Osteoporosis treatment and fracture incidence: the ...

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Mario Biondi, MD, Ospedale Morgagni Pierantoni, Forlì; Maria. Luisa Brandi, MD ... Augusto Manzara, MD, Ospedale Villa Scassi, Genoa; Antonia Matina,.
Osteoporos Int (2008) 19:1219–1223 DOI 10.1007/s00198-008-0566-6

ORIGINAL ARTICLE

Osteoporosis treatment and fracture incidence: the ICARO longitudinal study S. Adami & G. Isaia & G. Luisetto & S. Minisola & L. Sinigaglia & S. Silvestri & D. Agnusdei & R. Gentilella & R. Nuti & on behalf of the ICARO Study Group

Received: 6 November 2007 / Accepted: 11 January 2008 / Published online: 20 February 2008 # International Osteoporosis Foundation and National Osteoporosis Foundation 2008

Abstract Summary None of the available osteoporosis therapies completely abolish the risk of fracture. Among 862 patients on treatment with antiresorptive agents (alendronate, risedronate, and raloxifene) for >1 year a fragility fracture was observed in 9.5%/year. This incidence is considerably higher than that observed in randomized clinical trials. Introduction Available osteoporosis therapies reduced in randomized controlled trials (RCTs) the risk of fracture by 30–50%. The proportion of patients suffering from new fractures while on active treatment (“inadequate clinical treatment response” or ICR) can be derived from the data of the RCTs, where confounding factors are usually controlled

S. Adami (*) Rheumatology Department, University of Verona, Valeggio Sul Mincio Hospital (VR), 37067 Valeggio S/Mincio, Verona, Italy e-mail: [email protected] G. Isaia Internal Medicine Department, University of Turin, Turin, Italy e-mail: [email protected] G. Luisetto Endocrinology Department, University Hospital of Padova, Padova, Italy e-mail: [email protected] S. Minisola Clinical Sciences Department, “La Sapienza” University, Rome, Italy e-mail: [email protected] L. Sinigaglia Orthopedic Institute “G.Pini”, Milan, Italy e-mail: [email protected]

by the exclusion criteria. In the retrospective part of the ICARO study we observed a 8.9% annual incidence of ICR. Here we report the results of the longitudinal part of the study. Methods The study includes 862 women with severe postmenopausal osteoporosis. Ninety-two of these patients (10.7%) were defined as having ICR (9.5%/year) during therapy with antiresorptive drugs (alendronate, risedronate, and raloxifene) for at least 1 year. Results The ICR patients were comparable to patients who did not sustain clinical fractures with regard to body mass index, follow-up duration, number of prevalent vertebral fractures, type of osteoporosis treatment, proportion of S. Silvestri : R. Gentilella Eli-Lilly Italia S.p.A., Florence, Italy S. Silvestri e-mail: [email protected] R. Gentilella e-mail: [email protected] D. Agnusdei Eli-Lilly & Company, Via A.Gramsci 731, Sesto Fiorentino 50019 Florence, Italy e-mail: [email protected] R. Nuti Internal Medicine Department, University of Siena, “Le Scotte” Hospital, Siena, Italy e-mail: [email protected]

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patients taking calcium and vitamin D supplements, and compliance with treatment. Those with ICR were significantly older (p=0.032) and more frequently had multiple vertebral deformities (p=0.013). Conclusions The incidence of ICR during treatment with antiresorptive agents among patients with severe postmenopausal osteoporosis in a routine setting is considerably higher than that observed in randomized clinical trials. Keywords Alendronate . Fracture risk . Osteoporosis treatment . Raloxifene . Risedronate

Introduction The primary aim of therapeutic intervention in osteoporosis is to prevent fragility fractures. The therapies registered for the treatment of osteoporosis have been shown to reduce in large randomized controlled trials (RCTs) the risk of fracture in patients with osteoporosis [1]. Vertebral and non-vertebral fracture incidence is lowered by approximately 50% and 30% respectively. None of the available therapies are expected to completely abolish the risk of fracture. Thus, a significant proportion of patients is expected to sustain a new fracture despite an effective treatment, over a relatively short period of treatment [2–8], particularly patients at very high risk. This cannot be defined as treatment failure because the number or severity of fractures in patients on active therapy is much lower than in control patients. For this reason, the occurrence of a new fracture in treated patients is more appropriately defined as “inadequate clinical treatment response” (ICR) [9]. An estimate of the proportion of ICR can be derived from the data of RCTs, where most of the confounding factors are usually controlled by the exclusion criteria. From the retrospective analysis of the ICARO (Incidence and ChAracterization of inadequate clinical Responders in Osteoporosis) study, we observed a 8.9% annual incidence of ICR. Here we report the incidence of ICR in the longitudinal analysis of the same cohort of patients, all of them with prevalent vertebral fractures and on treatment with antiresorptive agents registered for osteoporosis treatment.

Materials and methods Study design The ICARO study is a multicenter, observational study on the management of osteoporosis, which was carried out in 55 centers evenly distributed over the Italian territory. The main aim of the study is the evaluation of incidence and risk factors for inadequate clinical response to osteoporosis

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treatment, defined as the occurrence of radiologically documented new vertebral or non-vertebral fragility fracture during therapy with antiresorptive drugs (alendronate, risedronate, and raloxifene) for at least 1 year. These patients are defined here as having an “Inadequate Clinical Response” (ICR) as opposed to having an “Adequate Clinical Response” (ACR) [9]. The ICARO study included a retrospective analysis of ICR incidence and a longitudinal prospective evaluation over a period of 1 year. The results of the retrospective analysis together with full description of the study protocol have been published elsewhere [9]. Investigators were asked to consecutively screen for study eligibility all postmenopausal women referred to the center for a scheduled visit. The inclusion criteria for the longitudinal part of the study were: 1. Women with a history of one or more vertebral deformities (radiologically documented) and/or hip fracture at the time of prescription. This identifies eligibility for full reimbursement for osteoporosis treatment according to the Italian rules (Nota 79) [10] 2. Patients who participated in the retrospective study or continuing or about to initiate treatment with one of the antiresorptive therapies available for the treatment of postmenopausal osteoporosis at the time of recruitment, i.e., alendronate, risedronate, and raloxifene The exclusion criteria were: 1. Age 75% in

Table 1 Characteristics of the study population

Age (years) Body mass index (kg/m2) Prevalent fracturesa 1 Vertebral 2 Vertebral ≥3 Vertebral Duration of previous treatment Months, mean (±SD) Range Retrospectivelyb ICR ACR New Treatment distribution Alendronate Risedronate Raloxifene Mixture Follow-up—treatment duration (months) Co-administration of calcium and vitamin D Compliance with treatment 75%

All patients N=862 (%)

ICR N=92 (%)

ACR N=770 (%)

ACR vs ICR p

67.7±7.7 25.8±4.4

69.2±8.0 26.1±4.9

67.5±7.7 25.6±4.1

0.032 ns

657 (76.2) 163 (18.9) 42 (4.5)

61 (66.3) 24 (26.1) 7 (7.7)

596 (77.4) 139 (18.1) 35 (4.6)

0.013

26.2±29.0 0–176

23.8±25.3 0–102

26.5±25.9 0–176

ns ns

176 (20.4) 571 (66.2) 115 (13.3)

20 (21.7) 60 (65.2) 12 (13.1)

156 (20.2) 511 (63.4) 103 (13.4)

ns

547 (64.1) 171 (21.2) 94 (11.0) 32 (3.8) 13.6±2.2 459 (53.5)

54 (59.3) 26 (28.6) 7 (7.7) 4 (4.4) 13.3±1.7 47 (51.1)

493 (64.6) 155 (20.3) 87 (11.4) 28 (3.7) 13.6±2.2 412 (53.5)

75 (8.7) 787 (91.3)

9 (9.8) 83 (90.2)

66 (8.6) 704 (91.4)

ns

ns ns ns

The values are expressed as mean ± standard deviations, ranges or absolute numbers (percentages in parentheses). The significance (p) was tested either by Student’s t test or the Chi-squared test a Nine patients had experienced both vertebral and hip fractures b ACR or ICR as assessed in the retrospective study [9]. “New” indicates patients not included in the retrospective study and undergoing treatment at the time of recruitment for 0 to 3 months

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91.3% of the patients) and all patients were still undergoing treatment by the time of the follow-up visit. Alendronate was the most frequently prescribed drug (64.1%), followed by risedronate (21.2%), raloxifene (11.0%), and a mixture of the three (3.8%). Ninety-two of these patients (10.7%) were defined as having an ICR according to the definition previously reported. This corresponds to an annual incidence of 9.5%. The vast majority of these patients (n=89) had one new vertebral fracture. The two cohorts of patients with an ACR and those with an ICR were comparable with regard to body mass index (BMI), follow-up duration, number of prevalent vertebral fractures, type of osteoporosis treatment, the proportion of patients classified as having an ICR in the retrospective phase or taking calcium and vitamin D supplements, and compliance with treatment. Patients with an ICR and those with an ACR were significantly different with regard to age (p=0.032) and a more severe disease at the time of recruitment, with a greater proportion of patients with more than one vertebral deformity (p=0.013). These differences did not change substantially after adjustment (co-variance or multiple regression logistic analyses) of the data for all available variables (data not shown).

Discussion The current treatment for osteoporosis includes a number of agents, with solid evidence from RCTs of efficacy in decreasing the risk of fracture. No osteoporosis drug therapy completely abolishes this risk and the proportion of patients suffering fractures in the active arm of the trials ranges from 2.1% to 18.1% over 3 years [1–8, 11], depending on the initial risk. Here we report the 1-year incidence of fragility fractures in patients treated with alendronate, risedronate, and raloxifene. The annualized incidence of 9.5% of patients with an inadequate clinical response (ICR) is almost superimposable on that found (8.9% yearly) in the retrospective phase of the ICARO study. Fracture is significantly related to the two most relevant risk factors for vertebral fracture, i.e., age and number of prevalent vertebral deformities. The proportion we found of ICR in the longitudinal ICARO study is considerably greater than that reported from RCTs with the three compounds tested here. By analyzing the retrospective study we hypothesized that the high proportion of ICRs might be related to patient selection due to the retrospective nature of the study and to the possibility that several patients with an ICR actually suffered a worsening of previous deformities rather than new vertebral fractures. These two limitations cannot be extended to the longitudinal arm of the study, since

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treatment compliance (>75% in 91.3% of the patients) is similar or superior to that reported in RCTs (typically close to 80%). In addition, only vertebral fractures occurring in previously intact vertebrae were taken into account. In addition, the mean age of the patients and the number of prevalent fractures are very close to those reported for the patients recruited in the prevalent fracture arm of the pivotal RCTs with alendronate, risedronate, and raloxifene [1], suggesting a similar level of initial fracture risk. In the three trials in patients with prevalent vertebral deformities on alendronate (FIT1), risedronate (VERT-NA), and raloxifene (MORE2) [2, 3, 5], the annualized incidence of vertebral fracture in the active arm was 2.7, 3.7, and 4.9% respectively, considerably lower than the 9% incidence we found. The only two plausible explanations for this striking difference are: the type of setting (real life vs clinical trials) with possibly more co-morbidity, and the duration of prior treatment, which was basically nil in the RCTs, but substantial (>2 years) among the patients described here. This latter difference may be clinically very important. The duration of RCTs ranges from 3 to 5 years and the subsequent follow-up for up to 8 to 10 years is limited to a subset of the patients and it is non-controlled. From this point of view, ours is the largest cohort with fracture incidence in the 2nd to 9th year of treatment. Our results raise serious concerns regarding the long-term maintenance of the antifracture efficacy of antiresorptive therapies, with no apparent difference among the three agents investigated here. In conclusion, in our study we have for the first time assessed fracture incidence over 1 year in patients treated with antiresorptive agents for several months. The incidence of inadequate clinical response was approximately 10%, considerably higher than that observed in the active arm of all previous pivotal RCTs with a similar disease severity. Our results suggest that the antifracture efficacy of antiresorptive agents might be lower in real life than that observed in RCTs, and tends to wear off after a few years of treatment. Acknowledgements Colleagues and centers that participated in the study (in alphabetical order): Carlina Albanese, MD, Policlinico Universitario Umberto I, Rome; Marco Antonelli, MD, Ospedale San Camillo Forlanini, Rome; Annamaria Aversa, MD, Ospedale S. Carlo Borromeo, Milan; Cataldo Bancheri, MD, Ospedale Sandro Pertini, Rome; Mario Barbagallo, MD, Policlinico Universitario, Palermo; Alfredo Bardoscia, Fondazione Maugeri, Cassano Murge (BA); Pietro Bertoni, MD, Policlinico San Marco, Mestre (VE); Gerolamo Bianchi, MD, Ospedale La Colletta, Arenzano (GE); Mario Biondi, MD, Ospedale Morgagni Pierantoni, Forlì; Maria Luisa Brandi, MD, Policlinico Universitario Careggi, Florence; Michele Calitro, MD, Ospedale Civile Caduti in Guerra, Canosa (BA); Rosario Cangelosi, MD, Ospedale San Biagio, Marsala (TP); Francesco Paolo Cantatore, MD, Ospedale Riuniti, Foggia; Giuliano Cenci, MD, Ospedale Santa Croce, Fano (Pesaro Urbino); Antonio Cianci, MD, Ospedale Ferrarotto S. Bambino, Catania; Giovanni

Osteoporos Int (2008) 19:1219–1223 Coppi, MD, Ospedale San Camillo Forlanini, Rome; Luca Dalle Carbonare, MD, Policlinico Universitario, Padova; Massimo D’Amore, MD, DIMIMP Università degli studi di Bari, Bari; Giovanni D’Avola, MD, Servizio Reumatologia ed Osteoporosi AUSL 3, Catania; Roberto De Candia, MD, Ospedale Civile San Bortolo, Vicenza; Antonio Del Puente, MD, Policlinico Universitario “Federico II”, Naples; Pier Giorgio Delvino, MD, Ospedale Sant’Andrea, Vercelli; Alessandro Di Felice, MD, Ospedale Civile Renzetti, Lanciano (CH); Paolo Filipponi, MD, Ospedale Civile, Umbertide (PG); Carmelo Erio Fiore, MD, Ospedale Garibaldi, Catania; Cristiano Maria Francucci, MD, Ospedale Umberto I, Ancona; Bruno Frediani, MD, Policlinico Universitario “Le Scotte”, Siena; Nicola Frisina, MD, Policlinico Universitario, Messina; Beatrice Fruttero, MD, Ospedale SS Annunziata, Savigliano (CN); Raffaele Ghirardi, MD, Ospedale C. Poma, Pieve di Coriano (MN); Diego Giuntini, MD, Ospedale Riuniti, Trieste; Andrea Giustina, MD, Spedali Civili, Brescia; Giovanni Lentini, MD, Ospedale Buccheri La Ferla, Palermo; Vincenzo Lo Cascio, MD, Policlinico Universitario “G. B. Rossi”, Verona; Vittorio Lucchese, MD, Ospedale Estense, Modena; Augusto Manzara, MD, Ospedale Villa Scassi, Genoa; Antonia Matina, MD, Policlinico Universitario, Palermo; Domenico Maugeri, MD, Ospedale Cannizzaro, Catania; Quirico Mela, MD, Policlinico Universitario, Monserrato (CA); Alfredo Nardi, MD, Ospedale S. Maria della Misericordia, Rovigo; Rita Occhipinti, MD, Ospedale Civile, Belluno; Giangiacomo Osella, MD, Ospedale S.Luigi Gonzaga, Orbassano (TO); Giuseppe Perpignano, MD, Policlinico Universitario, Monserrato (CA); Eustacchio Pisciotta, MD, Ospedale Civile Tinchi, Pisticci (MT); Giuseppe Quattrocchi, MD, Centro Riabilitazione Mandalari, Messina; Giovambattista Rini, MD, Policlinico Universitario, Palermo; Maurizio Rossini, MD, Policlinico Universitario, Verona; Stefano Savoca, MD, Ospedale Ascoli Tomaselli, Catania; Ferdinando Silveri, MD, Università Politecnica delle Marche, Jesi (AN); Giuseppe Termini, MD, Policlinico Universitario, Palermo. The study was supported by an unlimited grant from Eli-Lilly Italia. Data collection and statistical analysis were carried out by Medidata S.p.A. (Modena, Italy) under the supervision of one of the authors (SA).

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Conflicts of interest None.

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