Adolfo Diez-Perez

Publications of Adolfo Diez-Perez

• Vitamin D threshold to prevent aromatase inhibitor-related bone loss: the B-ABLE prospective cohort study.

  Authors: Daniel Prieto-Alhambra, Sonia Servitja, M Kassim Javaid, Laia Garrigós, Nigel K Arden, Cyrus Cooper, Joan Albanell, Ignasi Tusquets, Adolfo Diez-Perez, Xavier Nogues

  Breast cancer research and treatment. 03/2012;

  Aromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrationsAromatase inhibitor (AI)-related bone loss is associated with increased fracture rates. Vitamin D might play a role in minimising this effect. We hypothesised that 25-hydroxy-vitamin D concentrations [25(OH)D] after 3 months supplementation might relate to bone loss after 1 year on AI therapy. We conducted a prospective cohort study from January 2006 to December 2011 of a consecutive sample of women initiating AI for early breast cancer who were ineligible for bisphosphonate therapy and stayed on treatment for 1 year (N = 232). Serum 25(OH)D was measured at baseline and 3 months, and lumbar spine (LS) bone mineral density at baseline and 1 year. Subjects were supplemented with daily calcium (1 g) and vitamin D(3) (800 IU) and additional oral 16,000 IU every 2 weeks if baseline 25(OH)D was <30 ng/ml. Linear regression models were fitted to adjust for potential confounders. After 1 year on AI therapy, 232 participants experienced a significant 1.68 % [95 % CI 1.15-2.20 %] bone loss at LS (0.017 g/cm(2) [0.012-0.024], P < 0.0001). Higher 25(OH)D at 3 months protected against LS bone loss (-0.5 % per 10 ng/ml [95 % CI -0.7 to -0.3 %], adjusted P = 0.0001), and those who reached levels ≥40 ng/ml had reduced bone loss by 1.70 % [95 % CI 0.4-3.0 %; adjusted P = 0.005] compared to those with low 25(OH)D levels (<30 ng/ml). We conclude that improved vitamin D status using supplementation is associated with attenuation of AI-associated bone loss. For this population, the current Institute of Medicine target recommendation of 20 ng/ml might be too low to ensure good bone health.

• Adverse reactions and drug-drug interactions in the management of women with postmenopausal osteoporosis.

  Authors: René Rizzoli, Jean-Yves Reginster, Steven Boonen, Gérard Bréart, Adolfo Diez-Perez, Dieter Felsenberg, Jean-Marc Kaufman, John A Kanis, Cyrus Cooper

  Calcified tissue international. 06/2011; 89(2):91-104.

  The pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of thisThe pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of this review is to explore the risk of adverse drug reactions and drug-drug interactions with treatments for postmenopausal osteoporosis. We reviewed evidence for adverse reactions from regulatory documents, randomized controlled trials, pharmacovigilance surveys, and case series. Bisphosphonates are associated with gastrointestinal effects, musculoskeletal pain, and acute-phase reactions, as well as, very rarely, atrial fibrillation, atypical fracture, delayed fracture healing, osteonecrosis of the jaw, hypersensitivity reactions, and renal impairment. Cutaneous effects and osteonecrosis of the jaw are of concern for denosumab (both very rare), though there are no pharmacovigilance data for this agent yet. The selective estrogen receptor modulators are associated with hot flushes, leg cramps, and, very rarely, venous thromboembolism and stroke. Strontium ranelate has been linked to hypersensitivity reactions and venous thromboembolism (both very rare) and teriparatide with headache, nausea, dizziness, and limb pain. The solidity of the evidence base depends on the frequency of the reaction, and causality is not always easy to establish for the very rare adverse reactions. Drug-drug interactions are rare. Osteoporosis treatments are generally safe and well tolerated, though they are associated with a few very rare serious adverse reactions. While these are a cause for concern, the risk should be weighed against the benefits of treatment itself, i.e., the prevention of osteoporotic fracture.

• Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study.

  Authors: Daniel Prieto-Alhambra, M Kassim Javaid, Sonia Servitja, Nigel K Arden, Maria Martinez-García, Adolfo Diez-Perez, Joan Albanell, Ignasi Tusquets, Xavier Nogues

  Breast cancer research and treatment. 02/2011; 125(3):869-78.

  Aromatase inhibitor (AI)-associated arthralgia limits adherence to therapy in breast cancer. The pathophysiology may involve vitamin D status. We wished to establish the optimal concentration ofAromatase inhibitor (AI)-associated arthralgia limits adherence to therapy in breast cancer. The pathophysiology may involve vitamin D status. We wished to establish the optimal concentration of 25(OH)D that prevents or minimizes arthralgia. We used a prospective cohort of 290 women starting AI in whom baseline vitamin D was measured. All received daily vitamin D(3) (800 IU) with calcium. Women with baseline 25(OH)D concentration <30 ng/ml also received 16,000 IU of D(3) orally every 2 weeks. The primary outcome was incident or worsening joint pain derived from baseline and 3-month visual analogic scale (VAS) for joint pain. Regression models were used to analyse the association between vitamin D concentrations at 3 months and pain adjusting for age, BMI, season when the sample was drawn, aromatase inhibitor (exemestane vs. letrozole/anastrozole), prior tamoxifen therapy, baseline NTX, and previous fracture. 90% of women had a 25(OH)D <30 ng/ml at baseline. After supplementation (daily 800 IU and additional 16,000 IU every 2 weeks), 50% of them still failed to reach adequate concentrations at 3 months. In the whole cohort, there was an increase in joint pain (mean 1.16 points SD 2.66; P < 0.001) and the increase was significantly (P = 0.02) attenuated in those that reached concentrations of 25(OH)D of ≥40 ng/ml, with a lower risk of incident arthralgia (OR 0.12 ** [0.03 to 0.40]). A target concentration of 40 ng/ml 25OHD may prevent development of AI arthralgia but higher loading doses are required to attain this level in women with deficiency at baseline.

• Vitamin D deficiency and bone mineral density in postmenopausal women receiving aromatase inhibitors for early breast cancer.

  Authors: Xavier Nogues, Sonia Servitja, Maria Jesus Peña, Daniel Prieto-Alhambra, Rosa Nadal, Leonardo Mellibovsky, Joan Albanell, Adolfo Diez-Perez, Ignasi Tusquets

  Maturitas. 07/2010; 66(3):291-7.

  Aromatase inhibitors (AI) treatment leads to an increased risk of bone loss and fractures. In a group of women with early breast cancer (EBC) and baseline Vitamin D deficiency (<30 ng/ml) who areAromatase inhibitors (AI) treatment leads to an increased risk of bone loss and fractures. In a group of women with early breast cancer (EBC) and baseline Vitamin D deficiency (<30 ng/ml) who are treated with AI, we aim to describe: serum levels of Vitamin D, bone mineral density (BMD), calcium intake, and the increase of serum 25(OH)D accomplished in 3 months of treatment with Vitamin D supplements. Prospective, non-randomized clinical trial. In 232 consecutively included women with EBC in treatment with AI, we assessed baseline calcium intake, serum levels of 25(OH)D, BMD and, spine X-ray. All received Calcium and Vitamin D supplements, and those with vitamin deficiency received 16,000 IU Vitamin D every 2 weeks. Serum levels of 25(OH)D were newly assessed after treatment. All the baseline evaluation was performed before starting AI treatment. Mean age at baseline (+/-SD) was 63.2+/-8.8 years. In 150 (64.9%) cases, the women had been treated previously with tamoxifen; 101 (43.7%) started exemestane, 119 (51.5%) letrozole, and 11 (4.8%) anastrozole. The AI were initiated within 6 weeks after surgery or after the last cycle of chemotherapy. At baseline, 88.1% had 25(OH)D levels <30 ng/ml, 21.2% had severe deficiency (<10 ng/ml), and 25% of the participants had osteoporosis. Mean daily calcium intake was low (841+/-338). We found a significant association between 25(OH)D levels and BMD at baseline, which remained significant in femoral neck BMD after multivariate adjustment. Plasma 25(OH)D levels improved significantly at 3 months follow-up in those treated with high dose Vitamin D supplements: mean increase 32.55 ng/ml (95%CI 28.06-37.03). Our study suggests a high prevalence of commonly unrecognized Vitamin D deficiency in women with EBC treated with AI, a known osteopenic agent. Our results support the need for a routine assessment of 25(OH)D levels and, when necessary, supplementation in these patients.

• Microindentation for in vivo measurement of bone tissue mechanical properties in humans.

  Authors: Adolfo Diez-Perez, Roberto Güerri, Xavier Nogues, Enric Cáceres, Maria Jesus Peña, Leonardo Mellibovsky, Connor Randall, Daniel Bridges, James C Weaver, Alexander Proctor, Davis Brimer, Kurt J Koester, Robert O Ritchie, Paul K Hansma

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 02/2010; 25(8):1877-85.

  Bone tissue mechanical properties are deemed a key component of bone strength, but their assessment requires invasive procedures. Here we validate a new instrument, a reference point indentationBone tissue mechanical properties are deemed a key component of bone strength, but their assessment requires invasive procedures. Here we validate a new instrument, a reference point indentation (RPI) instrument, for measuring these tissue properties in vivo. The RPI instrument performs bone microindentation testing (BMT) by inserting a probe assembly through the skin covering the tibia and, after displacing periosteum, applying 20 indentation cycles at 2 Hz each with a maximum force of 11 N. We assessed 27 women with osteoporosis-related fractures and 8 controls of comparable ages. Measured total indentation distance (46.0 +/- 14 versus 31.7 +/- 3.3 microm, p = .008) and indentation distance increase (18.1 +/- 5.6 versus 12.3 +/- 2.9 microm, p = .008) were significantly greater in fracture patients than in controls. Areas under the receiver operating characteristic (ROC) curve for the two measurements were 93.1% (95% confidence interval [CI] 83.1-100) and 90.3% (95% CI 73.2-100), respectively. Interobserver coefficient of variation ranged from 8.7% to 15.5%, and the procedure was well tolerated. In a separate study of cadaveric human bone samples (n = 5), crack growth toughness and indentation distance increase correlated (r = -0.9036, p = .018), and scanning electron microscope images of cracks induced by indentation and by experimental fractures were similar. We conclude that BMT, by inducing microscopic fractures, directly measures bone mechanical properties at the tissue level. The technique is feasible for use in clinics with good reproducibility. It discriminates precisely between patients with and without fragility fracture and may provide clinicians and researchers with a direct in vivo measurement of bone tissue resistance to fracture.

• The tissue diagnostic instrument.

  Authors: Paul Hansma, Hongmei Yu, David Schultz, Azucena Rodriguez, Eugene A Yurtsev, Jessica Orr, Simon Tang, Jon Miller, Joseph Wallace, Frank Zok [......] Carol Chen, Mathilde Peters, David Kohn, Jenni Buckley, Xiaojuan Li, Lisa Pruitt, Adolfo Diez-Perez, Tamara Alliston, Valerie Weaver, Jeffrey Lotz

  The Review of scientific instruments. 06/2009; 80(5):054303.

  Tissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral diskTissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral disk degeneration, cancer, atherosclerosis, osteoarthritis, osteoporosis, and tooth decay. Here we introduce the tissue diagnostic instrument (TDI), a device designed to probe the mechanical properties of normal and diseased soft and hard tissues not only in the laboratory but also in patients. The TDI can distinguish between the nucleus and the annulus of spinal disks, between young and degenerated cartilage, and between normal and cancerous mammary glands. It can quantify the elastic modulus and hardness of the wet dentin left in a cavity after excavation. It can perform an indentation test of bone tissue, quantifying the indentation depth increase and other mechanical parameters. With local anesthesia and disposable, sterile, probe assemblies, there has been neither pain nor complications in tests on patients. We anticipate that this unique device will facilitate research on many tissue systems in living organisms, including plants, leading to new insights into disease mechanisms and methods for their early detection.

• The tissue diagnostic instrument

  Authors: Paul Hansma, Hongmei Yu, David Schultz, Eugene A. Yurtsev, Jessica Orr, Simon Tang, Jon Miller, Frank Zok, Richard Souza, Alexander Proctor, Xavier Nogues-Solan, M.Jesus Peña, Lisa Pruitt, Adolfo Diez-Perez, Tamara Alliston, Valerie Weaver, Jeff Lotz

  Review of Scientific Instruments. 05/2009;

  Tissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebralTissue mechanical properties reflect extracellular matrix composition and organization, and as such, their changes can be a signature of disease. Examples of such diseases include intervertebral disk degeneration, cancer, atherosclerosis, osteoarthritis, osteoporosis, and tooth decay. Here we introduce the tissue diagnostic instrument �TDI�, a device designed to probe the mechanical properties of normal and diseased soft and hard tissues not only in the laboratory but also in patients. The TDI can distinguish between the nucleus and the annulus of spinal disks, between young and degenerated cartilage, and between normal and cancerous mammary glands. It can quantify the elastic modulus and hardness of the wet dentin left in a cavity after excavation. It can perform an indentation test of bone tissue, quantifying the indentation depth increase and other mechanical parameters. With local anesthesia and disposable, sterile, probe assemblies, there has been neither pain nor complications in tests on patients. We anticipate that this unique device will facilitate research on many tissue systems in living organisms, including plants, leading to new insights into disease mechanisms and methods for their early detection. © 2009 American Institute of Physics. �DOI: 10.1063/1.3127602� I. INTRODUCTION The tissue diagnostic instrument �TDI� was redesigned from the bone diagnostic instrument1,2 so as to measure tissue mechanical properties subcutaneously and in vivo with additional probe assemblies and an adjustable compliance �Fig. 1�. It consists of a thin probe assembly that can penetrate skin and soft tissue to reach deep tissues. The disposable, sterilizable probe assembly consists of an outer reference probe made from a 23 gauge hypodermic needle and an inner test probe made from stainless steel wire ranging from 175 to 300 �m in diameter and from 2 to 90 mm in length. Since friction between the test probe and the reference probe increases with length, it is desirable to use only the length needed to access the desired tissue location. The test probe is held in a nickel tube that couples to a magnet, which in turn is linked to a force generator. During operation the force generator oscillates the probe within the tissue of interest and concurrently measures the force and displacement. The maximum values for force and displacement are 12 N and 600 �m. The probe is typically operated at a frequency of 4 Hz because this is rapid enough to allow hand holding yet sufficiently slow to allow easy decoupling of the elastic and viscous response of the tissue �see supplementary material3 for more details including force and displacement ranges.� II. MEASUREMENTS We first illustrate TDI use in human spinal disks that are composed of a thick outer ligament �annulus fibrosus� and a central swelling hydrogel �nucleus pulposus�. Spinal disk degeneration can be the underlying cause of back pain leading to significant morbidity and societal expense. Intervertebral disks are one of the most highly loaded tissues in the body, and consequently material property insufficiency can lead to damage accumulation, inflammation, and pain. Disk degen- REVIEW OF SCIENTIFIC INSTRUMENTS 80, 054303 �2009� 0034-6748/2009/80�5�/054303/6/$25.00 80, 054303-1 © 2009 American Institute of Physics Downloaded 28 May 2009 to 72.215.163.35. Redistribution subject to AIP license or copyright; see http://rsi.aip.org/rsi/copyright.jsp

• Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: Results of a five-year, randomized, placebo-controlled trial.

  Authors: Jean-Yves Reginster, Dieter Felsenberg, Steven Boonen, Adolfo Diez-Perez, Rene Rizzoli, Maria Luisa Brandi, Tim D Spector, Kim Brixen, Stefan Goemaere, Catherine Cormier, Adam Balogh, Pierre D Delmas, Pierre J Meunier

  Arthritis and rheumatism. 07/2008; 58(6):1687-95.

  OBJECTIVE: This study was undertaken to assess the effect of strontium ranelate on nonvertebral and vertebral fractures in postmenopausal women with osteoporosis in a 5-year, double-blind,OBJECTIVE: This study was undertaken to assess the effect of strontium ranelate on nonvertebral and vertebral fractures in postmenopausal women with osteoporosis in a 5-year, double-blind, placebo-controlled trial. METHODS: A total of 5,091 postmenopausal women with osteoporosis were randomized to receive either strontium ranelate at 2 gm/day or placebo for 5 years. The main efficacy criterion was the incidence of nonvertebral fractures. In addition, incidence of hip fractures was assessed, by post hoc analysis, in the subset of 1,128 patients who were at high risk of fractures (age 74 years or older with lumbar spine and femoral neck bone mineral density T scores -2.4 or less). The incidence of new vertebral fractures was assessed, using the semiquantitative method described by Genant, in the 3,646 patients in whom spinal radiography (a nonmandatory procedure) was performed during the course of the study. Fracture data were analyzed using the Kaplan-Meier survival method. RESULTS: Of the 5,091 patients, 2,714 (53%) completed the study up to 5 years. The risk of nonvertebral fracture was reduced by 15% in the strontium ranelate group compared with the placebo group (relative risk 0.85 [95% confidence interval 0.73-0.99]). The risk of hip fracture was decreased by 43% (relative risk 0.57 [95% confidence interval 0.33-0.97]), and the risk of vertebral fracture was decreased by 24% (relative risk 0.76 [95% CI 0.65-0.88]) in the strontium ranelate group. After 5 years, the safety profile of strontium ranelate remained unchanged compared with the 3-year findings. CONCLUSION: Our findings indicate that treatment of postmenopausal osteoporosis with strontium ranelate results in a sustained reduction in the incidence of osteoporotic nonvertebral fractures, including hip fractures, and vertebral fractures over 5 years.

• Bone mass of a 113-year-old man.

  Authors: Leonardo Mellibovsky, Mariona Bustamante, Pau Lluch, Xavier Nogues, Daniel Grinberg, Susana Balcells, Adolfo Diez-Perez

  The journals of gerontology. Series A, Biological sciences and medical sciences. 08/2007; 62(7):794-5.

  Osteoporosis is a common disease that affects elderly people. Aging induces loss of bone density and quality resulting in a progressive incidence of fragility fractures. In this study, we report theOsteoporosis is a common disease that affects elderly people. Aging induces loss of bone density and quality resulting in a progressive incidence of fragility fractures. In this study, we report the bone density of one of the oldest men in the world and of several of his first-degree relatives, as well as a genetic screen of these cases. No fractures have been suffered by any of them, and their bone mineral density (BMD) values in terms of z score were normal or lightly decreased. Neither mutations at the longevity-related gene KLOTHO nor the Gly171Val mutation of LRP5 associated with high bone mass was detected in the two centenarian stepbrothers.

• The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis.

  Authors: André G Uitterlinden, Stuart H Ralston, Maria Luisa Brandi, Alisoun H Carey, Daniel Grinberg, Bente L Langdahl, Paul Lips, Roman Lorenc, Barbara Obermayer-Pietsch, Jonathan Reeve [......] Joyce B J van Meurs, Jon Mangion, Fiona E A McGuigan, Huibert A P Pols, Wilfried Renner, Fernando Rivadeneira, Natasja M van Schoor, Serena Scollen, Rachael E Sherlock, John P A Ioannidis

  Annals of internal medicine. 09/2006; 145(4):255-64.

  BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remainsBACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures. DESIGN: Prospective multicenter large-scale association study. SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. PARTICIPANTS: 26,242 participants (18,405 women). MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

• Selective estrogen receptor modulators (SERMS).

  Authors: Adolfo Diez-Perez

  Arquivos brasileiros de endocrinologia e metabologia. 09/2006; 50(4):720-34.

  Hormone receptors and, specifically, estrogen receptors were described about four decades ago. For estrogens, there are two receptors, estrogen receptor alpha (ERalpha) and estrogen receptor betaHormone receptors and, specifically, estrogen receptors were described about four decades ago. For estrogens, there are two receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). The two receptors are coded by different genes and their tissue expression varies across organs. ERalpha is predominantly expressed in reproductive tissues (uterus, breast, ovaries) liver and central nervous system, whereas ERbeta is expressed in other tissues such as bone, endothelium, lungs, urogenital tract, ovaries, central nervous system and prostate. More than seventy molecules that belong to the SERMS class have been described. There are 5 chemical groups: triphenylethylenes, benzotiophenes, tetrahydronaphtylenes, indoles and benzopyrans. All of these non-hormonal compounds are capable of activating the ER, reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. Estrogens reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. They are also beneficial for the relief of menopausal symptoms. An ongoing debate that extends over the decades, relates to to overall benefit/risk profile of estrogen or estrogen-progestin therapy since these therapies can increase the risk of serious health disorders, such as breast cancer. SERMs have increased our understanding of hormone-receptor regulatory mechanisms. Their development has permitted a targeted efficacy profile avoiding some of the side effects of the hormone therapy. Their clinical utility relies today mostly on the effects on breast cancer and bone.

• Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study.

  Authors: Stuart H Ralston, André G Uitterlinden, Maria Luisa Brandi, Susana Balcells, Bente L Langdahl, Paul Lips, Roman Lorenc, Barbara Obermayer-Pietsch, Serena Scollen, Mariona Bustamante [......] Leonardo Mellibovsky, Francesca Del Monte, Huibert A P Pols, Jonathan Reeve, David M Reid, Wilfried Renner, Fernando Rivadeneira, Natasja M van Schoor, Rachael E Sherlock, John P A Ioannidis

  PLoS medicine. 04/2006; 3(4):e90.

  BACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous workBACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. METHODS AND FINDINGS: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. CONCLUSIONS: Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

• Anti-vertebral fracture efficacy of raloxifene: a meta-analysis.

  Authors: Ego Seeman, Gerald G Crans, Adolfo Diez-Perez, Karen V Pinette, Pierre D Delmas

  Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 03/2006; 17(2):313-6.

  In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced the risk of vertebral fracture. However, a systematic analysis of the anti-vertebral fracture efficacy ofIn the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced the risk of vertebral fracture. However, a systematic analysis of the anti-vertebral fracture efficacy of raloxifene, which includes the results of newly reported studies, has not been performed. A meta-analysis was carried out using all randomized, double-blind, placebo-controlled trials to determine whether the reduction in the risk for vertebral fracture, reported with raloxifene, was consistent among studies, and to define more accurately the point estimate of the odds ratio. Three prevention studies, two arms of the MORE trial, and three additional treatment studies in which fracture data were available from prospectively scheduled spinal radiographs were included in the analysis. A systematic review of the literature (MedLine, EMBASE) confirmed that no studies with raloxifene had been excluded from this analysis. The effects of raloxifene 60 mg/day (RLX60) and 120 mg/day pooled with 150 mg/day (RLX120/150) were analyzed by intention to treat. There was no significant heterogeneity among the studies included in the meta-analysis. Odds ratio estimates (95% CI) were 0.60 (0.49, 0.74) for RLX60 and 0.51 (0.41, 0.64) for RLX120/150. From these data we infer that raloxifene consistently reduces the risk of vertebral fracture in postmenopausal women.

• Recommendations for an update of the current (2001) regulatory requirements for registration of drugs to be used in the treatment of osteoporosis in postmenopausal women and in men.

  Authors: Jean-Yves Reginster, Eric Abadie, Pierre Delmas, René Rizzoli, Willard Dere, Philippevan der Auwera, Bernard Avouac, Maria Luisa Brandi, Anastasia Daifotis, Adolfo Diez-Perez [......] Andrea Laslop, Fritz Lekkerkerker, Bruce Mitlak, Per Nilsson, John Orloff, Mary Smillie, Andrew Taylor, Yannis Tsouderos, Dominique Ethgen, Bruno Flamion

  Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 02/2006; 17(1):1-7.

  Recent advances in the understanding of the epidemiology of osteoporosis suggest that certain parts of the current European guidelines for the registration of drugs in osteoporosis might be no longerRecent advances in the understanding of the epidemiology of osteoporosis suggest that certain parts of the current European guidelines for the registration of drugs in osteoporosis might be no longer substantiated. The object of this review is to provide the European regulatory authorities with an evidence-based working document providing suggestions for the revision of the "Note for guidance for the approval of drugs to be used in postmenopausal osteoporosis" (CPMP/EWP/552/95). Following an extensive review of the literature (1990-2004), the Group for the Respect of Ethics and Excellence in Science (GREES) organized a workshop including European regulators, academic scientists and representatives of the pharmaceutical industry. The outcomes of this meeting reflect the personal views of those who attended and should not, in any case, be seen as an official position paper of any regulatory agency. The group identified a certain number of points that deserve discussion. They mainly relate to the nature of the indication being granted to new chemical entities (treatment of osteoporosis in women at high risk of fracture instead of prevention and treatment of osteoporosis), the requirements of showing an anti-fracture efficacy on all or on major nonvertebral fractures (instead of the hip), the duration of pivotal trials (2 years instead of 3) and the possibility of considering bridging studies for new routes of administration, new doses or new regimens of previously approved drugs. The group also recommends that an indication could be granted for the treatment of osteoporosis in males on the basis of a placebo-controlled study, with bone mineral density changes after 1 year as the primary endpoint, for medications approved in the treatment of osteoporosis in women at high risk of fractures.

• Skeletal effects of raloxifene after 8 years: results from the continuing outcomes relevant to Evista (CORE) study.

  Authors: Ethel S Siris, Steven T Harris, Richard Eastell, Jose R Zanchetta, Stefan Goemaere, Adolfo Diez-Perez, John L Stock, Jingli Song, Yongming Qu, Pandurang M Kulkarni, Suresh R Siddhanti, Mayme Wong, Steven R Cummings

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 10/2005; 20(9):1514-24.

  In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations forIn the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE. INTRODUCTION: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. MATERIALS AND METHODS: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were > or =80% compliant with study medication in CORE. RESULTS: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio [HR], 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene. CONCLUSION: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.

• Treatment with raloxifene for 2 years increases vertebral bone mineral density as measured by volumetric quantitative computed tomography.

  Authors: Harry K Genant, Thomas Lang, Thomas Fuerst, Karen V Pinette, Chunmei Zhou, Daniel Thiebaud, Adolfo Diez-Perez

  Bone. 12/2004; 35(5):1164-8.

  Volumetric quantitative computed tomography (vQCT), using multiple thin-slice acquisition, measures three-dimensional volumetric bone mineral density (BMD, mg/cm3). vQCT is often used to measure BMDVolumetric quantitative computed tomography (vQCT), using multiple thin-slice acquisition, measures three-dimensional volumetric bone mineral density (BMD, mg/cm3). vQCT is often used to measure BMD of lumbar vertebrae and may detect early changes in trabecular, cortical, or integral BMD that extend beyond the technical limits of areal dual X-ray absorptiometry (DXA) BMD measurements. The objective of this study was to determine the effect of 2 years of raloxifene (RLX) treatment on several volumetric BMD measures in a subset of postmenopausal women (n=58) enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. Patients in this study were randomized to one of three treatment groups: placebo (n=21), RLX 60 mg/day (n=17), or RLX 120 mg/day (n=20), and all patients received daily calcium (500 mg) and vitamin D (400-600 IU) supplementation. Data from the raloxifene treatment groups were pooled for each analysis. Following 2 years of raloxifene treatment, there was a significant percent change from baseline in the vQCT regions of interest (ROIs) of midintegral BMD, total trabecular BMD, and total integral BMD (P<0.05) compared to placebo, while there was no significant change in the spinal DXA BMD measurement. These data provide the first longitudinal assessment by vQCT of changes in vertebral bone density after 2 years of treatment with raloxifene. vQCT appears to be a valuable technique for measuring the effects of raloxifene treatment in this population of postmenopausal women with osteoporosis.

• Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk.

  Authors: Somnath Sarkar, Jean-Yves Reginster, Gerald G Crans, Adolfo Diez-Perez, Karen V Pinette, Pierre D Delmas

  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 04/2004; 19(3):394-401.

  The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percentThe change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD. INTRODUCTION: The association between baseline BMD and fracture risk is well understood. However, the relationship between changes in BMD and fracture risk is not well defined. It has previously been demonstrated that BMD change was a poor predictor of vertebral fracture risk in raloxifene-treated women, whereas bone turnover markers were significantly associated with fracture risk. In the current analysis, we explore the prediction of vertebral fracture risk using changes in both BMD and bone turnover. MATERIALS AND METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of 7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3 years. Markers of bone turnover were measured in one-third of the study population (n = 2503), and the present analyses include these women. Logistic regression models were constructed using one-year percent changes in BMD and bone turnover and relevant baseline demographics to predict the risk of vertebral fracture with pooled raloxifene therapy at 3 years. All covariates were standardized before modeling to facilitate direct comparisons between changes in BMD and bone turnover. RESULTS AND CONCLUSION: Prevalent vertebral fracture status (p < 0.0001), baseline lumbar spine BMD (p < 0.0001), and number of years postmenopausal (p = 0.0005) were independent predictors of fracture risk in raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all treatment groups, indicating that changes in BMD and OC have different effects on fracture risk for the placebo and pooled raloxifene groups. The final model included significant baseline variables and change in OC (p = 0.01), whereas change in femoral neck BMD was not significant. After adjustment of each significant baseline variable, the percent change in OC was better able to predict the reduction in vertebral fracture risk than the percent change in femoral neck BMD in patients treated with raloxifene.

• Ataxic form of central pontine myelinolysis.

  Authors: Teresa Garzon, Leonardo Mellibovsky, Jaume Roquer, Xavier Perich, Adolfo Diez-Perez

  Lancet neurology. 01/2003; 1(8):517-8.

• Bisphosphonates.

  Authors: Adolfo Diez-Perez

  Maturitas. 09/2002; 43 Suppl 1:S19-26.

• The Association between Common Vitamin D Receptor Gene Variations and Osteoporosis: A Participant-Level Meta-Analysis

  Authors: André G Uitterlinden, Stuart H Ralston, Maria Luisa Brandi, Alisoun H Carey, Daniel Grinberg, Bente L Langdahl, Paul Lips, Roman Lorenc, Barbara Obermayer-Pietsch, Jonathan Reeve [......] Serena Scollen, Rachael E Sherlock, John P A Ioannidis, APOSS Investigators, EPOS Investigators, EPOLOS Investigators, FAMOS Investigators, Emma Duncan, LASA Investigators, Rotterdam Study Investigators