Tag Archives: human

Lipoic Acid Suppresses Osteoclasts

Abstract

Alpha-lipoic acid suppresses osteoclastogenesis despite increasing the receptor activator of nuclear factor kappaB ligand/osteoprotegerin ratio in human bone marrow stromal cells.

Growing evidence has shown a biochemical link between increased oxidative stress and reduced bone density. Although alpha-lipoic acid (alpha-LA) has been shown to act as a thiol antioxidant, its effect on bone cells has not been determined. Using proteomic analysis, we identified six differentially expressed proteins in the conditioned media of alpha-LA-treated human bone marrow stromal cell line (HS-5). One of these proteins, receptor activator of nuclear factor kappaB ligand (RANKL), was significantly up-regulated, as confirmed by immunoblotting with anti-RANKL antibody. ELISA showed that alpha-LA stimulated RANKL production in cellular extracts (membranous RANKL) about 5-fold and in conditioned medium (soluble RANKL) about 23-fold, but had no effect on osteoprotegerin (OPG) secretion. Despite increasing the RANKL/OPG ratio, alpha-LA showed a dose-dependent suppression of osteoclastogenesis, both in a coculture system of mouse bone marrow cells and osteoblasts and in a mouse bone marrow cell culture system, and reduced bone resorption in a dose-dependent manner. In addition, alpha-LA-induced soluble RANKL was not inhibited by matrix metalloprotease inhibitors, indicating that soluble RANKL is produced by alpha-LA without any posttranslational processing. In contrast, alpha-LA had no significant effect on the proliferation and differentiation of HS-5 cells. These results suggest that alpha-LA suppresses osteoclastogenesis by directly inhibiting RANKL-RANK mediated signals, not by mediating cellular RANKL production. In addition, our findings indicate that alpha-LA-induced soluble RANKL is not produced by shedding of membranous RANKL.

Koh JM, Lee YS, Byun CH, Chang EJ…
J. Endocrinol. Jun 2005
PMID: 15930166 | Free Full Text

Pineapple Guava Leaf Extract Enhances Bone Mineralization

Abstract

Bone mineralization enhancing activity of a methoxyellagic acid glucoside from a Feijoa sellowiana leaf extract.

The capability of an aqueous methanol extract obtained from the leaves of Feijoa sellowiana Berg. on possible prevention and treatment of osteoporosis has been examined by evaluating its stimulating effect on the two human osteoblastic cell lines HOS58 and SaOS-2. The extract was found to increase significantly the mineralization of cultivated human bone cell, whereby a clear increment (15.3 +/- 2.7%) in von Kossa positive area was determined when administering 25 microg/ml leaf extract. A phytochemical investigation of the extract has demonstrated the high phenolic content and led to the isolation and identification of twenty three of them, among which the new 3-methoxyellagic acid 4-O-beta-glucopyranoside was fully identified. All structures were elucidated on the basis of conventional analytical methods and confirmed by FTMS, 1D- and 2D-NMR data. The new compound was found to cause a significant increase of mineralized area at 20 microg/mL, while at lower concentrations the effect was not significant. However, an increase of the number of mineralized spots (nodules) at all tested concentrations of the compound was observed.

Ayoub NA, Hussein SA, Hashim AN, Hegazi NM…
Pharmazie Feb 2009
PMID: 19320288

Ellagic Acid and Walnut Have “Remarkable Osteoblastic Activity”

Abstract

Walnut extract (Juglans regia L.) and its component ellagic acid exhibit anti-inflammatory activity in human aorta endothelial cells and osteoblastic activity in the cell line KS483.

Epidemiological studies suggest that the incidence of CVD and postmenopausal osteoporosis is low in the Mediterranean area, where herbs and nuts, among others, play an important role in nutrition. In the present study, we sought a role of walnuts (Juglans regia L.) in endothelial and bone-cell function. As the endothelial cell expression of adhesion molecules has been recognised as an early step in inflammation and atherogenesis, we examined the effect of walnut methanolic extract and ellagic acid, one of its major polyphenolic components (as shown by HPLC analysis), on the expression of vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1 in human aortic endothelial cells. After incubating the cells with TNF-alpha (1 ng/ml) in the absence and in the presence of walnut extract (10-200 microg/ml) or ellagic acid (10- 7-10- 5 m), the VCAM-1 and ICAM-1 expression was quantified by cell-ELISA. We further evaluated the effect of walnut extract (10-50 microg/ml), in comparison with ellagic acid (10- 9-10- 6m), on nodule formation in the osteoblastic cell line KS483. Walnut extract and ellagic acid decreased significantly the TNF-alpha-induced endothelial expression of both VCAM-1 and ICAM-1 (P < 0.01; P < 0.001). Both walnut extract (at 10-25 microg/ml) and ellagic acid (at 10- 9-10- 8 m) induced nodule formation in KS483 osteoblasts. The present results suggest that the walnut extract has a high anti-atherogenic potential and a remarkable osteoblastic activity, an effect mediated, at least in part, by its major component ellagic acid. Such findings implicate the beneficial effect of a walnut-enriched diet on cardioprotection and bone loss.

Papoutsi Z, Kassi E, Chinou I, Halabalaki M…
Br. J. Nutr. Apr 2008
PMID: 17916277

Review: Reduction in Food Associated with Decreased Bone Mass in Older Persons

Abstract

Physiological and psychosocial age-related changes associated with reduced food intake in older persons.

Dietary intake changes during the course of aging. Normally an increase in food intake is observed around 55 years of age, which is followed by a reduction in food intake in individuals over 65 years of age. This reduction in dietary intake results in lowered levels of body fat and body weight, a phenomenon known as anorexia of aging. Anorexia of aging has a variety of consequences, including a decline in functional status, impaired muscle function, decreased bone mass, micronutrient deficiencies, reduced cognitive functions, increased hospital admission and even premature death. Several changes during lifetime have been implicated to play a role in the reduction in food intake and the development of anorexia of aging. These changes are both physiological, involving peripheral hormones, senses and central brain regulation and non-physiological, with differences in psychological and social factors. In the present review, we will focus on age-related changes in physiological and especially non-physiological factors, that play a role in the age-related changes in food intake and in the etiology of anorexia of aging. At the end we conclude with suggestions for future nutritional research to gain greater understanding of the development of anorexia of aging which could lead to earlier detection and better prevention.

de Boer A, Ter Horst GJ, Lorist MM
Ageing Res. Rev. Jan 2013
PMID: 22974653

Depression Associated with Bone Loss in Older Men

Abstract

Depressive symptoms and rates of bone loss at the hip in older men.

In this prospective cohort study, depressive symptoms were associated with higher rates of bone loss in older men. Poorer performance on physical function tests partly explained the association between depressive symptoms and bone loss, suggesting that efforts to increase exercise and improve physical performance in depressed men may be beneficial.
The aim of this study was to ascertain whether depressive symptoms are associated with increased rates of bone loss at the hip in older men.
A population-based prospective cohort study of 2,464 community-dwelling men, aged 68 and older, enrolled in the Osteoporosis in Men Sleep Ancillary Study had depressive symptoms assessed by the Geriatric Depression Scale (GDS). Subjects were categorized as depressed if GDS ≥6 at the initial examination. Bone mineral density (BMD) at the hip was measured using dual-energy X-ray absorptiometry at the initial and follow-up examination (average 3.4 years between exams). Use of antidepressant medications was assessed by interview and verified from medication containers at the two examinations. A computerized dictionary was used to categorize type of medication.
In a base model adjusted for age, race/ethnicity, and clinic site, the mean total hip BMD decreased 0.70 %/year in 136 men with a GDS score of ≥6 compared to 0.39 %/year in 2,328 men with a GDS score of <6 (p = 0.001). Walking speed and timed chair stand partly explained the association between depressive symptoms and rates of bone loss.
Depression, as defined by a score of 6 or greater on the Geriatric Depression Scale, is associated with an increased rate of bone loss at the hip in this cohort of older men. Adjustment for walking speed and timed chair stand attenuated the strength of the association, suggesting that differences in physical functioning do partially explain the observed association.

Diem SJ, Harrison SL, Haney E, Cauley JA…
Osteoporos Int Jan 2013
PMID: 22461074

TMG No Benefit for Bones in Homocystinuria

Abstract

The effect of oral betaine on vertebral body bone density in pyridoxine-non-responsive homocystinuria.

Five pyridoxine-non-responsive homocystinuric patients aged 5 to 32 years were treated with oral betaine, 3 g b.i.d, in a double-blind, placebo-controlled, two-year crossover study of its effect on bone mineralization. Betaine therapy significantly reduced mean plasma homocystine (36 +/- 9 (SEM) mumol L-1 to 9 +/- 4 mumol L-1), with variable increases in plasma methionine and no adverse effects. Bone density, measured by computerized tomographic scanning of vertebral bodies, was below normal in all patients at the start of the study, and was not significantly altered by betaine therapy administered according to this protocol.

Gahl WA, Bernardini I, Chen S, Kurtz D…
J. Inherit. Metab. Dis. 1988
PMID: 3148071

Why is this interesting? It’s interesting because several studies show an association between homocysteine and osteoporosis. TMG is known to lower homocysteine. Yet, in this study, there was no increase in bone density despite homocysteine being cut 75%.

GH Therapy for 2 Years Increases Bone Density in GH Deficiency

Abstract

Effects of two years of growth hormone (GH) replacement therapy on bone metabolism and mineral density in childhood and adulthood onset GH deficient patients.

The aim of the current study was to evaluate bone metabolism and mass before and after 2 years of GH replacement therapy in adults with childhood or adulthood onset GH deficiency. Thirty-six adults with GH deficiency, 18 with childhood onset, 18 with adulthood onset GH deficiency and 28 sex-, age-, height- and weight-matched healthy subjects entered the study. Biochemical indexes of bone turnover such as serum osteocalcin, serum carboxyterminal telopeptide of type-I procollagen, urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine, of soft tissue formation such as aminoterminal propeptide of type-III and bone mineral density were evaluated. Childhood onset GH deficient patients had significantly decreased bone (osteocalcin: 2.5+/-1.3 vs 6.6+/-4.8 mcg/l, p<0.001) and soft tissue formation (aminoterminal propeptide of type III: 273+/-49 vs 454+/-23 U/I, p<0.001) indexes and normal bone resorption indexes (serum carboxyterminal telopeptide of type-I procollagen: 105+/-48 vs 128+/-28 mcg/l p=NS; urinary hydroxyproline/creatinine: 0.19+/-0.16 vs 0.28+/-0.16 mmol/mol, p=NS; urinary deoxypyridinoline/creatinine: 21 +/-10 vs 25+/-8 mcmol/mol, p=NS) compared to healthy subjects. On the contrary, no significant difference in bone turnover indexes between adulthood onset GH deficient patients and healthy subjects was found. Moreover, significantly decreased bone mineral density at any skeletal site and at whole skeleton was found in GH deficient patients compared to healthy subjects (e.g. femoral neck: 0.74+/-0.13 vs 0.97+/-0.11 g/cm2, p<0.001). In addition, a significant reduction of bone mineral density was found in childhood compared to adulthood onset GH deficient patients at any skeletal site, except at femoral neck. After 3-6 months of treatment, both groups of patients had a significant increase in bone turnover and in soft tissue formation. In particular, in childhood onset GH deficient patients after 3 months osteocalcin increased from 2.5+/-1.3 to 7.9+/-2.1 mcg/l, p<0.001 aminoterminal propeptide of type-III from 273+/-49 to 359+/-15 U/I p<0.001; serum carboxyterminal telopeptide of type-I procollagen from 105+/-48 to 201+/-45 mcg/l, p<0.001; urinary hydroxyproline/creatinine from 0.19+/-0.16 to 0.81+/-0.17 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 21 +/-10 to 54+/-20 mcmol/mol, p<0.001; while in adulthood onset GH deficient patients after 6 months osteocalcin increased from 4.2+/-3.6 to 6.5+/-1.9 mcg/l, p<0.05; aminoterminal propeptide of type- III from 440+/-41 to 484+/-37 U/I, p<0.05; serum carboxyterminal telopeptide of type-I procollagen from 125+/-40 to 152+/-22 mcg/l, p<0.05; urinary hydroxyproline/creatinine from 0.24+/-0.12 to 0.54+/-0.06 mmol/mol, p<0.001; urinary deoxypyridinoline/creatinine from 23+/-8 to 42+/-5 mcmol/mol, p<0.001. No significant difference in bone turnover between pre- and post-treatment period was found after 18-24 months of GH therapy. Conversely, bone mineral density was slightly reduced after 3-6 months of GH therapy, while it was significantly increased after 18-24 months. In fact, femoral neck bone mineral density values significantly rose from 0.74+/-0.13 g/cm2 to 0.87+/-0.11 g/cm2 (pre-treatment vs 2 years of GH treatment values). In conclusion, patients with childhood or adulthood onset GH deficiency have osteopenia that can be improved by long-term treatment with GH.

Longobardi S, Di Rella F, Pivonello R, Di Somma C…
J. Endocrinol. Invest. May 1999
PMID: 10401706

GH Therapy Cuts Number With Osteopenia in Half in GH-Deficient Adults

Abstract

Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults.

To study the effects of GH treatment for up to 42 months on bone mineral density (BMD) and bone turnover.
BMD with dual energy X-ray absorptiometry, serum type I procollagen carboxy-terminal propeptide (PICP), serum type I collagen carboxy-terminal telopeptide (ICTP) and serum IGF-I were assessed in 71 adults with GH deficiency. There were 44 men and 27 women, aged 20 to 59 (median 43) years. Thirty-two patients completed 36 months and 20 patients 42 months of treatment.
The BMD increased for up to 30-36 months and plateaued thereafter. In the whole study group, the maximum increase of BMD was 5.0% in the lumbar spine (P<0. 001), 5.9% (P<0.01) in the femoral neck, 4.9% (NS, P>0.05) in the Ward’s triangle and 8.2% (P<0.001) in the trochanter area. The serum concentrations of PICP (202.6+/-11.5 vs 116.3+/-5.4 microg/l; mean+/-s.e.m.) and ICTP (10.5+/-0.6 vs 4.4+/-0.3 microg/l) doubled (P<0.001) during the first 6 months of GH treatment but returned to baseline by the end of the study (130.0+/-10.4 and 5.6+/-0.7 microg/l respectively), despite constantly elevated serum IGF-I levels (39. 6+/-4.1 nmol/l at 42 months vs 11.9+/-0.9 nmol/l at baseline; P<0.001). The responses to GH treatment of serum IGF-I, PICP, ICTP (P<0.001 for all; ANOVA) and of the BMD in the lumbar spine (P<0.05), in the femoral neck and the trochanter (P<0.001 for both) were more marked in men than in women. At the end of the study the BMD had increased at the four measurement sites by 5.7-10.6% (P<0.01-0.001) in patients with at least osteopenia at baseline and by 0.1-5.3% (NS P<0.05) in those with normal bone status (P<0.001 for differences between groups; ANOVA). Among patients who completed 36-42 months of treatment, the number of those with at least osteopenia was reduced to more than a half. The response of BMD to GH treatment was more marked in young than in old patients at three measurement sites (P<0. 05-<0.001; ANOVA). In the multiple regression analysis the gender and the pretreatment bone mass appeared to be independent predictors of three measurement sites, whereas the age independently determined only the vertebral BMD.
GH treatment in GH-deficient adults increased BMD for up to 30-36 months, with a plateau thereafter. Concurrently with the plateau in BMD the bone turnover rate normalized. From the skeletal point of view GH-deficient patients exhibiting osteopenia or osteoporosis should be considered as candidates for GH supplementation of at least 3-4 years.

Välimäki MJ, Salmela PI, Salmi J, Viikari J…
Eur. J. Endocrinol. Jun 1999
PMID: 10377504 | Free Full Text

From the full text:

Moreover, in more than a half of the patients the criteria of osteopenia disappeared or there was an improvement of the bone state from osteoporosis to osteopenia.

GH Therapy for 1 Year Increases Bone Turnover and Density in GH Deficiency

Abstract

Effects of growth hormone (GH) replacement on bone metabolism and mineral density in adult onset of GH deficiency: results of a double-blind placebo-controlled study with open follow-up.

It is known that GH stimulates bone turnover and that GH-deficient adults have a lower bone mass than healthy controls. In order to evaluate the influences of GH replacement therapy on markers of bone turnover and on bone mineral density (BMD) in patients with adult onset GH deficiency, a double-blind placebo-controlled study of treatment with recombinant human GH (rhGH; mean dose 2.4 IU daily) in 20 patients for 6 months and an extended open study of 6 to 12 months were conducted. Eighteen patients, fourteen men and four women, with a mean age of 44 years with adult onset GH deficiency were evaluated in the study. Compared with placebo, after 6 months serum calcium (2.39 +/- 0.02 vs 2.32 +/- 0.02 mmol/l, P = 0.037) and phosphate (0.97 +/- 0.06 vs 0.75 +/- 0.05 mmol/l, P = 0.011) increased and the index of phosphate excretion (0.03 +/- 0.03 vs 0.19 +/- 0.02, P < 0.001) decreased significantly, and there was a significant increase in the markers of bone formation (osteocalcin, 64.8 +/- 11.8 vs 17.4 +/- 1.8 ng/ml, P < 0.001; procollagen type I carboxyterminal propeptide (PICP), 195.3 +/- 26.4 vs 124.0 +/- 15.5 ng/ml, P = 0.026) as well as those of bone resorption (type I collagen carboxyterminal telopeptide (ICTP), 8.9 +/- 1.2 vs 3.3 +/- 0.5 ng/ml, P < 0.001; urinary hydroxyproline, 0.035 +/- 0.006 vs 0.018 +/- 0.002 mg/100 ml glomerular filtration rate, P = 0.009). BMD did not change during this period of time. IGF-I was significantly higher in treated patients (306 +/- 45.3 vs 88.7 +/- 22.5 ng/ml, P < 0.001). An analysis of the data compiled from 18 patients treated with rhGH for 12 months revealed similar significant increases in serum calcium and phosphate, and the markers of bone turnover (osteocalcin, PICP, ICTP, urinary hydroxyproline). Dual energy x-ray absorptiometry (DXA)-measured BMD in the lumbar spine (1.194 +/- 0.058 vs 1.133 +/- 0.046 g/cm2, P = 0.015), femoral neck (1.009 +/- 0.051 vs 0.936 +/- 0.034 g/cm2, P = 0.004), Ward’s triangle (0.881 +/- 0.055 vs 0.816 +/- 0.04 g/cm2, P = 0.019) and the trochanteric region (0.869 +/- 0.046 vs 0.801 +/- 0.033 g/cm2, P = 0.005) increased significantly linearly (compared with the individual baseline values). At 12 months, BMD in patients with low bone mass (T-score < -1.0 S.D.) increased more than in those with normal bone mass (lumbar spine 11.5 vs 2.1%, P = 0.030, and femoral neck 9.7 vs 4.2%, P = 0.055). IGF-I increased significantly in all treated patients. In conclusion, treatment of GH-deficient adults with rhGH increases bone turnover for at least 12 months. BMD in the lumbar spine and the proximal femur increases continuously in this time (open study) and the benefit is greater in patients with low bone mass. Therefore, GH-deficient patients exhibiting osteopenia or osteoporosis should be considered candidates for GH supplementation. However, long-term studies are needed to establish that the positive effects on BMD are persistent and are associated with a reduction in fracture risk.

Finkenstedt G, Gasser RW, Höfle G, Watfah C…
Eur. J. Endocrinol. Mar 1997
PMID: 9100553

GH for 36 vs. 6-12 Months

Abstract

Long-term change in the bone mineral density of adults with adult onset growth hormone (GH) deficiency in response to short or long-term GH replacement therapy.

Only two previous studies have assessed the effects of long-term GH replacement therapy on bone mineral density (BMD) in patients with adult onset GH deficiency. To date no study has looked at the long-term impact on BMD after a short course (6-12 months) of GH replacement. In two groups of patients with adult onset GH deficiency we have studied BMD either (a) after 3 years of continuous GH replacement or (b) 2 years after completion of a short course of GH.
An open GH therapeutic study in which patients were recruited from a previous double-blind placebo-controlled study. The BMD status of all patients was unknown to the physician and patient at the time of recruitment.
Group A (n = 7, three females) all received GH replacement continuously for 3 years. Group B (n = 8, five females) included six patients who received GH replacement for 6 months and two who received GH replacement for 12 months with BMD being measured at 6-monthly intervals.
Single photon absorptiometry (SPA) and later single X-ray absorptiometry (SXA) were used to measure forearm cortical BMD. Dual-energy X-ray absorptiometry (DXA) was used to measure lumbar spine, trochanteric, femoral neck and Ward’s area BMD.
In group A lumbar spine and trochanter BMD had increased significantly from baseline by 3.7% (DXA: median change = 0.045 g/cm2; P = 0.028) and 4.0% (DXA: median change = 0.031 g/cm2; P = 0.046), respectively. There were non-significant decreases in femoral neck (1.9%) (DXA: median change = -0.02 g/cm2; P = 0.39), Ward’s area (6.5%) (DXA: median change = -0.06 g/cm2; P = 0.09) and forearm (2.6%) (SPA/SXA: median change = -0.013 g/cm2; P = 0.18). In group B, compared with baseline, only trochanter BMD changed significantly, increasing by 5.9% (DXA: median change = 0.0485 g/cm2; P = 0.049). Lumbar spine (DXA: median change = -0.001 g/cm2) Ward’s area (DXA: median change = 0.0135 g/cm2), femoral neck (DXA: median change = -0.005 g/cm2) and forearm cortical (SPA/SXA; median change = -0.01 g/cm2) BMD did not change significantly (P = 0.67, P = 0.57, P = 0.86 and P = 0.31, respectively). Median percentage changes compared with baseline were -0.1%, 1.8%, -0.5% and -2.1%, respectively. From the time of completion of GH therapy however, BMD increased significantly at lumbar spine, (median change = 0.023 g/cm2), Ward’s area (median change = 0.03 g/cm2) and trochanter (median change = 0.056 g/cm2) (P = 0.036, P = 0.049 and P = 0.012, respectively) but not at the femoral neck (median change = 0.017 g/cm2; P = 0.31) or forearm (median change = 0 g/cm2; P = 0.75).
Long-term GH replacement therapy for three years appears to have beneficial effects on bone in patients with adult onset GH deficiency particularly at the lumbar spine and trochanter; the effects on femoral neck and forearm cortical BMD, however, are less impressive. A short course (6-12 months) of GH replacement therapy results in an increase in trochanter BMD several years later, and after an initial decline in BMD whilst on GH replacement, lumbar spine and Ward’s area BMD return towards their baseline values. These results emphasize that not all types of bone and skeletal sites respond to GH therapy identically. Furthermore a short course of GH replacement over 6-12 months may result in significant changes in BMD several years later.

Rahim A, Holmes SJ, Adams JE, Shalet SM
Clin. Endocrinol. (Oxf) Apr 1998
PMID: 9640413