Association between Dietary Patterns of Meat and Fish Consumption with Bone Mineral Density or Fracture Risk: A Systematic Literature

This systematic review aimed to investigate the association of fish and sea fish dietary patterns (FishDiet) and meat or processed meat dietary patterns (MeatDiet) with bone mineral density (BMD) and/or risk of fractures (RF). This review includes 37 studies with a total of 432,924 subjects. The results suggest that MeatDiet and FishDiet did not affect BMD or RF in 48.2% of the subjects with MeatDiet and in 86.5% of the subjects with FishDiet. Positive effects on bone were found in 3% of subjects with MeatDiet and in 12% with FishDiet. Negative effects on bone were observed in 2.7% of FishDiet and in 47.9% of MeatDiet. Major negative effects of MeatDiet were found in subjects located in the Netherlands, Greece, Germany, Italy, Norway, UK and Spain who do not sustain a Mediterranean diet (92.7%); in Korea (27.1%); in Brazil and Mexico (96.4%); and in Australia (62.5%). This study suggests that protein intake from fish or meat is not harmful to bone. Negative effects on bone linked to FishDiet are almost null. Negative effects on bone were associated to MeatDiet in the setting of a Western Diet but not in Mediterranean or Asian Diets.


Introduction
Primary osteoporosis prevention requires healthy behaviour, such as regular physical exercise, and adequate dietary intake of calcium, vitamin D and proteins [1]. In particular, proteins (derived from meat, fish, milk and eggs) are essential because they are incorporated into the organic matrix of bone as part of the collagen structure upon which mineralization occurs, and because dietary proteins influence the secretion and action of the osteotropic hormone insulin-like growth factor I (IGF-I), which is important for bone formation [2]. Minerals (in particular calcium and phosphorus because they compose roughly 80% to 90% of the mineral content of bone hydroxyapatite) and vitamins (e.g., vitamins D and K) are also crucial for carrying out metabolic processes and reactions in bone [3].
Other benefits for bone metabolism are derived from bioactive components found predominantly in vegetables, but also in some herbs and fruits: phytochemicals, antioxidants, and other bioactive compounds influence bone metabolism through a variety of mechanisms, but mainly through reducing oxidative stress and inflammation [4]. In particular, cellular studies on dried plum, citrus, berry fruits and bioactive compounds including lycopene, phenolics, flavonoids, resveratrol, phloridzin, isoflavones and pectin derived from tomato, grapes, apples, and citrus fruits seem to be promising. Furthermore, animal studies strongly suggest that commonly consumed antioxidant-rich fruits have a pronounced effect on trabecular bone volume, number, and thickness, and lower trabecular separation through enhancing bone formation and suppressing bone resorption [5].
Several studies have concluded that the incidence of osteoporosis and osteoporosis-related fractures vary across the European Union. Conspicuous differences are encountered in the incidence of osteoporosis, the lowest incidence being reported in the Mediterranean area [6]. The beneficial effect is primarily attributed to a specific pattern of eating habits that includes high consumption of vegetables, legumes, fruits, and grains; moderate to high intake of fish; low intake of saturated lipids; high intake of unsaturated lipids, particularly olive oil; low to moderate intake of dairy products; low intake of meat; and modest intake of alcohol mostly in the form of wine [7,8].
The most consistently followed approach to examine the potential relationship between dietary factors and skeletal health has been based on studies of particular nutrients, such as calcium and vitamin D. Although previous studies have mainly focused on the roles of calcium, vitamin D, protein, and dairy and soy products, increasing evidence suggests a positive association between fruit and vegetable components and bone health [9][10][11]. These components include potassium; manganese; vitamin B complex; vitamins C, E, and K; and phytochemicals (e.g., carotenoids, and genistein aglycone) [11,12]. Specifically, a recent study showed that genistein aglycone administration continued to decrease levels of bone resorption markers (pyrrolidonyl aminopeptidase (PYR), telopeptide of type I collagen and receptor activator of nuclear factor κ B (RANKL)) and increased new bone formation markers (insulin growth factor (IGF-I) and osteoprotegerin (OPG)), extending this effect to three years, and supporting greater bone formation [13].
The aim of this systematic review is to investigate the effect of dietary consumption of fish and meat (or their derivatives) on bone mineral density (BMD) in studies which evaluated the association between dietary pattern and bone mineral density and/or risk of fractures as the primary outcome.

Methods
This systematic review was performed according to the following steps suggested by Egger et al. [14]: (i) formulation of the revision question on the basis of considerations made in the abstract; and (ii) identification of relevant studies.
The search involved all cross sectional or longitudinal cohort studies published from 1 January 1958 to 31 March 2017. English written articles were identified by searching the Medline database [15], Scopus [16], Web of Science [17] and Google Scholar [18]. The analysis was carried out in the form of a systematic review of the reports.

Inclusion and Exclusion Criteria
Two reviewers (SP and MR) independently reviewed each report. For each of the relevant abstracts, full publications were retrieved for evaluation based on criteria established a priori. Original cross-sectional surveys or longitudinal cohort studies investigating the effects of meat or fish as dietary patterns in relation to BMD and risk of fractures (FR) were evaluated.
As suggested by Recommendations of the World Health Organization Task-Force for Osteoporosis, the subjects with BMD values more than 2.5 standard deviations below the young normal mean should be offered appropriate treatment but intervention can also be directed at menopausal women with BMD values between −1 and −2.5 standard deviation (SD) because of their increased future fracture risk, as well as to those with other risk factors [19].
Currently, the accepted "gold standard" method for bone mineral density (BMD) measurement and osteoporosis diagnosis is dual-energy X-ray absorptiometry. In addition the "quantitative ultrasound" (QUS) approaches, which are radiation-free, cheaper and portable, but they cannot be applied on the reference anatomical sites (lumbar spine and proximal femur) [20]. Changes in BMD T-score and FR were the primary outcome. No secondary outcomes were considered.
The eligible studies were required to report baseline and follow-up values of BMD, i.e., bone mass increase/decrease during the quartile (by years) during the survey, the correlation coefficient between dietary pattern and BMD. Trials were not included. Figure 1 reports the flow diagram of the study.
Nutrients 2017, 9, 1029 3 of 25 ultrasound" (QUS) approaches, which are radiation-free, cheaper and portable, but they cannot be applied on the reference anatomical sites (lumbar spine and proximal femur) [20]. Changes in BMD T-score and FR were the primary outcome. No secondary outcomes were considered. The eligible studies were required to report baseline and follow-up values of BMD, i.e., bone mass increase/decrease during the quartile (by years) during the survey, the correlation coefficient between dietary pattern and BMD. Trials were not included. Figure 1 reports the flow diagram of the study.

Data Collection
The following data were extrapolated from all the revised studies: The data obtained are summarized in Table 1.

Data Collection
The following data were extrapolated from all the revised studies: The data obtained are summarized in Table 1. There was no association of "meat-fish" pattern with incident frailty Meat: no effect on BMD; Fish: no effect on BMD. No effects on BMD were observed with meat and fish consumption.
Meat: no effect on BMD; Fish: no effect on BMD.
Cross-sectional study There were no consistent associations between dietary patterns and forearm BMD in adolescents.
Meat: no effect on BMD; Fish: no effect on BMD.  "Refined" group scores (Factor 3 for men) (meat dishes) and "Nuts and Meat" group scores (Factor 3 for women) (meat dishes) were associated with higher FN BMC and in women also FN BMD. "Social" group scores were associated with higher FN BMC but when further adjusted were not significant.
Meat: increases BMD Fish: no effect on BMD No differences at any BMD site were observed across the protein food clusters in either crude models or adjusted models.
Meat: no effect on BMD; Fish: no effect on BMD

Results
Regarding the association between meat and fish dietary patterns and BMD or risk of fractures, this search was based on the keywords ("Meat" OR "Fish" OR "dietary patterns") AND ("BMD" OR "bone mineral density" OR "osteoporosis" OR "risk of fractures") and it retrieved 80 articles. After screening, 67 papers were selected for full-text revision. After applying the inclusion and exclusion criteria, 30 studies were excluded and 37 studies were selected for the present systematic review.
In relation to FishDiet, positive effects were observed in 6915 subjects (97.8%) (Mexico) and no significant effects were observed in 156 subjects (2.2%) (Brazil). No adverse effects in relation to FishDiet were observed in these studies. In three studies [34,39,46] conducted in Australia, on MeatDiet, no positive effects were observed in relation to MeatDiet, adverse effects were observed in 1709 subjects (62.5%), while no significant effects were seen in 1024 subjects (37.5%). In relation to FishDiet, positive effects were seen in 2733 subjects (100%), with no adverse effects observed.

Discussion
The objective of this systematic review was to evaluate the impact of consumption of animal proteins (derived from fish and meat) on bone metabolism. We aimed to investigate the effects of FishDiet and MeatDiet on BMD or risk of fractures. The review included 37 clinical trials and 432,924 subjects.

The Relevant Data
This review suggests that FishDiet and Meat Diet as a dietary pattern were not associated with an increase/decrease in BMD or Risk of Fracture in 48.2% of subjects with MeatDiet and in 86.5% of subjects with FishDiet. This data was obtained adding all the subjects included in the studies with no statistical significance between the pattern "FishDiet or MeatDiet" and BMD or RF (in terms of OR or RR). These results are in accordance with a recent updated review of the literature which shows that a higher intake of animal protein is not harmful to bone, even though it was once thought that the acid generating components of a high protein diet were detrimental to bone [57].

Negative Effects and Non-Compliance to Mediterranean or Asian Diet
Negative effects on bone were observed in 2.7% of subjects of FishDiet and in 47.9% of subjects of MeatDiet. Major negative effects of MeatDiet were found in a higher number of subjects located in the Netherlands, Greece, Germany, Italy, Norway, the UK and Spain who do not sustain a Mediterranean diet (92.7%); in Korea (27.1%); in Brazil and Mexico (96.4%); and in Australia (62.5%). Firstly, this may be explained by the higher saturated fat content found in red meat compared to other animal protein sources. Saturated fat has been shown to have detrimental effects on bone health in adults, possibly by reducing calcium absorption from the intestine, reducing bone formation, and enhancing bone resorption.
However, several studies suggest that the positive effect of protein intake on bone health may be enhanced by greater calcium intake, perhaps because of increased absorption of calcium [58][59][60][61]. Secondly, as indicated in Figure 3, subjects with MeatDiet were associated with a non-compliance to Mediterranean or Asian diet. As suggested by Maurer et al., a Western-type diet is associated with osteoporosis and calcium nephrolithiasis [62]. Based on observations that calcium retention and inhibition of bone resorption result from alkali administration, it is assumed that the acid load inherent in this diet is responsible for increased bone resorption and calcium loss from bone [63].
As regards the situation in Europe, as suggested by the "Framingam study", the individuals in the processed protein foods cluster (high percentage of protein intake from cheese, processed meat, sweet baked products, pizza and French fries, snacks and white grains) presented with lower BMD compared to other clusters [64]. Processed meat is also high in sodium. High sodium diets have been shown to alter calcium metabolism and to increase bone resorption in postmenopausal women [65,66]. According to our results on the effects of meat consumption, conspicuous differences are observed in Europe regarding the incidence of osteoporosis, the lowest incidence being reported in the Mediterranean area. In fact, lower negative effects were reported in the Greek population due to their highest adherence to a Mediterranean diet [6,67].

The Positive Effects of FishDiet: Why and What?
The 11% of the subjects associated to FishDiet showed an increase of BMD and a decrease of risk of fractures. The highest positive effects were found in Asia (59.9%) (South Korea, China and Japan), North America (57.5%) (USA and Canada) and South America (97.8%) (Mexico). The fewest negative effects were reported in Australia. Fish and sea-fish potentially have a positive role in BMD mainly due to the well-known anti-inflammatory effects of n-3 fatty acids (FAs). Both pro-inflammatory and anti-inflammatory cytokines and hormones interact to regulate osteoblast and osteoclast differentiation and activity [68]. A beneficial interaction between calcium and n-3 FAs is plausible based on work done mainly in animal and in vitro models suggesting up-regulation of duodenal calcium absorption and decreased calcium excretion with treatment of n-3 FAs [69]. An interesting study by Kontogianni et al. (2009) described in a sample of adult Greek women that adherence to a dietary pattern close to the Mediterranean diet was positively related to BMD, suggesting the potential bone-preserving properties of this pattern through adult life [47].
As regards to the Asian Diet, the Asian population, whose soy and fish intake is higher compared to Western populations, shows a significantly lower incidence of osteoporotic fracture. In fact, several meta-analysis have revealed that supplementation of soy isoflavones with omega 3 improve bone health status in women [70].

Limitation of This Study
This study includes several limitations. The lack of studies performed in other parts of the world such as Africa, Russia, and large parts of Europe may also represent a limitation of our study. The interpretation of summary statistics of data presents some limitations related to methodological issues of the studies included. These studies come from different research environments and use different methods of assessment (such as the variation, over time, of BMD, Risk Ratio, etc.).
Finally, another limitation is that the assessment of bone status in terms of BMD variation or Risk of fractures, often used different adjustment methods, and some did not provide the adjusted rates.

Conclusions
This study suggests that protein intake from fish or meat is not harmful to bone. In particular, negative effects on bone linked to fish dietary pattern are almost null. As regards to meat dietary patterns, negative effects on bone were associated with meat consumption in the context of a Western diet but not in Mediterranean and Asian Diets.