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Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

Durante el embarazo y la lactancia la mujer debe formar y mantener el esqueleto del feto y del neonato, lo que demanda importantes adaptaciones hormonales y metabólicas. La absorción intestinal de calcio aumenta desde el inicio del embarazo siendo máxima en los últimos trimestres. Se produce una hipercalciuria que desaparece al suspender la lactancia. El calcio de la leche proviene de la reducción en su excreción urinaria y de un aumento de la resorción ósea. Las concentraciones de 1,25 (OH)(2) D(3) se duplican desde el comienzo del embarazo manteniéndose elevadas hasta el parto, debido a un aumento de la actividad de la 1-alfa-hidroxilasa placentaria, normalizándose durante la lactancia. Los estrógenos, prolactina y lactógeno placentario, hormonas implicadas en el aumento de la absorción intestinal de calcio, aumentan conjuntamente. La parathormona (PTH) se mantiene en rango normal o bajo, por lo tanto sus acciones fisiológicas serían ejercidas por el péptido relacionado con la PTH (PTHrP), cuyos niveles aumentan tardíamente en el embarazo y permanecen elevados durante el parto y la lactancia. La calcitonina se eleva durante el embarazo, cae durante la lactancia, y se normaliza al finalizar la misma. El papel fisiológico del factor de necrosis tumoral, interleuquina 1, interleuquina 6 y osteoprotegerina todavía no han sido aclarados. Los cambios analizados favorecen, en casos excepcionales, el desarrollo de osteoporosis generalizada y regional. El objetivo de este trabajo es revisar la bibliografía publicada sobre la fisiopatología y clínica de estas entidades.During pregnancy and lactation women have to form and maintain fetus and newborn skeleton. These processes require maternal hormonal and metabolic adjustments. During the first weeks of pregnancy, calcium intestinal absorption rise and reach a maximum in the last trimester. Hypercalciuria can be detected until lactation is stopped. During lactation, calcium that is present in maternal milk, results from lowering maternal calcium excretion and increasing bone resorption. Plasma 1,25 (OH)(2) D(3) levels increase two-fold early in pregnancy due to high placental 1-a-hydroxilase activity, remain high until delivery and decline to normal values during lactation. Estrogen, prolactin and placental lactogen, which are involved in calcium absorption, increase at the same time. Normal or even low levels of parathyroid hormone (PTH) can be detected during pregnancy. This suggests that their physiological actions could be mimicked by the parathyroid- related-peptide (PTHrP), which increases in late stages of pregnancy and remain high during delivery and lactation. Calcitonin levels increase during pregnancy, decline during lactation and return to normal values after lactation is stopped. The physiological roll of tumor necrosis factor, interleukin 6 and osteoprotegerin has not been elucidated yet. The above mentioned changes can exceptionally lead to generalized or regional osteoporosis. The aim of this article is to review the published bibliography concerning the physiopathology of these diseases.

Tanto la osteoporosis generalizada como la regional son enfermedades que excepcionalmente se asocian con el embarazo. El objetivo de este trabajo es revisar nuestra experiencia en el diagnóstico y tratamiento de estas afecciones. Entre 1984 y 2004 consultaron seis puérperas por osteoporosis y dos por osteoporosis regional. En el primer grupo tres pacientes refirieron fracturas vertebrales y las restantes grave desmineralización detectada por densitometría ósea (DEXA). Los síntomas comenzaron en el tercer trimestre o en el posparto inmediato. Cinco eran primíparas mientras que una era multípara y había amamantado por un tiempo prolongado. Los factores de riesgo detectados fueron: baja ingesta láctea, delgadez, osteoporosis familiar, amenorreas, tabaquismo y corticoterapia. El laboratorio mostró recambio óseo acelerado. La DEXA documentó marcada desmineralización especialmente en esqueleto axial. En todas se interrumpió la lactancia y se indicaron drogas anti-resortivas en cuatro, estrógenos en una y sólo calcio y vitamina D en otra. Todas, menos una, evolucionaron favorablemente independientemente del tratamiento utilizado. Dos pacientes consultaron por dolor y limitación funcional progresiva durante el embarazo, en cadera izquierda y pie derecho respectivamente. La DEXA mostró desmineralización del lado afectado. El diagnóstico de osteoporosis regional se confirmó por resonancia magnética nuclear. Los informes de laboratorio indicaron aumento del turnover óseo. Ambas fueron tratadas exitosamente con reposo y bifosfonatos.Both generalized and regional osteoporosis exceptionally occur during pregnancy and lactation. The aim of this paper is to show our experience in the diagnosis and treatment of these diseases. From 1984 to 2004 six lactating women with osteoporosis and two with regional osteoporosis consulted us. In the former group, three patients had vertebral fractures and the others experienced substantial demineralization detected by dual-energy X-ray absorptiometry (DXA). In all cases, symptoms began during the third trimester of pregnancy or immediately after delivery. Five of them were primiparous and one was multiparous with a long period of lactation. Risk factors were: low calcium intake, low weight, family history of osteoporosis, amenorrhea, cigarette consumption and corticosteroid therapy. Laboratory tests evidenced increased bone turnover. DXA scan showed substantial demineralization, particularly in axial skeleton. Lactation was interrupted in all women and four received anti-resorptive drugs, one estrogen and only calcium plus vitamin D the remaining. All of them, but one, evolved successfully. The women affected by regional osteoporosis complained of unilateral pain and progressive functional limitation of right foot and left hip respectively. Reduced bone mineral density at symptomatic sites was seen by DXA. Diagnosis was confirmed by typical magnetic resonance imaging pattern. Both patients cured with rest and bisphosfonates treatment.

El objetivo de este trabajo es presentar el inusual caso clínico de una paciente de 34 años que consultó para establecer diagnóstico de certeza y conducta terapéutica ante una hipercalcemia asintomática, detectada en un examen bioquímico de rutina. La elevación de la calcemia en ausencia de inhibición de la secreción de parathormona orientó hacia una patología paratiroidea. La persistencia de la hipercalcemia concomitante con hipocalciuria y coincidente con una relación clearance de calcio/clearance de creatinina inferior a 0.01, hicieron sospechar el diagnóstico de hipercalcemia hipocalciúrica familiar. La falta de antecedentes familiares llevó a realizar un estudio molecular de la paciente y su grupo familiar. Los resultados de los estudios nos permitieron concluir que la paciente es portadora de una mutación de novo (inactivante) del gen del receptor sensor del calcio. Se incluyen los datos del estudio molecular y una breve revisión bibliográfica del tema.The aim of this paper is to refer the unusual case of a 34 years old woman who consulted because of asymptomatic hypercalcemia, detected in a biochemical routine examination. The elevated values of serum calcium without blunted parathyroid hormone secretion suggested a parathyroid pathology. The concomitance of hypocalciuria with hypercalcemia and a calcium clearance/creatinine clearance ratio less than 0.01 reverted the diagnosis of familial hypocalciuric hypercalcemia, the first option. The absence of familial background led to the molecular study of the patient and her family. The latter confirmed the diagnosis of a de novo inactivating mutation of the calcium sensing receptor. Details on the molecular study and a brief review of this subject are included.

During pregnancy and lactation women have to form and maintain fetus and newborn skeleton. These processes require maternal hormonal and metabolic adjustments. During the first weeks of pregnancy, calcium intestinal absorption rise and reach a maximum in the last trimester. Hypercalciuria can be detected until lactation is stopped. During lactation, calcium that is present in maternal milk, results from lowering maternal calcium excretion and increasing bone resorption. Plasma 1,25 (OH)(2) D(3) levels increase two-fold early in pregnancy due to high placental 1-alpha-hydroxilase activity, remain high until delivery and decline to normal values during lactation. Estrogen, prolactin and placental lactogen, which are involved in calcium absorption, increase at the same time. Normal or even low levels of parathyroid hormone (PTH) can be detected during pregnancy. This suggests that their physiological actions could be mimicked by the parathyroid- related-peptide (PTHrP), which increases in late stages of pregnancy and remain high during delivery and lactation. Calcitonin levels increase during pregnancy, decline during lactation and return to normal values after lactation is stopped. The physiological roll of tumor necrosis factor, interleukin 6 and osteoprotegerin has not been elucidated yet. The above mentioned changes can exceptionally lead to generalized or regional osteoporosis. The aim of this article is to review the published bibliography concerning the physiopathology of these diseases.

The aim of this paper is to refer the unusual case of a 34 years old woman who consulted because of asymptomatic hypercalcemia, detected in a biochemical routine examination. The elevated values of serum calcium without blunted parathyroid hormone secretion suggested a parathyroid pathology. The concomitance of hypocalciuria with hypercalcemia and a calcium clearance/creatinine clearance ratio less than 0.01 reverted the diagnosis of familial hypocalciuric hypercalcemia, the first option. The absence of familial background led to the molecular study of the patient and her family. The latter confirmed the diagnosis of a de novo inactivating mutation of the calcium sensing receptor. Details on the molecular study and a brief review of this subject are included.