Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition.

Rebound bone loss following denosumab discontinuation is an important clinical challenge. Current treatment strategies to prevent this fail to suppress the rise and overshoot in osteoclast-mediated bone resorption. In this study, we use a murine model of denosumab treatment and discontinuation to show the temporal changes in osteoclast formation and activity during RANKL inhibition and withdrawal. We show that the cellular processes that drive the formation of osteoclasts and subsequent bone resorption following withdrawal of RANKL inhibition precede the rebound bone loss. Furthermore, a rise in serum TRAP and RANKL levels is detected before markers of bone turnover used in current clinical practice. These mechanistic advances may provide insight into a more defined window of opportunity to intervene with sequential therapy following denosumab discontinuation.

Stopping denosumab, a medication commonly used to improve bone mass by blocking formation of bone resorbing osteoclasts, leads to a rebound loss in the bone which was gained during treatment. Current strategies to prevent this bone loss fail in most cases as they are unable to prevent the rise and overshoot in bone resorption by osteoclasts. Thie stems from an incomplete understanding of how osteoclasts behave during denosumab treatment and after treatment is discontinued. We use a mouse model of this phenomenon to show how osteoclast formation and activity changes throughout this process. We show that increases in the processes that drive the formation of osteoclasts can be detected in the circulation before bone loss occurs. These findings could therefore provide insight into a targeted 'window of opportunity' to intervene and prevent the rebound bone loss following stopping denosumab in patients.

Effect of Vitamin E Supplement on Bone Turnover Markers in Postmenopausal Osteopenic Women: A Double-Blind, Randomized, Placebo-Controlled Trial.

Vitamin E is a strong anti-oxidative stress agent that affects the bone remodeling process. This study evaluates the effect of mixed-tocopherol supplements on bone remodeling in postmenopausal osteopenic women. A double-blinded, randomized, placebo-controlled trial study was designed to measure the effect of mixed-tocopherol on the bone turnover marker after 12 weeks of supplementation. All 52 osteopenic postmenopausal women were enrolled and allocated into two groups. The intervention group received mixed-tocopherol 400 IU/day, while the control group received placebo tablets. Fifty-two participants completed 12 weeks of follow-up. Under an intention-to-treat analysis, vitamin E produced a significant difference in the mean bone resorption marker (serum C-terminal telopeptide of type I collagen (CTX)) compared with the placebo group (-0.003 ± 0.09 and 0.121 ± 0.15, respectively (p < 0.001)). In the placebo group, the CTX had increased by 35.3% at 12 weeks of supplementation versus baseline (p < 0.001), while, in the vitamin E group, there was no significant change of bone resorption marker (p < 0.898). In conclusion, vitamin E (mixed-tocopherol) supplementation in postmenopausal osteopenic women may have a preventive effect on bone loss through anti-resorptive activity.

Effects of strawberries on bone biomarkers in pre- and stage 1-hypertensive postmenopausal women: a secondary analysis.

Postmenopausal women experience an increase in bone remodeling with the rate of bone resorption superseding the rate of bone formation. This results in a net bone loss with a subsequent increased risk for osteoporosis and fractures. High blood pressure (BP) has been associated with loss of bone mineral density and increased propensity to fractures. Strawberries are rich in polyphenols, which have been shown to have anti-hypertensive and bone-protective properties. Thus, we examined whether daily intake of strawberries would positively affect biomarkers of bone metabolism in postmenopausal women with pre- and stage 1-hypertension. Participants (age: 59 ± 6 years; body mass index: 31.5 ± 4.1 kg m-2; systolic BP: 140 ± 13 mmHg) were randomly assigned to consume (1) 50 g of freeze-dried strawberry powder (FDSP), (2) 25 g FDSP + 25 g of placebo powder, or (3) 50 g placebo powder for eight weeks. Results indicate a significant time-by-treatment interaction (P = 0.04) for serum insulin-like growth factor (IGF)-1, a hormone that plays a major role in bone formation. Serum concentrations of bone-specific alkaline phosphatase, a marker of bone formation, and tartrate-resistant acid phosphatase-5b, a specific marker of bone resorption, were not affected by FDSP compared to placebo. Although not statistically significant, after eight weeks, osteocalcin increased in the 50 g FDSP group with a large effect size (d = 0.6) when compared to the placebo-control group. Adiponectin increased by 5% and 6% in the 25 g and 50 g FDSP groups, respectively, while it declined in the placebo-control group by 25% (P = 0.03 for time-by-treatment interaction). Our findings suggest that consumption of 25 g FDSP increases IGF-1 in postmenopausal women with pre- and stage 1-hypertension. However, further studies are needed to assert the effectiveness of a strawberry intervention for bone health.

Anabolic Bone Stimulus Requires a Pre-Exercise Meal and 45-Minute Walking Impulse of Suprathreshold Speed-Enhanced Momentum to Prevent or Mitigate Postmenopausal Osteoporosis within Circadian Constraints.

Osteoporosis currently afflicts 8 million postmenopausal women in the US, increasing the risk of bone fractures and morbidity, and reducing overall quality of life. We sought to define moderate exercise protocols that can prevent postmenopausal osteoporosis. Our previous findings singled out higher walking speed and pre-exercise meals as necessary for suppression of bone resorption and increasing of markers of bone formation. Since both studies were amenable to alternate biomechanical, nutritional, and circadian interpretations, we sought to determine the relative importance of higher speed, momentum, speed-enhanced load, duration of impulse, and meal timing on osteogenic response. We hypothesized that: (1) 20 min of exercise one hour after eating is sufficient to suppress bone resorption as much as a 40-min impulse and that two 20 min exercise bouts separated by 7 h would double the anabolic effect; (2) early morning exercise performed after eating will be as effective as mid-day exercise for anabolic outcome; and (3) the 08:00 h 40-min. exercise uphill would be as osteogenic as the 40-min exercise downhill. Healthy postmenopausal women, 8 each, were assigned to a no-exercise condition (SED) or to 40- or 20-min exercise bouts, spaced 7 h apart, for walking uphill (40 Up and 20 Up) or downhill (40 Down and 20 Down) to produce differences in biomechanical variables. Exercise was initiated at 08:00 h one hour after eating in 40-min groups, and also 7 h later, two hours after the midday meal, in 20-min groups. Measurements were made of CICP (c-terminal peptide of type I collagen), osteocalcin (OC), and bone-specific alkaline phosphatase (BALP), markers of bone formation, and of the bone resorptive marker CTX (c-terminal telopeptide of type 1 collagen). The osteogenic ratios CICP/CTX, OC/CTX, and BALP/CTX were calculated. Only the 40-min downhill exercise of suprathreshold speed-enhanced momentum, increased the three osteogenic ratios, demonstrating the necessity of a 40-min, and inadequacy of a 20-min, exercise impulse. The failure of anabolic outcome in 40-min uphill exercise was attributed to a sustained elevation of PTH concentration, as its high morning elevation enhances the CTX circadian rhythm. We conclude that postmenopausal osteoporosis can be prevented or mitigated in sedentary women by 45 min of morning exercise of suprathreshold speed-enhanced increased momentum performed shortly after a meal while walking on level ground, or by 40-min downhill, but not 40-min uphill, exercise to avoid circadian PTH oversecretion. The principal stimulus for the anabolic effect is exercise, but the prerequisite for a pre-exercise meal demonstrates the requirement for nutrient facilitation.

Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH.

CONTEXT: Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear. OBJECTIVE: Based on the hypothesis that TSH may inhibit bone resorption, we explored whether offspring of long-lived families have lower bone turnover than controls at baseline as well as following a challenge with recombinant human TSH (rhTSH). METHODS: Bone turnover markers CTX and P1NP were measured in fasted morning samples from 14 offspring and 12 controls at baseline and at 24 hour intervals following 0.1 mg rhTSH i.m. administration for four consecutive days. RESULTS: At baseline, mean (SEM) CTX was 0.32 (0.03) ng/ml in offspring and 0.50 (0.04) ng/ml in controls, p < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, p < 0.01. Following rhTSH administration, both CTX and P1NP levels transiently increased over time and normalized towards baseline after 72 h (general linear modelling: CTX time p = 0.01, P1NP time p < 0.01); the response was similar between offspring and controls. CONCLUSIONS: Bone turnover markers were lower at baseline in offspring from long-lived families than in controls but increased similarly following an rhTSH challenge.

Nanomaterial-induced mesenchymal stem cell differentiation into osteoblast for counteracting bone resorption in the osteoporotic rats.

The current approach was designed to unearth the therapeutic potential of osteoblasts infusion, yielded from cultivating rat mesenchymal stem cells of bone marrow source in osteogenic differentiation media supplied with either hydroxyapatite nanoparticles (HA-NPs), chitosan/hydroxyapatite nanomaterials (C/HA-NPs), or chitosan nanoparticles, in the osteoporotic rats. The successful migration of the osteoblasts to the diseased bones of rats in C/HA-NPs and HA-NPs groups was evidenced by PCR screening of the Y-linked sex-determining gene (SRY) in the femoral bone tissue. Serum bone biomarker levels and gene expression patterns of cathepsin K, receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were assessed. Additionally, histological examination of the femoral bone tissues of rats was performed. The current outcomes revealed that osteoblast implantation, resulted from C/HA-NPs or HA-NPs group, significantly lessened bone sialoprotein level. In Addition, it yielded a significant decline in the gene expression patterns of cathepsin K, RANKL, and RANKL/OPG proportion as well as up-regulation in BMP-2 and Runx-2 gene expression levels as opposed to the untreated ovariectomized animals. Moreover, it could restrain bone resorption and refine bone histoarchitecture. Conclusively, this study sheds light on the therapeutic significance of osteoblasts transplantation in alleviating the intensity of the bone remodeling cycle, consequently representing a hopeful therapeutic approach for primary osteoporosis.

Effect of Vitamin D-Enriched Gouda-Type Cheese Consumption on Biochemical Markers of Bone Metabolism in Postmenopausal Women in Greece.

Considering the role of bone metabolism in understanding the pathogenesis of osteoporosis, the aim of the present study was to examine the effects of vitamin D-enriched cheese on the serum concentrations of the parathyroid hormone (PTH) and certain bone remodeling biomarkers in postmenopausal women in Greece. In a randomised, controlled dietary intervention, 79 postmenopausal women (55-75 years old) were randomly allocated either to a control (CG: n = 39) or an intervention group (IG: n = 40), consuming 60 g of either non-enriched or vitamin D3-enriched Gouda-type cheese (5.7 µg of vitamin D3), respectively, daily and for eight weeks during the winter. The serum concentrations of 25-hydroxy vitamin D (25(OH)D), PTH, bone formation (i.e., osteocalcin, P1NP) and bone resorption (i.e., TRAP-5b) biomarkers were measured. Consumption of the vitamin D-enriched cheese led to higher serum 25(OH)D concentrations of 23.4 ± 6.39 (p = 0.022) and 13.4 ± 1.35 (p < 0.001) nmol/L in vitamin D-insufficient women being at menopause for less and more than 5 years, respectively. In vitamin D-insufficient women that were less than 5 years at menopause, consumption of vitamin D-enriched cheese was also associated with lower serum PTH (Beta -0.63 ± 1.11; p < 0.001) and TRAP-5b (Beta -0.65 ± 0.23; p = 0.004) levels at follow-up, compared with the CG. The present study showed that daily intake of 5.7 µg of vitamin D through enriched cheese increased serum 25(OH)D concentrations, prevented PTH increase and reduced bone resorption in vitamin D-insufficient early postmenopausal women, thus reflecting a potential food-based solution for reducing the risk of bone loss occurring after menopause.

Associations between Postprandial Gut Hormones and Markers of Bone Remodeling.

Gut-derived hormones have been suggested to play a role in bone homeostasis following food intake, although the associations are highly complex and not fully understood. In a randomized, two-day cross-over study on 14 healthy individuals, we performed postprandial time-course studies to examine the associations of the bone remodeling markers carboxyl-terminal collagen type I crosslinks (CTX) and procollagen type 1 N-terminal propeptide (P1NP) with the gut hormones glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY) using two different meal types-a standardized mixed meal (498 kcal) or a granola bar (260 kcal). Plasma concentrations of total GIP, total GLP-1, total PYY, CTX, and P1NP were measured up to 240 min after meal intake, and the incremental area under the curve (iAUC) for each marker was calculated. The iAUC of CTX and P1NP were used to assess associations with the iAUC of GIP, GLP-1, and PYY in linear mixed effect models adjusted for meal type. CTX was positively associated with GIP and GLP-1, and it was inversely associated with PYY (all p < 0.001). No associations of P1NP with GIP or GLP-1 and PYY were found. In conclusion, the postprandial responses of the gut hormones GIP, GLP-1, and PYY are associated with the bone resorption marker CTX, supporting a link between gut hormones and bone homeostasis following food intake.

Copper as Dietary Supplement for Bone Metabolism: A Review.

While in vitro and animal studies of osteoblastic and osteoclastic activity as well as bone resistance for copper are numerous, and the results encouraging in terms of regulation, human studies are scarce. The aim of this narrative review was to investigate the correlation of blood copper, daily copper intake, and copper supplementation with bone mineral density. This review included 10 eligible studies: five studies concerned copper blood levels, one study concerned daily copper intake, and four studies concerned copper supplementation. Blood copper levels did not show statistically significant differences in four of the studies analyzed, while only one study showed differences between osteoporotic and healthy women, although only with women between 45 and 59 years of age and not between 60 and 80 years of age. The dietary copper intake among women with or without osteoporosis did not show any differences. Only one study with a small sample of subjects carried out these assessments; therefore, it is a topic that the literature must deepen with further studies. The two studies that analyzed the integration of copper (2.5-3 mg/day) only showed good results in terms of slowing down bone mineral loss and reducing resorption markers, confirming the effectiveness of copper supplementation on bone metabolism.

IgA Immune Complexes Induce Osteoclast-Mediated Bone Resorption.

Objective: Autoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption. Methods: Anti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption. Results: NET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts. Conclusion: IgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.

Serum cross-linked N-telopeptide of type I collagen across the canine life span: An investigation in intact and neutered male and female dogs.

In this study, we conducted study to explore the association between serum cross-linked N-telopeptide of type I collagen (NTx), a marker of bone resorption, and age, body weight, and blood biochemical parameters as well as the neutered and intact status in male and female dogs. We targeted 145 healthy dogs (aged 0.33-18.33 years); 70 were males (38 intact, 32 castrated), and 75 were females (31 intact, 44 ovariohysterectomized). We found that the NTx levels were significantly higher in dogs aged ≤2 years than in older dogs. NTx concentration tended to decrease with age in dogs aged ≤2 years, but not significantly, and remained constant in dogs aged >2 years. Accordingly, we investigated sex/sterilization status in two age cohorts (juvenile-to-young-adult, ≤2 years of age; adult-to-geriatric, >2 years of age). In the adult-to-geriatric cohort, NTx concentration was highest in intact males, followed by neutered males, neutered females, and intact females. The intact vs. neutered difference was significant in males, but not in females. Our results suggested that estradiol deficiency may not affect bone metabolism in female dogs, but androgen deficiency may affect bone metabolism in male dogs. Furthermore, age did not affect bone metabolism after 2 years. NTx concentrations were significantly higher in the juvenile-to-young-adult cohort than in the adult-to-geriatric cohort and tended to decrease with age, similar to young humans. This study unveils novel sex differences in canine serum NTx concentrations and suggests the effect of neutering on bone metabolism, showing that serum NTx concentrations change with age.

Low Energy Availability with and without a High-Protein Diet Suppresses Bone Formation and Increases Bone Resorption in Men: A Randomized Controlled Pilot Study.

Suppression of insulin-like growth factor 1 (IGF-1) and leptin secondary to low energy availability (LEA) may contribute to adverse effects on bone health. Whether a high-protein diet attenuates these effects has not been tested. Seven men completed three five-day conditions operationally defined as LEA (15 kcal kg fat-free mass (FFM)-1 day-1) with low protein (LEA-LP; 0.8 g protein·kg body weight (BW)-1), LEA with high protein (LEA-HP; 1.7 g protein·kg BW-1) and control (CON; 40 kcal·kg FFM-1·day-1, 1.7 g protein·kg BW-1). In all conditions, participants expended 15 kcal·kg FFM-1·day-1 during supervised cycling sessions. Serum samples were analyzed for markers of bone turnover, IGF-1 and leptin. The decrease in leptin during LEA-LP (-65.6 ± 4.3%) and LEA-HP (-54.3 ± 16.7%) was greater than during CON (-25.4 ± 11.4%; p = 0.02). Decreases in P1NP (p = 0.04) and increases in CTX-I (p = 0.04) were greater in LEA than in CON, suggesting that LEA shifted bone turnover in favour of bone resorption. No differences were found between LEA-LP and LEA-HP. Thus, five days of LEA disrupted bone turnover, but these changes were not attenuated by a high-protein diet.

Intermittent Hypoxic Therapy Inhibits Allogenic Bone-Graft Resorption by Inhibition of Osteoclastogenesis in a Mouse Model.

Systemic Intermittent Hypoxic Therapy (IHT) relies on the adaptive response to hypoxic stress. We investigated allogenic bone-graft resorption in the lumbar spine in 48 mice. The mice were exposed to IHT for 1 week before surgery or 1 week after surgery and compared with controls after 1 and 4 weeks. Complete graft resorption was observed in 33-36% of the animals in the control group, but none in the preoperative IHT group. Increased bone-graft volume was demonstrated by micro-computed tomography in the preoperative IHT group after 1 week (p = 0.03) while a non-significant difference was observed after 4 weeks (p = 0.12). There were no significant differences in the postoperative IHT group. Increased concentration of immune cells was localized in the graft area, and more positive tartrate-resistant acid phosphatase (TRAP) staining was found in controls compared with IHT allogenic bone grafts. Systemic IHT resulted in a significant increase of the major osteoclast inhibitor osteoprotegerin as well as osteogenic and angiogenic regulators Tgfbr3, Fst3l, Wisp1, and Vegfd. Inflammatory cytokines and receptor activator of nuclear factor kappa-B ligand (RANKL) stimulators IL-6, IL-17a, IL-17f, and IL-23r increased after 1 and 4 weeks, and serum RANKL expression remained constant while Ccl3 and Ccl5 decreased. We conclude that the adaptive response to IHT activates numerous pathways leading to inhibition of osteoclastic activity and inhibition of allogenic bone-graft resorption.

Risperidone accelerates bone loss in rats with autistic-like deficits induced by maternal lipopolysaccharides exposure.

AIMS: Patients with neurodevelopmental disorders, usually suffer from bone diseases. Many studies have revealed a higher risk of fracture after atypical antipsychotic drug Risperidone (RIS) treatment, which is usually used to treat such disorders. It remains debatable whether neurodevelopmental disorders by itself are the cause of bone diseases or pharmacotherapy may be the reason. MATERIALS AND METHODS: This study attempts to evaluate the biomechanical, histological, stereological, and molecular properties of bones in the offspring of Lipopolysaccharide (LPS) and saline-treated mothers that received saline, drug vehicle or the atypical antipsychotic drug risperidone (RIS) at different days of postnatal development. After postnatal drug treatment, animals were assessed for autistic-like behaviors. Then their bones were taken for evaluations. RESULTS: Maternal LPS exposure resulted in deficits in all behavioral tests and RIS ameliorated these behaviors (p < 0.01& p < 0.05). The administration of LPS and RIS individually led to a significant decrease in the biomechanical parameters such as bone stiffness, strength and the energy used to fracture of bone. The numerical density of osteocalcin-positive cells were significantly decreased in these groups. These rats also had decreased RUNX2 and osteocalcin gene expression. When LPS rats were treated with RIS, these conditions were accelerated (p < 0.001). DISCUSSIONS: The results of our preclinical study, consistent with previous studies in animals, explore that autistic-like deficits induced by prenatal exposure to LPS, can reduce bone stability and bone mass similar to those observed in neurodevelopmental disorders, and, for the first time, reveal that this condition worsened when these animals were treated with RIS.

Assessment of Bone Turnover Biomarkers in Lead-Battery Workers with Long-Term Exposure to Lead.

BACKGROUND: The major portion of lead in the body resides in skeletal system. The bone turnover affects the release of lead into the circulation from bones. The bone turnover biomarkers (BTM) in lead-battery workers with long-term exposure to lead have not been explored yet. OBJECTIVE: To evaluate the BTM (formation and resorption) in lead-battery workers with long-term exposure to lead in lead-battery manufacturing plant. METHODS: 176 male lead-exposed workers and 80 matched comparison group were studied. All participants were examined for blood lead levels (BLLs), bone formation biomarkers- serum osteocalcin (OC), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP)-and bone resorption biomarkers-serum pyridinoline (PYD), deoxypyridinoline (DPYD), tartarate-resistant acid phosphatase-5b (TRACP-5b), and urinary hydroxyproline (UHYP). RESULTS: We found a significantly higher bone formation biomarkers such as BALP (p=0.007) and bone resorption biomarkers, eg, PYD (p=0.048), TRCAP-5b (p=0.001), and UHYP (p=0.001) in lead-exposed workers. A significant (p=0.041) negative correlation (ρ ­0.128) was noted between BLLs and OC. A significant positive correlation was noted between BLLs and TRACP-5b (ρ 0.176, p=0.005) and UHYP (ρ 0.258, p=0.004). Serum OC (p=0.040) and UHYP (p=0.015) levels changed significantly with BLL level. Bone resorption biomarkers levels- PYD, TRACP-5b, and BALP-were higher among those with higher BLLs levels. The duration of exposure was significantly associated with BALP (p=0.037), DPYD (p=0.016), TRACP-5b (p=0.001), and UHYP (p=0.002) levels. CONCLUSION: Long-term lead exposure affects the bone turnover.

Calcium loss in sweat does not stimulate PTH release: A study of Bikram hot yoga.

It has been hypothesized that sweat loss during exercise causes a disruption in calcium homeostasis that activates bone resorption and over time leads to low bone mineral density. The purpose of this small pilot study was to determine whether dermal calcium loss from a bout of excessive sweating during light intensity physical activity triggers an increase in biomarkers of bone resorption. Biochemical markers related to bone homeostasis were measured before and after a 90 min Bikram hot yoga practice performed in a room heated to 105 °F with 40 % humidity. Participants were five females with a mean age of 47.4 ± 4.7 years. Nude body weight, serum total calcium (Ca2+), free ionized calcium, albumin, parathyroid hormone (PTH) and CTX-I were measured before and after a Bikram hot yoga practice. Mean estimated sweat loss was 1.54 ± 0.65 L, which elicited a 1.9 ± 0.9 % decrease in participant's body weight. Mean Ca2+ concentration in sweat was 2.9 ± 1.7 mg/dl and the estimated mean total calcium lost was 41.3 ± 16.4 mg. Serum ionized Ca2+ increased from 4.76 ± 0.29 mg/dl to 5.35 ± 0.36 mg/dl after the Bikram hot yoga practice (p = 0.0118). Serum PTH decreased from pre- 33.9 ± 3.3 pg/ml to post- 29.9 ± 2.1 pg/ml yoga practice (p = 0.0015) when adjusted for hemoconcentration (PTHADJ), implying a decrease in PTH secretion. We conclude that calcium loss in sweat during 90 min of Bikram hot yoga did not trigger an increase in PTH secretion and did not initiate bone resorption.

Energy Intake Deficiency Promotes Bone Resorption and Energy Metabolism Suppression in Japanese Male Endurance Runners: A Pilot Study.

It has been reported that male athletes face increased risk for low energy availability and resulting health consequences similar to female athletes. The present study aimed to reveal the energy status of Japanese male runners and to examine the association between energy deficiency and physiological characteristics such as energy metabolism, bone health, and hormonal status. Six male collegiate long-distance runners during a training season participated in this study. Energy intake (EI) was assessed using 3-day dietary records with food pictures. Exercise energy expenditure (EEE) was determined by the HR-VO2 method. Body composition and bone status were measured by dual-energy X-ray absorptiometry. Energy availability (EA) was calculated by subtraction of EEE from EI and normalized by fat-free mass (FFM). Energy balance (EB) was calculated EI minus estimated total energy expenditure (TEE). Resting energy expenditure (REE) was measured by indirect calorimetry using the Douglas bag technique, and blood sampling was conducted to assess hormonal status. The mean EA of the subjects was 18.9 ± 6.8 kcal/kg FFM/day, and severe negative EB (range: -1444 ~ -722 kcal/d) was observed. REE of four runners was suppressed, and moreover, bone resorption was promoted in all subjects. The data in our study suggested that energy deficiency could promote bone resorption and energy metabolism suppression in Japanese male endurance runners. Additional short- and long-term studies are needed to clarify the health risks caused by energy deficiency in male athletes and explore strategies to prevent health problems related to energy deficiency in long-distance runners.

Mineral bone disorder and osteoporosis in hemodialysis patients.

BACKGROUND: Bone disease is common in patients undergoing hemodialysis. It is the result of bone turnover abnormalities and the decrease of bone mineral density (BMD). We aimed to determine the usefulness of serum bone turnover markers and BMD measurement by dual-energy x-ray absorptiometry (DXA) in hemodialysis patients. METHODS: We conducted a cross-sectional study including 90 hemodialysis for more than 12 months. Bone mineral density was assessed by DXA. Peripheral blood samples were obtained from each patient before dialysis in a fasting state within a week of the DXA. Biochemical variables of calcium and phosphate were measured. One bone formation marker (bone-specific alkaline phosphatase (bAP), one bone resorption marker (carboxy-terminal telopeptides of type 1 collagen (CTX)) were measured. Total alkaline phosphatase (TAP), intact parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) which is a bone-derived hormone were also measured. RESULTS: CTX values were 6.25 times higher than the normal limit of the assay. Bone alkaline phosphatase levels were less than 10 ng/mL in 28.8% of cases. 23% of patients have osteoporosis and 45% have osteopenia. Femoral BMD had negative correlations with age and PTH levels. FGF23 levels were significantly increased in patients with osteoporosis affecting the lumbar. The levels of bAP and CTX showed a positive correlation. Both circulating bAP and CTX levels showed also positive correlations with PTH levels. Fractures, observed in 12.2% of cases, were associated with low PTH values and the existence of osteoporosis. CONCLUSIONS: Our study showed that osteoporosis and fracture are common in dialysis patients. The reduced BMD was associated with advanced age and elevated levels of PTH. Markers of bone turnover and FGF23 may play a role in the diagnosis of bone disease in hemodialysis patients. DXA measurement is necessary for the monitoring for bone loss.

Panax Notoginseng Saponins Prevent Bone Loss by Promoting Angiogenesis in an Osteoporotic Mouse Model.

With the aging of the population and the extension of life expectancy, osteoporosis is becoming a global epidemic. Although there are several drugs used to treat osteoporosis in clinical practice, such as parathyroid hormone or bisphosphonates, they all have some serious side effects. Therefore, a safer drug is called for osteoporosis, especially for the prevention in the early stage of the disease, not only the treatment in the later stage. Panax notoginseng saponin (PNS), a traditional Chinese herb, has been used as anti-ischemic drug due to its function on improving vascular circulation. In order to verify whether Panax notoginseng saponins (PNS) could be used to prevent osteoporosis, ovariectomy (OVX) was induced in female C57BL/C6J mice, followed by orally administration with 40 mg/kg/d, 80 mg/kg/d, and 160 mg/kg/d of three different dosages of PNS for 9 weeks. Serum biochemical analysis, micro-CT, histological evaluation, and immunostaining of markers of osteogenesis and angiogenesis were performed in the sham, osteoporotic (OVX), and treatment (OVX+PNS) groups. Micro-CT and histological evaluation showed that compared to sham group, the bone mass of OVX group reduced significantly, while it was significantly restored in the moderate-dose PNS (40 mg/kg and 80 mg/kg) treatment groups. The expression of CD31 and osteocalcin (OCN) in the bone tissue of treatment group also increased, suggesting that PNS activated osteogenesis and angiogenesis, which subsequently increased the bone mass. These results confirmed the potential function of PNS on the prevention of osteoporosis. However, in the high dose of PNS (160 mg/kg) group, the antiosteoportic effect had been eliminated, which also suggested the importance of proper dose of PNS for the prevention and treatment of osteoporosis in postmenopausal women.

Elevated levels of circulating fibroblast growth factor 23 with hypercalcemia following discontinuation of denosumab.

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.