Yogurt Consumption and Impact on Bone Health

CHAPTER

YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

29

René Rizzoli, Emmanuel Biver Geneva University Hospitals, Geneva, Switzerland

29.1 INTRODUCTION Fermented dairy products, particularly cheese, have been used for thousands of years to preserve milk, to make it more transportable, less perishable, readily available, and more digestible, because of lactose breakdown during the fermentation process. This processing of milk was an important development in early agriculture, which can be dated back to the sixth millennium BC in Northern Europe (Salque et al., 2013). Through their content in calcium, phosphorus, proteins, and micronutrients, dairy products play a role in the control of bone homeostasis (Table 29.1) (Rizzoli, 2014). Fermented milk products like yogurts may provide larger amounts of these nutrients than the same volume of plain milk because of enrichment with milk powder to make the yogurt matrix denser. Prebiotics like inulin, which may be added to yogurt to also increase matrix density, as well as probiotics, can influence intestinal calcium absorption and/or bone metabolism (Weaver, 2015). Finally, yogurt consumption may ensure a more regular ingestion of milk products because of various flavors and sweetness.

29.2 BONE HOMEOSTASIS At a given age, bone mass is determined by the amount of bone accumulated at the end of skeletal growth, the so-called peak bone mass, and by the amount of bone lost subsequently (Rizzoli et al., 2010). There is a large body of evidence linking nutritional intakes, particularly calcium and protein, to bone growth, and to bone loss later in life, both influencing fracture risk. Optimal dietary calcium and protein intakes are necessary for bone homeostasis during growth as well as in the elderly. Dairy products may represent the best dietary sources of calcium due to the high content, high absorptive rate, and relatively low cost (Rizzoli, 2014). For example, 250 mg of calcium may be obtained from a 200 mL glass of milk, a 180 g serving of yogurt, or 30 g of hard cheese. To attain from other dietary sources a calcium supply equivalent to one serving of dairy, 5–6 servings of vegetables (dark green leaves or legumes) or 10–12 servings of whole grain or refined grain foods would be required. Dairy products may represent up to 52%–65% of the RDI of calcium and 20%–28% of the protein requirement (Rizzoli, 2014).

Yogurt in Health and Disease Prevention. http://dx.doi.org/10.1016/B978-0-12-805134-4.00029-8 Copyright © 2017 Elsevier Inc. All rights reserved.

507

508

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

Table 29.1  Nutrients Content per 100 g Source

Calcium (mg)

Phosphorus (mg)

Protein (g)

Milk, 3.7% fat Milk, skimmed Yogurt, plain low fat Yogurt, fruit low fat Parmesan cheese Swiss cheese Cheddar cheese Cottage cheese Cream cheese Ice cream, vanilla

119 122 183 169 110 791 721 86 98 128

93 101 144 133 729 567 512 190 106 105

3.3 3.4 5.3 4.9 38 26.9 24.9 10.3 5.9 3.5

Depending on the preparation (no addition of milk powder), yogurt may have calcium, phosphorus, and protein contents similar to plain milk. Adapted from Rizzoli, R., Bischoff-Ferrari, H., Dawson-Hughes, B., Weaver, C., 2014. Nutrition and bone health in women after the menopause. Women’s Health 10, 599–608.   

29.3 BONE MASS ACCRUAL: ROLE OF DIETARY CALCIUM AND PROTEIN Peak bone mass is achieved for most parts of the skeleton by the end of the second decade of life (Rizzoli et al., 2010). Body mineral mass nearly doubles during puberty, through an increase in the size of the skeleton, with minor changes in volumetric bone density. Puberty is the period during which the sex difference in bone mass observed in adult subjects becomes fully expressed. This gender difference in bone mass mainly results from a greater increase in bone size (Seeman, 2003). It is estimated that a 10% increase in peak bone mass could reduce the risk of osteoporotic fractures during adult life by 50%, or to be equivalent to a 14-year delay in the occurrence of menopause (Hernandez et al., 2003). A recent evidence-based review of the literature since 2000 of factors influencing peak bone mass development concludes that good evidence is available for a positive role of dairy consumption, whilst the best evidence is for positive effects of calcium intake and physical activity (Weaver et al., 2016). In addition, a systematic review of observational studies that examined the association between dietary intake and childhood fractures concludes that fracture risk appears to be associated with milk avoidance (Handel et al., 2015).

29.3.1 CALCIUM AND BONE MASS ACCRUAL Calcium plays major roles in the regulation of various cell functions, in the central and peripheral nervous systems, in muscle, and in exo-/endocrine gland function (Rizzoli, 2008). In addition, this cation is implicated in the process of bone mineralization, by the formation of hydroxyapatite crystals. Several prospective randomized, double-blind, placebo-controlled intervention trials have concluded that calcium supplements increase bone mass gain, although the magnitude of the calcium

29.3  Bone Mass Accrual: Role of Dietary Calcium and Protein

509

effects appears to vary according to the skeletal sites examined, the stage of pubertal maturation at the time of the intervention, and the spontaneous dietary calcium intake (Bonjour et al., 1997; Chevalley et al., 2005a,b). The calcium effects could be modulated by an interaction with vitamin D receptor genotype (Ferrari et al., 1998). The positive effects of calcium supplementation have been ascribed to a reduction in bone remodeling. Some effects of calcium supplements on bone modeling have also been described in addition to bone remodeling (Bonjour et al., 1997, 2001a,b; Cadogan et al., 1997; Prentice et al., 2005). The influence on bone modeling has been illustrated for instance in a double-blind, placebo-controlled study in which calcium supplementation in prepubertal girls was associated with changes in projected scanned bone area and in standing height (Bonjour et al., 1997). Thus, calcium could enhance both the longitudinal and the cross-sectional growth of the bone. When bone mineral density was measured 7.5 years after the end of calcium supplementation, i.e., in young adult girls, it appeared that menarche occurred earlier in the calcium-supplemented group, and that persistent effects of calcium were mostly detectable in those subjects with an earlier puberty (Chevalley et al., 2005a,b). Most of the studies carried out in children and adolescents have shown that supplementation with either calcium or dairy foods over 1 to 3 years enhances the rate of bone mineral acquisition, compared with unsupplemented (or placebo) control groups. In general, these intervention trials increased the usual calcium intake of the supplemented children from about 600–800 mg/day to around 1000– 1300 mg/day. In a meta-analysis of 19 calcium intervention studies involving 2859 children, with doses of calcium supplementation varying between 300 and 1200 mg/day, and various sources of calcium (from calcium citrate-malate, calcium carbonate, calcium phosphate, calcium lactate-gluconate, calcium phosphate milk extract, or milk minerals), standardized mean differences (effect size) of calcium supplementation was 0.14 for whole body bone mineral content and upper limb bone mineral density (Winzenberg et al., 2006). At the upper limb, the effect persisted up to 18 months after cessation of calcium supplementation.

29.3.2 DIETARY PROTEIN AND BONE MASS ACCRUAL In children and adolescents, protein intakes influence bone growth and bone mass accumulation (Rizzoli et al., 2010). In “well” nourished children and adolescents, variations in the protein intake within the “normal” range can have a significant effect on skeletal growth and thereby modulate the genetic potential in peak bone mass attainment. Bone mineral density (BMD)/bone mineral content (BMC) changes in prepubertal boys are positively associated with spontaneous protein intake (Rizzoli et al., 2010). Furthermore, higher protein intakes interact with the positive influence of physical activity on proximal femur BMD in prepubertal boys (Chevalley et al., 2008) and also on bone microstructure in postpubertal boys (Chevalley et al., 2014) and in young adult males (Chevalley et al., 2016). Nutritional environmental factors appear to affect bone accumulation at specific periods during infancy and adolescence. In a prospective cohort of female and male adolescents aged 9–19 years, we found a positive correlation between lumbar and femoral bone mass yearly gain and calcium or protein intake (Bonjour et al., 2001a,b). This correlation was mainly detectable in prepubertal adolescents but not in those having reached a peri- or postpubertal stage. It remained statistically significant after adjustment for spontaneous calcium intakes. In another prospective longitudinal study in healthy children and adolescents of both genders, between the ages of 6 and 18, a positive association was found between long-term protein intakes, on one hand, and periosteal circumferences, cortical area, bone mineral content, and with a calculated strength strain index, on the other hand (Alexy et al., 2005). In this cohort

510

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

with a Western-style diet, protein intakes were around 2 g/kg body weight per day in prepubertal children, whereas they were around 1.5 g/kg per day in pubertal individuals. Overall, protein intakes accounted for 3%–4% of the bone parameters variance. It is quite possible that protein intake could be to a large extent related to growth requirement during childhood and adolescence. Only intervention studies could reliably address this question. To our knowledge, there is no large randomized controlled trial having specifically tested the effects of dietary protein supplements on bone mass accumulation, except for milk or dairy products. In addition to calcium, phosphorus, calories, and vitamins, 1 L of milk provides 32–35 g of proteins, mostly casein, but also whey proteins, which contain numerous growth-promoting elements. In growing children, long-term milk avoidance is associated with smaller stature and lower bone mineral mass, either at specific sites or at the whole body levels (Opotowsky and Bilezikian, 2003). Low milk intake during childhood and/or adolescence increases the risk of fracture before puberty (a 2.6-fold higher risk has been reported), and possibly later in life (Goulding et al., 2004). In a 7-year observational study, there was a positive influence of dairy product consumption on bone mineral density at the spine, hip, and forearm in adolescents, leading thereby to a higher peak bone mass (Matkovic et al., 2004). In this study, higher dairy product intakes were associated with greater total and cortical proximal radius cross-sectional area. Whereas calcium supplements could influence volumetric BMD, thus the remodeling process, dairy products may have an additional effect on bone growth and periosteal bone expansion, i.e., an influence on modeling. In agreement with this observation, milk consumption frequency and milk intake at ages 5–12 and 13–17 years were significant predictors of the height of 12–18 year-old adolescents, studied in the National Health and Nutrition Examination Survey 1999–2002 (Wiley, 2005). The earliest milk intervention controlled studies are by Orr (1928) and Leighton and Clark (1929). In British schoolchildren, 400–600 mL/day of milk had a positive effect on height gain over a 7-month period. Numerous intervention trials have demonstrated a favorable influence of dairy products on bone health during childhood and adolescence (Cadogan et al., 1997; Cheng et al., 2005). In an open randomized intervention-controlled trial, 568 mL/day milk supplement for 18 months in 12-year-old girls (Cadogan et al., 1997) provided an additional 420 mg/day calcium and 14 g/day protein intakes. In the milk-supplemented group, serum IGF-1 levels were 17% significantly higher. Compared to the control group, the intervention group had greater increases of whole body bone mineral density and bone mineral content. In another study, cheese supplements appeared to be more beneficial for cortical bone accrual than a similar amount of calcium supplied in the form of tablets (Cheng et al., 2005). The positive influence of milk on cortical bone thickness may be related to an effect on the modeling process, since metacarpal periosteal diameter was significantly increased in Chinese children receiving milk supplements (Zhu et al., 2005).

29.4 AGE-ASSOCIATED BONE LOSS AND FRACTURES: ROLE OF CALCIUM AND PROTEIN 29.4.1 CALCIUM Calcium and vitamin D supplements have been reported to reduce nonvertebral and hip fracture risk in older people (Chapuy et al., 1992). Two subsequently published large trials have challenged these

29.4  AGE-ASSOCIATED BONE LOSS AND FRACTURES

511

conclusions by being unable to detect significant antifracture effect in calcium- and vitamin D-treated individuals (Grant et al., 2005; Jackson et al., 2006). Neither study has targeted individuals at high fracture risk, and in both the adherence was poor. The clinical trial of the Women’s Health Initiative was carried out in healthy postmenopausal women with an average calcium intake above 1000 mg/day, 80% of whom were under 70 years of age. When the analysis was carried out in only the compliant subjects, a significant (29%) reduction in hip fracture risk compared to the placebo group was found (Jackson et al., 2006). A meta-analysis of nine randomized clinical trials, including a total of 53,260 patients, found that supplementation with vitamin D alone was not sufficient to significantly reduce the risk of hip fracture in postmenopausal women, whereas combined supplementation with vitamin D and calcium reduced the risk of hip fracture by 28% and the risk of nonvertebral fracture by 23% compared to supplementation with vitamin D alone (Boonen et al., 2007). Calcium supplements may be associated with mild gastrointestinal disturbances such as constipation, flatulence, nausea, gastric pain, and diarrhea. Calcium may also interfere with the intestinal absorption of iron and zinc. Recently it has been reported that calcium supplementation in healthy postmenopausal women was associated with an increased risk of cardiovascular events (Bolland et al., 2010), mainly in those with a high spontaneous calcium intake. The risk was not affected if calcium was from dietary origin. An expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases and the International Foundation for Osteoporosis reanalyzed the benefit/risk ratio of calcium–vitamin D supplementation and came to the following conclusions (Harvey et al., 2016): (1) calcium and vitamin D lead to a modest reduction in fracture risk; (2) there is no argument for providing calcium alone; (3) side effects of calcium supplementation include renal stones and gastrointestinal symptoms; (4) vitamin D rather than calcium may reduce fall risk; and (5) there is no current convincing evidence for an increased cardiovascular risk. They conclude that calcium–vitamin D supplementation can be recommended to subjects at high risk of calcium and vitamin D insufficiencies and in patients receiving antiosteoporosis pharmacological treatments.

29.4.2 PROTEIN Virtually all studies assessing a possible association between bone mass at various skeletal sites and spontaneous protein have found a positive relationship in children or adolescents (Chevalley et al., 2008; Alexy et al., 2005), in pre- or postmenopausal women, and in men (Darling et al., 2009). Unadjusted BMD was greater in the group with the higher protein intake in a large series of data collected in the frame of the Study of Osteoporotic Fracture (Sellmeyer et al., 2001). Dietary protein accounted for as much as 2% of bone mineral mass variance. A longitudinal follow-up in the frame of the Framingham study has demonstrated that the rate of bone mineral loss was inversely correlated to dietary protein intake (Hannan et al., 2000), and the risk of hip fracture tended to be lower in older adults with greater intakes of milk and milk + yogurt. The association with fracture risk was only partially explained by the effects on BMD (Sahni et al., 2014). In an analysis of dietary protein food clusters among middle-aged and older men and women, the same group found that BMD was higher in the low-fat milk cluster compared to the red meat protein food cluster and processed foods protein cluster (Mangano et al., 2015). In the large Nurses’ Health Study, a trend for a hip fracture incidence inversely related to protein intake has been reported (Feskanich et al., 1997). The same

512

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

study reported an increase of forearm fracture risk in the subjects with the highest protein intake of animal origin. In a prospective study carried out on more than 40,000 women, higher protein intake was associated with a reduced risk of hip fracture (Munger et al., 1999). The protective effect was observed with dietary protein of animal origin. In a case–control study, increasing protein intake was associated with a lower hip fracture risk of 65% in the highest quartile in the 50- to 69-year-old age class (Wengreen et al., 2004). In another study, fracture risk was increased when a high protein diet was accompanied by a low calcium intake, in agreement with the requirement of sufficient calcium intake to detect a favorable influence of dietary protein on bone (Meyer et al., 1997; Dargent-Molina et al., 2008). The review of prospective data examining the link between dairy consumption and fracture risk showed a high heterogeneity between studies, with some positive and negative studies (Rozenberg et al., 2016). It should be noted that the debate regarding the association between dairy intakes and fracture risk mainly came from the data in a cohort of Swedish women. In a meta-analysis of available data in 2010, after exclusion of this cohort, the relative risk of hip fracture for an increase of one glass of total milk intake per day in women was 0.95 (0.90–1.00), P = .049 (Bischoff-Ferrari et al., 2011). In the cohorts of Swedish women and men, there was a positive association between milk consumption and fracture risk in women (Michaëlsson et al., 2014). In contrast, there was a protective effect of soured milk and yogurt intakes on fracture risk, and the positive association between milk consumption and fracture risk was not found in men and was no more observed in women when milk consumption data were analyzed from each repeated questionnaire individually rather than using time updated exposures as in the primary analysis. Several mechanisms may be involved in the association with protein intake and bone health. A reduction in dietary protein may lead to a decline in calcium absorption and to secondary hyperparathyroidism (Kerstetter et al., 1997, 2005). A low (0.7 g/kg BW), but not a high, protein intake (2.1 g/kg), was associated with an increase in biochemical markers of bone turnover as compared with a diet containing 1.0 g/kg of protein (Kerstetter et al., 1999). It has been claimed that the source of proteins, animal versus vegetal, would differently affect calcium metabolism. This is based on the hypothesis that animal proteins would generate more sulfuric acid from sulfur-containing amino acids than a vegetarian diet. A vegetarian diet with protein derived from grains and legumes may deliver as many millimoles of sulfur per gram proteins as would a purely meat-based diet (Fenton et al., 2011). In the prospective Canadian Multicentre Osteoporosis Study there was a positive association between hip BMD changes and dairy protein intakes, with in parallel a negative association between spine BMD changes and plant protein intakes in postmenopausal women. There was no significant association with nondairy animal proteins intakes (Langsetmo et al., 2015). In this study, low-protein intake (below 15% total energy intake) was associated with increased fracture risk. A cross-sectional study in elderly women showed that peripheral cortical and trabecular bone mass assessed by QCT is positively correlated with dairy intake (Radavelli-Bagatini et al., 2014). Dietary proteins also influence both the production and action of IGF-1, particularly the growth hormone (GH)-insulin-like growth factor (IGF) system (Rizzoli, 2008). In humans, increased intake of aromatic, but not of branched-chain amino acids, is associated with increases in serum IGF-1, intestinal calcium absorption, and 24-h urinary calcium excretion, without any change in biochemical markers of bone turnover (Dawson-Hughes et al., 2007). Dairy products are particularly rich in aromatic amino acids. The restoration of the altered GH-IGF-1 system in the elderly by protein replenishment

29.5  Microbiota and Bone: Possible Mechanisms

513

is likely to favorably influence not only BMD but also muscle mass and strength, since these two variables are important determinants of the risk of falling. Intervention studies using a simple oral dietary casein-containing preparation that normalizes protein intake improve the clinical outcome after hip fracture and decrease mortality observed at 6 months (Tkatch et al., 1992; Schurch et al., 1998). It should be emphasized that a 20-g protein supplement, as administered in these studies, brought the intake from low to a level still below recommended dietary allowance (0.8 g/kg body weight), avoiding thus the risk of an excess of dietary protein. In these studies, the total length of stay in the orthopedic ward and convalescent hospital was significantly shorter in supplemented patients than in controls. In a multiple regression analysis, baseline IGF-1 concentrations, biceps muscle strength, together with protein supplements accounted for more than 30% of the variance of the length of stay in rehabilitation hospitals (r2 = 0.312, P < .0005), which was reduced by 25% in the protein-supplemented group (Schurch et al., 1998). In another controlled trial, dietary protein supplements favorably influenced bone metabolism in the elderly (Hampson et al., 2003). In a shortterm study on the kinetics and determinants of the IGF-1 response to protein supplements in a situation associated with low-baseline IGF-1 levels, such as the frail elderly, or patients with a recent hip fracture, we found that a 20 g/day protein supplement derived from dairy foods increased serum IGF-1 and IGF-binding protein-3 already by 1 week, with a maximal response by 2 weeks (Rodondi et al., 2009; Chevalley et al., 2010).

29.5 MICROBIOTA AND BONE: POSSIBLE MECHANISMS The most abundant cells (10E14) within the human body are located within the intestinal tract. This number is much higher than the number of cells in human body parenchymes (Huttenhower et al., 2012). These organisms are collectively called the gut microbiota (GM). They mostly refer to the large intestine content, but all parts of the GI tract are colonized with an increase in microorganism concentration from the duodenum to the distal colon. GM is now considered as an organ modulating the expression of genes involved in mucosal barrier function, immune system, food digestion, or energy metabolism as it is capable of fermenting undigested nutrients into short-chain fatty acids (Huttenhower et al., 2012). Various mechanisms have been proposed to link microbiota composition or production to bone metabolism.

29.5.1 INTESTINAL WALL PERMEABILITY Intestinal wall thickness and surface increases have been reported in relation to changes in microbiota (Trinidad et al., 1999; Mineo et al., 2006), leading to increases in solutes absorption. GM is also involved in digestion and release of dietary nutrients, which are then excreted in urine (Wu, 2014; Ross et al., 2013). Products from fatty acids metabolism, like short-chain fatty acids (acetate, propionate, butyrate) can directly modify local intestinal metabolism (Donohoe et al., 2011; Trinidad et al., 1996), support intestinal barrier function, and can modify bowel content pH, influencing thereby calcium availability and increasing its absorption (Weaver, 2015; Ammann et al., 1988). Since an increase in net intestinal calcium absorption can be achieved by just ingesting more calcium, a change in intestinal absorption is unlikely to account for the effects on bone metabolism.

514

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

29.5.2 ENDOCRINE PATHWAY MODIFICATIONS An increase in calcium absorption leads to a reduction in PTH production and thus decrease bone resorption. The gut endocrine system could be affected too, as germ-free (GF) animals have a lower serotonin secretion, in relation to reduced tryptophan hydroxylase-1 expression in the large intestine (Sjogren et al., 2012). Serotonin has been shown to lower bone formation (Yadav et al., 2008).

29.5.3 IMMUNE SYSTEM MODULATION GF animals, hence lacking microbiota, have immature mucosal immune systems (Macpherson and Harris, 2004). CD4 T-cells are decreased like was TNFα and IL6 production (Macpherson and Harris, 2004). GF mice have fewer CD4+ T-cells and germinal centers in the spleen, suggesting that microbiota can modulate immune system development (Macpherson and Harris, 2004). Presence of bioactive TNF alpha is necessary to detect ovariectomy-induced bone loss (Ammann et al., 1997). An association between inflammation and bone loss is well recognized. Depletion of T-cells by anti-CD4 and anti-CD8 antibodies prevents ovariectomy-induced bone loss in mice (Li et al., 2011).

29.6 EVIDENCE FOR A ROLE OF GUT MICROBIOTA IN BONE METABOLISM In GF mice of the Balb/B6 background, relative bone volume, trabecular number, and cortical area are markedly higher. In animals totally lacking GM, the osteoclasts number is reduced whilst bone formation rate is maintained, suggesting that higher bone mass and microstructure in GF mice is related to a decrease in bone resorption (Sjogren et al., 2012). When recolonized with a normal gut microbiota by 3 weeks of age, mice displayed a reduction in trabecular BMD and cortical area as compared to GF mice, together with higher levels of osteoclast precursors. Supporting a microbiota influence on bone mediated by inflammation-related bone resorption, GF animals have decreased frequency of CD4+ T-cells and CD11b+/GR 1 osteoclast precursors as well as lower bone interleukin-6 and TNFα mRNA expression. These animals displayed lower serotonin levels, but the latter were not changed upon recolonization despite normalization of bone mass, suggesting that serotonin is not the major cause of high bone mass in GF animals (Sjogren et al., 2012).

29.7 PREBIOTICS AND BONE The prebiotic inulin, which is derived from chicory roots, can be added to yogurt to increase the density of the matrix. Prebiotics are nondigestible fiber compounds that pass undigested through the upper part of the gastrointestinal tract and stimulate the growth and/or activity of bacteria that colonize the large bowel by acting as substrate for them. Prebiotics refer to galacto-oligosaccharides (GOSs), inulin, resistant starch, polydextrose, fructooligosaccharides (FOSs), xylooligosaccharides, and lactulose. Oligosaccharides are composed of 3–10 units of sugars. Their length influences the site of fermentation (Roberfroid et al., 2010). They resemble oligosaccharides occurring naturally in human milk. The mode of action implies the fermentation of fibers within the large intestine leading to the production of short-chain fatty acids such as acetate, propionate, valerate, isovalerate, or butyrate and isobutyrate. The multiple observed changes are an increase of calcium

29.7  Prebiotics and Bone

515

bioavailability (Ammann et al., 1988) through a reduction in bowel content pH (Ammann et al., 1988; Weaver et al., 2011), an increase in cecum weight and microvilli surface (Weaver et al., 2011), histone acetylation with epigenetic modulation (Bultman, 2016; Mathewson et al., 2016), as well as microbiota modifications, with an increase in the bifidobacteria species capable of metabolizing phytoestrogens (Matthies et al., 2012). Doses of GOS, FOS, fiber dextrin, inulin, agave fructans, up to 20 g/day, increase the number of bifidobacteria and lactobacilli and decrease that of coliforms. It is also possible that prebiotics have direct effects on the immune system, without metabolism (Bindels et al., 2015). At the bone level, FOS administration increases cortical and trabecular bone in mice, BMC in male rats (Garcia-Vieyra et al., 2014). Diet enriched in fibers enhances cortical thickness, cortical BMC, and trabecular BMD in rats (Weaver et al., 2011). FOSs are also associated with higher bone strength (Weaver et al., 2011). Regarding bone metabolism, agave fructans increases osteocalcin levels (GarciaVieyra et al., 2014), GOS/FOS stimulates osteoblast proliferation (Bryk et al., 2015), and FOS-inulin reduces the ratio bone resorption/bone formation in ovariectomized rats (Zafar et al., 2004). Femur and tibia breaking strength, distal femur total, and trabecular volumetric BMD, as well as proximal tibia volumetric BMD, increased in response to GOS supplementation (Weaver et al., 2011). It has been shown that onions and a mixture of vegetables decreased bone resorption, through a mechanism independent of their supply in alkali (Muhlbauer and Li, 1999; Muhlbauer et al., 2002). Though microbiota changes were not evaluated in these studies, the high-fiber content of these nutrients may have acted as prebiotics. Human sialylated milk oligosaccharides are less abundant in mother’s milk of severely stunted infants (Charbonneau et al., 2016). Human milk contains various glycans with prebiotic properties contributing to infant immune system development (He et al., 2014). Fermentation products enhance intestinal barrier function by stimulating the assembly of tight junctions (Peng et al., 2009). In a randomized controlled trial in adolescents, 8 g/day of FOS and inulin for 1 year increased whole body BMC (Abrams et al., 2005). In male adolescents, the consumption of 15 g of oligofructose per day was shown to stimulate fractional calcium absorption (van den Heuvel et al., 1999a,b). Among healthy adolescent girls aged 10–13 years, who consumed smoothie drinks twice daily supplemented or not with GOS for 3-week periods, increase in the fractional calcium absorption was observed compared with nonsupplemented controls (0.444, 0.419 vs. 0.393, respectively). The increase in absorption was greatest after 24 h, consistent with distal gut absorption (Whisner et al., 2013). Whether a small increase in fractional calcium absorption with GOS supplementation may result in a biologically significant increment in bone mineral accrual leading to higher peak bone mass in the long term remains to be demonstrated. This was accompanied by a higher amount of bifidobacteria in the stools (Whisner et al., 2013). Using a similar stable calcium absorption method, this author detected a 12% higher intestinal calcium absorption in adolescent boys and girls exposed to maize and corn fibers (Whisner et al., 2014). Soluble corn fiber increases calcium retention in postmenopausal women (Jakeman et al., 2016). In various populations of different ages from adolescents to postmenopausal women, and with various treatment durations with prebiotics, from 9 days to 1 year, higher intestinal calcium absorption was consistently detected (Holscher et al., 2015; Griffin et al., 2002; van den Heuvel et al., 1999a,b, 2000; Holloway et al., 2007). The amount of prebiotics to be ingested to produce significant bone effects is limited by the tolerance. Indeed, undigested saccharides/fibers fermentation in the large intestine may be associated with flatulence and abdominal discomfort, precluding amounts of prebiotics ingestion

516

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

sufficient to reach meaningful biological effects. In the studies by Whisner et al. (2016), this issue was addressed, and the tolerance to prebiotics amounts associated with increased calcium absorption was reported as good.

29.8 PROBIOTICS AND BONE Yogurt contains a starter bacteria consisting of Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus, and in probiotic yogurt a number of probiotic bacteria are added in addition to the starter bacteria. Another way to modify GM is to directly provide some bacteria to the GI tract, i.e., probiotics. Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. By adequate, one means an amount able to trigger the targeted effect. It depends on strain specificity, matrix, and sought targeted effect. The concentration is around 10e7 to 10e8 probiotic bacteria per gram, with serving size around 100–200 mg. Various species are considered as probiotics, such as Lactobacillus, Bifidobacterium, Escherichia, Enterococcus, and Bacillus subtilis. Yeasts like Saccharomyces have been used too. Probiotics are available in the form of yogurt, milk-based foods, powders, capsules, or solutions like ice cream and beer. Several studies investigated the influence of probiotics on bone metabolism. Lactobacillus reuteri increases femoral and vertebral BMD in male but not female intact mice (McCabe et al., 2013), prevents ovariectomy-induced bone loss (Britton et al., 2014) and type 1 diabetes–associated osteopenia (Zhang et al., 2015). These latter two models differ by the bone turnover pattern. The former is associated with an increased osteoclastic bone resorption whereas the latter is rather characterized by a low-bone formation. This would suggest that the probiotic L. reuteri is also capable of stimulating osteoblast activity, possibly by preventing TNFα suppression of Wnt10b in bone (Zhang et al., 2015). Lactobacillus paracasei prevents ovariectomy-dependent bone loss (Ohlsson et al., 2014; Chiang and Pan, 2011), together with a decrease in TNFα and IL1β expression in cortical bone. Ovariectomy-induced bone loss is also prevented by Lactobacillus helveticus fermented milk (Narva et al., 2007). The role of probiotics in attenuating bone damage induced by sex hormone deficiency has been extensively studied (Li et al., 2016). In this recent work, hypogonadal GF mice do not show bone loss like hypogonadal mice with intact gut microflora. In GF mice, there is no increase in osteoclasts in response to hypogonadism. When microflora is reintroduced in GF animals, there is a reversal of the osteoprotection observed in the absence of microflora. Estrogen deficiency alters the gut barrier function leading to endotoxemia. This does not occur in GF mice, which in addition do not have an increase in TNF alpha expressing CD4+ T-cells. In this model of hypogonadal mice, the probiotic Lactobacillus rhamnosus prevented estrogen deficiency–mediated bone loss and decreased TNFα and RANKL expression in intestine and bone marrow (Li et al., 2016). In humans, the main source of probiotics is fermented dairy products. However, with this kind of supply, the specific effects of probiotics as compared to calcium, protein phosphorus, or zinc are difficult to identify. Furthermore, there remains the problem of a sufficient amount of bacteria capable of reaching the distal part of the gastrointestinal tract. However, it has been reported that yogurt consumers had lower level of Enterobacteriaceae and higher beta-galactosidase activity, the latter and Bifidobacterium population being positively correlated to the amount of fermented products ingested (Alvaro et al., 2007). In a 12-year follow-up of the Framingham Offspring Study, yogurt intake was

29.8  Probiotics and Bone

517

associated with hip (trochanter) BMD alone. Yogurt intake showed a weak positive protective trend for hip fracture, while no other dairy groups showed a significant association (Sahni et al., 2013). During a median of 22 years, women of the Swedish Mammography Cohort with a high intake of cheese or fermented milk products compared with women with low intakes had lower mortality and fracture rates. For each serving the rate of mortality and hip fractures was reduced by 10%–15% (Michaëlsson et al., 2014). In 65-year-old women of the Geneva retiree cohort, yogurt consumers have higher lumbar spine BMD and distal tibia cortical area. Over a 3-year follow-up, women ingesting one or more yogurts per day have attenuated decrease of total hip BMD, distal radius cortical area and thickness, independently of total calcium and protein intakes (Biver et al., 2016). A number of controlled intervention trials have been conducted in adults testing the effects between fermented dairy product consumption on markers of bone activity. IGF-1 is an essential factor for longitudinal bone growth. IGF-1 can also exert anabolic effects on bone mass during adulthood. Consumption of a vitamin D and calcium-fortified soft cheese by healthy postmenopausal women increases protein intake, reduces the serum concentration of bone resorption biomarkers (TRAP 5b and CTX), and increases serum IGF-1, compatible with a nutrition-induced reduction in postmenopausal bone turnover rate (Bonjour et al., 2012). Similar findings were found in studies on elderly women using soft cheese or yogurt (Bonjour et al., 2009, 2013). Fortifying yogurt with calcium and vitamin D further reduces PTH and bone resorption markers levels (Bonjour et al., 2015). Bedtime consumption of fermented milk reduces nocturnal bone resorption (Adolphi et al., 2009). Supplementation with calcium from milk mineral has no additional effect unless inulin-type fructans and caseinphosphopeptides are added. Urinary calcium excretion increases at a constant bone resorption, suggesting a change in intestinal calcium absorption. Three servings a day of fortified milk and yogurt for 12 months induced more favorable changes in biochemical indexes of bone metabolism and BMD than calcium supplementation alone in postmenopausal women (Manios et al., 2007). Fermented, protein-fortified (12 vs. 3 g), isocaloric dairy product during 4 weeks slightly increase serum IGF-1 levels in young women with anorexia nervosa, without significant changes in bone turnover markers (Trombetti et al., 2016). From a health economic perspective, there is a potential nutrition economic impact of increased dairy consumption on osteoporotic fractures (Lotters et al., 2013). Similarly, eating one yogurt is costeffective in the general population above the age of 70 years and in all age groups in women with low BMD or prevalent vertebral fracture. The daily intake of two yogurts is cost-effective above 80 years in the general population and above 70 years in the two groups of women at increased risk of fractures (Ethgen et al., 2016). A major problem with probiotics administration is certainly that the amount of ingested bacteria is not sufficient to modify gut microbiota composition. Indeed, in adult monozygotic tweens, two servings a day of fermented milk products containing five different species of bacteria did not modify large intestine bacterial species composition. In contrast, when the same fermented milk products were given by gavage to gnotobiotic mice, there was a rapid change (in less than 24 h) in microbiome-encoded enzymes involved in carbohydrate metabolism (McNulty et al., 2011; Rizzoli et al., 2014). In the same study, Bifidobacterium animalis, ssp. lactis upregulated a locus involved in xylooligosaccharides catabolism in both mice and human metatranscriptome. Some issues remain to be further elucidated with pre- and probiotics. The doses in terms of both efficacy and tolerance are crucial factors. Timing and duration of administration should be further studied, as well as the offset of the effects upon pre- or probiotics discontinuation.

518

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

29.9 CONCLUSION Besides its effects on body weight or control of type 2 diabetes, yogurt consumption positively influences bone growth and bone homeostasis through different mechanisms involving intakes of key nutrients such as calcium, phosphorus, and proteins, as well as potentially pre- and probiotics. In this respect, gut microbiota may be implicated. Bone mass accrual, bone homeostasis, and attenuation of sex hormone deficiency-induced bone loss seem to benefit from pre- or probiotics ingestion, which modifies microbiota composition and metabolism.

REFERENCES Abrams, S.A., Griffin, I.J., Hawthorne, K.M., Liang, L., Gunn, S.K., Darlington, G., Ellis, K.J., 2005. A combination of prebiotic short- and long-chain inulin-type fructans enhances calcium absorption and bone mineralization in young adolescents. Am. J. Clin. Nutr. 82, 471–476. Adolphi, B., Scholz-Ahrens, K.E., de Vrese, M., Acil, Y., Laue, C., Schrezenmeir, J., 2009. Short-term effect of bedtime consumption of fermented milk supplemented with calcium, inulin-type fructans and caseinphosphopeptides on bone metabolism in healthy, postmenopausal women. Eur. J. Nutr. 48, 45–53. Alexy, U., Remer, T., Manz, F., Neu, C.M., Schoenau, E., 2005. Long-term protein intake and dietary potential renal acid load are associated with bone modeling and remodeling at the proximal radius in healthy children. Am. J. Clin. Nutr. 82, 1107–1114. Alvaro, E., Andrieux, C., Rochet, V., Rigottier-Gois, L., Lepercq, P., Sutren, M., Galan, P., Duval, Y., Juste, C., Dore, J., 2007. Composition and metabolism of the intestinal microbiota in consumers and non-consumers of yogurt. Br. J. Nutr. 97, 126–133. Ammann, P., Rizzoli, R., Fleisch, H., 1988. Influence of the disaccharide lactitol on intestinal absorption and body retention of calcium in rats. J. Nutr. 118, 793–795. Ammann, P., Rizzoli, R., Bonjour, J.P., Bourrin, S., Meyer, J.M., Vassalli, P., Garcia, I., 1997. Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency. J. Clin. Invest. 99, 1699–1703. Bindels, L.B., Delzenne, N.M., Cani, P.D., Walter, J., 2015. Towards a more comprehensive concept for prebiotics. Nat. Rev. Gastroenterol. Hepatol. 12, 303–310. Bischoff-Ferrari, H.A., Dawson-Hughes, B., Baron, J.A., et al., 2011. Milk intake and risk of hip fracture in men and women: a meta-analysis of prospective cohort studies. J. Bone Miner. Res. 26, 833–839. Biver, E., Durosier-Izart, C., Merminod, F., Chevalley, T., Ferrari, S., Rizzoli, R., 2016. Yogurt consumption is associated with attenuated cortical bone loss independently of total calcium and protein intakes and physical activity in postmenopausal women. J. Bone Miner. Res. 31 (Suppl. 1), S36. Bolland, M.J., Avenell, A., Baron, J.A., Grey, A., MacLennan, G.S., Gamble, G.D., Reid, I.R., 2010. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341, c3691. Bonjour, J.P., Carrie, A.L., Ferrari, S., Clavien, H., Slosman, D., Theintz, G., Rizzoli, R., 1997. Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. J. Clin. Invest. 99, 1287–1294. Bonjour, J.P., Chevalley, T., Ammann, P., Slosman, D., Rizzoli, R., 2001a. Gain in bone mineral mass in prepubertal girls 3.5 years after discontinuation of calcium supplementation: a follow-up study. Lancet 358, 1208–1212. Bonjour, J.P., Ammann, P., Chevalley, T., Rizzoli, R., 2001b. Protein intake and bone growth. Can. J. Appl. Physiol. – Revue canadienne de physiologie appliquee (Suppl. 26), S153–S166. Bonjour, J.P., Benoit, V., Pourchaire, O., Ferry, M., Rousseau, B., Souberbielle, J.C., 2009. Inhibition of markers of bone resorption by consumption of vitamin D and calcium-fortified soft plain cheese by institutionalised elderly women. Br. J. Nutr. 102, 962–966.

References

519

Bonjour, J.P., Benoit, V., Rousseau, B., Souberbielle, J.C., 2012. Consumption of vitamin D- and calcium-fortified soft white cheese lowers the biochemical marker of bone resorption TRAP 5b in postmenopausal women at moderate risk of osteoporosis fracture. J. Nutr. 142, 698–703. Bonjour, J.P., Benoit, V., Payen, F., Kraenzlin, M., 2013. Consumption of yogurts fortified in vitamin D and calcium reduces serum parathyroid hormone and markers of bone resorption: a double-blind randomized controlled trial in institutionalized elderly women. J. Clin. Endocrinol. Metab. 98, 2915–2921. Bonjour, J.P., Benoit, V., Atkin, S., Walrand, S., 2015. Fortification of yogurts with vitamin D and calcium enhances the inhibition of serum parathyroid hormone and bone resorption markers: a double blind randomized controlled trial in women over 60 living in a community dwelling home. J. Nutr. Health Aging 19, 563–569. Boonen, S., Lips, P., Bouillon, R., Bischoff-Ferrari, H.A., Vanderschueren, D., Haentjens, P., 2007. Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J. Clin. Endocrinol. Metab. 92, 1415–1423. Britton, R.A., Irwin, R., Quach, D., Schaefer, L., Zhang, J., Lee, T., Parameswaran, N., McCabe, L.R., 2014. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J. Cell. Physiol. 229, 1822–1830. Bryk, G., Coronel, M.Z., Lugones, C., Mandalunis, P., Rio, M.E., Gualtieri, A.F., de Portela, M.L., Zeni, S.N., 2015. Effect of a mixture of GOS/FOS® on calcium absorption and retention during recovery from protein malnutrition: experimental model in growing rats. Eur. J. Nutr. Bultman, S.J., 2016. Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol. Nutr. Food Res. Cadogan, J., Eastell, R., Jones, N., Barker, M.E., 1997. Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. BMJ 315, 1255–1260. Chapuy, M.C., Arlot, M.E., Duboeuf, F., Brun, J., Crouzet, B., Arnaud, S., Delmas, P.D., Meunier, P.J., 1992. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N. Engl. J. Med. 327, 1637–1642. Charbonneau, M.R., O’Donnell, D., Blanton, L.V., et al., 2016. Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell 164, 859–871. Cheng, S., Lyytikainen, A., Kroger, H., et al., 2005. Effects of calcium, dairy product, and vitamin D supplementation on bone mass accrual and body composition in 10–12-y-old girls: a 2-y randomized trial. Am. J. Clin. Nutr. 82, 1115–1126. Chevalley, T., Bonjour, J.P., Ferrari, S., Hans, D., Rizzoli, R., 2005a. Skeletal site selectivity in the effects of calcium supplementation on areal bone mineral density gain: a randomized, double-blind, placebo-controlled trial in prepubertal boys. J. Clin. Endocrinol. Metab. 90, 3342–3349. Chevalley, T., Rizzoli, R., Hans, D., Ferrari, S., Bonjour, J.P., 2005b. Interaction between calcium intake and menarcheal age on bone mass gain: an eight-year follow-up study from prepuberty to postmenarche. J. Clin. Endocrinol. Metab. 90, 44–51. Chevalley, T., Bonjour, J.P., Ferrari, S., Rizzoli, R., 2008. High-protein intake enhances the positive impact of physical activity on BMC in prepubertal boys. J. Bone Miner. Res. 23, 131–142. Chevalley, T., Hoffmeyer, P., Bonjour, J.P., Rizzoli, R., 2010. Early serum IGF-I response to oral protein supplements in elderly women with a recent hip fracture. Clin. Nutr. 29, 78–83. Chevalley, T., Bonjour, J.P., van Rietbergen, B., Ferrari, S., Rizzoli, R., 2014. Tracking of environmental determinants of bone structure and strength development in healthy boys: an eight-year follow up study on the positive interaction between physical activity and protein intake from prepuberty to mid-late adolescence. J. Bone Miner. Res. 29, 2182–2192. Chevalley, T., Bonjour, J.P., Audet, M.C., Merminod, F., van Rietbergen, B., Rizzoli, R., Ferrari, S., November 1, 2016. Prepubertal impact of protein intake and physical activity on weight bearing peak bone mass and strength in males. J. Clin. Endocrinol. Metab. jc20162449 [Epub ahead of print]. Chiang, S.S., Pan, T.M., 2011. Antiosteoporotic effects of Lactobacillus-fermented soy skim milk on bone mineral density and the microstructure of femoral bone in ovariectomized mice. J. Agric. Food Chem. 59, 7734–7742.

520

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

Dargent-Molina, P., Sabia, S., Touvier, M., Kesse, E., Breart, G., Clavel-Chapelon, F., Boutron-Ruault, M.C., 2008. Proteins, dietary acid load, and calcium and risk of postmenopausal fractures in the E3N French women prospective study. J. Bone Miner. Res. 23, 1915–1922. Darling, A.L., Millward, D.J., Torgerson, D.J., Hewitt, C.E., Lanham-New, S.A., 2009. Dietary protein and bone health: a systematic review and meta-analysis. Am. J. Clin. Nutr. 90, 1674–1692. Dawson-Hughes, B., Harris, S.S., Rasmussen, H.M., Dallal, G.E., 2007. Comparative effects of oral aromatic and branched-chain amino acids on urine calcium excretion in humans. Osteoporos. Int. 18, 955–961. Donohoe, D.R., Garge, N., Zhang, X., Sun, W., O’Connell, T.M., Bunger, M.K., Bultman, S.J., 2011. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526. Ethgen, O., Hiligsmann, M., Burlet, N., Reginster, J.Y., 2016. Cost-effectiveness of personalized supplementation with vitamin D-rich dairy products in the prevention of osteoporotic fractures. Osteoporos. Int. 27, 301–308. Fenton, T.R., Tough, S.C., Lyon, A.W., Eliasziw, M., Hanley, D.A., 2011. Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill’s epidemiologic criteria for causality. Nutr. J. 10, 41. Ferrari, S., Rizzoli, R., Manen, D., Slosman, D., Bonjour, J.P., 1998. Vitamin D receptor gene start codon polymorphisms (FokI) and bone mineral density: interaction with age, dietary calcium, and 3′-end region polymorphisms. J. Bone Miner. Res. 13, 925–930. Feskanich, D., Willett, W.C., Stampfer, M.J., Colditz, G.A., 1997. Milk, dietary calcium, and bone fractures in women: a 12-year prospective study. Am. J. Public Health 87, 992–997. Garcia-Vieyra, M.I., Del Real, A., Lopez, M.G., 2014. Agave fructans: their effect on mineral absorption and bone mineral content. J. Med. Food 17, 1247–1255. Goulding, A., Rockell, J.E., Black, R.E., Grant, A.M., Jones, I.E., Williams, S.M., 2004. Children who avoid drinking cow’s milk are at increased risk for prepubertal bone fractures. J. Am. Diet. Assoc. 104, 250–253. Grant, A.M., Avenell, A., Campbell, M.K., et al., 2005. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 365, 1621–1628. Griffin, I.J., Davila, P.M., Abrams, S.A., 2002. Non-digestible oligosaccharides and calcium absorption in girls with adequate calcium intakes. Br. J. Nutr. 87 (Suppl. 2), S187–S191. Hampson, G., Martin, F.C., Moffat, K., Vaja, S., Sankaralingam, S., Cheung, J., Blake, G.M., Fogelman, I., 2003. Effects of dietary improvement on bone metabolism in elderly underweight women with osteoporosis: a randomised controlled trial. Osteoporos. Int. 14, 750–756. Handel, M.N., Heitmann, B.L., Abrahamsen, B., 2015. Nutrient and food intakes in early life and risk of childhood fractures: a systematic review and meta-analysis. Am. J. Clin. Nutr. 102, 1182–1195. Hannan, M.T., Tucker, K.L., Dawson-Hughes, B., Cupples, L.A., Felson, D.T., Kiel, D.P., 2000. Effect of dietary protein on bone loss in elderly men and women: the Framingham Osteoporosis Study. J. Bone Miner. Res. 15, 2504–2512. Harvey, N.C., Biver, E., Kaufman, J.M., et al., 2016. The role of calcium supplementation in healthy musculoskeletal ageing : an expert consensus meeting of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the International Foundation for Osteoporosis (IOF). Osteoporos. Int. He, Y., Liu, S., Leone, S., Newburg, D.S., 2014. Human colostrum oligosaccharides modulate major immunologic pathways of immature human intestine. Mucosal Immunol. 7, 1326–1339. Hernandez, C.J., Beaupre, G.S., Carter, D.R., 2003. A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos. Int. 14, 843–847. Holloway, L., Moynihan, S., Abrams, S.A., Kent, K., Hsu, A.R., Friedlander, A.L., 2007. Effects of oligofructoseenriched inulin on intestinal absorption of calcium and magnesium and bone turnover markers in postmenopausal women. Br. J. Nutr. 97, 365–372.

References

521

Holscher, H.D., Caporaso, J.G., Hooda, S., Brulc, J.M., Fahey Jr., G.C., Swanson, K.S., 2015. Fiber supplementation influences phylogenetic structure and functional capacity of the human intestinal microbiome: follow-up of a randomized controlled trial. Am. J. Clin. Nutr. 101, 55–64. Huttenhower, C., et al., 2012. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214. Jackson, R.D., LaCroix, A.Z., Gass, M., et al., 2006. Calcium plus vitamin D supplementation and the risk of fractures. N. Engl. J. Med. 354, 669–683. Jakeman, S.A., Henry, C.N., Martin, B.R., McCabe, G.P., McCabe, L.D., Jackson, G.S., Peacock, M., Weaver, C.M., 2016. Soluble corn fiber increases bone calcium retention in postmenopausal women in a dose-dependent manner: a randomized crossover trial. Am. J. Clin. Nutr. 104, 837–843. Kerstetter, J.E., Caseria, D.M., Mitnick, M.E., Ellison, A.F., Gay, L.F., Liskov, T.A., Carpenter, T.O., Insogna, K.L., 1997. Increased circulating concentrations of parathyroid hormone in healthy, young women consuming a protein-restricted diet. Am. J. Clin. Nutr. 66, 1188–1196. Kerstetter, J.E., Mitnick, M.E., Gundberg, C.M., Caseria, D.M., Ellison, A.F., Carpenter, T.O., Insogna, K.L., 1999. Changes in bone turnover in young women consuming different levels of dietary protein. J. Clin. Endocrinol. Metab. 84, 1052–1055. Kerstetter, J.E., O’Brien, K.O., Caseria, D.M., Wall, D.E., Insogna, K.L., 2005. The impact of dietary protein on calcium absorption and kinetic measures of bone turnover in women. J. Clin. Endocrinol. Metab. 90, 26–31. Langsetmo, L., Barr, S.I., Berger, C., et al., 2015. Associations of protein intake and protein source with bone mineral density and fracture risk: a population-based cohort study. J. Nutr. Health Aging 19, 861–868. Leighton, G., Clark, M.L., 1929. Milk consumption and the growth of school children: second preliminary report on tests to the Scottish board of health. Br. Med. J. 1, 23–25. Li, J.Y., Tawfeek, H., Bedi, B., Yang, X., Adams, J., Gao, K.Y., Zayzafoon, M., Weitzmann, M.N., Pacifici, R., 2011. Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc. Nat. Acad. Sci. U.S.A. 108, 768–773. Li, J.Y., Chassaing, B., Tyagi, A.M., et al., 2016. Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics. J. Clin. Endocrinol. Metab. 126, 2049–2063. Lotters, F.J., Lenoir-Wijnkoop, I., Fardellone, P., Rizzoli, R., Rocher, E., Poley, M.J., 2013. Dairy foods and osteoporosis: an example of assessing the health-economic impact of food products. Osteoporos. Int. 24, 139–150. Macpherson, A.J., Harris, N.L., 2004. Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4, 478–485. Mangano, K.M., Sahni, S., Kiel, D.P., Tucker, K.L., Dufour, A.B., Hannan, M.T., 2015. Bone mineral density and protein-derived food clusters from the Framingham Offspring Study. J. Acad. Nutr. Diet. 115, 1605–1613 e1601. Manios, Y., Moschonis, G., Trovas, G., Lyritis, G.P., 2007. Changes in biochemical indexes of bone metabolism and bone mineral density after a 12-mo dietary intervention program: the Postmenopausal Health Study. Am. J. Clin. Nutr. 86, 781–789. Mathewson, N.D., Jenq, R., Mathew, A.V., et al., 2016. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat. Immunol. 17, 505–513. Matkovic, V., Landoll, J.D., Badenhop-Stevens, N.E., Ha, E.Y., Crncevic-Orlic, Z., Li, B., Goel, P., 2004. Nutrition influences skeletal development from childhood to adulthood: a study of hip, spine, and forearm in adolescent females. J. Nutr. 134, 701s–705s. Matthies, A., Loh, G., Blaut, M., Braune, A., 2012. Daidzein and genistein are converted to equol and 5-hydroxyequol by human intestinal Slackia isoflavoniconvertens in gnotobiotic rats. J. Nutr. 142, 40–46. McCabe, L.R., Irwin, R., Schaefer, L., Britton, R.A., 2013. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J. Cell. Physiol. 228, 1793–1798. McNulty, N.P., Yatsunenko, T., Hsiao, A., et al., 2011. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice and monozygotic twins. Sci. Transl. Med. 3, 106ra106.

522

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

Meyer, H.E., Pedersen, J.I., Løken, E.B., Tverdal, A., 1997. Dietary factors and the incidence of hip fracture in middle-aged Norwegians. A prospective study. Am. J. Epidemiol. 145, 117–123. Michaëlsson, K., Wolk, A., Langenskiöld, S., Basu, S., Warensjö Lemming, E., Melhus, H., Byberg, L., 2014. Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ 349, g6015. Mineo, H., Amano, M., Minaminida, K., Chiji, H., Shigematsu, N., Tomita, F., Hara, H., 2006. Two-week feeding of difructose anhydride III enhances calcium absorptive activity with epithelial cell proliferation in isolated rat cecal mucosa. Nutrition 22, 312–320. Muhlbauer, R.C., Li, F., 1999. Effect of vegetables on bone metabolism. Nature 401, 343–344. Muhlbauer, R.C., Lozano, A., Reinli, A., 2002. Onion and a mixture of vegetables, salads, and herbs affect bone resorption in the rat by a mechanism independent of their base excess. J. Bone Miner. Res. 17, 1230–1236. Munger, R.G., Cerhan, J.R., Chiu, B.C., 1999. Prospective study of dietary protein intake and risk of hip fracture in postmenopausal women. Am. J. Clin. Nutr. 69, 147–152. Narva, M., Rissanen, J., Halleen, J., Vapaatalo, H., Vaananen, K., Korpela, R., 2007. Effects of bioactive peptide, valyl-prolyl-proline (VPP), and Lactobacillus helveticus fermented milk containing VPP on bone loss in ovariectomized rats. Ann. Nutr. Metab. 51, 65–74. Ohlsson, C., Engdahl, C., Fak, F., Andersson, A., Windahl, S.H., Farman, H.H., Moverare-Skrtic, S., Islander, U., Sjogren, K., 2014. Probiotics protect mice from ovariectomy-induced cortical bone loss. PLoS One 9, e92368. Opotowsky, A.R., Bilezikian, J.P., 2003. Racial differences in the effect of early milk consumption on peak and postmenopausal bone mineral density. J. Bone Miner. Res. 18, 1978–1988. Orr, J.B., 1928. Influence of amount of milk consumption on the rate of growth of school children. Br. Med. J. 1, 140–141. Peng, L., Li, Z.R., Green, R.S., Holzman, I.R., Lin, J., 2009. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J. Nutr. 139, 1619–1625. Prentice, A., Ginty, F., Stear, S.J., Jones, S.C., Laskey, M.A., Cole, T.J., 2005. Calcium supplementation increases stature and bone mineral mass of 16- to 18-year-old boys. J. Clin. Endocrinol. Metab. 90, 3153–3161. Radavelli-Bagatini, S., Zhu, K., Lewis, J.R., Prince, R.L., 2014. Dairy food intake, peripheral bone structure, and muscle mass in elderly ambulatory women. J. Bone Miner. Res. 29, 1691–1700. Rizzoli, R., 2008. Nutrition: its role in bone health. Best Pract. Res. Clin. Endocrinol. Metab. 22, 813–829. Rizzoli, R., 2014. Dairy products, yogurts, and bone health. Am. J. Clin. Nutr. 99, 1256S–1262S. Rizzoli, R., Bianchi, M.L., Garabedian, M., McKay, H.A., Moreno, L.A., 2010. Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly. Bone 46, 294–305. Rizzoli, R., Bischoff-Ferrari, H., Dawson-Hughes, B., Weaver, C., 2014. Nutrition and bone health in women after the menopause. Women’s Health 10, 599–608. Roberfroid, M., Gibson, G.R., Hoyles, L., et al., 2010. Prebiotic effects: metabolic and health benefits. Br. J. Nutr. 2 (Suppl. 104), S1–S63. Rodondi, A., Ammann, P., Ghilardi-Beuret, S., Rizzoli, R., 2009. Zinc increases the effects of essential amino acids-whey protein supplements in frail elderly. J. Nutr. Health Aging 13, 491–497. Ross, A.B., Pere-Trepat, E., Montoliu, I., et al., 2013. A whole-grain-rich diet reduces urinary excretion of markers of protein catabolism and gut microbiota metabolism in healthy men after one week. J. Nutr. 143, 766–773. Rozenberg, S., Body, J.J., Bruyere, O., et al., 2016. Effects of dairy products consumption on health: benefits and beliefs – a commentary from the Belgian Bone Club and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases. Calcif. Tissue Int. 98, 1–17. Sahni, S., Tucker, K.L., Kiel, D.P., Quach, L., Casey, V.A., Hannan, M.T., 2013. Milk and yogurt consumption are linked with higher bone mineral density but not with hip fracture: the Framingham Offspring Study. Arch. Osteoporos. 8, 119.

References

523

Sahni, S., Mangano, K.M., Tucker, K.L., Kiel, D.P., Casey, V.A., Hannan, M.T., 2014. Protective association of milk intake on the risk of hip fracture: results from the Framingham original cohort. J. Bone Miner. Res. 29, 1756–1762. Salque, M., Bogucki, P.I., Pyzel, J., Sobkowiak-Tabaka, I., Grygiel, R., Szmyt, M., Evershed, R.P., 2013. Earliest evidence for cheese making in the sixth millennium BC in northern Europe. Nature 493, 522–525. Schurch, M.A., Rizzoli, R., Slosman, D., Vadas, L., Vergnaud, P., Bonjour, J.P., 1998. Protein supplements increase serum insulin-like growth factor-I levels and attenuate proximal femur bone loss in patients with recent hip fracture. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 128, 801–809. Seeman, E., 2003. The structural and biomechanical basis of the gain and loss of bone strength in women and men. Endocrinol. Metab. Clin. North Am. 32, 25–38. Sellmeyer, D.E., Stone, K.L., Sebastian, A., Cummings, S.R., 2001. A high ratio of dietary animal to vegetable protein increases the rate of bone loss and the risk of fracture in postmenopausal women. Study of Osteoporotic Fractures Research Group. Am. J. Clin. Nutr. 73, 118–122. Sjogren, K., Engdahl, C., Henning, P., Lerner, U.H., Tremaroli, V., Lagerquist, M.K., Backhed, F., Ohlsson, C., 2012. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 27, 1357–1367. Tkatch, L., Rapin, C.H., Rizzoli, R., Slosman, D., Nydegger, V., Vasey, H., Bonjour, J.P., 1992. Benefits of oral protein supplementation in elderly patients with fracture of the proximal femur. J. Am. Coll. Nutr. 11, 519–525. Trinidad, T.P., Wolever, T.M., Thompson, L.U., 1996. Effect of acetate and propionate on calcium absorption from the rectum and distal colon of humans. Am. J. Clin. Nutr. 63, 574–578. Trinidad, T.P., Wolever, T.M., Thompson, L.U., 1999. Effects of calcium concentration, acetate, and propionate on calcium absorption in the human distal colon. Nutrition 15, 529–533. Trombetti, A., Carrier, E., Perroud, A., Lang, F., Herrmann, F.R., Rizzoli, R., 2016. Influence of a fermented protein-fortified dairy product on serum insulin-like growth factor-I in women with anorexia nervosa: a randomized controlled trial. Clin. Nutr. 35, 1032–1038. van den Heuvel, E.G., Muijs, T., Van Dokkum, W., Schaafsma, G., 1999a. Lactulose stimulates calcium absorption in postmenopausal women. J. Bone Miner. Res. 14, 1211–1216. van den Heuvel, E.G., Muys, T., van Dokkum, W., Schaafsma, G., 1999b. Oligofructose stimulates calcium absorption in adolescents. Am. J. Clin. Nutr. 69, 544–548. van den Heuvel, E.G., Schoterman, M.H., Muijs, T., 2000. Transgalactooligosaccharides stimulate calcium absorption in postmenopausal women. J. Nutr. 130, 2938–2942. Weaver, C.M., 2015. Diet, gut microbiome, and bone health. Curr. Osteoporos. Rep. 13, 125–130. Weaver, C.M., Martin, B.R., Nakatsu, C.H., Armstrong, A.P., Clavijo, A., McCabe, L.D., McCabe, G.P., Duignan, S., Schoterman, M.H., van den Heuvel, E.G., 2011. Galactooligosaccharides improve mineral absorption and bone properties in growing rats through gut fermentation. J. Agric. Food Chem. 59, 6501–6510. Weaver, C.M., Gordon, C.M., Janz, K.F., Kalkwarf, H.J., Lappe, J.M., Lewis, R., O’Karma, M., Wallace, T.C., Zemel, B.S., 2016. The National Osteoporosis Foundation’s position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. Osteoporos. Int. 27, 1281–1386. Wengreen, H.J., Munger, R.G., West, N.A., Cutler, D.R., Corcoran, C.D., Zhang, J., Sassano, N.E., 2004. Dietary protein intake and risk of osteoporotic hip fracture in elderly residents of Utah. J. Bone Miner. Res. 19, 537–545. Whisner, C.M., Martin, B.R., Schoterman, M.H., Nakatsu, C.H., McCabe, L.D., McCabe, G.P., Wastney, M.E., van den Heuvel, E.G., Weaver, C.M., 2013. Galacto-oligosaccharides increase calcium absorption and gut bifidobacteria in young girls: a double-blind cross-over trial. Br. J. Nutr. 110, 1292–1303. Whisner, C.M., Martin, B.R., Nakatsu, C.H., McCabe, G.P., McCabe, L.D., Peacock, M., Weaver, C.M., 2014. Soluble maize fibre affects short-term calcium absorption in adolescent boys and girls: a randomised controlled trial using dual stable isotopic tracers. Br. J. Nutr. 112, 446–456.

524

CHAPTER 29  YOGURT CONSUMPTION AND IMPACT ON BONE HEALTH

Whisner, C.M., Martin, B.R., Nakatsu, C.H., Story, J.A., MacDonald-Clarke, C.J., McCabe, L.D., McCabe, G.P., Weaver, C.M., 2016. Soluble corn fiber increases calcium absorption associated with shifts in the gut microbiome: a randomized dose-response trial in free-living pubertal females. J. Nutr. 146, 1298–1306. Wiley, A.S., 2005. Does milk make children grow? Relationships between milk consumption and height in NHANES 1999–2002. Am. J. Human Biol. 17, 425–441. Winzenberg, T., Shaw, K., Fryer, J., Jones, G., 2006. Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials. BMJ 333, 775. Wu, G.D., 2014. Diet, the gut microbiome and the metabolome in IBD. Nestle Nutr. Inst. Workshop Ser. 79, 73–82. Yadav, V.K., Ryu, J.H., Suda, N., et al., 2008. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837. Zafar, T.A., Weaver, C.M., Zhao, Y., Martin, B.R., Wastney, M.E., 2004. Nondigestible oligosaccharides increase calcium absorption and suppress bone resorption in ovariectomized rats. J. Nutr. 134, 399–402. Zhang, J., Motyl, K.J., Irwin, R., MacDougald, O.A., Britton, R.A., McCabe, L.R., 2015. Loss of bone and Wnt10b expression in male type 1 diabetic mice is blocked by the probiotic Lactobacillus reuteri. Endocrinology 156, 3169–3182. Zhu, K., Du, X., Cowell, C.T., Greenfield, H., Blades, B., Dobbins, T.A., Zhang, Q., Fraser, D.R., 2005. Effects of school milk intervention on cortical bone accretion and indicators relevant to bone metabolism in Chinese girls aged 10–12 y in Beijing. Am. J. Clin. Nutr. 81, 1168–1175.