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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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Association between Hemodialysis Patient Outcomes and Compliance with KDOQI and KDIGO Targets for Mineral and Bone Metabolism.
Djukanović, L, Dimković, N, Marinković, J, Djurić, Ž, Knežević, V, Lazarević, T, Ljubenović, S, Marković, R, Rabrenović, V
Nephron. 2016;(3):168-74
Abstract
BACKGROUND Increased mortality of hemodialysis (HD) patients is associated with chronic kidney disease-mineral and bone disorders (CKD-MBD), and therefore, their correction may improve patient survival. Differences in targets recommended by KDOQI and KDIGO CKD-MBD guidelines directed us to compare the relative numbers of patients achieving these targets and to examine possible associations between compliance with the targets and patient outcome. METHODS A total of 1,744 patients (61.2% males, aged 58.7 ± 12.5 years) dialyzed in 20 HD centers in Serbia were monitored for 3 years. The number of participants achieving KDOQI/KDIGO guideline targets for serum phosphorus, calcium, and iPTH was determined. The Cox proportional hazards model was used to select variables significantly associated with risk of time to death. RESULTS A majority of patients were dialyzed thrice weekly for 4 h; 86.3% of them used phosphate binders and 49.3% vitamin D3. Proportions of patients achieving KDOQI and KDIGO targets were 49.5 and 44.4% for phosphorus, 53.2 and 76.7% for calcium, 21 and 42.8% for iPTH. Multivariate Cox analysis selected serum phosphorus level outside the KDIGO target, as well as serum iPTH levels outside KDOQI and KDIGO targets as significant mortality predictors. Areas under the receiver operating characteristic curves showed that achievement of both guideline targets for iPTH had similar survival predictive values. CONCLUSION Serum phosphorus levels outside KDIGO targets and iPTH levels outside both KDOQI and KDIGO targets were associated with a significantly higher risk of death. These findings may be useful in the management of CKD-MBD and for establishing local guidelines.
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COSMOS Project: Hemodialysis scenario in Europe.
Cannata-Andía, JB, Fernández Martín, JL
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2016;(4):381-8
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Relationship of Bone Metabolism Biomarkers and Periodontal Disease: The Osteoporotic Fractures in Men (MrOS) Study.
Schulze-Späte, U, Turner, R, Wang, Y, Chao, R, Schulze, PC, Phipps, K, Orwoll, E, Dam, TT
The Journal of clinical endocrinology and metabolism. 2015;(6):2425-33
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CONTEXT Periodontitis is an inflammatory disease of tooth-supporting tissue leading to bone destruction and tooth loss. Periodontitis affects almost 50% of adults greater than 30 years of age. OBJECTIVE This study evaluated the association between biomarkers linked to bone formation and resorption with the occurrence and progression of periodontal disease in older men (≥ 65 y). DESIGN The Osteoporotic Fractures in Men (MrOS) study is a prospective, observational study among men 65 years of age and older. SETTING This ancillary study, Oral and Skeletal Bone Loss in Older Men, was conducted at two of the six MrOS study sites (Birmingham, AL and Portland, OR). PATIENTS Patients underwent medical and dental evaluation. Diagnoses of periodontitis were based on clinical attachment loss, pocket depth, calculus, plaque, and bleeding on a random half-mouth. Bone metabolism biomarkers included serum levels of calcium, phosphate (Pi), alkaline phosphatase, albumin, carboxy-terminal collagen crosslinks (CTX), N-terminal propeptides of type I procollagen, isoform 5b of tartrate-resistant acid phosphatase, and urine alpha- carboxy-terminal collagen crosslinks (alpha-CTX) and beta-CTX and serum levels of calciotropic hormones vitamin D (25(OH)D) and PTH. MAIN OUTCOME MEASURES The aim of this study is to correlate bone metabolism biomarkers with prevalence and progression of periodontal disease in older men. RESULTS Patients with more severe periodontitis had significantly higher levels of PTH (P trend = .0004), whereas 25(OH)D was lower (P trend = .001). In a subset of men reevaluated at a second dental visit, improvement of periodontitis was associated with lower alpha-CTX, beta-CTX, and CTX levels at baseline after adjusting for age, site, and body mass index. CONCLUSION This study suggests that a distinct set of biomarkers of bone metabolism are associated with more severe periodontal disease (PTH, 25(OH)D) and periodontal progression (alpha-CTX, beta-CTX, and CTX) over time.
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Association between bone stiffness and nutritional biomarkers combined with weight-bearing exercise, physical activity, and sedentary time in preadolescent children. A case-control study.
Herrmann, D, Pohlabeln, H, Gianfagna, F, Konstabel, K, Lissner, L, Mårild, S, Molnar, D, Moreno, LA, Siani, A, Sioen, I, et al
Bone. 2015;:142-9
Abstract
Physical activity (PA) and micronutrients such as calcium (Ca), vitamin D (25OHD), and phosphate (PO) are important determinants of skeletal development. This case-control study examined the association of these nutritional biomarkers and different PA behaviours, such as habitual PA, weight-bearing exercise (WBE) and sedentary time (SED) with bone stiffness (SI) in 1819 2-9-year-old children from the IDEFICS study (2007-2008). SI was measured on the calcaneus using quantitative ultrasound. Serum and urine Ca and PO and serum 25OHD were determined. Children's sports activities were reported by parents using a standardised questionnaire. A subsample of 1089 children had accelerometer-based PA data (counts per minute, cpm). Moderate-to-vigorous PA (MVPA) and SED were estimated. Children with poor SI (below the 15th age-/sex-/height-specific percentile) were defined as cases (N=603). Randomly selected controls (N=1216) were matched by age, sex, and country. Odds ratios (OR) for poor SI were calculated by conditional logistic regression for all biomarkers and PA behaviour variables separately and combined (expressed as tertiles and dichotomised variables, respectively). ORs were adjusted for fat-free mass, dairy product consumption, and daylight duration. We observed increased ORs for no sports (OR=1.39, p<0.05), PA levels below 524 cpm (OR=1.85, p<0.05) and MVPA below 4.2% a day (OR=1.69, p<0.05) compared to WBE, high PA levels (<688 cpm) and high MVPA (6.7%), respectively. SED was not associated with SI. ORs were moderately elevated for low serum Ca and 25OHD. However, biomarkers were not statistically significantly associated with SI and did not modify the association between PA behaviours and SI. Although nutritional biomarkers appear to play a minor role compared to the osteogenic effect of PA and WBE, it is noteworthy that the highest risk for poor SI was observed for no sports or low MVPA combined with lower serum Ca (<2.5 mmol/l) or lower 25OHD (<43.0 nmol/l).
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Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis patients: the COSMOS study.
Fernández-Martín, JL, Martínez-Camblor, P, Dionisi, MP, Floege, J, Ketteler, M, London, G, Locatelli, F, Gorriz, JL, Rutkowski, B, Ferreira, A, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2015;(9):1542-51
Abstract
BACKGROUND Abnormalities in serum phosphorus, calcium and parathyroid hormone (PTH) have been associated with poor survival in haemodialysis patients. This COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) analysis assesses the association of high and low serum phosphorus, calcium and PTH with a relative risk of mortality. Furthermore, the impact of changes in these parameters on the relative risk of mortality throughout the 3-year follow-up has been investigated. METHODS COSMOS is a 3-year, multicentre, open-cohort, prospective study carried out in 6797 adult chronic haemodialysis patients randomly selected from 20 European countries. RESULTS Using Cox proportional hazard regression models and penalized splines analysis, it was found that both high and low serum phosphorus, calcium and PTH were associated with a higher risk of mortality. The serum values associated with the minimum relative risk of mortality were 4.4 mg/dL for serum phosphorus, 8.8 mg/dL for serum calcium and 398 pg/mL for serum PTH. The lowest mortality risk ranges obtained using as base the previous values were 3.6-5.2 mg/dL for serum phosphorus, 7.9-9.5 mg/dL for serum calcium and 168-674 pg/mL for serum PTH. Decreases in serum phosphorus and calcium and increases in serum PTH in patients with baseline values of >5.2 mg/dL (phosphorus), >9.5 mg/dL (calcium) and <168 pg/mL (PTH), respectively, were associated with improved survival. CONCLUSIONS COSMOS provides evidence of the association of serum phosphorus, calcium and PTH and mortality, and suggests survival benefits of controlling chronic kidney disease-mineral and bone disorder biochemical parameters in CKD5D patients.
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Biomarker-calibrated protein intake and bone health in the Women's Health Initiative clinical trials and observational study.
Beasley, JM, LaCroix, AZ, Larson, JC, Huang, Y, Neuhouser, ML, Tinker, LF, Jackson, R, Snetselaar, L, Johnson, KC, Eaton, CB, et al
The American journal of clinical nutrition. 2014;(4):934-40
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BACKGROUND The effects of dietary protein on bone health are controversial. OBJECTIVE We examined the relation between protein intake with fracture and bone mineral density (BMD) within the Women's Health Initiative (WHI). DESIGN This prospective analysis included 144,580 women aged 50-79 y at baseline in the WHI clinical trials (CTs) and observational study (OS) that recruited participants in 1993-1998 with follow-up through 2011. Self-reported clinical fractures were collected semiannually through the original end of the trials (WHI CTs) and annually (WHI OS) by questionnaires. Hip fracture was adjudicated by a central review of radiology reports. BMDs for total body, hip, and spine were measured at baseline and 3 and 6 y in 9062 women at 3 WHI clinics by using dual-energy X-ray absorptiometry. Protein intake was assessed via food-frequency questionnaire and calibrated by using biomarkers of energy and protein intakes. Associations between protein intake and fracture were estimated by using Cox proportional hazards regression, and the relation between protein intake and BMD was estimated by using linear regression. RESULTS Median biomarker-calibrated protein intake was 15% of energy intake. Per 20% increase in calibrated protein intake (percentage of energy), there was no significant association with total fracture (HR: 0.99; 95% CI: 0.97, 1.02) or hip fracture (HR: 0.91; 95% CI: 0.84, 1.00), but there was an inverse association with forearm fracture (HR: 0.93; 95% CI: 0.88, 0.98). Each 20% increase in calibrated protein intake was associated with a significantly higher BMD for total body (mean 3-y change: 0.003 g/cm²; 95% CI: 0.001, 0.005 g/cm²) and hip (mean 3-y change: 0.002 g/cm²; 95% CI: 0.001, 0.004 g/cm²). CONCLUSIONS Higher biomarker-calibrated protein intake within the range of usual intake was inversely associated with forearm fracture and was associated with better maintenance of total and hip BMDs. These data suggest higher protein intake is not detrimental to bone health in postmenopausal women.
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Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: results of the VITAL study.
Coyne, DW, Andress, DL, Amdahl, MJ, Ritz, E, de Zeeuw, D
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013;(9):2260-8
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BACKGROUND Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium-phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism. METHODS The VITAL study enrolled patients with CKD stages 2-4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study. RESULTS Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate. CONCLUSION Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification. TRIAL REGISTRATION Trial is registered with ClinicalTrials.gov, number NCT00421733.
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Characteristics of bone mineral metabolism in patients with stage 3-5 chronic kidney disease not on dialysis: results of the OSERCE study.
Górriz, JL, Molina, P, Bover, J, Barril, G, Martín-de Francisco, AL, Caravaca, F, Hervás, J, Piñera, C, Escudero, V, Molinero, LM, et al
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2013;(1):46-60
Abstract
OSERCE is a multi-centre and cross-sectional study with the aim of analysing the biochemical, clinical, and management characteristics of bone mineral metabolism alterations and the level of compliance with K/DOQI guideline recommendations in patients with chronic kidney disease (CKD) not on dialysis. The study included a total of 634 patients from 32 different Spanish nephrology units, all with CKD, estimated glomerular filtration rates <60 ml/min/1.73 m(2), and not on dialysis (K/DOQI stage: 33% stage 3, 46% stage 4, and 21% stage 5). In 409 of these patients, laboratory parameters were also measured in a centralised laboratory, including creatinine, calcium, phosphorous, intact parathyroid hormone (PTH), 25-OH-vitamin D, and 1,25-OH2-Vitamin D levels. The rates of non-compliance with the K/DOQI objectives for calcium, phosphorous, intact PTH, and calcium x phosphate product among these patients were 45%, 22%, 70%, and 4%, respectively. Of the 70% of patients with intact PTH levels outside of the target range established by the K/DOQI guidelines, 55.5% had values above the upper limit and 14.5% had values below the lower limit. Of the 45% of patients with calcium levels outside of the target range, 40% had values above the upper limit and 5% had values below the lower limit. Of the 22% of patients with phosphorous levels outside of the target range, 19% had values above the upper limit, and 3% had values below the lower limit. Finally, 4% of patients also had values for the calcium x phosphate product that were outside of the recommended range. Only 1.8% of patients complied with all four K/DOQI objectives. The values detected in centralised laboratory analyses were not significantly different from those measured in the laboratories at each institution. In addition, 81.5% of patients had a deficiency of calcidiol (25-OH-D3) (<30 ng/ml); of these, 35% had moderate-severe deficiency (<15 ng/ml) and 47% had mild deficiency (15-30 ng/ml). Calcitriol (1,25-OH2-D3) levels were deficient in 64.7% of patients. Whereas the calcidiol deficiency was not correlated with the CKD stage, calcitriol deficit were more pronounced at more advanced stages of CKD. The results of the OSERCE study confirm the difficulty in reaching the target values recommended by the K/DOQI guidelines in patients with CKD not on dialysis, in particular in the form of poor control of secondary hyperparathyroidism and vitamin D deficiency. With this in mind, we must review strategies for treating bone mineral metabolism alterations in these patients, and perhaps revise the target parameters set by current guidelines.
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Effects of raloxifene on lipid and bone metabolism in postmenopausal women with type 2 diabetes.
Mori, H, Okada, Y, Kishikawa, H, Inokuchi, N, Sugimoto, H, Tanaka, Y
Journal of bone and mineral metabolism. 2013;(1):89-95
Abstract
Evidence suggests that bone quality is poorer and fracture risk is higher in patients with diabetes, even those with normal bone mineral density. The aim of this study was to determine the effects of raloxifene on lipid, bone, and glucose metabolism in postmenopausal women with type 2 diabetes. The study subjects (144 postmenopausal women aged less than 80 years with type 2 diabetes) were randomly assigned into three groups: no medication, alfacalcidol 1 μg/day, or raloxifene hydrochloride 60 mg/day. The primary endpoint was the change in LDL-C at 6 months. Raloxifene significantly decreased the levels of bone metabolism markers NTX and BAP at 6 months in patients with diabetes. The primary endpoint, LDL-C at 6 months, was significantly lower in the raloxifene group than in the other two groups. However, percent changes in HDL-C were not significantly different among the three groups. Although glucose metabolism was unaffected, homocysteine, a bone quality marker, was significantly decreased at 6 months in the raloxifene group. The percent improvement in LDL-C did not correlate with percent improvement in any bone metabolism or bone quality markers. Raloxifene, unlike estrogen, improved LDL-C and decreased homocysteine, indicating that raloxifene can potentially improve LDL-C as well as bone quality in postmenopausal women with type 2 diabetes.