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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.
Zheng, Q, Kernozek, T, Daoud-Gray, A, Borer, KT
Nutrients. 2021;(11)
Abstract
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.
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Nutritional Therapy with Vitamin K1 Is Effective in the Improvement of Vitamin K Status and Bone Turnover Markers in Patients with Severe Motor and Intellectual Disabilities.
Kuwabara, A, Nagae, A, Kitagawa, M, Tozawa, K, Kumode, M, Tanaka, K
Journal of nutritional science and vitaminology. 2020;(3):278-284
Abstract
We have previously reported that patients with severe motor and intellectual disabilities (SMID) have a high prevalence of vitamin K deficiency both in the liver and bone. Thus, vitamin K therapy for SMID patients should be considered. In the present study, we have studied the efficacy of nutritional therapy with vitamin K1 for improving their vitamin K status and bone metabolism markers in patients with SMID. During the 3-mo period, 19 patients under enteral feeding received vitamin K1 treatment, the dose of which was determined to meet each subject's energy requirement. Biomarkers of vitamin K insufficiency; protein induced by vitamin K absence or antagonist-II (PIVKA-II), undercarboxylated osteocalcin (ucOC), intact osteocalcin (intact OC) and bone turnover markers (tartrate-resistant acid phosphatase-5b: TRACP-5b and bone alkaline phosphatase: BAP) were measured at baseline and post treatment. The ucOC/OC ratio was calculated as a more sensitive index than ucOC for vitamin K status in the bone. After treatment, the median vitamin K intake increased from 66 to 183 μg/d, and serum levels of PIVKA-II and ucOC/OC ratio were significantly decreased. Decrements of serum ucOC level and ucOC/OC ratio were significantly associated with vitamin K intake, indicating that both markers well reflect the dose-dependent vitamin K effects. Serum levels of BAP and TRACP-5b were significantly increased after vitamin K1 therapy. Nutritional therapy with vitamin K1 effectively improved the markers for vitamin K status and bone turnover, and was considered to be a good candidate for treatment in SMID patients.
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Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia.
Marktel, S, Scaramuzza, S, Cicalese, MP, Giglio, F, Galimberti, S, Lidonnici, MR, Calbi, V, Assanelli, A, Bernardo, ME, Rossi, C, et al
Nature medicine. 2019;(2):234-241
Abstract
ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß0 or severe ß+ mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6-76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10-1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome.
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No Added Value of 18F-Sodium Fluoride PET/CT for the Detection of Bone Metastases in Patients with Newly Diagnosed Prostate Cancer with Normal Bone Scintigraphy.
Zacho, HD, Jochumsen, MR, Langkilde, NC, Mortensen, JC, Haarmark, C, Hendel, HW, Jensen, JB, Petersen, LJ
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2019;(12):1713-1716
Abstract
The aim of this study was to determine if additional 18F-sodium fluoride PET/CT (NaF PET/CT) improves the prognostic accuracy in the initial staging of prostate cancer patients with normal bone scintigraphy undergoing prostatectomy. Methods: A prospective cohort study examined NaF PET/CT in intermediate- or high-risk prostate cancer with negative bone scintigraphy who were scheduled for prostatectomy. Biochemical response: PSA levels < 0.2 ng/mL at 6 wk and 6 mo postoperatively, PSA level ≥ 0.2 ng/mL was biochemical failure. Results: Eighty-one patients were included in the study; 75 patients (93%) achieved biochemical responses, 6 patients had biochemical failure. NaF PET/CT indicated bone metastasis in 1 patient (1.2%), was equivocal in 7 patients (8.6%), without bone metastases in 73 patients (90.1%). Eight patients with bone metastases or equivocal results on NaF PET/CT exhibited biochemical responses. All patients with biochemical failure had negative NaF PET/CT and bone scintigraphy for bone metastases. Conclusion: NaF PET/CT has no added value for bone staging in intermediate- and high-risk prostate cancer patients with normal bone scintigraphy results undergoing prostatectomy.
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Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study.
Hofmann, CE, Harmatz, P, Vockley, J, Högler, W, Nakayama, H, Bishop, N, Martos-Moreno, GÁ, Moseley, S, Fujita, KP, Liese, J, et al
The Journal of clinical endocrinology and metabolism. 2019;(7):2735-2747
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Abstract
CONTEXT Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited. OBJECTIVE To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years. DESIGN Phase 2 open-label study (July 2010 to September 2016). SETTING Twenty-two sites; 12 countries. PARTICIPANTS Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months. INTERVENTION Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously. MAIN OUTCOME MEASURES Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2). RESULTS During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment. CONCLUSIONS Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
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Effect of Cinacalcet Combined with Calcitriol on the Clinical Outcome and Bone Metabolism in Patients on Hemodialysis with Severe Secondary Hyperparathyroidism.
Yuan, F, Chen, X, Wang, C, Li, Z, Liu, H
Blood purification. 2018;(1-3):73-78
Abstract
OBJECTIVE To observe the clinical outcome and the effect of bone metabolism of cinacalcet combined with calcitriol in maintenance hemodialysis (MHD) patients with severe secondary hyperparathyroidism (SHPT). METHODS Thirty MHD patients with SHPT were enrolled into the study. All patients were given cinacalcet 25-75 mg and 0.5 μg calcitriol daily. Serum Ca, P, intact parathyroid hormone (iPTH), and bone metabolic markers were measured. The clinical symptoms and their changes were investigated. RESULTS The baseline levels of iPTH, Ca, and P were 1,787.3 ± 1,321 pg/mL, 2.54 ± 0.19 mmol/L, and 2.06 ± 0.15 mmol/L respectively. After 3 months treatment, iPTH decreased by 70%. Serum Ca and P fell to 2.39 ± 0.17 and 1.56 ± 0.50 mmol/L (p < 0.05), respectively. After 6 months, the bone-specific alkaline phosphatase, osteocalcin, and β-cross levels were decreased by 50, 37, and 49% respectively compared with corresponding values before treatment. A decline in the bone density patients was inhibited. CONCLUSION Cinacalcet combined with low dose calcitriol can improve high calcium, high phosphorus, and high iPTH in MHD patients with severe SHPT and also improve bone metabolism. It can be used as a favorable choice for SHPT treatment.
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Treatment of thoracic or lumbar burst fractures with Balloon Assisted Endplate Reduction using Tricalcium Phosphate cement: histological and radiological evaluation.
Kitzen, J, Schotanus, MGM, Plasschaert, HSW, Hulsmans, FH, Tilman, PBJ
BMC musculoskeletal disorders. 2017;(1):411
Abstract
BACKGROUND Short-segment pedicle-screw instrumentation is frequently used to stabilize thoracolumbar burst fractures. A recognized disadvantage of this procedure is recurrent kyphosis from intervertebral disc creep into the fractured central endplate. Balloon Assisted Endplate Reduction (BAER) using Tricalcium Phosphate bone cement (TCP) enables elevation of the centrally depressed endplate. Our objective was to evaluate the bone-tissue response to TCP and to analyse whether BAER using TCP can prevent recurrent kyphosis after removal of the instrumentation. METHODS Fourteen patients with traumatic thoracolumbar burst fractures were operated with BAER using TCP in combination with short-segment instrumentation. Nine months after surgery, instrumentation was removed and transpedicular biopsies were taken for histological and histochemical analysis. Roentgenograms pre- and postoperatively and at latest follow-up after removal of the instrumentation were evaluated. RESULTS Average follow-up was 2.6 years. Analysis of the biopsies showed a variable degree of bone remodelling with incorporation of TCP into newly formed bone matrix. No extensive foreign body reactions, inflammation, granulomatous responses or tissue necrosis were observed. Wedge-angle, kyphosis-angle and both the anterior-posterior and central-posterior vertebral body height ratios improved significant postoperatively (p < 0.001). After removal of the instrumentation no significant differences in wedge-angle or height ratios were seen (p = 0.12). The kyphosis-angle increased four degrees (p = 0.01). CONCLUSION TCP showed good histological osseointegration with no adverse events. TCP can therefore be safely used and could be beneficial in treatment of thoracolumbar burst fractures. BAER with TCP in combination with short-segment instrumentation might reduce recurrence of deformity even after removal of the instrumentation in comparison to short-segment instrumentation alone. TRIAL REGISTRATION This study is registered at the at the Dutch Trial Registry (NTR3498).
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Treatment with neridronate in children and adolescents with osteogenesis imperfecta: Data from open-label, not controlled, three-year Italian study.
Idolazzi, L, Fassio, A, Viapiana, O, Rossini, M, Adami, G, Bertoldo, F, Antoniazzi, F, Gatti, D
Bone. 2017;:144-149
Abstract
INTRODUCTION The present study assessed the long-term efficacy and safety of intravenous (i.v.) neridronate in children and adolescents affected by osteogenesis imperfecta (OI). METHODS 55 young patients (mean age 12.6±3.9years) affected by OI were included in the study. Neridronate was administered by i.v. infusion at a dose of 2mg/kg (maximum dose of 100mg) at intervals of three-months for three years. Dual X-ray absorptiometry of the lumbar spine, hip and ultradistal and proximal radius were evaluated every 6months. Blood calcium, phosphate, albumin, fasting urinary calcium/creatinine ratio were obtained at baseline and every 3months. Serum bone turnover markers total and bone alkaline phosphatase were performed every 12months in a proportion of patients. RESULTS Mean lumbar spine and total hip bone mineral density (BMD) and bone mineral content significantly increased from baseline compared to all subsequent time points (p<0.001). Mean ultradistal radius BMD significantly increased from month 18 (p=0.026). Levels of bone turnover markers significantly decreased from baseline to all post-baseline observation time points. There was no statistically significant effect on fracture risk (p=0.185), although a significant reduction was observed in the mean number of fractures occurring during treatment compared to pre-treatment values. The most frequent adverse events were arthralgia, fever, joint sprain. An acute phase reaction was reported in 26 (22.8%) patients. None of the reported serious adverse events was considered as treatment-related. CONCLUSION Long-term i.v. neridronate treatment has positive effects on BMD, bone turnover markers and fracture risk with a good safety profile.
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Early and Sustained Changes in Bone Metabolism After Severe Burn Injury.
Muschitz, GK, Schwabegger, E, Kocijan, R, Baierl, A, Moussalli, H, Fochtmann, A, Nickl, S, Tinhofer, I, Haschka, J, Resch, H, et al
The Journal of clinical endocrinology and metabolism. 2016;(4):1506-15
Abstract
CONTEXT Severe burn injury causes a massive stress response, consecutively heightened serum levels of acute phase proteins, cortisol, and catecholamines with accompanying disturbance in calcium metabolism. OBJECTIVE Evaluation of early and prolonged changes of serum bone turnover markers (BTMs) and regulators of bone metabolism. DESIGN Longitudinal observational design. SETTING University clinic. PATIENTS A total of 32 male patients with a median age of 40.5 years and a median burned total body surface area of 40% (83% patients with full thickness burn injury). INTERVENTIONS None. MAIN OUTCOME MEASURES Comparison of changes of BTM/regulators of bone metabolism in the early (d 2–7) and prolonged (d 7–56) phases after trauma. RESULTS All investigated BTM/regulators significantly changed. During the early phase, pronounced increases were observed for serum type 1 collagen cross-linked C-telopeptide, intact N-terminal propeptide of type I procollagen, sclerostin, Dickkopf-1, bone-specific alkaline phosphatase, fibroblast growth factor 23, and intact parathyroid hormone levels, whereas 25-hydroxyvitamin D, albumin, serum, and ionized calcium levels decreased. Changes of osteoprotegerin, osteocalcin, and phosphate were less pronounced but remained significant. In the prolonged phase, changes of intact N-terminal propeptide of type I procollagen were most pronounced, followed by elevated sclerostin, osteocalcin, bone-specific alkaline phosphatase, and lesser changes for albumin levels. Calcium and ionized calcium levels tardily increased and remained within the limit of normal. In contrast, levels of intact parathyroid hormone, fibroblast growth factor 23, C-reactive protein, and to a lesser extent serum type 1 collagen cross-linked C-telopeptide and phosphate levels declined significantly during this phase of investigation. CONCLUSIONS Ongoing changes of BTM and regulators of bone metabolism suggest alterations in bone metabolism with a likely adverse influence on bone quality and structure in male patients with severe burn injuries.
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On the combined effects of normobaric hypoxia and bed rest upon bone and mineral metabolism: Results from the PlanHab study.
Rittweger, J, Debevec, T, Frings-Meuthen, P, Lau, P, Mittag, U, Ganse, B, Ferstl, PG, Simpson, EJ, Macdonald, IA, Eiken, O, et al
Bone. 2016;:130-8
Abstract
Bone losses are common as a consequence of unloading and also in patients with chronic obstructive pulmonary disease (COPD). Although hypoxia has been implicated as an important factor to drive bone loss, its interaction with unloading remains unresolved. The objective therefore was to assess whether human bone loss caused by unloading could be aggravated by chronic hypoxia. In a cross-over designed study, 14 healthy young men underwent 21-day interventions of bed rest in normoxia (NBR), bed rest in hypoxia (HBR), and hypoxic ambulatory confinement (HAmb). Hypoxic conditions were equivalent to 4000m altitude. Bone metabolism (NTX, P1NP, sclerostin, DKK1) and phospho-calcic homeostasis (calcium and phosphate serum levels and urinary excretion, PTH) were assessed from regular blood samples and 24-hour urine collections, and tibia and femur bone mineral content was assessed by peripheral quantitative computed tomography (pQCT). Urinary NTX excretion increased (P<0.001) to a similar extent in NBR and HBR (P=0.69) and P1NP serum levels decreased (P=0.0035) with likewise no difference between NBR and HBR (P=0.88). Serum total calcium was increased during bed rest by 0.059 (day D05, SE 0.05mM) to 0.091mM (day D21, P<0.001), with no additional effect by hypoxia during bed rest (P=0.199). HAmb led, at least temporally, to increased total serum calcium, to reduced serum phosphate, and to reduced phosphate and calcium excretion. In conclusion, hypoxia did not aggravate bed rest-induced bone resorption, but led to changes in phospho-calcic homeostasis likely caused by hyperventilation. Whether hyperventilation could have mitigated the effects of hypoxia in this study remains to be established.