Evolution of Serum 25OHD in Response to Vitamin D3-Fortified Yogurts Consumed by Healthy Menopausal Women: A 6-Month Randomized Controlled Trial Assessing the Interactions between Doses, Baseline Vitamin D Status, and Seasonality.

BACKGROUND: Adequate vitamin D status contributes to bone fragility risk reduction and possibly other pathological conditions that occur with aging. In response to pharmaceutical vitamin D3 supplements, several studies have documented the influence of doses, baseline status, and seasonality on serum 25-hydroyvitamin D (s25OHD). OBJECTIVE: Using fortified yogurt, we investigated in one randomized controlled trial how both baseline status, as assessed by measuring s25OHD prior the onset of the trial, and the season of enrollment quantitatively influenced the response to the supplemented (Suppl.) of vitamin D3 (VitD3) in healthy community-dwelling women. METHODS: A 24-week controlled trial was conducted in menopausal women (mean age: 61.5). Participants were randomized into 3 groups (Gr): Gr.Suppl.0, time controls maintaining dietary habits; Gr.Suppl.5 and Gr.Suppl.10 consuming one and two 125-g servings of VitD3-fortified yogurts with 5- and 10-µg daily doses, respectively. The 16 intervention weeks lasted from early January to mid-August, the 8 follow-up weeks, without product, from late August to mid-October. Before enrollment, subjects were randomized into 2 s25OHD strata: low stratum (LoStr): 25-50 nmol/L; high stratum (HiStr): >50-75 nmol/L. RESULTS: All enrolled participants adhered to the protocol throughout the 24-week study: Gr.Suppl.0 (n = 45), Gr.Suppl.5 (n = 44), and Gr.Suppl.10 (n = 44). Over the 16 intervention and 8 follow-up weeks, s25OHD increased in both supplemented groups, more in Gr.Suppl.10 than in Gr.Suppl.5. At the end of the intervention, the subject proportion with s25OHD ≥ 50 nmol/L was 37.8, 54.5, and 63.6% in Gr.Suppl.0, Gr.Suppl.5, and Gr.Suppl.10, respectively. The constant rate of s25OHD per supplemental VitD3 microgram was greater in LoStr than HiStr. The s25OHD increase was greater with late (mid-March) than early (mid-January) inclusion. CONCLUSION: This randomized trial demonstrates (1) a dose-dependent s25OHD improvement related to fortified yogurt consumption; (2) an inversely baseline-dependent increase in s25OHD; and (3) a seasonal effect that highlights the importance of VitD3-fortified foods during winter, even at 5 µg/d, in healthy menopausal women.

Moderate amounts of vitamin D3 in supplements are effective in raising serum 25-hydroxyvitamin D from low baseline levels in adults: a systematic review.

There is controversy surrounding the designation of vitamin D adequacy as defined by circulating levels of the metabolite 25-hydroxyvitamin D (25(OH)D). Depending on the cutoff level chosen, dietary intakes of vitamin D may or may not provide sufficient impact upon vitamin D status measured as improvement in serum levels of 25(OH)D. We sought to examine whether modest daily doses (5-20 µg) as found in fortified foods or multivitamin supplements had a measureable impact on vitamin D status, defined as moving from below to above 50 nmol/L, or from less than 30 nmol/L to above 30 nmol/L. Published literature was searched for relevant articles describing randomized controlled trials. Exclusion criteria were: studies not involving humans; review articles; studies lacking blood level data pre- and post-treatment; no control group; bolus treatments (weekly, monthly, yearly); vitamin D < 5 µg or > 20 µg; baseline 25(OH)D ≥ 75 nmol/L; subjects not defined as healthy; studies < 8 weeks; and age < 19 years. Of the 127 studies retrieved, 18 publications with 25 separate comparisons met criteria. The mean rate constant, defined as change in 25(OH)D in nmol/L per µg vitamin D administered, was calculated as 2.19 ± 0.97 nmol/L per µg. There was a significant negative correlation (r = -0.65, p = 0.0004) between rate constant and administered dose. To determine impact of the dose reflecting the Estimated Average Requirement (EAR) of 10 µg administered in nine studies (10 comparisons), in every case mean 25(OH)D status rose either from "insufficient" (30-50 nmol/L) to "sufficient" (> 50 nmol/L) or from "deficient" (< 30 nmol/L) to "insufficient" (> 30 but < 50 nmol/L). Our study shows that when baseline levels of groups were < 75 nmol/L, for every microgram of vitamin D provided, 25(OH)D levels can be raised by 2 nmol/L; and further, when groups were deficient or insufficient in vitamin D, there was significant value in providing additional 10 µg per day of vitamin D.

Biochemical markers for assessment of calcium economy and bone metabolism: application in clinical trials from pharmaceutical agents to nutritional products.

Nutrition plays an important role in osteoporosis prevention and treatment. Substantial progress in both laboratory analyses and clinical use of biochemical markers has modified the strategy of anti-osteoporotic drug development. The present review examines the use of biochemical markers in clinical research aimed at characterising the influence of foods or nutrients on bone metabolism. The two types of markers are: (i) specific hormonal factors related to bone; and (ii) bone turnover markers (BTM) that reflect bone cell metabolism. Of the former, vitamin D metabolites, parathyroid hormone, and insulin-like growth factor-I indicate responses to variations in the supply of bone-related nutrients, such as vitamin D, Ca, inorganic phosphate and protein. Thus modification in bone remodelling, the key process upon which both pharmaceutical agents and nutrients exert their anti-catabolic or anabolic actions, is revealed. Circulating BTM reflect either osteoclastic resorption or osteoblastic formation. Intervention with pharmacological agents showed that early changes in BTM predicted bone loss and subsequent osteoporotic fracture risk. New trials have documented the influence of nutrition on bone-tropic hormonal factors and BTM in adults, including situations of body-weight change, such as anorexia nervosa, and weight loss by obese subjects. In osteoporosis-prevention studies involving dietary manipulation, randomised cross-over trials are best suited to evaluate influences on bone metabolism, and insight into effects on bone metabolism may be gained within a relatively short time when biochemical markers are monitored.

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.

CONTEXT: Nutritional prevention of bone deterioration with fortified foods seems particularly suitable in institutionalized elderly women at risk of vitamin D deficiency, secondary hyperparathyroidism, increased bone resorption, and osteoporotic fracture. OBJECTIVE: The objective was to evaluate whether fortification of yogurts with vitamin D and calcium exerts an additional lowering effect on serum PTH and bone resorption markers as compared with isocaloric and isoprotein dairy products in elderly women. DESIGN: A randomized double-blind controlled-trial, 56-day intervention was conducted in institutionalized women (mean age 85.5 years) consuming 2 125-g servings of either vitamin D- and calcium-fortified yogurt (FY) at supplemental levels of 10 µg/d vitamin D3 and 800 mg/d calcium or nonfortified control yogurt (CY) providing 280 mg/d calcium. MAIN OUTCOMES: The endpoints were serum changes from baseline (day 0) to day 28 and day 56 in 25-hydroxyvitamin-D (25OHD), PTH, and bone resorption markers tartrate-resistant acid phosphatase isoform-5b (TRAP5b), the primary outcome, and carboxyl-terminal cross-linked telopeptide of type I collagen (CTX). RESULTS: At day 56, serum 25OHD increased (mean ± SEM) by 25.3 ± 1.8 vs 5.2 ± 2.5 nmol/L in FY (n = 29) and CY (n = 27), respectively (P < .0001). The corresponding changes in PTH were -28.6% ± 7.2% vs -8.0% ± 4.3% (P = .0003); in TRAP5b, -21.9% ± 4.3% vs 3.0% ± 3.2% (P < .0001); and in CTX, -11.0% ± 9.7% vs -3.0% ± 4.1% (P = .0146), in FY and CY, respectively. At day 28, these differences were less pronounced but already significant for 25OHD, PTH, and TRAP5b. CONCLUSIONS: This study in institutionalized elderly at high risk for osteoporotic fracture suggests that fortification of dairy products with vitamin D3 and calcium provides a greater prevention of accelerated bone resorption as compared with nonfortified equivalent foods.

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.

The prevention of increased bone remodeling in postmenopausal women at low 10-y risk of osteoporotic fractures essentially relies on reinforcement of environmental factors known to positively influence bone health, among which nutrition plays an important role. In institutionalized women in their mid-eighties, we previously found that consumption of fortified soft plain cheese increased vitamin D, calcium, and protein intakes, reduced bone resorption biochemical markers, particularly the serum bone specific acid phosphatase tartrate resistant acid phosphatase, isoform 5b (TRAP 5b) that reflects osteoclast activity, and stimulated the serum bone anabolic factor insulin-like growth factor-I (IGF-I). Whether these effects occur in much younger women was tested in a prospective control study. Seventy-one healthy postmenopausal women aged 56.6 ± 3.9 y (mean ± SD) with low spontaneous supply of both Ca and vitamin D were randomized to consume daily (treated, n = 36) or not (controls, n = 35) two servings (2 × 100 g) of skimmed-milk, soft plain cheese for 6 wk. The vitamin D and Ca-fortified dairy product provided daily: 661 kJ, 2.5 µg vitamin D, 400 mg calcium, and 13.8 g protein. At the end of the intervention, the decrease in TRAP 5b and the increase in IGF-I were greater in the treated than in the control group (P < 0.02). The changes in serum carboxy terminal crosslinked telopeptide of type I collagen did not differ significantly between the two groups. In conclusion, like in elderly women, consumption by healthy postmenopausal women of a vitamin D and calcium-fortified dairy product that also increases the protein intake, reduces the serum concentration of the bone resorption biomarker TRAP 5b. This response, combined with the increase in serum IGF-I, is compatible with a nutrition-induced reduction in postmenopausal bone loss rate.

Protein intake and bone health.

Adequate nutrition plays an important role in the development and maintenance of bone structures resistant to usual mechanical stresses. In addition to calcium in the presence of an adequate supply of vitamin D, dietary proteins represent key nutrients for bone health and thereby function in the prevention of osteoporosis. Several studies point to a positive effect of high protein intake on bone mineral density or content. This fact is associated with a significant reduction in hip fracture incidence, as recorded in a large prospective study carried out in a homogeneous cohort of postmenopausal women. Low protein intake (< 0.8 g/kg body weight/day) is often observed in patients with hip fractures and an intervention study indicates that following orthopedic management, protein supplementation attenuates post-fracture bone loss, tends to increase muscle strength, and reduces medical complications and rehabilitation hospital stay. There is no evidence that high protein intake per se would be detrimental for bone mass and strength. Nevertheless, it appears reasonable to avoid very high protein diets (i. e. more than 2.0 g/kg body weight/day) when associated with low calcium intake (i. e. less than 600 mg/day). In the elderly, taking into account the attenuated anabolic response to dietary protein with ageing, there is concern that the current dietary protein recommended allowance (RDA), as set at 0.8 g/kg body weight/day, might be too low for the primary and secondary prevention of fragility fractures.

Calcium and phosphate: a duet of ions playing for bone health.

The acquisition and maintenance of bone mass and strength are influenced by environmental factors, including physical activity and nutrition. Among micronutrients, calcium (Ca) and inorganic (i) phosphate (P) are the two main constituents of hydroxyapatite, the bone mineral that strengthens the mechanical resistance of the organic matrix. Bone contains about 99% and 80% of the body's entire supply of Ca and P, respectively. The Ca/P mass ratio in bone is 2.2, which is similar to that measured in human milk. The initial step of Ca-Pi crystal nucleation takes place within matrix vesicles that bud from the plasma membrane of osteogenic cells and migrate into the extracellular skeletal compartment. They are endowed with a transport system that accumulates Pi inside the matrix vesicles, followed by the influx of Ca ions. This process leads to the formation of hydroxyapatite crystal and its subsequent association with the organic matrix collagen fibrils. In addition to this structural role, both Ca and Pi positively influence the activity of bone-forming and bone-resorbing cells. Pi plays a role in the maturation of osteocytes, the most abundant cells in bone. Osteocytes are implicated in bone mineralization and systemic Pi homeostasis. They produce fibroblast growth factor-23, a hormonal regulator of renal Pi reabsorption and 1,25-dihydroxy vitamin D production. This relationship is in keeping with the concept proposed several decades ago of a bone-kidney link in Pi homeostasis. In contrast to their tight association in bone formation and resorption, Ca and Pi renal reabsorption processes are independent from each other, driven by distinct molecular machineries. The distinct renal control is related to the different extraskeletal functions that Ca and Pi play in cellular metabolism. At both the renal and the intestinal levels, interactions of Ca and Pi have been documented that have important implications in the acquisition and maintenance of bone health, as well as in osteoporosis management. In the kidney, increased Pi intake enhances Ca reabsorption and Ca balance. During growth and adulthood, administration of Ca-Pi in a ratio close to that of dairy products leads to positive effects on bone health. In contrast, when separately ingested as pharmaceutical salt supplements, thus inducing large differences between Ca and Pi concentrations in the intestinal lumen, they might have adverse effects on bone health. In osteoporotic patients treated with anabolic agents, a Ca-Pi supplement appears to be preferable to carbonate or citrate Ca salt. In conclusion, Ca and Pi constitute a key duo for appropriate bone mineral acquisition and maintenance throughout life. Outside the skeleton, their essential but distinct physiological functions are controlled by specific transporters and hormonal systems that also serve to secure the appropriate supply of Ca and Pi for bone health. Key teaching points: Bone contains about 99% and 80% of the body's supply of Ca and P, respectively, as hydroxyapatite and has a Ca/P mass ratio of about 2.2, close to that measured in human milk. The first step of Ca-Pi crystal nucleation takes place within matrix vesicles that bud from the plasma membrane of osteogenic cells. In addition to their structural role, both Ca and Pi influence bone-forming and bone-resorbing cells. There is a bone-kidney link in Pi homeostasis in which fibroblast growth factor-23, a molecule produced by osteocytes, appears to play a pivotal role. In contrast to their tight association during bone formation and resorption, both intestinal and renal Ca and Pi processes are independent of each other. Observational and interventional studies suggest that Ca-Pi salt or dairy products can exert positive effects on bone acquisition and maintenance.

Early serum IGF-I response to oral protein supplements in elderly women with a recent hip fracture.

BACKGROUND & AIMS: In patients with recent hip fracture, reduced serum IGF-I in relation to protein undernutrition is frequent. Elevation of circulating IGF-I in response to a daily oral supplement of 20 g of casein was observed after 6 months. This study determined if the response to casein as compared to whey protein can be observed as early as after one week. METHODS: 45 women were randomized after recent hip fracture in 3 groups receiving a preparation of 20 g of casein, an isocaloric supplement of 20 g of whey protein or an isocaloric supplement of 15 g of whey protein combined with 5 g of essential amino acids (a.a.). RESULTS: A similar significant elevation of serum IGF-I was already observed after 7 days for casein (+37.3 microg/L), whey (+29.4) and for whey+a.a. (+34.3). From day 7-28, no further significant rise in IGF-I was recorded. CONCLUSION: After one week of protein supplementation, the percent increase of IGF-I was of similar magnitude to that previously observed after 6 months of protein supplementation. It suggests that in hip fracture patients, long-term effects of various protein preparations on IGF-I could be predicted from changes observed as early as 7 days after the onset of supplementation.

Inhibition of markers of bone resorption by consumption of vitamin D and calcium-fortified soft plain cheese by institutionalised elderly women.

Acceleration of bone remodelling increases the risk of fragility fractures. The objective of the present study was to explore in elderly women whether a vitamin D and Ca-fortified dairy product providing about 17-25 % of the recommended intakes in vitamin D, Ca and proteins would reduce secondary hyperparathyroidism and bone remodelling in a way that may attenuate age-related bone loss in the long term. Thirty-seven institutionalised women, aged 84.8 (sd 8.1) years, with low serum 25-hydroxyvitamin D (5.5 (sd 1.7) ng/ml) were enrolled into a multicentre open trial to consume during 1 month two servings of soft plain cheese made of semi-skimmed milk providing daily 686 kJ (164 kcal), 2.5 microg vitamin D, 302 mg Ca and 14.2 g proteins. The primary endpoint was the change in serum carboxy terminal cross-linked telopeptide of type I collagen (CTX), selected as a marker of bone resorption. Thirty-five subjects remained compliant. Mean serum changes were: 25-hydroyvitamin D, +14.5 % (P = 0.0051); parathyroid hormone (PTH), - 12.3 % (P = 0.0011); CTX, - 7.5 % (P = 0.01); tartrate-resistant acid phosphatase isoform 5b (TRAP 5b), - 9.9 % (P < 0.0001); albumin, +6.2 % (P < 0.0001); insulin-like growth factor-I (IGF-I),+16.9 % (P < 0.0001); osteocalcin, +8.3 % (P = 0.0166); amino-terminal propeptide of type 1 procollagen (P1NP),+19.3 % (P = 0.0031). The present open trial suggests that fortified soft plain cheese consumed by elderly women with vitamin D insufficiency can reduce bone resorption markers by positively influencing Ca and protein economy, as expressed by decreased PTH and increased IGF-I, respectively. The rise in the bone formation marker P1NP could be explained by a protein-mediated increase in IGF-I. Thus, such a dietary intervention might uncouple, at least transiently, bone resorption from bone formation and thereby attenuate age-related bone loss.

Minerals and vitamins in bone health: the potential value of dietary enhancement.

Nutrition is important to bone health, and a number of minerals and vitamins have been identified as playing a potential role in the prevention of bone diseases, particularly osteoporosis. Despite this, there is currently no consensus on maximum levels to allow in food or as dietary supplements. The benefits of supplementation of populations at risk of osteoporosis with Ca and vitamin D are well established. Prolonged supplementation of Ca and vitamin D in elderly has been shown to prevent bone loss, and in some intervention studies to prevent fragility fractures. Although P is essential to bone health, the average intake is considered to be more than sufficient and supplementation could raise intake to adverse levels. The role of vitamin K in bone health is less well defined, though it may enhance the actions of Ca and vitamin D. Sr administered in pharmacological doses as the ranelate salt was shown to prevent fragility fractures in postmenopausal osteoporosis. However, there is no hard evidence that supplementation with Sr salts would be beneficial in the general population. Mg is a nutrient implicated in bone quality, but the benefit of supplementation via foodstuffs remains to be established. A consensus on dietary supplementation for bone health should balance the risks, for example, exposure of vulnerable populations to values close to maximal tolerated doses, against evidence for benefits from randomised clinical trials, such as those for Ca and vitamin D. Feedback from community studies should direct further investigations and help formulate a consensus on dietary supplementation for bone health.

Inhibition of bone turnover by milk intake in postmenopausal women.

Increased postmenopausal bone turnover leads to bone loss and fragility fracture risk. In the absence of osteoporosis, risk preventive measures, particularly those modifying nutritional lifestyle, are appropriate. We tested the hypothesis that milk supplementation affects bone turnover related to biochemical markers in a direction that, in the long term, may be expected to reduce postmenopausal bone loss. Thirty healthy postmenopausal women aged 59.3 (SD 3.3) years were enrolled in a prospective crossover trial of 16 weeks. After a 4-week period of adaptation with diet providing 600 mg calcium plus 300 mg ingested as 250 ml semi-skimmed milk, participants were maintained during 6 weeks under the same 600 mg calcium diet and randomized to receive either 500 ml semi-skimmed milk, thus providing a total of 1200 mg calcium, or no milk supplement. In the next 6 weeks they were switched to the alternative regimen. At the end of the each period, i.e. after 4, 10 and 16 weeks, blood and urinary samples were collected. The changes in blood variables between the periods of 6 weeks without and with milk supplementation were: for parathyroid hormone, -3.2 pg/ml (P=0.0054); for crosslinked telopeptide of type I collagen, -624 pg/ml (P<0.0001); for propeptide of type I procollagen, -5.5 ng/ml (P=0.0092); for osteocalcin, -2.8 ng/ml (P=0.0014). In conclusion, a 6-week period of milk supplementation induced a decrease in several biochemical variables compatible with diminished bone turnover mediated by reduction in parathyroid hormone secretion. This nutritional approach to postmenopausal alteration in bone metabolism may be a valuable measure in the primary prevention of osteoporosis.

Gene-environment interactions in the skeletal response to nutrition and exercise during growth.

The amount of bone mineral mass acquired at the end of growth, the so-called 'peak bone mass', is considered to be a major risk factor for the occurrence of fragility fractures during adult life. Many interrelated factors can influence the accumulation of bone mass during growth, including genetics, sex, ethnicity, nutrition (e.g. calcium, vitamin D, protein), hormonal factors (e.g. sex steroids, insulin-like growth factor I), physical activity and exposure to various risk factors (e.g. alcohol, smoking, certain medications). Family and twin studies have estimated that up to 60-80% of the variance in peak bone mass is attributable to genetic factors. It can be predicted from epidemiological studies that a 10% increase in peak bone mass would reduce the risk of fragility fractures after the menopause by 50%. Intervention studies testing the effects of increasing either calcium intake or physical activity during growth provide evidence that modifying environmental factors can positively influence peak bone mass. Nevertheless, there is large interindividual variability in the response suggesting gene-environment interactions. A few studies have reported associations between some bone-related gene polymorphisms and the osteogenic response to loading or calcium supplementation. Identifying the functionally implicated genes interacting with mechanical loading and/or specific nutrients represents a formidable but hopefully not intractable challenge.

Calcium intake and vitamin D metabolism and action, in healthy conditions and in prostate cancer.

An association between Ca intake and the risk of prostate cancer has been reported in some but not all epidemiological studies. Assuming that a pathophysiological relationship would underlie this association, a favoured hypothesis proposes that relatively high Ca consumption could promote prostate cancer by reducing the production of 1,25-dihydroxyvitamin D (1,25(OH)2D; calcitriol), the hormonal form of vitamin D. The present review analyses the plausibility of this hypothesis by considering the quantitative relationships linking Ca intake to 1,25(OH)2D production and action in healthy conditions and in prostate cancer. Changes in the plasma level of 1,25(OH)2D in response to Ca intake are of very small magnitude as compared with the variations required to influence the proliferation and differentiation of prostate cancer cells. In most studies, 1,25(OH)2D plasma level was not found to be reduced in patients with prostate cancer. The possibility that the level of 1,25(OH)2D in prostate cells is decreased with a high-Ca diet has not been documented. Furthermore, a recent randomised placebo-controlled trial did not indicate that Ca supplementation increases the relative risk of prostate cancer in men. In conclusion, the existence of a pathophysiological link between relatively high Ca intake and consequent low production and circulation level of 1,25(OH)2D that might promote the development of prostate cancer in men remains so far an hypothesis, the plausibility of which is not supported by the analysis of available clinical data.

Dietary protein: an essential nutrient for bone health.

Nutrition plays a major role in the development and maintenance of bone structures resistant to usual mechanical loadings. In addition to calcium in the presence of an adequate vitamin D supply, proteins represent a key nutrient for bone health, and thereby in the prevention of osteoporosis. In sharp opposition to experimental and clinical evidence, it has been alleged that proteins, particularly those from animal sources, might be deleterious for bone health by inducing chronic metabolic acidosis which in turn would be responsible for increased calciuria and accelerated mineral dissolution. This claim is based on an hypothesis that artificially assembles various notions, including in vitro observations on the physical-chemical property of apatite crystal, short term human studies on the calciuric response to increased protein intakes, as well as retrospective inter-ethnic comparisons on the prevalence of hip fractures. The main purpose of this review is to analyze the evidence that refutes a relation of causality between the elements of this putative patho-physiological "cascade" that purports that animal proteins are causally associated with an increased incidence of osteoporotic fractures. In contrast, many experimental and clinical published data concur to indicate that low protein intake negatively affects bone health. Thus, selective deficiency in dietary proteins causes marked deterioration in bone mass, micro architecture and strength, the hallmark of osteoporosis. In the elderly, low protein intakes are often observed in patients with hip fracture. In these patients intervention study after orthopedic management demonstrates that protein supplementation as given in the form of casein, attenuates post-fracture bone loss, increases muscles strength, reduces medical complications and hospital stay. In agreement with both experimental and clinical intervention studies, large prospective epidemiologic observations indicate that relatively high protein intakes, including those from animal sources are associated with increased bone mineral mass and reduced incidence of osteoporotic fractures. As to the increased calciuria that can be observed in response to an augmentation in either animal or vegetal proteins it can be explained by a stimulation of the intestinal calcium absorption. Dietary proteins also enhance IGF-1, a factor that exerts positive activity on skeletal development and bone formation. Consequently, dietary proteins are as essential as calcium and vitamin D for bone health and osteoporosis prevention. Furthermore, there is no consistent evidence for superiority of vegetal over animal proteins on calcium metabolism, bone loss prevention and risk reduction of fragility fractures.

Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men.

The renal handling of inorganic phosphate (Pi) is controlled not only by PTH, but also by hitherto undetermined mechanisms dependent on phosphate intake. Recently, fibroblast growth factor (FGF)-23 was identified as a novel phosphaturic factor in tumor-induced osteomalacia and autosomal-dominant hypophosphatemic rickets. We hypothesized that phosphate intake could influence FGF-23 concomitantly to the changes in renal Pi handling. Twenty-nine healthy males were subjected to a 5-d low-phosphate diet and a phosphate binder, followed by a high-phosphate diet including supplements. Concomitant modifications in calcium intake allowed minimizing PTH changes in response to dietary phosphate. Serum FGF-23 levels significantly decreased on the low-phosphate diet, then increased with the oral phosphate load. Changes in FGF-23 were positively correlated with changes in 24-h urinary Pi excretion and negatively correlated with changes in the maximal tubular reabsorption of Pi and 1,25(OH)(2)D(3) (calcitriol), whereas PTH was not. In multivariate analysis, changes in FGF-23 remained the most significantly correlated to changes in 1,25(OH)(2)D(3) and maximal tubular reabsorption of Pi. Moreover, FGF-23 was positively correlated to serum osteocalcin, a marker of osteoblastic activity. In summary, FGF-23 was inversely related to renal Pi transport and serum calcitriol levels in healthy young men. These data suggest that FGF-23 may be implicated in the physiological regulation of Pi homeostasis in response to dietary phosphate changes, independent of PTH.

Interaction between calcium intake and menarcheal age on bone mass gain: an eight-year follow-up study from prepuberty to postmenarche.

Both late menarcheal age and low calcium intake (Ca intake) during growth are risk factors for osteoporosis, probably by impairing peak bone mass. We investigated whether lasting gain in areal bone mineral density (aBMD) in response to increased Ca intake varies according to menarcheal age and, conversely, whether Ca intake could influence menarcheal age. In an initial study, 144 prepubertal girls were randomized in a double-blind controlled trial to receive either a Ca supplement (Ca-suppl.) of 850 mg/d or placebo from age 7.9-8.9 yr. Mean aBMD gain determined by dual energy x-ray absorptiometry at six sites (radius metaphysis, radius diaphysis, femoral neck, trochanter, femoral diaphysis, and L2-L4) was significantly (P = 0.004) greater in the Ca-suppl. than in the placebo group (27 vs. 21 mg/cm(2)). In 122 girls followed up, menarcheal age was recorded, and aBMD was determined at 16.4 yr of age. Menarcheal age was lower in the Ca-suppl. than in the placebo group (P = 0.048). Menarcheal age and Ca intake were negatively correlated (r = -0.35; P < 0.001), as were aBMD gains from age 7.9-16.4 yr and menarcheal age at all skeletal sites (range: r = -0.41 to r = -0.22; P < 0.001 to P = 0.016). The positive effect of Ca-suppl. on the mean aBMD gain from baseline remained significantly greater in girls below, but not in those above, the median of menarcheal age (13.0 yr). Early menarcheal age (12.1 +/- 0.5 yr): placebo, 286 +/- 36 mg/cm(2); Ca-suppl., 317 +/- 46 (P = 0.009); late menarcheal age (13.9 +/- 0.5 yr): placebo, 284 +/- 58; Ca-suppl., 276 +/- 50 (P > 0.05). The level of Ca intake during prepuberty may influence the timing of menarche, which, in turn, could influence long-term bone mass gain in response to Ca supplementation. Thus, both determinants of early menarcheal age and high Ca intake may positively interact on bone mineral mass accrual.