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  • 1.
    Abrahamsson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Engström, Britt Edén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlsson, Anders F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?2013In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 169, no 6, p. 885-889Article in journal (Refereed)
    Abstract [en]

    Objective: The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia. Design: We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms. Results: Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements. Conclusion: These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

  • 2.
    Abrahamsson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Engström, Britt Edén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlsson, Anders F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hypoglycemia in everyday life after gastric bypass and duodenal switch2015In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 173, no 1, p. 91-100Article in journal (Refereed)
    Abstract [en]

    Design: Gastric bypass (GBP) and duodenal switch (DS) in morbid obesity are accompanied by marked metabolic improvements, particularly in glucose control. In recent years, episodes of severe late postprandial hypoglycemia have been increasingly described in GBP patients; data in DS patients are scarce. We recruited three groups of subjects; 15 GBP, 15 DS, and 15 non-operated overweight controls to examine to what extent hypoglycemia occurs in daily life. Methods: Continuous glucose monitoring (CGM) was used during 3 days of normal activity. The glycemic variability was measured by mean amplitude of glycemic excursion and continuous overall net glycemic action. Fasting blood samples were drawn, and the patients kept a food and symptom log throughout the study. Results: The GBP group displayed highly variable CGM curves, and 2.9% of their time was spent in hypoglycemia (< 3.3 mmol/l, or 60 mg/dl). The DS group had twice as much time in hypoglycemia (5.9%) and displayed CGM curves with little variation as well as lower HbA1c levels (29.3 vs 35.9 mmol/mol, P < 0.05). Out of a total of 72 hypoglycemic episodes registered over the 3-day period, 70 (97%) occurred in the postprandial state and only about one-fifth of the hypoglycemic episodes in the GBP and DS groups were accompanied by symptoms. No hypoglycemias were seen in controls during the 3-day period. Conclusion: Both types of bariatric surgery induce marked, but different, changes in glucose balance accompanied by frequent, but mainly unnoticed, hypoglycemic episodes. The impact and mechanism of hypoglycemic unawareness after weight-reduction surgery deserves to be clarified.

  • 3.
    Andersen, Kasper
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Farahmand, Bahman
    Ahlbom, Anders
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study2013In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 34, no 47, p. 3624-3631Article in journal (Refereed)
    Abstract [en]

    AIMS:

    We aimed to investigate the association of number of completed races and finishing time with risk of arrhythmias among participants of Vasaloppet, a 90 km cross-country skiing event.

    METHODS AND RESULTS:

    All the participants without cardiovascular disease who completed Vasaloppet during 1989-98 were followed through national registries until December 2005. Primary outcome was hospitalization for any arrhythmia and secondary outcomes were atrial fibrillation/flutter (AF), bradyarrhythmias, other supraventricular tachycardias (SVT), and ventricular tachycardia/ventricular fibrillation/cardiac arrest (VT/VF/CA). Among 52 755 participants, 919 experienced arrhythmia during follow-up. Adjusting for age, education, and occupational status, those who completed the highest number of races during the period had higher risk of any arrhythmias [hazard ratio (HR)1.30; 95% CI 1.08-1.58; for ≥5 vs. 1 completed race], AF (HR 1.29; 95% CI 1.04-1.61), and bradyarrhythmias (HR 2.10; 95% CI 1.28-3.47). Those who had the fastest relative finishing time also had higher risk of any arrhythmias (HR 1.30; 95% CI 1.04-1.62; for 100-160% vs. >240% of winning time), AF (1.20; 95% CI 0.93-1.55), and bradyarrhythmias (HR 1.85; 95% CI 0.97-3.54). SVT or VT/VF/CA was not associated with finishing time or number of completed races.

    CONCLUSIONS:

    Among male participants of a 90 km cross-country skiing event, a faster finishing time and a high number of completed races were associated with higher risk of arrhythmias. This was mainly driven by a higher incidence of AF and bradyarrhythmias. No association with SVT or VT/VF/CA was found.

  • 4.
    Andersson, Kristofer
    et al.
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Huddinge, Sweden..
    Dahllöf, Goran
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Huddinge, Sweden.;Ctr Pediat Oral Hlth Res, Stockholm, Sweden..
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Grigelioniene, Giedre
    Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Åström, Eva
    Karolinska Inst, Dept Woman & Child Hlth, Stockholm, Sweden.;Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Pediat Neurol & Musculoskeletal Disorders & Home, Stockholm, Sweden..
    Malmgren, Barbro
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Huddinge, Sweden..
    Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta - A retrospective cohort study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176466Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, caused mainly by mutations in the collagen I genes (COL1A1 and COL1A2). Dentinogenesis imperfecta (DGI) and other dental aberrations are common features of OI. We investigated the association between collagen I mutations and DGI, taurodontism, and retention of permanent second molars in a retrospective cohort of 152 unrelated children and adolescents with OI. The clinical examination included radiographic evaluations. Teeth from 81 individuals were available for histopathological evaluation. COL1A1/2 mutations were found in 104 individuals by nucleotide sequencing. DGI was diagnosed clinically and radiographically in 29% of the individuals (44/152) and through isolated histological findings in another 19% (29/152). In the individuals with a COL1A1 mutation, 70% (7/10) of those with a glycine substitution located C-terminal of p. Gly305 exhibited DGI in both dentitions while no individual (0/7) with a mutation N-terminal of this point exhibited DGI in either dentition (p = 0.01). In the individuals with a COL1A2 mutation, 80% (8/10) of those with a glycine substitution located C terminal of p. Gly211 exhibited DGI in both dentitions while no individual (0/5) with a mutation N-terminal of this point (p = 0.007) exhibited DGI in either dentition. DGI was restricted to the deciduous dentition in 20 individuals. Seventeen had missense mutations where glycine to serine was the most prevalent substitution (53%). Taurodontism occurred in 18% and retention of permanent second molars in 31% of the adolescents. Dental aberrations are strongly associated with qualitatively changed collagen I. The varying expressivity of DGI is related to the location of the collagen I mutation. Genotype information may be helpful in identifying individuals with OI who have an increased risk of dental aberrations.

  • 5.
    Banefelt, J.
    et al.
    Quantify Res, Stockholm, Sweden..
    Akesson, K.
    Lund Univ, Dept Orthopaed, Skane Univ Hosp, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Spangeus, A.
    Linkoping Univ, Dept Endocrinol, Dept Med & Hlth Sci, Linkoping, Sweden..
    Karlsson, L.
    Quantify Res, Stockholm, Sweden..
    Strom, O.
    Quantify Res, Stockholm, Sweden.;Karolinska Inst, Dept Learning Informat Management & Eth, Stockholm, Sweden..
    Ortsater, G.
    Quantify Res, Stockholm, Sweden..
    Libanati, C.
    UCB Pharma, Brussels, Belgium..
    Toth, E.
    UCB Pharma, Brussels, Belgium..
    Short-Term Fracture (Fx) Incidence And Risk Factors Following Fracture In A Swedish Database Study2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S365-S365Article in journal (Other academic)
  • 6.
    Björk, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Mellström, Dan
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    Ohlsson, Claes
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden..
    Karlsson, Magnus
    Department of Clinical Sciences and Orthopedic Surgery, Lund University, Skåne University Hospital, Malmö..
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Polymorphisms in the CYP2R1 gene are associated with 25OHD3 and bone mineral density, but not with calcium and phosphate concentrations (MrOS Sweden).Manuscript (preprint) (Other academic)
  • 7.
    Björk, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ribom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Scragg, Robert
    Section of Epidemiology & Biostatistics, School of Population Health, University of Auckland, Auckland, New Zeeland.
    Mellström, Dan
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Grundberg, Elin
    Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Quebec, Canada.
    Ohlsson, Claes
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Karlsson, Magnus
    Department of Clinical Sciences and Orthopedic Surgery, Lund University, Skåne University Hospital, Malmö..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Genetic variation in the vitamin D receptor gene is not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden.Manuscript (preprint) (Other academic)
  • 8. Bolinder, J.
    et al.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Johansson, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wilding, J.
    Langkilde, A. M.
    Sjöstrom, C. D.
    Sugg, J.
    Parikh, S.
    Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin2014In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 16, no 2, p. 159-169Article in journal (Refereed)
    Abstract [en]

    Aims

    Dapagliflozin, a highly selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycaemia and weight in patients with type2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. Long-term glycaemic control, body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment.

    Methods

    This randomized, double-blind, placebo-controlled study (NCT00855166) enrolled patients with T2DM [mean: age 60.7 years; HbA1c 7.2%; body mass index (BMI) 31.9 kg/m(2); body weight 91.5 kg] inadequately controlled on metformin. Patients (N=182) were randomly assigned 1:1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period. At week 102, changes from baseline in HbA1c, weight, waist circumference, total body fat mass as measured by dual-energy X-ray absorptiometry (DXA), serum markers of bone turnover, bone mineral density (BMD) as measured by DXA, and adverse events were evaluated.

    Results

    A total of 140 patients (76.9%) completed the study. Over 102 weeks, dapagliflozin-treated patients showed reductions in HbA1c by -0.3%, weight by -4.54 kg, waist circumference by -5.0 cm and fat mass by -2.80 kg without increase in rate of hypoglycaemia. Compared with placebo, no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks. One fracture occurred in each treatment group. The frequency of urinary tract infection (UTI) and genital infection was similar in both treatment groups.

    Conclusions

    Over 102 weeks, dapagliflozin improved glycaemic control, and reduced weight and fat mass, without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin.

  • 9.
    Borgström, F.
    et al.
    Quantify Res, Stockholm, Sweden..
    Olafsson, G.
    Quantify Res, Stockholm, Sweden..
    Jonsson, E.
    Quantify Res, Stockholm, Sweden..
    Ström, O.
    Quantify Res, Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Akesson, K.
    Skane Univ Hosp, Dept Orthoped, Lund, Sweden.;Lund Univ, Clin Sci Malmo, Lund, Sweden..
    Spangeus, A.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    A Simulation Model For The Treatment Pathway Of Osteoporosis2016In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 27, p. S60-S60Article in journal (Other academic)
  • 10.
    Burman, Pia
    et al.
    Lund Univ, Skane Univ Hosp Malmo, Dept Endocrinol, S-20502 Malmo, Sweden..
    Edén-Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ekman, Bertil
    Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Karlsson, Anders F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Schwarcz, Erik
    Univ Orebro, Fac Med & Hlth, Dept Internal Med, SE-70182 Orebro, Sweden..
    Wahlberg, Jeanette
    Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Limited value of cabergoline in Cushing's disease: a prospective study of a 6-week treatment in 20 patients2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 174, no 1, p. 17-24Article in journal (Refereed)
    Abstract [en]

    Context and objective: The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after >= 1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD. Design: Twenty patients (19 naive and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5-5 mg/week over 6 weeks. Methods: Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end. Results: At study end, the median cabergoline dose was 5 mg, range 2.5-5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study. Conclusions: Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.

  • 11.
    Carlzon, Daniel
    et al.
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Svensson, Johan
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Petzold, Max
    Univ Gothenburg, Sahlgrenska Acad, Ctr Appl Biostat, Gothenburg, Sweden..
    Karlsson, Magnus K.
    Lund Univ, Skane Univ Hosp, Dept Orthopaed & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Haghsheno, Mohammad-Ali
    Univ Gothenburg, Inst Clin Sci, Dept Urol, Gothenburg, Sweden..
    Damber, Jan-Erik
    Univ Gothenburg, Inst Clin Sci, Dept Urol, Gothenburg, Sweden..
    Mellström, Dan
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Ohlsson, Claes
    Univ Gothenburg, Inst Med, Sahlgrenska Acad CBAR, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Insulin-like growth factor I and risk of incident cancer in elderly men - results from MrOS (Osteoporotic Fractures in Men) in Sweden2016In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 84, no 5, p. 764-770Article in journal (Refereed)
    Abstract [en]

    ObjectiveStudies of the association between circulating IGF-I and cancer risk have shown conflicting results. We have previously observed a U-shaped association between IGF-I and cancer mortality. This study test the hypotheses of a U-shaped association between IGF-I and incident cancer. DesignElderly men (2368), randomly recruited from the general community. MethodsIGF-I was measured in a cohort of elderly men. Complete data for incident cancer were obtained from the Swedish Cancer Registry. Statistical analyses included Cox proportional hazards regressions with or without a spline approach. ResultsThree hundred and sixty-nine participants had incident cancer after baseline. Prostate cancer was most frequent (n = 140). There was no association between serum IGF-I and all cancer or prostate cancer incidence. However, there was a nonlinear association between IGF-I and nonprostate cancer incidence (P = <005). Exploratory analyses were performed for low and high serum IGF-I (quintiles 1 and 5) vs intermediate (quintiles 2-4, referent). There was a tendency of increased nonprostate cancer risk in men with high IGF-I (HR = 126, 95% confidence interval (CI): 092-171, P = 015). After excluding participants with follow-up of less than 26 years (half median follow-up time), to control for potential diagnostic delay, the association was statistically significant (HR = 155, CI: 103-235). ConclusionThere was a significant nonlinear association between IGF-I and nonprostate cancer. No association between IGF-I and prostate cancer was observed. Future studies are warranted to further investigate this nonlinear association, including whether IGF-I concentration is a reproducible, and useful, risk marker of nonprostate cancer.

  • 12. Carlzon, Daniel
    et al.
    Svensson, Johan
    Petzold, Max
    Karlsson, Magnus K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Tivesten, Asa
    Mellstrom, Dan
    Ohlsson, Claes
    Both Low and High Serum IGF-1 Levels Associate With Increased Risk of Cardiovascular Events in Elderly Men2014In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 11, p. E2308-E2316Article in journal (Refereed)
    Abstract [en]

    Context: Most previous prospective studies suggest that low serum IGF-1 associates with increased risk of cardiovascular disease (CVD) events whereas other studies suggest that high serum IGF-1 associates with increased risk of CVD events. Objective: We tested the hypothesis that not only low, but also high serum IGF-1 levels associate with increased risk of CVD events in elderly men. Setting and Design: Serum IGF-1 levels were measured in 2901 elderly men (age 69-81 years) included in the Swedish cohort of the prospective, population-based Osteoporotic Fractures in Men Study (MrOS), Sweden cohort. Data for CVD events were obtained from national Swedish registers with no loss of followup. Results: During followup (median, 5.1 y) 589 participants experienced a CVD event. The association between serum IGF-1 and risk of CVD events was nonlinear, and restricted cubic spline Cox regression analysis revealed a U-shaped association between serum IGF-1 levels and CVD events (P < .01 for nonlinearity). Low as well as high serum IGF-1 (quintile 1 or 5 vs quintiles 2-4) significantly associated with increased risk for CVD events (hazard ratio [HR] = 1.25, 95% confidence interval, [CI], 1.02-1.54; and HR = 1.35, 95% CI 1.10-1.66, respectively). These associations remained after adjustment for prevalent CVD and multiple risk factors. High serum IGF-1 associated with increased risk of coronary heart disease (CHD) events but not with risk of cerebrovascular events. Conclusions: Both low and high serum IGF-1 levels are risk markers for CVD events in elderly men. The association between high serum IGF-1 and CVD events is mainly driven by CHD events.

  • 13. Ellegaard, Maria
    et al.
    Karlsson, Magnus
    Lorentzon, Mattias
    Ohlsson, Claes
    Mellstrom, Dan
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Schwarz, Peter
    Jorgensen, Niklas Rye
    Single-nucleotide polymorphism in the P2Y(2) receptor gene is associated with bone mineral density in a cohort of Swedish elderly men2014In: Purinergic Signalling Purinergic Signalling, ISSN 1573-9538, E-ISSN 1573-9546, Vol. 10, no 4, p. 751-751, article id B015Article in journal (Other academic)
  • 14. Eriksson, Anna L.
    et al.
    Movérare-Skrtic, Sofia
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Karlsson, Magnus
    Mellström, Dan
    Ohlsson, Claes
    High-Sensitivity CRP Is an Independent Risk Factor for All Fractures and Vertebral Fractures in Elderly Men: The MrOS Sweden Study2014In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 29, no 2, p. 418-423Article in journal (Refereed)
    Abstract [en]

    Epidemiological studies have shown low-grade inflammation measured by high-sensitivity C-reactive protein (hs-CRP) to be associated with fracture risk in women. However, it is still unclear whether hs-CRP is also associated with fracture risk in men. We therefore measured serum levels of hs-CRP in 2910 men, mean age 75 years, included in the prospective population-based MrOS Sweden cohort. Study participants were divided into tertile groups based on hs-CRP level. Fractures occurring after the baseline visit were validated (average follow-up 5.4 years). The incidence for having at least one fracture after baseline was 23.9 per 1000 person-years. In Cox proportional hazard regression analyses adjusted for age, hs-CRP was related to fracture risk. The hazard ratio (HR) of fracture for the highest tertile of hs-CRP, compared with the lowest and the medium tertiles combined, was 1.48 (95% CI, 1.20-1.82). Multivariate adjustment for other risk factors for fractures had no major effect on the associations between hs-CRP and fracture. Results were essentially unchanged after exclusion of subjects with hs-CRP levels greater than 7.5mg/L, as well as after exclusion of subjects with a first fracture within 3 years of follow-up, supporting that the associations between hs-CRP and fracture risk were not merely a reflection of a poor health status at the time of serum sampling. Femoral neck bone mineral density (BMD) was not associated with hs-CRP, and the predictive role of hs-CRP for fracture risk was essentially unchanged when femoral neck BMD was added to the model (HR, 1.37; 95% CI, 1.09-1.72). Exploratory subanalyses of fracture type demonstrated that hs-CRP was clearly associated with clinical vertebral fractures (HR, 1.61; 95% CI, 1.12-2.29). We demonstrate, using a large prospective population-based study, that elderly men with high hs-CRP have increased risk of fractures, and that these fractures are mainly vertebral. The association between hs-CRP and fractures was independent of BMD. (c) 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

  • 15.
    Feudjo Tepie, M.
    et al.
    Amgen Ltd, Uxbridge, Middx, England..
    Banefelt, J.
    Quantify Res, Stockholm, Sweden..
    Ström, O.
    Quantify Res, Stockholm, Sweden..
    Ortsater, G.
    Quantify Res, Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Åkesson, K.
    Skane Univ Hosp, Dept Orthoped, Lund, Sweden.;Lund Univ, Clin Sci Malmo, Lund, Sweden..
    Sprafka, J. M.
    Amgen Inc, Thousand Oaks, CA 91320 USA..
    Wagman, R. B.
    Amgen Inc, Thousand Oaks, CA 91320 USA..
    Denosumab (DMAB) Freedom Extension Pseudo Control Study: A Retrospective Cohort Study Of Comorbidities In Swedish Women With Postmenopausal Osteoporosis (PMO)2016In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 27, p. S154-S154Article in journal (Other academic)
  • 16. Ghanei, Iman
    et al.
    Rosengren, Bjorn E.
    Hasserius, Ralph
    Nilsson, Jan-Ake
    Mellstrom, Dan
    Ohlsson, Claes
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Karlsson, Magnus K.
    The prevalence and severity of low back pain and associated symptoms in 3,009 old men2014In: European spine journal, ISSN 0940-6719, E-ISSN 1432-0932, Vol. 23, no 4, p. 814-820Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to evaluate the prevalence and severity of low back pain (LBP) and the influence of sciatica and neurological deficits in old men. Mister osteoporosis Sweden includes 3,014 community-dwelling men aged 69-81 years. At study start 3,009 participants answered questions on LBP, low back pain and sciatica (LBP + SCI) or low back pain and sciatica with associated neurological deficits (LBP + SCI + NEU) during the preceding 12 months. Data are presented as proportions or medians with mid-quartile ranges. Differences between groups were tested by chi(2) test and Kruskall-Wallis test. 24 % had experienced LBP without SCI, 8 % LBP + SCI and 14 % LBP + SCI + NEU. 10 % of the men with LBP, 22 % of those with LBP + SCI, and 36 % of those with LBP + SCI + NEU rated the pain as severe (p < 0.001). 23 % of the men with LBP, 31 % of those with LBP + SCI and 50 % of those with LBP + SCI + NEU reported limitation in activity of daily living (ADL) (p < 0.001). Men with only LBP had to restrict their activities for 7 days (3-14), those with LBP + SCI 6 days (2-14) and those with LBP + SCI + NEU 10 days (3-30) (p < 0.05). The 1-year prevalence of LBP in community living men aged 69-81 years was close to 50 % but for individuals with LBP or LBP + SCI the morbidity was low with more than two-thirds having no limitations in ADL. In men with LBP + SCI + NEU more than one-third rated the pain as severe and close to half had limitations in ADL.

  • 17.
    Harvey, N. C.
    et al.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Tremona Rd, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Tremona Rd, Southampton, Hants, England..
    Johansson, H.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden.;Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Oden, A.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden.;Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Karlsson, M. K.
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Rosengren, B. E.
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Tremona Rd, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Tremona Rd, Southampton, Hants, England.;Univ Oxford, NIHR Musculoskeletal Biomed Res Unit, Oxford, England..
    McCloskey, E.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Beech Hill Rd, Sheffield S10 2RX, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    FRAX predicts incident falls in elderly men: findings from MrOs Sweden2016In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 27, no 1, p. 267-274Article in journal (Refereed)
    Abstract [en]

    A Summary Falls and fractures share several common risk factors. Although past falls is not included as an input variable in the FRAX calculator, we demonstrate that FRAX probability predicts risk of incident falls in the MrOs Sweden cohort. Introduction Although not included in the FRAXA (R) algorithm, it is possible that increased falls risk is partly dependent on other risk factors that are incorporated into FRAX. The aim of the present study was to determine whether fracture probability generated by FRAX might also predict risk of incident falls and the extent that a falls history would add value to FRAX. Methods We studied the relationship between FRAX probabilities and risk of falls in 1836 elderly men recruited to the MrOS study, a population-based prospective cohort of men from Sweden. Baseline data included falls history, clinical risk factors, bone mineral density (BMD) at femoral neck, and calculated FRAX probabilities. Incident falls were captured during an average of 1.8 years of follow-up. An extension of Poisson regression was used to investigate the relationship between FRAX, other risk variables, and the time-to-event hazard function of falls. All associations were adjusted for age and time since baseline. Results At enrolment, 15.5 % of the men had fallen during the preceding 12 months (past falls) and 39 % experienced one or more falls during follow-up (incident falls). The risk of incident falls increased with increasing FRAX probabilities at baseline (hazard ratio (HR) per standard deviation (SD), 1.16; 95 % confidence interval (95%CI), 1.06 to 1.26). The association between incident falls and FRAX probability remained after adjustment for past falls (HR per SD, 1.12; 95%CI, 1.03 to 1.22). High compared with low baseline FRAX score (>15 vs <15 % probability of major osteoporotic fracture) was strongly predictive of increased falls risk (HR, 1.64; 95%CI, 1.36 to 1.97) and remained stable with time. Whereas past falls were a significant predictor of incident falls (HR, 2.75; 95%CI, 2.32 to 3.25), even after adjustment for FRAX, the hazard ratio decreased markedly with increasing follow-up time. Conclusions Although falls are not included as an input variable, FRAX captures a component of risk for future falls and outperforms falls history with an extended follow-up time.

  • 18.
    Harvey, N. C.
    et al.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    Johansson, H.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Oden, A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Karlsson, M. K.
    Lund Univ, Skane Univ Hosp, Clin & Mol Osteoporosis Res Unit, Dept Orthoped & Clin Sci, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Skane Univ Hosp, Clin & Mol Osteoporosis Res Unit, Dept Orthoped & Clin Sci, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    McCloskey, E. V.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    The Predictive Value Of Past Falls For Incident Falls Decreases, But That Of Frax Remains Stable, With Increasing Follow-Up Time: Findings From MROS Sweden2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, p. S143-S143Article in journal (Other academic)
  • 19.
    Harvey, N. C.
    et al.
    Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Botnar Res Ctr, Oxford, England..
    Oden, A.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    Orwoll, E.
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Lapidus, J.
    Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Div Biostat, Portland, OR 97201 USA..
    Kwok, T.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China..
    Karlsson, M.
    Lund Univ, Dept Orthopaed & Clin Sci, Skane Univ Hosp, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Botnar Res Ctr, Oxford, England..
    Kanis, J. A.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenberg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Johansson, H.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    McCloskey, E. V.
    Univ Sheffield, Ctr Metab Bone Dis, Med Sch, Sheffield, S Yorkshire, England..
    Mobility Related Risk Factors Predict Incident Fractures Independently Of Frax: The Osteoporotic Fractures In Men (MROS) Study2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S61-S61Article in journal (Other academic)
  • 20.
    Harvey, N. C.
    et al.
    Univ Oxford, Musculoskeletal Epidemiol, Botnar Res Ctr, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England..
    Oden, A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Orwoll, E.
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Lapidus, J.
    Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Div Biostat, Portland, OR 97201 USA..
    Kwok, T.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China..
    Karlsson, M.
    Lund Univ, Dept Orthopaed & Clin Sci, Skane Univ Hosp, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Oxford, Musculoskeletal Epidemiol, Botnar Res Ctr, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England..
    McCloskey, E.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenberg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Johansson, H.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    PRIOR FALLS PREDICT INCIDENT FRACTURES INDEPENDENTLY OF FRAX: The Osteoporotic Fractures In Men (MROS) Study2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S259-S259Article in journal (Other academic)
  • 21.
    Harvey, Nicholas C.
    et al.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England..
    Oden, Anders
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden.;Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Orwoll, Eric
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Lapidus, Jodi
    Oregon Hlth & Sci Univ, Div Biostat, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA..
    Kwok, Timothy
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China..
    Karlsson, Magnus K.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Rosengren, Björn E.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci Malmo, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, Cyrus
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton SO16 6YD, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Southampton, Hants, England.;Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England.;Univ Oxford, NIHR Oxford Biomed Res Ctr, Oxford, England..
    McCloskey, Eugene
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England.;Univ Sheffield, Ctr Integrated Res Musculoskeletal Ageing CIMA, Mellanby Ctr Bone Res, Sheffield, S Yorkshire, England..
    Kanis, John A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England.;Catholic Univ Australia, Inst Hlth & Aging, Melbourne, Vic, Australia..
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Mellström, Dan
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Johansson, Helena
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden.;Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England.;Catholic Univ Australia, Inst Hlth & Aging, Melbourne, Vic, Australia..
    Falls Predict Fractures Independently of FRAX Probability: A Meta-Analysis of the Osteoporotic Fractures in Men (MrOS) Study2018In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 33, no 3, p. 510-516Article in journal (Refereed)
    Abstract [en]

    Although prior falls are a well-established predictor of future fracture, there is currently limited evidence regarding the specific value of falls history in fracture risk assessment relative to that of other clinical risk factors and bone mineral density (BMD) measurement. We therefore investigated, across the three Osteoporotic Fractures in Men (MrOS) Study cohorts, whether past falls predicted future fracture independently of FRAX and whether these associations varied with age and follow-up time. Elderly men were recruited from MrOS Sweden, Hong Kong, and USA. Baseline data included falls history (over the preceding 12 months), clinical risk factors, BMD at femoral neck, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the associations between falls, FRAX probability, and incident fracture, adjusting for age, time since baseline, and cohort in base models; further models were used to investigate interactions with age and follow-up time. Random-effects meta-analysis was used to synthesize the individual country associations. Information on falls and FRAX probability was available for 4365 men in USA (mean age 73.5 years; mean follow-up 10.8 years), 1823 men in Sweden (mean age 75.4 years; mean follow-up 8.7 years), and 1669 men in Hong Kong (mean age 72.4 years; mean follow-up 9.8 years). Rates of past falls were similar at 20%, 16%, and 15%, respectively. Across all cohorts, past falls predicted incident fracture at any site (hazard ratio [HR]=1.69; 95% confidence interval [CI] 1.49, 1.90), major osteoporotic fracture (MOF) (HR=1.56; 95% CI 1.33, 1.83), and hip fracture (HR=1.61; 95% CI 1.27, 2.05). Relationships between past falls and incident fracture remained robust after adjustment for FRAX probability: adjusted HR (95% CI) any fracture: 1.63 (1.45, 1.83); MOF: 1.51 (1.32, 1.73); and hip: 1.54 (1.21, 1.95). In conclusion, past falls predicted incident fracture independently of FRAX probability, confirming the potential value of falls history in fracture risk assessment.

  • 22.
    Holgersson, Magdalena Bentmar
    et al.
    Lund Univ, Dept Translat Med, Jan Waldenstroms Gata 35,Bldg 91,Plan 10, S-20502 Malmo, Sweden..
    Ruhayel, Yasir
    Skane Univ Hosp, Dept Urol, Malmo, Sweden..
    Karlsson, Magnus
    Lund Univ, Dept Orthoped & Clin Sci, Malmo, Sweden..
    Giwercman, Aleksander
    Lund Univ, Dept Translat Med, Jan Waldenstroms Gata 35,Bldg 91,Plan 10, S-20502 Malmo, Sweden..
    Bjartell, Anders
    Lund Univ, Dept Translat Med, Jan Waldenstroms Gata 35,Bldg 91,Plan 10, S-20502 Malmo, Sweden.;Skane Univ Hosp, Dept Urol, Malmo, Sweden..
    Ohlsson, Claes
    Gothenburg Univ, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Gothenburg, Sweden.;Gothenburg Univ, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Dept Geriatr, Gothenburg, Sweden..
    Mellstrom, Dan
    Gothenburg Univ, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Gothenburg, Sweden.;Gothenburg Univ, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Dept Geriatr, Gothenburg, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Haghsheno, Mohammad-Ali
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Urol,Sahlgrenska Canc Ctr, Gothenburg, Sweden..
    Damber, Jan-Erik
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Urol,Sahlgrenska Canc Ctr, Gothenburg, Sweden..
    Giwercman, Yvonne Lundberg
    Lund Univ, Dept Translat Med, Jan Waldenstroms Gata 35,Bldg 91,Plan 10, S-20502 Malmo, Sweden..
    Lower prostate cancer risk in Swedish men with the androgen receptor E213 A-allele2017In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 28, no 3, p. 227-233Article in journal (Refereed)
    Abstract [en]

    In a previous population-based study on 3369 European men with self-reported prostate cancer (PCa), it was shown that androgen receptor (AR) haplotype designated H2 was associated with high levels of serum PSA (prostate-specific antigen) concentration, and, at the same time, with low risk for PCa. The aim of this study was to replicate this finding in other cohorts, with registry-based cancer diagnosis. Using data from two population-based cohorts; the Malmo Diet and Cancer Study (MDCS, n = 12,121) and the Swedish Osteoporotic fractures in men study (MrOS, n = 1,120), 628 men with PCa and 1,374 controls were identified and genotyped. PCa data were collected from the Swedish national cancer registry. PCa odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for carriers of the particular AR haplotype, tagged by the rs6624304 T-allele. The 15% of men who were carriers of the AR haplotype H2 had approximately one-third lower risk for PCa diagnosis compared to those with the most common H1 variant (OR 0.65; 95% CI 0.45-0.94; p = 0.021). The same trend, although not statistically significant (OR 0.75; 95% CI 0.47-1.24; p = 0.275), was observed in MrOS Sweden. When both cohorts were merged, an even more significant result was observed (OR 0.68; 95% CI 0.51-0.90; p = 0.008). Swedish men with the variant AR haplotype H2, tagged by rs6624304, have significantly lower risk of PCa compared to those with the more common variant.

  • 23.
    Holmlund-Suila, Elisa
    et al.
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Viljakainen, Heli
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Hytinantti, Timo
    Helsinki Matern Hosp, Helsinki, Finland..
    Andersson, Sture
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Makitie, Outi
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Fibroblast Growth Factor 23 Concentrations Reflect Sex Differences in Mineral Metabolism and Growth in Early Infancy2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 85, no 4, p. 232-241Article in journal (Refereed)
    Abstract [en]

    Background: The role of fibroblast growth factor 23 (FGF23) in the regulation of mineral homeostasis in early life is inadequately understood. We aimed to explore the effects of vitamin D supplementation on serum FGF23 and to elucidate longitudinal changes in FGF23, in addition to studying its association with mineral metabolism in early infancy. Methods: Altogether 113 healthy infants received vitamin D 3 10, 30 or 40 mu g/day from age 0.5 to 3.0 months. Cord blood at birth and capillary blood samples at 3 months were analyzed for serum 25-hydroxyvitamin D, parathyroid hormone, phosphate, calcium and intact and C-terminal FGF23. Results: In repeated-measures ANCOVA, intact FGF23 concentration increased with time (p < 0.001) and C-terminal FGF23 decreased (p < 0.001). At 3 months, girls had a higher concentration of intact FGF23 (51 vs. 26 pg/ml, p < 0.001) and a greater increase over time (Delta FGF23 intact 45 vs. 16 pg/ml, p = 0.001) than boys. Vitamin D did not affect serum intact or C-terminal FGF23 concentrations. Girls showed a positive correlation between phosphate and intact FGF23 (p = 0.004), whereas in boys phosphate and C-terminal FGF23 correlated inversely (p = 0.006). Conclusions: A substantial sex-related difference in intact FGF23 concentration exists during early infancy, possibly related to differences in skeletal growth between boys and girls. (C) 2016 S. Karger AG, Basel

  • 24.
    Johansson, H.
    et al.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Harvey, N. C.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    Oden, A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Karlsson, M. K.
    Lund Univ, Skane Univ Hosp, Dept Orthoped & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Rosengren, B.
    Lund Univ, Skane Univ Hosp, Dept Orthoped & Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Cooper, C.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    McCloskey, E. V.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Kanis, J. A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Ohlsson, C.
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Waning Long-Term Predictive Value Of Falls History For Incident Fracture: MROS Sweden2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, p. S42-S42Article in journal (Other academic)
  • 25.
    Johansson, H.
    et al.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Oden, A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Karlsson, M.
    Lund Univ, Skane Univ Hosp, Dept Orthopaed & Clin Sci, Malmo, Sweden..
    Lorentzon, M.
    Sahlgrens Acad, Inst Med, Dept Internal Med & Clin Nutr, Geriatr Med, Molndal, Sweden..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Rosengren, B.
    Lund Univ, Dept Clin Sci Malmo, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Skane Univ Hosp, Dept Orthoped, Malmo, Sweden..
    Mellström, D.
    Sahlgrens Acad, Inst Med, Dept Internal Med & Clin Nutr, Geriatr Med, Molndal, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    OhIsson, C.
    Univ Gothenburg, Gothenburg, Sweden..
    Harvey, N. C.
    Univ Southampton, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    McCloskey, E.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Femoral Neck BMD Is Still The Preferred Site In The Assessment Of Hip Fracture In Elderly Men (10-Year Follow-Up Of MROS Sweden)2016In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 27, p. S58-S59Article in journal (Other academic)
  • 26. Johansson, Helena
    et al.
    Oden, Anders
    Karlsson, Magnus
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Mccloskey, Eugene
    Kanis, John A.
    Ohlsson, Claes
    Mellstrom, Dan
    Adiponectin and 10-year probability of fracture in elderly men: MR OS Sweden2013In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 24, no Suppl. 1, p. S47-S47Article in journal (Other academic)
  • 27.
    Jonsson, E.
    et al.
    Quantify Res, Stockholm, Sweden..
    Hansson-Hedblom, A.
    Quantify Res, Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Akesson, K.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Unit, Malmo, Sweden..
    Spangeus, A.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Borgstrom, F.
    Quantify Res, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Kanis, J. A.
    Catholic Univ Australian, Melbourne, Vic, Australia.;Univ Sheffield, Sheffield, S Yorkshire, England..
    Cost-Effectiveness Of Complying With Treatment Guidelines In Sweden2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S440-S440Article in journal (Other academic)
  • 28.
    Jonsson, E.
    et al.
    Quantify Res, Hantverkargatan 8, SE-11221 Stockholm, Sweden..
    Hansson-Hedblom, A.
    Quantify Res, Hantverkargatan 8, SE-11221 Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Akesson, K.
    Lund Univ, Dept Clin Sci, Clin & Mol Osteoporosis Unit, Malmo, Sweden..
    Spangeus, A.
    Linkoping Univ, Dept Endocrinol Med & Hlth, Linkoping, Sweden..
    Kanis, J. A.
    Univ Sheffield, Sheffield, S Yorkshire, England.;Catholic Univ Australia, Melbourne, Vic, Australia..
    Borgstrom, F.
    Quantify Res, Hantverkargatan 8, SE-11221 Stockholm, Sweden.;Karolinska Inst, LIME MMC, Stockholm, Sweden..
    A health economic simulation model for the clinical management of osteoporosis2018In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 29, no 3, p. 545-555Article in journal (Refereed)
    Abstract [en]

    The objective was to estimate the burden of osteoporosis in Sweden based on current clinical practice and the cost-effectiveness of improvements in the management of osteoporosis over the clinical management compared to current clinical practice. Results showed that better compliance to treatment guidelines is associated with better projected outcomes and cost-savings.

    Introduction

    The purpose of this study is to estimate the burden of osteoporosis in Sweden based on current clinical practice and the cost-effectiveness of improvements in the management of osteoporosis over the clinical management compared to current clinical practice.

    Methods

    The analysis was carried out using a model that simulates the individual patients considered for pharmacological treatment during 1 year and their projected osteoporosis treatment pathway, quality-adjusted life years (QALYs) and costs over their remaining lifetime. All patients regardless of treatment or no treatment were simulated. Information on current management of osteoporosis in terms of patient characteristics and treatment patterns were derived from a Swedish osteoporosis research database based on national registers and patient records. Current (standard) clinical management was compared with alternative scenarios mirroring Swedish treatment guidelines.

    Results

    The national burden in terms of lost QALYs was estimated at 14,993 QALYs and the total economic cost at €776M. Scenario analyses showed that 382–3864 QALYs could be gained at a cost/QALY ranging from cost-saving to €31368, depending on the scenario. The margin of investment, i.e. the maximum amount that could be invested in the healthcare system to achieve these improvements up to the limit of the willingness to pay/QALY, was estimated at €199M on a population level (€3,634/patient).

    Conclusions

    The analysis showed that better compliance to treatment guidelines is associated with better projected outcomes and cost-savings. From a cost-effectiveness perspective, there is also considerable room for investment to achieve these improvements in the management of osteoporosis.

  • 29.
    Jonsson, E.
    et al.
    Quantify Res, Stockholm, Sweden..
    Strom, O.
    Quantify Res, Stockholm, Sweden.;Karolinska Inst, LIME MMC, Stockholm, Sweden..
    Spangeus, A.
    Linkoping Univ Hosp, Linkoping, Sweden..
    Akesson, K.
    Lund Univ, Skane Univ Hosp, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Borgstrom, R.
    Quantify Res, Stockholm, Sweden.;Karolinska Inst, LIME MMC, Stockholm, Sweden..
    Banefelt, J.
    Quantify Res, Stockholm, Sweden..
    Toth, E.
    UCB Pharma, Brussels, Belgium..
    Libanati, C.
    UCB Pharma, Brussels, Belgium..
    Charokopou, M.
    UCB Pharma, Brussels, Belgium..
    Risk Of Major Osteoporotic Fracture (Hip, Vertebral, Radius, Humerus [Mof]) After First, Second And Third Fragility Fracture In A Swedish General Population Cohort2017In: Value in Health, ISSN 1098-3015, E-ISSN 1524-4733, Vol. 20, no 9, p. A528-A528Article in journal (Other academic)
  • 30.
    Jonsson, Emma
    et al.
    Quantify Res, Hantverkargatan 8, S-11221 Stockholm, Sweden..
    Eriksson, Daniel
    Quantify Res, Hantverkargatan 8, S-11221 Stockholm, Sweden..
    Åkesson, Kristina
    Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Salomonsson, Stina
    Karolinska Inst, Ctr Mol Med, Stockholm, Sweden.;Merck Sharp & Dohme Sweden, Sollentuna, Sweden..
    Borgström, Fredrik
    Quantify Res, Hantverkargatan 8, S-11221 Stockholm, Sweden.;Karolinska Inst, LIME MMC, Stockholm, Sweden..
    Ström, Oskar
    Quantify Res, Hantverkargatan 8, S-11221 Stockholm, Sweden..
    Swedish osteoporosis care2015In: ARCHIVES OF OSTEOPOROSIS, ISSN 1862-3522, Vol. 10, no 1, article id 24Article in journal (Refereed)
    Abstract [en]

    Mini-abstract The objective of this study was to review and describe the current state of Swedish osteoporosis care and to highlight ongoing challenges. This report encompasses quantitative health outcomes based on Swedish registry data as well as organizational and management aspects. Executive summary Swedish osteoporosis care is characterized by a significant burden of disease, difficulties in identifying high-risk patients, and fragmented pathways for patients in need of secondary fracture prevention. This report aimed to describe the current state, gaps, and challenges in Swedish osteoporosis care, using Swedish national databases, questionnaires, and interviews with healthcare representatives. A secondary aim was to develop quality and process measures to compare differences between counties and to use those measures to describe the interaction between quantitative health outcomes and aspects of care organization and management. In conjunction with fractures, a considerably smaller proportion of men are treated than women, and a smaller proportion of older women are treated compared to younger groups. Between 3 and 16 % of patients receive treatment after a fracture, and the treatment rate in this patient group can likely increase. In addition to an unsatisfactory treatment rate, a limited number of those treated continue treatment throughout the recommended treatment durations, leading to increased risk of fracture. With a substantial variation between counties, there is a clear difficulty to identify non-persistent patients and switch to an alternative treatment. Collaboration around the patient across specialties has been lacking, and systems for secondary prevention have been concentrated to a few counties. However, when this study was conducted, there was a general trend towards implementing regional care programs. This report suggests possible strategies for improving quality of care and, hopefully, it can provide a basis for future evaluations and regional improvement of osteoporosis care in Sweden and other countries.

  • 31.
    Kanis, J. A.
    et al.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Oden, A.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Harvey, N. C.
    Univ Southampton, Southampton Gen Hosp, MRC Lifecourse Epidemiol Unit, Southampton, Hants, England..
    Leslie, W. D.
    Univ Manitoba, Med & Radiol, Winnipeg, MB, Canada..
    Hans, D.
    Univ Lausanne Hosp, Ctr Bone Dis, Lausanne, Switzerland..
    Johansson, H.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    Barkmann, R.
    Klin Diagnost Radiol, Sekt Biomed Bildgebung, Kiel, Germany..
    Boutroy, S.
    Univ Lyon, Hosp Civils Lyon, Hop E Herriot, INSERM UMR 1033, Lyon, France..
    Brown, J. P.
    CHU Quebec, Res Ctr, Quebec City, PQ, Canada.;Univ Laval, Quebec City, PQ, Canada..
    Chapurlat, R. D.
    INSERM Unit 433, Lyon, France..
    Elders, P.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    Fujita, Y.
    Kinki Univ, Fac Med, Dept Publ Hlth, Osaska Sayama, Japan..
    Glueer, C. C.
    Univ Kiel, Diagnost Radiol, Biomed Imaging, Kiel, Germany..
    Goltzman, D.
    Royal Victoria Hosp, Dept Med, Montreal, PQ H3A 1A1, Canada.;Royal Victoria Hosp, Dept Physiol, Montreal, PQ H3A 1A1, Canada.;McGill Univ, Montreal, PQ, Canada..
    Iki, M.
    Kinki Univ, Dept Publ Hlth, Fac Med, Osaka, Japan..
    Karlsson, M. K.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Orthoped & Clin Sci, Skane Univ Hosp, Malmo, Sweden..
    Kindmark, Andreas
    Univ Uppsala Hosp, Dept Med Sci, Uppsala, Sweden..
    Kurtunatani, N.
    Nara Med Univ, Dept Community Hlth & Epidemiol, Sch Med, Kashihara, Nara 634, Japan..
    Kwok, A.
    Chinese Univ Hong Kong, Jockey Club, Ctr Osteoporosis Care & Control, Hong Kong, Hong Kong, Peoples R China..
    Leung, J.
    Chinese Univ Hong Kong, Jockey Club, Ctr Osteoporosis Care & Control, Hong Kong, Hong Kong, Peoples R China..
    Lippuner, K.
    Univ Hosp Bern, CH-3010 Bern, Switzerland..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lorentzon, M.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Mellstrom, D.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Merlijn, T.
    Oei, L.
    Deakin Univ, Epi Ctr Healthy Ageing, Sch Med, Geelong, Vic 3217, Australia..
    Ohlsson, C.
    Univ Gothenburg, CBAR, Sahlgrenska Acad, Gothenburg, Sweden..
    Pasco, J. A.
    Deakin Univ, Epi Ctr Healthy Ageing, Sch Med, Geelong, Vic 3217, Australia..
    Rivadeneira, F.
    Erasmus Univ, Dept Internal Med, Med Ctr, Rotterdam, Netherlands.;Erasmus Univ, Dept Epidemiol, Med Ctr, Rotterdam, Netherlands..
    Rosengren, B.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Orthoped & Clin Sci, Skane Univ Hosp, Malmo, Sweden..
    Sornay-Rendu, E.
    Szulc, P.
    Tamaki, J.
    Osaka Med Coll, Dept Hyg & Publ Hlth, Takatsuki, Osaka 569, Japan..
    McCloskey, E. V.
    Univ Sheffield, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    A Meta-Analysis Of Trabecular Bone Score In Fracture Risk Prediction And Its Interaction With Frax2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, p. S46-S46Article in journal (Other academic)
  • 32. Karlsson, Magnus K
    et al.
    Ribom, Eva L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, J-Å
    Karlsson, Caroline
    Cöster, Maria
    Vonschewelov, Thord
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ohlsson, Claes
    Mellström, Dan
    Lorentzon, Mattias
    Leung, P C
    Lau, Edith
    Cauley, Jane A
    Barrett-Connor, Elizabeth
    Stefanick, Marcia L
    Orwoll, Eric
    Rosengren, Björn E
    International and ethnic variability of falls in older men2014In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 42, no 2, p. 194-200Article in journal (Refereed)
    Abstract [en]

    Aims: Fallers and especially recurrent fallers are at high risk for injuries. The aim of this study was to evaluate fall epidemiology in older men with special attention to the influence of age, ethnicity and country of residence. Methods: 10,998 men aged 65 years or above recruited in Hong Kong, the United States (US) and Sweden were evaluated in a cross-sectional retrospective study design. Self-reported falls and fractures for the preceding 12 months were registered through questionnaires. Group comparisons were done by chi-square test or logistic regression. Results: The proportion of fallers among the total population was 16.5% in ages 65-69, 24.8% in ages 80-84 and 43.2% in ages above 90 (P <0.001). The corresponding proportions of recurrent fallers in the same age groups were 6.3%, 10.1% and 18.2%, respectively (P <0.001), and fallers with fractures 1.0%, 2.3% and 9.1%, respectively (P <0.001). The proportion of fallers was highest in the US, intermediate in Sweden and lowest in Hong Kong (in most age groups P <0.05). The proportion of fallers among white men in the US was higher than in white men in Sweden (all comparable age groups P <0.01) but there were no differences in the proportion of fallers in US men with different ethnicity. Conclusions: The proportion of fallers in older men is different in different countries, and data in this study corroborate with the view that society of residence influences fall prevalence more than ethnicity.

  • 33.
    Khamisi, Selwan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lindgren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Karlsson, F Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    A rare case of dyshormonogenetic fetal goiter responding to intra-amniotic thyroxine injections2014In: European thyroid journal, ISSN 2235-0640, Vol. 3, no 1, p. 51-56Article in journal (Refereed)
    Abstract [en]

    Fetal goiter was detected by routine ultrasound in early pregnancy, gestational week (GW) 18, in a 28-year-old woman with no thyroid history, normal thyroid hormone levels and no TSH receptor or thyroid peroxidase antibodies. An umbilical cord blood sample was drawn in GW 23. The analysis indicated fetal hypothyroidism with TSH >100 mU/l (reference value 6.8 ± 2.9, mean ± SD), fT4 3.8 pmol/l (reference value 16.5 ± 5.3, mean ± SD). Intra-amniotic injections of thyroxine were given in conjunction with ultrasound every 7-10 days, in total nine times during GW 24-33. A dose of 10 µg thyroxine/kg of estimated fetal weight per day was administered on six occasions, and 5 µg/kg/day the last three times. Upon injections of thyroxine further growth of the goiter was reduced. Elevated amniotic TSH levels fell from 13 to 2.5 mU/l (reference range 0.04-0.51). Throughout pregnancy, fetal heart rate and skeletal maturation were within normal limits. In week 34, chorioamnionitis was suspected and the child was delivered by cesarean section. Cord blood revealed TSH 596 mU/l (reference value 8.0 ± 5.12, mean ± SD), fT4 4.4 pmol/l (reference value 19.3 ± 4.3, mean ± SD) and total T3 1.18 nmol/l (reference value 0.5 ± 0.3, mean ± SD); the newborn was put on thyroxine supplementation. Psychomotor development of the child, now 3 years old, has been uneventful. The reported experience of treating dyshormonogenetic fetal goiter is limited but growing, creating a need for guidelines on administration of intra-amniotic thyroxine and monitoring treatment.

  • 34.
    Kherad, Mehrsa
    et al.
    Lund Univ, Skane Univ Hosp, Dept Orthoped Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Rosengren, Bjorn E.
    Lund Univ, Skane Univ Hosp, Dept Orthoped Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Hasserius, Ralph
    Lund Univ, Skane Univ Hosp, Dept Orthoped Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Nilsson, Jan-Ake
    Lund Univ, Skane Univ Hosp, Dept Orthoped Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Redlund-Johnell, Inga
    Lund Univ, Skane Univ Hosp, Dept Orthoped Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Ohlsson, Claes
    Gothenburg Univ, Sahlgrenska Univ Hosp, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden..
    Mellstrom, Dan
    Gothenburg Univ, Sahlgrenska Univ Hosp, Inst Med, Geriatr Med, Gothenburg, Sweden..
    Lorentzon, Mattiaz
    Gothenburg Univ, Sahlgrenska Univ Hosp, Inst Med, Geriatr Med, Gothenburg, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Karlsson, Magnus K.
    Lund Univ, Skane Univ Hosp, Dept Orthoped Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden.;Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin & Mol Osteoporosis Res Unit, Malmo, Sweden..
    Risk factors for low back pain and sciatica in elderly men-the MrOS Sweden study2017In: Age and Ageing, ISSN 0002-0729, E-ISSN 1468-2834, Vol. 46, no 1, p. 64-71Article in journal (Refereed)
    Abstract [en]

    Introduction: the aim of this study was to identify whether factors beyond anatomical abnormalities are associated with low back pain (LBP) and LBP with sciatica (SCI) in older men. Material and methods: Mister Osteoporosis Sweden includes 3,014 men aged 69-81 years. They answered questionnaires on lifestyle and whether they had experienced LBP and SCI during the preceding 12 months. About 3,007 men answered the back pain (BP) questions, 258 reported BP without specified region. We identified 1,388 with no BP, 1,361 with any LBP (regardless of SCI), 1,074 of those with LBP also indicated if they had experienced LBP (n = 615), LBP+ SCI (n = 459). Results: about 49% of those with LBP and 54% of those with LBP+ SCI rated their health as poor/very poor (P < 0.001). Men with any LBP to a greater extent than those without BP had poor self-estimated health, depressive symptoms, dizziness, fall tendency, serious comorbidity (diabetes, stroke, coronary heart disease, pulmonary disease and/or cancer) (all P < 0.001), foreign background, were smokers (all P < 0.01), had low physical activity and used walking aids (all P < 0.05). Men with LBP+ SCI to a greater extent than those with LBP had lower education, lower self-estimated health, comorbidity, dizziness and used walking aids (all P < 0.001). Conclusions: in older men with LBP and SCI, anatomical abnormalities such as vertebral fractures, metastases, central or lateral spinal stenosis or degenerative conditions may only in part explain prevalent symptoms and disability. Social and lifestyle factors must also be evaluated since they are associated not only with unspecific LBP but also with LBP with SCI.

  • 35.
    Kristjansdottir, H.
    et al.
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Gothenburg, Sweden..
    Lewerin, C.
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Gothenburg, Sweden..
    Lerner, U.
    Univ Gothenburg, Dept Internal Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Clin Nutr, Gothenburg, Sweden..
    Waern, E.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Geriatr Med, Gothenburg, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Johansson, H.
    Australian Catholic Univ, Inst Hlth & Aging, Melbourne, Vic, Australia..
    Sundh, D.
    Sahlgrens Acad, Geriatr Med, Dept Internal Med, Gothenburg, Sweden.;Sahlgrens Acad, Inst Med, Clin Nutr, Gothenburg, Sweden..
    Karlsson, M.
    Skane Univ Hosp, Lund Univ, Dept Orthopaed & Clin Sci, Malmo, Sweden..
    Cummings, S.
    Calif Pacific Med Ctr, San Francisco Coordinating Ctr, San Francisco, CA USA..
    Zetterberg, H.
    Univ Gothenburg, Dept Psychiat & Neurochem, Gothenburg, Sweden..
    Lorentzon, M.
    Sahlgrens Acad, Dept Internal Med, Geriatr Med, Molndal, Sweden.;Sahlgrens Acad, Inst Med, Clin Nutr, Molndal, Sweden..
    Ohlsson, C.
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg, Sweden..
    Mellstrom, D.
    Sahlgrens Acad, Dept Internal Med, Geriatr Med, Molndal, Sweden.;Sahlgrens Acad, Inst Med, Clin Nutr, Molndal, Sweden..
    Both High And Low Serum Serotonin Levels Predict Incident Non-Vertebral Fractures2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S181-S182Article in journal (Other academic)
  • 36.
    Langdahl, Bente L.
    et al.
    Aarhus Univ Hosp, Dept Endocrinol & Internal Med, Tage Hansens Gade 2, DK-8000 Aarhus, Denmark..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Benhamou, Claude-Laurent
    Orleans Hosp, Orleans, France..
    Marin, Fernando
    Eli Lilly & Co, Windlesham, Surrey, England..
    Kapetanos, George
    Papageorgiou Gen Hosp, Thessaloniki, Greece..
    Kocjan, Tomaz
    Univ Med Ctr, Ljubljana, Slovenia..
    Lespessailles, Eric
    Orleans Hosp, Orleans, France.;Univ Orleans, EA 4708 I3MTO, Orleans, France..
    Napoli, Nicola
    Univ Campus Biomed, Rome, Italy..
    Nikolic, Tatjana
    Univ Hosp, Zagreb, Croatia..
    Petto, Helmut
    Eli Lilly & Co, Windlesham, Surrey, England..
    Moll, Thomas
    Eli Lilly & Co, Windlesham, Surrey, England..
    Lindh, Erik
    Eli Lilly & Co, Windlesham, Surrey, England..
    Fracture Rate, Quality of Life and Back Pain in Patients with Osteoporosis Treated with Teriparatide: 24-Month Results from the Extended Forsteo Observational Study (ExFOS)2016In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 99, no 3, p. 259-271Article in journal (Refereed)
    Abstract [en]

    We describe the pre-planned interim analysis of fracture outcomes, health-related quality of life (HRQoL) and back pain in patients with severe osteoporosis treated with teriparatide for up to 24 months in the Extended Forsteo (Forsteo(A (R)) is a registered trade name of Eli Lilly and Company) Observational Study (ExFOS), a prospective, multinational, observational study. Data on incident clinical fractures, HRQoL (EQ-5D questionnaire) and back pain [100 mm visual analogue scale (VAS)] were collected. The number of patients with fractures was summarised in 6-month intervals and fracture rate over each 6-month period was assessed using logistic regression for repeated measures. Changes from baseline in EQ-5D and back pain VAS were analysed using mixed models for repeated measures. Of 1454 patients in the active treatment cohort, 90.6 % were female and 14.4 % were taking glucocorticoids. During teriparatide treatment (median duration 23.7 months), 103 patients (7.1 %) sustained a total of 122 incident clinical fractures (21 % vertebral, 79 % non-vertebral). A 49 % decrease in the odds of fractures and a 75 % decrease in the odds of clinical vertebral fractures were observed in the > 18- to 24-month period versus the first 6-month period (both p < 0.05). EQ-5D scores and back pain VAS scores were significantly improved from baseline at each post-baseline observation during teriparatide treatment. In conclusion, patients with severe osteoporosis showed a significant reduction in the incident fracture rate during 24 months of teriparatide treatment in routine clinical practice, accompanied by a significant improvement in HRQoL and reduction in back pain. Results should be interpreted in the context of the non-controlled design of this observational study.

  • 37. Langdahl, Bente L.
    et al.
    Teglbjaerg, Christence Stubbe
    Ho, Pei-Ran
    Chapurlat, Roland
    Czerwinski, Edward
    Kendler, David L.
    Reginster, Jean-Yves
    Kivitz, Alan
    Lewiecki, E. Michael
    Miller, Paul D.
    Bolognese, Michael A.
    McClung, Michael R.
    Bone, Henry G.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Abrahamsen, Bo
    Gruntmanis, Ugis
    Yang, Yu-Ching
    Wagman, Rachel B.
    Mirza, Faisal
    Siddhanti, Suresh
    Orwoll, Eric
    A 24-Month Study Evaluating the Efficacy and Safety of Denosumab for the Treatment of Men With Low Bone Mineral Density: Results From the ADAMO Trial2015In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. 1335-1342Article in journal (Refereed)
    Abstract [en]

    Context: One in 4 men in the United States aged >50 years will have an osteoporosis-related fracture. Fewer data are available on osteoporosis treatment in men than in women. Objective: The purpose of this study was to evaluate denosumab therapy in men with low bone mineral density (BMD). Design: This was a phase 3 study with 2 treatment periods: a previously reported 12-month double-blind, placebo-controlled phase and a 12-month open-label phase. Setting: This was a multicenter study conducted in North America and Europe. Participants: A total of 228 men entered the open-label phase and 219 completed the study. Intervention: Men from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of denosumab sc every 6 months. Main Outcome Measures: BMD, serum collagen type I C-telopeptide, and safety were measured. Results: During the open-label phase, continued BMD increases occurred with long-term denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all P < .01). The crossover group showed BMD gains after 12 months of denosumab treatment similar to those of the long-term denosumab group during the first treatment year. Significant reductions in serum collagen type I C-teleopeptide were observed after denosumab administration. Adverse event rates were similar between groups, and no new safety signals were identified. Conclusions: In men with low BMD, denosumab treatment for a second year continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. BMD increased in men initiating denosumab during the second year. These effects were similar to those previously seen in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy.

  • 38.
    Larsson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Schipani, Ernestina
    Ohlsson, Claes
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Tenenhouse, Harriet S
    Juppner, Harald
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Transgenic mice expressing Fibroblast Growth Factor-23 under the control of the α1 (I) collagen promoter exhibit growth retardation, Osteomalacia and disturbed phosphate homeostasis2004In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 145, no 7, p. 3087-3094Article in journal (Refereed)
    Abstract [en]

    Mutations in the fibroblast growth factor 23 gene, FGF23, cause autosomal dominant hypophosphatemic rickets (ADHR). The gene product, FGF-23, is produced by tumors from patients with oncogenic osteomalacia (OOM), circulates at increased levels in most patients with X-linked hypophosphatemia (XLH) and is phosphaturic when injected into rats or mice, suggesting involvement in the regulation of phosphate (Pi) homeostasis. To better define the precise role of FGF-23 in maintaining Pi balance and bone mineralization, we generated transgenic mice that express wild-type human FGF-23, under the control of the alpha1(I) collagen promoter, in cells of the osteoblastic lineage. At 8 wk of age, transgenic mice were smaller (body weight = 17.5 +/- 0.57 vs. 24.3 +/- 0.37 g), exhibited decreased serum Pi concentrations (1.91 +/- 0.27 vs. 2.75 +/- 0.22 mmol/liter) and increased urinary Pi excretion when compared with wild-type littermates. The serum concentrations of human FGF-23 (undetectable in wild-type mice) was markedly elevated in transgenic mice (>7800 reference units/ml). Serum PTH levels were increased in transgenic mice (231 +/- 62 vs. 139 +/- 44 pg/ml), whereas differences in calcium and 1,25-dihydroxyvitamin D were not apparent. Expression of Npt2a, the major renal Na(+)/Pi cotransporter, as well as Npt1 and Npt2c mRNAs, was significantly decreased in the kidneys of transgenic mice. Histology of tibiae displayed a disorganized and widened growth plate and peripheral quantitative computerized tomography analysis revealed reduced bone mineral density in transgenic mice. The data indicate that FGF-23 induces phenotypic changes in mice resembling those of patients with ADHR, OOM, and XLH and that FGF-23 is an important determinant of Pi homeostasis and bone mineralization.

  • 39.
    Laxman, Navya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    miRNA and Asymmetric siRNA: Small RNAs with Large Effects on Bone Metabolism2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    RNA interference (RNAi) is a post-transcriptional gene silencing process elicited by double-stranded RNA, such as micro-RNA (miRNA) and small interfering RNA (siRNA). They are 18-25 nucleotide long, small non-coding RNAs acting as critical regulators in eukaryotic genome expression. They play an important role in regulating a wide range of biological processes such as cell cycle control, differentiation, aging and apoptosis. However, their role in supporting skeletal development and bone homeostasis is still poorly understood.

    Osteoporotic fractures constitute a tremendous and growing problem in our ageing populations, with an annual incidence of approximately 60000 osteoporotic fractures in Sweden. Osteoporosis is referred as the “Silent epidemic” because bone loss is gradual and a basically symptomless development until a fracture occurs.

    Results presented in this thesis provide a novel insight into crucial roles of   miRNAs in regulating bone homeostasis. The initial aim for the thesis was to perform global miRNA expression profiling in human bone cells, and to correlate these levels to global mRNA levels. We identified and functionally characterized several miRNAs that were differentially expressed and acted in important bone signaling pathways such as the Wnt and BMP pathways. These miRNAs included hsa-miR-29b, hsa-miR-30c2 and hsa-miR-125b, which we found targeting genes highly relevant to bone metabolism e.g. COL1A1, SPARC, RUNX2, BGLAP and FRZB.

    Thereafter, the effect on the microRNAome upon external stimuli (e.g., Dexamethasone and Parathyroid hormone) was assessed by SOLiD sequencing. We observed a substantial difference in the expression of miRNAs between PTH and DEX treated cells. Understanding the changes in miRNAome in human bone cells under different conditions could provide new insight in bone remodeling, specifically differentiation and functional properties of osteoblasts.

    Based on these studies, we furthermore identified Dlx5 as potential common target of miR-203 and miR-320b and these miRNAs negatively regulate BMP-2-induced osteoblast differentiation.

    To activate the RNAi pathway, siRNA or miRNA molecules must be conveyed into the cytoplasm of target cells. Since challenges in cellular delivery of these small silencing RNA molecules so far have limited their clinical utility, we developed a new siRNA design that demonstrates a novel carrier-free cellular delivery. This development could potentially have a major impact in RNAi therapeutics.

    In conclusion, this thesis provides novel insight of miRNAs that play a major role in the regulation of bone remodeling and differentiation and functional properties of osteoblasts. Our findings may have diagnostic and/or therapeutic implications in disorders of bone metabolism.

    List of papers
    1. Global miRNA expression and correlation with mRNA levels in primary human bone cells
    Open this publication in new window or tab >>Global miRNA expression and correlation with mRNA levels in primary human bone cells
    Show others...
    2015 (English)In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 21, no 8, p. 1433-1443Article in journal (Refereed) Published
    Abstract [en]

    MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, alpha 1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

    Keywords
    miRNA, mRNA, osteoblasts, interindividual variation, differential expression
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-260282 (URN)10.1261/rna.049148.114 (DOI)000358016000005 ()26078267 (PubMedID)
    Funder
    Swedish Research Council
    Available from: 2015-08-21 Created: 2015-08-18 Last updated: 2017-12-04Bibliographically approved
    2. Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone
    Open this publication in new window or tab >>Second generation sequencing of microRNA in Human Bone Cells treated with Parathyroid Hormone or Dexamethasone
    Show others...
    2016 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 84, p. 181-188Article in journal (Refereed) Published
    Abstract [en]

    We investigated the impact of treatment with parathyroid hormone (PTH) and dexamethasone (DEX) for 2 and 24 h by RNA sequencing of miRNAs in primary human bone (HOB) cells. A total of 207 million reads were obtained, and normalized absolute expression retrieved for 373 most abundant miRNAs. In naive control cells, 7 miRNAs were differentially expressed (FDR < 0.05) between the two time points. Ten miRNAs exhibited differential expression (FDR < 0.05) across two time points and treatments after adjusting for expression in controls and were selected for downstream analyses. Results show significant effects on miRNA expression when comparing PTH with DEX at 2 h with even more pronounced effects at 24 h. Interestingly, several miRNAs exhibiting differences in expression are predicted to target genes involved in bone metabolism e.g. miR-30c2, miR-203 and miR-205 targeting RUNX2, and miR-320 targeting beta-catenin (CTNNB1) mRNA expression. CTNNB1 and RUNX2 levels were decreased after DEX treatment and increased after PTH treatment. Our analysis also identified 2 putative novel miRNAs in PTH and DEX treated cells at 24 h. RNA sequencing showed that PTH and DEX treatment affect miRNA expression in HOB cells and that regulated miRNAs in turn are correlated with expression levels of key genes involved in bone metabolism.

    Keywords
    miRNA; osteoblasts; RNA sequencing; differential expression
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-264440 (URN)10.1016/j.bone.2015.12.053 (DOI)000370914600021 ()26748295 (PubMedID)
    Funder
    Swedish Research Council, 2009-2852
    Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2017-12-01Bibliographically approved
    3. miR-203 and miR-320 regulate Bone Morphogenetic Protein-2-induced osteoblast differentiation by targeting Distal-less Homeobox 5 (Dlx5)
    Open this publication in new window or tab >>miR-203 and miR-320 regulate Bone Morphogenetic Protein-2-induced osteoblast differentiation by targeting Distal-less Homeobox 5 (Dlx5)
    2017 (English)In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, no 1, article id E4Article in journal (Refereed) Published
    Abstract [en]

    MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17–24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism.

    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-264442 (URN)10.3390/genes8010004 (DOI)
    Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2017-12-01Bibliographically approved
    4. Endosmolytic cell penetrating siRNA for carrier free transfection
    Open this publication in new window or tab >>Endosmolytic cell penetrating siRNA for carrier free transfection
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-264443 (URN)
    Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2015-11-24
  • 40.
    Laxman, Navya
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    miR-203 and miR-320 regulate Bone Morphogenetic Protein-2-induced osteoblast differentiation by targeting Distal-less Homeobox 5 (Dlx5)2017In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, no 1, article id E4Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are a family of small, non-coding RNAs (17–24 nucleotides), which regulate gene expression either by the degradation of the target mRNAs or inhibiting the translation of genes. Recent studies have indicated that miRNA plays an important role in regulating osteoblast differentiation. In this study, we identified miR-203 and miR-320b as important miRNAs modulating osteoblast differentiation. We identified Dlx5 as potential common target by prediction algorithms and confirmed this by knock-down and over expression of the miRNAs and assessing Dlx5 at mRNA and protein levels and specificity was verified by luciferase reporter assays. We examined the effect of miR-203 and miR-320b on osteoblast differentiation by transfecting with pre- and anti-miRs. Over-expression of miR-203 and miR-320b inhibited osteoblast differentiation, whereas inhibition of miR-203 and miR-320b stimulated alkaline phosphatase activity and matrix mineralization. We show that miR-203 and miR-320b negatively regulate BMP-2-induced osteoblast differentiation by suppressing Dlx5, which in turn suppresses the downstream osteogenic master transcription factor Runx2 and Osx and together they suppress osteoblast differentiation. Taken together, we propose a role for miR-203 and miR-320b in modulating bone metabolism.

  • 41.
    Laxman, Navya
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Grundberg, Elin
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Global miRNA expression and correlation with mRNA levels in primary human bone cells2015In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 21, no 8, p. 1433-1443Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, alpha 1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

  • 42. Lewerin, C.
    et al.
    Nilsson-Ehle, H.
    Jacobsson, S.
    Johansson, H.
    Sundh, V.
    Karlsson, M. K.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lorentzon, M.
    Kanis, J. A.
    Lerner, U. H.
    Cummings, S. R.
    Ohlsson, C.
    Mellström, D.
    Low holotranscobalamin and cobalamins predict incident fractures in elderly men: the MrOS Sweden2014In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 25, no 1, p. 131-140Article in journal (Refereed)
    Abstract [en]

    Summary

    In a population-based study on cobalamin status and incident fractures in elderly men (n  = 790) with an average follow-up of 5.9 years, we found that low levels of metabolically active and total cobalamins predict incident fractures, independently of body mass index (BMI), bone mineral density (BMD), plasma total homocysteine (tHcy), and cystatin C.

    Introduction

    Cobalamin deficiency in elderlies may affect bone metabolism. This study aims to determine whether serum cobalamins or holotranscobalamin (holoTC; the metabolic active cobalamin) predict incident fractures in old men.

    Methods

    Men participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) Sweden cohort and without ongoing vitamin B medication were included in the present study (n = 790; age range, 70–81 years).

    Results

    During an average follow-up of 5.9 years, 110 men sustained X-ray-verified fractures including 45 men with clinical vertebral fractures. The risk of fracture (adjusted for age, smoking, BMI, BMD, falls, prevalent fracture, tHcy, cystatin C, 25-OH-vitamin D, intake of calcium, and physical activity (fully adjusted)), increased per each standard deviation decrease in cobalamins (hazard ratio (HR), 1.38; 95 % confidence intervals (CI), 1.11–1.72) and holoTC (HR, 1.26; 95 % CI, 1.03–1.54), respectively. Men in the lowest quartile of cobalamins and holoTC (fully adjusted) had an increased risk of all fracture (cobalamins, HR = 1.67 (95 % CI, 1.06–2.62); holoTC, HR = 1.74 (95 % CI, 1.12–2.69)) compared with quartiles 2–4. No associations between folate or tHcy and incident fractures were seen.

    Conclusions

    We present novel data showing that low levels of holoTC and cobalamins predicting incident fracture in elderly men. This association remained after adjustment for BMI, BMD, tHcy, and cystatin C. However, any causal relationship between low cobalamin status and fractures should be explored in a prospective treatment study.

  • 43.
    Lewerin, Catharina
    et al.
    Univ Gothenburg, Sect Hematol & Coagulat, Dept Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Nilsson-Ehle, Herman
    Univ Gothenburg, Sect Hematol & Coagulat, Dept Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Karlsson, Magnus K.
    Lund Univ, Clin & Mol Osteoporosis Res Unit, Dept Clin Sci & Orthoped, Malmo, Sweden..
    Herlitz, Hans
    Univ Gothenburg, Dept Mol & Clin Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Lorentzon, Mattias
    Univ Gothenburg, CBAR, Dept Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden.;Univ Gothenburg, Dept Geriatr Med, Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Ohlsson, Claes
    Univ Gothenburg, CBAR, Dept Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Mellström, Dan
    Univ Gothenburg, CBAR, Dept Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden.;Univ Gothenburg, Dept Geriatr Med, Internal Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Low serum iron is associated with high serum intact FGF23 in elderly men: The Swedish MrOS study2017In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 98, p. 1-8Article in journal (Refereed)
    Abstract [en]

    Background: Fibroblast growth factor (FGF23) is a protein that is produced by osteoblasts and osteocytes. Increased serum levels of FGF23 have been associated with increased risks of osteoporotic fractures and cardiovascular disease, particularly in participants with poor renal function. Serum iron (Fe) has been suggested as a regulator of FGF23 homeostasis. Objective: To determine whether Fe and iron status are determinants of the levels of intact FGF23 (iFGF23) in elderly men. Methods: The MrOS study is a population-based study of elderly men (N = 1010; mean age, 75.3 years; range, 69-81 years). The levels of Fe, transferrin saturation (TS), and ferritin were evaluated in relation to the serum concentrations of iFGF23 before and after adjustments for confounders. Results: TS<15% was found in 3.5% (34/977) of the participants, who had a higher median level iFGF23 compared with the remaining subjects (47.4 mu rnol/L vs. 41.9 mu mol/L, p = 0.008). The levels of iFGF23 correlated negatively (un-adjusted) with the levels of Fe (r = -0.17, p < 0.001), TS (r = -0.16, p < 0.001) and serum ferritin (r = -0.07, p = 0.022). In addition, in participants with estimated glomerular filtration rate eGFRCystatin C > 60 mL/min, the levels of iFGF23 correlated (age-adjusted) negatively with the levels of Fe (r = -0.15, p < 0.001) and TS (r = -0.17, p < 0.001). The level of iFGF23 correlated positively (un-adjusted) with lumbar spine bone mineral density (BMD) (r = 0.14, p < 0.001), total body BMD (r = 0.11, p = 0.001), and total hip BMD (r = 0.09, p = 0.004). The corresponding correlations, when adjusted for age, weight, and height were: r = 0.08, p = 0.018; r = 0.05, p = 0.120; and r = 0.02, p = 0.624, respectively. No associations were found between BMD and the levels of Fe or TS. Multiple step-wise linear regression analyses [adjusting for age, body mass index (BMI), comorbidity index, cystatin C, C-reactive protein (hs-CRP), serum vitamin D 25-OH (25OHD), phosphate, calcium, parathyroid hormone (PTH), erythropoietin, hemoglobin, lumbar spine BMD, apolipoprotein B/A1 ratio] were performed in three separate models with Fe, TS or ferritin as potential explanatory variables. Fe and TS, but not ferritin, were independent predictors of iFGF23 level (standardized beta-values: -0.10, p <0.001; 0.10, p <0.001; and -0.05, p = 0.062, respectively). Conclusion: Low levels of Fe in elderly men are associated with high levels of iFGF23, independently of markers of inflammation and renal function, suggesting an iron-related pathway for FGF23 regulation. (C) 2017 Elsevier Inc. All rights reserved.

  • 44.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Astrom, Eva
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Grigelioniene, Giedre
    Malmgren, Barbro
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic epidemiology, prevalence, and genotype-phenotype correlations in the Swedish population with osteogenesis imperfecta2015In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 23, no 8, p. 1042-1050Article in journal (Refereed)
    Abstract [en]

    Osteogenesis imperfecta (OI) is a rare hereditary bone fragility disorder, caused by collagen I mutations in 90% of cases. There are no comprehensive genotype-phenotype studies on 4100 families outside North America, and no population-based studies determining the genetic epidemiology of OI. Here, detailed clinical phenotypes were recorded, and the COL1A1 and COL1A2 genes were analyzed in 164 Swedish OI families (223 individuals). Averages for bone mineral density (BMD), height and yearly fracture rate were calculated and related to OI and mutation type. N-terminal helical mutations in both the alpha 1-and alpha 2-chains were associated with the absence of dentinogenesis imperfecta (P<0.0001 vs 0.0049), while only those in the alpha 1-chain were associated with blue sclera (P = 0.0110). Comparing glycine with serine substitutions, alpha 1-alterations were associated with more severe phenotype (P = 0.0031). Individuals with type I OI caused by qualitative vs quantitative mutations were shorter (P < 0.0001), but did not differ considering fractures or BMD. The children in this cohort were estimated to represent >95% of the complete Swedish pediatric OI population. The prevalence of OI types I, III, and IV was 5.16, 0.89, and 1.35/100 000, respectively (7.40/100 000 overall), corresponding to what has been estimated but not unequivocally proven in any population. Collagen I mutation analysis was performed in the family of 97% of known cases, with causative mutations found in 87%. Qualitative mutations caused 32% of OI type I. The data reported here may be helpful to predict phenotype, and describes for the first time the genetic epidemiology in > 95% of an entire OI population.

  • 45.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rubin, Carl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Malmgren, B.
    Karolinska Inst, Dept Dent Med, Div Pediat Dent, Stockholm, Sweden..
    Grigelioniene, G.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp Stockholm, Dept Clin Genet, Stockholm, Sweden..
    Soderhall, S.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Åstrom, E.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate2016In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 87, p. 11-18Article in journal (Refereed)
    Abstract [en]

    Background: Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe 01; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated.

    Materials and methods: COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n = 33, type III n = 25 and type IV n = 21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non vertebral and vertebral fractures were collected prior to, and at several time points during treatment.

    Results: An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to A LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p < 0.0003, < 0.0001 and 0.0003 for all 01 types 1, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4 yrs Pamidronate. Twice as many boys as girls with 01 type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p = 0.0236). Greater Delta LS BMD, but smaller Delta fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11 years of age at treatment initiation. (p < 0.0001).

    Conclusion: Pamidronate treatment in children with all types of 01 increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type.

  • 46.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Langdahl, Bente
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapy of Endocrine Disease: Treatment of osteogenesis imperfecta in adults2014In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 171, no 2, p. R79-R90Article, review/survey (Refereed)
    Abstract [en]

    Background: Osteogenesis imperfecta (OI) is a heterogeneous rare connective tissue disorder commonly caused by mutations in the collagen type I genes. Pharmacological treatment has been most extensively studied in children, and there are only few studies comprising adult OI patients. Objectives: i) To review the literature on the current medical management of OI in children and adults, and thereby identify unmet medical needs and ii) to present an overview of possible future treatment options. Results: Individualization and optimization of OI treatment in adults remain a challenge, because available treatments do not target the underlying collagen defect, and available literature gives weak support for treatment decisions for adult patients. Conclusions: Bisphosphonates are still the most widely used pharmacological treatment for adult OI, but the current evidence supporting this is sparse and investigations on indications for choice and duration of treatment are needed.

  • 47.
    Ljunggren, Östen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Benhamou, C. L.
    Dekker, J.
    Kapetanos, G.
    Kocjan, T.
    Langdahl, B. L.
    Napoli, N.
    Petto, H.
    Nikolic, T.
    Lindh, E.
    Study description and baseline characteristics of the population enrolled in a multinational observational study of extended teriparatide use (ExFOS)2014In: Current Medical Research and Opinion, ISSN 0300-7995, E-ISSN 1473-4877, Vol. 30, no 8, p. 1607-1616Article in journal (Refereed)
    Abstract [en]

    Objective: To better characterize patients who are currently being prescribed teriparatide in Europe, this article describes the study design and baseline characteristics of participants of the Extended Forsteo* Observational Study (ExFOS). Research design and methods: ExFOS is a noninterventional, multicenter, prospective, observational study in men and women with osteoporosis treated with teriparatide during the course of normal clinical practice for up to 24 months and with a post-treatment follow-up of at least 18 months. Main outcome measures: Baseline characteristics, including history of fracture and back pain, and health-related quality of life (HRQoL, assessed using the EuroQol-5 Dimension [EQ-5D]). Results: Of 1607 patients enrolled, 90.9% were women. At baseline, mean (standard deviation [SD]) age was 70.3 (9.8) years, and 85.8% of patients had a history of fracture (64.7% with >= 2 fragility fractures). Of those with historic fractures, 90.8% had vertebral fractures (67.8% had thoracic fractures). The mean (SD) of reported bone mineral density T-scores were -3.0 (1.2), -2.4 (1.0), and -2.5 (0.9) for lumbar spine, total hip (left), and femoral neck (left), respectively. Overall, 39.3% of patients had experienced >= 1 fall during the 12 months before enrollment. At baseline, 11.4% of patients were osteoporosis-treatment naive and 15% were currently using glucocorticoids. The mean (SD) visual analog scale score for back pain during the last month was 50.7 (26.9), and 62.1% of patients experienced daily or almost daily back pain. The median EQ-5D health state value at baseline was 0.62 (first and third quartiles: 0.19, 0.74). Conclusions: Baseline characteristics of the ExFOS study cohort indicate that patients prescribed teriparatide in Europe have severe osteoporosis with highly prevalent vertebral fractures, frequent and disabling back pain, and a poor HRQoL, despite previous pharmacotherapy for osteoporosis. Limitations include non-randomization, lack of a comparator group, and patient self-report for data on prior medication and fracture history.

  • 48.
    Lodefalk, Maria
    et al.
    Univ Orebro, Dept Paediat, Fac Med & Hlth, SE-70182 Orebro, Sweden.;Univ Orebro, Univ Hlth Care Res Ctr, SE-70182 Orebro, Sweden..
    Frykholm, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Esbjorner, Elisabeth
    Univ Orebro, Dept Paediat, Fac Med & Hlth, SE-70182 Orebro, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Hypercalcaemia in a Patient with 2p13.2-p16.1 Duplication2016In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 85, no 3, p. 213-218Article in journal (Refereed)
    Abstract [en]

    Background: Partial duplication of 2p is a rare condition that causes facial anomalies, psychomotor delay, and growth failure. Hypercalcaemia is rare in children. So far, duplication of 2p has never been associated with hypercalcaemia. Methods: Here, we report a girl with a partial duplication of 2p presenting with moderate to severe hypercalcaemia at the age of 2 years. She also had hypercalciuria, nephrocalcinosis, decreased renal function, and secondary hyperparathyroidism at presentation. She was thoroughly investigated, including genetic testing of the CYP24A1, CASR, ALPL, and NOD2 genes, to determine the cause of hypercalcaemia. Results: 1,25-dihydroxyvitamin D levels were increased. Hypercalcaemia and hypercalciuria responded well to glucocorticoids but not to cinacalcet. Hyperparathyroidism resolved with improving renal function. Apart from the known duplication of 2p, no pathogenic variants were detected in the studied genes. The duplication of 2p contains the PPP3R1 gene, which encodes for the calcineurin B subunit. Conclusion: We conclude that partial duplication of 2p can be associated with hypercalcaemia and hypercalciuria and hypothesise that the underlying mechanism is an increased extra-renal, parathyroid hormone-independent 25-hydroxyvitamin D 1 alpha-hydroxylase activity, leading to raised amounts of 1,25-dihydroxyvitamin D. The increased enzymatic activity could possibly be caused by calcineurin B subunit-related macrophage stimulation.

  • 49.
    Malmgren, B.
    et al.
    Karolinska Inst, Div Pediat Dent, Dept Dent Med, Stockholm, Sweden..
    Andersson, K.
    Karolinska Inst, Div Pediat Dent, Dept Dent Med, Stockholm, Sweden..
    Lindahl, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Grigelioniene, G.
    Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Zachariadis, V.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Dahllof, G.
    Karolinska Inst, Div Pediat Dent, Dept Dent Med, Stockholm, Sweden..
    Astrom, E.
    Karolinska Univ Hosp, Neuropediat Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Tooth agenesis in osteogenesis imperfecta related to mutations in the collagen type I genes2017In: Oral Diseases, ISSN 1354-523X, E-ISSN 1601-0825, Vol. 23, no 1, p. 42-49Article in journal (Refereed)
    Abstract [en]

    BackgroundOsteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, mainly caused by mutations in the collagen type I genes (COL1A1 and COL1A2). Tooth agenesis is a common feature of OI. We investigated the association between tooth agenesis and collagen type I mutations in individuals with OI. Subjects and methodsIn this cohort study, 128 unrelated individuals with OI were included. Panoramic radiographs were analyzed regarding dentinogenesis imperfecta (DGI) and congenitally missing teeth. The collagen I genes were sequenced in all individuals, and in 25, multiplex ligation-dependent probe amplification was performed. ResultsMutations in the COL1A1 and COL1A2 genes were found in 104 of 128 individuals. Tooth agenesis was diagnosed in 17% (hypodontia 11%, oligodontia 6%) and was more frequent in those with DGI (P=0.016), and in those with OI type III, 47%, compared to those with OI types I, 12% (P=0.003), and IV, 13% (P=0.017). Seventy-five percent of the individuals with oligodontia (6 missing teeth) had qualitative mutations, but there was no association with OI type, gender, or presence of DGI. ConclusionThe prevalence of tooth agenesis is high (17%) in individuals with OI, and OI caused by a qualitative collagen I mutation is associated with oligodontia.

  • 50. McCloskey, Eugene V
    et al.
    Odén, Anders
    Harvey, Nicholas C
    Leslie, William D
    Hans, Didier
    Johansson, Helena
    Barkmann, Reinhard
    Boutroy, Stephanie
    Brown, Jacques
    Chapurlat, Roland
    Elders, Petra Jm
    Fujita, Yuki
    Glüer, Claus-C
    Goltzman, David
    Iki, Masayuki
    Karlsson, Magnus
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kotowicz, Mark
    Kurumatani, Norio
    Kwok, Timothy
    Lamy, Oliver
    Leung, Jason
    Lippuner, Kurt
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lorentzon, Mattias
    Mellström, Dan
    Merlijn, Thomas
    Oei, Ling
    Ohlsson, Claes
    Pasco, Julie A.
    Rivadeneira, Fernando
    Rosengren, Björn
    Sornay-Rendu, Elisabeth
    Szulc, Pawel
    Tamaki, Junko
    Kanis, John A
    A meta-analysis of trabecular bone score in fracture risk prediction and its relationship to FRAX2016In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 31, no 5, p. 940-948Article in journal (Refereed)
    Abstract [en]

    Trabecular bone score (TBS) is a grey-level textural index of bone microarchitecture derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images. TBS is a BMD-independent predictor of fracture risk. The objective of this meta-analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual level data from 17,809 men and women in 14 prospective population-based cohorts. Baseline evaluation included TBS and the FRAX risk variables and outcomes during follow up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% CI: 1.35-1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10-year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR 1.32, 95%CI: 1.24-1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95%CI: 1.65, 1.87 vs. 1.70, 95%CI: 1.60-1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines.

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