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Publications (10 of 11) Show all publications
Kharazmi, M., Michaëlsson, K., Schilcher, J., Eriksson, N., Melhus, H., Wadelius, M. & Hallberg, P. (2019). A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture. Calcified Tissue International, 105(1), 51-67
Open this publication in new window or tab >>A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture
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2019 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Genome-wide association study, Atypical fractures, Bisphosphonate, Drug-related side effects and adverse reactions, Pharmacogenetics
National Category
Orthopaedics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-386428 (URN)10.1007/s00223-019-00546-9 (DOI)000469477400005 ()31006051 (PubMedID)
Funder
Swedish Research Council, 521-2011-2440; 521-2014-337; 2015-035270Swedish Heart Lung FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceErik, Karin och Gösta Selanders FoundationÖstergötland County Council
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Kharazmi, M., Scheer, H. & Hallberg, P. (2017). Reduced obstacles, maximized vision (ROMV): a new technique to facilitate laryngoscopy for endotracheal intubation. Upsala Journal of Medical Sciences, 122(1), 68-69
Open this publication in new window or tab >>Reduced obstacles, maximized vision (ROMV): a new technique to facilitate laryngoscopy for endotracheal intubation
2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 68-69Article in journal, Editorial material (Refereed) Published
Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-321027 (URN)10.1080/03009734.2016.1246494 (DOI)000396476600011 ()27849129 (PubMedID)
Available from: 2017-04-28 Created: 2017-04-28 Last updated: 2018-01-13Bibliographically approved
Kharazmi, M., Hallberg, P., Schilcher, J., Aspenberg, P. & Michaëlsson, K. (2016). Mortality After Atypical Femoral Fractures: A Cohort Study. Journal of Bone and Mineral Research, 31(3), 491-497
Open this publication in new window or tab >>Mortality After Atypical Femoral Fractures: A Cohort Study
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2016 (English)In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 31, no 3, p. 491-497Article in journal (Refereed) Published
Abstract [en]

Although osteoporotic fracture rates can be reduced by bisphosphonates, prolonged therapy is associated with higher risk of atypical femoral fractures. Ordinary fragility fractures are linked to high mortality rates. We aimed to determine whether atypical femoral fractures also confer excess mortality. Radiographs were reviewed for all patients ≥55 years of age who had experienced a subtrochanteric or femoral shaft fracture in Sweden in 2008-2010. The fractures were classified as either atypical or ordinary. Data on medication use, coexisting conditions, and date of death were obtained from national registers. We estimated multivariable-adjusted relative risks of death after atypical femoral fractures compared with ordinary subtrochanteric or femoral shaft fractures and calculated age- and sex-standardized mortality ratios (SMRs) for atypical and ordinary fractures compared with the population average. During a mean of 4 years of follow-up, 39 of 172 (23%) patients with an atypical fracture had died compared with 588 of 952 (62%) with an ordinary fracture, corresponding to a relative risk of 0.51 (95% CI 0.38-0.68). The lower risk was evident in both users and non-users of bisphosphonates. No patient with atypical fracture died in the first year after fracture. Individuals with an ordinary fracture had a higher mortality risk than the general population (SMR 1.82; 95% CI 1.69-1.99) but no excess risk was found in patients with atypical fracture (SMR 0.92; 95% CI 0.65-1.26). We conclude that in contrast to ordinary subtrochanteric and femoral shaft fractures, atypical femoral fractures are not associated with excess mortality.

National Category
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-273522 (URN)10.1002/jbmr.2767 (DOI)000373596800003 ()26676878 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2018-01-10Bibliographically approved
Kharazmi, M., Bjornstad, L., Hallberg, P., Wanbro, J., Carlsson, A.-P., Habib, S. & Warfvinge, G. (2015). Mandibular bone exposure and osteonecrosis as a complication of general anaesthesia [Letter to the editor]. Upsala Journal of Medical Sciences, 120(3), 215-216
Open this publication in new window or tab >>Mandibular bone exposure and osteonecrosis as a complication of general anaesthesia
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2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 215-216Article in journal, Letter (Refereed) Published
National Category
Surgery Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-262145 (URN)10.3109/03009734.2015.1010667 (DOI)000359819800010 ()25783744 (PubMedID)
Available from: 2015-09-09 Created: 2015-09-09 Last updated: 2017-12-04Bibliographically approved
Kharazmi, M., Carlsson, A.-P. & Hallberg, P. (2015). Mandibular Bone Exposure and Osteonecrosis in a Patient With an Uncomplicated Medical History [Letter to the editor]. The Journal of craniofacial surgery (Print), 26(5), 1719-1720
Open this publication in new window or tab >>Mandibular Bone Exposure and Osteonecrosis in a Patient With an Uncomplicated Medical History
2015 (English)In: The Journal of craniofacial surgery (Print), ISSN 1049-2275, E-ISSN 1536-3732, Vol. 26, no 5, p. 1719-1720Article in journal, Letter (Refereed) Published
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-276780 (URN)10.1097/SCS.0000000000001775 (DOI)000369611000108 ()26107001 (PubMedID)
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-11-30Bibliographically approved
Kharazmi, M., Michaëlsson, K. & Hallberg, P. (2015). Prodromal Symptoms in Patients with Bisphosphonate-Associated Atypical Fractures of the Femur. Journal of Bone and Mineral Metabolism, 33(5), 516-522
Open this publication in new window or tab >>Prodromal Symptoms in Patients with Bisphosphonate-Associated Atypical Fractures of the Femur
2015 (English)In: Journal of Bone and Mineral Metabolism, ISSN 0914-8779, E-ISSN 1435-5604, Vol. 33, no 5, p. 516-522Article in journal (Refereed) Published
Abstract [en]

Symptoms have been reported to precede bisphosphonate-associated atypical fractures (AFs) of the femoral shaft. We aimed to determine the frequency and clinical characteristics of such prodromal symptoms. We searched the Swedish national database of spontaneously reported adverse drug reactions for all cases of AF associated with bisphosphonates from January 2006 to March 2013. To confirm diagnostic accuracy and to characterize and determine the frequency of any prodromal symptoms we retrieved copies of medical journals and radiographs for patients who consented to participate in the study. The frequency of prodromal symptoms was compared with that of patients where information was based only on narratives from the adverse drug reaction case reports. A total of 45 reports of AF were identified. We were able to obtain medical records and x-rays for 21 cases and diagnostic accuracy was confirmed for all. Medical records revealed prodromal symptoms in 86 % (n = 18), most commonly pain in the ipsilateral thigh (14 out of 18 patients) preceding the fracture for weeks or longer. Awareness of such symptoms may facilitate early diagnosis and possible prevention of the AF.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-242715 (URN)10.1007/s00774-014-0611-9 (DOI)000360706700006 ()25319555 (PubMedID)
Available from: 2015-01-30 Created: 2015-01-30 Last updated: 2018-11-30
Kharazmi, M. & Hallberg, P. (2014). Bisphosphonate-associated atypical femoral fractures and one-year mortality [Letter to the editor]. Upsala Journal of Medical Sciences, 119(4), 357-358
Open this publication in new window or tab >>Bisphosphonate-associated atypical femoral fractures and one-year mortality
2014 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 4, p. 357-358Article in journal, Letter (Refereed) Published
National Category
Other Medical Sciences not elsewhere specified
Identifiers
urn:nbn:se:uu:diva-240918 (URN)10.3109/03009734.2014.959213 (DOI)000345722500011 ()25231006 (PubMedID)
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2017-12-05Bibliographically approved
Kharazmi, M., Hallberg, P. & Michaëlsson, K. (2014). Gender related difference in the risk of bisphosphonate associated atypical femoral fracture and osteonecrosis of the jaw [Letter to the editor]. Annals of the Rheumatic Diseases, 73(8), 1594-1594
Open this publication in new window or tab >>Gender related difference in the risk of bisphosphonate associated atypical femoral fracture and osteonecrosis of the jaw
2014 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no 8, p. 1594-1594Article in journal, Letter (Refereed) Published
National Category
Orthopaedics Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-230034 (URN)10.1136/annrheumdis-2013-205080 (DOI)000338696800032 ()24788545 (PubMedID)
Available from: 2014-08-19 Created: 2014-08-19 Last updated: 2018-01-11
Kharazmi, M., Carlsson, A.-P. & Hallberg, P. (2014). Oral surgery: Prominent bone shelves [Letter to the editor]. British Dental Journal, 216(10), 544-545
Open this publication in new window or tab >>Oral surgery: Prominent bone shelves
2014 (English)In: British Dental Journal, ISSN 0007-0610, E-ISSN 1476-5373, Vol. 216, no 10, p. 544-545Article in journal, Letter (Refereed) Published
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-276782 (URN)10.1038/sj.bdj.2014.406 (DOI)24852964 (PubMedID)
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2017-05-02Bibliographically approved
Kharazmi, M., Hallberg, P., Warfvinge, G. & Michaëlsson, K. (2014). Risk of atypical femoral fractures and osteonecrosis of the jaw associated with alendronate use compared with other oral bisphosphonates [Letter to the editor]. Rheumatology, 53(10), 1911-1913
Open this publication in new window or tab >>Risk of atypical femoral fractures and osteonecrosis of the jaw associated with alendronate use compared with other oral bisphosphonates
2014 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 53, no 10, p. 1911-1913Article in journal, Letter (Refereed) Published
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-233261 (URN)10.1093/rheumatology/keu286 (DOI)000343422400034 ()25099769 (PubMedID)
Available from: 2014-10-01 Created: 2014-10-01 Last updated: 2017-12-05Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4666-0624

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