DEMAB - A post-authorisation safety study (PASS) of a new osteoporosis medication (Denosumab Global Safety Assessment Among Women With Postmenopausal Osteoporosis (PMO) and Men With Osteoporosis in Multiple Observational Databases)
DEMAB is a Scandinavian research collaboration between Norway, Denmark and Sweden. It is a post-authorisation safety study (PASS) of a new osteoporosis medication that went on sale in autumn 2010 in Norway; Prolia. Project leader in Norway is Grethe S. Tell at the University of Bergen, Department of Global Public Health and Primary Care. Jannicke Igland is the new project manager from November 2023
Hip fractures are an important cause of permanent disability and death and are mainly due to osteoporosis. Several drugs have been developed that aim to reduce the risk of fractures among patients with osteoporosis. A new drug, Prolia (the active substance is called Denosumab), came on the market in 2010. This drug has been tested in extensive and thorough clinical studies according to scientific rules and principles, and found to be able to reduce the risk of hip fractures (1, 2, 3).
Such randomized clinical trials are most often carried out over a relatively short period of time, usually a few years. During this time, the drug's effectiveness and possible side effects are assessed, and it is on the basis of these results that the drug is approved for sale or not. However, it is possible that any side effects and adverse consequences of drugs do not become apparent until after longer use. Therefore, the health authorities in the USA (U.S. Food and Drug Administration - FDA) and Europe (European Medicines Agency - EMA) have decided that a ten-year study must be carried out after the drug goes on sale, in which possible side effects of the drug Prolia must be mapped. It is published two articles evaluating the methods used in the study (4, 5). DEMAB studien er registrert i EU PAS registeret (6).
This is an open cohort study with annual assessments and reports of descriptive findings. The study includes up to 10 years of follow-up in the Scandinavian countries and in the USA. Two articles have already been published evaluating the methods used in the study. Preliminary results are only reported to the European and American health authorities.
The study is based on data from the Norwegian Patient Registry and the Norwegian Prescribed Drug Registry, both national health registers. Data has been collected for over ten years, and several hundred thousand people are included in the data set.
The Regional Committees for Medical and Health Research Ethics (REK) has approved that the study is carried out without the consent of those whose data is included. The committee has asked the research team to state that we can keep collected data until the end of October 2025. After that, it may be appropriate to keep data for five years after the end of the project to check the analyses. The study has also been approved by the Norwegian Data Protection Authority. The approvals have been given, among other things, because it would be completely impossible to obtain consent from all women in Norway aged 55 and over, and because it is impossible for the researchers to identify individuals (see below).
Such studies, which are based on national health registers, are always carried out without the consent of those registered (after approval from REK). For example, many studies have been carried out based on data from the Medical Birth Registry to study factors that can influence pregnancy outcomes.
The advantage of using data from the national health registers is that these are complete and cover the entire population. The 'weaknesses' of such studies are that there is then no information about the individual person apart from what is recorded in the registers, which in the DEMAB study is information about drug use and hospital stays. We therefore have no information about individual conditions that may affect the results of the studies, such as e.g. weight, height, smoking and diet.
The data is de-identified, meaning that the researchers do not have the opportunity to identify individuals. The data sets and the statistical analyzes are stored and carried out on secure data servers at the University of Bergen.
Two articles have already been published evaluating the methods used in the study. Preliminary results are only reported to the European and American health authorities.
We have written two articles based on Norwegian data collected in the DEMAB study. In the first article, we wrote about increased mortality among women after a hip fracture if the women have several underlying diseases at the same time (7). The second article has not yet been published, but has been submitted to a scientific journal for review. Here we look at the extent to which women who are treated with Prednisolone (a type of cortisone) also start drug treatment against osteoporosis.
The DEMAB study is presented in the June 2020 issue of Osteoporosebladet.
Another current national study that deals with osteoporosis and fractures is the NoFRACT study. This is a large Norwegian multicentre study to prevent bone fractures in patients who have already had a bone fracture. A standardized prevention program has been introduced at seven hospitals in Norway, and the study will measure the effect of this intervention in national registers. See: https://www.med.uio.no/helsam/forskning/prosjekter/nofract/
There is also a national research network within osteoporosis and fractures: NOREPOS (Norwegian Epidemiological Osteoporosis Studies). See: http://www.norepos.no/. As part of this collaboration, the researchers have collected information on all hip fractures in Norway from 1994 to 2013, and the purpose is to study risk factors for hip fractures, in order to answer the question of why Norway is at the top of the world in hip fractures.
Initiation of anti-osteoporotic drugs in high-risk female patients starting glucocorticoid treatment: a population study in Norway. Arch Osteoporos. 2020 Aug 5;15(1):121.
1 Eastell R, Christiansen C, Grauer A, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res. 2011 Mar;26(3):530-7.
2 Cummings SR, San Martin J, McClung MR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361(8): 756-65.
3 Xue F, Ma H, Stehman-Breen C, et al. Design and methods of a postmarketing pharmacoepidemiology study assessing long-term safety of Prolia® (denosumab) for the treatment of postmenopausal osteoporosis. Pharmacoepidemiol Drug Saf 2013;22(10):1107-14.
4 Gammelager H, Sværke C, Noerholt SE, et al. Validity of an algorithm to identify osteonecrosis of the jaw in women with postmenopausal osteoporosis in the Danish National Registry of Patients. Clin Epidemiol. 2013;1(5):263-7.
5 Bergdahl J, Jarnbring F, Ehrenstein V, et al. Evaluation of an algorithm ascertaining cases of osteonecrosis of the jaw in the Swedish National Patient Register. Clin Epidemiol. 2013;5:1-7.
6 EU PAS register http://www.encepp.eu/encepp/viewResource.htm?id=30483.
7 Lunde A, Tell GS, Pedersen AB, et al. The Role of Comorbidity in Mortality After Hip Fracture: A Nationwide Norwegian Study of 38,126 Women With Hip Fracture Matched to a General-Population Comparison Cohort. Am J Epidemiol 2019;188(2):398-407.