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Because intestinal calcium absorption may be an important independent determinant of calcium balance and therefore bone mass, we have studied this factor and other potential predictors in 196 healthy postmenopausal women. Gut calcium absorption was measured in each subject by a stable strontium method and expressed as a fractional absorption. The fractional absorption was significantly negatively correlated with years since menopause (YSM) (r = -0.15 P < 0.05) and dietary calcium intake (r = -0.15 P < 0.05), and significantly positively correlated with 24-hour urine calcium excretion (r = 0.31 P < 0.001) and body mass index (r = 0.20 P < 0.01). Apart from YSM, these factors remained as correlates in multiple regression analysis; the standardized regression coefficient was largest for 24-hour urine calcium excretion (0.32). Fractional absorption of calcium was not correlated with vertebral bone density. Thus, intestinal calcium absorption, although falling with increasing menopausal age and increasing calcium intake, is best correlated with the urine calcium excretion. This indicates either that gut calcium absorption is regulated in response to the magnitude of the urine calcium excretion or that the kidney maintains calcium balance by excreting what is absorbed by the intestine. The mechanisms whereby gut and renal calcium handling are correlated are uncertain. [ABSTRACT FROM AUTHOR]

Eighteen postmenopausal osteoporotic (PMO) women on placebo therapy were followed for 1 year. Serial measurements of calcium balance and kinetics, bone histomorphometry, photon absorptiometry, and radiogrammetry were obtained. Few significant changes in balance and kinetics or bone histology were seen in these women over time. Photon absorptiometry and radiogrammetry of the femoral cortex showed a significant annual bone loss however. When compared with premenopausal and healthy postmenopausal women, the annual bone loss in those with PMO was significantly greater. The ability of balance studies, photon absorptiometry, and radiogrammetry to predict the magnitude of this bone loss was similar. Finally, there was an illustration of the use of the estimated variance provided by this study for estimating sample size for future studies. [ABSTRACT FROM AUTHOR]

In 10 patients with Paget's disease of bone and 2 patients with osteoporosis, we studied the effects of hypocalcemia and hypophosphatemia induced by disodium-(3-amino-1-hydroxypropylidene)-1,-bisphosphonate (APD) treatment on the serum concentration of PTH and 1,25-dihydroxyvitamin D [1,25(OH)D] and on calcium absorption and balance. The fall in serum calcium and phosphate was associated with a rise in the serum concentration of PTH and 1,25(OH)D, coupled with increases in net calcium absorption and calcium balance. The concentration of 1,25(OH)D was significantly related ( P<0.001) to the serum calcium ( r=0.66), the serum phosphate ( r=0.78), and the serum PTH ( r=0.71), confirming the interrelated control of these parameters on 1,25(OH)D production. Moreover, the rise in 1,25(OH)D caused an appropriate rise in calcium absorption ( r=0.74) and calcium balance ( r=0.86), showing that this vitamin D metabolite contributes as a hormone to calcium homeostasis. [ABSTRACT FROM AUTHOR]

Optimizing peak bone mass in early life is one of key preventive strategies against osteoporosis. Fructus ligustri lucidi (FLL), the fruit of Ligustrum lucidum Ait., is a commonly prescribed herb in many kidney-tonifying traditional Chinese medicinal formulas to alleviate osteoporosis. Previously, FLL extracts have been shown to have osteoprotective effect in aged or ovariectomized rats. In the present study, we investigated the effects of FLL ethanol extract on bone mineral density (BMD) and mechanical properties in growing male rats and explored the underlying mechanisms. Male weaning Sprague-Dawley rats were randomized into four groups and orally administrated for 4 months an AIN-93G formula-based diet supplementing with different doses of FLL ethanol extract (0.40, 0.65, and 0.90 %) or vehicle control, respectively. Then calcium balance, serum level of Ca, P, 25(OH)D, 1,25(OH)D, osteocalcin (OCN), C-terminal telopeptide of type I collagen (CTX-I), and parathyroid hormone, bone microarchitecture, and calcium absorption-related genes expression in duodenum and kidney were analyzed. The results demonstrated that FLL ethanol extract increased BMD of growing rats and improved their bone microarchitecture and mechanical properties. FLL ethanol extract altered bone turnover, as evidenced by increasing a bone formation maker, OCN, and decreasing a bone resorption maker, CTX-I. Intriguingly, both Ca absorption and Ca retention rate were elevated by FLL ethanol extract treatment, possibly through the mechanisms of up-regulating the transcriptions of calcitropic genes in kidney (1α-hydroxylase) and duodenum (vitamin D receptor, calcium transporter calbindin-D9k, and transient receptor potential vanilloid 6). In conclusion, FLL ethanol extract increased bone mass gain and improved bone properties via modulating bone turnover and up-regulating calcium absorption-related gene expression in kidney and duodenum, which could then activate 1,25(OH)D-dependent calcium transport in male growing rats. [ABSTRACT FROM AUTHOR]

Maintenance of a skeleton capable of resisting the stresses of everyday life is dependent on the mechanical forces applied to the skeleton during normal activity in a 1-G environment. When the effects of 1-G on the longitudinal skeleton are removed, as with space travel or inactivity, bone and bone mineral are lost because bone resorption is greater than bone formation. Ninety healthy young men were studied during 5-36 weeks of continuous bed rest. During inactivity, urinary calcium increases rapidly and by the sixth week of bed rest, output has risen by 100 mg/day, plateaus for several weeks, and then decreases but remains above ambulatory baseline thereafter. This occurred even though they received vitamin D supplements throughout the study. Calcium balance becomes negative after 2 weeks and by the end of the first month, 200 mg/day is lost. The loss continues at this rate for at least 36 weeks. Calcaneal mineral loses 5% of its mass each month. Attempts to prevent disuse osteoporosis with both mechanical and biochemical means, including exercise, skeletal compression, increased hydrostatic pressure to the lower body, supplemental calcium and/or phosphorus, calcitonin, or etidronate were not successful. [ABSTRACT FROM AUTHOR]

The oophorectomized (OOX) rat has been proposed as a good model of postmenopausal osteoporosis in women. The aim of this study was to compare the effect of OOX in 6-month-old rats to the effects of menopause in women with respect to bone mass, the renal handling of calcium and phosphorus, and calcitropic hormones. To more closely replicate the human situation the rats were pair fed a 0.1% calcium diet. Thirty four, 6-month-old rats were randomized to sham operation or OOX. Whole body and regional bone density was performed at baseline and 6 weeks postoperation. Blood and 24-hour urine samples were obtained at baseline, 1, 3, and 6 weeks and assayed for various biochemical variables, parathyroid hormone (PTH), and calcitriol. The OOX rats lost significantly more bone than the sham-operated rats (change in global bone mineral density, sham -1.7 +/- 2.0%, OOX -3.9 +/- 2.6%, P < 0.001). In the OOX animals, an increase in the 24-hour urine calcium was observed at 1 and 3 weeks, which had returned to sham-operated levels by 6 weeks. In the whole group, the increase in urine calcium at 1 week was negatively correlated with the change in bone mass at 6 weeks (r = -0.39, P = 0. 029). OOX resulted in an increased filtered load of calcium and phosphorus. There was an increase in the maximal renal tubular reabsorption of phosphorus (TmP-GFR) but no clear change in renal calcium handling. Neither calcitriol nor parathyroid hormone showed a significant change as a result of OOX. As in postmenopausal women, following oophorectomy in the rat, there was significant generalized bone loss and a negative calcium balance. This was associated with an initial rise in urine calcium due to a rise in the filtered calcium load; plasma phosphorus and TmP-GFR also rose. The rat model may differ from postmenopausal bone loss in that the initial rise in urine calcium was not present at later time points as occurs in natural menopause in women. Calcitropic hormone levels did not change. This study has shown that the 6-month-old OOX rat fed a 0.1% calcium diet has many similarities of calcium and phosphorus homeostasis to that seen at menopause in women. [ABSTRACT FROM AUTHOR]

Chronic metabolic acidosis (CMA) is known to have a detrimental effect on bone metabolism as a result of accelerated bone resorption and impaired bone formation. Typically, a number of compensatory adaptations must have occurred which may help palliate negative calcium balance and acidemia, e.g., increased intestinal calcium and phosphorus absorption. The final outcome with respect to bone remodeling after exposure to CMA for several months was, therefore, elusive. Herein, we investigated bone changes in male rats fed 1.5% NH4Cl in drinking water for up to 10 months to induce CMA with plasma pH of 7.2–7.3. Significant decreases in bone mineral density and content were detected by dual-energy X-ray absorptiometry after 6 months of CMA, whereas histomorphometric analysis revealed a significant decrease in bone volume already at week 2 after CMA induction. Exposure to CMA longer than 2 weeks also decreased trabecular number, trabecular thickness, osteoblast surface, mineral apposition rate, and bone formation rate, while increasing trabecular separation, osteoclast surface, and eroded surface. Bone resorption was rapid during weeks 2–16 (acceleration phase) and thereafter persisted at a slower rate (stationary phase) until week 40. Furthermore, CMA markedly reduced the total calcium content in bone and enhanced urinary calcium excretion as measured by atomic absorption spectrophotometry. It could be concluded that, after exposure to a long-standing acidemia, the enhanced bone resorption and suppressed bone formation led to osteopenia throughout the 10-month period, with accelerated bone loss seen only during the first 6 months. Thereafter, the compensatory adaptations appeared to help stabilize bone mass at a subnormal level. [ABSTRACT FROM AUTHOR]

The article focuses on glucocorticoid-induced osteoporosis in children. Glucocorticoids are used in a variety of diseases affecting children and adolescents, and studies show adverse effects on bone mass and growth. The long-term administration of glucocorticoids increases parathyroid hormone secretion because of the negative calcium balance resulting from both the inhibition of intestinal calcium absorption and the increase in calcium renal excretion. Bisphosphonate therapy must be seriously considered in children and adolescents only after all other measures have been tried and have failed to ameliorate bone loss. In children osteonecrotic lesions are often asymptomatic and spontaneous improvement or even resolution may occur.

A high sucrose diet reduces dentin apposition of growing rats. The mechanisms of reduction are unclear, but disturbances in calcium balance or in mineralization of predentin may explain them. In this experiment, 29 Sprague-Dawley rats, 21 days old, were weaned and randomized into calcium-deficient, high-sucrose or standard-diet groups for 3 weeks. They were given food and water ad libitum. During the experiment, animals were individually housed in metabolic cages where urine samples were collected. At ages of 21 and 40 days mineralizing dentin was marked using I.P. injections of oxytetracycline hydrochloride. At 42 days of age, the animals were anesthetized and their blood was collected by cardiac puncture. Right hemimandibles were sectioned sagittally and left hemimandibles were fixed, decalcified, and cut into histological sections. Dentin appositions were measured planimetrically, predentin width, from histological sections. Ca, K, and Na levels of serum and urine were measured flame photimetrically and P levels were measured by the UV method. Statistical analyses were done using one-way analysis of variation (ANOVA) Tuckey's HSD t test. In the calcium-deficient group, hypocalcemia, reduced dentin apposition, and increased predentin width were noticed when compared with the control group (P<0.05). Also, the increase in predentin width, caused by calcium deficiency, was significant compared with sucrose-fed animals (P<0.05). Sucrose diet reduced dentinogenesis, increased Ca excretion to urine, but also reduced urinary levels of P, K, and Na, and the differences were significant for the controls (P<0.05). In conclusion, despite the same kind of reduced dentinogenesis in calcium-deficient and high-sucrose groups, calcium imbalance or reduced mineralization of predentin does not explain reduced dentinogenesis in sucrose-fed animals. [ABSTRACT FROM AUTHOR]

Components of the renin–angiotensin–aldosterone system (RAAS) are present on bone cells. One measure of RAAS activity, the aldosterone-renin-ratio (ARR), is used to screen for primary aldosteronism. Associations between ARR and bone mineral density are conflicting. This study investigated associations between ARR and peripheral quantitative computed tomography (pQCT) and impact microindentation (IMI). Male participants (n = 431) were from the Geelong Osteoporosis Study. "Likely" primary aldosteronism was defined as ARR ≥ 70 pmol/mIU. Another group, "possible" primary aldosteronism, was defined as either ARR ≥ 70 pmol/mIU or taking a medication that affects the RAAS, but not a beta blocker, and renin < 15 mU/L. Using pQCT, images at 4% and 66% of radial (n = 365) and tibial (n = 356) length were obtained. Using IMI measurements, bone material strength index (BMSi; n = 332) was determined. Associations between ARR or likely/possible primary aldosteronism and IMI or pQCT-derived bone parameters were tested using median regression. ARR and aldosterone values were not associated with any of the pQCT-derived bone variables in either unadjusted or adjusted analyses. Men with likely primary aldosteronism (n = 16), had lower adjusted total bone area (radial 66% site, − 12.5%). No associations were observed for men with possible primary aldosteronism (unadjusted or adjusted). No associations with BMSi were observed (p > 0.05). There were no associations between ARR or aldosterone and pQCT-derived bone parameters. Men with likely primary aldosteronism had lower bone area, suggesting clinically high levels of ARR may have a negative impact on bone health. [ABSTRACT FROM AUTHOR]

In several studies on patients with rheumatoid arthritis, an association of bone loss with a persistently high disease activity has been found. The aim of our study was to investigate the relation between disease activity and serum levels of vitamin D metabolites, parathyroid hormone (PTH), and parameters of bone turnover in patients with rheumatoid arthritis. A total of 96 patients (83 women and 13 men) were divided into three groups according to disease activity measured by serum levels of C-reactive protein (CRP). In the whole group, serum levels of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (P < 0.001) and PTH (P < 0.05) were negatively correlated to disease activity. The urinary excretion of collagen crosslinks--pyridinoline (Pyd) (P < 0.001) and deoxypyridinoline (Dpd) (P < 0.05)--showed a positive correlation with disease activity. The inverse correlation between serum 1,25(OH)2D3 and disease activity was separately evident in patients with (P < 0.001) and without (P < 0.01) glucocorticoid treatment, in pre- (P < 0.01) and postmenopausal (P < 0.001) women, and in men (P < 0.01). 1,25(OH)2D3 and PTH serum levels were positively correlated to serum bone alkaline phosphatase (ALP) (P < 0.01). The results indicate that high disease activity in patients with rheumatoid arthritis is associated with an alteration in vitamin D metabolism and increased bone resorption. The decrease of 1,25(OH)2D3 levels in these patients may contribute to a negative calcium balance and inhibition of bone formation. Furthermore, low levels of 1,25(OH)2D3 as an endogenous immunomodulator suppressing activated T cells and the proliferation of cells may accelerate the arthritic process in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Calcitriol is used in the treatment of osteoporosis but the indications for its use have not been clearly defined. Because it stimulates calcium absorption, we have tended to select osteoporotic patients with low calcium absorption for this therapy and now report the results. We measured the hourly fractional rate of calcium absorption (alpha) with 45Ca and fasting urinary calcium/creatinine (Ca/Cr) and hydroxyproline/creatinine (OHPr/Cr) in 103 postmenopausal women aged 68 (0.67SE) years with vertebral compression fractures (77) or forearm or vertebral bone density below the young normal range (26). They were given 0.25 microg daily of calcitriol (Rocaltrol, Roche, Basle, Switzerland) with a 1 g calcium supplement daily for 6-12 weeks, when the biochemical tests were repeated. Initial OHPr/Cr was inversely related to initial alpha (P = 0.001) and positively to initial Ca/Cr (P < 0.001). alpha rose on therapy from 0.47 (0.018) to 0.59 (0.018) per hour (P < 0. 001) and OHPr/Cr fell in the whole group from 19.1 (0.83) to 13.8 (0. 58) (P < 0.001). The change in alpha on therapy (corrected for the "regression to the mean effect") was inversely related to initial alpha (P < 0.001) as was the change in OHPr/Cr (P = 0.001). There was no relationship, however, between initial Ca/Cr and either the rise in alpha or the fall in OHPr/Cr on therapy. The data support the concept that low calcium absorption is a cause of negative calcium balance in postmenopausal osteoporosis and that the effectiveness of calcitriol therapy is inversely related to the initial rate of calcium absorption. [ABSTRACT FROM AUTHOR]

Conventional glucocorticoids exert a negative influence on calcium balance, and long-term treatment with these agents leads to osteopenia. Deflazacort is an oxazoline derivative of prednisolone with documented calcium-sparing properties when compared to prednisone on a weight basis. The purpose of the present study was to determine the relative antiinflammatory potency of deflazacort and prednisone. In a randomized, cross-over, double-blind trial, 11 patients, all suffering from polymyalgia rheumatica, and all on a stable maintenance dose of prednisone, were treated with equimolar doses of prednisone and deflazacort (i.e., weight ratio 1:1.2) for two consecutive 2-week periods. Following deflazacort treatment, significant rises compared with initial values were seen in erythrocyte sedimentation rate (ESR), plasma fibrinogen, serum alkaline phosphatase, and general pain and tenderness. No changes were seen following prednisone treatment. Subsequently, in a similar regimen, prednisone was compared with deflazacort at a weight ratio of 1:1.2 in 10 patients, 1:1.5 in another 10 patients, and 1:1.8 in still another 10 patients for purposes of dose titration. Again, significant rises were seen in ESR, plasma fibrinogen, and serum alkaline phosphatase following the lowest dose of deflazacort, whereas no changes were seen following the higher doses of deflazacort or prednisone. In conclusion, the relative antiinflammatory potency of deflazacort and prednisone lies between 0.83 and 0.66 on a weight basis (1.02 and 0.82 on a molar basis) as evaluated by clinical and biochemical parameters reflecting disease activity in polymyalgia. This disease appears to represent a sensitive, reliable and reproducible clinical model for assessment of the relative antiinflammatory potency of glucocorticoids. [ABSTRACT FROM AUTHOR]

Chronic diabetes mellitus in the rat is attended by a reduced bone turnover and growth arrest, decreased circulating immunoreactive parathyroid hormone (iPTH), and hypercorticosteronism. Since chronic insulin deficiency in the rat is associated with intestinal hyperabsorption of calcium and a positive calcium balance that may account for the decreased iPTH, as well as other hormonal alterations observed in these animals, we studied the effect of long-term (5 week) dietary calcium restriction (0.1% Ca, 0.8% P) in control and streptozotocin-induced diabetic rats. Chronic diabetic rats reared on a normal calcium (1.2% Ca) diet had increased serum calcium and phosphate (Pi) concentrations and were markedly hypercalciuric and phosphaturic compared with controls. Serum corticosterone was increased and iPTH markedly decreased in the diabetic animals. Dietary Ca restriction (0.1% Ca) decreased urinary calcium excretion and resulted in a comparable phosphaturic response in both control and diabetic rats. Moreover, although Ca restriction in diabetic animals had no appreciable effect on serum insulin, serum glucose, or urinary glucose excretion, it was associated with a marked increase in circulating iPTH; this resulted in serum concentrations comparable with that observed in control animals reared on the low Ca diet. These results support the hypothesis that the decreased circulating iPTH observed in chronic diabetic rats results predominantly from their intestinal hyperabsorption of Ca. In contrast to control animals, diabetic rats reared on a low Ca diet failed to maintain their serum Ca despite the marked increase in serum iPTH and striking decrease in calciuria, thus underscoring the reliance of these animals on intestinal hyperabsorption of Ca to maintain Ca balance under conditions of adequate Ca intake. Serum corticosterone was insignificantly altered by dietary Ca restriction in control rats; hypercorticosteronism, characteristically observed in diabetic rats, was normalized by Ca restriction. We conclude that a primary disturbance in Ca homeostasis may contribute, in part, to hormonal alterations observed in chronic experimental diabetes. [ABSTRACT FROM AUTHOR]

Prolonged therapeutic administration of prednisone or other corticosteroids frequently produces severe osteopenia with an increased incidence of bone fractures. Recent efforts to decrease the severity of corticosteroid-induced osteopenia have included the development of corticosteroid analogues designed to possess diminished bone-wasting effects relative to their anti-inflammatory activity. We compared the effects of an oxazoline derivative of prednisolone, oxazacort (azacortinol), with those of prednisone on mineral metabolism in man. After a 12-day equilibration period on a 600 mg/day calcium diet, normal volunteers were studied for 15 days during treatment with either prednisone (20 mg/day, 12 subjects) or oxazacort (25 mg/day, 10 subjects). There was no difference between the two groups with regard to the effects of each corticosteroid on serum ionized calcium, phosphate, alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), and 25-hydroxyvitamin D (25OHD) concentrations. Both corticosteroids suppressed intestinalCa absorption to a similar degree after 15 days of treatment (prednisone: −28.5±7.5, oxazacort: −30.2±4.4% of initial values). Although both corticosteroids increased 24-h urinary calcium excretion significantly above pretreatment values, this effect was less marked in the oxazacort-treated subjects. The mean cumulative 15-day increase in urinary calcium excretion in the prednisone-treated group (+326 ± 54 mg/g creatinine/24 h) was more than twice as great as that in the oxazacort-treated group (+146 ± 48 mg/g creatinine/24 h), a difference significant at P<0.001. It is concluded that the increase in urinary calcium excretion, and presumably the negative calcium balance, produced by a 2-week administration of oxazacort is significantly less pronounced than that produced by an equivalent dose of prednisone. [ABSTRACT FROM AUTHOR]

We have examined the effects of H, CO, and HCO concentrations during metabolic and respiratory acidosis and alkalosis on bone resorption in vitro. Rat fetal bones prelabeled withCaCl were cultured at 2%, 5%, and 10% CO for up to 120 h, and the release ofCa was measured in devitalized bones (non-cell-mediatedCa release) and in live bones (cell-mediatedCa release) cultured with or without PTH and 1,25(OH)D. Non-cell-mediated mineral loss was linearly related to H concentration but not to CO or HCO concentration. This effect was observed on both labeled and stable calcium. Over a wide pH range (6.9-7.5) H, CO, or HCO concentrations did not influence cell-mediated bone resorption in control or in PTH-and 1,25(OH)D-stimulated cultures. However, inhibition of cell-mediated bone resorption was observed at higher or lower pH irrespective of CO or HCO concentrations. These observations demonstrate that the bone mineral mobilizing effect of acidosis in vitro is mainly due to the effect of changing H concentration on devitalized bone. Effects on cell-mediated bone resorption and hormonal response were observed only at extremes of pH. The effects of H were independent of changes in CO or HCO concentration and could be responsible for the negative calcium balance and increased urinary loss observed in metabolic acidosis in vivo, but do not explain the reported differences in effects on calcium metabolism between respiratory and metabolic acidosis. [ABSTRACT FROM AUTHOR]

The study investigates the association of coffee consumption and odds of osteoporosis/osteopenia among individuals older than 50 years in the United States. In NHANES 2005-2014, drinking ≤ 2 cups(16 oz) of coffee per day can reduce the risk of osteoporosis/osteopenia at the femoral neck and lumbar spine in US adults. Previous epidemiological studies revealed that daily coffee intake reduced the incidence of a cluster of metabolic diseases, however, the link between coffee consumption and prevalence of osteoporosis/osteopenia still remain inconclusive and awaits further confirmation. Based on data collection from 2005 to 2014 survey cycles, National Health and Nutrition Examination Survey (NHANES), a sample size of 8789 participants aged 50 and above completing two nonconsecutive 24-h dietary recalls were eventually enrolled for analysis. Associations between coffee intake and BMD were assessed. A lower odds of having femoral neck osteopenia/osteoporosis (FOO) was observed in participants with moderate intake of coffee (≤ 2 cups per day), rather than other beverages (OR 0.83; 95% CI, 0.72-0.95; p = 0.01). Moreover, significant associations existed between daily caffeine intake and both FOO and lumbar-spine osteopenia/osteoporosis (LOO). Even after adjusting for decaffeinated coffee, tea, sugar-sweetened beverages (SSBs), and coffee consumption, osteopenia and osteoporosis the odds remained lower at both femoral and neck levels. Our data suggest moderate habitual coffee intake (≤ 2 cups coffee/day) would have protective effects against osteoporosis/osteopenia of femoral neck and spine, among US adults over the age of 50., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Extracellular vesicles (EVs) are potent means of cell-to-cell communication. They are released in biological fluids, including blood, urine, and saliva, and can be exploited to identify new biomarkers of diseases. We hypothesized that EVs contain molecular cargos involved in bone metabolism, possibly mirroring biological differences between postmenopausal and disuse osteoporosis. We tested this hypothesis in primary murine osteoblasts subjected to steroid depletion or to unloading, and in the serum of animal models of osteoporosis induced by ovariectomy or hindlimb tail suspension. EVs were isolated by ultracentrifugation and analysed by transmission electron microscopy, cytofluorimetry, immunoblotting and RT-PCR. Large-scale analyses were performed by Real-Time arrays and Proteome Profiler™ Antibody arrays. Finally, precise titration of analytes was carried out by ELISA assay. In vitro, we confirmed an increased release of EVs enriched in surface RANKL by primary mouse osteoblasts subjected to steroid depletion or simulated microgravity compared to controls. In vivo, circulating EVs isolated from the sera of control female mice expressed RANKL along with other genes associated with bone metabolism. Serum EVs from ovariectomized or hindlimb tail-suspended mice showed distinct molecular profiles. They expressed RANKL with different kinetics, while transcriptomic and proteomic profiles uncovered unique molecular signatures that discriminated the two conditions, unveiling exclusive molecules expressed in time- and osteoporosis type-dependent manner. These results suggest that circulating EVs could represent a new tool for monitoring the onset and the progression of diverse types of the disease in mice, paving the way for their exploitation to diagnose human osteoporosis in liquid biopsies. [ABSTRACT FROM AUTHOR]

Clomiphene citrate, a mixed estrogen agonist-antagonist, protects mature ovariectomized breeder rats from changes in total body calcium and from deterioration of femur structure. Over 6 months, mature ovariectomized rats took up calcium at the rate of 0.7 ± 0.5 mg/day, while normal controls gained 2.5±0.7 mg/day (mean±SE) as measured by whole body neutron activation analysis. Injections of clomiphene (20 mg/kg/week) kept ovariectomized rats in positive calcium balance at 2.0±0.5 mg/day. Reductions in total femur calcium content, cortical thickness, and visible trabeculae of femurs in ovariectomized animals were prevented by chronic clomiphene administration. These results in animals suggest a possible new line of investigation of the use of antiestrogenic drugs as therapeutic agents for hormone-dependent osteoporosis in animals and humans. [ABSTRACT FROM AUTHOR]

Life expectancy of people living with HIV (PLWH) is now close to that of the HIV-uninfected population. As a result, age-related comorbidities, including osteoporosis, are increasing in PLWH. This narrative review describes the epidemiology of bone fragility in PLWH, changes of bone features over the course of HIV infection and their determinants, as well as the available evidence regarding the management of osteoporosis in PLWH. The risk of fracture is higher and increases about 10 years earlier compared to the general population. The classical risk factors of bone fragility are very widespread and are major determinants of bone health in this population. The majority of bone loss occurs during virus replication and during immune reconstitution at antiretroviral therapies (ART) initiation, which both increase osteoclast activity. Abnormalities in bone formation and mineralization have also been shown in histomorphometric studies in untreated PLWH. Measurement of bone mineral density (BMD) is the first line tool for assessing fracture risk in postmenopausal women, men above 50 years, and other HIV-infected patients with clinical risk factors for osteoporosis. FRAX underestimates fracture probability in PLWH. In case of indication for anti-osteoporotic drug, bisphosphonates remain the reference option. Calcium and vitamin D supplementation should be considered as ART initiation, since it may attenuate bone loss at this stage. Bone-protective ART regimens improve BMD compared to other regimens, but to a lesser extent than bisphosphonate, and without available data on their influence on the incidence of fracture. [ABSTRACT FROM AUTHOR]

Pregnancy-associated osteoporosis (PAO) is a rare condition of skeletal fragility affecting women in pregnancy or the postpartum period. During normal pregnancy and lactation, substantial changes in calcium metabolism and skeletal physiology occur in order to meet the demands of the developing foetus. Whilst these adaptations are reversible and generally of no clinical consequence for the mother, a small number of women will develop osteoporosis and suffer fragility fractures. Vertebral fractures occur most commonly in PAO and are often multiple. Due to the rarity of PAO, systematic study to date has been limited. Aetiology is poorly understood, but traditional osteoporosis risk factors and genetic factors are likely to play a role. A small number of cases may be due to an underlying metabolic bone disorder or monogenic condition. Management of PAO is challenging, due both to a poor evidence base and the fact that spontaneous improvement in BMD is known to occur once pregnancy and lactation are complete. Bisphosphonates, denosumab and teriparatide have all been used in individual patients, but the data supporting their use are currently limited. [ABSTRACT FROM AUTHOR]

The aim of the present study was to compare the bioavailability of calcium from calcium carbonate and milk and to investigate if 1,200 IU of cholecalciferol a day increased intestinal absorption of calcium. Both young women and a group of older persons of both sexes were included to study the influence of age and sex. In total, 53 healthy women and men were included: a group of 23 younger women (median age 30) and an older group of 15 women and 15 men (median age 66). The study period was 4 weeks; each participant completed four treatment regimens randomly: CaCO3, CaCO3 + 1,200 IU of cholecalciferol, milk, and placebo. All regimens were distributed three times a day and consisted of 1,200 mg of elementary calcium. The 24-hour urine calcium excretion was used as a method. Total urinary calcium excretion rates (mmol/day) were as follows (mean ± SD): placebo 4.41 ± 2.17, milk 5.17 ± 2.33, CaCO3 5.83 ± 2.03, and CaCO3 + D 6.06 ± 2.46. All regimens compared to placebo were significant. Addition of cholecalciferol to the CaCO3 regimen increased calcium excretion but insignificantly: 0.27 ± 2.84 mmol/day. The increase in calcium excretion during the milk regimen was significant only for the old group: 0.96 vs. 0.28 mmol/day. No other difference was found according to age and sex. The bioavailability of calcium carbonate and milk was demonstrated. Additional cholecalciferol (1,200 IU) to individuals in positive calcium balance with serum 25(OH)D levels >50 nmol/L only marginally increased calcium absorption in a short-term intervention. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism (HypoPT) and pseudohypoparathyroidism (PHP) are diseases with abnormal calcium and phosphate homeostasis and low and high PTH levels, respectively. It has been hypothesized that this could dispose to vascular calcifications and thereby perhaps also cardiovascular morbidity. The aim of this study was to assess lower leg arterial calcifications (LLAC) in patients with HypoPT or PHP. Using a cross-sectional design, we measured the LLAC using a high-resolution peripheral quantitative computed tomography (HR-pQCT) scanner in 72 patients with HypoPT and 25 patients with PHP and compared them with findings in 61 controls. LLAC were found in only two (3%) of the controls. Compared to the controls, LLAC were significantly more prevalent in patients with HypoPT (N = 12, [17%], p < 0.01) and PHP (N = 4, [16%], p < 0.04). Compared to the patients without calcifications, patients with calcifications had higher plasma calcium levels and a lower eGFR, as well as they were older and more often males. Plasma phosphate levels and the calcium-phosphate product were not associated with LLAC. In conclusion, we found that HypoPT and PHP are associated with an increased prevalence of vascular calcifications. [ABSTRACT FROM AUTHOR]

The possibility that low-calcium intake in renal stone formers could lead to reduced bone mineral content was investigated in 123 male patients with idiopathic urolithiasis. Radius bone mineral content (BMC) was measured by single photon absorptiometry. Two groups of patients were analyzed: group 1 (n = 63) maintained on a free diet; group 2 (n = 60) maintained on a low-calcium diet (350 mg/day +/- 20 SEM) for 3.9 years +/- 0.6 SEM. The two groups of patients were investigated after a standard reduction of calcium intake for at least 1 week. The urinary excretion of calcium and of hydroxyproline, and the serum alkaline phosphatase activity were higher in both groups than in normal subjects submitted to the same low-calcium diet. Both groups of stone formers showed lowered radius BMC values at 3 cm (distal) and 8 cm (proximal) above the styloid process, but distal BMC was significantly lower in group 2 than in group 1. The results suggest that low-calcium intake could worsen the already decreased BMC of idiopathic renal stone formers. [ABSTRACT FROM AUTHOR]

Chronic kidney disease-mineral bone disorder (CKD-MBD) after kidney transplantation is a mix of pre-existing disorders and new alterations. The final consequences are reflected fundamentally as abnormal mineral metabolism (hypercalcemia, hypophosphatemia) and bone alterations [high or low bone turnover disease (as fibrous osteitis or adynamic bone disease), an eventual compromise of bone mineralization, decrease bone mineral density and bone fractures]. The major cause of post-transplantation hypercalcemia is the persistence of severe secondary hyperparathyroidism, and treatment options include calcimimetics or parathyroidectomy. On turn, hypophosphatemia is caused by both the persistence of high blood levels of PTH and/or high blood levels of FGF23, with its correction being very difficult to achieve. The most frequent bone morphology alteration is low bone turnover disease, while high-turnover osteopathy decreases in frequency after transplantation. Although the pathogenic mechanisms of these abnormalities have not been fully clarified, the available evidence suggests that there are a number of factors that play a very important role, such as immunosuppressive treatment, persistently high levels of PTH, vitamin D deficiency and hypophosphatemia. Fracture risk is four-fold higher in transplanted patients compared to general population. The most relevant risk factors for fracture in the kidney transplant population are diabetes mellitus, female sex, advanced age (especially > 65 years), dialysis vintage, high PTH levels and low phosphate levels, osteoporosis, pre-transplant stress fracture and high doses or prolonged steroids therapy. Treatment alternatives for CKD-MBD after transplantation include minimization of corticosteroids, use of calcium and vitamin D supplements, antiresorptives (bisphosphonates or Denosumab) and osteoformers (synthetic parathyroid hormone). As both mineral metabolism and bone disorders lead to increased morbidity and mortality, the presence of these changes after transplantation has to be prevented (if possible), minimized, diagnosed, and treated as soon as possible. [ABSTRACT FROM AUTHOR]

Bone is not only a mineralized and apparently non-vital structure that provides support for locomotion and protection to inner organs. An increasing number of studies are unveiling new biologic functions and connections to other systems, giving the rise to new fields of research, such as osteoimmunology. The bone marrow niche, a new entity in bone physiology, seems to represent the site where a complex crosstalk between bone and immune/inflammatory responses takes place. An impressive interplay with the immune system is realized in bone marrow, with reciprocal influences between bone cells and haematopoietic cells. In this way, systemic chronic inflammatory diseases realize a crosstalk with bone, resulting in bone disease. Thus, pathogenetic links between chronic kidney disease-mineral bone disorders and osteoporosis, cardiovascular disease, and ageing are common. The aim of this narrative review is to provide a general view of the progresses in the field of bone research and their potential clinical implications, with emphasis on the links with inflammation and the connections to osteoimmunology and chemokines. [ABSTRACT FROM AUTHOR]

Osteoporosis is a state of bone fragility with reduced skeletal resistance to trauma, and consequently increased risk of fracture. A wide range of conditions, including traditional risk factors, lifestyle choices, diseases and their treatments may contribute to bone fragility. It is therefore not surprising that the multi-morbid patient with chronic kidney disease (CKD) is at a particularly high risk. CKD is associated with reduced bone quantity, as well as impaired bone quality. Bone fragility in CKD is a composite of primary osteoporosis, accumulation of traditional and uremia-related risk factors, assaults brought on by systemic disease, and detrimental effects of drugs. Some risk factors are modifiable and represent potential targets for intervention. This review provides an overview of the heterogeneity of bone fragility in CKD. [ABSTRACT FROM AUTHOR]

Hyperphosphatemia is common in chronic kidney disease (CKD). Often seen as the "silent killer" because of its dramatic effect on vascular calcifications, hyperphosphatemia explains, at least partly, the onset of the complex mineral and bone disorders associated with CKD (CKD-MBD), together with hypocalcemia and decreased 1-25(OH)2 vitamin D levels. The impact of CKD-MBD may be immediate with abnormalities of bone and mineral metabolism with secondary hyperparathyroidism and increased FGF23 levels, or delayed with poor growth, bone deformities, fractures, and vascular calcifications, leading to increased morbidity and mortality. The global management of CKD-MBD has been detailed in international guidelines for adults and children, however, with difficulties to obtain an agreement on the ideal PTH targets. The clinical management of hyperphosphatemia is a daily challenge for nephrologists and pediatric nephrologists, notably because of the phosphate overload in occidental diets that is mainly due to the phosphate "hidden" in food additives. The management begins with a dietary restriction of phosphate intake, and is followed by the use of calcium-based and non-calcium-based phosphate binders, and/or the intensification of dialysis. The objective of this review is to provide an overview of the pathophysiology of hyperphosphatemia in CKD, with a focus on its deleterious effects and a description of the clinical management of hyperphosphatemia in a more global setting of CKD-MBD. [ABSTRACT FROM AUTHOR]

Osteoporosis and nephrolithiasis are common multifactorial disorders with high incidence and prevalence in the adult population worldwide. Both are associated with high morbidity and mortality if not correctly diagnosed and accurately treated. Nephrolithiasis is considered a risk factor for reduced bone mineral density. Aim of this retrospective longitudinal study was to evaluate if osteoporosis is a predictive factor for the nephrolithiasis occurrence. Free-living subjects referring to "COMEGEN" general practitioners cooperative operating in Naples, Southern Italy. Twelve thousand seven hundred ninety-four Caucasian subjects (12,165 female) who performed bone mineral density by dual-energy X-ray absorptiometry and have a negative personal history for nephrolithiasis. Subjects aged less than 40 years or with signs or symptoms suggestive of secondary osteoporosis were excluded from the study. In a mean lapse of time of 19.5 months, 516 subjects had an incident episode of nephrolithiasis. Subjects with osteoporosis had an increased risk of nephrolithiasis than subjects without osteoporosis (Hazard Ratio = 1.33, 95% Confidence Interval 1.01–1.74, p = 0.04). Free-living adult subjects over the age of 40 with idiopathic osteoporosis have an increased risk of incident nephrolithiasis, suggesting the advisability of appropriate investigation and treatment of the metabolic alterations predisposing to nephrolithiasis in patients with osteoporosis. The study protocol was approved by the ASL Napoli 1 Ethical Committee, protocol number 0018508/2018 [ABSTRACT FROM AUTHOR]

The article focuses on a study of Idiopathic juvenile osteoporosis (IJO), the descriptive term applied to a primary osteoporosis of unknown etiology present in children. The study included a total of 61 children who fulfilled the description of IJO. The majority presented with pain in the back or feet, muscular weakness and limitations in free movements. The cardinal features of IJO are onset of symptoms prior to puberty, pain in the back and extremities, a characteristic gait with difficulty in walking, radiological evidence of osteoporotic new bone and multiple fractures typically of the metaphyses and vertebral bodies. In the early stages of the disease biomarkers suggested increased bone resorption. With the exception of the most severe cases, patients with IJO experience a complete recovery within 3-4 years.

Purpose: Hyponatremia and hypokalemia are common among elderly and have been associated with osteoporosis, we evaluate the role of these electrolytes as risk for fragility fractures.Methods: This study is divided in two parts: one retrospective and one prospective. We retrospectively collected data on urgently admitted patients for femoral fragility fractures (Fx) or for acute myocardial infarction (AMI), and patients admitted for elective hip/knee replacement surgery for osteoarthrosis (OA). Age, sex, serum sodium, potassium, creatinine, and comorbidities were recorded. We enrolled prospectively in-patients from our unit: age, sex, comorbidities, drugs, and fragility fractures were recorded. Blood electrolytes were measured. Cognitive function, nutrition, muscular strength, and balance were evaluated by standard tests. The mortality rate was recorded with a follow-up after hospital discharge.Results: The retrospective study included 2166 subjects: 702 Fx and 1464 controls (907 AMI, 557 OA): the prevalence of hyponatremia was similar in Fx and AMI, whereas it was higher in Fx with respect to OA (p < 0.001) as well as hypokalemia (p < 0.001). Sodium decrease was associated with higher fracture risk. Among the 284 subjects included in the prospective study, 50 patients were hyponatremic, more likely malnourished, and presented a higher prevalence of fragility fractures (p = 0.008). They had a higher mortality after hospital discharge (HR = 1.80, p = 0.005), however, this association disappears after correction for confounding variables.Conclusions: We suggest that hyponatremia and hypokalemia have to be considered as a marker of poor health more than an independent fracture risk. [ABSTRACT FROM AUTHOR]

Loop diuretics (LD) may affect bone health by inhibiting renal calcium reuptake. However, whether vitamin D status and dietary calcium intake modify the association between LD and bone outcome is unclear. Therefore, this study aimed to evaluate whether vitamin D level or calcium intake modify the association between LD and various indices of bone health including bone mineral density (BMD) and Trabecular Bone Score (TBS). From The Rotterdam Study, a prospective population-based cohort study, we used data from 6990 participants aged > 45 year with a DXA scan (2002-2008), 6908 participants with femoral neck (FN)-BMD, 6677 participants with lumbar spine (LS)-BMD and 6476 participants with LS-TBS measurements. Use of LD was available from pharmacy dispensing records. Vitamin D (25(OH)D) level was measured in serum, and dietary calcium intake was measured with a validated food frequency questionnaire. Almost eight percent of the participants used LD. The association between LD (past-users compared to never-users) and LS-TBS was significantly different by 25(OH)D concentrations (P for interaction = 0.04). A significantly lower LS-TBS among LD past-users was observed for 25(OH)D ≥ 50 nmol/l compared to ≤ 20 and 20-50 nmol/l (β = - 0.036, 95% CI - 0.060; - 0.013 vs. β = - 0.012, 95% CI - 0.036; 0.013 and β = - 0.031, 95% CI - 0.096; 0.034, respectively). However, no other significant effect modification by 25(OH)D and dietary calcium intake was found in the associations between LD use and bone health outcomes (P-interaction > 0.13). This study suggests that the association between LD use and indices of bone health is not consistently modified by vitamin D or dietary calcium intake. [ABSTRACT FROM AUTHOR]

Some epidemiological studies suggested caffeine consumption as the cause for bone mineral density loss. Certain genes involved in this process are regulated by vitamin D receptor (VDR). Therefore, we investigated if caffeine can affect inducible expression of VDR-regulated genes, some of them being involved in bone mineralization process. By employing reporter gene assay, polymerase chain reaction, and western blotting, we monitored the VDR activity and expression in cell cultures of intestinal (LS180), osteosarcoma (HOS), and normal human osteoblasts in vitro. While caffeine stimulated calcitriol-inducible VDR-dependent nanoluciferase activity in stable reporter cell line IZ-VDRE (derived from LS180), it rather modulated mRNA levels of target genes, like CYP24A1, BGLAP, SPP1, and TNSF11 in LS180 and HOS cells. However, caffeine significantly decreased calcitriol-inducible CYP24A1, TNSF11, and SPP1 transcripts in osteoblasts. This decrease had non-linear U-shaped profile. Our in vitro data demonstrate biphasic action of caffeine on the expression of certain calcitriol-inducible VDR-regulated genes in normal human osteoblasts. [ABSTRACT FROM AUTHOR]