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David A Hanley - One of the best experts on this subject based on the ideXlab platform.

  • causal assessment of dietary acid load and bone disease a systematic review meta analysis applying hill s epidemiologic criteria for causality
    Nutrition Journal, 2011
    Co-Authors: Tanis R Fenton, Andrew W Lyon, Suzanne Tough, Misha Eliasziw, David A Hanley
    Abstract:

    Background: Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill’s criteria. Methods: Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined. Results: Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine Calcium excretion, Calcium Balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine Calcium excretion rates were consistent with osteoporosis development; however Calcium Balance studies did not demonstrate loss of whole body Calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis.

  • meta analysis of the effect of the acid ash hypothesis of osteoporosis on Calcium Balance
    Journal of Bone and Mineral Research, 2009
    Co-Authors: Tanis R Fenton, Andrew W Lyon, Michael Eliasziw, Suzanne Tough, David A Hanley
    Abstract:

    The acid-ash hypothesis posits that protein and grain foods, with a low potassium intake, produce a diet acid load, net acid excretion (NAE), increased urine Calcium, and release of Calcium from the skeleton, leading to osteoporosis. The objectives of this meta-analysis were to assess the effect of changes in NAE, by manipulation of healthy adult subjects' acid-base intakes, on urine Calcium, Calcium Balance, and a marker of bone metabolism, N-telopeptides. This meta-analysis was limited to studies that used superior methodological quality for the study of Calcium metabolism. We systematically searched the literature and included studies if subjects were randomized to the interventions and followed the recommendations of the Institute of Medicine's Panel on Calcium and Related Nutrients for Calcium studies. Five of 16 studies met the inclusion criteria. The studies altered the amount and/or type of protein. Despite a significant linear relationship between an increase in NAE and urinary Calcium (p < 0.0001), there was no relationship between a change of NAE and a change of Calcium Balance (p = 0.38; power = 94%). There was no relationship between a change of NAE and a change in the marker of bone metabolism, N-telopeptides (p = 0.95). In conclusion, this meta-analysis does not support the concept that the calciuria associated with higher NAE reflects a net loss of whole body Calcium. There is no evidence from superior quality Balance studies that increasing the diet acid load promotes skeletal bone mineral loss or osteoporosis. Changes of urine Calcium do not accurately represent Calcium Balance. Promotion of the "alkaline diet" to prevent Calcium loss is not justified.

  • phosphate decreases urine Calcium and increases Calcium Balance a meta analysis of the osteoporosis acid ash diet hypothesis
    Nutrition Journal, 2009
    Co-Authors: Tanis R Fenton, Andrew W Lyon, Michael Eliasziw, Suzanne Tough, David A Hanley
    Abstract:

    The acid-ash hypothesis posits that increased excretion of "acidic" ions derived from the diet, such as phosphate, contributes to net acidic ion excretion, urine Calcium excretion, demineralization of bone, and osteoporosis. The public is advised by various media to follow an alkaline diet to lower their acidic ion intakes. The objectives of this meta-analysis were to quantify the contribution of phosphate to bone loss in healthy adult subjects; specifically, a) to assess the effect of supplemental dietary phosphate on urine Calcium, Calcium Balance, and markers of bone metabolism; and to assess whether these affects are altered by the b) level of Calcium intake, c) the degree of protonation of the phosphate. Literature was identified through computerized searches regarding phosphate with surrogate and/or direct markers of bone health, and was assessed for methodological quality. Multiple linear regression analyses, weighted for sample size, were used to combine the study results. Tests of interaction included stratification by Calcium intake and degree of protonation of the phosphate supplement. Twelve studies including 30 intervention arms manipulated 269 subjects' phosphate intakes. Three studies reported net acid excretion. All of the meta-analyses demonstrated significant decreases in urine Calcium excretion in response to phosphate supplements whether the Calcium intake was high or low, regardless of the degree of protonation of the phosphate supplement. None of the meta-analyses revealed lower Calcium Balance in response to increased phosphate intakes, whether the Calcium intake was high or low, or the composition of the phosphate supplement. All of the findings from this meta-analysis were contrary to the acid ash hypothesis. Higher phosphate intakes were associated with decreased urine Calcium and increased Calcium retention. This meta-analysis did not find evidence that phosphate intake contributes to demineralization of bone or to bone Calcium excretion in the urine. Dietary advice that dairy products, meats, and grains are detrimental to bone health due to "acidic" phosphate content needs reassessment. There is no evidence that higher phosphate intakes are detrimental to bone health.

Tanis R Fenton - One of the best experts on this subject based on the ideXlab platform.

  • causal assessment of dietary acid load and bone disease a systematic review meta analysis applying hill s epidemiologic criteria for causality
    Nutrition Journal, 2011
    Co-Authors: Tanis R Fenton, Andrew W Lyon, Suzanne Tough, Misha Eliasziw, David A Hanley
    Abstract:

    Background: Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill’s criteria. Methods: Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined. Results: Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine Calcium excretion, Calcium Balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine Calcium excretion rates were consistent with osteoporosis development; however Calcium Balance studies did not demonstrate loss of whole body Calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis.

  • meta analysis of the effect of the acid ash hypothesis of osteoporosis on Calcium Balance
    Journal of Bone and Mineral Research, 2009
    Co-Authors: Tanis R Fenton, Andrew W Lyon, Michael Eliasziw, Suzanne Tough, David A Hanley
    Abstract:

    The acid-ash hypothesis posits that protein and grain foods, with a low potassium intake, produce a diet acid load, net acid excretion (NAE), increased urine Calcium, and release of Calcium from the skeleton, leading to osteoporosis. The objectives of this meta-analysis were to assess the effect of changes in NAE, by manipulation of healthy adult subjects' acid-base intakes, on urine Calcium, Calcium Balance, and a marker of bone metabolism, N-telopeptides. This meta-analysis was limited to studies that used superior methodological quality for the study of Calcium metabolism. We systematically searched the literature and included studies if subjects were randomized to the interventions and followed the recommendations of the Institute of Medicine's Panel on Calcium and Related Nutrients for Calcium studies. Five of 16 studies met the inclusion criteria. The studies altered the amount and/or type of protein. Despite a significant linear relationship between an increase in NAE and urinary Calcium (p < 0.0001), there was no relationship between a change of NAE and a change of Calcium Balance (p = 0.38; power = 94%). There was no relationship between a change of NAE and a change in the marker of bone metabolism, N-telopeptides (p = 0.95). In conclusion, this meta-analysis does not support the concept that the calciuria associated with higher NAE reflects a net loss of whole body Calcium. There is no evidence from superior quality Balance studies that increasing the diet acid load promotes skeletal bone mineral loss or osteoporosis. Changes of urine Calcium do not accurately represent Calcium Balance. Promotion of the "alkaline diet" to prevent Calcium loss is not justified.

  • phosphate decreases urine Calcium and increases Calcium Balance a meta analysis of the osteoporosis acid ash diet hypothesis
    Nutrition Journal, 2009
    Co-Authors: Tanis R Fenton, Andrew W Lyon, Michael Eliasziw, Suzanne Tough, David A Hanley
    Abstract:

    The acid-ash hypothesis posits that increased excretion of "acidic" ions derived from the diet, such as phosphate, contributes to net acidic ion excretion, urine Calcium excretion, demineralization of bone, and osteoporosis. The public is advised by various media to follow an alkaline diet to lower their acidic ion intakes. The objectives of this meta-analysis were to quantify the contribution of phosphate to bone loss in healthy adult subjects; specifically, a) to assess the effect of supplemental dietary phosphate on urine Calcium, Calcium Balance, and markers of bone metabolism; and to assess whether these affects are altered by the b) level of Calcium intake, c) the degree of protonation of the phosphate. Literature was identified through computerized searches regarding phosphate with surrogate and/or direct markers of bone health, and was assessed for methodological quality. Multiple linear regression analyses, weighted for sample size, were used to combine the study results. Tests of interaction included stratification by Calcium intake and degree of protonation of the phosphate supplement. Twelve studies including 30 intervention arms manipulated 269 subjects' phosphate intakes. Three studies reported net acid excretion. All of the meta-analyses demonstrated significant decreases in urine Calcium excretion in response to phosphate supplements whether the Calcium intake was high or low, regardless of the degree of protonation of the phosphate supplement. None of the meta-analyses revealed lower Calcium Balance in response to increased phosphate intakes, whether the Calcium intake was high or low, or the composition of the phosphate supplement. All of the findings from this meta-analysis were contrary to the acid ash hypothesis. Higher phosphate intakes were associated with decreased urine Calcium and increased Calcium retention. This meta-analysis did not find evidence that phosphate intake contributes to demineralization of bone or to bone Calcium excretion in the urine. Dietary advice that dairy products, meats, and grains are detrimental to bone health due to "acidic" phosphate content needs reassessment. There is no evidence that higher phosphate intakes are detrimental to bone health.

Judith A Marlett - One of the best experts on this subject based on the ideXlab platform.

  • increasing amounts of dietary fiber provided by foods normalizes physiologic response of the large bowel without altering Calcium Balance or fecal steroid excretion
    The American Journal of Clinical Nutrition, 1998
    Co-Authors: Valerie S Haack, J G Chesters, Nicholas W Vollendorf, J A Story, Judith A Marlett
    Abstract:

    Nine healthy, young men consumed constant diets to determine selected large-bowel, serum cholesterol and triacylglycerol, and Calcium Balance responses to 3 amounts of fiber provided by a mixture of fruit, vegetables, and grains. The diets, each consumed for I mo, contained 16. 30, and 42 g total fiber/d, of which 2.9, 4.8, and 7.7 g, respectively, was soluble. Mean daily wet and dry stool weights increased with each fiber addition. The first fiber addition increased defecation frequency and decreased fecal pH. bile acid concentration, and neutral steroid concentration; the second addition had no further effect. Mean weight of each defecation and stool moisture did not increase and serum cholesterol and triacylglycerol concentrations, Calcium Balance, and gastrointestinal transit time did not decrease as fiber intake increased. We conclude that 1) fiber provided by a mixed-food diet increases stool weight as effectively as does wheat or oat bran; 2) even high amounts of dietary fiber do not change transit time or defecation frequency if they are already 1 and 2-3 d, respectively: 3) food patterns consistent with the food pyramid and incorporating legumes and whole grains are necessary to achieve recommended fiber intakes of 20-35 g/d, even if energy intake is > 12.55 MJ (3000 kcal); 4) soluble fiber provided by a mixture of whole foods has no effect on serum cholesterol concentrations or output of fecal bile acids; and 5) mixed-food fiber has little effect on Calcium Balance when Calcium intakes are high (≥ 1.5 g/d).

  • increasing amounts of dietary fiber provided by foods normalizes physiologic response of the large bowel without altering Calcium Balance or fecal steroid excretion
    The American Journal of Clinical Nutrition, 1998
    Co-Authors: Valerie S Haack, J G Chesters, Nicholas W Vollendorf, J A Story, Judith A Marlett
    Abstract:

    Nine healthy, young men consumed constant diets to determine selected large-bowel, serum cholesterol and triacylglycerol, and Calcium Balance responses to 3 amounts of fiber provided by a mixture of fruit, vegetables, and grains. The diets, each consumed for 1 mo, contained 16, 30, and 42 g total fiber/d, of which 2.9, 4.8, and 7.7 g, respectively, was soluble. Mean daily wet and dry stool weights increased with each fiber addition. The first fiber addition increased defecation frequency and decreased fecal pH, bile acid concentration, and neutral steroid concentration; the second addition had no further effect. Mean weight of each defecation and stool moisture did not increase and serum cholesterol and triacylglycerol concentrations, Calcium Balance, and gastrointestinal transit time did not decrease as fiber intake increased. We conclude that 1) fiber provided by a mixed-food diet increases stool weight as effectively as does wheat or oat bran; 2) even high amounts of dietary fiber do not change transit time or defecation frequency if they are already approximately 1 and 2-3 d, respectively; 3) food patterns consistent with the food pyramid and incorporating legumes and whole grains are necessary to achieve recommended fiber intakes of 20-35 g/d, even if energy intake is > 12.55 MJ (3000 kcal); 4) soluble fiber provided by a mixture of whole foods has no effect on serum cholesterol concentrations or output of fecal bile acids; and 5) mixed-food fiber has little effect on Calcium Balance when Calcium intakes are high (> or = 1.5 g/d).

Richard Singer - One of the best experts on this subject based on the ideXlab platform.

  • regional citrate anticoagulation in membrane based plasma exchange safety efficacy and effect on Calcium Balance
    Nephrology, 2018
    Co-Authors: Daniel Christiadi, Richard Singer, Chari Mercado
    Abstract:

    AIM To assess the efficacy, safety and Calcium Balance of a membrane based regional citrate anticoagulation plasma exchange protocol. METHODS This was an observational, prospective, single centre study of membrane separation plasma exchange using regional citrate anticoagulation. It was performed using a fixed dose pre-filter citrate infusion that was based on the plasma flow rate. Patients received a post filter Calcium infusion that was modified during treatment based on systemic ionized Calcium monitoring. Post filter ionized Calcium was not assessed. Safety and efficacy were assessed by extraction of clinical events and laboratory data contemporaneously recorded in electronic health records. RESULTS Thirty-six sessions in five patients were performed. No patients developed symptomatic hypocalcaemia, and no patient had a recorded ionized Calcium below 0.81 mmol/L. Filter clotting occurred in two sessions. The mean net Calcium gained was 9.6 ± 1.8 mmol per session. CONCLUSION Regional citrate anticoagulated membrane separation plasma exchange can be performed safely and effectively without the need for post filter ionized Calcium monitoring. The algorithm employed resulted in a net Calcium gain.

  • regional citrate anticoagulation in hemodialysis an observational study of safety efficacy and effect on Calcium Balance during routine care
    Canadian journal of kidney health and disease, 2016
    Co-Authors: Richard Singer, Oliver Williams, Chari Mercado, Bonny Chen, Girish Talaulikar, Giles Walters, Darren M Roberts
    Abstract:

    Regional citrate hemodialysis anticoagulation is used when heparin is contraindicated, but most protocols require large infusions of Calcium and frequent intradialytic plasma ionized Calcium measurements. The objective of this study was to determine the safety, efficacy, and effect on Calcium Balance of regional citrate anticoagulation using sparse plasma ionized Calcium sampling. The design of this study was observational. The setting of this study was the hospital hemodialysis center. The subjects of this study were the hospital hemodialysis patients. Dialysate Calcium concentration by atomic absorption spectroscopy and total dialysate weight were used as measurements. Regional citrate anticoagulation was introduced using zero Calcium dialysate, pre-dialyzer citrate infusion, and post-dialyzer Calcium infusion. Infusions were adjusted based on pre- and post-dialyzer Calcium measurements obtained at least twice during a 4-h dialysis. The protocol was simplified after the first 357 sessions to dispense with post-dialyzer Calcium measurements. Heparin-anticoagulated sessions were performed using acetate-acidified 1.25 mmol/L Calcium or citrate-acidified 1.5 mmol/L Calcium dialysate. Calcium Balance assessment was by complete dialysate recovery. Safety and efficacy were assessed prospectively using a point-of-care database to record ionized Calcium and clinical events. Groups were compared using t test, ANOVA, Wilcoxon rank sum, or Kruskal-Wallis as appropriate. Seventy-five patients received regional citrate-anticoagulated dialysis over 1051 dialysis sessions. Of these, 357 dialysis sessions were performed using the original citrate anticoagulation protocol and 694 using the simplified protocol. Dialysis was effective and safe. Only 3 dialyzers clotted; 1 patient suffered symptomatic hypercalcemia and none suffered symptomatic hypocalcemia. Calcium Balance was assessed in 15 regional citrate-anticoagulated dialysis sessions and 30 heparin-anticoagulated sessions. The median Calcium loss was 0.8 mmol/h dialyzed in both groups (p = 0.43), and end of treatment ionized Calcium was the same in both groups (1.07 ± 0.04 mmol/L). Our findings for Calcium Balance, efficacy, and safety are valid only for the protocol studied, which excluded patient with severe liver dysfunction. Regional citrate dialysis can be performed safely and effectively using a sparse plasma Calcium sampling protocol. The Calcium Balance induced by this protocol is not different to that seen in standard heparin-anticoagulated dialysis, but in the absence of prospective studies, it is unknown whether this is optimal for patient care.

Man Sau Wong - One of the best experts on this subject based on the ideXlab platform.

  • Oleanolic Acid and Ursolic Acid Improve Bone Properties and Calcium Balance and Modulate Vitamin D Metabolism in Aged Female Rats.
    Frontiers in pharmacology, 2018
    Co-Authors: Sisi Cao, Xiaoli Dong, Xue-lian Tian, Liping Zhou, Murray J. Favus, Man Sau Wong
    Abstract:

    Oleanolic acid (OA) and ursolic acid (UA) are the major chemical constituents in Fructus Ligustri Lucidi (FLL), a kidney-tonifying Chinese herb that is previously shown to improve bone properties and enhance Calcium Balance in aged female rats. The present study was designed to study if OA and UA act as the active ingredients in FLL to exert the positive effects on bone and mineral metabolism in aged rats. Aged (13-month-old) Sprague-Dawley female rats were randomly assigned to four groups with oral administration of drug or vehicle treatment for 12 weeks: medium Calcium diet (MCD, 0.6% Calcium), high Calcium diet (HCD, 1.2% Calcium), MCD + FLL (700 mg/kg/day), MCD + OA (23.6 mg/kg/day) + UA (8.6 mg/kg/day). A group of mature (3-month-old) female rats fed with MCD was included as positive control. The results demonstrated that FLL and OA+UA increased bone mineral density and improved microarchitectural properties of aged female rats. The osteoprotective effects of FLL and OA+UA might be, at least in part, associated with their actions on enhancing Calcium Balance and suppressing age-induced secondary hyperparathyroidism in aged female rats. FLL and OA+UA also significantly induced renal CYP27B1 protein expression and OA+UA treatment decreased CYP24A1 mRNA and protein expressions in aged female rats. In addition, FLL and OA+UA significantly increased the promoter activity, mRNA and protein expressions of renal CYP27B1 in vitro in human proximal tubule HKC-8 cells. The present findings suggest that OA+UA can be regarded as the active ingredients of FLL and might be a potential drug candidate for prevention and treatment of osteoporosis.

  • fructus ligustri lucidi extract improves Calcium Balance and modulates the calciotropic hormone level and vitamin d dependent gene expression in aged ovariectomized rats
    Menopause, 2008
    Co-Authors: Yan Zhang, Xiaoli Dong, Pingchung Leung, Chuntao Che, Man Sau Wong
    Abstract:

    Objective: Fructus ligustri lucidi (FLL) is a widely used herb in China that is classically included in antiaging formulas for the treatment of age-related symptoms. Our laboratory previously showed that FLL could regulate Calcium Balance in young ovariectomized (OVX) rats. In the present study, we aimed to determine whether FLL could regulate Calcium Balance in aged OVX rats and to study the potential mechanisms that mediate its action in vivo. Design: Aged OVX rats were orally administered an ethanol extract of FLL and its vehicle and fed with diets containing different levels of Calcium [low Calcium diet (LCD), 0.1% Ca; medium Calcium diet (MCD), 0.6% Ca; and high Calcium diet (HCD), 1.2% Ca] for 12 weeks. Results: Significant reductions in urinary and fecal Calcium excretion were found in the FLL-treated animals, resulting in a significant induction of Calcium retention in rats fed with the MCD and HCD. FLL treatment significantly increased the serum 1,25-dihydroxyvitamin D 3 level and slightly decreased the serum parathyroid hormone level in OVX rats fed with the MCD and HCD. When OVX rats were challenged by LCD, the inductions of serum parathyroid hormone and 1,25-dihydroxyvitamin D 3 were decreased by FLL administration. FLL treatment significantly up-regulated duodenal vitamin D receptor and Calcium transport protein 1 mRNA expression in rats fed with the HCD. FLL treatment reduced the expression of renal vitamin D receptor and 25-hydroxyvitamin D-24-hydroxylase mRNA in OVX rats fed with the LCD and MCD. Conclusions: Twelve weeks of FLL treatment could reduce Calcium loss, modulate the parathyroid hormone-vitamin D axis, and increase vitamin D-dependent Calcium transport in aged OVX rats, suggesting that FLL might be useful as an alternative medicine for improving Calcium Balance in postmenopausal women.

  • effects of fructus ligustri lucidi extract on bone turnover and Calcium Balance in ovariectomized rats
    Biological & Pharmaceutical Bulletin, 2006
    Co-Authors: Yan Zhang, Pingchung Leung, Wan Ping Lai, Xin Sheng Yao, Man Sau Wong
    Abstract:

    The aim of this study was to evaluate the effect of Fructus Ligustri Lucidi (FLL), a kidney-tonifying Chinese herbal medicine, on the biochemical markers of bone turnover, Calcium metabolism and Balance in osteoporotic rat model developed by ovariectomy. Four weeks after surgical operation, animals were randomly assigned to one of the four treatments for 14 weeks: sham-operated control treated with vehicle (sham, n=8), ovariectomized group treated with vehicle (OVX, n=8), OVX group treated with 17β-estradiol (E2, n=10, 2 μg/kg/d) and OVX group treated with FLL extracts (FLL, n=10, 550 mg/kg/d). Serum osteocalcin and urinary deoxypyridinoline levels were upregulated in rats in response to OVX, suggesting that the bone turnover rate was accelerated in these animals. Treatment of OVX rats with FLL extract could prevent OVX-induced increase in bone turnover by suppression of both serum osteocalcin (p<0.05, vs. OVX) and urinary deoxypyridinoline (p<0.05, vs. OVX) levels. In addition, FLL extract could prevent OVX-induced loss of Calcium in rats by increasing the intestinal Calcium absorption rate (p<0.01, vs. OVX), suppressing urinary Ca excretion (p<0.05, vs. OVX) as well as increasing bone Calcium content (p<0.05, vs. OVX). Our study is the first to report that FLL can modulate bone turnover and Calcium Balance in OVX rats and it might be a potential candidate for prevention and treatment of postmenopausal osteoporosis.