Osteoporosis: Bouxsein ML

Engelke K, Adams JE, Armbrecht G, Augat P, Bogado CE, Bouxsein ML, Felsenberg D, Ito M, Prevrhal S, Hans DB, Lewiecki EM. · Institute of Medical Physics, University of Erlangen, Germany; Synarc, Hamburg, Germany. <> · J Clin Densitom. · Pubmed #18442757 No free full text.

Abstract: The International Society for Clinical Densitometry (ISCD) has developed Official Positions for the clinical use of dual-energy X-ray absorptiometry (DXA) and non-DXA technologies. While only DXA can be used for diagnostic classification according to criteria established by the World Health Organization, DXA and some other technologies may predict fracture risk and be used to monitor skeletal changes over time. ISCD task forces reviewed the evidence for clinical applications of non-DXA techniques and presented reports with recommendations at the 2007 ISCD Position Development Conference. Here we present the ISCD Official Positions for quantitative computed tomography (QCT) and peripheral QCT (pQCT), with supporting medical evidence, rationale, controversy, and suggestions for further study. QCT is available for bone mineral density measurements at the spine, hip, forearm, and tibia. The ISCD Official Positions presented here focus on QCT of the spine and pQCT of the forearm. Measurements at the hip may have clinical relevance, as this is an important fracture site; however, due to limited medical evidence, definitive advice on its use in clinical practice cannot be provided until more data emerge.

Bonner FJ, Sinaki M, Grabois M, Shipp KM, Lane JM, Lindsay R, Gold DT, Cosman F, Bouxsein ML, Weinstein JN, Gallagher RM, Melton LJ, Salcido RS, Gordon SL. · Medical Director, Rehabilitation Hospital of South Jersey, Vineland, NJ, USA. · Osteoporos Int. · Pubmed #12759719 No free full text.

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Bouxsein ML. · Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · Nat Clin Pract Rheumatol. · Pubmed #18431371 No free full text.

Abstract: Fractures that result from osteoporosis are an enormous and growing concern for public health systems; as the population ages, the number of fractures worldwide will double or triple in the next 50 years. The ability of a bone to resist fracture depends not only on the amount of bone present, but also on the spatial distribution of the bone mass, the cortical and trabecular microarchitecture, and the intrinsic properties of the materials that comprise the bone. Although low bone mineral density is one of the strongest risk factors for fracture, a number of clinical studies have demonstrated the limitations of using measurements of areal bone mineral density by dual-energy X-ray absorptiometry to assess fracture risk and to monitor responses to therapy. As a result, new, noninvasive imaging techniques that are capable of assessing various components of bone strength are being developed. These techniques include three-dimensional assessments of bone density, geometry and microarchitecture, as well as integrated measurements of bone strength by engineering analyses. Although they show strong potential, further development and validation of these techniques is needed to define their role in the clinical management of individuals with osteoporosis.

Rosen CJ, Bouxsein ML. · The Jackson Laboratory in Bar Harbor, ME 04401, USA. · Nat Clin Pract Rheumatol. · Pubmed #16932650 No free full text.

Abstract: Osteoporosis and obesity, two disorders of body composition, are growing in prevalence. Interestingly, these diseases share several features including a genetic predisposition and a common progenitor cell. With aging, the composition of bone marrow shifts to favor the presence of adipocytes, osteoclast activity increases, and osteoblast function declines, resulting in osteoporosis. Secondary causes of osteoporosis, including diabetes mellitus, glucocorticoids and immobility, are associated with bone-marrow adiposity. In this review, we ask a provocative question: does fat infiltration in the bone marrow cause low bone mass or is it a result of bone loss? Unraveling the interface between bone and fat at a molecular and cellular level is likely to lead to a better understanding of several diseases, and to the development of drugs for both osteoporosis and obesity.

Bouxsein ML, Karasik D. · Orthopedic Biomechanics Laboratory, RN115, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA. · Curr Osteoporos Rep. · Pubmed #16822403 No free full text.

Abstract: Although low bone mineral density is among the strongest risk factors for fracture, a number of clinical studies have demonstrated the limitations of bone mineral density measurements in assessing fracture risk and monitoring the response to therapy. These observations have brought renewed attention to the broader array of factors that influence skeletal fragility, including bone size, shape, and microarchitecture. This article reviews the relationship between bone geometry and skeletal fragility, focusing on the impact of bone geometry on bone strength and fracture risk. It also reviews recent data on the effect of osteoporosis therapies on femoral geometry. It is clear that characteristics of a bone's size and shape strongly influence its biomechanical strength, but there is no consensus as to the geometric parameters that improve prediction of fracture risk. Recent data from hip structure analysis indicate that antiresorptive and anticatabolic treatments alter femoral geometry, but this observation depends on several assumptions that have not been tested in subjects treated with osteoporosis therapies. Current knowledge is limited, in part, by the predominant use of two-dimensional techniques to assess bone geometry. Additional studies that incorporate three-dimensional imaging are needed to better define the relationship between bone geometry and skeletal fragility, and to establish the clinical utility of bone geometry measurements.

Thomas T, Feron JM, Delmas PD, Kaufman J, Tosi L, Cummings S, Lane J, Johnell O, Bouxsein ML. · Département de Rhumatologie, Inserm 0366, CHU de Saint-Etienne, boulevard Pasteur, 42055 Saint-Etienne Cedex 02. · Rev Chir Orthop Reparatrice Appar Mot. · Pubmed #16800073 No free full text.

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Bouxsein ML. · Department of Orthopaedic Surgery, Harvard Medical School and Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA. · Best Pract Res Clin Rheumatol. · Pubmed #16301186 No free full text.

Abstract: Strategies to reduce fracture risk must be based on a sound understanding of the mechanisms that underline the increased incidence of fractures with age and with certain diseases. There is evidence that in addition to bone minerals density, other factors influence bone strength. The chapter reviews the biomechanical aspects of age-related fractures, including the interacting roles of traumatic loading and bone strength, and the factors that determine a bones resistances to fracture. Also discussed are the mechanisms by which anti-catabolic and anabolic therapies for osteoporosis may affect bone strength. Finally, several current and future methodologies for improving assessment of bone strength in patients are evaluated.

Bouxsein ML. · Orthopaedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. · J Musculoskelet Neuronal Interact. · Pubmed #15758280 links to  free full text

This publication has no abstract.

Bouxsein ML, Kaufman J, Tosi L, Cummings S, Lane J, Johnell O. · Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. · J Am Acad Orthop Surg. · Pubmed #15615504 No free full text.

Abstract: Fragility fractures resulting from low trauma events such as a fall from standing height affect up to one half of women and one third of men after age 50 years. These fractures are frequently associated with osteoporosis. History of a fragility fracture is among the strongest risk factors for future fracture. Therefore, optimal care of the patient with a fragility fracture includes not only treatment of the presenting fracture itself but also evaluation and treatment of the underlying cause or causes to prevent future fractures. However, despite the availability of therapeutic agents that reduce fracture risk among osteoporotic patients who have had a fracture, most patients with fragility fractures are not evaluated for osteoporosis or treated adequately to reduce the risk of future fracture. Orthopaedic surgeons are the first and often the only physicians seen by fracture patients. Thus, they have the unique opportunity to serve as primary advocates to ensure that appropriate action is taken to reduce the risk of future fracture.

Bouxsein ML. · Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. · Clin Cornerstone. · Pubmed #15035555 No free full text.

Abstract: Bone density and bone quality have been cited as primary contributors to bone strength. Although a precise definition of bone quality remains elusive, characteristics other than bone density, such as trabecular architecture, bone turnover, and mineralization of the bone matrix may be important factors in the pathophysiology of osteoporosis and the mechanisms that underlie fracture. Small increases in bone mineral density (BMD) have resulted in greater than expected reductions in the risk of fracture. Indeed, therapeutic increases in BMD account for only a small proportion of the reduction in fracture risk. This observation suggests that the size, shape, distribution, and composition of bone may have important effects on bone strength and, therefore, the risk of fracture.

Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ, Anonymous00024. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94105, USA. · N Engl J Med. · Pubmed #14500804 links to  free full text

Abstract: BACKGROUND: Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. METHODS: A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. RESULTS: The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. CONCLUSIONS: There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy.

Bouxsein ML, Parker RA, Greenspan SL. · Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. · Osteoporos Int. · Pubmed #10663352 No free full text.

Abstract: Alendronate significantly increases bone mass and reduces hip and spine fractures in postmenopausal women. To determine whether forearm densitometry could be used to monitor the efficacy of alendronate, we examined changes in bone mineral density (BMD) at the forearm (one-third distal, mid-distal, ultradistal radius) versus changes at the hip (femoral neck, total hip) and spine (posteroanterior and lateral) in a double-masked, randomized, placebo-controlled clinical trial of 120 elderly women (mean age 70 +/- 4 years) treated with alendronate for 2.5 years. We found that among women in the treatment group, BMD increased by 4.0-12.2% at the hip and spine sites (all p<0.001), whereas BMD increased only nominally at the one-third distal radius (1.3%, p<0.001) and mid-radius (0.8%, p<0.05), and remained stable at the ultradistal radius. At baseline, forearm BMD correlated with that of the hip (r = 0.55-0.64, p<0.001), femoral neck (r = 0.54-0.61, p<0.001) and posteroanterior spine (r = 0.56-0.63, p<0.001). Changes in radial BMD after 1 year of therapy were not correlated with changes in hip and spine BMD after 2.5 years of therapy. In contrast, short-term changes in total hip and spine BMD were generally positively associated with long-term changes in total hip, femoral neck and spine BMD (r = 0.30-0.71, p<0.05). Furthermore, long-term BMD changes at the forearm did not correlate with long-term hip and spine BMD changes, in contrast to the moderate correlations seen between spine and hip BMD at 2.5 years (r = 0.38-0.45, p<0.01). We conclude that neither short- nor long-term changes in forearm BMD predict long-term changes in overall BMD for elderly women on alendronate therapy, suggesting that measurements of clinically relevant central sites (hip and spine) are necessary to assess therapeutic efficacy.

Bouxsein ML, Chen P, Glass EV, Kallmes DF, Delmas PD, Mitlak BH. · Eli Lilly and Company, Indianapolis, Indiana, USA. · J Bone Joint Surg Am. · Pubmed #19487509 No free full text.

Abstract: BACKGROUND: Vertebral fractures increase the risk of new vertebral fractures; however, we are not aware of any study addressing the risk of new vertebral fractures adjacent to existing vertebral fractures. Therefore, we sought to determine the influence of the number and severity of prevalent (preexisting) vertebral fractures on the risk of new adjacent vertebral fractures and to determine whether teriparatide (rhPTH [recombinant human parathyroid hormone] [1-34]) or raloxifene treatment reduces the incidence of adjacent vertebral fractures in postmenopausal women with osteoporosis. METHODS: Data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial were analyzed to determine the incidences of new adjacent and new nonadjacent vertebral fractures in the placebo groups and the effect of treatment with raloxifene and teriparatide on the incidence of new adjacent vertebral fractures as compared with that of new nonadjacent vertebral fractures. RESULTS: Of 1226 untreated postmenopausal women with one or more prevalent vertebral fractures at baseline, 196 (16.0%) had a total of 292 new vertebral fractures during the two-year follow-up period, with 108 (8.8%) of the 1226 women having at least one new fracture adjacent to a prevalent fracture. Of the 292 new vertebral fractures, 136 (47%) were adjacent to a previously existing vertebral fracture. The risk of a new adjacent vertebral fracture was 2.5-fold higher than the risk of a new nonadjacent vertebral fracture (4.03% compared with 1.59%). The incidence of new adjacent vertebral fractures increased with both the number and the severity of prevalent vertebral fractures. Teriparatide reduced the risk of any new, new adjacent, and new nonadjacent vertebral fractures by 72%, 75%, and 70%, respectively, compared with the rates in the placebo group. Similarly, compared with the placebo, raloxifene treatment reduced the risk of any new vertebral fracture, new adjacent vertebral fracture, and new nonadjacent vertebral fracture by 54%, 54%, and 53%, respectively. CONCLUSIONS: In untreated postmenopausal women with osteoporosis, nearly half of the incident vertebral fractures occur adjacent to an existing vertebral fracture. Both teriparatide and raloxifene can significantly reduce the occurrence of new adjacent and nonadjacent vertebral fractures.

Rozental TD, Vazquez MA, Chacko AT, Ayogu N, Bouxsein ML. · Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. · J Hand Surg Am. · Pubmed #19345861 No free full text.

Abstract: PURPOSE: To compare healing rates of distal radius fractures in patients on bisphosphonate therapy at the time of injury to rates in those not on bisphosphonate therapy. METHODS: A total of 196 consecutive patients treated for distal radius fractures were included in this study. Patients currently on bisphosphonate therapy at the time of injury (bisphosphonate group, n = 43) were compared to the remaining patient group (control group, n = 153). Demographic information was recorded from the patients' medical records, and radiographs were reviewed to determine fracture healing. Patients were further stratified according to age, gender, fracture complexity, type of treatment, and comorbidities. Univariate and multivariate regression were used to identify factors associated with time to radiographic fracture union. RESULTS: The mean time to union was 55 (+/-17) days in the bisphosphonate group versus 49 (+/-14) days in the control group. Bisphosphonate use and surgical treatment were associated with a longer time to radiographic union. Bisphosphonate use was associated with increased healing times when individually controlling for age, gender, fracture complexity, or comorbidities. Bisphosphonate use was also associated with longer time to healing after adjusting for age, gender, and treatment type. Surgical fracture fixation was associated with a longer time to healing after adjusting for bisphosphonate use. CONCLUSIONS: Current bisphosphonate use and surgical treatment were both associated with longer times to radiographic union of distal radius fractures. However, the small differences in healing times (<1 week) are not considered clinically relevant. Although further studies are needed to better define the effects of bisphosphonate therapy on fracture healing, our results suggest that bisphosphonate therapy can be continued after distal radius fractures without notable deleterious effects. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.

Pierroz DD, Rufo A, Bianchi EN, Glatt V, Capulli M, Rucci N, Cavat F, Rizzoli R, Teti A, Bouxsein ML, Ferrari SL. · Service of Bone Diseases, Department of Rehabilitation and Geriatrics, WHO Center for Osteoporosis Prevention, Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland. · J Bone Miner Res. · Pubmed #19113915 No free full text.

Abstract: PTH-stimulated intracellular signaling is regulated by the cytoplasmic adaptor molecule beta-arrestin. We reported that the response of cancellous bone to intermittent PTH is reduced in beta-arrestin2(-/-) mice and suggested that beta-arrestins could influence the bone mineral balance by controlling RANKL and osteoprotegerin (OPG) gene expression. Here, we study the role of beta-arrestin2 on the in vitro development and activity of bone marrow (BM) osteoclasts (OCs) and Ephrins ligand (Efn), and receptor (Eph) mRNA levels in bone in response to PTH and the changes of bone microarchitecture in wildtype (WT) and beta-arrestin2(-/-) mice in models of bone remodeling: a low calcium diet (LoCa) and ovariectomy (OVX). The number of PTH-stimulated OCs was higher in BM cultures from beta-arrestin2(-/-) compared with WT, because of a higher RANKL/OPG mRNA and protein ratio, without directly influencing osteoclast activity. In vivo, high PTH levels induced by LoCa led to greater changes in TRACP5b levels in beta-arrestin2(-/-) compared with WT. LoCa caused a loss of BMD and bone microarchitecture, which was most prominent in beta-arrestin2(-/-). PTH downregulated Efn and Eph genes in beta-arrestin2(-/-), but not WT. After OVX, vertebral trabecular bone volume fraction and trabecular number were lower in beta-arrestin2(-/-) compared with WT. Histomorphometry showed that OC number was higher in OVX-beta-arrestin2(-/-) compared with WT. These results indicate that beta-arrestin2 inhibits osteoclastogenesis in vitro, which resulted in decreased bone resorption in vivo by regulating RANKL/OPG production and ephrins mRNAs. As such, beta-arrestins should be considered an important mechanism for the control of bone remodeling in response to PTH and estrogen deprivation.

Brouwers JE, Ruchelsman M, Rietbergen B, Bouxsein ML. · Eindhoven University of Technology, Eindhoven, The Netherlands. · Osteoporos Int. · Pubmed #19066708 links to  free full text

Abstract: SUMMARY: Compressive fatigue properties of whole vertebrae, which may be clinically relevant for osteoporotic vertebral fractures, were determined in untreated, intact rats and zoledronic-acid-treated, ovariectomized rats. Typical fatigue behavior was found and was similar to that seen in other species. Fatigue properties were comparable between both groups. INTRODUCTION: Osteoporosis is often treated with bisphosphonates, which reduce fracture risk. Effects of bisphosphonates on fatigue strength, which may be clinically relevant for vertebral fractures, are unknown. We determined vertebral, compressive fatigue properties in normal and zoledronic acid (ZOL)-treated, OVX rats. METHODS: Thirty-five-week old Wistar rats were divided into SHAM-OVX (n = 7) and OVX with ZOL treatment (n = 5; single injection, 20 microg/kg b.w. s.c.). After 16 weeks, vertebral trabecular microarchitecture and cortical thickness were determined using micro-CT. Vertebrae were cyclically compressed in load-control at 2 Hz starting at 0.75% apparent strain. A line parallel to the apparent strain curve was drawn at 0.5% higher offset, after which the intersection was defined as the time to failure and the apparent strain at failure. Data were compared using Student's t test. RESULTS: Morphology and fatigue properties were the same in both groups. Samples failed between 10 min and 15 h. Force-displacement curves displayed typical fatigue behavior. Displacement increased over time due to mostly creep and to decreasing secant stiffness. CONCLUSIONS: We established a technique to determine compressive fatigue properties in the rat vertebral body. Our initial results indicate that ZOL-treated OVX rats have similar vertebral fatigue properties as SHAM-OVX controls.

Nielson CM, Bouxsein ML, Freitas SS, Ensrud KE, Orwoll ES, Anonymous00064. · Bone and Mineral Unit, Department of Medicine, Oregon Health and Science University, Portland, Oregon 97239-3098, USA. · J Clin Endocrinol Metab. · Pubmed #19017753 No free full text.

Abstract: BACKGROUND: Greater thickness of the tissue extending laterally from the greater trochanter has been associated with a lower risk of hip fracture in women. The effect of trochanteric soft tissue thickness on the risk of incident hip fracture has not been evaluated in men. METHODS: We measured trochanteric soft tissue thickness by dual-energy x-ray absorptiometry for all incident hip fracture cases (n = 70) and 222 randomly selected noncases in older men (> or =65 yr) enrolled in the Osteoporotic Fractures in Men (MrOS) Study. Differences in tissue thickness between cases and controls were examined. Changes in fall force and factor-of-risk (the ratio of force from a sideways fall to femoral bone strength) associated with tissue thickness were determined. The relative risk for incident hip fracture per SD decrease in tissue thickness was calculated. RESULTS: Mean trochanteric soft tissue thickness did not differ significantly between cases and noncases (29.1 +/- 11.9 vs 31.0 +/- 11.5 mm; P = 0.2). Although increased tissue thickness reduced both the estimates of fall force and the factor-of-risk, tissue thickness was not associated with the risk of hip fracture (age- and bone mineral density-adjusted relative risk per sd decrease in tissue thickness = 0.90; 95% confidence interval, 0.70-1.16). CONCLUSIONS: In this study of elderly community-dwelling men, we found no significant association between trochanteric soft tissue thickness and incident hip fracture. Trochanteric soft tissue thickness in these men was less than previously reported in older women and may explain the difference between these results and those reported in women.

Bouxsein ML, Delmas PD. · Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. · Nat Clin Pract Endocrinol Metab. · Pubmed #18838969 No free full text.

Abstract: Vertebral fractures are the most common fracture among the elderly, have a detrimental effect on patients' quality of life, and increase the risk of future fractures. Yet, two-thirds of vertebral fractures remain undiagnosed; therefore, improved detection methods are needed. In this Practice Point commentary, we discuss the study by McCloskey et al., in which low radiation dose imaging with a bone densitometer was used for vertebral fracture assessment (VFA) in a prospective cohort of elderly women. Participants were enrolled in a randomized, double-blind, placebo-controlled trial of the oral bisphosphonate clodronate. Prevalent vertebral fractures detected by VFA were associated with an elevated risk of subsequent osteoporotic fractures, including hip fractures. This finding remained significant after adjustment for age, weight and treatment effect, and in a few instances even after adjustment for femoral BMD. Here, we highlight the importance of identifying vertebral fractures, and the potentially substantial role of VFA in the clinical evaluation and management of patients suspected to have osteoporosis.

Ackert-Bicknell CL, Demissie S, Marín de Evsikova C, Hsu YH, DeMambro VE, Karasik D, Cupples LA, Ordovas JM, Tucker KL, Cho K, Canalis E, Paigen B, Churchill GA, Forejt J, Beamer WG, Ferrari S, Bouxsein ML, Kiel DP, Rosen CJ. · The Jackson Laboratory, Bar Harbor, Maine 04609, USA. · J Bone Miner Res. · Pubmed #18707223 No free full text.

Abstract: Adult BMD, an important risk factor for fracture, is the result of genetic and environmental interactions. A quantitative trait locus (QTL) for the phenotype of volumetric BMD (vBMD), named Bmd8, was found on mid-distal chromosome (Chr) 6 in mice. This region is homologous to human Chr 3p25. The B6.C3H-6T (6T) congenic mouse was previously created to study this QTL. Using block haplotyping of the 6T congenic region, expression analysis in the mouse, and examination of nonsynonymous SNPs, peroxisome proliferator activated receptor gamma (Pparg) was determined to be the most likely candidate gene for the Bmd8 QTL of the 630 genes located in the congenic region. Furthermore, in the C3H/HeJ (C3H) strain, which is the donor strain for the 6T congenic, several polymorphisms were found in the Pparg gene. On challenge with a high-fat diet, we found that the 6T mouse has a lower areal BMD (aBMD) and volume fraction of trabecular bone (BV/TV%) of the distal femur compared with B6 mice. Interactions between SNPs in the PPARG gene and dietary fat for the phenotype of BMD were examined in the Framingham Offspring Cohort. This analysis showed that there was a similar interaction of the PPARG gene and diet (fat intake) on aBMD in both men and women. These findings suggest that dietary fat has a significant influence on BMD that is dependent on the alleles present for the PPARG gene.

Rozental TD, Makhni EC, Day CS, Bouxsein ML. · Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Stoneman 10, Boston, MA 02215, USA. · J Bone Joint Surg Am. · Pubmed #18451385 No free full text.

Abstract: BACKGROUND: Fragility fractures are associated with a significant increase in the risk of future fracture, but the rates of evaluation to identify osteoporosis after such injuries are low. The purpose of this study was to determine the rates of evaluation and treatment of osteoporosis following distal radial fractures and to test two interventions in the outpatient clinic to improve evaluation and treatment rates. METHODS: In the first part of the study, the medical records of 298 consecutive patients treated for a fragility fracture of the distal part of the radius were reviewed. Primary outcome measures were a bone mineral density examination and treatment with osteoporosis medication within six months after the fracture. In the second part of the study, fifty patients with a fragility fracture of the distal part of the radius were prospectively randomized to receive one of two interventions. These consisted of (1) the orthopaedic surgeon ordering a bone mineral density examination and forwarding the results to the primary care physician or (2) the orthopaedic surgeon sending a letter to the primary care physician outlining guidelines for osteoporosis screening. Patients were contacted at six months after the fracture to determine the rates of evaluation and treatment for osteoporosis. RESULTS: The first part of the study revealed that, following a distal radial fracture, 21.3% of 240 patients had a bone mineral density examination and 78.7% were never screened. Osteopenia was the most common diagnosis among those screened (57%). Most (72.5%) of the 240 patients received no medication, whereas 6.7% received calcium and vitamin D; 11.3%, bisphosphonates; 2.5%, hormone replacement therapy; and 7.1%, a combination regimen. The treatment rate for the patients who had undergone a bone mineral density examination was 2.5-fold higher than the rate for those who had not had bone mineral density testing (53% compared with 21%, p < 0.001). In the second part of the study, the patients randomized to Intervention 1 had two to threefold greater rates of bone mineral density testing (93% compared with 30%, p < 0.001), discussion of osteoporosis with their primary care physician (89% compared with 35%, p < 0.001), and initiation of osteoporosis therapy (74% compared with 26%, p < 0.001) compared with patients randomized to Intervention 2. CONCLUSIONS: Rates of evaluation and treatment for osteoporosis after fragility fractures remain low (21.3% and 27.5%, respectively). Patients who undergo a bone mineral density examination are more likely to receive treatment. Ordering a bone mineral density examination in the orthopaedic clinic can dramatically improve osteoporosis evaluation and treatment rates following fragility fractures of the distal part of the radius.

Keaveny TM, Bouxsein ML. · Department of Mechanical Engineering, University of California, Berkeley, California 94720-1740, USA. · J Bone Miner Res. · Pubmed #18410232 No free full text.

Abstract: Because of the dichotomous nature of a bone fracture, when Phi, the ratio of the applied impact force to the bone strength, is greater than a critical value--the biomechanical fracture threshold--fracture should occur. We sought to elucidate the conceptual implications of this biomechanical fracture threshold with application to hip fracture. We used data from the PaTH study, a 2-yr clinical trial in postmenopausal women treated with alendronate, PTH, or their combination. Outcomes included the force applied to the hip in a sideways fall as estimated from subject height and weight; femoral strength as determined by QCT-based finite element analysis; the load-to-strength ratio Phi; and total hip areal BMD from DXA. Results indicated that those with "very low" femoral strength (<2000 N) invariably had load-to-strength ratio Phi values well above the theoretical biomechanical fracture threshold (Phi = 1), but those with "moderately low" femoral strength (2000-4000 N) displayed Phi values both above and below the theoretical biomechanical fracture threshold. This finding implies that the risk of a hip fracture can be high in those with only moderately low BMD because femoral strength can be low relative to fall impact forces. The observed weak correlation between areal BMD and the load-to-strength ratio Phi (r2 = 0.14) suggests that consideration of the biomechanical fracture threshold may improve fracture risk assessment, particularly for those in the osteopenic range. Regarding treatment effects, only those subjects having load-to-strength ratio Phi values within a relatively narrow "transition zone" of +/- 20% of the assumed biomechanical fracture threshold at baseline were predicted to change fracture status during the trial. In theory, outcomes of fracture trials may be dominated by the responses of those within the "transition zone" at baseline, and treatment benefits in terms of fracture efficacy may depend the patient's baseline status with respect to the biomechanical fracture threshold. We conclude that consideration of the theoretical implications of the biomechanical fracture threshold may lead to new insights and advances in the assessment and treatment of osteoporosis.

McManus JF, Davey RA, Maclean HE, Doust EA, Chiu WS, Sims NA, Bouxsein ML, Glatt V, Zajac JD, Danks JA. · Department of Medicine, University of Melbourne, Austin Health, Studley Road, Heidelberg, VIC, Australia. · Bone. · Pubmed #18387351 No free full text.

Abstract: Human parathyroid hormone (hPTH) is currently the only treatment for osteoporosis that forms new bone. Previously we described a fish equivalent, Fugu parathyroid hormone 1 (fPth1) which has hPTH-like biological activity in vitro despite fPth1(1-34) sharing only 53% identity with hPTH(1-34). Here we demonstrate the in vivo actions of fPth1(1-34) on bone. In study 1, young male rats were injected intermittently for 30 days with fPth1 [30 microg-1,000 microg/kg body weight (b.w.), (30fPth1-1,000fPth1)] or hPTH [30 microg-100 microg/kg b.w. (30hPTH-100hPTH)]. In proximal tibiae at low doses, the fPth1 was positively correlated with trabecular bone volume/total volume (TbBV/TV) while hPTH increased TbBV/TV, trabecular thickness (TbTh) and trabecular number (TbN). 500fPth1 and 1000fPth1 increased TbBV/TV, TbTh, TbN, mineral apposition rate (MAR) and bone formation rate/bone surface (BFR/BS) with a concomitant decrease in osteoclast surface and number. In study 2 ovariectomized (OVX), osteopenic rats and sham operated (SHAM) rats were injected intermittently with 500 microg/kg b.w. of fPth1 (500fPth1) for 11 weeks. 500fPth1 treatment resulted in increased TbBV/TV (151%) and TbTh (96%) in the proximal tibiae due to increased bone formation as assessed by BFR/BS (490%) and MAR (131%). The effect was restoration of TbBV/TV to SHAM levels without any effect on bone resorption. 500fPth1 also increased TbBV/TV and TbTh in the vertebrae (L6) and cortical thickness in the mid-femora increasing bone strength at these sites. fPth1 was similarly effective in SHAM rats. Notwithstanding the low amino acid sequence homology with hPTH (1-34), we have clearly established the efficacy of fPth1 (1-34) as an anabolic bone agent.

Black DM, Bouxsein ML, Palermo L, McGowan JA, Newitt DC, Rosen E, Majumdar S, Rosen CJ, Anonymous00041. · Department of Epidemiology and Biostatistics, University of California-San Francisco, 185 Berry Street, San Francisco, CA 94107, USA. · J Clin Endocrinol Metab. · Pubmed #18349061 links to  free full text

Abstract: CONTEXT: Daily PTH administration increases bone mineral density (BMD) and reduces fracture risk. However, cost and compliance significantly limit clinical use. OBJECTIVE: Our objective was to determine whether less frequent PTH administration increases lumbar spine BMD. PARTICIPANTS, DESIGN, AND SETTING: Fifty postmenopausal women ages 45-70 yr with femoral neck BMD T-score between -1.0 and -2.0 participated in a double-blind, randomized, placebo-controlled trial at St. Joseph Hospital, Bangor, ME. INTERVENTION: Subjects received sc injections of daily PTH(1-84) (100 mug) or placebo for 1 month, followed by weekly injections (PTH or placebo) for 11 months. OUTCOMES: Change in lumbar spine dual-energy x-ray absorptiometry areal BMD (primary) was assessed. Secondary outcomes included volumetric BMD at spine and hip by quantitative computed tomography, trabecular bone microarchitecture by magnetic resonance imaging of distal radius, and biochemical bone turnover markers. RESULTS: At 12 months, lumbar spine areal BMD increased 2.1% in PTH-treated women compared with placebo (P = 0.03). Vertebral trabecular volumetric BMD increased 3.8% in PTH-treated women compared with placebo group (P = 0.08). PTH-treated women also had higher distal radial trabecular bone volume, number, and thickness compared with placebo-treated women (P < 0.04). After 1 month of daily PTH, N-terminal propeptide of type I collagen (P1NP) was markedly increased compared with placebo (P < 0 .0001), and a difference persisted, although lessened, throughout the study. Bone resorption indices were unchanged in PTH-treated women and were reduced in the placebo group. CONCLUSION: Once-weekly PTH after 1 month of daily treatment increases spine BMD, radial trabecular bone, and bone formation markers in postmenopausal women. These results suggest that less frequent alternatives to daily PTH dosing for 2 yr could be effective. Additional studies are required to define the optimal frequency of PTH administration.

Bouxsein ML, Delmas PD. · Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. · J Bone Miner Res. · Pubmed #18318643 links to  free full text

Abstract: Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance.

Mukherjee S, Raje N, Schoonmaker JA, Liu JC, Hideshima T, Wein MN, Jones DC, Vallet S, Bouxsein ML, Pozzi S, Chhetri S, Seo YD, Aronson JP, Patel C, Fulciniti M, Purton LE, Glimcher LH, Lian JB, Stein G, Anderson KC, Scadden DT. · Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. · J Clin Invest. · Pubmed #18219387 links to  free full text

Abstract: Drug targeting of adult stem cells has been proposed as a strategy for regenerative medicine, but very few drugs are known to target stem cell populations in vivo. Mesenchymal stem/progenitor cells (MSCs) are a multipotent population of cells that can differentiate into muscle, bone, fat, and other cell types in context-specific manners. Bortezomib (Bzb) is a clinically available proteasome inhibitor used in the treatment of multiple myeloma. Here, we show that Bzb induces MSCs to preferentially undergo osteoblastic differentiation, in part by modulation of the bone-specifying transcription factor runt-related transcription factor 2 (Runx-2) in mice. Mice implanted with MSCs showed increased ectopic ossicle and bone formation when recipients received low doses of Bzb. Furthermore, this treatment increased bone formation and rescued bone loss in a mouse model of osteoporosis. Thus, we show that a tissue-resident adult stem cell population in vivo can be pharmacologically modified to promote a regenerative function in adult animals.