provide support for the use of the newer bone turnover markers for monitoring treatment of osteoporosis, if care is taken to minimize sources of variability.

Ferrar L, Jiang G, Schousboe JT, DeBold CR, Eastell R. · Academic Unit of Bone Metabolism, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom. · J Bone Miner Res. · Pubmed #17967136 No free full text.

Abstract: We compared SQ and ABQ diagnosis of VF imaged by radiography and X-ray absorptiometry. Mild ABQ VF had stronger associations with osteoporosis than mild SQ VF. Interobserver agreement (radiographic diagnosis) was better for ABQ. INTRODUCTION: Vertebral fracture (VF) assessment from images acquired by X-ray absorptiometry (VFA) is often based on a semiquantitative approach (SQ); prevalent VF is identified if vertebral height appears reduced by >20%. Algorithm-based qualitative definition of osteoporotic VF (ABQ) requires evidence of endplate depression, and there is no threshold for reduction in vertebral height. The aims of this study were to (1) compare the prevalence of VFs; (2) compare the characteristics of women with and without VFs; (3) compare interobserver agreement; and (4) compare agreement between methods and imaging modalities for ABQ and SQ definitions of VFs. MATERIALS AND METHODS: Spine radiographs and absorptiometry images for 203 elderly women were assessed using ABQ (readers ABQ-1 and ABQ-2). These readings were compared with SQ assessments (readers SQ-1 and SQ-2) of the same images performed in a previous study. Agreement between readers and methods was assessed by kappa (kappa) statistics. RESULTS: The prevalence of VF was 15-18% (radiography) and 12-24% (VFA) for ABQ and SQ, respectively. Women with ABQ or SQ fractures were older and had lower BMD than those without fracture (p < 0.01). Mild ABQ (but not SQ) VF was associated with low BMD. Kappa scores for interobserver agreement for radiography and VFA, respectively, were as follows: ABQ, kappa = 0.74 (95% CI, 0.60, 0.87) and 0.65 (95% CI, 0.48, 0.81); SQ, kappa = 0.53 (95% CI, 0.46, 0.60) and 0.51 (95% CI, 0.44, 0.58). For agreement between ABQ-1 and SQ-1, kappa = 0.55 (95% CI, 0.39, 0.72) for radiography and 0.41 (95% CI, 0.25, 0.58 for VFA. CONCLUSIONS: The prevalence of radiographic VF identified by ABQ and SQ was similar, but on VFA was 50% higher for SQ. Mild ABQ VF was associated with low BMD. Interobserver agreement for radiographic diagnosis was significantly better for ABQ than for SQ. Agreement between ABQ and SQ was moderate.

Ferrar L, Jiang G, Armbrecht G, Reid DM, Roux C, Glüer CC, Felsenberg D, Eastell R. · Academic Unit of Bone Metabolism, Division of Clinical Sciences (North), University of Sheffield, Sheffield, UK. · Bone. · Pubmed #17499570 No free full text.

Abstract: INTRODUCTION AND HYPOTHESIS: Diagnosis of prevalent osteoporotic vertebral fracture is complicated by normal or developmental variation in vertebral shape or size and non-osteoporotic deformities that appear to have 'reduced' height. Using our visual approach, the algorithm-based qualitative method (ABQ) a vertebra with apparent "reduced" height without evidence of osteoporotic endplate depression is classified as non-osteoporotic short vertebral height (SVH). We aimed to determine whether ABQ classification of SVH represents true or false negative diagnosis of osteoporotic vertebral fracture, by testing the associations with clinical outcomes of osteoporosis or vertebral fracture. METHODS: The ABQ method was used to assess spinal radiographs acquired at baseline for a subset of 904 postmenopausal women participating in the Osteoporosis and Ultrasound Study (OPUS). The sample was enriched with vertebral fracture cases. Subjects were categorized by ABQ diagnosis as (i) normal, (ii) non-osteoporotic short vertebral height (SVH) or (iii) osteoporotic vertebral fracture. RESULTS: Women were classified by ABQ as follows: osteoporotic vertebral fracture, n=231; SVH, n=376 and normal, n=297. Women with vertebral fracture were older, with lower height, weight and height loss than those classified as SVH or normal. Women with SVH were heavier and older, with greater historical height loss than normal women. Age-adjusted SD units (z-scores) for BMD were lower than expected among women with osteoporotic vertebral fracture, but not among those with SVH. There was a significant association between diagnosis of osteoporotic vertebral fracture and history of low-trauma non-vertebral and vertebral fracture (p<0.001, odds ratios=3.2 and 20.6, respectively). There was also an association between diagnosis of SVH and previous low-trauma non-vertebral fracture (p<0.05, odds ratio=1.7). CONCLUSIONS: Short vertebral height without evidence of central endplate fracture in postmenopausal women is largely unrelated to osteoporosis. Quantitative morphometry should not be used alone for the assessment of vertebral fracture in clinical decision making: we recommend differential diagnosis of morphometric vertebral deformities by an expert reader to rule out non-osteoporotic deformities with short vertebral height.

Boonen S, McClung MR, Eastell R, El-Hajj Fuleihan G, Barton IP, Delmas P. · Leuven University Center for Metabolic Bone Diseases and Division of Geriatric Medicine, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium. · J Am Geriatr Soc. · Pubmed #15507059 No free full text.

Abstract: OBJECTIVES: To determine the efficacy of risedronate in reducing vertebral fracture risk in women aged 80 and older with osteoporosis. DESIGN: Pooled analysis of data from three randomized, double-blind, controlled, 3-year-fracture-endpoint trials conducted from November 1993 to April 1998: Hip Intervention Program (HIP), Vertebral Efficacy with Risedronate Therapy-Multinational (VERT-MN), and VERT-North America (NA). SETTING: Office-based practices, research centers, and osteoporosis clinics in Europe, North America, and Australia. PARTICIPANTS: Osteoporotic (femoral neck bone mineral density T-score < -2.5 standard deviations or at least one prevalent vertebral fracture) women aged 80 and older. INTERVENTION: Patients received placebo (n=688) or risedronate 5 mg/d (n=704) for up to 3 years. All patients received 1,000 mg/d calcium and, if baseline levels were low, up to 500 IU/d vitamin D. MEASUREMENTS: Cumulative incidence of new vertebral fractures. RESULTS: After 1 year, the risk of new vertebral fractures in the risedronate group was 81% lower than with placebo (95% confidence interval=60-91%; P<.001). The number of women who needed to be treated to prevent one new vertebral fracture after 1 year was 12. This early onset of efficacy was consistent across the clinical programs, and antifracture efficacy was confirmed over 3 years. Risedronate was well tolerated, with a safety profile comparable with that of placebo. CONCLUSION: These findings provide the first evidence that, even in the very old, reducing bone resorption rate remains an effective treatment strategy for osteoporosis. Because each therapeutic agent used for the treatment of osteoporosis may have unique characteristics, the observations made in this study should not be assumed to apply to other bisphosphonates.

Watts NB, Cooper C, Lindsay R, Eastell R, Manhart MD, Barton IP, van Staa TP, Adachi JD. · University of Cincinnati Osteoporosis Center, Cincinnati, OH, USA. · J Clin Densitom. · Pubmed #15319494 No free full text.

Abstract: Low bone mineral density (BMD) is correlated with increased fracture risk. Whether greater BMD increases induced by osteoporosis drugs are related to greater decreases in fracture risk is controversial. We analyzed the relationship between BMD change and fracture risk in postmenopausal osteoporotic women receiving antiresorptive treatment. The analysis combined data from three pivotal risedronate fracture end-point trials. Women received risedronate (n = 2047) or placebo (n = 1177) daily for up to 3 yr. The BMD and vertebral radiographs were assessed periodically during 3 yr. The estimated risk of new vertebral fracture was compared between patients whose BMD increased and those whose BMD decreased. Risedronate-treated patients whose BMD decreased were at a significantly greater risk (p = 0.003) of sustaining a vertebral fracture than patients whose BMD increased. The fracture risk was similar (about 10%) in risedronate-treated patients whose increases in BMD were < 5% (the median change from baseline) and in those whose increases were >/= 5% (p = 0.453). The changes in lumbar spine BMD explained only 18% (95% confidence interval [CI], 10%, 26%; p < 0.001) of risedronate's vertebral fracture efficacy. Although patients showing an increase in BMD had a lower fracture risk than patients showing a decrease in BMD, greater increases in BMD did not necessarily predict greater decreases in fracture risk.

Glüer CC, Eastell R, Reid DM, Felsenberg D, Roux C, Barkmann R, Timm W, Blenk T, Armbrecht G, Stewart A, Clowes J, Thomasius FE, Kolta S. · Medical Physics, Department of Diagnostic Radiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. · J Bone Miner Res. · Pubmed #15068502 No free full text.

Abstract: We compared the performance of five QUS devices with DXA in a population-based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA. INTRODUCTION: Quantitative ultrasound (QUS) methods have found widespread use for the assessment of bone status in osteoporosis, but their optimal use remains to be established. To determine QUS performance for current devices in direct comparison with central DXA, we initiated a large population-based investigation, the Osteoporosis and Ultrasound Study (OPUS). MATERIALS AND METHODS: A total of 463 women 20-39 years of age and 2374 women 55-79 years of age were measured on five different QUS devices along with DXA of the spine and the proximal femur. Their vertebral fracture status was evaluated radiographically. The association of QUS and DXA with vertebral fracture status was evaluated using logistic regression. RESULTS: All QUS approaches tested discriminated women with and without osteoporotic vertebral fractures (20% height reduction), with age-adjusted standardized odds ratios ranging 1.2-1.3 for amplitude-dependent speed of sound (AD-SOS) at the finger phalanges, 1.2-1.4 for broadband ultrasound attenuation (BUA) at the calcaneus, and 1.4-1.5 for speed of sound (SOS) at the calcaneus, 1.4-1.6 for DXA of the total femur, and 1.5-1.6 for DXA at the spine. For more severe fractures (40% height reduction), age-adjusted standardized odds ratios increased to up to 1.9 for DXA of the spine and 2.3 for SOS of the calcaneus. CONCLUSIONS: In conclusion, all five QUS devices tested showed significant age-adjusted differences between subjects with and without vertebral fracture. When selecting the strongest variable, QUS of the calcaneus worked as well as central DXA for identification of women at high risk for prevalent osteoporotic vertebral fractures. QUS-based case-finding strategies would allow halving the number of radiographs in high-risk populations, and this strategy works increasingly well for women with more severe vertebral fractures. It is likely that the good performance of QUS was in part achieved by rigorous quality assurance measures that should also be used in clinical practice.

Clowes JA, Peel NF, Eastell R. · Bone Metabolism Group, University of Sheffield, Sheffield, United Kingdom S57 AU. · J Clin Endocrinol Metab. · Pubmed #15001596 links to  free full text

Abstract: Long-term adherence and persistence with any therapy are very poor ( approximately 50%). Adherence to therapy is defined as the percentage of prescribed medication taken, and persistence is defined as continuing to take prescribed medication. We examined whether monitoring by nursing staff could enhance adherence and persistence with antiresorptive therapy and whether presenting information on response to therapy provided additional benefit. In addition we evaluated the impact of monitoring on treatment efficacy. Seventy-five postmenopausal women with osteopenia were randomized to 1) no monitoring, 2) nurse-monitoring, or 3) marker-monitoring. All subjects were prescribed raloxifene. At 12, 24, and 36 wk, the nursing staff reviewed subjects in the monitored (nurse-monitoring or marker-monitoring) groups using a predefined protocol. The marker-monitored group were also presented a graph of response to therapy using percentage change in urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, at each visit. Biological response to therapy at 1 yr was determined using the percent change in bone mineral density (BMD) and uNTX. Treatment adherence and persistence were assessed using electronic monitoring devices. Survival analysis showed that the monitored group increased cumulative adherence to therapy by 57% compared with no monitoring (P = 0.04). There was a trend for the monitored group to persist with therapy for 25% longer compared with no monitoring (P = 0.07). Marker measurements did not improve adherence or persistence to therapy compared with nurse-monitoring alone. Adherence at 1 yr was correlated with percent change in hip (BMD) (r = 0.28; P = 0.01) and percent change in uNTX (r = -0.36; P = 0.002). In conclusion, monitoring of patients increased adherence to therapy by 57% at 1 yr. Increased adherence to therapy increased the effectiveness of raloxifene therapy determined using surrogate end points.

Cooper MS, Blumsohn A, Goddard PE, Bartlett WA, Shackleton CH, Eastell R, Hewison M, Stewart PM. · Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. · J Clin Endocrinol Metab. · Pubmed #12915682 links to  free full text

Abstract: Individual susceptibility to glucocorticoid-induced osteoporosis is difficult to predict clinically. We recently characterized expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in human osteoblasts. This enzyme generates active cortisol (or prednisolone) from inactive cortisone (or prednisone) and regulates glucocorticoid action in vitro. We, thus, hypothesized that osteoblastic 11beta-HSD1 mediates susceptibility to glucocorticoid-induced osteoporosis. Twenty healthy males ingested 5 mg prednisolone twice daily for 7 d, and relationships between changes in bone turnover markers and urinary measures of corticosteroid metabolism were examined. The bone formation markers osteocalcin and N-terminal propeptide of type I collagen decreased in all subjects (P < 0.001), but resorption markers were unchanged. The extent of fall in formation markers correlated with baseline 11beta-HSD1 activity with high activity predicting the greatest fall [for osteocalcin d 4 and 7, r = -0.58 and -0.56 (P < 0.01); for N-terminal propeptide of type I collagen d 4, r = -0.51 (P < 0.05)]. There was no correlation with measures of glucocorticoid inactivation or total corticosteroid metabolite production. Urinary measures of 11beta-HSD1 activity predict the response of bone formation markers to glucocorticoids, and this appears to reflect increased generation of active glucocorticoids within osteoblasts. Measures of 11beta-HSD1 activity may predict individual susceptibility to glucocorticoid-induced osteoporosis, and these data should facilitate the development of bone-sparing glucocorticoids.

Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas PD. · Bone Metabolism Group, University of Sheffield, Sheffield, United Kingdom. · J Bone Miner Res. · Pubmed #12817758 No free full text.

Abstract: Changes in the level of biochemical markers of bone resorption with risedronate treatment for osteoporosis were examined as a surrogate for the decrease in fracture risk. Greater decreases in bone resorption markers were associated with greater decreases in vertebral (and nonvertebral) fractures. Antifracture efficacy of antiresorptive therapies is only partially explained by increases in bone mineral density. Early decreases in bone resorption may also play a role. We tested this hypothesis by measuring two bone resorption markers, the C-telopeptide of type I collagen (CTX) and the N-telopeptide of type I collagen (NTX), in osteoporotic patients in risedronate vertebral fracture trials. We studied 693 women with at least one vertebral deformity (mean age, 69 +/- 7 years) who received calcium (and vitamin D if required) and placebo or risedronate 5 mg daily for 3 years. The reductions in urinary CTX (median, 60%) and NTX (51%) at 3-6 months with risedronate therapy were significantly associated (p < 0.05) with the reduction in vertebral fracture risk (75% over 1 year and 50% over 3 years). The changes in both CTX and NTX accounted for approximately one-half (CTX, 55%; NTX, 49%) of risedronate's effect in reducing the risk of vertebral fractures in the first year and approximately two-thirds (CTX, 67%; NTX, 66%) over 3 years compared with placebo. The changes in CTX and NTX accounted for 77% and 54%, respectively, of risedronate's effect in reducing the risk of nonvertebral fractures over 3 years compared with placebo. The relationships between vertebral fracture risk and changes from baseline in CTX and NTX were not linear (p < 0.05). There was little further improvement in fracture benefit below a decrease of 55-60% for CTX and 35-40% for NTX. The decrease in bone resorption in patients taking risedronate accounts for a large proportion of the reduction in fracture risk. There may be a level of bone resorption reduction below which there is no further fracture benefit.

Delmas PD, Ensrud KE, Adachi JD, Harper KD, Sarkar S, Gennari C, Reginster JY, Pols HA, Recker RR, Harris ST, Wu W, Genant HK, Black DM, Eastell R, Anonymous00151. · University of Claude Bernard of Lyon, Hôpital Edouard Herriot, Service de Rhumatologie et de Pathologie Osseuse, Lyon 69437, France. · J Clin Endocrinol Metab. · Pubmed #12161484 links to  free full text

Abstract: The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis randomized to placebo, or raloxifene 60 or 120 mg/d [JAMA 282(1999): 637]. This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr. New vertebral fractures was assessed from radiographs taken at baseline, yr 2-4. The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr. A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr. The 4-yr cumulative relative risks (RR) for one or more new vertebral fractures were 0.64 [95% confidence interval (CI) 0.53, 0.76] with raloxifene 60 mg/d and 0.57 (95% CI 0.48, 0.69) with raloxifene 120 mg/d. In yr 4 alone, raloxifene 60 mg/d reduced the new vertebral fracture risk by 39% [RR 0.61 (95% CI 0.43, 0.88)], which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups, irrespective of prevalent fracture status. The nonvertebral fracture risk was not significantly reduced [RR 0.93 (95% CI 0.81, 1.06)]. The safety profile after 4 yr was similar to that observed after 3 yr. Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis. The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr.