Genetic Contribution of Femoral Neck Bone Geometry to the Risk of Developing Osteoporosis: A Family-Based Study.

Femoral neck geometry parameters are believed to be as good as bone mineral density as independent factors in predicting hip fracture risk. This study was conducted to analyze the roles of genetic and environmental factors in femoral properties measured in a sample of Spanish families with osteoporotic fractures and extended genealogy. The "Genetic Analysis of Osteoporosis (GAO) Project" involved 11 extended families with a total number of 376 individuals. We studied three categorical phenotypes of particular clinical interest and we used a Hip structural analysis based on DXA to analyze 17 strength and geometrical phenotypes of the hip. All the femoral properties had highly significant heritability, ranging from 0.252 to 0.586. The most significant correlations were observed at the genetic level (ρG). Osteoporotic fracture status (Affected 2) and, particularly, low bone mass and osteoporotic condition (Affected 3) had the highest number of significant genetic correlations with diverse femoral properties. In conclusion, our findings suggest that a relatively simple and easy to use method based on DXA studies can provide useful data on properties of the Hip in clinical practice. Furthermore, our results provide a strong motivation for further studies in order to improve the understanding of the pathophysiological mechanism underlying bone architecture and the genetics of osteoporosis.

Heritability of bone mineral density in a multivariate family-based study.

There is evidence for a genetic contribution to bone mineral density (BMD×). Different loci affecting BMD have been identified by diverse linkage and genome-wide association studies. We studied the heritability of and the correlations among six densitometric phenotypes and four bone mass/fracture phenotypes. For this purpose, we used a family-based study of the genetics of osteoporosis, the Genetic Analysis of Osteoporosis Project. The primary aim of our study was to examine the roles of genetic and environmental factors in determining osteoporosis-related phenotypes. The project consisted of 11 extended families from Spain. All of them were selected through a proband with osteoporosis. BMD was measured using dual-energy X-ray absorptiometry. The proportion of variance of BMD attributable to significant covariates ranged from 25% (for femoral neck BMD) to 48% (for whole-body total BMD). The vast majority of the densitometric phenotypes had highly significant heritability, ranging from 0.252 (whole-body total BMD) to 0.537 (trochanteric BMD) after correcting for covariate effects. All of the densitometric phenotypes showed high and significant genetic correlations (from -0.772 to -1.000) with a low bone mass/osteopenia condition (Affected 3). Our findings provide additional evidence on the heritability of BMD and a strong genetic correlation between BMD and bone mass/fracture phenotypes in a Spanish population. Our results emphasize the importance of detecting genetic risk factors and the benefit of early diagnosis and especially therapeutic and preventive strategies.

Development of a new tool for assessing health-related quality of life in patients with primary hyperparathyroidism.

BACKGROUND: Several studies in recent years have evaluated Health Related Quality of Life (HRQoL) of patients with primary hyperparathyroidism (PHPT). No disease specific questionnaires are available to assess the impact of the disease. The aim of this research is to describe the development of a new disease specific Quality of Life (QoL) questionnaire for use specifically with PHPT patients. METHODS: A conceptual model was developed describing the impact of the disease and its symptoms on QoL domains. A literature review was conducted to identify the most relevant domains. A focus group with experts was used to validate the domains; 24 patients were also interviewed to complement the information from the patient's perspective. A content analysis of the interviews was performed to identify items related with the impact of the disease, leading to PHPQoL-V.1 which was presented to a sample of 67 patients. Reliability was assessed by Cronbach's coefficient alpha and item-total score correlations. Validity was assessed by a factor analysis performed to determine the number of domains. Rasch analysis was carried out in order to refine the questionnaire items. RESULTS: 259 items were extracted from the interviews that were subsequently reduced to 34 items. Cronbach's coefficient alpha was 0.92. The factor analysis extracted two domains (physical and emotional). After Rasch analysis the questionnaire PHPQoL-V.2 kept 16 items (9 physical and 7 emotional). The questionnaire was developed in a Spanish population and the final version was translated to English through translation and back-translation. CONCLUSION: The first disease specific HRQoL questionnaire for PHPT patients (PHPQoL-16) has been developed. Validation studies designed to assess measurement properties of this tool are currently underway.

Fat tissue measurements by dual-energy x-ray absorptiometry: cross-calibration of 3 different fan-beam instruments.

Analysis of total tissue composition and, particularly, body fat measurements has become progressively important in the diagnosis and follow-up of patients with different clinical conditions. Dual-energy X-ray absorptiometry (DXA) fan-beam scanners are widely used to measure body composition, but the development of translational equations to be able to compare data of different scanning systems is necessary. The aim of this study was to assess the extent of agreement for regional measurements of body composition among the following 3 fan-beam DXA scanners: (1) Hologic Discovery (Hologic, Inc., Waltham, MA), (2) Lunar iDXA (GE Healthcare, Madison, WI), and (3) Lunar Prodigy Advance (GE Healthcare, Madison, WI). The study population consisted of 91 adult healthy volunteers (40 males and 51 females; mean age 48.5±14.4yr) who underwent DXA evaluation of the lumbar spine, hip, and whole body in each machine on the same day. Agreement among the 3 scanners was evaluated according to the Bland-Altman method and Lin's concordance correlation coefficient. Results showed a better agreement and concordance for the Lunar iDXA scanner than for any of them with the Hologic scanner. Differences were higher for any tissue or region than for the whole tissue mass. Translational equations were developed to ensure comparability of body composition measurements obtained with each of these 3 scanners.

Risk factors for prediction of inadequate response to antiresorptives.

Some patients sustain fractures while on antiresorptives. Whether this represents an inadequate response (IR) to treatment or a chance event has not been elucidated. We performed a study to identify which patients are more likely to fracture while on treatment. This is a multicentric, cross-sectional study of postmenopausal women on antiresorptives for osteoporosis in 12 Spanish hospitals, classified as adequate responders (ARs) if on treatment with antiresorptives for 5 years with no incident fractures or inadequate responders (IRs) if an incident fracture occurred between 1 and 5 years on treatment. Poor compliance, secondary osteoporosis, and previous anti-osteoporosis treatment other than the assessed were exclusion criteria. Clinical, demographic, analytical, dual-energy X-ray absorptiometry (DXA) variables, and proximal femur structure analysis (ImaTx™) and structural/fractal analyses of distal radius were performed. A total of 179 women (76 IRs; mean (SD): age 68.2 (9.0) years; 103 ARs, age 68.5 (7.9) years) were included. History of prior fracture (p = 0.005), two or more falls in the previous year (p = 0.032), low lumbar spine bone mineral density (BMD) (p = 0.02), 25 hydroxyvitamin D (p = 0.017), and hip ImaTx fracture load index (p = 0.004) were associated with IR. In the logistic regression models a fracture before treatment (odds ratio [OR], 3.60; 95% confidence interval [CI], 1.47-8.82; p = 0.005) and levels of 25 hydroxyvitamin D below 20 ng/mL (OR, 3.89; 95% CI, 1.55-9.77; p = 0.004) significantly increased risk for IR, while increased ImaTx fracture load (OR, 0.96; 95% CI, 0.93-0.99; p = 0.006; per every 100 units) was protective, although the latter became not significant when all three variables were fitted into the model. Therefore, we can infer that severity of the disease, with microarchitectural and structure deterioration, as shown by previous fracture and hip analysis, and low levels of 25 hydroxy vitamin D carry higher risk of inadequate response to antiresorptives. More potent regimes should be developed and adequate supplementation implemented to solve this problem.

Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib.

BACKGROUND: In a multicenter clinical trial in North America and Europe that tested the cathepsin K (catK) inhibitor balicatib for the treatment of osteoporosis, several patients developed hardening of the skin. OBJECTIVE: We sought to characterize these observed adverse events. METHODS: Patients with skin hardening were examined by a local dermatologist. All of those patients except one had at least one biopsy specimen taken from affected skin, which was read by local and two central dermatopathologists. Workup was directed for consideration of systemic scleroderma. RESULTS: Nine patients of 709 treated with balicatib developed skin hardening and were given a diagnosis of morphea-like skin changes. No such events were observed in patients taking placebo or the lowest balicatib dose. After discontinuation of balicatib, skin changes resolved completely in 8 and partially in one patient. LIMITATIONS: Each patient was seen by a different dermatologist in 6 different countries. CONCLUSIONS: These observations are likely dose-related adverse effects of balicatib. Although catK was originally thought to be expressed only in osteoclasts, it has more recently also been found in lung and dermal fibroblasts and been implicated in the degradation of the extracellular matrix in the lung and the skin. It is therefore plausible that the observed dermal fibrosis in balicatib-treated patients is a result of impaired degradation of extracellular matrix proteins and may represent a class effect of catK inhibitors. We recommend that further exploration of catK inhibition for the treatment of osteoporosis or cancer should include monitoring for similar adverse effects.

Back pain during different sequential treatment regimens of teriparatide: results from EUROFORS.

OBJECTIVE: To investigate changes in back pain in postmenopausal women with severe osteoporosis who received teriparatide for 24 months or switched at 12 months to raloxifene or no active treatment. STUDY DESIGN AND METHODS: This prospective, controlled, randomised, open-label, 2-year study enrolled 868 postmenopausal women with osteoporosis and a recent fragility fracture. After 12 months of teriparatide (20 microg/day), 507 patients were randomised to further teriparatide (n = 305), raloxifene 60 mg/day (n = 100), or no active treatment (n = 102) for another 12 months (substudy 1); in substudy 2, 199 patients continued teriparatide. All received calcium and vitamin D supplementation. Back pain was self-assessed by patients using a visual analogue scale (0-100 mm). Changes in back pain were analysed using a mixed model for repeated measures. RESULTS: During year 1, back pain decreased from a mean (SD) of 48.9 mm (24.0) at baseline by 11.5 mm (p < 0.001) in the total study population. In substudy 1, mean change in back pain from month 12 (randomisation) to 24 months was -2.2, -4.4 and +0.7 mm in the teriparatide (p = 0.076), raloxifene (p = 0.041), and no active treatment groups (p = 0.751). There were no between-group differences from randomization to 18 or 24 months. In a sensitivity analysis excluding patients with low baseline back pain (VAS < 30 mm), mean change from randomisation to endpoint was significant for teriparatide (-3.9 mm, p = 0.006) and raloxifene (-6.3 mm, p = 0.018) groups. Subgroup analyses of 503 patients who received teriparatide for up to 2 years showed that patients with a recent vertebral fracture had a greater decrease in back pain than those without (p < 0.05). Those with and without mild back pain (>or=30 mm), and those with and without severe back pain (>or=60 mm) at baseline all had a statistically significant reduction in back pain after 24 months (p < 0.05). CONCLUSIONS: Teriparatide treatment is associated with significant reductions in back pain regardless of the presence of recent vertebral fracture. These results need to be considered with caution due to the open-label design of the study.

A link between bone mineral density and serum adiponectin and visfatin levels in acromegaly.

CONTEXT: Two adipokines highly expressed in fat mass, adiponectin with antiinflammatory and antiatherogenic properties and visfatin with an insulin-mimetic effect, are potential contributors to bone metabolism. In acromegaly, data on adiponectin are contradictory, and there are no data on visfatin. OBJECTIVES: The aim of the study was to evaluate adiponectin and visfatin in acromegaly, compared to control subjects, and to analyze their relationship with body composition and bone markers. METHODS: Bone markers [osteocalcin, total amino-terminal propeptide of type 1 procollagen (total P1NP), carboxy-terminal telopeptide (beta-Crosslaps)], body composition (by dual-energy x-ray absorptiometry), adiponectin (by ELISA), and visfatin (by immunoanalysis)] were evaluated in 60 acromegalic patients (24 males and 36 females) and in 105 age- and gender-matched healthy controls (33 males and 72 females). Acromegalic patients were classified as controlled, with normal IGF-I and nadir GH no greater than 1 microg/liter (n = 41), or active (n = 19). RESULTS: Acromegalic patients had lower adiponectin (P < 0.01), more lean body mass (P < 0.01), more total body mass (P < 0.01), higher bone formation markers (osteocalcin and total P1NP, P < 0.05 and P < 0.01, respectively), but less bone resorption markers (beta-Crosslaps, P < 0.001) than controls. No differences in visfatin and BMD were found between patients and controls. Adiponectin correlated negatively with BMD (r = -0.374; P < 0.05) and lean mass (r = -0.301; P < 0.05) and positively with age (r = 0.341; P < 0.001) in acromegaly. Visfatin correlated negatively with BMD (r = -0.359; P < 0.05). BMD was the predictor for adiponectin and visfatin. CONCLUSIONS: Acromegalic patients present hypoadiponectinemia and a favorable bone marker profile. Adiponectin and visfatin could be a link between fat mass and bone in acromegaly.

Persistent body fat mass and inflammatory marker increases after long-term cure of Cushing's syndrome.

OBJECTIVE: Although increased central fat mass is characteristic of active Cushing's syndrome (CS), little is known about body composition and secretion of adipokines after long-term recovery of CS. The aim of this study was to evaluate central fat mass and its correlation with adipokines and cardiovascular risk factors in patients after long-term remission of CS. METHODS: Thirty-seven women with CS in remission (27 of pituitary and 10 of adrenal origin; mean age, 50 +/- 14 yr; mean time of hormonal cure, 11 +/- 6 yr) were enrolled and compared to 14 women with active CS and 85 gender-, age-, and body mass index-matched healthy controls. Total and trunk fat mass were measured by dual-energy x-ray absorptiometry scanning. Laboratory parameters and adipokine levels [including adiponectin, visfatin, soluble TNFalpha-receptor 1 (sTNF-R1), sTNF-R2, and IL-6] were measured. RESULTS: Cured CS patients had more total and trunk fat mass than controls. Cured and active CS had higher levels of sTNF-R1 and IL-6 and lower adiponectin levels than controls. Higher insulin levels and blood pressure in both groups of CS patients and higher apolipoprotein B in cured CS were observed compared to controls. sTNF-R1 correlated positively with percentage of trunk fat mass and remained significant after adjusting for anthropometric parameters. CONCLUSION: Despite long-term cure, patients who have suffered CS exhibit persistent accumulation of central fat, as in active hypercortisolemia, with the consequent unfavorable adipokine profile, leading to a state of low-grade inflammation. This situation determines a persistent and increased cardiovascular risk in these patients.

Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing's syndrome.

Endogenous hypercortisolism and high-dose and long-term glucocorticoid (GC) therapy reduce bone mass. Patients in remission after successful treatment of Cushing's syndrome (CS) often present hypoadrenalism and require long-term GC replacement. The aim of our study was to evaluate whether this GC "replacement" had any further effect on bone in women after long-term remission of CS. Thirty-seven women (mean age: 50 +/- 14 yr; 27 of pituitary and 10 of adrenal origin) with cured CS (mean time of cure: 11 +/- 6 yr), 14 with active CS, and 85 sex-, body mass index (BMI)-, and age-matched controls were enrolled. BMD and BMC were measured by DXA scanning. Bone biochemical markers were also measured. Duration and dose of GC replacement and duration of endogenous hypercortisolism were calculated. Cured and active CS patients had less BMC, BMD, and osteocalcin than controls (p < 0.01). These differences were observed in estrogen-sufficient women but not in those with estrogen deficiency. Duration of GC treatment (mean: 42 mo; range, 2-420 mo) and endogenous hypercortisolism (mean: 70 mo; range, 13-241 mo) negatively correlated with BMC and lumbar spine BMD. After regression analysis, the main predictor of abnormal BMC and BMD was the duration of GC replacement (p < 0.01). Patients treated for CS persistently have less bone mass despite long-term cure. Both duration of endogenous hypercortisolism and mainly exogenous "replacement" therapy with GC negatively affect bone mass. Thus, the additional deleterious effect of GC for the treatment of adrenal axis suppression should be considered.

Comparative effects of teriparatide and strontium ranelate on bone biopsies and biochemical markers of bone turnover in postmenopausal women with osteoporosis.

We assessed the effects on bone remodeling and histomorphometry after daily subcutaneous injections of teriparatide (n = 39, 20 microg/d) or oral strontium ranelate (SrR, n = 40, 2 g/d) in postmenopausal women with osteoporosis. Evaluable biopsies were obtained from 29 patients in the teriparatide group and 22 in the SrR group after 6 mo of treatment. The mean +/- SD mineralization surfaces as a percent of bone surfaces (MS/BS, %) at the trabecular level were 7.73 +/- 1.48% for teriparatide and 5.25 +/- 1.15% for SrR (p = 0.219) and at the endocortical level were 17.22 +/- 3.06% and 9.70 +/- 2.07%, respectively (p = 0.052). Cortical porosity was 5.40 +/- 0.41% in the teriparatide and 4.14 +/- 0.40% in the SrR group (p = 0.037). Teriparatide induced significant increases from baseline in bone formation and resorption markers, reaching statistical significance for amino-terminal propeptide of type I collagen (PINP) after 1 mo (+57%, p < 0.001). SrR induced small, but statistically significant, reductions from baseline in PINP at 3 (-14%, p = 0.005) and 6 mo (-19%, p < 0.001) and in serum beta-C-terminal telopeptide of type I collagen (beta-CTX) at 1 and 3 mo (-11%, for both, p < 0.05). There were more patients with adverse events after SrR (70%) than teriparatide (41%) treatment (p = 0.013). In conclusion, the changes in biochemical markers of bone formation confirmed bone-forming activity of teriparatide but not of SrR treatment. The effects of SrR on bone remodeling and cell activity were modest, indicating that its effects on fracture reduction may be predominantly mediated through a different mechanism than that observed with anabolic or more potent antiresorptive agents.

Sequential treatment of severe postmenopausal osteoporosis after teriparatide: final results of the randomized, controlled European Study of Forsteo (EUROFORS).

It is unclear which treatment should be given after stopping teriparatide therapy for severe osteoporosis. In a prospective, randomized, controlled, 2-yr study, we compared BMD effects and clinical safety of three follow-up treatments (anabolic with teriparatide, antiresorptive with raloxifene, or no active treatment) after 1 yr of teriparatide. Postmenopausal women with osteoporosis and a recent fragility fracture received open-label teriparatide (20 microg/d) for 12 mo before they were randomized (3:1:1) to continue teriparatide (n = 305), switch to raloxifene 60 mg/d (n = 100), or receive no active treatment for the second year (n = 102). All patients received calcium and vitamin D supplementation. Changes in areal BMD from baseline to 24 mo were analyzed using mixed-model repeated measures. Daily teriparatide treatment for 2 yr significantly increased spine BMD by 10.7%. Patients receiving raloxifene in year 2 had no further change in spine BMD from year 1 (change from baseline, 7.9%), whereas patients receiving no active treatment had a BMD decrease of 2.5% in year 2 (change from baseline, +3.8%). At the total hip, BMD increases from baseline at 2 yr were 2.5% with teriparatide, 2.3% with raloxifene, and 0.5% with no active treatment; the respective changes at the femoral neck were 3.5%, 3.1%, and 1.3%. The study had insufficient power to assess antifracture efficacy. In conclusion, BMD increases progressively over 2 yr of teriparatide therapy in women with severe osteoporosis. After discontinuation of teriparatide, raloxifene maintains spine BMD and increases hip BMD.

Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment.

Previous antiresorptive (AR) treatment may influence the response to teriparatide. We examined BMD response and safety in a subgroup of 503 postmenopausal women with osteoporosis who received teriparatide for 24 mo. Patients were divided into three groups based on their prior AR treatment: treatment-naïve (n = 84); pretreated with no evidence of inadequate treatment response (n = 134); and pretreated showing an inadequate response to AR treatment (n = 285), which was predefined based on the occurrence of fractures, persistent low BMD, and/or significant BMD loss while on therapy. Changes in BMD from baseline were analyzed using mixed model repeated measures. Lumbar spine BMD increased significantly from baseline at 6, 12, 18, and 24 mo in all three groups. The mean gain in spine BMD over 24 mo was greater in the treatment-naïve group (0.095 g/cm(2); 13.1%) than in the AR pretreated (0.074 g/cm(2); 10.2%; p < 0.005) and inadequate AR responder (0.071 g/cm(2); 9.8%; p < 0.001) groups. The corresponding increases in total hip BMD were 3.8%, 2.3%, and 2.3%, respectively. Early decreases in hip BMD in the inadequate AR responder group were reversed by 18 mo of treatment. Increases in BMD between 18 and 24 mo were highly significant. Nausea (13.3%) and arthralgia (11.7%) were the most commonly reported adverse events. Asymptomatic hypercalcemia was reported in 5.0% of patients. Teriparatide treatment for 24 mo is associated with a significant increase in BMD in patients with and without previous AR use. Prior AR treatment modestly blunted the BMD response to teriparatide. Safety was consistent with current prescribing label information.

Monitoring teriparatide-associated changes in vertebral microstructure by high-resolution CT in vivo: results from the EUROFORS study.

UNLABELLED: We introduce a method for microstructural analysis of vertebral trabecular bone in vivo based on HRCT. When applied to monitor teriparatide treatment, changes in structural variables exceeded and were partially independent of changes in volumetric BMD. INTRODUCTION: Monitoring of osteoporosis therapy based solely on bone densitometry is insufficient to assess anti-fracture efficacy. Assessing bone microstructure in vivo is therefore of importance. We studied whether it is possible to monitor effects of teriparatide on vertebral trabecular microstructure independent of BMD by high-resolution CT (HRCT). MATERIALS AND METHODS: In a subset of 65 postmenopausal women with established osteoporosis who participated in the EUROFORS study, HRCT scans of T(12), quantitative CT of L(1)-L(3), and DXA of L(1)-L(4) were performed after 0, 6, and 12 mo of teriparatide treatment (20 microg/d). We compared BMD and 3D microstructural variables in three groups of women, based on prior antiresorptive treatment: treatment-naïve; pretreated; and pretreated women showing inadequate response to treatment. RESULTS: We found statistically highly significant increases in most microstructural variables and BMD 6 mo after starting teriparatide. After 12 mo, apparent bone volume fraction (app. BV/TV) increased by 30.6 +/- 4.4% (SE), and apparent trabecular number (app. Tb.N.) increased by 19.0 +/- 3.2% compared with 6.4 +/- 0.7% for areal and 19.3 +/- 2.6% for volumetric BMD. The structural changes were partially independent of BMD as shown by a significantly larger standardized increase and a standardized long-term precision at least as good as DXA. Patients who had shown inadequate response to prior osteoporosis treatment did show improvements in BMD and structural measures comparable to treatment-naïve patients. CONCLUSIONS: HRCT is a feasible method for longitudinal microstructural analysis of human vertebrae in vivo, offers information beyond BMD, and is sufficiently precise to show profound effects of teriparatide after 12 mo.

La propuesta de rediseño del Servicio de Medicina Interna del Hospital de la Santa Cruz y San Pablo / The proposed redesign of the Internal Medicine Service of the Hospital de la Santa Cruz y San Pablo

Objetivo: La sociedad para la cual trabajan los hospitales está sufriendo cambios demográficos, tecnológicos y culturales. El servicio de Medicina Interna (SMI) del Hospital de la Santa Cruz y San Pablo considera estos cambios como oportunidades de mejora. Presentamos la metodología aplicada y las propuestas para la reingeniería de dicho servicio. Método: Se ha utilizado la técnica del grupo nominal para identificar y priorizar objetivos, seleccionar problemas e intervenciones a implementar. En estos grupos han participado todos los estamentos sanitarios, junto con asociaciones de vecinos de nuestro entorno hospitalario, autoridades sanitarias externas al hospital, así cómo enfermos y sus familiares. El rediseño se inició en 1998 y persiste abierto hasta ahora. Resultados: Se consideró que los puntos fuertes del SMI eran su polivalencia y su adaptabilidad a diversos escenarios. Los 7 objetivos seleccionados identifican los clientes externos e internos. Entre los 5 problemas priorizados, 3 se centran en la mejora de la gestión de procesos y 2 en la formación de habilidades no clínicas. Finalmente, se proponen un conjunto de 23 puntos con influencia en la actividad diaria asistencial, y dirigidos a impulsar la participación de todos los miembros del equipo en los objetivos del servicio/hospital y en la resolución de los problemas de los ciudadanos. Conclusiones: Nuestra propuesta de rediseñar el SMI aporta 2 aspectos importantes. El primero objetiva la importancia de trabajar con una metodología específica y participativa. El segundo identifica objetivos, detecta problemas, propone intervenciones de mejora y selecciona un conjunto de resultados, que deben permitir el rediseño de nuestro SMI. Esta propuesta de rediseño, sigue abierta e incorpora mejoras (AU)