Livsstil, genetik och läkemedelsbehandling för att förebygga fragilitetsfrakturer

Tidsperiod: 2016-01-01 till 2019-12-31

Projektledare: Karl Michaëlsson

Medarbetare: Alicja Wolk, Håkan Melhus, Liisa Byberg

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 4 000 000 SEK

Fragility fractures are common in Sweden but we don’t know why. With increasing age, the importance of lifestyle seems to become more important than genetic constitution. The significance of diet, physical activity and pharmacologic interventions on the risk of osteoporotic fractures will be examined by several different designs. To thoroughly examine diet and fracture risk, large longitudinal prospective studies with repeat examinations are needed. Dietary habits of 110,000 women and men have been examined. During follow-up more than 25,000 experienced at least one fracture and 33,461 died. In addition, we have established a subcohort of 5022 women. These women have again been interviewed regarding dietary habits and also investigated by bone scans and biological marker analyses. Reexaminations will yet again be done on average 10 years after the first bone scans so that changes in the phenotypes can be linked to dietary habits. By use of these large cohorts, we are starting to redraw the map concerning dietary recommendations to prevent fragility fractures, e.g., the interaction between dairy consumption and antioxidant intake. These epidemiological study attempts will be supported by interventional efforts. Therefore, in a one-year long placebo-controlled randomized clinical trial we will evaluate the effect of a moderate dose of vitamin E on bone mineral density, bone turnover and oxidative stress markers among women with consistently reported low intake of vitamin E. In another cross-over randomized clinical trial we will evaluate the short-term effects on oxidative stress and inflammation by non-fermented and fermented dairy products. Vitamin D is widely promoted to not only improve skeletal health but also to have general health benefits. Sales are increasing but the health benefits are also questioned. A major problem is the definition of vitamin D insufficiency, with different recommendations covering essentially the whole exposure range in the population. Needed is a well-defined evidence-based cutoff for insufficiency by use of a valid method of serum 25-hydroxyvitamin D, calculation of free bioavailable vitamin D, consideration of the influence by fat mass and the use of well-defined outcomes. For this purpose we have access to two suitable cohorts, covering the adult life span. Physical activity is associated with reduced risk of falling but whether physical activity may reduce the risk of fractures is controversial. Prospective studies conducted to quantitatively assess the dose-response relation between physical activity and fracture risk are warranted. In an attempt to delineate thresholds in fracture risk we need to use a broad exposure range, preferentially estimated as metabolic equivalents. Such a broad range can be found by combining three large cohort studies, including one with Vasaloppet skiers (n=200,000). Using the wide range of exposure combined with the large size of the material, it would theoretically be possible to construct public health recommendations for the level of physical activity needed to reduce fracture rates. Bisphosphonate treatment reduces bone remodeling and is in some risk groups effective for the prevention of osteoporotic fractures. A serious complication of atypical femoral fractures has, however, recently been identified. In a new nation-wide cohort and case-control study we plan to examine long-term absolute and relative risks of atypical fractures with use of different bisphosphonates and denosumab. In another large cohort study (n=450,000) we will evaluate the effectiveness of bone-specific treatment, calcium and vitamin D supplementation on fracture and mortality rates. These studies are needed to determine the net long-term benefit or harm with bone-antiresorptive therapy. Finally, we aim to discover common pathogenetic mechanisms for the known linkage between cardiovascular diseases and osteoporosis. In three cohort studies, we will therefore use proteomics to discover c