Showing papers in "Calcified Tissue International in 1997"
TL;DR: The results presented here along with previously reported changes in osteonal bone show a relation between bone age and ``crystallinity/maturity'' (a parameter dependent on crystallite size, hydroxyapatite-like stoichiometry, abundance of substituting ions such as CO32−) as deduced by the 1020/1030 cm−1 ratio.
Abstract: Fourier transform infrared microspectroscopy (FTIRM) has been used to study the changes in mineral and matrix content and composition in replicate biopsies of nonosteoporotic human cortical and trabecular bone. Changes in osteonal bone in these same samples were reported previously. Spectral maps along and across the lamellae were obtained from iliac crest biopsies of two necropsy cases. Mineral:matrix ratios, calculated from the integrated areas of the phosphate ν1, ν3 band at 900–1200 cm−1 and the amide I band at ≈1585–1725 cm−1, respectively, were relatively constant in both directions of analysis, i.e., along and across the lamellae. Analysis of the components of the ν1, ν3 phosphate band with a combination of second-derivative spectroscopy and curve fitting revealed the presence of 11 major underlying moieties. Of these, the ratio of the relative areas of the two underlying bands at ≈1020 and ≈1030 cm−1 has been shown to be a sensitive index of variation in crystal perfection in both human osteonal bone and in synthetic, poorly crystalline apatites. This ratio was calculated in both cortical and trabecular bone from human iliac crest biopsies along and across the lamellae. The ratio decreased, going from the periosteum to the medullary cavity in the cortical bone, and from the periphery towards the center of trabeculae. These observations were consistent within serial sections obtained from the same biopsy, multiple biopsies obtained from the same necropsy specimen, and biopsies obtained from the two different necropsy specimens. The results presented here along with previously reported changes in osteonal bone show a relation between bone age and ``crystallinity/maturity'' (a parameter dependent on crystallite size, hydroxyapatite-like stoichiometry, abundance of substituting ions such as CO32−; the more crystalline/mature, the more hydroxyapatite-like stoichiometry, the bigger the crystallite size, the less the ion substitution by ions such as CO32−) as deduced by the 1020/1030 cm−1 ratio. Invariably, younger normal bone is less mature/crystalline than older. These results provide a ``baseline'' for description of mineral properties, to which diseased bones may be compared.
263 citations
TL;DR: It is suggested that BMP-2 may act in a paracrine fashion in concert with other BMPs it induces to stimulate bone cell differentiation and bone formation during remodeling.
Abstract: Normal bone formation is a prolonged process that is carefully regulated and involves sequential expression of growth regulatory factors by osteoblasts as they proliferate and ultimately differentiate. Since this orderly sequence of gene expression by osteoblasts suggests a cascade effect, and BMP-2 is capable of initiating and maintaining this effect, we examined the effects of BMP-2 on expression of other BMPs and compared these effects with the expression pattern of bone cell differentiation marker genes in primary cultures of fetal rat calvarial (FRC) osteoblasts. To examine the gene expression profile during bone cell differentiation and bone formation, we also examined the effects of rBMP-2 on bone formation in vivo and in vitro. rBMP-2 stimulated bone formation on the periosteal surface of mice when 500 ng/day rBMP-2 was injected subcutaneously. When rBMP-2 was added to primary cultures of FRC osteoblasts, it accelerated mineralized nodule formation in a time and concentration-dependent manner (10–40 ng/ml). rBMP-2 (40 ng/ml) enhanced BMP-3 and -4 mRNA expression during the mineralization phase of primary cultures of FRC osteoblasts. Enhancement of BMP-3 and -4 mRNA expression by rBMP-2 was associated with increased expression of bone cell differentiation marker genes, alkaline phosphatase (ALP), type I collagen, osteocalcin (OC), osteopontin (OP), and bone sialoprotein (BSP). These results suggest that BMP-2 enhances expression of other BMP genes during bone cell differentiation. BMP-2 may act in a paracrine fashion in concert with other BMPs it induces to stimulate bone cell differentiation and bone formation during remodeling.
237 citations
TL;DR: Fourier transform infrared microspectroscopy (FTIRM) was applied to the study of human osteonal and cortical bone from iliac crest biopsies of untreated osteoporotic patients, indicating significant differences in the mineral properties as expressed by crystal size and perfection.
Abstract: Historically, osteoporosis has been defined as a disease in which there is ``too little bone, but what there is, is normal.'' As a result of research design and sample selection limitations, published data contradict and confirm the historical definition. Because of these limitations, it has been hard to assess the contribution of mineral quality to mechanical properties, and to select therapeutic protocols that optimize bone mineral properties. The coupling of an optical microscope to an infrared spectrometer enables the acquisition of spectral data at known sites in a histologic section of mineralized tissue without loss of topography and/or orientation. The use of second-derivative spectroscopy coupled with curve-fitting techniques allows the qualitative and quantitative assessment of mineral quality (crystallite size and perfection, mineral:matrix ratio) at well-defined morphologic locations.
222 citations
TL;DR: It is concluded that in SCI, the loss of bone mass in the proximal tibia can be partially reversed by regular long-term FES cycle exercise, however, one exercise session per week is insufficient to maintain this increase.
Abstract: Spinal cord injured (SCI) individuals have a substantial loss of bone mass in the lower limbs, equaling approximately 50% of normal values in the proximal tibia, and this has been associated with a high incidence of low impact fractures. To evaluate if this inactivity-associated condition in the SCI population can be reversed with prolonged physical training, ten SCI individuals [ages 35.3 ± 2.3 years (mean ± standard error [SE]); post injury time: 12.5 ± 2.7 years, range 2–24 years; level of lesion: C6–Th4; weight: 78 ± 3.8 kg] performed 12 months of Functional Electrical Stimulated (FES) upright cycling for 30 min per day, 3 days per week, followed by six months with only one weekly training session. Bone mineral density (BMD) was determined before training and 12 and 18 months later. BMD was measured in the lumbar spine, the femoral neck, and the proximal tibia by dual energy absorptiometry (DEXA, Nordland XR 26 MK1). Before training, BMD was in the proximal tibia (52%), as well as in the femoral neck, lower in SCI subjects than in controls of same age (P 0.05). After 12 months of training, the BMD of the proximal tibia had increased 10%, from 0.49 ± 0.04 to 0.54 ± 0.04 g/cm2 (P 0.05). No changes were observed in the lumbar spine or in the femoral neck in response to FES cycle training. It is concluded that in SCI, the loss of bone mass in the proximal tibia can be partially reversed by regular long-term FES cycle exercise. However, one exercise session per week is insufficient to maintain this increase.
212 citations
TL;DR: The lack of change in IL-1 in vivo and in vitro does not support the hypothesis that this cytokine plays a major role in the acute phase reaction, and the cellular mechanism of the interaction among aminobisphosphonates, Il-6, and TNFα requires further investigations.
Abstract: We studied the acute phase response, including specific cytokine production, [interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor α(TNFα)] following a single dose of Aredia (disodium pamidronate) in patients with increased bone turnover and, in vitro, the role played by specific cytokines in the acute-phase reaction which may follow the administration of aminobisphosphonates. An in vivo exploratory study was done on 24 in- and outpatients with increased bone turnover given a single intravenous dose of pamidronate 60 mg. Measurements were taken at baseline and at 24, 48, and 72 hours. The main outcome measures were changes from baseline in serum IL-1, IL-6, and TNFα. In addition, C-reactive protein (CRP), white blood cell count (WCC), lymphocyte count, and elastase concentration were measured. Symptomatic evaluation was made of fever, bone pain, and rigors. In vitro, whole blood from eight healthy volunteers was exposed to various concentrations of the three bisphosphonates—pamidronate, clodronate, and zoledronate. Measurements were taken immediately before and at 3, 6, and 10 hours after exposure to drugs. The main outcome measures were changes in serum IL-1, IL-6, and TNFα. In vivo, there was a statistically significant (P < 0.001) increase in median values of TNFα in all post-baseline measurements. Median values for IL-6 also showed a significant (P < 0.001) increase at 24 hours after dosing. There were no statistically significant changes in median IL-1 values. Few patients showed any change from baseline in total WCC or in lymphocyte count, but 62.5% of patients with normal range baseline values for CRP increased to above normal levels after treatment. Fourteen patients experienced fever; 2 reported rigors. There was no correlation between fever and changes in cytokines. There were no serious adverse experiences or premature discontinuations due to poor tolerability, and 91% of the patients expressed willingness to receive pamidronate again. In vitro, an increase in TNFα and a mild increase in IL-6 was seen with all bisphosphonates, with the greatest effects seen with the highest concentration of both pamidronate and zoledronate. No changes were observed in IL-1 with any agent. Significant changes in both TNFα and IL-6 were observed within 3 days of a single dose of pamidronate in patients treated for the first time confirming previous findings. However, the lack of change in IL-1 in vivo and in vitro does not support the hypothesis that this cytokine plays a major role in the acute phase reaction. The cellular mechanism of the interaction among aminobisphosphonates, Il-6, and TNFα requires further investigations. The results of the in vitro study are consistent with the in vivo findings.
204 citations
TL;DR: Reduced bone formation and significant disorders of bone mineral metabolism, such as vitamin D deficiency, reduced parathyroid hormone levels, and hypogonadism are involved in patients referred for orthotopic liver transplantation.
Abstract: The purpose of this study was to determine the prevalence of osteoporosis, to estimate the bone turnover and hormonal status, and to identify the factors associated with bone disease in patients with end-stage liver disease who were referred for orthotopic liver transplantation. A prospective study was performed on 58 cirrhotic patients (6 with primary biliary cirrhosis, 14 with alcoholic cirrhosis, and 38 with posthepatitic cirrhosis), who were referred for orthotopic liver transplantation. Patients, excluding those with primary biliary cirrhosis, were classified in Child-Pugh groups according to the severity of liver disease (class B [28 patients], class C [24 patients]). Biochemical parameters of bone mineral metabolism and standard liver function tests were measured in all patients. Additionally, serum osteocalcin, urinary hydroxyproline/creatinine ratio, serum intact parathyroid hormone, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, follicle-stimulating hormone, and luteinizing hormone levels were determined in patients and controls within the same age range. Plasma testosterone, sex hormone-binding globulin levels, and free testosterone index were obtained for all men included in the study. Bone mass of the lumbar spine and femur were measured by dual X-ray absorptiometry (DPX-L), and were expressed as a standard deviation of mean values (Z-score) from a sex and age-matched control group. Spinal X-rays were obtained to assess vertebral fractures. Osteoporosis was considered as a factor in spinal bone mineral density with a Z-score below 2 or at least one vertebral fracture. Twenty-five patients (43%) had osteoporosis, with lower bone mass measurements in the lumbar spine than in the femoral neck (P < 0.005). Alcoholic and Child-Pugh C patients showed the lowest femoral bone mineral density values. Cirrhotic patients showed lower osteocalcin levels than controls (14.3 +/- 5.9 vs. 18.2 +/- 8.1 ng/ml; P < 0.05) and showed increased urinary hydroxyproline (125.1 +/- 51.5 vs. 107.9 +/- 26.6 nM/mg creatinine; P < 0.05). Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone levels were significantly lower in cirrhotic patients than in controls (10.3 +/- 9.1 vs. 23.1 +/- 26.6 ng/ml; P = 0.000), (12.9 +/- 9.1 vs. 48.3 +/- 11.5 pg/ml; P = 0.000), (16.6 +/- 9.2 vs. 27.9 +/- 8.2 pg/ml; P = 0.000), with no differences between Child-Pugh groups. Alcoholic Child-Pugh C patients showed the lowest 25-hydroxyvitamin D serum values (4.5 +/- 2.2 ng/ml; P < 0.05). Male patients had lower testosterone levels than controls (302.5 +/- 229.4 vs. 556.7 +/- 146.5 ng/dl; P = 0.000), with increased sex hormone-binding globulin values. Levels of testosterone and gonadotropin were related to Child-Pugh classification. No correlation was found between bone mass and hormonal values. A significant decrease in bone mass, particularly in the lumbar spine, is seen in end-stage cirrhotic patients. Reduced bone formation and significant disorders of bone mineral metabolism, such as vitamin D deficiency, reduced parathyroid hormone levels, and hypogonadism are involved. Moreover, severity and etiology of the liver disease are the main risk factors for developing bone loss and mineral metabolism disorders in patients referred for orthotopic liver transplantation.
204 citations
TL;DR: It was concluded that degenerative factors, except for scoliosis, showed an influence on BMD as measured by DXA, which increased rapidly between 55 and 70 years of age.
Abstract: The purpose of this study is to evaluate degenerative factors in a postmenopausal patient group and differentiate the influence on bone mineral density (BMD) measurements by dual-energy X-ray absorptiometry (DXA). The patients and methods included an investigation of 144 postmenopausal women (mean 63.3 years) with PA-DXA of the spine. Degenerative factors (osteophytes, osteochondrosis, scoliosis, and vascular calcification) were evaluated from plain lumbar radiographs, their estimated probability was analyzed as a function of age, and their influence on BMD measured by PA-DXA was determined. The results of the study revealed osteophytes in 45.8%, vascular calcifications in 24.3%, scoliosis in 22.2%, osteochondrosis in 21.5%. The estimated probability for degenerative factors increased from 35 to 80% in the 55- to 70- year age group. Osteophytes and osteochondrosis were associated with up to a 14% increase in BMD values (P < 0.001). Vascular calcifications showed a positive trend, whereas scoliosis did not show a discernible influence.
161 citations
TL;DR: Data suggest that of the small proteoglycans, biglycan may play a more significant role than decorin in the regulation of mineralization.
Abstract: The small leucine-rich bone proteoglycans, biglycan and decorin, can be purified by chromatography on hydroxyapatite columns, demonstrating their potential affinities for bone apatite. To determine their effects on in vitro apatite formation and growth, a mixture of the chondroitin-sulfate (CS) bone proteoglycans, or purified fractions of the dermatan sulfate (DS) containing proteoglycans, DS-decorin and DS-biglycan obtained from skin and articular cartilage, respectively, were analyzed in a gelatin gel diffusion system in which apatite formation occurs in the absence of proteins in a 3.5 day period. Low concentrations of the bone CS-proteoglycan mixture and low DS-biglycan concentrations (5–25 μg/ml) increased apatite formation relative to proteoglycan-free controls at 3.5 days. The CS-proteoglycan mixture was less effective at 50 μg/ml than at 10 μg/ml. DS-biglycan was similarly most effective at 5–25 μg/ml. At 5 days, when apatite growth and proliferation were assessed, 10 and 50 μg/ml of both CS-bone proteoglycan and DS-biglycan increased mineral yields. DS-decorin, in contrast, had no significant effect on mineral accumulation at any of these concentrations. In seeded growth experiments, 1 and 10 μg/ml CS-proteoglycan and 10 and 50 μg/ml DS-biglycan were significant effective inhibitors of mineral accretion, whereas DS-decorin showed no tendency to inhibit seeded growth. Using molar extinction coefficients to determine concentrations, the binding of DS-biglycan and DS-decorin to apatite (specific surface 54 m2/g) was determined using a Langmuir adsorption isotherm model. DS-biglycan had a greater affinity for apatite than DS-decorin (0.285 ml/μmol versus 0.0098 ml/μmol). DS-biglycan binding was more specific with fewer binding sites (3.5 μmol/m2 compared with 18.2 μmol/m2 for DS-decorin). Data suggest that of the small proteoglycans, biglycan may play a more significant role than decorin in the regulation of mineralization.
154 citations
TL;DR: The main portion of AP particles in bone is concluded to be biaxially oriented on the basis of the classification of orientation for elongated polyethylene, which suggests that there are more than two types of morphology in the AP particle in bone mineral.
Abstract: X-ray pole figure analysis was performed on apatite (AP) crystals in bone mineral and collagen molecules in the bone matrix. For AP in bone mineral, the (0002) plane (c-axis) and {2130} plane were examined. The diffraction peaks from both planes were well isolated from other diffraction peaks in the bone. To investigate the orientation of collagen molecules in the bone matrix, demineralized bone by EDTA treatment was used. For collagen, the diffraction peak from about the 0.3 nm period along the helix axis of the collagen molecule was investigated. The c-axis of AP and the helical axis of the collagen molecule have strongly preferred orientations in a direction parallel to the bone axis. The c-axis of AP has an appreciable pole density peak in the radial and tangential direction of the bone, whereas collagen molecules were almost uniaxially oriented in the bone axis direction though having an appreciable distribution. This suggests that there are more than two types of morphology in the AP particle in bone mineral: one with the c-axis almost parallel to the bone axis and the other in which the c-axis is oriented almost perpendicular to the bone axis. The {2130} plane has isolated peaks of pole density in pole figures in both radial and tangential directions. On the basis of the classification of orientation for elongated polyethylene, the main portion of AP particles in bone is concluded to be biaxially oriented.
151 citations
TL;DR: There is significant diurnal variation in the markers of bone mineral metabolism for elderly men and women, and the peak value, which on average would be 20% higher than the mean value for urinary NTX, highlights the importance of the timing of sample collection for appropriate interpretation of therapeutic response.
Abstract: The diurnal variation of markers of bone mineral metabolism have been documented in pre- and early postmenopausal women. Such rhythms have clinical implications for timing of sample collection and assessment of therapeutic intervention. To examine the diurnal variation of bone turnover in the elderly, we examined markers of bone formation [serum osteocalcin (OC) and bone-specific alkaline phosphatase (B-ALP)]; a marker of bone resorption (urinary N-telopeptide cross-linked collagen type 1 [NTX]); and serum calcium and parathyroid hormone (PTH) over 24 hours. Subjects were healthy community-dwelling elderly who were on no medications known to significantly alter bone mineral metabolism. Subjects included 14 women [74 ± 6 years (mean ± SD)] and 14 men (80 ± 5 years). Over the 24-hour sampling period, mean serum OC, B-ALP, and calcium values were similar in elderly men and women. However, mean serum PTH was significantly higher in elderly men compared with women (P < 0.05). The magnitude of the diurnal variation of urinary NTX was significantly higher in women compared with men (P < 0.05). There was a significant diurnal variation for serum OC, B-ALP, calcium, PTH, and urinary NTX in both elderly men and women. The magnitude of the diurnal variation was approximately 10–20% of mean value for OC and B-ALP, 30% for PTH, and up to 40% for urinary NTX. We conclude that there is significant diurnal variation in the markers of bone mineral metabolism for elderly men and women. The peak value, which on average would be 20% higher than the mean value for urinary NTX, highlights the importance of the timing of sample collection for appropriate interpretation of therapeutic response. In addition, gender-related differences, including relatively higher levels of serum PTH and lower levels of urinary NTX in elderly men, may help explain differences in rates of bone loss in this age group.
147 citations
TL;DR: This poster presents a poster presented at the 2016 U.S. Conference on Osteoporosis and Sports Medicine entitled “Preparatory studies of Bone and Mineral Diseases: Foundations of Precision Medicine, 2nd Ed.”.
Abstract: 1Departments of Orthopedics and Medicine, University of Massachusetts Medical Center, Worcester, Maine, USA 20regon Osteoporosis Center, Portland, Oregon, USA 'Departments of Radiology and Medicine, University of California San Francisco, San Francisco, California, USA 4University of Colorado Health Science Center, Denver, Colorado, USA 5Division of Bone and Mineral Diseases, Washington University, St. Louis, Missouri, USA
TL;DR: Identification of effective nutrition supplements may be necessary to improve lumbar spine and femoral neck bone mineral density levels and to reduce the risk of osteoporosis among long-term female vegetarians.
Abstract: This study examined bone density among postmenopausal Buddhist nuns and female religious followers of Buddhism in southern Taiwan and related the measurements to subjects characteristics including age, body mass, physical activity, nutrient intake, and vegetarian practice. A total of 258 postmenopausal Taiwanese vegetarian women participated in the study. Lumbar spine and femoral neck bone mineral density (BMD) were measured using dual-photon absorptimetry. BMD measurements were analyzed first as quantitative outcomes in multiple regression analyses and next as indicators of osteopenia status in logistic regression analyses. Among the independent variables examined, age inversely and body mass index positively correlated with both the spine and femoral neck BMD measurements. They were also significant predictors of the osteopenia status. Energy intake from protein was a significant correlate of lumbar spine BMD only. Other nutrients, including calcium and energy intake from nonprotein sources, did not correlate significantly with the two bone density parameters. Long-term practitioners of vegan vegetarian were found to be at a higher risk of exceeding lumbar spine fracture threshold (adjusted odds ratio = 2.48, 95% confidence interval = 1.03-5.96) and of being classified as having osteopenia of the femoral neck (3.94, 1.21-12.82). Identification of effective nutrition supplements may be necessary to improve BMD levels and to reduce the risk of osteoporosis among long-term female vegetarians.
TL;DR: Intermittent intravenous pamidronate effectively achieves primary prevention of GIOP, as assessed by BMD measurements over 1 year, as measured by dual-energy X-ray absorptiometry.
Abstract: The aim of this study was to assess whether early intermittent I.V. administration of disodium pamidronate can effectively achieve primary prevention of glucocorticoid-induced osteoporosis (GIOP). A total of 27 in- or outpatients who required first-time, long-term corticosteroid therapy at a daily dose of at least 10 mg prednisolone were studied. Patients were randomly selected to receive either pamidronate and calcium or calcium alone. Patients allocated to pamidronate treatment (pamidronate group) received a first intravenous infusion of 90 mg pamidronate simultaneously with the initiation of their steroid treatment. Subsequently, they received 30 mg pamidronate, intravenously, every 3 months, for as long as steroid therapy was continued. As with the control patients (calcium group), they were put on a daily 800-mg elemental calcium supplement given as calcium carbonate. Lumbar spine and hip (total and subregions) bone mineral densities (BMDs) were measured at the start and every 3-months by dual-energy X-ray absorptiometry (Hologic(R) QDR-2000). Over 1 year, the pamidronate group showed a significant BMD increase in the lumbar spine (3.6%), and at all sites of the hip (2.2% at the femoral neck). In the calcium group, a significant BMD reduction was registered at the lumbar spine (-5.3%) and at the femoral neck (-5.3%). Differences between the groups were significant at all sites measured. Intermittent intravenous pamidronate effectively achieves primary prevention of GIOP, as assessed by BMD measurements over 1 year.
TL;DR: Quantitative computed tomography proved to be a successful estimator for the prediction of the mechanical stability of healing bones and may be useful for treatment decisions in particular clinical situations.
Abstract: An experimental fracture model was used to assess bone mineral density at the fracture site by peripheral computed tomography and to compare the model with biomechanical, histological, and radiographic methods for the quantification of the fracture repair process. Transverse osteotomies in the mid-diaphysis of 28 tibia of sheep were externally fixed and mineral densities, cross-sectional areas, flexural rigidities, tissue composition, and projected callus area were calculated after 9 weeks of healing time. BMD measured by pQCT was strongly correlated with histologically determined percentages of mineralized tissue in the osteotomy gap (R = 0.71) and in the periosteal callus (R2 = 0.62). The percentage of mineralized tissue in the osteotomy gap was the best predictor of the flexural rigidity of the tibiae (R2 = 0.74). Because of high correlations with the histological findings, the volumetric BMD at the level of the osteotomy gap was also strongly correlated with the biomechanical findings (R2 = 0.70). Neither the cross-sectional area in pQCT nor the projected callus area in plane film radiography were positively correlated to the flexural rigidity of the tibiae. Quantitative computed tomography proved to be a successful estimator for the prediction of the mechanical stability of healing bones. The noninvasive procedure is a reliable tool for the quantification of the fracture repair process in experimental studies and may be useful for treatment decisions in particular clinical situations.
TL;DR: In spite of the many features of HIV infection that might be expected to cause a reduction in BMD such as cytokine activation, decreased physical activity, small bowel disease, hypogonadism, and direct infection of osteogenic cells by HIV, it is found that the HIV patients studied did not appear to show excessive loss in bone mineral over time.
Abstract: The Object of this study was to determine whether HIV infection is associated with decreased bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry at total body, lumbar spine, and hip in 45 men with HIV infection and compared with sex, age, and weight-matched controls. Repeat scans were performed after a mean interval of 15 months in 21 patients to determine whether there were detectable losses of BMD. Compared with controls, the HIV patients had marginally lower BMD at the lumbar spine (P= 0.04) but there was no significant difference in total body or hip BMD. None of the patients had reduced BMD to levels associated with a diagnosis of osteoporosis. On longitudinal follow-up, a small decrease in total body BMD (−1.6%; P= 0.02) was observed but there was no significant change in spine and hip BMD. In spite of the many features of HIV infection that might be expected to cause a reduction in BMD such as cytokine activation, decreased physical activity, small bowel disease, hypogonadism, and direct infection of osteogenic cells by HIV, we found only minimal differences in BMD between HIV patients and controls. Furthermore, the HIV patients studied did not appear to show excessive loss in bone mineral over time.
TL;DR: Higher androgen serum levels in males together with a higher AR expression at certain skeletal sites may contribute to the development of sex-related differences in skeletal morphology.
Abstract: There are obvious sexual differences in adult skeletal morphology which for the most part are related to differences in size. Higher androgen serum levels in males exert potent osteoanabolic effects and therefore may contribute to this sexual dimorphism of the skeleton. The presence of androgen receptors (AR) in bone cells is a prerequisite for a direct osteoanabolic action of androgens. To investigate the possibility that, in addition to gender-related differences in androgen serum levels, there are also gender-related differences in the osteoblastic expression pattern of the androgen receptor, we examined AR mRNA expression, androgen binding sites, and mitogenic responses to the androgen dihydrotestosterone (DHT) in human osteoblastic cell (HOC) populations. HOCs were isolated from bone biopsy specimens derived from different skeletal sites of healthy adult males and females (2–69 years old). We found that male and female HOCs of all examined ages express similar AR mRNA levels and similar numbers of androgen binding sites. Using whole-cell-binding assays, we observed 3129–8417 androgen binding sites per femoral HOC with apparent KDs of 1.45–2.83 nM depending on the age of the investigated HOC population. Mandibular and cortical HOC of both sexes expressed higher AR mRNA levels, significantly more androgen binding sites per cell, and exhibited significantly greater mitogenic responses to DHT than iliac crest-derived and trabecular HOC of the same skeletal system and the same skeletal-site, respectively. In early adulthood, HOCs of both sexes appear to express somewhat higher AR mRNA levels and to possess more androgen binding sites than prepubertal and senescent HOC. Because sex hormone serum levels rise in puberty, we investigated the regulation of the AR mRNA expression by various steroids. We found that dexamethasone (dexa) and in some experiments also 17β-estradiol (E2) and 1,25-dihydroxyvitamin D3 (D3) increased AR mRNA levels and androgen binding in HOC cultures. A pretreatment with dexa, E2, and D3 significantly increased the mitogenic response of HOCs to DHT. We conclude that (1) higher androgen serum levels in males together with a higher AR expression at certain skeletal sites may contribute to the development of sex-related differences in skeletal morphology, (2) glucocorticoids induce AR gene expression in HOC cultures, and (3) glucocorticoids, E2, and D3 enhance the mitogenic action of DHT.
TL;DR: The data suggest that alendronate is effective in preventing glucocorticoid-induced bone loss in sarcoid patients and counteracted the increase in markers of bone resorption induced by glucoc Corticosteroid therapy.
Abstract: Prolonged corticosteroid administration, as often required in the treatment of sarcoidosis, increases the risk of osteoporosis and fracture. The aim of the present study was to evaluate the usefulness of alendronate, a third generation bisphosphonate, in preventing corticosteroid-induced osteoporosis. Forty-three consecutive, previously untreated, sarcoid patients (17 men and 26 premenopausal women) were included in the study: 13 needed no treatment and served as controls (Group 1) and 30 needed glucocorticoids (prednisone) and were randomly selected to also receive either placebo (n = 15, Group 2) or alendronate 5 mg/day (n = 15, Group 3). Bone mineral density (BMD) at the ultradistal radius by dual photon absorptiometry (Osteograph 1000, NIM, Verona, Italy) and biochemical markers of bone turnover were measured at baseline and after 6 and 12 months of glucocorticoid therapy. No significant difference was found between Groups 2 and 3 in the mean cumulative dose of prednisone (4945 ± 1956 mg and 5110 ± 2013 mg, respectively). At the end of the study period, BMD increased by 0.8% in the alendronate-treated group; in the placebo-treated group, BMD decreased by 4.5%. The difference between groups was significant (P < 0.01, ANOVA). A significant decrease in markers of bone formation was found in all patients treated with prednisone (Groups 2 and 3), independently of alendronate. Alendronate, however, counteracted the increase in markers of bone resorption induced by glucocorticoid therapy. Our data suggest that alendronate is effective in preventing glucocorticoid-induced bone loss in sarcoid patients. Further studies on alendronate use in steroid-induced osteoporosis are needed.
TL;DR: Low bone turnover in runners, indicated by lower levels of PTH and biochemical markers of bone metabolism, point to an influence of endurance running at the cellular level.
Abstract: Bone metabolism in endurance trained athletes - a comparison to population-based controls based on DXA, SXA, quantitative ultrasound and biochemical markers.
TL;DR: The results show that the micro-CT based on 2D images is a useful tool for imaging and nondestructively quantifying the microarchitecture of trabecular bone in unprocessed surgical bone specimens.
Abstract: Recently, an imaging technique using microcomputed tomography (micro-CT) has emerged as a method for nondestructively assessing the microarchitecture of unprocessed surgical bone biopsy specimens. Using micro-CT, two-dimensional (2D) axial images were obtained from undecalcified transiliac bone biopsies which were taken from 15 patients with various metabolic bone diseases. Total area, bone area, and bone perimeter were determined, from which the bone volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular separation (Tb.Sp) were calculated semiautomatically and instantaneously. To evaluate the validity of this technique as a useful tool, the results were compared with those obtained from conventional histomorphometry. There were significant correlations between the two techniques for all parameters, with correlation coefficients ranging from 0.759 (Tb.N, P < 0.005) to 0.949 (BV/TV, P < 0.0001). Different resolutions seem to lead to major differences in perimeter values measured by the two methods. These factors may explain why the correlation coefficients of Tb.N and Tb.Th estimated from the perimeter and area is lower than that of BV/TV. Our results show that the micro-CT based on 2D images is a useful tool for imaging and nondestructively quantifying the microarchitecture of trabecular bone in unprocessed surgical bone specimens.
TL;DR: Exercise induces endocrine changes which point to anabolic effects on muscle and bone tissue, and osteocalcin, IGF BP3, and PTH revealed no clearcut pattern.
Abstract: The purpose of this study was to evaluate the responses of hormones, growth factors, and biomarkers involved in bone and muscle metabolism during exercise and in recovery One leg knee-extension exercise and concomitant sampling from the artery and vein were performed In 12 healthy individuals (6 men and 6 women; age 21-36 years) blood was drawn from the femoral artery and vein at rest, after 10 minutes warm-up, after 15 minutes work at 61% of peak one leg VO2, and after 5 minutes work at peak one leg VO2, as well as 5, 30, and 60 minutes in recovery Blood flow in the femoral vein was measured using the thermodilution technique Arteriovenous differences were measured over working thigh for growth hormone (GH), insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGF BP3), parathyroid hormone (PTH) and bone biomarkers, ie, the carboxyterminal propeptide of type I procollagen (PICP), the carboxyterminal cross-linked telopeptide of type I collagen (ICTP), osteocalcin, and bone-specific alkaline phosphatase (b-ALP) There was an uptake of GH (31 +/- 12 mU x min(-1), P < 0001; mean +/- SE) over thigh during exercise and a release of IGF-I at the end of exercise (60 +/- 36 microg x min(-1); P < 001) PICP was also released after the maximal exercise (23 +/- 12 microg x min(-1); P < 001) as well as ICTP (05 +/- 03 microg x min(-1); P < 005) and b-ALP (02 +/- 01 microkat x min(-1); P < 005) Osteocalcin, IGF BP3, and PTH revealed no clearcut pattern In the present study, exercise induces endocrine changes which point to anabolic effects on muscle and bone tissue
TL;DR: It is concluded that in patients with multiple sclerosis, physical disuse is the main determinant for the reduction in bone mass, and glucocorticoid treatment is the major determinant of the Reduction in fat-free mass and thus also contributes to the reduction of bone mass.
Abstract: Multiple sclerosis (MS) is associated with reduced bone mass and vitamin D deficiency. The underlying pathophysiology of the bone disease is uncertain, however, acute and long-term glucocorticoid use, progressive immobilization, vitamin D deficiency, and possibly skeletal muscle atrophy are likely to be determinants. The aims of this study were to determine (a) whether multiple sclerosis is associated with reduced fat-free mass and (b) whether in patients with multiple sclerosis, ambulation ability or glucocorticoid use is associated with bone mass and/or fat-free mass. Seventy-one female patients with MS were compared with 71 healthy, age-matched female controls. Total body bone mineral content (TBBMC, kg), fat mass (FM, kg), and fat-free mass (FFM, kg) were measured using dual X-ray absorptiometry. Disability status was graded according to the Kurtzke Expanded Disability Status Scale (EDSS) as ambulatory, with or without aide (EDSS score of 0 to 6.5), or predominantly wheelchair bound (EDSS score > 6.5). The patients with MS, when compared to age-comparable controls, had deficits in TBBMC (≈ 8%, −0.3 ± 0.1 SD, P < 0.04) and FFM (≈ 5%, −0.3 ± 0.1 SD, P < 0.01). Both TBBMC and FFM were negatively associated with EDSS score (r= 0.33, P < 0.01, and r= 0.41, P < 0.01, respectively). Patients with MS who were nonambulatory had even greater deficits in TBBMC and FFM as compared with age-matched controls (−0.6 ± 0.1 SD, P < 0.01, and −0.6 ± 0.1 SD, P < 0.01, respectively). By contrast, as compared with age-comparable controls, ambulatory patients with MS had no deficits in bone mass or soft tissue mass. When compared with ambulatory patients with MS, nonambulatory patients with MS had deficits in TBBMC and FFM (P < 0.01 and P < 0.01, respectively). The difference in TBBMC was largely caused by the difference in fat-free mass, whereas the difference in FFM was largely caused by the difference in glucocorticoid use based on analysis of covariance. We conclude that in patients with multiple sclerosis, physical disuse is the main determinant for the reduction in bone mass. Glucocorticoid treatment is the major determinant of the reduction in fat-free mass and thus also contributes to the reduction in bone mass.
TL;DR: Because of the enormous clinical significance of the proximal femur for osteoporosis in humans, and the opportunity for studying bone BMD, mass, structure, and strength at the same skeletal location, the femoral neck appears superior to other skeletal sites routinely used for bone histomorphometry or mechanical testing in the Ovx rat model.
Abstract: Eighty mature Sprague-Dawley rats were weight matched before ovariectomy (Ovx) or Sham surgery (Sham). Sham rats had free access to food and water throughout the experiment, whereas Ovx rats were kept on the pair-fed diet. Rats were euthanized at 4, 8, and 12 weeks after surgery, and had received fluorochrome bone markers at 9 and 2 days prior to euthanasia. In addition 10 rats were euthanized at the time of surgery serving as baseline controls. All rats were also scanned for body composition and bone mineral parameters by DEXA before surgery and euthanasia. Left proximal femurs (femoral necks) were used for bone histomorphometry, whereas right femurs were used for in vitro DEXA measurements and mechanical testing. Despite pair-feeding, ovariectomized rats had increased body weights and fat body mass, whereas the percent lean body mass steadily declined throughout the experiment. Mineral density of the whole femur and femoral neck was significantly higher in the Sham rats relative to Ovx animals. Ovariectomy reduced trabecular number and thickness, and increased trabecular separation and bone marrow space at the femoral midneck location. The structure of the remaining trabeculae was dramatically changed toward simpler struts as revealed by nodal analyses. Cortical thickness in Ovx rats was reduced because of the high endocortical resorption, which, in addition to cancellous bone resorption, resulted in fewer endocortico-trabecular connections. Femoral necks obtained from ovariectomized rats had reduced strength and were less stiff relative to controls. Because of the enormous clinical significance of the proximal femur for osteoporosis in humans, and the opportunity for studying bone BMD, mass, structure, and strength at the same skeletal location, the femoral neck appears superior to other skeletal sites routinely used for bone histomorphometry or mechanical testing in the Ovx rat model.
TL;DR: Results clearly show that young female volleyball players have a high bone mass, and the demonstrated high bonemass seems to be related to the type of loading subjected to each BMD site.
Abstract: The purpose of this cross-sectional study was to evaluate bone mass in female athletes participating in an impact loading sport (volleyball), and especially to investigate whether any changes in bone mass might be related to the type and magnitude of weightbearing loading and muscle strength. The volleyball group consisted of 13 first division players (age 20.9 +/- 3.7 years) training for about 8 hours/week, and the reference group consisted of 13 nonactive females (age 25.0 +/- 2.4 years) not participating in any kind of regular or organized sport activity. The groups were matched according to weight and height. Areal bone mineral density (BMD) was measured in total body, head, lumbar spine, femoral neck, Ward's triangle, trochanter, the whole femur, and humerus using dual-energy-X-ray absorptiometry. Isokinetic concentric peak torque of the quadricep and hamstring muscles was measured using an isokinetic dynamometer. Compared with the controls, the volleyball players had a significantly (P < 0.05-0.01) higher BMD of the total body (6.1%), lumbar spine (13.2%), femoral neck (15.8%), Ward's triangle (17.9%), trochanter (18.8%), nondominant femur (8.2%), and humerus (dominant 9.5%, nondominant 10.0%), but not of the head and the dominant whole femur. The dominant humerus showed significantly higher BMD than the nondominant humerus in both the volleyball and nonactive group (P < 0.05). There was no significant difference in muscle strength of the thigh between the two groups. In the nonactive group, muscle strength in the quadriceps, and especially hamstrings, was correlated to BMD of the adjacent bones (whole femur, hip sites) and also to distant sites (humerus). However, in the volleyball group there were no correlations between muscle strength and BMD of the adjacent bones, but quadricep strength correlated to BMD of the humerus. These results clearly show that young female volleyball players have a high bone mass. The demonstrated high bone mass seems to be related to the type of loading subjected to each BMD site. Muscle strength of the thigh seems to have little impact on BMD in female volleyball players.
TL;DR: Intestinal calcium absorption was significantly lower in BB and tt genotypes than, in bb and TT genotypes, respectively, and in AABBtt genotype than in either aabbTT or AaBbTt genotype, consistent with a possible role of VDR alleles on intestinal calcium absorption.
Abstract: Several studies have shown that bone mass and bone turnover are genetically determined. This genetic component is thought to be mediated in part by polymorphisms at the vitamin D receptor (VDR) locus, even though the underlying molecular mechanisms are still unknown. To evaluate a possible site of differential action of the VDR gene alleles we examined their correlation with intestinal calcium absorption in 120 Caucasian postmenopausal women (aged 61 ± 0.6 years). VDR gene polymorphisms for Apa I, Bsm I, and Taq I restriction endonucleases were assessed by Southern blotting analysis. The most common genotypes observed in our population were AaBbTt (37%), AABBtt (20%), aabbTT (15%), AabbTT (15%), and AABbTt (9%). Although there was some evidence of 13% higher lumbar BMD values in aabbTT genotype with respect to AABBtt genotype, this difference of approximately 0.1 g/cm2 did not reach statistical significance, possibly because of the limited number of observations. On the contrary, no relationship was found between genotypes and femoral neck BMD values. Intestinal calcium absorption was significantly lower in BB and tt genotypes than, in bb and TT genotypes, respectively, and in AABBtt genotype than in either aabbTT or AaBbTt genotypes (P= 0.0015 ANOVA). No significant differences in intact PTH, alkaline phosphatase, 25OHD3, and 1,25(OH)2D3 were found among subjects with different VDR genotypes. These results are consistent with a possible role of VDR alleles on intestinal calcium absorption.
TL;DR: Findings show that smoking by healthy young males is associated with decreased bone mass, and Serum levels of dehydroepiandrosterone sulfate were lower in smokers and correlated with femoral BMD measurements.
Abstract: Smoking is related to a decreased bone mass and increased risk of osteoporotic fractures. Nevertheless, the effect of smoking in males is poorly understood. The purpose of this study was to assess the repercussion of smoking on bone mass in otherwise healthy male smokers and its relationship with markers of mineral metabolism and hormone profile. We measured bone mineral density (BMD) in 57 healthy males (26 nonsmokers, 31 smokers; aged 20–45 years) by dual X-ray absorptiometry (DXA, Hologic QDR1000) in the lumbar spine and proximal femur. In a subset we measured biochemical markers of bone metabolism and hormonal profile. We found significant differences in BMD between heavy smokers (more than 20 cigarettes/day) and nonsmokers in all skeletal sites. Serum levels of dehydroepiandrosterone sulfate (S-DHEAS) were lower in smokers and correlated with femoral BMD measurements. No significant differences in bone turnover markers were found. Our findings show that smoking by healthy young males is associated with decreased bone mass.
TL;DR: The synthetic isoflavone derivative ipriflavone is able to reduce bone loss in various types of animal models of experimental osteoporosis providing a rationale on its use in the prevention and treatment of postmenopausal and senile osteoporeosis in humans.
Abstract: The evidence that natural isoflavones protect against several chronic diseases is both observational and experimental. In humans, epidemiologic findings clearly show a higher incidence of some common types of cancer (i.e., breast, prostate, and colon) and of coronary heart diseases in Western populations exposed to limited amounts of soybean isoflavones (i.e., genistein, daidzein) in the diet. Further evidence for cancer and cardiac protection and antiatherogenic effects resulting from soybean isoflavones administration has been noted in various experimental animal models. Isoflavones may also prevent postmenopausal bone loss and osteoporosis. In fact, genistein has been reported to be as active as estrogens in maintaining bone mass in ovariectornized rats. Moreover, the synthetic isoflavone derivative ipriflavone is able to reduce bone loss in various types of animal models of experimental osteoporosis providing a rationale on its use in the prevention and treatment of postmenopausal and senile osteoporosis in humans. The mechanism through which isoflavones may exert the abovementioned effects seems to depend, at least in part, on their mixed estrogen agonist-antagonist properties. An alternative hypothetical mechanism could derive from other biochemical actions of isoflavones such as inhibition of enzymatic activity, in particular protein kinases, or activation of an “orphan” receptor distinct from the estrogen type I receptor.
TL;DR: It is found in this open randomized study that calcidiol was the most effective drug in the prevention and treatment of bone loss in patients after cardiac transplantation.
Abstract: Cardiac transplantation is associated with severe bone loss caused by glucocorticoids, immunosuppressive treatment, and other factors. Treatment protocols for the prevention of bone loss is being studied. Forty patients who underwent cardiac transplantation were randomly given calcitonin (n = 13; 100 UI/d, nasal route), etidronate (n = 14; cyclical treatment 400 mg p.o./d/2 weeks/3 months), or calcidiol (n = 13; 32,000 IU/weekly) therapy for at least 18 months. Serum parameters (Ca, P, alkaline phosphatase, osteocalcin, intact PTH), urinary calcium, and vertebral mineral density (VMD; L2-L4, DXA Hologic QDR 1000) were measured immediately before treatment and after 6, 12, and 18 months of therapy after cardiac transplantation. Patients with cardiac transplantation had a VMD significantly lower than age and sex-matched Spanish controls. Prevalence of osteoporosis (Z-score below -2 SD) was 30%. Osteocalcin levels increased at 6, 12, and 18 months of treatment in the three groups. After 18 months of treatment, VMD increased significantly in the calcidiol 4.9%, vs. -1.19% and -0.19% in the calcitonin and etidronate groups, respectively. A lower incidence of fracture was found in patients treated with calcidiol during the study. In summary, we have found in this open randomized study that calcidiol was the most effective drug in the prevention and treatment of bone loss in patients after cardiac transplantation.
TL;DR: Findings provide evidence that, among other factors, the activity of the growth hormone-IGF-I-axis is of importance for skeletal integrity.
Abstract: Peripheral quantitative computed tomography (pQCT) allows the separate determination of cortical and trabecular bone mineral density in the peripheral skeleton. This cross-sectional study was designed to examine the effects of healthy aging on pQCT measurements at the ultradistal radius. In a well-defined sample of 129 community-based women, aged 70–87 years, the differences in cortical and trabecular density over the age range were equivalent to losses of −0.41% and −0.65% per year, respectively. To investigate the mechanism of this age-related decline, we assessed relationships between both parameters and height, weight, body mass index, dietary calcium intake, grip strength, and serum concentrations of insulin-like growth factor-I (IGF-I), calcidiol (25(OH)D3), calcitriol (1,25(OH)2D3), parathyroid hormone (PTH), and sex hormone binding globulin (SHBG). Multiple regression was used to adjust for potential confounders. Age was not significant after controlling for other covariables. Body mass index, grip strength, serum IGF-I, 25(OH)D3, and PTH (1–84) were found to be independent predictors of total bone density. Including (total or free) 1,25(OH)2D3 did not improve the model precision. These findings provide evidence that, among other factors, the activity of the growth hormone-IGF-I-axis is of importance for skeletal integrity. Grip strength, serum IGF-I, and PTH (1–84) were discovered to be significantly related to cortical but not to trabecular density, suggesting that different mechanisms may be involved in compact and cancellous bone loss.
TL;DR: Young females showed biochemical signs of increased bone collagen turnover and altered homeostasis of calcium and PTH after a single bout of moderate endurance exercise.
Abstract: We investigated the short-term (1 hour-3 days) effects of a 45 minute run on calcium, parathyroid hormone, the carboxyterminal propeptide of type I procollagen (PICP), and the immunoactive carboxyterminal telopeptide of type I collagen in serum (ICTP) in young females Fourteen healthy young women, aged 252 ± 06 years (mean ± SEM) with regular menstruations, participated The test was outdoor jogging for 45 minutes at an intensity of 50% of VO2 max Blood samples were collected 15 minutes before the test and 1, 24, and 72 hours after the test The measured values were adjusted for changes in plasma volume A significant decrease of ionized calcium was observed at 1 hour (P < 0001) and 72 hours (P < 005) and a significant increase of parathyroid hormone (PTH) was noted 24 (P < 001) and 72 hours (P < 005) after the test A significant decrease of PICP at 1 hour (P < 005) was followed by an increase after 24 (P < 001) and 72 hours (P < 0001) and a significant increase in ICTP was noted at 24 and 72 hours (P < 005) A strong positive correlation was found between serum levels of PICP and ICTP (r = 055–084; P < 005) throughout the experiment In conclusion, young females showed biochemical signs of increased bone collagen turnover and altered homeostasis of calcium and PTH after a single bout of moderate endurance exercise
TL;DR: A concerted action of the endothelial cell polypeptide ET-1 and 1,25(OH)2D3 may mediate an osteoanabolic effect of the vascular and endocrine vitamin D system.
Abstract: Endothelial cell products may affect bone cell function, since trabecular and cortical bone are in close proximity to vascular endothelial cells. Incubation of cultured human osteoblastic cells with the endothelial cell polypeptide endothelin-1 (ET-1) resulted in a time- and dose-dependent stimulation of cell proliferation. Furthermore, markers of differentiated osteoblastic function, i.e., alkaline phosphatase and type-I collagen, were dose-dependently increased in response to ET-1. The effects of ET-1 on cell growth and function reached a maximum at higher ET-1 concentrations, and osteoblastic cells bound ET-1 specifically with a KD of 35 pM, corresponding to the biologic effects of ET-1 on bone cells. Under baseline conditions osteoblastic cells expressed 16,800 binding sites per cell. The effect of ET-1 was dependent on its binding to the endothelin-1 receptor A (ETRA), since an inhibitor of ET-1 binding blocked the biologic effects of ET-1. Northern blot analyses revealed that cultured human osteoblastic cells possess the transcript for the ETRA. Expression of ETRA mRNA was under control of 1,25-dihydroxyvitamin D3 [1,25 (OH)2D3]. Incubation of osteoblastic cells with 1,25(OH)2D3 increased ETRA mRNA levels, corresponding to an increased effect of ET-1 on osteoblastic proliferation and function. Thus, a concerted action of the endothelial cell polypeptide ET-1 and 1,25(OH)2D3 may mediate an osteoanabolic effect of the vascular and endocrine vitamin D system.