Balancing Altered Calcium Metabolism with Bone Health in Sarcoidosis.

Abnormal calcium metabolism in sarcoidosis patients can lead to hypercalcemia, hypercalciuria, and kidney stones. Hypercalcemia in sarcoidosis is usually due to increased activity of 1α-hydroxylase in macrophages of pulmonary granulomata, resulting in low levels of 25-hydroxyvitamin D and high levels of calcitriol. Vitamin D supplementation may be dangerous for some sarcoidosis patients and is recommended only for those with decreased 25-hydroxyvitamin D and reduced or normal calcitriol level. Diagnosis, treatment of osteoporosis, and maintenance of bone health are complex issues for sarcoidosis patients. An approach to diagnosis and treatment of bone fragility is presented.

Current concepts regarding calcium metabolism and bone health in sarcoidosis.

PURPOSE OF REVIEW: Vitamin D supplementation is widespread used in the general population. In sarcoidosis, up to 50% of patients, especially postmenopausal women and those taking corticosteroids, show evidence of increased bone fragility. The purpose of this review is to provide an evidence-based rationale on how to treat sarcoidosis patients with bone health issues. RECENT FINDINGS: Evidence from observational studies show that decreased 25-hydroxy vitamin D is common in sarcoidosis. However, the great majority of sarcoidosis patents have normal or often elevated levels of 1,25-dihydroxy vitamin D (calcitriol), a marker associated with disease activity. High calcitriol levels may often be associated with hypercalcemia and hypercalcuria. The few interventional randomized controlled studies in the field, suggest that vitamin D supplementation may not be well tolerated because of hypercalcemia, moreover without substantial benefit on bone health and risk for fractures in these patients. SUMMARY: Vitamin D supplementation may be withheld in sarcoidosis patients with bone fragility, unless calcitriol levels are below normal limits. A treating scheme is proposed.

Factors affecting bone mineral mass loss after lower-limb fractures in a pediatric population.

BACKGROUND: The purpose of this study was to assess the effects of the durations of cast immobilization and non-weight-bearing periods, and decreases in vigorous physical activity (VPA) on bone mineral parameters in a pediatric population treated for a lower-limb fracture. METHODS: Fifty children and teenagers who had undergone a cast-mediated immobilization for a leg or ankle fracture were prospectively recruited. The durations of cast immobilization and non-weight-bearing periods were recorded for each participant. Dual-energy x-ray absorptiometry scans were performed at the time of fracture treatment (baseline) and at cast removal. Physical activity during cast immobilization was assessed using accelerometers. RESULTS: A strong negative correlation was found between the total duration of cast immobilization and decreases in both calcaneal bone mineral density (BMD) (r=-0.497) and total lower-limb bone mineral content (BMC) (r=-0.405). A strong negative correlation was also noted between the durations of the non-weight-bearing periods and alterations in calcaneal BMD (r=-0.420). No apparent correlations were found between lower BMD and BMC and decreased VPA. CONCLUSIONS: Bone mineral loss was correlated to the total duration of cast immobilization for all measurement sites on the affected leg, whereas it was only correlated to the durations of non-weight-bearing periods for calcaneal BMD and total lower-limb BMC. However, no correlations were noted between bone mineral loss and decreased VPA.

Bone loss after heart transplant: effect of alendronate, etidronate, calcitonin, and calcium plus vitamin D3.

OBJECTIVE: To compare the effects of calcitonin, etidronate, and alendronate in preventing bone loss during the first 2 years after heart transplant. METHODS: A total of 222 heart transplant recipients (mean [SD] age, 52.4 [10] years, 85% male) were evaluated. Patients with normal bone mineral density (reference group, n = 102) received 1000 mg/d calcium plus 800 IU/d vitamin D3. The rest were assigned to 200 IU/d of calcitonin (n=42), 400 mg/d etidronate orally for 14 days quarterly (n = 33), or 10 mg/d alendronate (n = 45). All patients received calcium and vitamin D. Bone mineral density was assessed by dual-energy x-ray absorptiometry in the lumbar spine, the entire femur, and the femoral neck at baseline and 6, 12, and 24 months after transplant. RESULTS: At 2 years after transplant, bone mineral density in the lumbar spine had decreased in the reference group (-3.07%), calcitonin group (-0.93%), and etidronate group (-1.87%) but not in the alendronate group (+4.9%; P <.001). After 2 years, bone mineral density in the entire femur decreased in all groups (-3.2% in the reference group, -3.6% in the calcitonin group, -4.6% in the etidronate group, and -0.5% in the alendronate group) but bone loss was significantly lower in the alendronate group (P <.001). Bone mineral density in the femoral neck also decreased in all groups. The incidence of vertebral fractures did not differ among groups. Adverse events were similar between groups. CONCLUSIONS: Alendronate therapy in heart transplant recipients was associated with a significant increase in bone mineral density in the lumbar spine and less bone loss at the hip.

Exercise equipment used in microgravity: challenges and opportunities.

A variety of physiological changes are experienced by astronauts during both short- and long-duration space missions. These include space motion sickness, spatial disorientation, orthostatic hypotension, muscle atrophy, bone demineralization, increased cancer risk, and a compromised immune system. This review focuses on countermeasures used to moderate these changes, particularly exercise devices that have been used by National Aeronautics and Space Administration astronauts over the past six decades as countermeasures to muscle atrophy and bone loss. The use of these devices clearly has shown that a microgravity environment places unusual demands on both the equipment and the human users. While it is of paramount importance to overcome microgravity-induced musculoskeletal deconditioning, it also is imperative that the exercise system (i) is small and lightweight, (ii) does not require an external power source, (iii) produces 1g-like benefits to both bones and muscles, (iv) requires relatively short durations of exercise, and (v) does not affect the surrounding structure or environment negatively through noise and/or induced vibrations.

The effects of metformin and alendronate in attenuating bone loss and improving glucose metabolism in diabetes mellitus mice.

BACKGROUND: To explore the anti-osteoporosis and anti-diabetes effects and potential underlying mechanisms of treatment with metformin and alendronate in diabetes mellitus mice. METHODS: Eight-week-old C57 BL/KS db/db and db/+ female mice were evaluated according to the following treatment group for 12 weeks: control group, diabetes mellitus group, diabetes mellitus with metformin group, diabetes mellitus with Alendronate group, diabetes mellitus with metformin plus alendronate group. Glucose level, glucose tolerance test, bone mineral density, bone microarchitecture, bone histomorphometry, serum biomarkers, and qPCR analysis. RESULTS: Combined metformin and alendronate can improve progression in glucose metabolism and bone metabolism, including blood glucose levels, blood glucose levels after 4 and 16 hours fasting, glucose tolerance test results, insulin sensitivity and reduces bone loss than the diabetes group. The use of alendronate alone can increase significantly serum glucagon-like peptide-1 levels than the diabetes group. The use of metformin alone can improve bone microstructure such as Tb.Sp and Tb.N of spine in diabetic mice. CONCLUSION: The combined use of alendronate and metformin has an anti-diabetes and anti-osteoporotic effect compared with diabetic mice, but they appear to act no obvious synergistically between alendronate and metformin.

[Hepatic osteodystrophy in patients with liver cirrhosis].

The article presents research data of BMD in 106 patients with liver cirrhosis. The core group of examined patients presented with LC patients the etiology of alcohol--37.7% and primary biliary cirrhosis--35.8%. In 68.9% of patients with established deficits of bone mineral density, by 24.6%--at the level of osteoporosis. Was detected influence of the etiology of the disease on the frequency of osteopenia and osteoporosis containment. Was made analysis of dependence of the frequency of osteopenia, and/or osteoporosis of population risk factors, duration of disease, grade of liver failure on the Child-Pugh. A comparative assessment of the effectiveness treatment of disorders of BMD active metabolite of vitamin D3--alpha caltsidol and drugs from the group of bisphosphonates.

Dietary supplementation with glycosaminoglycans reduces locomotor problems in broiler chickens.

This study aimed to assess the influence of glycosaminoglycan (chondroitin and glucosamine sulfates) supplementation in the diet on the performance and incidence of locomotor problems in broiler chickens. A completely randomized design was carried out in a 3 × 3 factorial scheme (3 levels of chondroitin sulfate -0, 0.05, and 0.10%; and 3 levels of glucosamine sulfate -0, 0.15, and 0.30%). Each treatment was composed of 6 replications of 30 broilers each. The performance of broilers (average weight, weight gain, feed intake, feed conversion, and productive viability) was assessed at 7, 21, 35, and 42 d of age, whereas the gait score, valgus and varus deviations, femoral degeneration, and tibial dyschondroplasia were assessed at 21 and 42 d of age. Increasing levels of glucosamine sulfate inclusion linearly increased the weight gain from 1 to 35 and from 1 to 42 d of age of broilers (P = 0.047 and P = 0.039, respectively), frequency of broilers with no femoral degeneration in the right and left femurs, and the proliferating cartilage area of proximal epiphysis at 42 d of age (P = 0.014, P < 0.0001, and P = 0.028, respectively). The increasing inclusion of chondroitin and glucosamine sulfates led to an increase in the frequency of broilers on the gait score scale 0 (P = 0.007 and P = 0.0001, respectively) and frequency of broilers with no valgus and varus deviations (P = 0.014 and P = 0.0002, respectively) also at 42 d of age. Thus, chondroitin and glucosamine sulfates can be used in the diet of broiler chickens to reduce their locomotor problems.

Antiresorptive and anabolic agents in the prevention and reversal of bone fragility.

Bone volume, microstructure and its material composition are maintained by bone remodelling, a cellular activity carried out by bone multicellular units (BMUs). BMUs are focally transient teams of osteoclasts and osteoblasts that respectively resorb a volume of old bone and then deposit an equal volume of new bone at the same location. Around the time of menopause, bone remodelling becomes unbalanced and rapid, and an increased number of BMUs deposit less bone than they resorb, resulting in bone loss, a reduction in bone volume and microstructural deterioration. Cortices become porous and thin, and trabeculae become thin, perforated and disconnected, causing bone fragility. Antiresorptive agents reduce fracture risk by reducing the rate of bone remodelling so that fewer BMUs are available to remodel bone. Bone fragility is not abolished by these drugs because existing microstructural deterioration is not reversed, unsuppressed remodelling continues producing microstructural deterioration and unremodelled bone that becomes more mineralized can become brittle. Anabolic agents reduce fracture risk by stimulating new bone formation, which partly restores bone volume and microstructure. To guide fracture prevention, this Review provides an overview of the structural basis of bone fragility, the mechanisms of remodelling and how anabolic and antiresorptive agents target remodelling defects.

Protective effect of grape or apple juices in bone tissue of rats exposed to cadmium: role of RUNX-2 and RANK/L expression.

The aim of this study was to investigate if grape or apple juices are able to protect bone tissue of rats exposed to cadmium. For this purpose, histopathological analysis and immunohistochemistry for RUNX-2 and RANK-L were investigated in this setting. A total of 20 adult Wistar rats were distributed into four groups (n = 5), as follows: control group, cadmium group, cadmium and grape juice group, and Cadmium and apple juice group. Control group received a single intraperitoneal (i.p.) water injection. Cadmium group received a single i.p. injection of cadmium chloride (1.2 mg/kg body weight) diluted in water. Cadmium and grape juice and cadmium and apple juice groups received a single i.p. injection of cadmium chloride (1.2 mg/kg body), and after 15 days, the rats were treated with grape or apple juices for 15 days, by gavage. All animals were euthanized 30 days after the beginning of experiment. Histopathological analysis in rat femur revealed extensive bone loss in rats intoxicated with cadmium. Grape or apple juices were able to increase bone formation. Cadmium inhibited RUNX-2 immunoexpression whereas cadmium increased RANK-L immunoexpression in rat bone cells. Grape or apple juices increased RUNX-2 and decreased RANK-L immunoexpression after cadmium intoxication. Taken together, our results demonstrate that grape or apple juices are able to exert therapeutic activity following cadmium intoxication in rat bone tissue as result of stimulatory effect of bone formation by RUNX-2 upregulation and RANK-L downregulation.

[Bone metabolism disturbances in anorexia nervosa]. / Zaburzenia metabolizmu kostnego w jadlowstrkcie psychicznym.

Osteoporosis is a frequent complications of anorexia nervosa (AN). The etiology of osteoporosis in AN is multifactorial. Multiaxial hormonal disturbances and chronic undernutrition cause decrease or the lack of increase of bone mineral density (BMD), expected in adolescence. Both processes result from increased resorption and insufficient bone formation and/or mineralization. Decreased BMD persist in adult patients with a history of AN in the adolescence. There are no guidelines concerning treatment of osteoporosis in AN. The authors present review of the literature concerning bone metabolism in AN.

Vitamin D supplementation during pregnancy on infant anthropometric measurements and bone mass of mother-infant pairs: A randomized placebo clinical trial.

INTRODUCTION: Based on the essential role of vitamin D in the regulation of calcium metabolism, we evaluated the effects of 2000IUvitamin D/day in late pregnancy on infant's anthropometric measurements and bone mass parameters of mother-infant pairs. MATERIAL AND METHODS: In this randomized clinical trial, the main inclusion criteria were: aged 18 or older, no history of internal diseases and pregnancy complications, and a singleton live fetus. The intervention group received two 1000IU vitamin D3 pills (2000IU) daily from weeks 26-28 until childbirth. Maternal serum 25-hydroxyvitamin D, infants' anthropometric measurements (at birth, 4th and 8th weeks postnatal), and maternal and infant bone mass parameters were examined. RESULTS: The two groups were not statistically different in relation to baseline 25-hydroxyvitamin D concentrations. However, there was a significant difference between the study groups with regard to change in vitamin D status over time (p<0.001). In cross-sectional analysis, the two groups were not different with respect to anthropometric measurements in three time points. Also, in repeated measure analysis, the two groups did not show any statistical differences concerning the infants' anthropometric measurements. The bone mass measurements of all the 28 mothers who belonged to the two study groups were not different. Finally, the bones mass measurements of the infants in the two study groups were not different. CONCLUSION: Ingestion of 2000IUvitamin D3/day during late pregnancy did not improve anthropometric measurements of infants from birth until the 8th week postnatal, nor improve the maternal and infant bone mass measurements.

Exercise and pharmacological countermeasures for bone loss during long-duration space flight.

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

Pulsed electromagnetic fields inhibit bone loss in streptozotocin-induced diabetic rats.

Evidences have shown that pulsed electromagnetic fields (PEMFs) can partially prevent bone loss in streptozotocin (STZ)-induced diabetic rats. However, the precise mechanisms accounting for these favorable effects are unclear. This study aimed to investigate the effects of PEMFs on bone mass and receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) and Wnt/ß-catenin signaling pathway in STZ rats. Thirty 3-month-old Sprague Dawley rats were randomly divided into the following three groups (n = 10): control group (injection of saline vehicle), DM group (injection of STZ), and PEMFs group (injection of STZ + PEMFs exposure). One week following injection of STZ, rats in the PEMFs group were subject to PEMFs stimulus for 40 min/day, 5 days/week, and lasted for 12 weeks. After 12 week intervention, the results showed that PEMFs increased serum bone-specific alkaline phosphatase level and bone mineral density, and inhibited deterioration of bone microarchitecture and strength in STZ rats. Furthermore, PEMFs up-regulated the mRNA expressions of low-density lipoprotein receptor-related protein 5, ß-catenin and runt-related gene 2 (Runx2), and down-regulated dickkopf1 in STZ rats. However, mRNA expressions of RANKL and OPG were not affected by PEMFs. PEMFs can prevent the diabetes-induced bone loss and reverse the deterioration of bone microarchitecture and strength by restoring Runx2 expression through regulation of Wnt/ß-catenin signaling, regardless of its no glucose lowering effect.

Chronic Kidney Disease-Mineral Bone Disorder in the Elderly Peritoneal Dialysis Patient.

PURPOSE: The purpose of this paper was to review the literature concerning the treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) in the elderly peritoneal dialysis (PD) patient. RESULTS: Chronic kidney disease-mineral bone disorder is a major problem in the elderly PD patient, with its associated increased fracture risk, vascular calcification, and accelerated mortality fracture risk. Peritoneal dialysis, however, bears a lower risk than hemodialysis (HD). The approach to CKD-MBD prophylaxis and treatment in the elderly PD patient is similar to other CKD patients, with some important differences. Avoidance of hypercalcemia, hyperphosphatemia, and hyperparathyroidism is important, as in other CKD groups, and is generally easier to attain. Calcium-free phosphate binders are recommended for normocalcemic and hypercalcemic patients. Normalization of vitamin D levels to > 75 nmol/L (> 30 pg/L) and low-dose active vitamin D therapy is recommended for all patients. Hyperparathryoidism is to be avoided by using active vitamin D and cinacalcet. Particular attention should be paid to treating protein malnutrition. Fracture prophylaxis (exercise, use of walkers, dwelling modifications) are important. Hypomagnesemia is common in PD and can be treated with magnesium supplements. Vitamin K deficiency is also common and has been identified as a cause of vascular calcification. Accordingly, warfarin treatment for this age group is problematic. CONCLUSION: While treatment principles are similar to other dialysis patient groups, physicians should be aware of the special problems of the elderly group.

Prevention of bone demineralization by calcium supplementation in precocious puberty during gonadotropin-releasing hormone agonist treatment.

We have previously demonstrated a negative impact on peak bone mass in girls with precocious puberty treated with GnRH agonist (GnRHa). Several studies have shown that a high calcium intake positively influences bone mass in prepubertal girls and leads to a higher peak bone mass. The aim of this study was to evaluate the effect of calcium supplementation in girls with precocious puberty during GnRHa treatment. Forty girls affected by true central precocious puberty and treated with the GnRHa triptorelin were studied for 2 yr. After diagnosis, the patients were randomly assigned to three groups: group A, treated only with GnRHa; group B, treated for 12 months solely with GnRHa and then supplemented with calcium gluconolactate/carbonate (1 g calcium/day in two doses) for 12 months; and group C, treated from the beginning with combined GnRHa and calcium. Bone mineral density (BMD) at the lumbar spine was measured by dual energy x-ray absorptiometry at the beginning of the study and after 12 and 24 months and was expressed as the calculated true volumetric density (BMDv) in milligrams per cm3. Group A showed a decrease in absolute BMDv levels, in SD score for chronological age (CA), and even more in SD score for bone age (BA). Group B showed the same behavior during the first year, but this trend was reversed in the second year, when calcium supplementation was added to GnRHa treatment. Group C showed an increase in absolute BMDv levels and in SD score for CA and BA. BMDv variations (expressed as absolute values, SD score for CA, and SD score for BA) became statistically significant at 24 months between groups C and A (P = 0.036, P = 0.032, and P = 0.025, respectively). The behavior of the lumbar spine BMDv in the three groups is consistent with a positive effect of calcium supplementation during GnRHa treatment. In calcium-supplemented patients, the normal process of bone mass accretion at puberty is preserved despite GnRHa treatment. Therefore, the reduction in BMD during GnRHa treatment in girls with precocious puberty is at least completely reversible and preventable if calcium supplementation is associated from the beginning.

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment.

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and -1.3% in the menstruating group and -7.5 and -10.4% in the amenorrhoeic group (P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and -0.3%, and -3.5 and -5.8% (P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine -3.0% compared with controls -7.4% at three years (P=0.003), but no significant difference was found in the femoral neck: -1.7% versus -2.8%, respectively (P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine -5.8% versus -9.7% (P=0.008) and femoral neck -3.5% versus -5.1% (P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

NASA' s life sciences and space radiation biology.

Plans for the various missions in which men and women are expected to participate during the next 10 years are outlined. Such missions include flights of up to three months duration in low earth orbit as well as possible short excursions to geosynchronous orbit. Research activities are described which cover the full spectrum of physiological and psychological responses to space flight. These activities are shown to contribute to the ongoing Shuttle program and the future Space Station. The paper includes a summary of the major technical thrusts needed to support extended habitation in space.

Combined injury syndrome in space-related radiation environments.

The risk of combined injury (CI) to space travelers is a function of exposure to anomalously large surges of a broad spectrum of particulate and photon radiations, conventional trauma (T), and effects of weightlessness including decreased intravascular fluid volume, and myocardial deconditioning. CI may occur even at relatively low doses of radiation which can synergistically enhance morbidity and mortality from T. Without effective countermeasures, prolonged residence in space is expected to predispose most individuals to bone fractures as a result of calcium loss in the microgravity environment. Immune dysfunction may occur from residence in space independent of radiation exposure. Thus, wound healing would be compromised if infection were to occur. Survival of the space traveler with CI would be significantly compromised if there were delays in wound closure or in the application of simple supportive medical or surgical therapies. Particulate radiation has the potential for causing greater gastrointestinal injury than photon radiation, but bone healing should not be compromised at the expected doses of either type of radiation in space.