(26-02-16) Milk intake and risk of mortality and fractures in women and men: cohort studies

1. Karl Michaëlsson, professor1,
2. Alicja Wolk, professor2,
3. Sophie Langenskiöld, senior lecturer3,
4. Samar Basu, professor3,
5. Eva Warensjö Lemming, researcher14,
6. Håkan Melhus, professor5,
7. Liisa Byberg, associate professor1
Author affiliations
1. Correspondence to: K Michaëlsson [email protected]
Accepted 22 September 2014

Abstract
Objective To examine whether high milk consumption is associated with mortality and fractures in women and men.
Design Cohort studies.
Setting Three counties in central Sweden.
Participants Two large Swedish cohorts, one with 61 433 women (39-74 years at baseline 1987-90) and one with 45 339 men (45-79 years at baseline 1997), were administered food frequency questionnaires. The women responded to a second food frequency questionnaire in 1997.
Main outcome measure Multivariable survival models were applied to determine the association between milk consumption and time to mortality or fracture.
Results During a mean follow-up of 20.1 years, 15 541 women died and 17 252 had a fracture, of whom 4259 had a hip fracture. In the male cohort with a mean follow-up of 11.2 years, 10 112 men died and 5066 had a fracture, with 1166 hip fracture cases. In women the adjusted mortality hazard ratio for three or more glasses of milk a day compared with less than one glass a day was 1.93 (95% confidence interval 1.80 to 2.06). For every glass of milk, the adjusted hazard ratio of all cause mortality was 1.15 (1.13 to 1.17) in women and 1.03 (1.01 to 1.04) in men. For every glass of milk in women no reduction was observed in fracture risk with higher milk consumption for any fracture (1.02, 1.00 to 1.04) or for hip fracture (1.09, 1.05 to 1.13). The corresponding adjusted hazard ratios in men were 1.01 (0.99 to 1.03) and 1.03 (0.99 to 1.07). In subsamples of two additional cohorts, one in males and one in females, a positive association was seen between milk intake and both urine 8-iso-PGF2α (a biomarker of oxidative stress) and serum interleukin 6 (a main inflammatory biomarker).
Conclusions High milk intake was associated with higher mortality in one cohort of women and in another cohort of men, and with higher fracture incidence in women. Given the observational study designs with the inherent possibility of residual confounding and reverse causation phenomena, a cautious interpretation of the results is recommended.
Introduction
A diet rich in milk products is promoted to reduce the likelihood of osteoporotic fractures. Milk contains 18 of 22 essential nutrients, including calcium, phosphorus, and vitamin D of especial importance for the skeleton. Intestinal uptake of these nutrients is enhanced by the enzymatic capacity to digest lactose into D-glucose and D-galactose by mutation in the lactase gene, a variant common in those with northern European ancestry.1 2 An intake of dairy foods corresponding to three or four glasses of milk a day has been suggested to save at least 20% of healthcare costs related to osteoporosis.3
A high intake of milk might, however, have undesirable effects, because milk is the main dietary source of D-galactose. Experimental evidence in several animal species indicates that chronic exposure to D-galactose is deleterious to health and the addition of D-galactose by injections or in the diet is an established animal model of aging.4 5 6 7 Even a low dose of D-galactose induces changes that resemble natural aging in animals, including shortened life span caused by oxidative stress damage, chronic inflammation, neurodegeneration, decreased immune response, and gene transcriptional changes.5 7 A subcutaneous dose of 100 mg/kg D-galactose accelerates senescence in mice.5 This is equivalent to 6-10 g in humans, corresponding to 1-2 glasses of milk. Based on a concentration of lactose in cow’s milk of approximately 5%, one glass of milk comprises about 5 g of D-galactose. The increase of oxidative stress with aging and chronic low grade inflammation is not only a pathogenetic mechanism of cardiovascular disease and cancer in humans8 9 but also a mechanism of age related bone loss and sarcopenia.9 10 The high amount of lactose and therefore D-galactose in milk with theoretical influences on processes such as oxidative stress and inflammation makes the recommendations to increase milk intake for prevention of fractures a conceivable contradiction.
Because of the high content of lactose in milk, we hypothesised that high consumption of milk may increase oxidative stress, which in turn affects the risk of mortality and fracture. Meta-analyses of cohort studies for the association between dairy and milk intake in relation to mortality11 and fractures12 13 have displayed no clear pattern of risk, and evidence from randomised trials are lacking. Separating milk intake from the consumption of other dairy products may be of importance since a less pronounced induction of oxidative stress and inflammation in humans is expected with cheese and fermented dairy products (for example, soured milk and yogurt) because of their lower or non-existent lactose and galactose content,14 15 possible probiotic antioxidant and anti-inflammatory effects,16 17 18 and effects on gut microbiota.19 20 21 Indeed, a high intake of fermented milk products has been associated with a decreased risk of cardiovascular diseases,18 22 23 24 whereas a high milk intake is related to a tendency of an unfavourable risk profile for the development of diabetes and cardiovascular disease.18 23 24 We therefore assessed the relation between high milk intake with risk of death and fractures in women and men. We also studied biological markers of oxidative stress and inflammation in relation to milk intake in humans.
Methods
We used two community based cohorts, the Swedish Mammography Cohort25 26 and the Cohort of Swedish Men,27 to analyse the association of milk consumption and mortality and fracture rates. Figure 1⇓ shows the study sample. In 1987-90, all 90 303 women aged 39-74 years residing in two Swedish counties (Uppsala and Västmanland, both in central Sweden) received a postal invitation to a routine mammography screening. Enclosed with this invitation was a questionnaire covering both diet (food frequency questionnaire) and lifestyle, which was completed by 74% of the women. In 1997, a subsequent, expanded questionnaire was sent to those who were still living in the study area (response rate 70%). In the present study 61 433 women in the Swedish Mammography Cohort with baseline data from 1987-90 and 38 984 with updated information from 1997 were available for analysis.
The Cohort of Swedish Men was created in the autumn of 1997. All men, aged 45-79 years, residing in Örebro and Västmanland counties in central Sweden were invited to participate in the study (n=100 303). Enclosed with this invitation was a questionnaire covering both diet (food frequency questionnaire) and lifestyle, which was completed by 48 850 men. Despite the response rate of 49%, the Cohort of Swedish Men is considered representative of Swedish men in this age range in terms of age distribution, educational level, and prevalence of being overweight.27 After exclusions, the final sample included 45 339 men (fig 1).

Sources: BMJ 2014; 349 doi: http://dx.doi.org/10.1136/bmj.g6015 (Published 28 October 2014) Cite this as: BMJ 2014;349:g6015

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