Nutrition influence on bone health

Division of Bone Diseases
Department of Medical Specialties, Geneva
University Hospitals and Faculty of Medicine

Nutrition influence on bone health

Interview with R. Rizzoli , Switzerland

Nutritional intake is an environmental factor influencing both bone capital accumulation—which is fully achieved by the end of the second decade of life—and bone loss occurring during the second half of life. Nutrients may directly modify bone turnover, or do so indirectly through changes in calciotropic hormone levels. Studies of the association between nutrition and bone phenotypic expression may provide inconsistent results, partly because of the low accuracy and reproducibility of the various tools to assess dietary intakes. Dietary calcium and protein are nutrients affecting bone growth and age-related bone loss. An optimal intake of both is mandatory for the maintenance of bone health.

Medicographia. 2012; 34:213-220 (see French abstract on page 220)

What are the contributions of genetics and nutrition to bone mass?

More than 60% of bone mass variance is determined by genetic factors.1 Environmental factors account for the non-genetic influences, among them nutritional intakes and lifestyle. Nutrition can modulate the effects of genetics. Conversely, genetic background can determine the response to nutrition. Dietary intakes can influence bone metabolism and structure through different mechanisms. Products of nutrient metabolism may directly modify bone turnover, or do so indirectly through influence on secretion and circulating concentrations of calciotropic hormone, which affects bone remodeling and bone balance. Some effects of nutrition may even be more indirect. For instance, general malnutrition is associated with muscle wasting, thus submitting bone structure to less constraint. Moreover, the relationship between dietary intakes and bone health could be transient, and differ from long-term effects.

Furthermore, a clear relationship between bone variables and nutrition may be difficult to firmly establish, because of the poor accuracy and low reproducibility of the various methods to assess dietary intakes (eg, food diary, last 24-hour recall, food frequency questionnaire or nutritional intakes history) since all rely on the subject’s memory. In evidence-based medicine, randomized controlled trials with homogenous results are considered to provide a higher level of evidence than observational studies,2 the opinion of experts and/or personal clinical experience being at the bottom of the hierarchy. In the field of nutrition and bone, many concepts are based on association studies or, even worse, on experts’ personal beliefs. A causal relationship based on associations is weak. Nutrient intervention studies with a specific bone outcome are difficult to carry out and require large cohorts of subjects. Furthermore, the outcomes could be influenced by interaction with a large variety of confounding factors including social or genetic factors.

Bone mass at any given age is determined by the amount of bone accumulated at the end of skeletal growth—the socalled peak bone mass—and by the amount of bone that is subsequently lost.3 There is a large body of evidence linking nutritional intakes—particularly calcium and protein—to bone growth and to bone loss later in life, with both processes influencing fracture risk. Optimal dietary calcium and protein are necessary for bone homeostasis during growth as well as in the elderly.

When does bone mass accrual occur?

In most parts of the skeleton, peak bone mass is achieved by the end of the second decade of life.4 Total body mineral mass nearly doubles during puberty, through an increase in the size of the skeleton, with minor changes in volumetric bone density, ie, the amount of bone in bone.3 A very small proportion of bone consolidation may occur during the third decade, particularly in males. Puberty is the period during which the sex difference in bone mass observed in adult subjects becomes fully expressed. The important gender difference in bone mass that develops during pubertal maturation appears to result from a greater increase in bone size.5 There is no sex difference in volumetric trabecular density at the end of the period of maturation, ie, in young healthy adults in their third decade. The significantly greater mean areal bone mineral density (BMD) values observed in the lumbar spine and in the midfemoral or midradial diaphysis in young healthy adult males as compared with females appear to be essentially due to a more prolonged period of pubertal maturation rather than a greater maximal rate of bone accretion.6 It is estimated that a 10% increase in peak bone mass could reduce the risk of osteoporotic fractures during adult life by 50%, or be equivalent to a 14-year delay in the occurrence of menopause. Children with upper limb fractures may have a 1% to 5% reduction in BMD as compared with controls.7-9

What role does calcium play in bone development and what is the effect of calcium supplementation on bone mass?

Calcium plays major roles in the regulation of various cell functions, in the central and peripheral nervous systems, in muscle, and in the function of exo-/endocrine glands.10 In addition, this cation is implicated in the process of bone mineralization, by the formation of hydroxyapatite crystals. Extracellular calcium concentration has to be maintained as constant as possible, because of the high sensitivity of many cell systems or organs to small variations in extracellular calcium concentrations.

Figure 1
Figure 1. Influence of dietary protein on mineral and muscle
homeostasis through the growth hormone IGF-I system.

Abbreviations: abs, absorption; GH, growth hormone; IGF-I, insulin-like growth
factor I; Pi, inorganic phosphate; TmPi/GFR, renal tubular reabsorption of Pi.

Several prospective randomized, double-blind, placebo-controlled intervention trials have concluded that calcium supplementation increases bone mass gain, although the magnitude of the calcium 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.11-14 The effects of calcium could be modulated by an interaction with vitamin D receptor genotype.15 The positive effects of calcium supplementation have essentially been ascribed to a reduction in bone remodeling. Indeed, in one of the above-mentioned studies, the plasma level of osteocalcin, a biochemical marker of bone remodeling in adults, was significantly reduced in the calcium-supplemented children.14 Some effects of calcium supplements on bone modeling have been described as well.11,16-18 In a double-blind, placebo-controlled study on the effects of calcium supplementation in pre-pubertal girls, changes in projected scanned bone area and in standing height have suggested that calcium supplementation may influence bone modeling in addition to bone remodeling.11 Morphometric analysis of the changes observed in the lumbar spine and in femoral diaphysis suggests that 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— ie, in young adult girls—it appeared that menarche occurred earlier in the calcium-supplemented group, and that the persistent effects of calcium were mostly detectable in those subjects with an earlier puberty.19

Most of the studies carried out over 1 to 3 years in children and adolescents have shown that supplementation with either calcium or dairy foods 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. A recent meta-analysis has reviewed 19 calcium intervention studies involving 2859 children,20 with doses of calcium supplementation varying between 300 and 1200mg/day, using either calcium citrate malate, calcium carbonate, calcium phosphate, calcium lactate gluconate, calcium phosphate milk extract, or milk minerals. Calcium supplementation had a positive effect on total body bone mineral content and upper limb bone mineral density, with standardized mean differences (effect size) of 0.14 for both. At the upper limb, the effect persisted for up to 18 months after cessation of calcium supplementation. In the same study, calcium supplementation had no significant effect on weight, height, or body fat.

What is the effect of protein intake on bone growth and bone mass accrual?

In children and adolescents, protein intakes influence bone growth and bone mass accumulation.3 In “well-nourished” children and adolescents, variations in the protein intake with in the “normal” range may have a significant effect on skeletal growth and thereby modulate the genetic potential in peak bone mass attainment (Figure 1).

Changes in BMD and bone mineral content (BMC) in pre-pubertal boys are positively associated with spontaneous protein intake. Furthermore, higher protein intake enhances the positive influence of physical activity on BMC in pre-pubertal boys (Figure 2).13 Nutritional environmental factors seem to affect bone accumulation at specific periods during infancy and adolescence. In a prospective survey carried out in a cohort of female and male subjects aged 9 to 19 years, food intake was assessed twice, at a one-year interval, using a 5-day dietary diary method that consisted in weighing all consumed foods.21 In this cohort of adolescents, we found a positive correlation between yearly lumbar and femoral bone mass gain, and calcium or protein intake.22 This correlation was mainly detectable in pre-pubertal children, but not in those having reached a peri- or post-pubertal stage. It remained statistically significant after adjustment for spontaneous calcium intakes.

In a prospective longitudinal study performed in healthy children and adolescents of both sexes, between the ages of 6 and 18, dietary intakes were recorded over 4 years, using an annually assessed 3-day diary.23 Long-term protein intakes were found to be significantly positively associated with periosteal circumference, cortical area, bone mineral content, and calculated strength strain index. In this cohort with a Western- style diet, protein intakes were around 2 g/kg body weight per day in pre-pubertal children, and they were around 1.5 g/kg per day in pubertal individuals. There was no association between bone variables and intakes of nutrients with high sulfur containing amino acids, or intake of calcium. Overall, protein intakes accounted for 3% to 4% of bone parameter 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 would be able to reliably address this question. To our knowledge, there is no large randomized controlled trial that has specifically tested the effects of dietary protein supplements—other than milk or dairy products— on bone mass accumulation.

Figure 2
Figure 2. Influence of protein intake on the impact of increased physical activity on bone mineral content, projected scanned bone area and areal bone mineral density of the femoral neck in prepubertal boys aged 7.4±0.4 years.

Data are presented in Z-scores (± SEM). Increased physical activity is associated with a significant increase in femoral neck BMC, area and aBMD in subjects having protein intake above (>), but not below (<) the median. Analyzed by ANOVA, the interaction between physical activity and protein intake was P=0.012 at the FN BMC, P=0.040 at the FN area, and P=0.132 at the FN aBMD. Abbreviations: aBMD, areal bone mineral density; BMC, bone mineral content; FN, femoral neck; SEM, standard error of the mean.
After reference 13: Chevalley et al. J Bone Miner Res. 2008;23(1):131-142. © 2008, American Society for Bone and Mineral Research.

What is the effect of dairy product intake on bone growth?

In addition to calcium, phosphorus, calories, and vitamins, one liter of milk provides 32 to 35 g of protein, mostly casein, but also whey protein, which contains 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 for the whole body.24 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.8 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, thereby leading to a higher peak bone mass.25 In this study, calcium supplements did not affect spine BMD. However, higher dairy product intakes were associated with a greater total and cortical proximal radius cross-sectional area. Based on these observations, it was suggested that, whereas calcium supplements could influence volumetric BMD, and thus the remodeling process, dairy products may have an additional effect on bone growth and periosteal bone expansion, ie, an influence on modeling.25 In agreement with this observation, milk consumption frequency and milk intake at age 5-12 and 13-17 years were significant predictors of the height of 12-18 year-old adolescents, studied in the 1999- 2002 NHANES survey (National Health and Nutrition Examination Survey).26

The earliest milk intervention controlled studies were by Orr,27 and Leighton and Clark.28 In British school children, 400 to 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.17,29 In an open randomized intervention controlled trial, 568 mL/day milk supplement for 18 months in 12-year-old girls17 provided an additional 420 mg/day calcium and 14 g/day protein intakes at the end of the study. In the milk-supplemented group, serum insulin-like growth factor-I (IGF-I) levels were 17% significantly higher. Compared with the control group, the intervention group had greater increases of whole body BMD and BMC.

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.29 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.

What is the importance of calcium intake in adults?

After menopause, changes in sex hormone levels and nutrition are associated with an increase in bone remodeling and bone fragility. In adults, obligatory calcium losses have to be offset by sufficient calcium intakes and efficacious intestinal absorption (Table I). Otherwise, bone is used as a source of calcium to maintain homeostasis of extracellular calcium concentration. This homeostatic mechanism is altered in the elderly.30 With increased remodeling rate, the number of resorption cavities in cancellous tissue is higher, influencing bone strength and stiffness independently of bone mass.31 Thus, slowing down the rate of activation of new remodeling sites should be associated with a decrease in bone fragility. The effect of calcium on bone remodeling is usually ascribed to an inhibition of the secretion of parathyroid hormone, whose plasma level tends to increase with aging.32-34 Mineral waters with high calcium content could provide useful quantities of bioavailable calcium, independently from their sulfate content.35

Table I
Table I. Changes in calcium metabolism in the elderly.

What is the effect of calcium supplementation on fracture risk?

The anti-fracture efficacy of specific bone turnover or bone mass modifying agents has always been tested in vitamin D and calcium replete patients,36 except for hormone replacement therapy. Thus, any anti-fracture efficacy demonstrated with these agents is above that achieved with calcium and vitamin D. The doses of calcium used in these trials varied between 500 and 1500 mg daily.

Earlier studies have shown a reduction in non-vertebral, or hip fracture risk associated with calcium and vitamin D.34,37 Two subsequently published large trials have challenged these conclusions by being unable to detect significant anti-fracture effect in calcium and vitamin D treated individuals.38,39 Neither study targeted individuals at high fracture risk, and in both studies 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 with the placebo group was found.

Similarly, whereas in a prevention trial conducted in women over the age of 70, randomized to calcium 1200 mg daily or placebo for 5 years, there was no fracture risk reduction in an intention-to-treat analysis,40 a 34% fracture risk reduction was detected in the 57% of the patients who took at least 80% of the medication. In contrast, in another prevention trial performed for 5 years in healthy postmenopausal women with a mean age of 74 years, the favorable effects of calcium on bone loss or bone turnover were not associated with any anti-fracture efficacy, even in a per-protocol analysis.41 Persistence and compliance with calcium supplementation regimens were low, with poor compliance impairing efficacy.

A meta-analysis of 9 randomized clinical trials, including a total of 53 260 patients, found that whereas supplementation with vitamin D alone was not sufficient to significantly reduce the risk of hip fracture in postmenopausal women, combined supplementation with vitamin D and calcium reduced the risk of hip fracture by 28% and the risk of nonvertebral fracture by 23% compared with supplementation with vitamin D alone.42 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,43 mainly in those with a high spontaneous calcium intake.

What is the effect of protein intake on fracture risk?

Virtually all studies assessing a possible association between bone mass at various skeletal sites and spontaneous protein intake, have found a positive, rather than a negative, relationship in children or adolescents,13,23 preor postmenopausal women,44 and men. Unadjusted BMD was greater in the group with the higher protein intake in a large series of data collected within the framework of the Study of Osteoporotic Fracture.45 Dietary protein accounted for asmuch as 2% of bone mineral mass variance. A longitudinal follow-up within the framework of the Framingham study has demonstrated that the rate of bone mineral loss was inversely correlated with dietary protein intake.46 In contrast, very few surveys have reported that high protein intake was associated with lower bone mass. In a cross-sectional study, a protein intake close to 2 g/kg body weight was associated with reduced BMD only at one out of the two forearm sites measured in young college women.47

The large Nurse Health Study reported an inversely related trend for hip fracture incidence to protein intake.48 The same study reported an increase in the risk of forearm fracture in the subjects with the highest protein intake of animal origin. In a prospective study carried out on more than 40 000 women in Iowa, higher protein intake was associated with a reduced risk of hip fracture.49 The protective effect was observed with dietary protein of animal origin. In a case-control study, increasing protein intake was associated with a 65% lower hip fracture risk in the highest quartile in the 50- to 69-year-old age group.50

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.51 In a longitudinal study, hip fracture incidence was positively related to a higher ratio of animal-to-vegetal protein intake, whereas protein of vegetable origin was protective.45

Does high protein intake affect bone metabolism?

Whereas high protein intake has been claimed to be a risk factor for osteoporosis, further studies indicate that a reduction in dietary protein may lead to a decline in calcium absorption and to secondary hyperparathyroidism (Figure 3).52,53

A low (0.7 g/kg body weight), and 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.54 High meat diets (1.6 g/kg body weight of protein compared with 0.9 g/kg) for 8 weeks did not affect calcium retention nor indices of bone metabolism.55

Figure 3
Figure 3. Low protein intake and fracture risk.

Do animal and vegetal proteins have different effects on calcium metabolism?

It has been claimed that the source of proteins, animal versus vegetal, differently affect calcium metabolism. This is based on the hypothesis that animal proteins may 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. In a cross-sectional survey, BMD was higher in subjects with diets rich in fruits and vegetables, which are presumably rich in alkali.56,57

However, this issue is further complicated by the fact that the vegetable intake–induced decrease in bone resorption has been shown to be independent of acid-base changes and that potassium, but not sodium, bicarbonate (ie, the same anion),58 or citrate administration, reduces urinary calcium excretion.

What is the relationship between dietary protein intake and IGF-I?

Dietary proteins influence both the production and action of IGF-I, particularly the growth hormone (GH)– insulin-like growth factor (IGF) system.59 Protein restriction has been shown to reduce IGF-I plasma levels by inducing a resistance to the action of GH at the hepatic level, and by an increase in the metabolic clearance rate of IGF-I. In addition to calcium, magnesium, and other multivalent cations, calcium-sensing receptors sense amino acids, specifically L-amino acids, thereby modulating parathyroid hormone secretion.60 In humans, increased intake of aromatic, but not branched-chain, amino acids is associated with increases in serum IGF-I, intestinal calcium absorption, and 24-hour urinary calcium excretion, without any change in the biochemical markers of bone turnover.61

In an adult female rat experimental model of selective protein deprivation, with isocaloric low protein diets supplemented with identical amounts of minerals,62-64 a decrease in BMD was observed at skeletal sites formed by trabecular or cortical bone in animals fed a low casein diet, but receiving the same amount of energy. This was associated with a marked and early decrease in plasma IGF-I of 40%. Protein replenishment with essential amino acid supplements in the same relative proportion as in casein caused an increase in IGF-I to a level higher than in rats fed the control diet, and improved bone strength more than bone mineral mass, in relation with an increase in cortical thickness, as demonstrated by micro quantitative computerized tomography.62 Intrinsic bone tissue properties were modified by protein intake changes.65

Thus, in the elderly, a restoration of the altered GH-IGF-I system by protein replenishment 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 preparation that normalizes protein intake improved the clinical outcome after hip fracture.66-68 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 RDA (0.8 g/kg body weight), thus avoiding the risk of an excess of dietary protein.

Follow-up showed a lower rate of complications (bedsore, severe anemia, intercurrent lung or renal infections), and deaths were still observed at six months.67 The total length of stay in the orthopedic ward and convalescent hospital was significantly shorter in supplemented patients than in controls. In a double blind, placebo-controlled study, protein repletion with 20 g protein supplement daily for 6 months as compared with an isocaloric placebo, produced greater gains in serum prealbumin, IGF-I, and IgM, and an attenuated proximal femur BMD decrease.68 In a multiple regression analysis, baseline IGF-I 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<0.0005), which was reduced by 25% in the protein supplemented group.68 In another controlled trial, dietary protein supplements favorably influenced bone metabolism in the elderly.69 In a short-term study on the kinetics and determinants of the IGF-I response to protein supplements in a situation associated with low baseline IGF-I levels, such as the frail elderly, or patients with a recent hip fracture, we found that a 20 g/day protein supplement increased serum IGF-I and IGF binding protein-3 starting after one week, with a maximal response after 2 weeks.70,71

Taken together, these results indicate that a reduction in protein intakes may be detrimental for maintaining bone integrity and function in the elderly.

Acknowledgements. Ms Katy Giroux is warmly acknowledged for her excellent secretarial assistance.

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Keywords: dietary calcium; dietary protein; fracture; IGF-I; osteoporosis; peak bone mass