Benefits and safety of dietary protein for bone health-an expert consensus paper endorsed by the European Society for Clinical and Economical Aspects of Osteopororosis, Osteoarthritis, and Musculoskeletal Diseases and by the International Osteoporosis Foundation.

A summary of systematic reviews and meta-analyses addressing the benefits and risks of dietary protein intakes for bone health in adults suggests that dietary protein levels even above the current RDA may be beneficial in reducing bone loss and hip fracture risk, provided calcium intakes are adequate. Several systematic reviews and meta-analyses have addressed the benefits and risks of dietary protein intakes for bone health in adults. This narrative review of the literature summarizes and synthesizes recent systematic reviews and meta-analyses and highlights key messages. Adequate supplies of dietary protein are required for optimal bone growth and maintenance of healthy bone. Variation in protein intakes within the "normal" range accounts for 2-4% of BMD variance in adults. In older people with osteoporosis, higher protein intake (≥ 0.8-g/kg body weight/day, i.e., above the current RDA) is associated with higher BMD, a slower rate of bone loss, and reduced risk of hip fracture, provided that dietary calcium intakes are adequate. Intervention with dietary protein supplements attenuate age-related BMD decrease and reduce bone turnover marker levels, together with an increase in IGF-I and a decrease in PTH. There is no evidence that diet-derived acid load is deleterious for bone health. Thus, insufficient dietary protein intakes may be a more severe problem than protein excess in the elderly. Long-term, well-controlled randomized trials are required to further assess the influence of dietary protein intakes on fracture risk.

Impact of nutrition on muscle mass, strength, and performance in older adults.

Muscle strength plays an important role in determining risk for falls, which result in fractures and other injuries. While bone loss has long been recognized as an inevitable consequence of aging, sarcopenia-the gradual loss of skeletal muscle mass and strength that occurs with advancing age-has recently received increased attention. A review of the literature was undertaken to identify nutritional factors that contribute to loss of muscle mass. The role of protein, acid-base balance, vitamin D/calcium, and other minor nutrients like B vitamins was reviewed. Muscle wasting is a multifactorial process involving intrinsic and extrinsic alterations. A loss of fast twitch fibers, glycation of proteins, and insulin resistance may play an important role in the loss of muscle strength and development of sarcopenia. Protein intake plays an integral part in muscle health and an intake of 1.0-1.2 g/kg of body weight per day is probably optimal for older adults. There is a moderate [corrected] relationship between vitamin D status and muscle strength. Chronic ingestion of acid-producing diets appears to have a negative impact on muscle performance, and decreases in vitamin B12 and folic acid intake may also impair muscle function through their action on homocysteine. An adequate nutritional intake and an optimal dietary acid-base balance are important elements of any strategy to preserve muscle mass and strength during aging.

Pubertal timing and body mass index gain from birth to maturity in relation with femoral neck BMD and distal tibia microstructure in healthy female subjects.

UNLABELLED: Childhood body mass index (BMI) gain is linked to hip fracture risk in elderly. In healthy girls, menarcheal age is inversely related to BMI gain during childhood and to femoral neck areal bone mass density (aBMD) and distal tibia structural components at maturity. This study underscores the importance of pubertal timing in age-related fragility fracture risk. INTRODUCTION: Recent data point to a relationship between BMI change during childhood and hip fracture risk in later life. We hypothesized that BMI development is linked to variation in pubertal timing as assessed by menarcheal age (MENA) which in turn, is related to peak bone mass (PBM) and hip fracture risk in elderly. METHODS: We studied in a 124 healthy female cohort the relationship between MENA and BMI from birth to maturity, and DXA-measured femoral neck (FN) aBMD at 20.4 year. At this age, we also measured bone strength related microstructure components of distal tibia by HR-pQCT. RESULTS: At 20.4 ± 0.6 year, FN aBMD (mg/cm(2)), cortical thickness (µm), and trabecular density (mg HA/cm(3)) of distal tibia were inversely related to MENA (P = 0.023, 0.015, and 0.041, respectively) and positively to BMI changes from 1.0 to 12.4 years (P = 0.031, 0.089, 0.016, respectively). Significant inverse (P < 0.022 to <0.001) correlations (R = -0.21 to -0.42) were found between MENA and BMI from 7.9 to 20.4 years, but neither at birth nor at 1.0 year. Linear regression indicated that MENA Z-score was inversely related to BMI changes not only from 1.0 to 12.4 years (R = -0.35, P = 0.001), but also from 1.0 to 8.9 years, (R = -0.24, P = 0.017), i.e., before pubertal maturation. CONCLUSION: BMI gain during childhood is associated with pubertal timing, which in turn, is correlated with several bone traits measured at PBM including FN aBMD, cortical thickness, and volumetric trabecular density of distal tibia. These data complement the reported relationship between childhood BMI gain and hip fracture risk in later life.

IOF position statement: vitamin D recommendations for older adults.

This position paper of the International Osteoporosis Foundation makes recommendations for vitamin D nutrition in elderly men and women from an evidence-based perspective.

Global vitamin D status and determinants of hypovitaminosis D.

UNLABELLED: This review describes the vitamin D status in different regions of the world with the objective of understanding the scope of hypovitaminosis D and the factors related to its prevalence that may contribute to the pathogenesis of osteoporosis and fragility fractures. INTRODUCTION: Vitamin D status has been linked to the pathogenesis of hip fractures as well as other skeletal and non-skeletal disorders. The purpose of this review is to provide a global perspective of vitamin D status across different regions of the world and to identify the common and significant determinants of hypovitaminosis D. METHODS: Six regions of the world were reviewed-Asia, Europe, Middle East and Africa, Latin America, North America, and Oceania-through a survey of published literature. RESULTS: The definition of vitamin D insufficiency and deficiency, as well as assay methodology for 25-hydroxyvitamin D or 25(OH)D, vary between studies. However, serum 25(OH)D levels below 75 nmol/L are prevalent in every region studied whilst levels below 25 nmol/L are most common in regions such as South Asia and the Middle East. Older age, female sex, higher latitude, winter season, darker skin pigmentation, less sunlight exposure, dietary habits, and absence of vitamin D fortification are the main factors that are significantly associated with lower 25(OH)D levels. CONCLUSION: Reports from across the world indicate that hypovitaminosis D is widespread and is re-emerging as a major health problem globally.

Regulation of the metabolism of 25-hydroxyvitamin D3 in primary cultures of chick kidney cells.

A primary chick kidney cell culture is described, capable of forming 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], and 1,24,25-trihydroxyvitamin D3 [1,24,25(OH)3D3] over several days. The apparent Km values were 0.125 microM for the 1-hydroxylase and 2.1 microM for the 24-hydroxylase. Exogenous 1,25(OH)2D3 decreased 1-hydroxylase and increased 24-hydroxylase within 4 h. 24,25(OH)2D3 produced similar effects, but only in the absence of fetal calf serum. R and S isomers of 1,24,25(OH)3D3 were about fives times less active than 1,25(OH)2D3. Bovine parathyroid hormone stimulated the 1- and reduced the 24-hydroxylase in 6 h, but this only occurred in cultures either previously treated with 1,25(OH)2D3 and EGTA to lower Ca to 0.8 mM or in cultures grown in the presence of 25-hydroxyvitamin D3 (25(OH)D3). Under the latter condition, the sensitivity to bovine parathyroid hormone was enhanced, 0.04 U/ml producing a maximum response. Synthetic aminoterminal tetratriacontapeptide (1-34) human parathyroid hormone was equally effective. In the absence of D metabolites, estradiol for 6 h produced a dose-dependent inhibition of the 1-hydroxylase, but no change in the 24-hydroxylase. Progesterone, testosterone, and corticosterone had no significant effect. In cultures grown in the presence of 25(OH)D3 no reproducible effects were obtained with either 1 microM estradiol or 1 microM testosterone, alone or in combination, but 5 microM corticosterone decreased the 1- and increased the 24-hydroxylase. Changes in Ca and P concentrations of the medium as well as addition of ethane-l-hydroxy-1, 1-diphosphate for 48 h did not affect any of the hydroxylase activities. The modulation of the hydroxylase activities by vitamin D3 metabolites and parathyroid hormone suggests that these factors regulate the renal hydroxylase by direct actions, whereas it would appear that ethane-1-hydroxy-1,1-diphosphate, Ca, P, and steroid may exert their influence indirectly.

Role of 1,25-dihydroxyvitamin D3 on intestinal phosphate absorption in rats with a normal vitamin D supply.

In vitamin D-deficient rats, impaired intestinal phosphorus (P) absorption can be corrected by 1,25-dihydroxyvitamin D(3)[1,25-(OH)(2)D(3)]. In the present study, it was investigated whether changes in 1,25-(OH)(2)D(3) production can influence intestinal P transport also in animals with a normal supply of vitamin D. The intestinal P absorption was evaluated in rats using both the in situ duodenal loop technique and the determination of the overall gastrointestinal absorption under three conditions known to influence the production of 1,25-(OH)(2)D(3): (a) variation in dietary P, (b) thyroparathyroidectomy (TPTX) with or without administration of parathyroid hormone (PTH), and (c) treatment with disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP). In all circumstances changes in duodenal absorption paralleled the changes in the overall fractional absorption. (a) Lowering dietary P stimulated P absorption. (b) TPTX decreased P absorption. This effect was corrected either by the administration of PTH or by the administration of 1,25-(OH)(2)D(3). (c) EHDP, when given at a dose known to inhibit 1,25-(OH)(2)D(3) formation, decreased the duodenal P absorption in both intact and TPTX animals. This effect was corrected by 1,25-(OH)(2)D(3). In the TPTX-EHDP-treated animals, the administration of PTH did not rectify the low duodenal P absorption. These results support the thesis that, in rats with normal vitamin D supply, variations in the endogenous production of 1,25-(OH)(2)D(3) change the rate of P absorption. However, these changes are in such magnitude that they are of relatively small importance when compared to the effect of variation in the dietary intake of P. These results also strongly suggest that the action of PTH on duodenal P transport is mediated by its effect on 1,25-(OH)(2)D(3) production, inasmuch as the effect of the hormone is abolished after blocking the renal 1-hydroxylation with EHDP.

Effect of 1,25-dihydroxyvitamin D3 on the renal handling of Pi in thyroparathyroidectomized rats.

The kidney adapts its tubular capacity to transport inorganic phosphate (P(i)) according to the dietary supply of P(i) in both intact and thyropara-thyroidectomized (TPTX) rats. However, in TPTX rats the capability of the renal tubule to adapt to a high P(i) diet is diminished. In TPTX rats the production of the active vitamin D(3) metabolite, 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], is also reduced. 1,25-(OH)(2)D(3) has been shown to have a marked effect on P(i) metabolism. Therefore the question arises whether the deficient production of 1,25-(OH)(2)D(3) contributes to the alteration of the tubular transport of P(i) observed in chronically TPTX rats. In the present investigation, vitamin D-replete rats were sham operated (SHAM) or thyroparathyroidectomized and then pair fed diets containing either 0.2 or 1.2 g/100 g P for 7 days. During this period, groups of SHAM and TPTX rats received i.p. 2 x 13 pmol/day of 1,25-(OH)(2)D(3), a dose which was shown to just normalize the decreased intestinal absorption of Ca and P(i) in TPTX rats. The capacity of tubular P(i) transport was then assessed by measuring the fractional excretion of P(i) (FEP(i)) at increasing plasma P(i) concentration ([P(i)](Pl)) obtained by acute infusion of P(i). The results show that in SHAM rats fed either P diet, 1,25-(OH)(2)D(3) has no effect on the renal handling of P(i). In TPTX rats fed 1.2 g/100 g P diet, 1,25-(OH)(2)D(3) increases FEP(i) over a wide range of [P(i)](Pl.) In TPTX rats fed a 0.2 g/100 g P diet, 1,25-(OH)(2)D(3) does not alter FEP(i) up to a [P(i)](Pl) of 3.0-3.5 mM, but does increase it at higher [P(i)](Pl.) In fact, on both diets TPTX rats supplemented with 1,25-(OH)(2)D(3) appear to have the same renal handling of P(i) as SHAM counterparts. The effect of 1,25-(OH)(2)D(3) was not associated with a change in urine pH or in urinary excretion of cyclic AMP and was maintained under marked extracellular volume expansion. It was associated with a rise in plasma calcium in the TPTX rats fed the high, but not the low, P diet. In TPTX rats fed 1.2 g/100 g P diet, 25-hydroxyvitamin D(3) in doses of 2 x 130 or 2 x 1,300 pmol/day i.p. did not increase FEP(i.)In conclusion, 1,25-(OH)(2)D(3) administered in physiological amounts to TPTX rats restores to normal the capability of the renal tubule to excrete P(i) and to adapt to large variation in dietary P(i). The results suggest that 1,25-(OH)(2)D(3) plays an important role in the regulation of the renal handling of P(i) and that the chronic change in the tubular capacity to transport P(i) after TPTX may be due to the decreased formation of 1,25-(OH)(2)D(3).

Inorganic phosphate homeostasis. Renal adaptation to the dietary intake in intact and thyroparathyroidectomized rats.

The possibility of renal tubular adaptation to variations in dietary inorganic phosphate (Pi) was investigated in intact and thyroparathyroidectomized (TPTX) rats pair-fed diets containing low, normal, and high amounts of Pi for periods up to 10 days. Clearances were measured before and during active i.v. infusions with Pi in conscious animals. Thus tubular reabsorption of phosphate (TRPi) could be assessed over a wide range of plasma phosphate concentrations ([Pi]P1). It was found that the renal tubule could adapt its capacity to transport Pi according to the dietary Pi: TRPi was always higher, for a given [Pi]P1, in the animals fed low than in those fed higher Pi diets. This diet-induced modification also occurred in the absence of thyroparathyroid glands, in the presence of the same calcemia and urinary pH, and during marked extracellular volume expansion. A time-course study in rats TPTX both before and during the administration of the experimental diets showed that a difference in the tubular handling of Pi was detectable as early as 3 days after switching the animals from a normal to low- or high-Pi diets. These results indicate that factors other than parathyroid hormone are implicated in the tubular response to variations in the dietary intake of inorganic phosphate.

Inhibition of parathyroid hormone secretion and parathyroid hormone-independent diminution of tubular calcium reabsorption by WR-2721, a unique hypocalcemic agent.

Hypocalcemia has been observed in patients receiving WR-2721 [S-,2-(3-aminopropylamino)-, ethylphosphorothioic acid]. WR-2721 is a compound that, after being dephosphorylated, provides protection of normal tissues against radio- and chemotherapy. The hypocalcemic response was accompanied by a decrease in the plasma level of parathyroid hormone (PTH) and by hypomagnesemia. Our present studies in rats on the mechanism of the hypocalcemic effect of WR-2721 indicate that: (a) The phosphorylated and dephosphorylated form of WR-2721 induced an equal dose-dependent decrement in plasma calcium. (b) In intact rats a maximal hypocalcemic dose of WR-2721 reduced urinary cyclic AMP excretion from 70.5 +/- 6.3 to 38.2 +/- 3.1 pmol/ml glomerular filtration rate (GFR), a level comparable to that observed (35.9 +/- 5.2 pmol/ml GFR) in thyroparathyroidectomized (TPTX) rats. (c) WR-2721 given to TPTX rats did not significantly interfere with the calcemic effect of bovine PTH 1-34 infused at 2.5 IU/h. Likewise, the drug did not impair the PTH actions on the renal Ca and inorganic phosphate (Pi) handling, and on the urine cyclic AMP excretion. (d) In TPTX rats made normocalcemic by low Pi diet, the hypocalcemic effect of WR-2721 was only about 25% of that observed in intact animals. However, it was associated with increased urine Ca per milliliter GFR, indicating a PTH-independent inhibitory effect on tubular Ca reabsorption. (e) In WR-2721-treated intact rats, prevention of hypomagnesemia by infusing magnesium chloride did not reduce hypocalcemia. In conclusion, the hypocalcemic effect of WR-2721 is not dependent upon the presence of a phosphate group in the molecule and is not causally related to hypomagnesemia. WR-2721 appears to be a unique hypocalcemic pharmacologic agent with strong inhibitory activity on PTH secretion and additional PTH-independent action on renal Ca reabsorption.

Normalization of hypercalcemia associated with a decrease in renal calcium reabsorption in Leydig cell tumor-bearing rats treated with WR-2721.

The Rice-500 Leydig cell tumor (LCT) in Fischer rats is a model of humoral hypercalcemia of malignancy (HHM). In this model, the elevation of plasma calcium (Ca) does not result merely from an increased bone resorption, but also from an enhanced tubular Ca reabsorption (TRCa). We investigated the hypocalcemic response to WR-2721 [S-2,2-(3-aminopropylamino)-, ethylphosphorothioic acid] in LCT-bearing Fischer rats. WR-2721 is a potent inhibitor of normal and aberrant parathyroid hormone (PTH) secretion. Moreover, it exerts a PTH-independent inhibitory effect on TRCa. In hypercalcemic LCT-bearing rats WR-2721 induced a fall in plasma Ca from 3.24 +/- 0.12 to 2.66 +/- 0.23 mmol/liter within 2 h after one single injection of 0.7 mmol/kg body wt. The decrement in plasma Ca was associated with a marked increase in urinary Ca excretion, indicating an inhibition of TRCa. The elevated urine cyclic AMP of LCT-bearing rats, however, was not altered by WR-2721 treatment. These results suggest that in this HHM model, WR-2721 can normalize calcemia through its PTH-independent inhibitory effect on TRCa. WR-2721 could therefore be an effective drug to treat human hypercalcemia of malignancy, particularly in those tumors wherein a markedly enhanced renal Ca reabsorption contributes to the elevation of the plasma Ca level.

Resistance to the phosphaturic and calcemic actions of parathyroid hormone during phosphate depletion. Prevention by 1,25-dihydroxyvitamin D3.

Recent observations indicate that in thyroparathyroidectomized (TPTX) rats fed a low (0.2 g/100 g) phosphorus diet, the tubular phosphaturic response to parathyroid hormone (PTH) remains markedly blunted even when it is assessed at normal or high plasma concentration and filtered load of inorganic phosphate (Pi). Because 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] decreases the tubular capacity to reabsorb Pi when chronically administered to TPTX rats, we have studied whether this vitamin D(3) metabolite could specifically increase the phosphaturic response to PTH in phosphate-deprived animals. The results show that in Vitamin D-replete TPTX rats fed a low (0.2 g/100 g) phosphorus diet, 1,25(OH)(2)D(3) (2 x 13 pmol/d i.p. for 7 d) markedly enhanced the acute tubular phosphaturic response to PTH (2.5 IU/h i.v.) without affecting the action of the peptide hormone on Ca reabsorption and cyclic-3',5'-AMP excretion. The influence of 1,25(OH)(2)D(3) on the phosphaturic response to PTH could not be ascribed to an increased plasma concentration and(or) filtered load of Pi during the administration of the peptide hormone. However, it could be, at least in part, related to the elevation in the basal level of plasma Pi which was observed in the 1,25(OH)(2)D(3)-treated animals. The results also indicate that 1,25(OH)(2)D(3) significantly enhanced the calcemic response to PTH, which was blunted in these conditions of phosphate deprivation. Unlike 1,25-(OH)(2)D(3), 25-hydroxyvitamin D(3) did not unmask the phosphaturic effect of PTH in phosphate-depleted animals, even when given in doses 100 times larger. Thus, 1,25(OH)(2)D(3) displays a selective and powerful activity in preventing the occurrence of tubular resistance to the phosphaturic action of PTH during Pi depletion. This finding suggests the existence of an important interaction between dietary Pi, 1,25(OH)(2)D(3), and PTH in the homeostasis of phosphate.

Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency.

To evaluate the role of tumor necrosis factor (TNF alpha) in bone loss resulting from estrogen deficiency, the effects of ovariectomy were explored in six-month-old transgenic mice expressing high blood levels of a soluble TNF receptor type I (sTNFR1)-FcIgG3 fusion protein, which neutralizes TNF alpha, and in their nontransgenic littermates used as controls. These transgenic mice were identical to control mice in bone mass (evaluated by bone mineral density and content) and strength. 12 weeks after ovariectomy, the decrease in bone mass and increase in osteocalcin (marker of bone turnover) found in control mice were not observed in transgenic mice, which were not different from sham-operated mice, transgenic or not. This observation suggests a critical role for TNF alpha in the pathogenesis of bone loss induced by estrogen deficiency, a common cause of morbidity in postmenopausal women.

Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial.

High calcium intake during childhood has been suggested to increase bone mass accrual, potentially resulting in a greater peak bone mass. Whether the effects of calcium supplementation on bone mass accrual vary from one skeletal region to another, and to what extent the level of spontaneous calcium intake may affect the magnitude of the response has, however, not yet been clearly established. In a double-blind, placebo-controlled study, 149 healthy prepubertal girls aged 7.9+/-0.1 yr (mean+/-SEM) were either allocated two food products containing 850 mg of calcium (Ca-suppl.) or not (placebo) on a daily basis for 1 yr. Areal bone mineral density (BMD), bone mineral content (BMC), and bone size were determined at six sites by dual-energy x-ray absorptiometry. The difference in BMD gain between calcium-supplemented (Ca-suppl.) and placebo was greater at radial (metaphysis and diaphysis) and femoral (neck, trochanter, and diaphyses) sites (7-12 mg/cm2 per yr) than in the lumbar spine (2 mg/cm2 per yr). The difference in BMD gains between Ca-suppl. and placebo was greatest in girls with a spontaneous calcium intake below the median of 880 mg/d. The increase in mean BMD of the 6 sites in the low-calcium consumers was accompanied by increased gains in mean BMC, bone size, and statural height. These results suggest a possible positive effect of calcium supplementation on skeletal growth at that age. In conclusion, calcium-enriched foods significantly increased bone mass accrual in prepubertal girls, with a preferential effect in the appendicular skeleton, and greater benefit at lower spontaneous calcium intake.

Food fortification for bone health in adulthood: a scoping review.

Food fortification can deliver essential micronutrients to large population segments without modifications in consumption pattern, suggesting that fortified foods may be formulated for populations at risk for fragility fractures. This scoping review determined the extent to which randomized controlled studies have been carried out to test the impact of fortified foods on bone outcomes, searching PubMed for all studies using the terms 'fortified AND bone', and 'fortification AND bone'. Studies were restricted to English language, published between 1996 and June 2015. From 360 articles, 24 studies met the following criteria: human study in adults ⩾18 years (excluding pregnancy or lactation); original study of a fortified food over time, with specific bone outcomes measured pre- and post intervention. Six studies involved adults <50 years; 18 involved adults ⩾50 years. Singly or in combination, 17 studies included calcium and 16 included vitamin D. There were 1 or 2 studies involving either vitamin K, magnesium, iron, zinc, B-vitamins, inulin or isoflavones. For adults <50 years, the four studies involving calcium or vitamin D showed a beneficial effect on bone remodeling. For adults ⩾50 years, n=14 provided calcium and/or vitamin D, and there was a significant bone turnover reduction. No consistent effects were reported in studies in which addition of vitamin K, folic acid or isoflavone was assessed. Results from this scoping review indicate that up to now most studies of fortification with bone health have evaluated calcium and/or vitamin D and that these nutrients show beneficial effects on bone remodeling.

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.

BACKGROUND: Calcium supplementation during childhood and adolescence is considered an early means of preventing osteoporosis in adults. Prepuberty is an opportune time for detecting the benefits of calcium in girls. OBJECTIVE: The objective was to assess whether calcium supplementation increases bone mass gain in prepubertal boys in a skeletal site-specific manner. METHODS: In a 12-month double-blind, placebo-controlled trial with 1-yr follow-up, 235 healthy prepubertal boys aged 7.4 +/- 0.4 yr (mean +/- sd) were randomized to receive two food products providing 850 mg/d calcium (calcium supplement group, n = 116) or an isocaloric placebo (n = 119). Areal bone mineral density (aBMD) was determined by dual-energy x-ray absorptiometry at radius (two sites), hip (two sites), femoral diaphysis (FDia), and L2-L4 vertebrae. RESULTS: At 12 months, aBMD gain was greater at the FDia and at the mean of the five appendicular skeletal sites in the calcium supplement group in both intention-to-treat analysis [76 +/- 32 vs. 64 +/- 33 mg/cm(2).yr; difference, 12.0 (95% confidence interval, CI, 3.6-20.3), P = 0.006; and 33 +/- 16 vs. 28 +/- 16 mg/cm(2).yr; difference, 5.1 (95% CI, 0.9-9.2); P = 0.018, respectively] and active treatment analysis [81 +/- 32 vs. 64 +/- 31 mg/cm(2).yr; difference, 17.2 (95% CI, 7.9-26.5); n = 174, P < 0.001; and 35 +/- 16 vs. 28 +/- 14 mg/cm(2).yr; difference, 7.5 (95% CI, 2.9-12.2); P = 0.002]. There was no beneficial effect of calcium on lumbar spine. The calcium effect was still detectable by ANOVA repeated measures analysis at the FDia (P = 0.004) and at the mean of the five appendicular skeletal sites (P = 0.002) 1 yr after the end of intervention (active treatment analysis). There was no change in bone size. CONCLUSION: In prepubertal boys, calcium-enriched foods increased aBMD at several appendicular skeleton sites, but not at the lumbar spine, and this without any bone size change. This effect was maintained 1 yr after treatment discontinuation.

Phosphate homeostasis, 1,25-dihydroxyvitamm D(3), and hyperparathyroidism in early chronic renal failure.

In early chronic renal failure, low plasma levels of calcitriol (1,25[OH](2)D(3)) do not seem to be merely the consequence of a reduced mass of functional nephrons. Indeed, this alteration can be considered as a compensatory mechanism, as analyzed according to a new concept of inorganic phosphate (P(i)) homeostasis that integrates both 1,25(OH)(2)D(3) production and renal P(i) reabsorption as essential regulating elements. Accordingly, the observed reduction in the renal production of 1,25(OH)(2)D(3) that occurs concomitantly with a decrease in tubular P(i) reabsorptive capacity (TmP(i)/GFR) may well represent a secondary adaptive response to a primary alteration in P(i) homeostasis. This crucial alteration in P(i) homeostasis would consist of an overload of a putative regulated intracellular P(i) pool, the localization of which remains to be determined. The observed hypophosphatemia, hypocalcemia, and PTH hypersecretion would represent alterations secondary to a low TmP(i)/GFR and to reduced 1,25(OH)(2)D(3) production. According to this pathophysiologic sequence, 1,25(OH)(2)D(3), rather than PTH as proposed in a former theory, would be "traded off" to preserve P(i) homeostasis in early chronic renal failure. Both theories predict that dietary P(i) restriction represents a logical preventive therapy at least until the nature of the primary defect in P(i) homeostasis is understood. However, assuming that low 1,25(OH)(2)D(3) levels in early chronic renal failure represent a compensatory phenomenon, this new theory suggests that calcitriol should be only administered at a later stage of the disease, when the production of 1,25(OH)(2)D(3) becomes inappropriately low to maintain mineral homeostasis.

The vitamin d receptor gene and calcium metabolism.

Dietary Ca(2+) is essential for the development and maintenance of bone mineral mass. The vitamin D endocrine system plays a fundamental role in the regulation of Ca(2+) homeostasis, and mutations affecting genes implicated in vitamin D metabolism or vitamin D receptor (VDR) functions are responsible for severe alterations in skeletal growth. In addition, vitamin D is also implicated in the pathophysiology and treatment of adult bone disorders associated with impaired mineralization of bone matrix. Very recently, common polymorphisms in the 3'- and 5'-end region of the VDR gene have been suggested as possible determinants of bone mineral mass and, hence, of the risk of osteoporosis. None of these polymorphisms appear to be associated unequivocally with bone mineral mass or biochemical variables of Ca(2+) and phosphate metabolism, except perhaps VDR 3'-end polymorphisms before puberty. As these associations are so inconsistent, interactions with environmental factors, particularly dietary intake, and with other polymorphisms have to be considered.

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.

OBJECTIVE: To evaluate whether fortification of yogurts with vitamin D and calcium exerts an additional lowering effect on serum parathyroid hormone (PTH) and bone resorption markers (BRM) as compared to iso-caloric and iso-protein dairy products in aged white women at risk of fragility fractures. DESIGN: A randomized double-blind controlled trial. SETTING: A community dwelling home. PARTICIPANTS: Forty-eight women over 60 years (mean age 73.4). INTERVENTION: Consumption during 84 days of two 125 g servings of either vitamin D and calcium-fortified yogurts (FY) at supplemental levels of 10 µg vitamin D3/d and 520 mg/d of calcium (total=800 mg/d), or non fortified control yogurts (CY) providing 280 mg/d of calcium. MEASUREMENTS: Serum changes from baseline (D0) to D28, D56 and D84 in 25OHD, PTH and in two BRM: Tartrate-resistant-acid-phosphatase-isoform-5b (TRAP5b) and carboxy-terminal-cross-linked-telopeptide of type-I-collagen (CTX). RESULTS: The 10 years risk of major and hip fractures were 13.1 and 5.0%, and 12.9 and 4.2 %, in FY and CY groups, respectively. From D0 to D84, serum 25OHD increased (mean±SE) from 34.3±2.4 to 56.3±2.4 nmol/L in FY (n=24) and from 35.0±2.5 to 41.3±3.0 nmol/L in CY (n=24), (P=0.00001). The corresponding changes in PTH were from 64.1±5.1 to 47.4±3.8 ng/L in FY and from 63.5±4.6 to 60.7±4.2 ng/L in CY (P=0.0011). After D84, TRAP5b was reduced significantly (P=0.0228) and CTX fell though not significantly (P=0.0773) in FY compared to CY. CONCLUSION: This trial in aged white women living in a community dwelling home at risk for osteoporotic fractures confirms that fortification of dairy products with vitamin D3 and calcium should provide a greater prevention of secondary hyperparathyroidism and accelerated bone resorption as compared to non-fortified equivalent foods.