A genome-wide genomic score added to standard recommended stratification tools does not improve the identification of patients with very low bone mineral density.

The role of integrating genomic scores (GSs) needs to be assessed. Adding a GS to recommended stratification tools does not improve the prediction of very low bone mineral density. However, we noticed that the GS performed equally or above individual risk factors in discrimination. PURPOSE: We aimed to investigate whether adding a genomic score (GS) to recommended stratification tools improves the discrimination of participants with very low bone mineral density (BMD). METHODS: BMD was measured in three thoracic vertebrae using CT. All participants provided information on standard osteoporosis risk factors. GSs and FRAX scores were calculated. Participants were grouped according to mean BMD into very low (<80 mg/cm3), low (80-120 mg/cm3), and normal (>120 mg/cm3) and according to the Bone Health and Osteoporosis Foundation recommendations for BMD testing into an "indication for BMD testing" and "no indication for BMD testing" group. Different models were assessed using the area under the receiver operating characteristics curves (AUC) and reclassification analyses. RESULTS: In the total cohort (n=1421), the AUC for the GS was 0.57 (95% CI 0.52-0.61) corresponding to AUCs for osteoporosis risk factors. In participants without indication for BMD testing, the AUC was 0.60 (95% CI 0.52-0.69) above or equal to AUCs for osteoporosis risk factors. Adding the GS to a clinical risk factor (CRF) model resulted in AUCs not statistically significant from the CRF model. Using probability cutoff values of 6, 12, and 24%, we found no improved reclassification or risk discrimination using the CRF-GS model compared to the CRF model. CONCLUSION: Our results suggest adding a GS to a CRF model does not improve prediction. However, we noticed that the GS performed equally or above individual risk factors in discrimination. Clinical risk factors combined showed superior discrimination to individual risk factors and the GS, underlining the value of combined CRFs in routine clinics as a stratification tool.

Fragility fractures and health-related quality of life: does socio-economic status widen the gap? A population-based study.

Studying 12,839 fracture cases and 91,426 controls, we found that fractures of the spine and hip are associated with clinically important HRQoL deficits up to 5 years post-fracture. Fracture cases with a low educational attainment are more likely to report very low HRQoL due to a low pre-fracture HRQoL. INTRODUCTION: The aim of this study was to explore the short-term and long-term impact of fractures on health-related quality of life (HRQoL) and to study the effect of educational attainment as a proxy for socio-economic status (SES) on post-fracture HRQoL. METHODS: In a population-based survey including 12,839 fracture cases and 91,426 controls, HRQoL was measured using the physical component score (PCS) and the mental component score (MCS) of the 12-Item Short Form Health Survey (SF-12). Information about fractures, age, sex, ethnicity, comorbidity and SES was obtained from national registers. Multiple regression analysis was conducted to measure the mean HRQoL difference, termed deficit, between non-fracture controls and fracture cases (all fractures combined and fractures at six different skeletal sites). RESULTS: PCS and MCS were significantly lower among fracture cases than among controls. Statistically and clinically important PCS deficits (≥ 5 points) were observed among people with fractures of the spine and hip up to 5 years post-fracture and among people with upper arm fractures up to 1 year post-fracture. Greater deficits were observed for MCS but not for PCS in post-fracture HRQoL in the low than in the high SES group. CONCLUSION: Fractures of the spine and hip are associated with clinically important deficits in physical HRQoL up to 5 years post-fracture. Low educational attainment widened the gap in mental but not in physical post-fracture HRQoL. However, due to low pre-fracture PCS and MCS, people with a low educational attainment and fractures were more likely to report very low HRQoL post-fracture.

The effect of vitamin MK-7 on bone mineral density and microarchitecture in postmenopausal women with osteopenia, a 3-year randomized, placebo-controlled clinical trial.

We conducted a randomized placebo-controlled double-blinded clinical trial of MK-7 or placebo daily for 3 years in postmenopausal women with osteopenia. BMD decreased at all sites without differences between the MK-7 and placebo-treated women. Changes in bone turnover markers and microstructure were similar between the two groups. INTRODUCTION: Vitamin K is a cofactor in the carboxylation of osteocalcin (OC) and carboxylated OC promotes mineralization of bone. Clinical studies suggest that vitamin K2 prevents bone loss. The aim of the study was to investigate the effect of vitamin K2 as an add-on to calcium and vitamin D supplementation on osteocalcin, bone mass, and microarchitecture in postmenopausal women. METHODS: We conducted a randomized placebo-controlled double-blinded clinical trial, including 142 postmenopausal women with osteopenia who received vitamin K2 (375 µg MK-7) or placebo daily for 3 years. Both groups received vitamin D3 (38 µg/day) and calcium (800 mg/day). We measured bone turnover markers in serum and bone mineral density and microarchitecture by DXA and HRpQCT. RESULTS: Undercarboxylated osteocalcin decreased in the MK-7-group (- 65.2 ± 23.5%) (mean ± SD) compared with the placebo group (- 0.03 ± 38.5%), p < 0.01 after 1 year. After 3 years, aBMD decreased at all sites without differences between the MK-7 and placebo-treated women (p > 0.09). aBMD decreased at the total hip by 1.5 ± 2.5% and 2.4 ± 2.7% in the MK-7 and the placebo groups, respectively, at the femoral neck by 1.5 ± 3.5% and 1.0 ± 5.0% in the MK-7 and the placebo groups, respectively, and at the lumbar spine by 1.8 ± 3.9% and 1.1 ± 3.1% in the MK-7 and the placebo groups, respectively. Changes in bone turnover markers were also similar between the two groups.We have previously reported improved microarchitecture with MK-7 after 1 year. However, changes in microstructure over 3 years were similar between the two groups, as assessed by both HRpQCT and DXA trabecular bone score. CONCLUSION: Treatment with MK-7 375 µg daily as an add-on to calcium and vitamin D increased carboxylation of osteocalcin. However, treatment of postmenopausal women with osteopenia for 3 years did not affect biochemical markers of bone turnover, bone mineral density, or bone microarchitecture. TRIAL REGISTRATION: The study was registered at Clinicaltrial.gov : NCT01922804 .

Randomized, controlled trial to assess the safety and efficacy of odanacatib in the treatment of men with osteoporosis.

Odanacatib (ODN) was investigated as an osteoporosis treatment in 292 men. Compared with placebo, odanacatib improved bone mineral density and led to sustained bone resorption decreases while producing relatively little bone formation reduction that leveled off with time. However, increased risk of stroke in another study stopped further odanacatib development. INTRODUCTION: ODN, a selective oral cathepsin K inhibitor, was in development for osteoporosis treatment. This phase 3, double-blind, randomized, placebo-controlled, 24-month study investigated ODN safety and efficacy in men with osteoporosis. METHODS: Men with idiopathic osteoporosis or osteoporosis due to hypogonadism and a lumbar spine or hip (total hip [TH], femoral neck [FN], or trochanter) bone mineral density (BMD) T-score of ≤ - 2.5 to ≥ - 4.0 without prior vertebral fracture or ≤ - 1.5 to ≥ - 4.0 with one prior vertebral fracture were randomized (1:1) to once-weekly ODN 50 mg or placebo. All received 5600 IU vitamin D3 weekly and calcium supplementation as needed (≥ 1200 mg daily). The primary efficacy outcome was changed from baseline in lumbar spine BMD versus placebo. RESULTS: Overall, 292 men, mean age 68.8 years, were randomly assigned to ODN or placebo. Versus placebo, ODN increased BMD from baseline at the lumbar spine, TH, FN, and trochanter by 5.6%, 2.0%, 1.7%, and 2.1%, respectively (all p < 0.01), and decreased uNTx/Cr (68%, p < 0.001), sCTx (77%, p < 0.001), sP1NP (16%, p = 0.001), and sBSAP (8%, p = 0.019). The between-group bone formation marker decrease peaked at 3 months, then returned toward baseline. The safety profile, including cardiovascular events, was similar between groups. CONCLUSION: Though a promising osteoporosis therapy for men, ODN development was discontinued due to increased risk of stroke in the LOFT phase 3 trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT01120600 (registered May 11, 2010).

Socio-economic inequalities in fragility fracture outcomes: a systematic review and meta-analysis of prognostic observational studies.

Individuals with low socio-economic status (SES) have a higher risk of dying following hip fracture compared with individuals with high SES. Evidence on social inequalities in non-hip fractures is lacking as well as evidence on the impact of SES on health-related quality of life post fracture. INTRODUCTION: Fragility fractures, especially of the hip, cause substantial excess mortality and impairment in health-related quality of life (HRQoL). This systematic review and meta-analysis aimed to investigate the association between socio-economic status (SES) and post-fracture mortality and HRQoL. METHODS: PubMed, EMBASE and CINAHL databases were searched from inception to the last week of November 2018 for studies reporting an association between SES and post-fracture mortality and/or HRQoL among people aged ≥ 50 years. Risk ratios (RRs) were meta-analyzed using a standard inverse-variance-weighted random effects model. Studies using individual-level and area-based SES measures were analyzed separately. RESULTS: A total of 24 studies from 15 different countries and involving more than one million patients with hip fractures were included. The overall risk of mortality within 1-year post-hip fracture in individuals with low SES was 24% higher than in individuals with high SES (RR 1.24, 95% CI 1.19 to 1.29) for individual-level SES measures, and 14% (RR 1.14, 95% CI 1.09 to 1.19) for area-based SES measures. The quality of the evidence for the outcome mortality was moderate. Using individual SES measures, we estimated the excess HRQoL loss to be 5% (95% CI - 1 to 10%) among hip fracture patients with low SES compared with high SES. CONCLUSIONS: We found a consistently increased risk of post-hip fracture mortality with low SES across SES measures and across countries with different political structures and different health and social care infrastructures. The impact of SES on post-fracture HRQoL remains uncertain due to sparse and low-quality evidence.

A single dose of zoledronate preserves bone mineral density for up to 2 years after a second course of romosozumab.

This phase 2 study evaluated the efficacy and safety of transitioning to zoledronate following romosozumab treatment in postmenopausal women with low bone mass. A single dose of 5 mg zoledronate generally maintained the robust BMD gains accrued with romosozumab treatment and was well tolerated. INTRODUCTION: Follow-on therapy with an antiresorptive agent is necessary to maintain the skeletal benefits of romosozumab therapy. We evaluated the use of zoledronate following romosozumab treatment. METHODS: This phase 2, dose-finding study enrolled postmenopausal women with low bone mineral density (BMD). Subjects who received various romosozumab doses or placebo from months 0-24 were rerandomized to denosumab (60 mg SC Q6M) or placebo for 12 months, followed by open-label romosozumab (210 mg QM) for 12 months. At month 48, subjects who had received active treatment for 48 months were assigned to no further active treatment and all other subjects were assigned to zoledronate 5 mg IV. Efficacy (BMD, P1NP, and ß-CTX) and safety were evaluated for 24 months, up to month 72. RESULTS: A total of 141 subjects entered the month 48-72 period, with 51 in the no further active treatment group and 90 in the zoledronate group. In subjects receiving no further active treatment, lumbar spine (LS) BMD decreased by 10.8% from months 48-72 but remained 4.2% above the original baseline. In subjects receiving zoledronate, LS BMD was maintained (percentage changes: - 0.8% from months 48-72; 12.8% from months 0-72). Similar patterns were observed for proximal femur BMD in both groups. With no further active treatment, P1NP and ß-CTX decreased but remained above baseline at month 72. Following zoledronate, P1NP and ß-CTX levels initially decreased but approached baseline by month 72. No new safety signals were observed. CONCLUSION: A zoledronate follow-on regimen can maintain robust BMD gains achieved with romosozumab treatment.

Do femoral fractures in adult patients with osteogenesis imperfecta imitate atypical femoral fractures? A case series.

Atypical femoral fractures (AFFs) are low-energy femoral fractures with characteristic radiological features and a suspected relation to treatment with bisphosphonate (BP) or denosumab. In osteogenesis imperfecta (OI), BP is currently the drug of choice when medical treatment is indicated. Due to bone deformities, the radiologic appearance of femoral fractures may be different in patients with OI and patients with osteoporosis. We investigated the prevalence and appearance of femoral fractures in a cohort of adult patients with confirmed OI (55 patients, age range 19-69 years, 26 women (47%) and 35 patients (64%) had received BP treatment), who attended the outpatient clinic at Aarhus University Hospital. The fractures were evaluated according to major and minor AFF criteria. In our OI cohort, we found that eight out of 55 patients had suffered a femoral fracture in adult year: five women and three men, aged 25 to 54 years. One patient had OI type I, two had OI type III, four had OI type IV, and one had OI type V. All fractures were associated with no or minimal trauma. Four patients had fractures that fulfilled the criteria of AFFs. Two of the four patients had received long-term BP treatment prior to the fracture and three patients had severe deformities of the femur. Femoral fractures in OI imitate AFFs. This suggests that bone deformity, collagen deficiencies, and alterations in mineralization of bone may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment. Bone deformities should be monitored as part of the management of adult patients with OI. Continuous dull or aching pain in the groin or thigh should lead to radiographic examination. The radiologic appearance of femoral fractures may be different in patients with osteogenesis imperfecta (OI) and patients with osteoporosis, thus imitate atypical femoral fractures (AFF). We found that bone deformity, collagen deficiencies, and alterations in bone mineralization may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment.

Local bone loss in patients with anti-citrullinated peptide antibody and arthralgia, evaluated with high-resolution peripheral quantitative computed tomography.

OBJECTIVE: To investigate bone changes in the metacarpophalangeal (MCP) joints of anti-citrullinated peptide antibody (ACPA)-positive patients with arthralgia, but not arthritis, compared to healthy controls. METHOD: Using a cross-sectional study design, patients were recruited from hospitals and private care rheumatologists, and controls from a test subject website. All subjects underwent medical history interview, clinical examination, and biochemical screening including ACPA. Patients with positive ACPA, arthralgia, and no rheumatic disease were included. Controls without a history or signs of rheumatological disease or positive ACPA were included. A 2.7-cm-long region around the second and third MCP joints was evaluated using high-resolution peripheral quantitative computed tomography with a voxel size of 82 µm. RESULTS: Twenty-nine ACPA-positive patients and 29 healthy controls were evaluated. Trabecular volumetric bone mineral density and bone volume fraction did not differ between the groups. In addition, the cortical bone was not affected in patients, as we found no difference in average cortical thickness and cortical bone area between the groups. In contrast, the trabeculae were significantly (p < 0.05) thinner in both second and third MCP heads compared with controls, whereas trabecular number and trabecular separation did not differ between the groups. No erosions were demonstrated and the number of non-specific breaks did not differ between the groups. CONCLUSION: Trabecular bone changes were observed in ACPA-positive patients with arthralgia compared with healthy controls. The results may reflect inflammatory up-regulated trabecular bone resorption leading to early bone loss before the onset of clinical arthritis.

Temporomandibular disorders and psychosocial status in osteogenesis imperfecta - a cross-sectional study.

BACKGROUND: Osteogenesis Imperfecta (OI) is characterized by a number of deviations in the orofacial region. The aims of the present study were to investigate the occurrence of temporomandibular disorders, to evaluate the psychosocial status, and to assess the dental occlusion in a population of adult OI patients. METHODS: Participants (n = 75) were classified with mild OI, type I (n = 56), or moderate-severe OI, type III and IV (n = 19). OI patients were examined according to the Research Diagnostic Criteria for Temporomandibular Disorders (axis I and II). RESULTS: Temporomandibular disorders and functional limitations in the orofacial region were rare and did not differ between patients with mild and moderate-severe OI (P > 0.050). No significant differences between Graded Chronic Pain Scale grades 0, 1, and 2 were found in mild OI vs. moderate-severe OI (P > 0.160). Few patients (16%) had signs of depression, but close to half (48%) had signs of somatization. Patients with moderate-severe OI had a lower mean number of teeth compared to patients with mild OI (P <  0.050). In general, malocclusions were prevalent, and mandibular overjet and posterior cross-bite were found more often in moderate-severe OI compared with mild (P <  0.050). CONCLUSIONS: Patients with moderate-severe OI had more malocclusions than patients with mild OI. The psychosocial status of OI patients was remarkably healthy considering the severity of this disabling systemic disorder. The bodily pain complaints frequently reported in OI patients were not largely reflected in the orofacial area as painful temporomandibular disorders.

Subsequent fracture rates in a nationwide population-based cohort study with a 10-year perspective.

SUMMARY: Fractures after the age of 50 are frequently observed in Denmark, and many of these may be osteoporotic. This study examined the incidence of all and subsequent fractures in a 10-year period from 2001 to 2011. The incidence of subsequent fractures was high, especially following hip fracture. INTRODUCTION: The purpose of this study is to examine patterns of subsequent fractures and mortality rates over a 10-year period in patients already suffering from fracture. METHODS: The study was designed as a nationwide, register-based follow-up study. Patients were included if diagnosed with an index fracture (ICD-10 codes: S22.x, S32.x, S42.x, S52.x, S62.x, S72.x, S82.x, S92.x, T02.x, T08.x, T10.x and T12.x) between January 1st, 2001 and December 31st, 2001 and if older than 50 years at time of fracture. The patients were investigated for future subsequent fractures from January 1st, 2002 to December 31st, 2011. RESULTS: In this study, we demonstrated that patients with fractures (especially hip fractures) have a high risk of subsequent fractures, especially hip fracture. Other fractures, which are not commonly considered as osteoporotic fractures, such as lower leg, were frequently observed in the 10 years following index fracture. The cumulative incidence proportion (CIP) of subsequent fractures during the 10-year follow-up period was high for all recurrent fractures (9-46 %). Subsequent hip fracture, regardless of index fracture, had the highest CIP across the study period, ranging from 9 to 40 %. Appendicular fractures were often followed by a recurrent fracture, or subsequent fractures at a more proximal location in the same limb, i.e. forearm fractures were followed by humerus fractures. These results have not been previously demonstrated to this extent, and according to our knowledge, no previous studies have estimated cumulative 10-year subsequent fracture incidences for any non-hip fractures. CONCLUSION: Patients suffering a fracture (and especially a hip fracture) have a high incidence of subsequent fracture. Fractures after the age of 50 may be considered an early warning of increased risk for future fractures in many patients.

Effectiveness and characteristics of multifaceted osteoporosis group education--a systematic review.

UNLABELLED: The characteristics and effectiveness of osteoporosis multifaceted group education were determined from a systematic review of international literature. Findings showed that these educational programmes may be beneficial in a variety of important factors for the prevention, treatment and management of osteoporosis. INTRODUCTION: This systematic review investigated quantitative studies on osteoporosis multifaceted group education. The purpose was to investigate the characteristics as well as the effectiveness of this form of osteoporosis patient education. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guided this systematic review. Relevant databases were searched until January 2013. RESULTS: Seven studies published between 1993 and 2011 including osteoporosis patients with or without fractures were found. The multifaceted educational programmes all consisted of three overall themes: (1) Knowledge of osteoporosis, (2) Medication and diet and (3) Exercise, but with different foci across the studies. Overall, 24 outcome measures representing six topics were applied: (1) Health-related quality of life, (2) Psychosocial function, (3) Pain, (4) Physical activity, (5) Knowledge and (6) Medication and diet. The review showed that multifaceted osteoporosis group education can increase the patients' knowledge of osteoporosis as well as their health-related quality of life, physical activity and psychosocial functioning. It has the potential to increase adherence to both pharmacological and non-pharmacological treatments. CONCLUSIONS: Multifaceted group education may have a positive impact on the patients' ability to engage in preventing and managing osteoporosis. Further research directed towards the complexity of multifaceted group education is needed. In addition, research investigating the educational needs of specific groups of osteoporotic patients is required.

Functional polymorphisms in the P2X7 receptor gene are associated with osteoporosis.

UNLABELLED: The P2X(7) receptor is an ATP-gated cation channel. We investigated the effect of both loss-of-function and gain-of-function polymorphisms in the P2X(7) receptor gene on BMD and risk of vertebral fractures and found that five polymorphisms and haplotypes containing three of these polymorphisms were associated with BMD and fracture risk. INTRODUCTION: The P2X(7) receptor is an ATP-gated cation channel. P2X(7) receptor knockout mice have reduced total bone mineral content, and because several functional polymorphisms have been identified in the human P2X(7) receptor gene, we wanted to investigate the effect of these polymorphisms on BMD and risk of vertebral fractures in a case-control study including 798 individuals. METHODS: Genotyping was carried out using TaqMan assays. BMD was measured using dual energy X-ray absorptiometry, and vertebral fractures were assessed by lateral spinal X-rays. RESULTS: The rare allele of a splice site polymorphism, 151 + 1: G-T, was associated with increased fracture risk and reduced BMD in women. Two other loss-of-function polymorphisms, Glu496Ala and Gly150Arg, were also associated with BMD. The Glu496Ala variant allele was associated with decreased lumbar spine BMD in women and decreased total hip BMD in men. The 150Arg allele was associated with decreased total hip BMD in women and men combined. The minor allele of the gain-of-function polymorphism, Ala348Thr, was associated with reduced fracture risk and increased BMD at all sites in men. The Gln460Arg variant allele, which has been associated with increased receptor function in monocytes, was associated with increased total hip BMD in women. With the exception of His155Tyr for which we found conflicting results in men and women, our results are consistent with the phenotype of the knockout mouse. Analysis of a haplotype containing Ala348Thr, Gln460Arg, and Glu496Ala showed that the effects of the haplotypes on BMD and fracture were driven by Ala348Thr in men and by Gln460Arg and Glu496Ala in women. CONCLUSION: In conclusion, we found that functional polymorphisms in the P2X(7) receptor gene and haplotypes containing three of these polymorphisms are associated with osteoporosis.

Polymorphisms of muscle genes are associated with bone mass and incident osteoporotic fractures in Caucasians.

The interaction between muscle and bone is complex. The aim of this study was to investigate if variations in the muscle genes myostatin (MSTN), its receptor (ACVR2B), myogenin (MYOG), and myoD1 (MYOD1) were associated with fracture risk, bone mineral density (BMD), bone mineral content (BMC), and lean body mass. We analyzed two independent cohorts: the Danish Osteoporosis Prevention Study (DOPS), comprising 2,016 perimenopausal women treated with hormone therapy or not and followed for 10 years, and the Odense Androgen Study (OAS), a cross-sectional, population-based study on 783 men aged 20-29 years. Nine tag SNPs in the four genes were investigated. In the DOPS, individuals homozygous for the variant allele of the MSTN SNP rs7570532 had an increased risk of any osteoporotic fracture, with an HR of 1.82 (95 % CI 1.15-2.90, p = 0.01), and of nonvertebral osteoporotic fracture, with an HR of 2.02 (95 % CI 1.20-3.41, p = 0.01). The same allele was associated with increased bone loss (BMC) at the total hip of 4.1 versus 0.5 % in individuals either heterozygous or homozygous for the common allele (p = 0.006), a reduced 10-year growth in bone area at the total hip of 0.4 versus 2.2 and 2.3 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.01), and a nonsignificantly increased 10-year loss of total-hip BMD of 4.4 versus 2.7 and 2.9 % in individuals heterozygous or homozygous for the common allele, respectively (p = 0.08). This study is the first to demonstrate an association between a variant in MSTN and fracture risk and bone loss. Further studies are needed to confirm the findings.

A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis.

UNLABELLED: This paper provides a framework for the development of national guidelines for the management of glucocorticoid-induced osteoporosis in men and women aged 18 years and over in whom oral glucocorticoid therapy is considered for 3 months or longer. INTRODUCTION: The need for updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation and the European Calcified Tissue Society, which set up a joint Guideline Working Group at the end of 2010. METHODS AND RESULTS: The epidemiology of GIO is reviewed. Assessment of risk used a fracture probability-based approach, and intervention thresholds were based on 10-year probabilities using FRAX. The efficacy of intervention was assessed by a systematic review. CONCLUSIONS: Guidance for glucocorticoid-induced osteoporosis is updated in the light of new treatments and methods of assessment. National guidelines derived from this resource need to be tailored within the national healthcare framework of each country.

Effects of COLIA1 polymorphisms and haplotypes on perimenopausal bone mass, postmenopausal bone loss and fracture risk.

UNLABELLED: One thousand seven hundred seventeen perimenopausal women from the Danish Osteoporosis Prevention Study were genotyped for the -1997G/T, -1663indelT and +1245G/T polymorphisms in the COLIA1 gen. We found that the -1997T allele and a haplotype containing it were associated with reduced bone mineral density (BMD) and increased bone turnover at menopause and after 10 years of follow-up. INTRODUCTION: We wanted to investigate whether the -1997G/T, -1663indelT and +1245G/T polymorphisms in the COLIA1 gene are associated with perimenopausal bone mass, early postmenopausal bone loss and interact with hormone treatment. METHODS: One thousand seven hundred seventeen perimenopausal women from the Danish Osteoporosis Prevention Study were genotyped, and haplotypes were determined. BMD was examined by dual X-ray absorptiometry. RESULTS: Women carrying the -1997T variant had lower BMD at all measured sites: lumbar spine BMD 1.030 ± 0.137 g/cm(2), 1.016 ± 0.147 g/cm(2) and 0.988 ± 0.124 g/cm(2) in women with the GG, GT and TT genotypes, respectively (p < 0.05) and total hip BMD 0.921 ± 0.116 g/cm(2), 0.904 ± 0.123 g/cm(2) and 0.887 ± 0.109 g/cm(2) in women with the GG, GT and TT genotypes, respectively (p = 0.01). The effect remained after 10 years although statistical significance was lost. Haplotype 3 (-1997T-1663ins + 1245G) was associated with lower bone mass and higher levels of bone turnover. Compared with haplotype 1, haplotype 3 carriers had lower BMD at the lumbar spine, femoral neck and total hip by 0.016 ± 0.007 g/cm(2), 0.015 ± 0.006 g/cm(2) and 0.017 ± 0.006 g/cm(2), respectively (p < 0.05-0.005). No association with postmenopausal changes in bone mass and fracture risk and no overall interaction with the effects of hormone therapy could be demonstrated for any of the polymorphisms in COLIA1. CONCLUSIONS: The -1997G/T polymorphism and haplotype 3 are significantly associated with perimenopausal bone mass, and these effects were sustained up to 10 years after menopause. No association between the -1663indelT or +1245G/T polymorphisms and peri- or postmenopausal bone mass could be demonstrated.

Fracture rate and back pain during and after discontinuation of teriparatide: 36-month data from the European Forsteo Observational Study (EFOS).

UNLABELLED: In this observational study in postmenopausal women with severe osteoporosis, the incidence of fractures was decreased during 18 months of teriparatide treatment with no evidence of further change in the subsequent 18-month post-teriparatide period when most patients took other osteoporosis medications. Fracture reduction was accompanied by reductions in back pain. INTRODUCTION: To describe fracture outcomes and back pain in postmenopausal women with severe osteoporosis during 18 months of teriparatide treatment and 18 months post-teriparatide in normal clinical practice. METHODS: The European Forsteo Observational Study (EFOS) was a prospective, multinational, observational study. Data on incident clinical fractures and back pain (100 mm Visual Analogue Scale [VAS] and questionnaire) were collected. Fracture data were summarised in 6-month intervals and analysed using logistic regression with repeated measures. Changes from baseline in back pain VAS were analysed using a repeated measures model. RESULTS: A total of 208 (13.2%) of 1,576 patients sustained 258 fractures during 36 months of follow-up: 34% were clinical vertebral fractures and 66% non-vertebral fractures. The adjusted odds of fracture were reduced during teriparatide treatment and there was no evidence of further change in the 18-month post-teriparatide period, during which 63.3% patients took bisphosphonates. A 74% decrease in the adjusted odds of fracture in the 30- to <36-month period compared with the first 6-month period was observed (p < 0.001). Back pain decreased during teriparatide treatment and this decrease was sustained after teriparatide discontinuation. Adjusted mean back pain VAS decreased by 26.3 mm after 36 months (p < 0.001) from baseline mean of 57.8 mm. CONCLUSIONS: In a real-life clinical setting, the risk of fracture decreased during teriparatide treatment, with no evidence of further change after teriparatide was discontinued. The changes in back pain seen during treatment were maintained for at least 18 months after teriparatide discontinuation. These results should be interpreted in the context of the design of an observational study.

Polymorphisms of the peroxisome proliferator-activated receptor γ (PPARγ) gene are associated with osteoporosis.

UNLABELLED: Stimulation of PPARγ turns mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the PPARγ gene on BMD and fracture risk in two Danish cohorts and found opposing effects of certain SNPs and haplotypes in the two cohorts probably owing to environmental factors. INTRODUCTION: Stimulation of PPARγ causes development of mesenchymal stem cells to adipocytes instead of osteoblasts leading to decreased osteoblast number and BMD. The aim of this study was to examine the effect of PPARG polymorphisms on BMD and fracture risk in two Danish cohorts: AROS, a case-control population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for 10 years. On the basis of linkage disequilibrium between SNPs throughout the gene and previous studies we chose 10 polymorphisms for investigation. METHODS: In AROS, individuals heterozygous for the polymorphisms rs12497191, rs4135263, and rs1151999 had an increased risk of vertebral fractures (OR = 1.48-1.76, p = 0.005-0.04) compared with individuals homozygous for the common allele. In DOPS, individuals heterozygous for rs1151999 had an increased BMD at the hip sites (p ≤ 0.02). An interaction between rs1151999 and diet was found on BMD in both cohorts. RESULTS: For the polymorphism rs1152003 there was an interaction with body weight on BMD at all sites in both cohorts (p ≤ 0.07). Stratified analyses revealed that in the high weight group in AROS individuals homozygous for the variant allele had a decreased BMD (p ≤ 0.02), whereas the same pattern was found in the low weight group in DOPS (p ≤ 0.03). A number of haplotype associations were found as well, the direction of which was opposite in the two cohorts. CONCLUSION: Our study suggests an association SNPs in PPARG and haplotypes thereof and BMD and fracture risk. The effect however appears to be modifiable by environmental factors.

Polymorphisms in the ALOX12 gene and osteoporosis.

UNLABELLED: ALOX12 produces ligands for PPARγ thereby turning mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the ALOX12 gene on BMD and fracture risk in two Danish cohorts and found four polymorphisms and a haplotype thereof to be associated with BMD and fracture risk. INTRODUCTION: Stimulation of the PPARγ with ligands produced by the ALOX enzymes drives mesenchymal stem cells in an adipocyte direction at the expense of osteoblasts leading to decreased osteoblast number and BMD. Previously, polymorphisms in the ALOX12 gene have been associated with osteoporosis. METHODS: We examined the effect of ALOX12 polymorphisms on BMD and the risk of fractures in two Danish cohorts: AROS, a case-control population comprising 809 individuals and DOPS, a population comprising 1,716 perimenopausal women allocated to hormone therapy or not at baseline and followed for up to 10 years. On the basis of linkage disequilibrium (LD) between SNPs throughout the gene and previous genetic association studies we chose ten polymorphisms for investigation. Genotyping was carried out using the Sequenom MassARRAY genotyping system and TaqMan assays. RESULTS: In AROS, individuals heterozygous for the polymorphisms rs3840880, rs9897850, rs2292350 and rs1126667 had a 3.0-4.7% decreased lumbar spine BMD (p = 0.02-0.06) and an increased risk of vertebral fractures (p < 0.05) compared with individuals homozygous for either allele. In DOPS, none of the individual SNPs were associated with BMD or incident fractures. In both cohorts, the above-mentioned SNPs comprised an LD-block (pairwise D´ = 1.0, r (2) = 0.45-0.97). A haplotype comprising all the common alleles (frequency 9%) was associated with decreased bone loss at the hip (p < 0.05) and decreased incidence of osteoporotic fractures (p < 0.05) in DOPS and increased femoral neck BMD in AROS (p < 0.05). CONCLUSION: Our study suggests that genetic variants in ALOX12 may influence BMD and fracture risk.

The expression and regulation of bone-acting cytokines in human peripheral adipose tissue in organ culture.

The humoral cross-talk between bone and fat is an area of increasing interest. We investigated the expression and regulation of the bone-acting cytokines; bone morphogenetic protein 2 (BMP2), connective tissue growth factor (CTGF), osteoprotegerin (OPG), and transforming growth factor beta (TGFB1). Subcutaneous adipose tissue was aspirated from lean, healthy women. Tissue samples were incubated with interleukin 1-ß (IL1-ß), tumor necrosis factor-α (TNF-α), cortisol, troglitazone, IL1-ß + troglitazone, or vehicle. Gene expression in the adipose tissue was analyzed using qPCR and protein levels in the incubation media were analyzed using ELISA. OPG expression and secretion was diminished by 40.8% and 43.1% respectively, by cortisol, and OPG expression was diminished by 67.5% by troglitazone (p<0.05). The proinflammatory cytokines IL1-ß and TNF-α significantly increased the expression of CTGF (p<0.05) by 65.1% and 101.3%, respectively, and the expression and secretion of OGP by 62.3-165.8% (p<0.05). This interleukin 1-ß mediated increase in CTGF- and OPG expression and secretion was ameliorated by troglitazone. Troglitazone and related drugs are known to have adverse effects on bone. We suggest that this could be mediated via altered cytokine production in adipose tissue. Moreover, obese individuals have a low-grade inflammation in their adipose tissue and have higher bone mineral density than lean individuals. We suggest that this inflammation may increase the expression and secretion of OPG and CTGF and thereby increase BMD. In conclusion, bone acting cytokines are produced in the adipose tissue and may affect bone through endocrine mechanisms.

Genotypes and haplotypes of the estrogen receptor genes, but not the retinoblastoma-interacting zinc finger protein 1 gene, are associated with osteoporosis.

Osteoporosis is a common age-related disease with a strong genetic influence. Polymorphisms of ESR1 have consistently been shown to be associated with bone mineral density (BMD) and fracture; however, in regulating bone metabolism, ESR1 interacts with both ESR2 and RIZ1. We therefore examined the effects of polymorphisms in the ESR1, ESR2, and RIZ1 genes and their haplotypes on vertebral fractures and BMD in a case-control study comprising 462 osteoporotic patients and 336 controls. In ESR1, we found the variant C allele of the XbaI polymorphism to be associated with decreased risk of vertebral fractures in women (P < 0.01), whereas in men, the T allele seemed protective (P = 0.05). The variant G allele of the PvuII polymorphism decreased the risk of vertebral fractures independently of lumbar spine BMD in women (P = 0.04) but had no effect in men. Haplotype X-P-H (XbaI:C, PvuII:G, and a high number of TA repeats) was associated with decreased risk of vertebral fractures in women (P = 0.04) but not men. In ESR2, the G allele of the AluI polymorphism was associated with increased fracture risk (P = 0.04), and the haplotype that comprises rs1256031:T and AluI:A increased lumbar spine BMD by 0.04 +/- 0.02 g/cm(2) (P < 0.05) and decreased the risk of vertebral fractures (P = 0.04). There was no effect of the RIZ1 polymorphism on BMD or fracture risk and no evidence of interaction between the polymorphisms and haplotypes thereof. We confirm that genetic variants in ESR1 and ESR2, but not RIZ1, are important in osteoporosis. We found no evidence of interaction between polymorphisms, but we found that the effects of genetic variants in ESR1 might be sex dependent.