Hyponatremia and fractures: should hyponatremia be further studied as a potential biochemical risk factor to be included in FRAX algorithms?

The Fracture Risk Assessment Tool (FRAX®) was developed by the WHO Collaborating Centre for metabolic bone diseases to evaluate fracture risk of patients. It is based on patient models that integrate the risk associated with clinical variables and bone mineral density (BMD) at the femoral neck. The clinical risk factors included in FRAX were chosen to include only well-established and independent variables related to skeletal fracture risk. The FRAX tool has acquired worldwide acceptance despite having several limitations. FRAX models have not included biochemical derangements in estimation of fracture risk due to the lack of validation in large prospective studies. Recently, there has been an increasing number of studies showing a relationship between hyponatremia and the occurrence of fractures. Hyponatremia is the most frequent electrolyte abnormality measured in the clinic, and serum sodium concentration is a very reproducible, affordable, and readily obtainable measurement. Thus, we think that hyponatremia should be further studied as a biochemical risk factor for skeletal fractures prediction, particularly those at the hip which carries the greatest morbidity and mortality. To achieve this will require the collection of large patient cohorts from diverse geographical locations that include a measure of serum sodium in addition to the other FRAX variables in large numbers, in both sexes, over a wide age range and with wide geographical representation. It would also require the inclusion of data on duration and severity of hyponatremia. Information will be required both on the risk of fracture associated with the occurrence and length of exposure to hyponatremia and to the relationship with the other risk variables included in FRAX and also the independent effect on the occurrence of death which is increased by hyponatremia.

Paratiroidectomía en pacientes renales crónicos en Argentina: estudios prequirúrgicos, tipos de cirugía, recurrencia y persistencia / Parathyroidectomy in chronic kidney disease patients in Argentina: pre surgical studies, types of surgery, recurrence and persistence

La paratiroidectomía (PTx) es el tratamiento de elección en pacientes con HPT 2º severo, refractario al tratamiento médico. Se cuenta con muy poca información en Argentina de este procedimiento, por lo cual se realizó este estudio. Material y Métodos: Se incluyeron 255 pacientes con PTx entre el año 2003 al 2007 de un registro voluntario. Se evaluaron los estudios de localización prequirúrgicos, de laboratorio de metabolismo fosfocálcico previo y posterior a la cirugía y el tipo de técnica quirúrgica utilizada. Se analizó la persistencia y recidiva del HPT postcirugía. Resultados: La tasa de PTx fue de 2,7/1000 pacientes año. 83% de los pacientes tuvieron ecografía de cuello y 59% Sesta Mibi con Tc 99. Hubo una correlación positiva (p<0.001) entre el número de glándulas detectadas por ecografía y Sesta Mibi. La paratiroidectomía realizada fue: subtotal en 77%, total con autoimplante en 14% y total sin autoimplante en 9%. Hubo descensos significativos de Ca y P, fosfatasa alcalina y PTH (1744 ± 788 pg/ml a 247 ±450 pg/ml; p<0.0001) postcirugía. A los 2,4 ±2,5 meses de la PTx, el 72% de los pacientes tenía PTH <250 pg/ml, 19,8% tenía persistencia y 8,3% había recidivado. De acuerdo al tipo de cirugía la persistencia y recidiva fueron para PTx subtotal 22% y 8,3%, PTx total con implante 11% y 11% y PTx total sin autoimplante 13% y 4% respectivamente. La realización de Sesta Mibi no influyó en los resultados de la PTx. No se observaron diferencias entre los centros en relación con persistencia y recidiva. Conclusiones: La tasa de PTx fue muy baja, la ecografía fue el método de localización prequirúrgico preferido y la PTX subtotal la técnica quirúrgica más utilizada. La PTx fue exitosa en la mayoría de los pacientes y la persistencia y recidiva no estuvieron relacionadas con la técnica.

Parathyroidectomy (PTx) is the selecte treatment for patients with severe secondary hyperparathyroidism, refractory to medical treatment. There is not enough information about this procedure in Argentina, that is the reason why we performed this study. Material and Methods: 255 patients with PTx were included from the year 2003 to 2007 on a voluntary register. Studies of pre-surgical localization, phosphocalcic metabolism laboratories before and after surgery were evaluated, and the type of surgical technique used. The persistence and recurrence of post-surgical hyperparathyroidism was analyzed. Results: The PTx rate was 2,7/1000 patients year. 83% of the patients had neck echography and 59% Sestamibi scans with Tc 99. There was a positive correlation (p<0,001) between the number of detected glands by echography and Sestamibi. The parathyroidectomy performed was: subtotal in 77%, total with self-implant in 14% and total without self-implant in 9%. There were significant falls of Ca and P, Alkaline Phosphatase and PTH (1744±788 pg/ml to 247±450 pg/ml; p<0.0001) post-surgical. 2.4 ±2,5 months after the PTx, 72% of patients had PTH <250 pg/ml, 19,8% had persistence and 8,3% had recurrence. According to the type of surgery, the persistence and recurrence were for subtotal PTx 22% and 8,3%, total PTx with implant 11% and 11%, and total PTx without selfimplant 13% and 4% respectively. The performance of the Sestamibi scan did not affect the PTx results. No noticeable differences were observed among the centers for persistence and recurrence. Conclusions: The PTx rate was very low, echography was the preferred method of pre-surgical localization, and subtotal PTx was the most used surgical technique. PTx was successful in most of the patients, and persistence and recurrence were not related to the technique.

Hipovitaminosis D en pacientes hemodiálizados (HD): factores relacionados e influencia sobre la fuerza muscular / Hypovitaminosis D in patients on hemodialysis (HD): related factors and influence on muscle strength

Introducción: La deficiencia de 25 (OH) vitamina D es una alteración prevalente en los pacientes con enfermedad renal crónica (ERC) , sin embargo en nuestro medio no es medida de manera rutinaria y por ende no suele hacerse reposición vitamínica. Nuestro objetivo fue determinar la prevalencia y los factores relacionados a deficiencia de 25 (OH) D en pacientes con ERC en hemodiálisis (HD), particularmente la relación con la función y masa muscular. Métodos: Efectuamos un estudio prospectivo, multicéntrico, en pacientes adultos en HD crónica que no estuvieran recibiendo ningún derivado de la vitamina D. Se midieron en sangre los niveles de 25(OH) D, Hemoglobina, PCR, Albúmina, Ca, P, FAL, PTHi. Se realizó la medición de la fuerza del puño con dinamómetro, y la prueba de sentado-parado. Se aplicó el índice de Karnofsky para clasificar el estado funcional., Se realizó una bioimpedanciometría (BCM; Frese nius Medical Care) en aquellos pacientes sin, contraindicación. Resultados: Se incluyeron 138 pacientes. La 25(OH) vitamina fue de 20.43 ± 10.5 ng/ml, la prevalencia de insuficiencia /defi ciencia 87% (37% con menos de 15 ng/ml). Las concentraciones de vitamina D/deficiencia mostraron correlación/relación significativa con la edad, la presencia de diabetes, los niveles de hemoglobina y albúmina, la fuerza y la masa muscular y la clase funcional (p<0.05) . Conclusión: Alta prevalencia de hipovitaminosis D en pacientes hemodializados particularmente gerontes y diabéticos. Esto estaría relacionado con la desnutrición, anemia, clase funcional y la fuerza/masa muscular de los pacientes, estos últimos dos factores no reportados hasta ahora. Todos estos factores deben ser considerados al momento de la sustitución vitamínica y en la evaluación de la efectividad de la misma.

Background: 25 (OH) vitamin D deficiency is a prevailing alteration in patients with chronic kidney disease (CKD); however, in our environment, it is not routinely measured and, therefore, vitamin replacement is unusual. Our purpose was assessing the prevalence of and the factors related to 25 (OH) vitamin D deficiency in patientswith CKD in hemodialysis (HD), especially the relation to function and muscle mass. Methods: We conducted a prospective, multicenter study in adult patients on chronic HD who were not receiving any vitamin D derivative. Blood levels of 25 (OH) D, Hemoglobin, CRP, Albumin, Ca,P, ALP and PTHi were measured. The handgrip strength was measured with a dynamometer and the sitting-rising test was carried out. A bioimpedance analysis (BCM; Fresenius Medical Care) was conducted in the patients who had no contraindications. Results: 138 patients were included. The levels of 25 (OH) vitamin D were 20.43±10.5 ng/ml; the insufficiency/deficiency had 87% prevalence (and 37% prevalence with less than 15 ng/ml). Vitamin D concentrations/ deficiency showed a significant correlation with/ relation to age, diabetes, hemoglobin and albumin levels, muscle strength and mass, and functional class (p<0.05). Conclusion: High prevalence of hypovitaminosis D in patients on hemodialysis, particularly in the elderly and in patients with diabetes. This should be related to undernutrition, anemia, the functional class and the muscle strength/mass of patients, the latter two being unreported factors until now. All these factors should be considered when vitamin replacement is conducted and when its effectiveness is assessed.

Hipovitaminosis D en pacientes hemodiálizados (HD): factores relacionados e influencia sobre la fuerza muscular / Hypovitaminosis D in patients on hemodialysis (HD): related factors and influence on muscle strength

Introducción: La deficiencia de 25 (OH) vitamina D es una alteración prevalente en los pacientes con enfermedad renal crónica (ERC) , sin embargo en nuestro medio no es medida de manera rutinaria y por ende no suele hacerse reposición vitamínica. Nuestro objetivo fue determinar la prevalencia y los factores relacionados a deficiencia de 25 (OH) D en pacientes con ERC en hemodiálisis (HD), particularmente la relación con la función y masa muscular. Métodos: Efectuamos un estudio prospectivo, multicéntrico, en pacientes adultos en HD crónica que no estuvieran recibiendo ningún derivado de la vitamina D. Se midieron en sangre los niveles de 25(OH) D, Hemoglobina, PCR, Albúmina, Ca, P, FAL, PTHi. Se realizó la medición de la fuerza del puño con dinamómetro, y la prueba de sentado-parado. Se aplicó el índice de Karnofsky para clasificar el estado funcional., Se realizó una bioimpedanciometría (BCM; Frese nius Medical Care) en aquellos pacientes sin, contraindicación. Resultados: Se incluyeron 138 pacientes. La 25(OH) vitamina fue de 20.43 ± 10.5 ng/ml, la prevalencia de insuficiencia /defi ciencia 87% (37% con menos de 15 ng/ml). Las concentraciones de vitamina D/deficiencia mostraron correlación/relación significativa con la edad, la presencia de diabetes, los niveles de hemoglobina y albúmina, la fuerza y la masa muscular y la clase funcional (p<0.05) . Conclusión: Alta prevalencia de hipovitaminosis D en pacientes hemodializados particularmente gerontes y diabéticos. Esto estaría relacionado con la desnutrición, anemia, clase funcional y la fuerza/masa muscular de los pacientes, estos últimos dos factores no reportados hasta ahora. Todos estos factores deben ser considerados al momento de la sustitución vitamínica y en la evaluación de la efectividad de la misma.(AU)

Background: 25 (OH) vitamin D deficiency is a prevailing alteration in patients with chronic kidney disease (CKD); however, in our environment, it is not routinely measured and, therefore, vitamin replacement is unusual. Our purpose was assessing the prevalence of and the factors related to 25 (OH) vitamin D deficiency in patientswith CKD in hemodialysis (HD), especially the relation to function and muscle mass. Methods: We conducted a prospective, multicenter study in adult patients on chronic HD who were not receiving any vitamin D derivative. Blood levels of 25 (OH) D, Hemoglobin, CRP, Albumin, Ca,P, ALP and PTHi were measured. The handgrip strength was measured with a dynamometer and the sitting-rising test was carried out. A bioimpedance analysis (BCM; Fresenius Medical Care) was conducted in the patients who had no contraindications. Results: 138 patients were included. The levels of 25 (OH) vitamin D were 20.43±10.5 ng/ml; the insufficiency/deficiency had 87% prevalence (and 37% prevalence with less than 15 ng/ml). Vitamin D concentrations/ deficiency showed a significant correlation with/ relation to age, diabetes, hemoglobin and albumin levels, muscle strength and mass, and functional class (p<0.05). Conclusion: High prevalence of hypovitaminosis D in patients on hemodialysis, particularly in the elderly and in patients with diabetes. This should be related to undernutrition, anemia, the functional class and the muscle strength/mass of patients, the latter two being unreported factors until now. All these factors should be considered when vitamin replacement is conducted and when its effectiveness is assessed.(AU)

Evaluation of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hemodialysis patients.

UNLABELLED: Hemodialyzed patients have decreased bone strength not completely characterized. We evaluated bone microarchitecture in hemodialysis patients and compared it to that of subjects without renal disease by high-resolution peripheral quantitative computed tomography (HR-pQCT). Hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women. INTRODUCTION: Although fracture risk is greatly increased in dialysis patients, the corresponding decreased in bone strength has not been completely characterized. METHODS: We evaluated volumetric bone mineral density (vBMD) and bone microstructure by HR-pQCT at the distal radius and tibia in 50 hemodialyzed (HD) patients (30 females, mean age 53.2 ± 6 years and 20 males, mean age 59.1 ± 11 years) and 50 sex- and age-matched controls. RESULTS: At the distal radius HD, women showed a 29% reduction in total and trabecular density and trabecular bone volume fraction (p < 0.0001) compared to controls. Trabecular number was reduced by 25% (p < 0.0001), while trabecular separation was increased by 51%. Cortical thickness (-40%, p < 0.0001) and cortical area (-42%, p < 0.0001) were the parameters most reduced, while compact density was the parameter least reduced (-15%, p < 0.0001). Similar findings were found at the tibia. In HD men, HR-pQCT at the distal radius and tibia showed a reduction in volumetric density and microstructure parameters to a lesser extent than in women. In the hemodialyzed group, cortical thickness at the radius was negatively correlated with age both in women and men. At the distal radius and tibia, we found significant negative correlations between Log iPTH and total alkaline phosphatase with cortical vBMD(r = -0.48, p < 0.01; r = -0.69, p < 0.001), thickness (-0.37, p < 0.05; r = -0.60, p < 0.001), and area ((r = -0.43, p = 0.02; r = -0.65, p < 0.001) but only in women. CONCLUSION: We conclude that hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women.

Regulacin de la mineralizacin sea por factores inorgnicos y peptdicos / Regulation of Bone Mineralization by inorganic and peptide factors

La mineralizacin ortotpica comienza con la produccin de las vesculas de matriz, por brotacin polarizada de la superficie de condrocitos, osteoblastos y odontoblastos. Esta transcurre en dos etapas. La primera es la formacin de cristales de hidroxiapatita dentro de las vesculas de matriz, seguido por la propagacin de la hidroxiapatita a travs de la membrana de la vescula dentro de la matriz extracelular. En la regulacin de la mineralizacin ortotpica, aparte de las clulas tejido especficas, intervienen un gran nmero de enzimas, factores inorgnicos y peptdicos, que tienen complejas interacciones. Para que la mineralizacin normal contine se necesita un ajustado balance entre los niveles de fosfato inorgnico (Pi) y de pirofosfato inorgnico (PPi) extracelular. El PPi antagoniza la habilidad del Pi para cristalizar con el calcio y formar hidroxiapatita y por lo tanto suprime su propagacin. Se han identificado tres molculas reguladoras centrales de los niveles extracelulares de PPi: la fosfatasa alcalina tejido-no especfica (TNAP), que hidroliza el PPi, la nucletido pirofosfato fosfodiesterasa 1 (NPP1), que genera PPi de nuclesidos trifosfato y la protena transmembrana de mltiples-pasos ANK, que media la transferencia intracelular al extracelular de PPi. A su vez existen dos protenas SIBLING llamadas DMP1 y MEPE reguladoras de la mineralizacin. La expresin de DMP1 por el osteocito se induce en forma marcada en respuesta a la carga mecnica incrementando la mineralizacin sea. La protena MEPE contiene un motivo peptdico proteasa resistente llamado ASARM, que se cree es un candidato a ser un inhibidor de la mineralizacin (minhibina). La osteropontina es otro inhibidor de la mineralizacin en su forma fosforilada y su secrecin est marcadamente reducida en los ratones "knockout" para NPP1. Los datos actuales parecen sostener la hiptesis que estas molculas podran ser las transductoras del "strain" seo y participar en la regulacin de la mineralizacin del espacio osteoctico perilacunar.

Orthotopic mineralization begins with the production of matrix vesicles that are produced by polarized budding of the surface of condrocytes, osteoblasts and odontoblasts. It occurs in two steps: The first one is the formation of hydroxiapatite crystals within the matrix vesicles, followed by the propagation of the hydroxiapatite crystals through the membrane vesicle into the extra cellular matrix. In the regulation of orthotopic mineralization, apart from tissue-specific cells, a great number of enzymes, inorganic and peptide factors participate, that have complex interactions among them. Inorganic pyrophosphate (PPi) antagonizes the ability of phosphate (Pi) to crystallize with calcium and to form hydroxiapatite, thus suppressing its propagation. For the normal mineralization to continue, an adjusted balance of the extra cellular Pi and PPi levels is needed. Three molecules have been identified that have a central role in the regulation of extra cellular PPi levels: tissue non-specific alkaline phosphatase (TNAP), which hydrolyzes PPi, the nucleotide pyrophosphatase phosphodiesterase 1 (NPP1), which generates PPi from triphosphate nucleosides, and the multiple-steps transmembrane protein ANK which transfers PPi from the intracellular to the extracellular compartment. There are, in turn, two SIBLING proteins called DMP1 and MEPE that regulate mineralization. The expression of DMP1 by the osteocyte is dramatically induced in response to mechanical loading increasing bone mineralization. MEPE protein contains a protease resistant motif called ASARM, which is believed to be the candidate for the mineralization inhibitor (minhibin). Osteopontin is another mineralization inhibitor in its phosphorilated form and its secretion is markedly reduced in knockout mice for NPP1. Present data seem to support the hypothesis that these molecules could be the translators of bone strain and participate in the regulation of mineralization of the perilacunar osteocytic space.

El eje hueso-riñón en el control del fósforo sérico y la mineralización ósea / Bone-Kidney axis in the control of serum phosphorus and bone mineralization

El eje hueso-riñón ha sido pensado como un mecanismo por el cual el esqueleto se comunica con el riñón para coordinar la mineralización de la matriz extracelular ósea con el manejo renal del fosfato. Osteoblastos /osteocitos están bien preparados para coordinar las homeostasis sistémica de fósforo y la mineralización ósea, ya que ellos expresan todos los componentes implicados en un posible eje hueso-riñón, incluyendo al PHEX, FGF-23, MEPE, y DMP1. Los efectos autocrinos de proteínas de la familia SIBLING como MEPE y DMP1 sobre los osteoblastos podrían regular la producción de proteínas de matriz extracelular que intervienen en la mineralización. El riñón provee uno de los efectores de este eje que regula el balance de fosfato a través de la expresión apical de los cotransportadores sodio/fosfato NaPi-IIa y NaPi-IIc en el túbulo proximal. Central en este eje es el FGF-23, producido por los osteoblastos que tiene acciones fosfatúricas sobre el riñón. Cuando se descubrió que el FGF23, la primera fosfatonina era de origen osteoblástico/osteocitico, quedó establecido el eje hueso-riñón. Probar definitivamente la existencia de este eje hueso-riñón y definir exactamente su rol fisiológico requerirá de investigaciones adicionales

The bone-kidney axis has been thought as a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracelular matrix with the renal handling of phosphate. Osteoblasts / osteocytes are well suited for coordinating systemic phosphate homeostasis and mineralization, since they express all of the implicated components of a possible bone-kidney axis, including PHEX, FGF-23, MEPE, and DMP1. In addition, autocrine effects of SIBLING proteins as MEPE and DMP1 on osteoblasts could regulate the production of ECM proteins that regulate mineralization. The kidney provides one of the effectors of the axis that regulates phosphate balance through the apical expression of NaPi-IIa and NaPi-IIc in proximal tubules. Central in this axis is FGF-23, produced by osteoblasts that has phosphaturic actions on the kidney. When FGF23, the first phosphatonin, was discovered to be of osteoblastic/osteocyte origin, the bone kidney axis was established. Proving the existence of this bone-kidney axis and defining its physiological role will require additional investigations

[Relationship between renal function and bone mineral density in postmenopausal women that undergo bone mass evaluation]. / Relación entre función renal y densidad mineral ósea en mujeres posmenopáusicas que realizan evaluación de masa ósea.

As osteoporosis and renal insufficiency are two prevalent pathologies in the aging population we decided to evaluate retrospectively the renal function (estimated by formula) in postmenopausal women who came to our Institute for bone mass determination to establish the relationship between them. Thus, we studied 300 postmenopausal women with a mean age of 66.9 +/- 6.8 years who had a bone densitometry performed; we chose total femur bone mineral density (TFBMD) for defining osteopenia and osteoporosis as this measurement included substantial amounts of both trabecular and cortical bone; osteopenia/osteoporosis was diagnosed using T score criteria recommended by the WHO. We also measured BMD at the femoral neck. Renal function was estimated by the Cockcroft-Gault formula using serum creatinine determination. We found osteoporosis in 61 patients (20.3%). Of them, el 81.9% have renal insufficiency (estimated creatinine clearance-ECrC < or = 60 ml/min), compared to 54% of 239 women who had normal BMD/osteopenia (p < 0.001). Six of 61 (9.8%) women with osteoporosis had severe renal insufficiency (ECrC < or = 36 ml/min) versus 4/239 (1.6%) women with normal BMD/osteopenia (p = 0.001). Women with osteoporosis were older, and had a significantly lower weight and ECrC compared to patients without osteoporosis (ECrC 52 +/- 11 ml/min vs 59 +/- 12 ml/min; p < 0.0001). We found a significant positive correlation between TFBMD and ECrC (r = 0.389) as well as with weight (r = 0.422) and a negative correlation between age and ECrCE (r = -0.51) and with TFBMD (r = -0.22). In the multiple regression analysis only weight continued to correlate significantly with TFBMD (Beta = 0.344). When FNBMD was considered as the dependent variable, we found a significantly negative correlation with age (r = -0.30) and significantly positive correlations with height (r = 0. 16), weight (r = 0.33) and ECcr (r = 0.39). In the multiple regression analysis only age (Beta = -0.20) and weight (Beta = 0.20) continued having an independent correlation FNBMD. We conclude that our data confirm that there exists a substantial prevalence of renal insufficiency, even severe, among patients with densitometric osteoporosis that should be kept in mind when one is considering the prescription of medications as bisphosphonates that have renal clearance, so as not to jeopardize the efficacy and the security of these drugs.

[Relationship between weight, body composition and bone mass in peritoneal dialysis]. / Relación entre peso, composición corporal y masa osea en diálisis peritoneal.

Patients in chronic dialysis show a decrease in total bone mass. The factors that determine this decrease are not well known. In normal populations weight and its compartments are important determinants of bone mass. We studied total bone mineral content (TBMC), a measure of bone mass, and body composition using DEXA densitometry in 65 patients (45 females and 20 males) who had been in peritoneal dialysis for a mean of 40.3 +/- 23.2 months. Forty-eight patients (73.8%) had been previously in hemodialysis. The mean total time in dialysis for these patients was 76.8 months. As a group patients showed a very significant positive correlation between TBMC and weight, height, and lean body mass. A negative correlation was found between TBMC with the time in dialysis and iPTH. In men we found significant simple positive correlations between TBMC and weight, height and lean body mass. In women we found simple positive correlations of TBMC with weight, height and lean body mass and a negative correlation with iPTH. In the multiple regression analysis, lean body mass was the only body composition parameter that had a significantly positive correlation with TBMC in men; in women only height correlated positively with TBMC and iPTH continued to correlate negatively with bone mass. When we considered pre and postmenopausal women separately, bone mass was correlated positively with height and lean body mass and negatively with iPTH in postmenopausal women and only with height in pre-menopausal females. We conclude that the lean body mass compartment. is the most important component of weight that determines TBMC in peritoneal dialysis patients particularly in males and postmenopausal women. In postmenopausal women, secondary hyperparathyroidism seems to be particularly detrimental on bone mass.

Evaluation of cortical bone by peripheral quantitative computed tomography in renal transplant recipients.

BACKGROUND: The absolute risk of fractures in renal transplant patients is 3 times that of matched controls. Most of the symptomatic fractures are peripheral, suggesting a greater compromise of cortical bone. Peripheral quantitative computed tomography (pQCT) is a new imaging technique that allows separate noninvasive evaluations of cortical and trabecular bones. We investigated cortical bone by pQCT in 12 renal transplant patients (seven men and five women) for comparison with 27 normal controls. METHODS: pQCT (XCT 960, Stratec, Pforheim, Germany) was performed upon the distal radius of the nondominant forearm (15% the length of the ulna, proximal from the radius end plate). We evaluated total and cortical bone mineral density (TBMD, cBMD), total (cross-sectional) and cortical area (TA, cA), cortical thickness (cThk), endosteal and periosteal circumferences, and the buckling ratio (r/cThK). RESULTS: Compared with normal controls transplant patients as a whole showed a significant increase in TA, in endosteal circumference (P < .001), and in the buckling ratio (P < .001) with a significant reduction in cThK (P < .001). Female patients had a marked decrease in cA (51.4 vs 69.3 [pixel n]; P < .0001) and cThK (2.08 vs 2.78 mm; P < .0001). Male patients also had a decrease in cThK (2.54 vs 3.30 mm; P = .0001) and an increase in endosteal perimeter (31.2 vs 26.4 mm; P < .0001). Total time on dialysis prior to renal graft correlated negatively with cortical thickness (r = .62; P < .01). CONCLUSIONS: Our results suggest that a marked thinning of cortical bone may explain the increased incidence of peripheral fractures among renal transplant patients.

Biomechanical background for a noninvasive assessment of bone strength and muscle-bone interactions.

New concepts and methods of study in bone biomechanics defy the prevailing idea that bone strength is determined by a systemically-controlled "mineralized mass" which grows until reaching a peak and then is lost at individually-specific rates. In case of bones, "mass" represents actually the substratum of a structure, the stiffness of which does not depend on the mass, but on the intrinsic stiffness and the spatial distribution of the mineralized material. A feed-back system called "bone mechanostat" seems to orient the osteoblastic and osteoclastic processes of bone, modeling and remodeling, according to the sensing by osteocytes of strains caused in the structure by mechanical usage of the skeleton, in specific directions as determined principally by the customary contractions of regional muscles and impact forces. The endocrine-metabolic systems, crucial for the normal skeletal development, modulate the work of osteocytes, blasts and clasts in a systemic way (i.e., not related to a specific direction of the stimuli). Therefore, they tend actually to interact with, rather than contribute to, the biomechanical control of bone structure. Furthermore, no feed-back loop enabling a cybernetic relationship of those systems with bone is known. Instead of passively letting hormones regulate their "mass" in order to optimize their strength, bones would actively self-regulate their architecture following an anisotropic pattern in order to optimize their stiffness (the only known variable to be ever controlled in the skeleton) and strength "despite of" the endocrine systems. Three practical questions derive from those ideas: 1. Osteoporoses are not "intense osteopenias" but "osteopenic fragilities". 2. The diagnosis of osteopenia could be solved densitometrically; but that of bone fragility is a biomechanical problem which requires auxiliary resources for evaluating the stiffness and the spatial distribution of the mineralized material. 3. Osteopenias and osteoporoses should be on time evaluated as related to the mass or strength of the regional muscles, respectively, in order to differentiate between the "primary" (intrinsic lesion of the mechanostat) or "secondary" (systemic) etiologies and the biomechanical origin (disuse) in each case, with important therapeutic implications.

Distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómico dominante por mutación del factor de crecimiento fibroblástico 23 en una familia / Different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation in one family

In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR) in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient No 1: a 60 year old female who consulted for bone pain: Bone densitometry showed osteoporosis. Laboratory assays showed hypophosphatemia with low renal phosphate threshold, high total alkaline phosphatase, normal intact PTH and normal serum calcium. With neutral phosphate and calcitriol, the biochemical parameters normalized and bone densitometry improved significantly in less than a year. Patient No 2 her grand daughter consulted at 1 year and 8 months of age for growth retardation (height at percentile 3) and genu varum. Laboratory assays showed low serum phosphate and high total alkaline phosphatase; thickening and irregular epiphyseal borders of the wrists were observed radiologically. She began treatment with calcitriol and phosphorus with normalization of laboratory parameters and increase in growth (height increasing to percentile 50 after 20 months of therapy). Patient No 3: mother of patient No 2, she had no clinical manifestations and normal densitometry but presented low serum phosphate (1.9 mg/dl) that normalized with neutral phosphate therapy. Patient No 4: he was the youngest son of Patient No 1, who had had hypophosphatemic rickets, by age 5; his serum phosphate normalized without treatment At age 29, he presented normal serum phosphate and bone densitometry. Genomic DNA analysis performed in patient No 3, showed missense mutation with substitution of arginine at position 179 for glutamine. The family was catalogued as having autosomal dominant hypophosphatemic rickets/osteomalacia.

Describimos distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómicodominante en 4 miembros de una misma familia y su respuesta al tratamiento. Paciente N° 1: de sexofemenino de 60 años que consultó por dolores costales y pélvicos, con osteoporosis densitométrica, hipofosfatemia con bajo umbral renal de fósforo, PTH intacta normal y calcemia normal. Tratada con fósforo neutro y calcitriol logró la normalización bioquímica y una notable mejoría de la densitometría en menos de un año. Paciente N° 2: su nieta, consultó al año y ocho meses de edad por presentar talla en percentil 3 y genu varum. En el laboratorio mostró hipofosfatemia y fosfatasa alcalina total muy elevada y en la Rx de mano, ensanchamiento y deflecamiento epifisario compatible con raquitismo. Tratada con fósforo neutro y calcitriol, normalizó los parámetros bioquímicos y logró un ascenso en el percentil de talla de 3 a 50 a los 20 meses de tratamiento. Paciente N° 3: la madre de la paciente N° 2, quien sin ninguna manifestación clínica y con densitometría ósea normal presentó hipofosfatemia que se normalizócon tratamiento con fosfato neutro. Paciente N° 4: el tío de la paciente N° 2, tuvo raquitismo hipofosfatémico de niño,y luego de los 5 años normalizó el fósforo sin tratamiento. Estudiado a los 29 años presentó fósforo normal y densitometría ósea normal. El análisis del ADN genómico de la paciente N° 3 mostró una mutación con sentido erróneo en el gen del factor de crecimiento fifroblástico 23 (sustitución de arginina por una glutamina en posición 179). Por lo tanto se llegó al diagnóstico de raquitismo/osteomalacia hipofosfatémico autosómico dominante.

Distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómico dominante por mutación del factor de crecimiento fibroblástico 23 en una familia / Different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation in one family

In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR) in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient No 1: a 60 year old female who consulted for bone pain: Bone densitometry showed osteoporosis. Laboratory assays showed hypophosphatemia with low renal phosphate threshold, high total alkaline phosphatase, normal intact PTH and normal serum calcium. With neutral phosphate and calcitriol, the biochemical parameters normalized and bone densitometry improved significantly in less than a year. Patient No 2 her grand daughter consulted at 1 year and 8 months of age for growth retardation (height at percentile 3) and genu varum. Laboratory assays showed low serum phosphate and high total alkaline phosphatase; thickening and irregular epiphyseal borders of the wrists were observed radiologically. She began treatment with calcitriol and phosphorus with normalization of laboratory parameters and increase in growth (height increasing to percentile 50 after 20 months of therapy). Patient No 3: mother of patient No 2, she had no clinical manifestations and normal densitometry but presented low serum phosphate (1.9 mg/dl) that normalized with neutral phosphate therapy. Patient No 4: he was the youngest son of Patient No 1, who had had hypophosphatemic rickets, by age 5; his serum phosphate normalized without treatment At age 29, he presented normal serum phosphate and bone densitometry. Genomic DNA analysis performed in patient No 3, showed missense mutation with substitution of arginine at position 179 for glutamine. The family was catalogued as having autosomal dominant hypophosphatemic rickets/osteomalacia.(AU)

Describimos distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómicodominante en 4 miembros de una misma familia y su respuesta al tratamiento. Paciente Nº 1: de sexofemenino de 60 años que consultó por dolores costales y pélvicos, con osteoporosis densitométrica, hipofosfatemia con bajo umbral renal de fósforo, PTH intacta normal y calcemia normal. Tratada con fósforo neutro y calcitriol logró la normalización bioquímica y una notable mejoría de la densitometría en menos de un año. Paciente Nº 2: su nieta, consultó al año y ocho meses de edad por presentar talla en percentil 3 y genu varum. En el laboratorio mostró hipofosfatemia y fosfatasa alcalina total muy elevada y en la Rx de mano, ensanchamiento y deflecamiento epifisario compatible con raquitismo. Tratada con fósforo neutro y calcitriol, normalizó los parámetros bioquímicos y logró un ascenso en el percentil de talla de 3 a 50 a los 20 meses de tratamiento. Paciente Nº 3: la madre de la paciente Nº 2, quien sin ninguna manifestación clínica y con densitometría ósea normal presentó hipofosfatemia que se normalizócon tratamiento con fosfato neutro. Paciente Nº 4: el tío de la paciente Nº 2, tuvo raquitismo hipofosfatémico de niño,y luego de los 5 años normalizó el fósforo sin tratamiento. Estudiado a los 29 años presentó fósforo normal y densitometría ósea normal. El análisis del ADN genómico de la paciente Nº 3 mostró una mutación con sentido erróneo en el gen del factor de crecimiento fifroblástico 23 (sustitución de arginina por una glutamina en posición 179). Por lo tanto se llegó al diagnóstico de raquitismo/osteomalacia hipofosfatémico autosómico dominante.(AU)

[Whole PTH and 1-84/84 PTH ratio for the non invasive determination of low bone turnover in renal osteodysthrophy]. / Utilidad de la determinación de PTH entera y del cociente PTH 1-84/7-84 en el diagnóstico no invasivo de osteodistrofia de bajo recambio.

The conventional intact PTH assays detect not only PTH 1-84 but also inactive fragments (as PTH 7-84) that accumulate in renal failure. There has been a recent development of a new PTH assay that measures only true 1-84 PTH (Whole PTH or CAP assay, Scantibodies). As 7-84 PTH fragment is antagonistic on bone effects of 1-84 PTH, Moniere-Faugere has suggested that 1-84/7-84 PTH ratio less than 1 is predictive of low turnover. We evaluated the usefulness of CAP assay and the 1-84/7-84 PTH ratio as markers of bone turnover in a groups of 24 patients in peritoneal dialysis (PD). Patients were classified as having low bone turn over if they had a Total PTH (similar to intact PTH) of less than 100 pg/ml. We also measured serum CrossLaps (CTX) as another serum resorption marker. Patients had a mean Whole PTH of 95.5 pg/ml and a mesan total PTH of 155.4 pg/l (range 9 to 900). Whole PTH represented 69.1% of total PTH. Fifteen patients (62.5%) had a total PTH of less than 100. These patients had a 1-84/7-84 relationship of 1.9 +/- 1.8 while 9 patients with Total PTH more than 100 had a relationship of 1.29 +/- 0.6 (p = NS). There was a tight correlation between Whole PTH and total PTH (r = 0.98; p < 0.0001) and with serum CTX (r = 0.78; p < 0.0001). We conclude that 1-84/7-84 ratio does not seem useful in the prediction of low bone turnover and that Whole PTH does not seem to be more useful than intact PTH in the prediction of bone turnover in this population. Future studies should correlate this markers with direct measurements of bone turnover in bone biopsies to demonstrate their usefulness in the prediction of the type of renal osteodystrophy.