Osteoporosis: Compston JE

Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, Peters E, Hanley DA, Chaudry SR, Dempster DW, Glorieux FH, Neville AJ, Talwar RM, Clokie CM, Al Mardini M, Paul T, Khosla S, Josse RG, Sutherland S, Lam DK, Carmichael RP, Blanas N, Kendler D, Petak S, St-Marie LG, Brown J, Evans AW, Rios L, Compston JE, Anonymous00076. · Divisions of Endocrinology and Geriatrics, McMaster University, Hamilton, Ontario, Canada. · J Rheumatol. · Pubmed #18528958 No free full text.

Abstract: OBJECTIVE: Following publication of the first reports of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates in 2003, a call for national multidisciplinary guidelines based upon a systematic review of the current evidence was made by the Canadian Association of Oral and Maxillofacial Surgeons (CAOMS) in association with national and international societies concerned with ONJ. The purpose of the guidelines is to provide recommendations regarding diagnosis, identification of at-risk patients, and prevention and management strategies, based on current evidence and consensus. These guidelines were developed for medical and dental practitioners as well as for oral pathologists and related specialists. METHODS: The multidisciplinary task force established by the CAOMS reviewed all relevant areas of research relating to ONJ associated with bisphosphonate use and completed a systematic review of current literature. These evidence-based guidelines were developed utilizing a structured development methodology. A modified Delphi consensus process enabled consensus among the multidisciplinary task force members. These guidelines have since been reviewed by external experts and endorsed by national and international medical, dental, oral surgery, and oral pathology societies. RESULTS: Recommendations regarding diagnosis, prevention, and management of ONJ were made following analysis of all current data pertaining to this condition. ONJ has many etiologic factors including head and neck irradiation, trauma, periodontal disease, local malignancy, chemotherapy, and glucocorticoid therapy. High-dose intravenous bisphosphonates have been identified as a risk factor for ONJ in the oncology patient population. Low-dose bisphosphonate use in patients with osteoporosis or other metabolic bone disease has not been causally linked to the development of ONJ. Prevention, staging, and treatment recommendations are based upon collective expert opinion and current data, which has been limited to case reports, case series, surveys, retrospective studies, and 2 prospective observational studies. Recommendations: In all oncology patients, a thorough dental examination including radiographs should be completed prior to the initiation of intravenous bisphosphonate therapy. In this population, any invasive dental procedure is ideally completed prior to the initiation of high-dose bisphosphonate therapy. Non-urgent procedures are preferably delayed for 3 to 6 months following interruption of bisphosphonate therapy. Osteoporosis patients receiving oral or intravenous bisphosphonates do not require a dental examination prior to initiating therapy in the presence of appropriate dental care and good oral hygiene. Stopping smoking, limiting alcohol intake, and maintaining good oral hygiene should be emphasized for all patients receiving bisphosphonate therapy. Individuals with established ONJ are most appropriately managed with supportive care including pain control, treatment of secondary infection, removal of necrotic debris, and mobile sequestrate. Aggressive debridement is contraindicated. CONCLUSION: Our multidisciplinary guidelines, which provide a rational evidence-based approach to the diagnosis, prevention, and management of bisphosphonate-associated ONJ in Canada, are based on the best available published data and the opinion of national and international experts involved in the prevention and management of ONJ.

Collier JD, Ninkovic M, Compston JE. · Department of Gastroenterology, John Radcliffe Hospital, Oxford, OX3 9DU, UK. · Gut. · Pubmed #11788576 links to  free full text

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Kanis JA, Compston JE, Anonymous00024. · No affiliation provided · Osteoporos Int. · Pubmed #18528723 No free full text.

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Compston JE. · Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Eur J Gastroenterol Hepatol. · Pubmed #12072590 No free full text.

Abstract: Reduced bone mineral density has been reported in patients with inflammatory bowel disease and recent studies indicate that there is also an increase in the relative risk of fracture. Absolute risk of fracture is, however, generally low and thus measurement of bone mineral density as a screening procedure for all patients with inflammatory bowel disease may be inappropriate. In one study, urinary excretion of N-telopeptides, which reflects whole body bone resorption, was shown to be negatively related to bone mineral density, raising the possibility that this measurement could be used to select those in whom bone densitometry is required. However, the value of this approach in predicting fracture risk remains unproven and the relative contributions of clinical risk factors, biochemical markers of bone turnover and bone mineral density measurements to fracture risk in patients with inflammatory bowel disease require further study.

Compston JE. · No affiliation provided · Rheumatology (Oxford). · Pubmed #11136870 links to  free full text

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Compston JE. · No affiliation provided · Bone. · Pubmed #11113386 No free full text.

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Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, Peters E, Hanley DA, Chaudry SR, Lentle B, Dempster DW, Glorieux FH, Neville AJ, Talwar RM, Clokie CM, Mardini MA, Paul T, Khosla S, Josse RG, Sutherland S, Lam DK, Carmichael RP, Blanas N, Kendler D, Petak S, Ste-Marie LG, Brown J, Evans AW, Rios L, Compston JE, Anonymous00115. · Divisions of Endocrinology and Geriatrics, McMaster University, Oakville, ON L6J 1X8, Canada. · J Rheumatol. · Pubmed #19286860 No free full text.

Abstract: In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%-12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.

Compston JE. · University of Cambridge School of Clinical Medicine, and Addenbrooke's Hospital, Box 157, Cambridge CB2 2QQ, UK. · Curr Rheumatol Rep. · Pubmed #17437672 No free full text.

Abstract: Glucocorticoid-induced osteoporosis is a common but still relatively neglected problem, with a low level of awareness among primary and secondary care physicians. Fractures appear early after initiation of treatment, and effective prophylaxis requires primary prevention in those at high risk of fracture. Bisphosphonates are the treatment of choice, and calcium and vitamin D supplements are also indicated in the majority of individuals. Organized care programs together with the use of evidence-based guidelines have the potential to improve significantly the management of this serious complication of glucocorticoid therapy.

Poole KE, Compston JE. · Addenbrooke's Hospital, Cambridge CB2 2QQ. · BMJ. · Pubmed #17170416 No free full text.

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Compston JE. · School of Clinical Medicine, University of Cambridge, Cambridge CB2 2QQ, UK. · Bone. · Pubmed #17045858 No free full text.

Abstract: Intermittent administration of parathyroid hormone peptides has anabolic skeletal effects and reduces fracture risk in postmenopausal women with osteoporosis but the cellular and structural mechanisms by which these effects are mediated have not been fully established. In cancellous and endocortical bone, there is evidence that both modelling and remodelling-based formation contribute to the increase in bone mass although the contribution of these at different time points in the response to PTH has not been established. Despite the large increase in spine bone mineral density, however, significant increases in iliac crest cancellous bone volume and trabecular thickness have not been consistently demonstrated, possibly reflecting site-specific differences in PTH-induced skeletal effects and/or the large sampling and measurement variance associated with assessment of iliac crest cancellous bone volume and structure. In iliac crest cortical bone, increased cortical thickness has been demonstrated, due at least in part to increased endosteal bone formation; there is also some evidence for increased formation on periosteal surfaces. At some sites an increase in cortical porosity may also occur and the overall effects on cortical bone strength, particularly at the hip, remain to be established. Studies in iliac crest bone indicate a trend towards a lower mineralisation density of bone matrix and increased heterogeneity of mineralisation, consistent with new bone formation. In addition, there is a reduction in mineral crystallinity and a shift towards more divalent collagen cross-links, indicating a change towards a younger bone profile. The potential clinical implications of these effects on bone are currently unknown. The stimulatory effect of PTH peptides on bone formation may favour their use in low turnover bone disease and in states of advanced bone loss. Furthermore, if beneficial effects on cortical bone strength are confirmed, efficacy at non-vertebral sites might be superior to those observed with antiresorptive drugs. Better definition of the effects of intermittent PTH administration on cancellous and cortical bone remodelling and structure at different skeletal sites may inform these speculations and is an important area for future research.

Compston JE. · Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK. · J Musculoskelet Neuronal Interact. · Pubmed #15615123 links to  free full text

Abstract: For many years hormone replacement therapy (HRT) was regarded as the gold standard for treatment of osteoporosis. In recent years this status has been challenged, because of the lack of a robust evidence base for anti-fracture efficacy, emerging evidence of adverse extraskeletal effects and the demonstrated efficacy of a number of alternative options in the prevention of osteoporotic fractures. The current consensus is that HRT is no longer regarded as a front-line option for prevention of osteoporotic fractures and that its use for this purpose should be restricted to women with osteoporosis who have menopausal symptoms and to older women who are intolerant of other therapies and/or express a strong preference for HRT despite being informed about potential adverse effects. Nevertheless, the mechanisms by which estrogen exerts its beneficial skeletal effects remain a major area of research that has important implications for the development of novel therapies.

Compston JE. · Department of Medicine, University of Cambridge School of Clinical Medicine, United Kingdom. · Liver Transpl. · Pubmed #12682881 links to  free full text

Abstract: Osteoporosis remains a serious potential complication of liver transplantation, although its incidence may be significantly reduced by the use of lower doses of glucocorticoids. Additional factors likely to contribute to its pathogenesis include other immunosuppressive agents, particularly cyclosporin A and FK506, vitamin D insufficiency, secondary hyperparathyroidism, hypogonadism and pre-existing bone disease. Bone density assessment and spinal X-rays should be performed before transplantation to assess subsequent fracture risk and vitamin D and gonadal status assessed. Measures should be taken to optimise bone health prior to transplantation; in those with low bone mineral density and/or previous fragility fracture, prophylaxis against bone loss after transplantation should be considered. Although anti-fracture efficacy has not been established for any agent there is evidence, mainly in patients undergoing other forms of solid organ transplantation, that repeated infusions of pamidronate may be effective in preventing bone loss.

Compston JE. · Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. · Physiol Rev. · Pubmed #11152762 links to  free full text

Abstract: Sex steroids are essential for skeletal development and the maintenance of bone health throughout adult life, and estrogen deficiency at menopause is a major pathogenetic factor in the development of osteoporosis in postmenopausal women. The mechanisms by which the skeletal effects of sex steroids are mediated remain incompletely understood, but in recent years there have been considerable advances in our knowledge of how estrogens and, to a lesser extent androgens, influence bone modeling and remodeling in health and disease. New insights into estrogen receptor structure and function, recent discoveries about the development and activity of osteoclasts, and lessons learned from human and animal genetic mutations have all contributed to increased understanding of the skeletal effects of estrogen, both in males and females. Studies of untreated and treated osteoporosis in postmenopausal women have also contributed to this knowledge and have provided unequivocal evidence for the potential of high-dose estrogen therapy to have anabolic skeletal effects. The development of selective estrogen receptor modulators has provided a new approach to the prevention of osteoporosis and other major diseases of menopause and has implications for the therapeutic use of other steroid hormones, including androgens. Further elucidation of the mechanisms by which sex steroids affect bone thus has the potential to improve the clinical management not only of osteoporosis, both in men and women, but also of a number of other diseases related to sex hormone status.

Tobias JH, Compston JE. · Rheumatology Unit, University of Bristol Division of Medicine, Bristol Royal Infirmary, UK. · Bone. · Pubmed #9951780 No free full text.

Abstract: How estrogen therapy influences bone metabolism in postmenopausal women has previously been studied using several approaches, including bone densitometry, measurement of biochemical markers of bone turnover, and histomorphometry. Taken together, these investigations suggest that conventional doses of estrogen protect from bone loss predominantly through suppression of bone resorption, with little evidence to suggest that a stimulatory action on osteoblasts is also involved. In contrast, studies of patients treated with estradiol implants suggest that, following prolonged exposure to relatively high estrogen levels, an additional stimulatory effect on osteoblast function is observed. The suggestion that estrogen stimulates osteoblast activity in postmenopausal women under certain circumstances is consistent with other evidence that estrogen is an important physiological regulator of osteoblast activity. Furthermore, these findings raise the possibility that it may be useful to develop strategies for treating postmenopausal osteoporosis that aim to reproduce the stimulatory action of relatively high estrogen levels on bone formation in postmenopausal women.

Minaur NJ, Kounali D, Vedi S, Compston JE, Beresford JN, Bhalla AK. · The Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath BA1 1RL, UK. · Rheumatology (Oxford). · Pubmed #12096222 links to  free full text

Abstract: OBJECTIVE: To determine the effect of methotrexate (MTX) on bone mineral density (BMD) in rheumatoid arthritis (RA). METHODS: One hundred and sixteen non-steroid-treated RA subjects (90 women) were studied in a prospective, longitudinal, non-randomized study. Subjects started MTX (n=36) or sulphasalazine (n=23) or continued long-term (>5 yr) treatment with MTX (n=28) or other disease-modifying anti-rheumatic drugs (n=29). BMD was estimated at entry and after 1 yr. Markers of bone turnover were measured at entry and at 1 yr, and additionally at 3 and 6 months in those starting treatment. Bone biopsies were taken before and after MTX treatment in four subjects. The primary outcome was change in BMD Z score and secondary outcomes were changes in bone turnover markers and bone formation by histomorphometry. RESULTS: Univariate analysis of covariance found that MTX at baseline was associated with reduced BMD at the femoral neck. However, femoral neck BMD was also associated with radiological damage score for the hand. Multivariate analysis and discriminant analysis of the subset of post-menopausal women showed that reduced bone density associated with MTX was due to confounders such as disease activity. There was no adverse effect of MTX on bone turnover markers or on measures of bone formation in biopsies. CONCLUSIONS: No adverse effect of low-dose MTX (mean 10 mg/week) on bone formation in RA was found.

Ninkovic M, Love S, Tom BD, Bearcroft PW, Alexander GJ, Compston JE. · Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. · J Hepatol. · Pubmed #12076867 No free full text.

Abstract: BACKGROUND/AIMS: Increased rates of bone loss and fracture have been reported after liver transplantation. The aim of this study was to investigate the effects of a pre-transplant infusion of pamidronate on fracture incidence and bone loss during the first year after transplantation. METHODS: Ninety-nine adults awaiting orthotopic liver transplantation (OLT) were randomised to pamidronate or no treatment. Spinal X-rays were obtained at baseline and after 12 months. Bone mineral density (BMD) was measured at the lumbar spine (L1-4) and femoral neck at baseline, and 3, 6, and 12 months after OLT. RESULTS: The incidence of fractures in the first year after OLT was 8%, four patients within the pamidronate treated group and two in the untreated group developing fractures (P=0.40). No significant spinal bone loss occurred in either group during the first year. However, significant and sustained bone loss occurred at the femoral neck in both groups. No significant differences were seen between pamidronate treated or untreated groups at either site. CONCLUSIONS: Pamidronate in the regimen used had no significant effect on fracture rate or BMD post-transplant. The low incidence of fracture and absence of spinal bone loss indicate that bone disease after liver transplantation may be less common than previously reported.

Vedi S, Ninkovic M, Garrahan NJ, Alexander GJ, Compston JE. · Department of Medicine, Box 157, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge CB2 2QQ, UK. · Transpl Int. · Pubmed #12072899 No free full text.

Abstract: Osteoporosis is a common and serious complication of solid organ transplantation. Effective therapeutic regimens have not been established but evidence that increased bone turnover is responsible for bone loss early after transplantation provides a rationale for the use of anti-resorptive agents in the peri-operative period. We have examined the effects of a single pre-operative infusion of pamidronate, 60 mg, on bone remodelling and turnover in a prospective study of 12 patients, four male and eight female aged 19-61 years, with chronic liver disease, who formed a subgroup of a larger randomised controlled single-blind study. Iliac-crest biopsies were obtained before and 3 months after liver transplantation and histomorphometry performed using image analysis. In untreated patients ( n=5) a significant increase in bone formation rate at tissue level was demonstrated at 3 months in comparison to pre-operative values (0.035+/-0.013 vs. 0.161+/-0.12 microm(2)/microm/day; mean +/- SD, P=0.003). In patients treated with pamidronate ( n=7) no significant increase in bone formation rate was demonstrated at 3 months, although there was a trend towards an increase in indices of bone turnover. In this group there was also a significant reduction in erosion cavity length (210.4+/-63.8 vs. 179.8+/-67.5 microm; P=0.03) and non-significant reductions in other indices of erosion cavity size. These results indicate that pre-operative administration of pamidronate in patients with chronic liver disease prevents, at least in part, the increase in bone turnover which occurs in untreated patients after transplantation.

Compston JE. · Department of Medicine, Box 157, Level 5, Addenbrooke's Hospital, Hills. Road, Cambridge CB2 2QQ, UK. · Gut. · Pubmed #10375295 links to  free full text

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Vilariño-Güell C, Miles LJ, Duncan EL, Ralston SH, Compston JE, Cooper C, Langdahl BL, Maclelland A, Pols HA, Reid DM, Uitterlinden AG, Steer CD, Tobias JH, Wass JA, Brown MA. · Institute of Musculoskeletal Sciences, Botnar Research Centre, Nuffield Orthopaedic Centre, University of Oxford, Headington, Oxford, UK. · Calcif Tissue Int. · Pubmed #17885720 No free full text.

Abstract: We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z< -2.0) and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (785 unrelated individuals, mean age 118 months), were genotyped for the five most informative SNPs (minor allele frequency >5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021-0.047). This association was restricted to the youngest tertile of the population (age 16-39 years, P = 0.013-0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.

Compston JE, Seeman E. · Department of Medicine, University of Cambridge Clinical School, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. · Lancet. · Pubmed #16980096 No free full text.

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Shead EF, Haworth CS, Gunn E, Bilton D, Scott MA, Compston JE. · Department of Haematology, NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom. · Am J Respir Crit Care Med. · Pubmed #16675777 links to  free full text

Abstract: RATIONALE: Adults with cystic fibrosis (CF) are at increased risk of developing osteoporosis. During infective exacerbations, increased production of proinflammatory cytokines and markers of bone resorption have been reported. OBJECTIVE: The aim of this study is to investigate the growth and proliferation of potential osteoclast precursor cells before, during, and after intravenous antibiotic treatment of infective exacerbations in patients with CF. METHODS: Hematopoietic precursor cell growth was examined using colony formation assays using Methocult culture medium. Circulating potential osteoclast precursors were identified using four-color flow cytometry by CD14, CD33, CD34, and CD45 expression. RESULTS: At the start of an infective exacerbation increases in hematopoietic precursor colony formation (15.42 colonies/10(5) cells plated, p = 0.025), proliferation (28.5%, p < 0.001), and the numbers of circulating potential osteoclast precursors (6.5%, p < 0.001) were seen in comparison with baseline levels. These increases declined after treatment with intravenous antibiotics to a level close to baseline. CONCLUSIONS: The results demonstrate an increase in the production of potential osteoclast precursors in the peripheral blood during CF infective exacerbations. This may result in increased bone resorption and contribute to bone loss in patients with CF.

Compston JE, McConachie C, Stott C, Hannon RA, Kaptoge S, Debiram I, Love S, Jaffa A. · Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK. · Osteoporos Int. · Pubmed #15889315 No free full text.

Abstract: Osteoporosis is a serious complication of anorexia nervosa and in affected adolescents may result in a permanent deficit in bone mass. The pathophysiology of this bone disease has not been clearly defined. In this prospective study of 26 young women with anorexia nervosa aged 13-20 years (mean 16.5) we have measured changes in bone mineral density, total body composition and biochemical indices of bone turnover over 1 year. Over this period there was a mean weight gain of 10 kg and significant height gain with baseline and final values for body mass index of 14.2+/-1.7 and 17.6+/-2.3 kg/m2 (P<0.001). However, no significant changes were seen in bone mineral density in the spine or proximal femur during the study; total body bone mineral content was significantly higher than baseline at 3 months and 12 months (P=0.001 and P<0.0001), but total body bone mineral density at 3 months was significantly lower than baseline (P=0.003). Serum osteocalcin and bone-specific alkaline phosphatase values increased significantly and remained higher than baseline at all time points whereas urinary NTX/creatinine excretion showed a non-significant increase over the first 6 months of the study, but at 12 months, the mean value was significantly lower than baseline. Mean serum 25-hydroxyvitamin D levels showed a significant decrease at 6 months (P<0.05), but returned towards baseline thereafter. There was a significant increase in serum parathyroid hormone levels at all time points compared to baseline, these occurring within the normal range. These results indicate that although weight gain in young anorexics is associated with linear growth, bone mineral density does not increase. Whether this deficit can be corrected subsequently requires longer-term prospective studies.

Boivin G, Vedi S, Purdie DW, Compston JE, Meunier PJ. · INSERM Unité 403, Faculté de Médecine R. Laennec, Université C. Bernard-Lyon 1, 69372 Lyon Cedex 08, France. · Bone. · Pubmed #15777681 No free full text.

Abstract: The beneficial skeletal effects of menopausal estrogen replacement therapy (HRT) are well documented. The role of secondary mineralization of bone as a determinant of bone quality is now well established in postmenopausal women treated with bisphosphonates or SERMs. The aim of present study was to investigate the effect of conventional and high doses of estrogen on the main parameters reflecting the degree of mineralization of bone (DMB). Bone biopsies were obtained from 20 women with osteopenia or osteoporosis before and after 24 months (18 to 38 months) of conventional HRT, and from 19 women who had received high doses of estradiol (implant 100 mg every 3-6 months for 1.5-20 years). DMB parameters (mean DMB, DMB Freq. Max. and Heterogeneity Index of the individual distributions of DMB) were measured using quantitative microradiography in cortical, cancellous, and total bone and expressed as g mineral/cm(3) bone. Values obtained in women before HRT were lower than those reported in pre- and postmenopausal control women. After conventional HRT, there was an increase in mean DMB (total bone) of 4.4 +/- 1.9% (mean +/- SEM) versus pre-treatment values (4.1 +/- 2.1% in cortical bone, 4.5 +/- 2.3% in cancellous bone); these differences did not reach statistical significance (P = 0.055). Results were similar for DMB Freq. Max. but Heterogeneity Index was not significantly changed. After high dose estradiol therapy, mean DMB (total bone) was 6.9 +/- 1.9% higher than in untreated women (8.6 +/- 2.1% in cortical bone, 6.5 +/- 2.1% in cancellous bone); this difference was statistically significant (P </= 0.03). Results were similar for DMB Freq. Max. but once again Heterogeneity Index was not significantly modified. The increases in mean DMB were due to a shift of the curves towards high DMB with a decrease of the low DMB values, as confirmed by the absence of changes in the Heterogeneity Index. Estrogen therapy is associated with an increased degree of mineralization of bone induced by a prolongation of secondary mineralization, similar to that observed with other antiresorptive agents. However, this increase was about two-fold lower than that observed after alendronate therapy (10 mg/day/3 years) in postmenopausal osteoporotic women.

Ralston SH, Galwey N, MacKay I, Albagha OM, Cardon L, Compston JE, Cooper C, Duncan E, Keen R, Langdahl B, McLellan A, O'Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass J, Bennett ST. · Rheumatic Diseases Unit, University of Edinburgh Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland, UK. · Hum Mol Genet. · Pubmed #15746152 links to  free full text

Abstract: Osteoporosis is a common disease with a strong genetic component, characterized by reduced bone mass and an increased risk of fracture. Bone mineral density (BMD) is a highly heritable trait and a key determinant of osteoporotic fracture risk, but the genes responsible are incompletely defined. Here, we identified quantitative trait loci (QTL) for regulation of BMD by a genome wide scan involving 3691 individuals from 715 families, who were selected because of reduced BMD values at the lumbar spine (LS-BMD) or femoral neck (FN-BMD) in probands. Linkage analysis was conducted in the study group as a whole with correction for age, gender, weight and height. Further analyses were conducted for men and women separately to identify gender-specific QTL and for those under and over the age of 50 years to distinguish QTL for peak bone mass from those that influence bone mass in older people. No regions of suggestive or significant linkage were identified when data from all subjects were analyzed together. On subgroup analysis, however, we identified a significant QTL for FN-BMD on chromosome 10q21 (LOD score +4.42; men < or =50 years) and two suggestive QTL for LS-BMD on chromosomes 18p11 (LOD score +2.83; women >50 years) and 20q13 (LOD score +3.20; women < or =50 years). We identified five other QTL for BMD with LOD scores of greater than +2.20 on chromosomes 3q25, 4q25, 7p14, 16p13 and 16q23. This study provides evidence for gender-specific, site-specific and age-specific QTL, which regulate BMD in humans, and illustrates the importance of conducting subgroup analysis to detect these loci.

Koay MA, Woon PY, Zhang Y, Miles LJ, Duncan EL, Ralston SH, Compston JE, Cooper C, Keen R, Langdahl BL, MacLelland A, O'Riordan J, Pols HA, Reid DM, Uitterlinden AG, Wass JA, Brown MA. · Institute of Musculoskeletal Sciences, University of Oxford, The Botnar Research Centre, Nuffield Orthopaedic Centre, Headington, Oxford, UK. · J Bone Miner Res. · Pubmed #15355556 No free full text.

Abstract: Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD. INTRODUCTION: Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50-80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population. MATERIALS AND METHODS: To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score > 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA. RESULTS: PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of >5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p < 1 x 10(-5) in men only, p = 0.0019 in both men and women). This association was also observed in comparisons of osteoporotic probands and unrelated elevated BMD in women (p = 0.03), along with associations with markers in exons 8 (C135242T, p = 0.007) and 9 (C141759T, p = 0.02). Haplotypes composed of two to three of the SNPs G121513A, C135242T, G138351A, and C141759T were strongly associated with BMD when comparing osteoporotic probands and high BMD cases (p < 0.003). An SNP at nucleotide C165215T in exon 18 was linked to BMD at the lumbar spine, femoral neck, and total hip (parametric LOD scores = 2.8, 2.5, and 2.2 and nonparametric LOD scores = 0.3, 1.1, and 2.2, respectively) but was not genetically associated with BMD variation. CONCLUSION: These results show that common LRP5 polymorphisms contribute to the determination of BMD in the general population.