Tag Archives: human

High Salt Diet May be a Risk Factor for Osteoporosis in Korean Women


Association between Urinary Sodium Excretion and Bone Health in Male and Female Adults.

High salt intake is a well-known risk factor for osteoporosis, but the association between bone mass and urinary sodium excretion has not been studied as yet. This study investigates the hypothesis that urinary sodium excretion is negatively associated with bone mass and the risk of osteoporosis.
This cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey, 2008-2011. Participants (n = 16,279) were divided into age groups; men were categorized as younger than 50 years of age or 50 years or greater, women were categorized as pre- or post-menopausal. Multivariate linear regression analysis showed that urinary sodium excretion was negatively associated with bone mineral content (BMC) and bone mineral density (BMD) in premenopausal and postmenopausal women. Sodium excretion was negatively associated with BMC and BMD of the lumbar spine in women with normal bone health, osteopenia and osteoporosis, but there was no association in men. Increased sodium excretion was significantly associated with risk for osteoporosis/osteopenia in premenopausal women. This study demonstrates that urinary sodium excretion is negatively associated with bone health, suggesting that high salt intake could be a possible risk factor for osteoporosis in Korean women, but not in men.

Park Y, Kwon SJ, Ha YC
Ann. Nutr. Metab. 2016
PMID: 26967579

Protein Intake Above the Current RDA May Help Prevent Fractures


Dietary Protein Intake above the Current RDA and Bone Health: A Systematic Review and Meta-Analysis.

Dietary intake of protein is fundamental for optimal acquisition and maintenance of bone across all life stages; however, it has been hypothesized that intakes above the current recommended dietary allowance (RDA) might be beneficial for bone health. We utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines when preparing and reporting this systematic review and meta-analysis. A literature search strategy through April 11, 2017, was developed for the following 3 databases: PubMed, Ovid Medline, and Agricola. Included studies were those randomized controlled trials and prospective cohort studies among healthy adults ages 18 and older that examined the relationships between varying doses of protein intake at or above the current U.S. RDA (0.8 g/kg/d or 10%-15% of total caloric intake) from any source on fracture, bone mineral density (BMD)/bone mineral content (BMC), and/or markers of bone turnover. Twenty-nine articles were included for data extraction (16 randomized controlled trials [RCTs] and 13 prospective cohort studies). Meta-analysis of the prospective cohort studies showed high vs low protein intakes resulted in a statistically significant 16% decrease in hip fractures (standardized mean difference [SMD] = 0.84, 95% confidence interval [CI], 0.73, 0.95; I(2) = 36.8%). Data from studies included in these analyses collectively lean toward the hypothesis that protein intake above the current RDA is beneficial to BMD at several sites. This systematic review supports that protein intakes above the current RDA may have some beneficial role in preventing hip fractures and BMD loss. There were no differences between animal or plant proteins, although data in this area were scarce. Larger, long-term, and more well-controlled clinical trials measuring fracture outcomes and BMD are needed to adequately assess whether protein intake above the current RDA is beneficial as a preventative measure and/or intervention strategy for osteoporosis. Key teaching points: Bone health is a multifactorial musculoskeletal issue, and optimal protein intakes are key in developing and maintaining bone throughout the life span. Dietary protein at levels above the current RDA may be beneficial in preventing hip fractures and BMD loss. Plant vs animal proteins do not seem to differ in their ability to prevent bone loss; however, data in this area are scarce. Larger, long-term RCTs using women not using hormone replacement therapy (HRT) are needed to adequately assess the magnitude of impact that protein intakes above the RDA have on preventing bone loss.

Wallace TC, Frankenfeld CL
J Am Coll Nutr Aug 2017
PMID: 28686536

Hesperidin Increases Calcium Retention 5.5% in Postmenopausal Women


Effect of Hesperidin With and Without a Calcium (Calcilock) Supplement on Bone Health in Postmenopausal Women.

Citrus fruits contain unique flavanones. One of the most abundant of the flavanones, hesperidin, has been shown to prevent bone loss in ovariectomized rats.
The objective of the study was to measure the effect of hesperidin with or without calcium supplementation on bone calcium retention in postmenopausal women. The study was a double-blind, placebo-controlled, randomized-order crossover design of 500 g hesperidin with or without 500 mg calcium supplement in 12 healthy postmenopausal women. Bone calcium retention was determined from urinary excretion of the rare isotope, (41)Ca, from bone. Calcium plus hesperidin, but not hesperidin alone, improved bone calcium retention by 5.5% (P < .04). Calcium supplementation (Calcilock), in combination with hesperidin, is effective at preserving bone in postmenopausal women.

Martin BR, McCabe GP, McCabe L, Jackson GS…
J. Clin. Endocrinol. Metab. Mar 2016
PMID: 26751193

Calcium-Collagen Chelate Reduces Sclerostin in Women


A calcium-collagen chelate dietary supplement attenuates bone loss in postmenopausal women with osteopenia: a randomized controlled trial.

Menopause leads to an increased risk for osteoporosis in women. Although drug therapies exist, increasing numbers of people prefer alternative therapies such as dietary supplements, for example, calcium, vitamin D, and collagen hydrolysates for the prevention and treatment of osteoporosis. We have previously shown that a 3-month intervention using a calcium-collagen chelate (CC) dietary supplement was efficacious in improving bone mineral density (BMD) and blood biomarkers of bone turnover in osteopenic postmenopausal women. This study reports the long-term efficacy of CC in reducing bone loss in postmenopausal women with osteopenia. Thirty-nine women were randomly assigned to one of two groups: 5 g of CC containing 500 mg of elemental calcium and 200 IU vitamin D (1,25-dihydroxyvitamin D3) or control (500 mg of calcium and 200 IU vitamin D) daily for 12 months. Total body, lumbar, and hip BMD were evaluated at baseline, 6 and 12 months using dual-energy X-ray absorptiometry. Blood was collected at baseline, 6 and 12 months to assess levels of blood biomarkers of bone turnover. Intent-to-treat (ITT) analysis was performed using repeated measures analysis of variance pairwise comparisons and multivariate analysis to assess time and group interactions. The loss of whole body BMD in women taking CC was substantially lower than that of the control group at 12 months in those who completed the study and the ITT analysis, respectively (CC: -1.33% and -0.33% vs. control: -3.75% and -2.17%; P=.026, P=.035). The CC group had significantly reduced levels of sclerostin and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) (P<.05), and higher bone-specific alkaline phosphatase/TRAP5b ratio (P<.05) than control at 6 months. These results support the use of CC in reducing bone loss in osteopenic postmenopausal women.

Elam ML, Johnson SA, Hooshmand S, Feresin RG…
J Med Food Mar 2015
PMID: 25314004

Resveratrol and SIRT1 Reduces Sclerostin Expression In-Vitro


Low sirtuin 1 levels in human osteoarthritis subchondral osteoblasts lead to abnormal sclerostin expression which decreases Wnt/β-catenin activity.

Wnt/β-catenin (cWnt) signaling plays a key role in osteogenesis by promoting the differentiation and mineralization of osteoblasts, activities altered in human osteoarthritic subchondral osteoblast (OA Ob). Sclerostin (SOST) has been shown to alter cWnt signaling. Sirtuin 1 (SIRT1) acts as a novel bone regulator and represses SOST levels in Ob. However the role of SIRT1 and SOST in OA Ob remains unknown. Herein, we explored the role played by SIRT1 and SOST on the abnormal mineralization and cWnt signaling in OA Ob.
Primary human normal and OA Ob were prepared from tibial plateaus. SOST levels were evaluated by immunohistochemistry, the expression and production of genes by qRT-PCR and WB analysis. Their inhibitions were performed using siRNA. cWnt signaling was measured by the TOPflash TCF/lef luciferase reporter assay. Mineralization was determined by alizarin red staining.
SOST levels were significantly increased in OA Ob compared to normal and were linked with elevated TGF-β1 levels in these cells. SIRT1 expression was significantly reduced in OA Ob compared to normal yet not modified by TGF-β1. Specific inhibition of SIRT1 increased TGF-β1 and SOST expressions in OA Ob, while stimulating SIRT1 activity with β-Nicotinamide mononucleotide reduced the expression of TGF-β1 and SOST, and increased mineralization in OA Ob. Resveratrol also reduced SOST expression in OA Ob. Reduced cWnt signaling, β-catenin levels, and mineralization in OA Ob were all corrected via reducing SOST expression.
These data indicate that high level of SOST is responsible, in part, for the reduced cWnt and mineralization of human OA Ob, which in turn is linked with abnormal SIRT1 levels in these pathological cells.

Abed É, Couchourel D, Delalandre A, Duval N…
Bone Feb 2014
PMID: 24184155

Oxytocin Associated with Bone Density in Postmenopausal Women


Oxytocin, a new determinant of bone mineral density in post-menopausal women: analysis of the OPUS cohort.

Oxytocin (OT), a neurohypophysial hormone regulated by estrogen and leptin, may play a role in bone metabolism in humans as suggested by animal studies. This study assessed the relationship between OT and bone status in a large population of postmenopausal women.
Subjects were included in the Osteoporosis and Ultrasound study, a 6-year prospective study in a population-based cohort. Final visit data were used for this cross-sectional study. OT, leptin, and estradiol serum levels were measured in 1097 postmenopausal women and compared with bone mineral density (BMD), fractures, and the bone turnover markers (BTMs) procollagen type 1 N-terminal propeptide, bone alkaline phosphatase, and C-telopeptide of type 1 collagen.
The median age was 70.8 years, 16% were osteoporotic, 48% were osteopenic, and 29% had at least one fracture. The OT serum level was related to spine (r = +0.12, P = .0002) and total hip BMD (r = +0.21, P < .0001) and with BTM (procollagen type 1 N-terminal propeptide: r = -0.13, P < .0001, bone alkaline phosphatase: r = -0.07, P = .02, C-telopeptide of type 1 collagen: r = -0.18, P < .0001). The relationship of OT with BMD was independent of BTM. After adjustment for confounding factors, the correlation between OT serum level and BMD remains significant at the hip in women with unmeasurable estradiol or leptin above the median value. There was no significant relationship between OT serum levels and fractures.
High OT levels are associated with high BMD, especially at the hip in women with low estradiol or high leptin serum levels. The mechanism may be explained by the effect of OT on bone turnover.

Breuil V, Panaia-Ferrari P, Fontas E, Roux C…
J. Clin. Endocrinol. Metab. Apr 2014
PMID: 24446658

Oxytocin is Lower in Osteoporotic Women


Oxytocin and bone remodelling: relationships with neuropituitary hormones, bone status and body composition.

There is growing evidence that oxytocin, which regulates appetite, plays a role in bone remodelling and improves osteoporosis. We previously showed a significant decrease in circulating oxytocin levels in postmenopausal osteoporotic women compared to healthy controls. However, factors involved in the pathophysiology of osteoporosis, such as estrogens and leptin, are known to regulate oxytocin secretion. Herein, we evaluated the relationships between oxytocin and other hormonal factors known to regulate bone remodeling and body composition in postmenopausal osteoporotic women, compared to healthy controls.
In 20 postmenopausal women with severe osteoporosis compared to 16 healthy controls, we measured serum levels of oxytocin, high sensitive estradiol, testosterone, FSH, LH, SHBG, TSH, osteocalcin, serum type I collagen carboxy-terminal telopeptide, leptin. Bone mineral density and body composition were also measured with DXA.
Osteoporotic women had significantly lower oxytocin, leptin and LH serum levels and higher CTX and SHBG; all other biological parameters were similar in both groups. Fat mass and lean mass were significantly decreased in osteoporotic women. Oxytocin serum levels were significantly correlated to bone mineral density but not to any other measured parameter, including leptin, estradiol and age. In a logistic regression analysis, osteoporosis remained significantly correlated to oxytocin, regardless of age.
Low oxytocin serum levels appeared to be associated with severe osteoporosis, independently of other factors associated with osteoporosis or known to regulate oxytocin serum levels, such as estradiol or leptin, reinforcing the concept that oxytocin may be involved in the pathophysiology of postmenopausal osteoporosis.

Breuil V, Amri EZ, Panaia-Ferrari P, Testa J…
Joint Bone Spine Dec 2011
PMID: 21441053

Oxytocin is Lower in Osteoporosis


Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis.

Osteoporosis constitutes a major worldwide public health burden characterized by enhanced skeletal fragility. Bone metabolism is the combination of bone resorption by osteoclasts and bone formation by osteoblasts. Whereas increase in bone resorption is considered as the main contributor of bone loss that may lead to osteoporosis, this loss is accompanied by increased bone marrow adiposity. Osteoblasts and adipocytes share the same precursor cell and an inverse relationship exists between the two lineages. Therefore, identifying signaling pathways that stimulate mesenchymal stem cells osteogenesis at the expense of adipogenesis is of major importance for developing new therapeutic treatments. For this purpose, we identified by transcriptomic analysis the oxytocin receptor pathway as a potential regulator of the osteoblast/adipocyte balance of human multipotent adipose-derived stem (hMADS) cells. Both oxytocin (OT) and carbetocin (a stable OT analogue) negatively modulate adipogenesis while promoting osteogenesis in both hMADS cells and human bone marrow mesenchymal stromal cells. Consistent with these observations, ovariectomized (OVX) mice and rats, which become osteoporotic and exhibit disequilibrium of this balance, have significant decreased OT levels compared to sham-operated controls. Subcutaneous OT injection reverses bone loss in OVX mice and reduces marrow adiposity. Clinically, plasma OT levels are significantly lower in postmenopausal women developing osteoporosis than in their healthy counterparts. Taken together, these results suggest that plasma OT levels represent a novel diagnostic marker for osteoporosis and that OT administration holds promise as a potential therapy for this disease.

Elabd C, Basillais A, Beaupied H, Breuil V…
Stem Cells Sep 2008
PMID: 18583541 | Free Full Text

Oxytocin Reverses Osteoporosis in Female but Not Male Mice


Oxytocin reverses osteoporosis in a sex-dependent manner.

The increase of life expectancy has led to the increase of age-related diseases such as osteoporosis. Osteoporosis is characterized by bone weakening promoting the occurrence of fractures with defective bone regeneration. Men aged over 50 have a prevalence for osteoporosis of 20%, which is related to a decline in sex hormones occurring during andropause or surgical orchidectomy. As we previously demonstrated in a mouse model for menopause in women that treatment with the neurohypophyseal peptide hormone oxytocin (OT) normalizes body weight and prevents the development of osteoporosis, herein we addressed the effects of OT in male osteoporosis. Thus, we treated orchidectomized mice, an animal model suitable for the study of male osteoporosis, for 8 weeks with OT and then analyzed trabecular and cortical bone parameters as well as fat mass using micro-computed tomography. Orchidectomized mice displayed severe bone loss, muscle atrophy accompanied by fat mass gain as expected in andropause. Interestingly, OT treatment in male mice normalized fat mass as it did in female mice. However, although OT treatment led to a normalization of bone parameters in ovariectomized mice, this did not happen in orchidectomized mice. Moreover, loss of muscle mass was not reversed in orchidectomized mice upon OT treatment. All of these observations indicate that OT acts on fat physiology in both sexes, but in a sex specific manner with regard to bone physiology.

Beranger GE, Djedaini M, Battaglia S, Roux CH…
Front Endocrinol (Lausanne) 2015
PMID: 26042090 | Free Full Text

Sclerostin Inhibitor Increases Bone Strength More than the Controls in Rats


Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.

The development of bone-rebuilding anabolic agents for potential use in the treatment of bone loss conditions, such as osteoporosis, has been a long-standing goal. Genetic studies in humans and mice have shown that the secreted protein sclerostin is a key negative regulator of bone formation, although the magnitude and extent of sclerostin’s role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, we used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis. Six-month-old female rats were ovariectomized and left untreated for 1 yr to allow for significant estrogen deficiency-induced bone loss, at which point Scl-AbII was administered for 5 wk. Scl-AbII treatment in these animals had robust anabolic effects, with marked increases in bone formation on trabecular, periosteal, endocortical, and intracortical surfaces. This not only resulted in complete reversal, at several skeletal sites, of the 1 yr of estrogen deficiency-induced bone loss, but also further increased bone mass and bone strength to levels greater than those found in non-ovariectomized control rats. Taken together, these preclinical results establish sclerostin’s role as a pivotal negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.

Li X, Ominsky MS, Warmington KS, Morony S…
J. Bone Miner. Res. Apr 2009
PMID: 19049336