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  • 1.
    Bornefalk, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dahlen, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ljunggren, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Age-dependent effect of oral glucocorticoids on markers of bone resorption in patients with acute asthma1998In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 63, no 1, p. 9-13Article in journal (Refereed)
    Abstract [en]

    It is generally accepted that bone formation is depressed during corticosteroid treatment, but the effects of glucocorticoids on bone resorption are less well characterized. We have investigated the effects of short-term treatment with high-dose oral glucocorticoids on biochemical markers of bone turnover in 20 consecutive patients with asthma who sought help for acute respiratory obstruction in our emergency department. Serum concentrations of the carboxy-terminal cross-linked telopeptide of type 1 collagen (1CTP), reflecting bone resorption, and the carboxy-terminal propeptide of type 1 procollagen (P1CP), reflecting bone formation, were measured by radioimmunoassay. Changes of the circulating levels of the bone resorption marker 1CTP after treatment were age dependent with a significant negative correlation (r = -0.54, P = 0.01). The dependency on age remained when correcting, in a multiple linear regression analysis, for 1CTP levels at admission, weight, sex, and daily maintenance dose of inhaled glucocorticoids. Circulating levels of P1CP were suppressed in the whole group 1 week after initiation of glucocorticoid therapy, from 123.3 +/- 10.2 ng/ml at admission to 88.1 +/- 6.3 ng/ml after 1 week (P < 0.01). The changes in P1CP levels were not related to age. Our data indicate that bone formation is suppressed by glucocorticoids in all age groups, whereas the effect of glucocorticoids on markers of bone resorption is dependent on age.

  • 2.
    Brahm, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Relationships between bone mass measurements and lifetime physical activity in a Swedish population1998In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 62, no 5, p. 400-412Article in journal (Refereed)
    Abstract [en]

    Lifetime occupational and leisure time activities were assessed by a questionnaire in order to evaluate their relationship to bone mass measurements and biochemical markers of bone metabolism in a population of 61 women and 61 men, randomly selected from a Swedish population register, to represent ages between 22 and 85 years. We also considered possible confounders by using questions about smoking habits, milk consumption, hormone replacement therapy (HRT), and menopausal age. Bone mineral density (BMD) and bone mineral content (bone mass, BMC) of the total body, lumbar spine, and proximal femur (neck, trochanter, Ward's triangle) were measured by dual energy X-ray absorptiometry (DXA), and BMD of the forearm with single energy X-ray absorptiometry (SXA). In addition, both DXA and SXA provided information on bone area. Quantitative ultrasound measurements (QUS) at the heel were performed to assess the speed of sound (SOS) and broadband ultrasound attenuation (BUA). Fasting blood samples were analyzed for biochemical markers of bone metabolism as well as parathyroid hormone (PTH) and total serum calcium. After adjustment for confounding factors, neither BMD nor QUS measurements were consistently related to lifetime leisure time or occupational activities; nor were there any consistent patterns relating biochemical markers of bone metabolism to bone mass measurements. However, physical activity seemed to influence bone mass, area, and width more than density. In men, high levels of leisure time activity were associated with raised values for lumbar spine area (6.2%) and width (3.3%) as well as for femoral neck area (5.5%) compared with their low activity counterpart. Men exposed to high levels of occupational activity demonstrated lower lumbar spine BMD (10.9%) and area (5.3%) than men with low activity levels. Within an unselected Swedish population, estimation of lifetime occupational and sport activities as well as bedrest, using a questionnaire, demonstrated no major effects on bone density. However, the association between high levels of lifetime activity and raised values for bone mass, area, and width indicate that geometrical changes in bone may provide better estimations of mechanically induced bone strength than bone density, at least in men.

  • 3.
    Brändström, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gerdhem, P.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Obrant, K. J.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkesson, K.
    Single nucleotide polymorphisms in the human gene for osteoprotegerin are not related to bone mineral density or fracture in elderly women2004In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 74, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Osteoprotegerin (OPG), a secreted member of the tumor necrosis factor receptor family, is a potent inhibitor of osteoclast activation and differentiation. In animal models OPG prevents bone loss, and in humans bone resorption can be reduced by injections of OPG. OPG may also play a role in cardiovascular disease since mice lacking the OPG gene display arterial calcification. In a screening effort of the OPG gene, we recently discovered a single nucleotide polymorphism in the promoter region of OPG (T950C), and reported an association with vascular morphology and function in 59 healthy individuals. Due to the pronounced effect of OPG on bone turnover, the present study was conducted to investigate whether OPG polymorphisms are also associated with bone mineral density or with fracture. The relationship between single nucleotide polymorphisms in the promoter region of OPG (T950C) and the first intron (C1217T), and bone mineral density, measured by DXA in the hip or spine or ultrasound of the heel, was investigated in the Malmö OPRA-study of 1044 women, all 75 years old. The possible relation to fracture incidence was also analyzed. Among the 858 and 864 individuals respectively, genotyped, no significant associations between the investigated single nucleotide polymorphisms and bone mineral density measurements (T950C P = 0.50-0.64, C1217T P = 0.51-1.00), quantitative ultrasound measurements of the calcaneus, or fractures (T950C P = 0.61-0.66, C1217T P = 0.14-0.33) were found. Thus, our results show that polymorphisms in the OPG gene, one of which has previously been found to be associated with cardiovascular morphology and function, are not associated with bone mineral density in elderly Swedish women.

  • 4. Gerdhem, P.
    et al.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Obrant, K.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Åkesson, K.
    Association of the collagen type 1 (COL1A 1) Sp1 binding site polymorphism to femoral neck bone mineral density and wrist fracture in 1044 elderly Swedish women2004In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 74, no 3, p. 264-269Article in journal (Refereed)
    Abstract [en]

    Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis and related fragility fractures. A polymorphism of the binding site for the transcription factor Sp1 of the collagen I alpha 1 gene (COLIA1) has shown an association to bone mass and fracture, but the findings have not been consistent, which may be related to population differences. The Sp1 polymorphism was determined in 1044 women, all 75 years old, participating in the population-based Osteoporosis Prospective Risk Assessment study in Malmö (OPRA). Bone mineral density, heel ultrasound and all previous fractures were registered. BMD was 2.7% lower in the femoral neck in women carrying at least one copy of the "s" allele ( P = 0.027). There was no difference in bone mass at any other site, weight, BMI or age at menopause. Women with a prevalent wrist fracture (n = 181) had an increased presence of the "s" allele. The odds ratio for prevalent wrist fracture was 2.73 (95% CI 1.1-6.8) for the ss homozygotes and 1.4 (95% CI 1.0-2.0) for the Ss heterozygotes when compared with the SS homozygotes. In conclusion, in this large and homogeneous cohort of 75-year-old Swedish women, there was an association among the Sp1 COLIA1 polymorphism, bone mass, and fracture. The presence of at least one copy of the "s" allele was associated with lower femoral neck BMD and previous wrist fracture and in addition, it was related to an increased risk for wrist fracture.

  • 5.
    Hill, Tom R.
    et al.
    Newcastle Univ, Human Nutr Res Ctr, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Verlaan, Sjors
    Nutricia Adv Med Nutr, Danone Nutricia Res, Utrecht, Netherlands; Amsterdam UMC, Dept Internal Med, Sect Gerontol & Geriatr, Amsterdam, Netherlands.
    Biesheuvel, Egbert
    Nutricia Adv Med Nutr, Danone Nutricia Res, Utrecht, Netherlands.
    Eastell, Richard
    Univ Sheffield, Northern Gen Hosp, Metab Bone Ctr, Acad Unit Bone Metab, Sheffield, S Yorkshire, England.
    Bauer, Juergen M.
    Carl von Ossietzky Univ Oldenburg, Dept Geriatr Med, Oldenburg, Germany.
    Bautmans, Ivan
    Vrije Univ Brussel VUB, Frailty Ageing Res Grp FRIA, Brussels, Belgium.
    Brandt, Kirsten
    Newcastle Univ, Human Nutr Res Ctr, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Donini, Lorenzo M.
    Sapienza Univ Rome, Dept Expt Med, Sect Med Pathophysiol Endocrinol & Human Nutr, Rome, Italy.
    Maggio, Marcello
    Univ Parma, Sect Geriatr, Dept Clin & Expt Med, Parma, Italy.
    Mets, Tony
    Vrije Univ Brussel VUB, Frailty Ageing Res Grp FRIA, Brussels, Belgium.
    Seal, Chris J.
    Newcastle Univ, Human Nutr Res Ctr, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
    Wijers, Sander L. J.
    Nutricia Adv Med Nutr, Danone Nutricia Res, Utrecht, Netherlands.
    Sieber, Cornel
    Friedrich Alexander Univ Erlangen Nurnberg, Inst Biomed Ageing, Erlangen, Germany.
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Aspray, Terry J.
    Newcastle Univ, Freeman Hosp, Bone Clin, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England.
    A Vitamin D, Calcium and Leucine-Enriched Whey Protein Nutritional Supplement Improves Measures of Bone Health in Sarcopenic Non-Malnourished Older Adults: The PROVIDE Study2019In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 4, p. 383-391Article in journal (Refereed)
    Abstract [en]

    Alterations in musculoskeletal health with advanced age contribute to sarcopenia and decline in bone mineral density (BMD) and bone strength. This decline may be modifiable via dietary supplementation. To test the hypothesis that a specific oral nutritional supplement can result in improvements in measures of bone health. Participants (n 380) were participants of the PROVIDE study, a 13-week, multicenter, randomized, controlled, double-blind, 2 parallel-group study among non-malnourished older participants (≥ 65 years) with sarcopenia [determined by Short Physical Performance Battery (SPPB; 0-12) scores between 4 and 9, and a low skeletal muscle mass index (SMI; skeletal muscle mass/BW × 100) ≤ 37% in men and ≤ 28% in women using bioelectric impedance analysis] Supplementation of a vitamin D, calcium and leucine-enriched whey protein drink that comprises a full range of micronutrients (active; 2/day) was compared with an iso-caloric control. Serum 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), biochemical markers of bone formation (osteocalcin; OC, procollagen type 1 amino-terminal propeptide; P1NP) and resorption (carboxy-terminal collagen crosslinks; CTX), insulin like growth factor 1 (IGF-1) and total-body BMD were analysed pre- and post-intervention. Serum 25(OH)D concentrations increased from 51.1 ± 22.9 nmol/L (mean ± SD) to 78.9 ± 21.1 nmol/L in the active group (p < 0.001 vs. control). Serum PTH showed a significant treatment difference (p < 0.001) with a decline in the active group, and increase in the control group. Serum IGF-1 increased in the active group (p < 0.001 vs. control). Serum CTX showed a greater decline in the active group (p = 0.001 vs. control). There were no significant differences in serum OC or P1NP between groups during the intervention. Total body BMD showed a small (0.02 g/cm2; ~ 2%) but significant increase in the active group after supplementation (p = 0.033 vs. control). Consuming a vitamin D, calcium and leucine-enriched whey protein supplement for 13 weeks improved 25(OH)D, suppressed PTH and had small but positive effects on BMD, indicative of improved bone health, in sarcopenic non-malnourished older adults.

  • 6.
    Kharazmi, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Schilcher, Jorg
    Linkoping Univ, Fac Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    Eriksson, Niclas
    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.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala Univ, Dept Med Sci, Uppsala, Sweden.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture2019In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed)
    Abstract [en]

    Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n=51) with population-based controls (n=4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n=324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p<5x10(-8) was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p<5.7x10(-6)). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

  • 7.
    Kindmark, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Inhibitory effects of 9-cis and all-trans retinoic acid on 1,25(OH)2 vitamin D3 induced bone resorption1995In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 57, no 3, p. 242-244Article in journal (Refereed)
    Abstract [en]

    The effects of retinoic acid (RA), and calcitriol are mediated by specific nuclear receptors (RARs and VDR, respectively). Induction of RAR and VDR responsive elements in target genes requires a cofactor, the retinoid-X-receptor (RXR), with its ligand 9-cis RA. We have previously demonstrated the expression of RARs and RXRs in osteoblasts, and herein investigated the effects of the retinoids all-trans RA and 9-cis RA alone and combined with calcitriol on bone resorption in vitro, measured by 45Ca-release from prelabeled neonatal mouse calvarial bones. All-trans RA and 9-cis RA were powerful stimulators of bone resorption and essentially equipotent. At threshold concentrations (1 nM) both 9-cis RA and at-RA markedly inhibited the resorption induced by calcitriol (1 pM). The findings are compatible with a physiological role for retinoids in bone metabolism.

  • 8.
    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.

  • 9. Langdahl, Bente L.
    et al.
    Rajzbaum, Gerald
    Jakob, Franz
    Karras, Dimitrios
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lems, Willem F.
    Fahrleitner-Pammer, Astrid
    Walsh, J. Bernard
    Barker, Clare
    Kutahov, Alexey
    Marin, Fernando
    Reduction in fracture rate and back pain and increased quality of life in postmenopausal women treated with teriparatide: 18-month data from the European Forsteo Observational Study (EFOS)2009In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 85, no 6, p. 484-493Article in journal (Refereed)
    Abstract [en]

    The European Forsteo Observational Study was designed to examine the effectiveness of teriparatide in postmenopausal women with osteoporosis treated for up to 18 months in normal clinical practice in eight European countries. The incidence of clinical vertebral and nonvertebral fragility fractures, back pain, and health-related quality of life (HRQoL, EQ-5D) were assessed. Spontaneous reports of adverse events were collected. All 1,648 enrolled women were teriparatide treatment-naive, 91.0% of them had previously received other anti-osteoporosis drugs, and 72.8% completed the 18-month study. A total of 168 incident clinical fractures were sustained by 138 (8.8%) women (821 fractures/10,000 patient-years). A 47% decrease in the odds of fracture in the last 6-month period compared to the first 6-month period was observed (P < 0.005). Mean back pain VAS was reduced by 25.8 mm at end point (P < 0.001). Mean change from baseline in EQ-VAS was 13 mm by 18 months. The largest improvements were reported in the EQ-5D subdomains of usual activities and pain/discomfort. There were 365 adverse events spontaneously reported, of which 48.0% were considered related to teriparatide; adverse events were the reason for discontinuation for 79 (5.8%) patients. In conclusion, postmenopausal women with severe osteoporosis who were prescribed teriparatide in standard clinical practice had a significant reduction in the incidence of fragility fractures and a reduction in back pain over an 18-month treatment period. This was associated with a clinically significant improvement in HRQoL. Safety was consistent with current prescribing information. These results should be interpreted in the context of the open-label, noncontrolled design of the study.

  • 10.
    Leavy, Breiffni
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Physiotherapy, Huddinge, Sweden; Stockholms Sjukhem Fdn, Stockholm, Sweden.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Åberg, Anna Cristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Dalarna Univ, Sch Educ Hlth & Social Studies, Falun, Sweden.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    The Impact of Disease and Drugs on Hip Fracture Risk2017In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 00, no 1, p. 1-12Article in journal (Refereed)
    Abstract [en]

    We report the risks of a comprehensive range of disease and drug categories on hip fracture occurrence using a strict population-based cohort design. Participants included the source population of a Swedish county, aged ≥50 years (n = 117,494) including all incident hip fractures during 1 year (n = 477). The outcome was hospitalization for hip fracture (ICD-10 codes S72.0-S72.2) during 1 year (2009-2010). Exposures included: prevalence of (1) inpatient diseases [International Classification of Diseases (ICD) codes A00-T98 in the National Patient Register 1987-2010] and (2) prescribed drugs dispensed in 2010 or the year prior to fracture. We present age- and sex-standardized risk ratios (RRs), risk differences (RDs) and population attributable risks (PARs) of disease and drug categories in relation to hip fracture risk. All disease categories were associated with increased risk of hip fracture. Largest risk ratios and differences were for mental and behavioral disorders, diseases of the blood and previous fracture (RRs between 2.44 and 3.00; RDs (per 1000 person-years) between 5.0 and 6.9). For specific drugs, strongest associations were seen for antiparkinson (RR 2.32 [95 % CI 1.48-1.65]; RD 5.2 [1.1-9.4]) and antidepressive drugs (RR 1.90 [1.55-2.32]; RD 3.1 [2.0-4.3]). Being prescribed ≥10 drugs during 1 year incurred an increased risk of hip fracture, whereas prescription of cardiovascular drugs or ≤5 drugs did not appear to increase risk. Diseases inferring the greatest PARs included: cardiovascular diseases PAR 22 % (95 % CI 14-29) and previous injuries (PAR 21 % [95 % CI 16-25]; for specific drugs, antidepressants posed the greatest risk (PAR 16 % [95 % CI 12.0-19.3]).

  • 11.
    Lidén, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wilén, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Polymorphism at the Sp 1 binding site in the collagen type I alpha 1 gene does not predict bone mineral density in postmenopausal women in sweden1998In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 63, no 4, p. 293-295Article in journal (Refereed)
    Abstract [en]

     Polymorphisms at the binding site of the Sp 1 transcription factor of the collagen type I alpha1 gene have recently been suggested to be an important marker for low bone mineral density (BMD) and vertebral fracture in a population of predominantly postmenopausal British women. We examined whether the unfavorable "s" allele was associated with low BMD in 64 patients with primary osteoporosis and in 72 healthy controls. We found no statistically significant differences between COLIA1 genotypes with regard to BMD at the spine and femoral neck. In 36 patients with severe osteoporosis with vertebral fracture the genotype frequencies were similar to that observed in 67 age-matched controls. These data indicate that the Sp 1 polymorphisms in the COLIA1 gene are unlikely to be of clinical value in identifying Swedish subjects who are at risk of postmenopausal osteoporosis.

  • 12.
    Lind, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hu, Lijuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Sugars, Rachael
    Andersson, Göran
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Microarray Profiling of Diaphyseal Bone of Rats Suffering from Hypervitaminosis A2012In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 90, no 3, p. 219-229Article in journal (Refereed)
    Abstract [en]

    Vitamin A is the only known compound that produces spontaneous fractures in rats. In an effort to resolve the molecular mechanism behind this effect, we fed young male rats high doses of vitamin A and performed microarray analysis of diaphyseal bone with and without marrow after 1 week, i.e., just before the first fractures appeared. Of the differentially expressed genes in cortical bone, including marrow, 98% were upregulated. In contrast, hypervitaminotic cortical bone without marrow showed reduced expression of 37% of differentially expressed genes. Gene ontology (GO) analysis revealed that only samples containing bone marrow were associated with a GO term, which principally represented extracellular matrix. This is consistent with the histological findings of increased endosteal/marrow osteoblast number. Fourteen genes, including Cyp26b1, which is known to be upregulated by vitamin A, were selected and verified by real-time PCR. In addition, immunohistochemical staining of bone sections confirmed that the bone-specific molecule osteoadherin was upregulated. Further analysis of the major gene-expression changes revealed apparent augmented Wnt signaling in the sample containing bone marrow but reduced Wnt signaling in cortical bone. Moreover, induced expression of hypoxia-associated genes was found only in samples containing bone marrow. Together, these results highlight the importance of compartment-specific analysis of bone and corroborate previous observations of compartment-specific effects of vitamin A, with reduced activity in cortical bone but increased activity in the endosteal/marrow compartment. We specifically identify potential key osteoblast-, Wnt signaling-, and hypoxia-associated genes in the processes leading to spontaneous fractures.

  • 13.
    Michaëlsson, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wolk, Alicja
    Bergström, R.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Diet, bone mass, and osteocalcin: A cross-sectional study1995In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 57, no 2, p. 86-93Article in journal (Refereed)
    Abstract [en]

    To determine the relationships among nutrients intake, bone mass, and bone turnover in women we have investigated these issues in a population-based, cross-sectional, observational study in one county in central Sweden. A total of 175 women aged 28-74 at entry to the study were included. Dietary assessment was made by both a semiquantitative food frequency questionnaire and by four 1-week dietary records. Dual energy X-ray absorptiometry was performed at five sites: total body, L2-L4 region of the lumbar spine, and three regions of the proximal femur. Serum concentrations of osteocalcin (an osteoblast-specific protein reflecting bone turnover) were measured by a radioimmunoassay. Linear regression models, with adjustment for possible confounding factors were used for statistical analyses. A weak positive association was found between dietary calcium intake as calculated from the semiquantitative food frequency questionnaire and total body bone mineral density (BMD) among premenopausal women. No association emerged between dietary calcium intake and site-specific bone mass, i.e., lumbar spine and femoral neck, nor was an association found between dietary calcium intake and serum osteocalcin. BMD at some of the measured sites was positively associated with protein and carbohydrates and negatively associated with dietary fat. In no previous studies of diet and bone mass have dietary habits been ascertained so carefully and the results adjusted for possible confounding factors. Neither of the two methods of dietary assessment used in this study revealed any effect of calcium intake on BMD at fracture-relevant sites among these healthy, mostly middle-aged women. A weak positive association was found between calcium intake estimates based on the food frequency questionnaire and total body BMD. In this study population the preventive effect of high dietary calcium on osteoporosis is probably very weak. The independent significance of protein, carbohydrates, and fat is uncertain.

  • 14.
    Mitchell, Adam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Type 2 Diabetes in Relation to Hip Bone Density, Area, and Bone Turnover in Swedish Men and Women: A Cross-Sectional Study2018In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 103, no 5, p. 501-511Article in journal (Refereed)
    Abstract [en]

    Men and women with type 2 diabetes mellitus (T2DM) have higher risk of hip fracture, but the mechanisms are not fully understood. We aimed to investigate how T2DM, glucose, and insulin were associated with femoral bone mineral density (BMD), bone mineral area (BMA), and bone turnover markers. We used two cross-sectional cohorts: the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 452, mean age 82 years) and the Swedish Mammography Cohort Clinical (SMCC, n = 4713, mean age 68 years). We identified men and women with normal fasting glucose (NFG), impaired fasting plasma glucose (IFG), and T2DM. BMD and BMA at the total hip and femoral shaft were measured using dual energy X-ray absorptiometry (DXA). Bone turnover markers; CrossLaps and osteocalcin were measured in women. Linear regression models were applied. Men and women showed a progressively higher BMD following the clinical cutoffs of fasting glucose from NFG to IFG to T2DM. In contrast, there was a progressively lower BMA. Men and women with T2DM, compared to those with NFG, had lower BMA at the total hip (- 1.7%; 95% CI - 3.2, - 0.2 and - 1.0%; 95% CI - 1.6, - 0.4) and the femoral shaft (- 2.0%; 95% CI - 3.5, - 0.4 and - 0.6%; 95% CI - 1.2, - 0.01), respectively. T2DM was associated with lower concentrations of CrossLaps (- 8.1%; 95% CI - 12.7, - 3.6) and osteocalcin (- 15.2%; 95% CI - 19.0, - 11.2). These cross-sectional results indicate that those with T2DM have smaller bone area and lower bone turnover, which could increase the risk of hip fracture.

  • 15.
    Napoli, Nicola
    et al.
    Univ Campus Biomed, Div Endocrinol & Diabet, Alvaro del Portillo 21, I-00128 Rome, Italy.
    Langdahl, Bente. L.
    Aarhus Univ Hosp, Aarhus, Denmark.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Lespessailles, Eric
    Univ Orleans, Orleans, France;Reg Hosp Orleans, Orleans, France.
    Kapetanos, George
    Papageorgiou Gen Hosp, Thessaloniki, Greece.
    Kocjan, Tomaz
    Univ Med Ctr, Ljubljana, Slovenia.
    Nikolic, Tatjana
    Univ Hosp, Zagreb, Croatia.
    Eiken, Pia
    Hillerod Hosp, Dept Cardiol Nephrol & Endocrinol, Hillerod, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
    Petto, Helmut
    Eli Lilly & Co, Windlesham, Surrey, England.
    Moll, Thomas
    Eli Lilly & Co, Windlesham, Surrey, England.
    Lindh, Erik
    Eli Lilly & Co, Windlesham, Surrey, England.
    Marin, Fernando
    Eli Lilly & Co, Windlesham, Surrey, England.
    Effects of Teriparatide in Patients with Osteoporosis in Clinical Practice: 42-Month Results During and After Discontinuation of Treatment from the European Extended Forsteo (R) Observational Study (ExFOS)2018In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 103, no 4, p. 359-371Article in journal (Refereed)
    Abstract [en]

    This study aimed to describe clinical outcomes in patients prescribed teriparatide and followed up for 18months after stopping the drug in real-life conditions. The Extended Forsteo (R) Observational Study analysed incident clinical fractures in 6-month intervals using logistic regression with repeated measures. Changes in back pain (visual analogue scale) and health-related quality of life (HRQoL; EQ-5D questionnaire) were analysed using mixed models for repeated measures. Patients were analysed if they had a post-baseline visit, regardless of whether and for how long they took teriparatide. Of 1531 patients analysed (90.7% female, mean age: 70.3years), 76 (5.0%) never took teriparatide. Median treatment duration was 23.6months. The adjusted odds of clinical fracture decreased by 47% in the >12- to 18-month treatment period (p=0.013) compared with the first 6-month period, with no statistically significant reduction in the >18- to 24-month interval. The clinical fracture rate remained stable during the 18 months' post-teriparatide, when approximately 98% of patients took osteoporosis medication (51% bisphosphonates). Clinical vertebral fractures were reduced at every time period compared with the first 6months. Adjusted mean back pain scores decreased and EQ-5D scores increased significantly at each post-baseline observation. In a real-life clinical setting, the risk of clinical fractures declined during 24months of teriparatide treatment. This reduction was maintained 18months after stopping teriparatide. In parallel, patients reported significant improvements in back pain and HRQoL. The results should be interpreted in the context of the non-controlled design of this observational study.

  • 16.
    Stiger, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gillberg, Peter
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wolk, Alicja
    Michaelsson, Karl
    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.
    Association between repeat length of exon 1 CAG microsatellite in the androgen receptor and bone density in men is modulated by sex hormone levels2008In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 82, no 6, p. 427-35Article in journal (Refereed)
    Abstract [en]

    In this study we examined whether the androgen receptor (AR) gene CAG repeat polymorphism and serum androgen levels are associated with bone mineral density (BMD) and changes in BMD during 2-3 years in 229 healthy men 41-76 years old. Microsatellite analysis was performed on an automated sequencer. Indices of bioavailable testosterone (free testosterone [FT] and free androgen index) were calculated. BMD was measured using both dual-energy Xray absorptiometry and quantitative ultrasound. All participants completed a questionnaire regarding major possible osteoporosis risk factors. In linear regression analysis there was a modest positive association, which was independent of age and body mass index (BMI), between AR repeat length and BMD at all sites. Although this association was significant independent of BMI, analyses in the subgroup of obese men (BMI > 30) did not reach significance, while the effect was enhanced when analyzing only nonobese men (BMI < or = 30). There was no association between the AR gene polymorphism and rate of bone loss, FT, and BMD or testosterone and bone loss. Interestingly, the association between AR and BMD was modified by total testosterone. The lowest age- and BMI-adjusted average femoral neck BMD was found among men in the lowest tertile for both AR repeat length and FT, whereas men within the higher categories of these variables displayed the highest BMD. In conclusion, there is a positive association between the AR CAG repeat polymorphism and BMD, which is modified by androgen levels in healthy men.

  • 17.
    Wagner, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pedersen, Nancy
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Heritable and environmental factors in the causation of clinical vertebral fractures2012In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 90, no 6, p. 458-464Article in journal (Refereed)
    Abstract [en]

    Vertebral fractures are common osteoporotic fractures, and their incidence is greater in Scandinavia than in other European regions. Vertebral fractures are strongly associated with low bone mineral density, which has a predominant genetic etiology. The heritability of radiological vertebral deformities has been estimated in one recent family study. The objective of our study was to determine the genetic liability to clinical vertebral fractures and to what extent individual-specific environmental factors can explain the variance of these fractures. Participants were ascertained from the Swedish Twin Registry. Twin pairs born 1896-1944 formed the study base, a total of 33,432 subjects. Vertebral fractures after the age of 50 years were identified in the National Patient Register ( = 1,037) or by self-report ( = 35). The age-adjusted heritability for all vertebral fractures was 0.17 (95 % CI 0.00-0.40). Restricting the fracture cases to low-energy causes of injury, the heritability was 0.24 (95 % CI 0.00-0.47). Individual-specific environmental influences were found to explain one-third of the variance in vertebral fracture occurrence before the age of 70 years (0.33, 95 % CI 0.16-0.56), whereas they explained most of the variance among those 80 years of age or older (0.83, 95 % CI 0.61-1.00). We conclude that the occurrence of clinical vertebral fractures is largely explained by environmental influences and not by genetic factors. Individual-specific environmental influences such as lifestyle become more important with increasing age, and it is of importance to identify those environmental factors that cause more fracture cases in Scandinavia than in other European settings.

  • 18. Walsh, J. Bernard
    et al.
    Lems, Willem F.
    Karras, Dimitrios
    Langdahl, Bente L.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fahrleitner-Pammer, Astrid
    Barrett, Annabel
    Rajzbaum, Gerald
    Jakob, Franz
    Marin, Fernando
    Effectiveness of Teriparatide in Women Over 75 Years of Age with Severe Osteoporosis: 36-Month Results from the European Forsteo Observational Study (EFOS)2012In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 90, no 5, p. 373-383Article in journal (Refereed)
    Abstract [en]

    This predefined analysis of the European Forsteo Observational Study (EFOS) aimed to describe clinical fracture incidence, back pain, and health-related quality of life (HRQoL) during 18 months of teriparatide treatment and 18 months post-teriparatide in the subgroup of 589 postmenopausal women with osteoporosis aged a parts per thousand yen75 years. Data on clinical fractures, back pain (visual analogue scale, VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. A repeated-measures model analyzed changes from baseline in back pain VAS and EQ-VAS. During the 36-month observation period, 87 (14.8 %) women aged a parts per thousand yen75 years sustained a total of 111 new fractures: 37 (33.3 %) vertebral fractures and 74 (66.7 %) nonvertebral fractures. Adjusted odds of fracture was decreased by 80 % in the 30 to < 36-month interval compared with the first 6-month interval (P < 0.009). Although the older subgroup had higher back pain scores and poorer HRQoL at baseline than the younger subgroup, both age groups showed significant reductions in back pain and improvements in HRQoL postbaseline. In conclusion, women aged a parts per thousand yen75 years with severe postmenopausal osteoporosis treated with teriparatide in normal clinical practice showed a reduced clinical fracture incidence by 30 months compared with baseline. An improvement in HRQoL and, possibly, an early and significant reduction in back pain were also observed, which lasted for at least 18 months after teriparatide discontinuation when patients were taking other osteoporosis medication. The results should be interpreted in the context of an uncontrolled observational study.

  • 19.
    Yuan, Shuai
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wan, Zihao
    Chinese Univ Hong Kong, Fac Med, Dept Orthopaed & Traumatol, Shatin, Hong Kong, Peoples R China.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Associations of Smoking and Alcohol and Coffee Intake with Fracture and Bone Mineral Density: A Mendelian Randomization Study2019In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 6, p. 582-588Article in journal (Refereed)
    Abstract [en]

    The causal associations of smoking and alcohol and coffee intake with fracture and bone mineral density are unknown. We investigated the associations using Mendelian randomization (MR). Summary-level data from UK Biobank for bone fractures (main outcome) (53,184 cases; 373,611 non-cases) and estimated bone mineral density (eBMD) (n = 426,824 individuals) were used. Single-nucleotide polymorphisms associated with smoking initiation (n = 378) and alcohol (n = 99) and coffee (n = 15) intake at the genome-wide significance threshold (P = 5 x 10(-8)) were identified from published genome-wide association studies. Univariable and multivariable inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO methods were used for statistical analyses. Genetic predisposition to smoking initiation was associated with fracture but not eBMD. The odds ratio of fracture per one-unit increase in log odds of smoking was 1.09 (95% confidence interval 1.04, 1.15; P = 8.58 x 10(-4)) after adjustment for alcohol intake in the multivariable MR analysis. The association remained in complementary analyses. Genetically predicted alcohol and coffee intake was not associated with fracture or eBMD. Nevertheless, genetic liability to alcohol dependence, based on variants in the ALD1B gene, was associated with fracture and lower eBMD. The odds ratio was 1.06 (95% confidence interval 1.01, 1.12; P = 0.018) per genetically predicted one-unit higher log odds of liability to alcohol dependence. This MR study strengthens the causal inference on an association between smoking and higher fracture risk but found no linear association of modestly higher alcohol and coffee intake with fracture or BMD. However, alcohol dependence may increase fracture risk.

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