A high activity index of stearoyl-CoA desaturase is associated with increased risk of fracture in men

SCD is a key enzyme in the biosynthesis of MUFAs from SFAs, i.e., in lipogenesis. In this prospective, population-based cohort study of men, the overall risk of fracture was substantially increased among the men with high levels of estimated SCD activity. The risk was concentrated in the highest quintile, with a continuous increase within this category, and it was independent of BMI. Thus, despite a positive effect of increased fat mass on weight-bearing, our results indicate that increased endogenous lipogenesis has negative effects on bone. Although we could only analyze a subgroup, the finding that an increase in SCD activity index from 50 to 70 years is associated with an even higher risk, gives further support to this.

We included not only height and weight in our multivariable model, but also a number of lifestyle factors. Adjustment for these factors had only modest effects on the estimates, indicating that the association between SCD activity index and fracture risk cannot be explained by these potential confounders. Instead our results suggest that the dietary fat quality and endogenous fatty acid metabolism may be important. It should be emphasized that increased SCD activity index does not directly reflect increased proportions of palmitoleic acid in the diet, since the content of this fatty acid is normally small in the diet. Rather, it reflects increased endogenous desaturation of palmitic acid by SCD leading to increased palmitoleic acid, as a consequence of a high intake of palmitic acid in the diet [11]. Interestingly, in glycogen storage disease type 1, the synthesis of palmitic acid is increased 40-fold [18] and osteopenia is a known complication in this disease [19‐22]. Furthermore, in animal studies, inclusion of palmitic acid as the major source of fat causes a reduction in bone ash and bone calcium levels [23, 24].

Alternatively, although unlikely in a Western diet with a high dietary intake of fat [25], an increased SCD activity index could be a consequence of a high intake of carbohydrates. At low fat intakes, the amount of palmitoleic acid in serum has been reported to reflect the hepatic pool of carbon flux from carbohydrates to fatty acids [26], e.g., in rats rendered obese by sucrose administration, SCD activity index increases dramatically in liver and plasma [27].

SFAs, high carbohydrate diets, and insulin all appear to be able to induce SCD expression, whereas dietary PUFAs and leptin seem to inhibit SCD mRNA transcription [11]. Therefore, the relationship between SCD and risk of fracture may reflect compensatory up-regulation of SCD to continuous intake of e.g., a diet high in SFAs (such as dairy products, solid margarines, and meat products) and low in PUFAs, rather than a metabolically harmful effect of increased activity in itself [17]. Consistent with this, a recent analysis of NHANES III by Corwin et al. [28] found that SFAs are inversely associated with bone density at several hip sites, particularly in men <50 years of age.

SCD activity can also be estimated as the oleic/stearic acid (18:1/18:0) ratio [6]. However, the predictive value of this ratio in serum in the ULSAM cohort has previously been shown to be considerably less than for palmitoleic/palmitic acid due to a much higher dietary proportion of oleic acid [17], and was therefore not analyzed in this study.

Mounting evidence indicates an important role of PPARγ in skeletal metabolism. PPARγ haploinsufficient mice have increased bone mass and decreased adipogenesis, whereas activation of PPARγ with the agonist rosiglitazone causes bone loss and increased bone marrow adiposity in mice [29, 30]. Thiazolidinedione use has recently been shown to cause bone loss also in humans [31]. In a randomized clinical trial rosiglitazone increased SCD activity index, and in one patient with partial lipodystrophy and type 2 diabetes due to dominant-negative mutation in the PPARγ gene, it restored SCD activity index, indicating a pivotal role of PPARγ function in SCD regulation, at least in adipose tissue [7]. The activation of PPARγ by natural ligands, such as oxidized fatty acids, plays an important role in the development of atherosclerosis [32]. Oxidized lipids also inhibit osteoblast development in vitro and bone formation in vivo, and serve as substrates for PPARγ, which redirects differentiation of mesenchymal cells from osteoblasts to adipocytes. PPAR also enhances many adipocyte genes and diminishes Cbfa1/Runx2, needed for osteoblast development. All these effects could reduce bone formation and promote atherogenesis [33]. Atherosclerosis could be one of the common factors which would explain the reported relationship between cardiovascular disease and osteoporosis [34]. Our findings are consistent with previous findings from the ULSAM cohort regarding serum fatty acid profile and the risk of developing cardiovascular disease [16, 35]. Moreover, inflammation plays an important role in atherogenesis. Part of the inflammatory response is activation of T cells with release of cytokines, especially of RANKL, which is a key molecule in bone resorption [33].

We have previously found an association between serum retinol and fracture risk in ULSAM (12). Retinol is a fat-soluble vitamin found in dietary fat from animal sources, i.e., in food that may also contain high levels of SFAs. However, inclusion of retinol in the multivariable model had only minor effects on the rate ratio.

Our population-based study had the advantage of involving men with similar age followed from a time before they reached the high incidence ages for fractures, and we used hospital-record verification of fractures. In addition, we used serum levels of individual fatty acids, rather than dietary assessments of fat intake.

There are some limitations of this study. The study population consisted only of men and therefore our results need to be verified in women. Since direct measures of SCD activity is very difficult to obtain in larger studies, we used the ratio between two fatty acids. Whether the ratio mainly reflects SCD activity in adipose tissue, liver, or both still remains to be elucidated. Unfortunately, bone mineral density data were not available. Another limitation of the study is the lack of dietary records at baseline and the resulting lack of knowledge about the intake of e.g., SFAs and PUFAs in the studied population.

In conclusion, the results of our study suggest that a high SCD activity, indicating elevated endogenous lipogenesis, substantially increases the risk of fractures. Previous experimental work showing a reciprocal relationship between bone and fat supports this conclusion.