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Feb 8, 2014 - Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis. E. Cairoli & C. Eller-Vainicher ...
Osteoporos Int (2014) 25:1401–1410 DOI 10.1007/s00198-014-2619-3

ORIGINAL ARTICLE

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis E. Cairoli & C. Eller-Vainicher & F. M. Ulivieri & V. V. Zhukouskaya & S. Palmieri & V. Morelli & P. Beck-Peccoz & I. Chiodini

Received: 23 October 2013 / Accepted: 9 January 2014 / Published online: 8 February 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Abstract Summary Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8 % of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure. Introduction To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO). Methods We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10year probability of a major osteoporotic fracture ≥7.5 %, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥2 incident fragility fractures and/or a BMD decrease greater than the least significant change. Results Bisphosphonate treatment failure was observed in 25.8 % of patients. Age, body mass index, years since E. Cairoli (*) : C. Eller-Vainicher : V. V. Zhukouskaya : S. Palmieri : V. Morelli : P. Beck-Peccoz : I. Chiodini Unit of Endocrinology and Metabolic Diseases, Department of Clinical Sciences and Community Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Padiglione Granelli, Via F. Sforza 35, 20122 Milan, Italy e-mail: [email protected] F. M. Ulivieri Unit of Nuclear Medicine, Department of Clinical Sciences and Community Health, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Padiglione Granelli, Via F. Sforza 35, 20122 Milan, Italy

menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95 % CI 1.10–9.50, P=0.034) and baseline alkaline phosphatase total activity levels ≥66.5 U/L (OR 4.22, 95 % CI 1.48–12.01, P=0.007), regardless of age, number of falls, LS BMD, and baseline SDI. Conclusions The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates. Keywords Alkaline phosphatase . Bisphosphonates . Primary osteoporosis . Treatment failure

Introduction Nowadays, the antiresorptive treatments, especially bisphosphonates, are the main therapies for osteoporosis and their goal is the reduction of the fracture risk. Although they are effective in the majority of patients, some individuals do not adequately respond to these drugs [1, 2]. The prevalence of the inadequate response to the antiresorptive drugs is largely discordant among the different studies, varying from 9.5 to 53 % [3–11]. These different findings may be due firstly to the fact that the criteria for defining an inadequate response to antiresorptive drugs have been different among the different studies, being based on a BMD decrease that exceeds a specific threshold after a given period of treatment [2, 3, 12], on the occurrence of new fragility fractures [6, 7, 9, 11, 13], or on both criteria [4, 5, 8, 10, 14, 15]. In some studies, the changes in biochemical markers of bone turnover were also considered in

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the evaluation of the response to treatment [15–17]. Recently, a working group of the International Osteoporosis Foundation (IOF) provided the guidelines concerning the definition of the failure of therapies used to reduce the risk of fractures [15]. Moreover, in the previous studies the patients with secondary osteoporosis [3, 4, 6, 7, 11], hypovitaminosis D [3–11] or with unsatisfactory compliance were not excluded [3–8]. This may have biased the true prevalence of the inadequate response to the antiresorptive drugs. Indeed, several authors identified the presence of a secondary osteoporosis [2, 3, 5, 6, 11] and/or hypovitaminosis D [2, 4–6, 8–11] or the poor compliance [2, 3, 5, 6] as the factors that may account for an inadequate clinical outcome of the therapy. These predictable factors are of utmost importance since it is well known that in patients with secondary osteoporosis, the medical treatment may be suboptimal or ineffective [18]. Moreover, the pivotal trials, which first demonstrated the efficacy of bisphosphonates in preventing the incident fractures, included calcium and vitamin D supplementation [19, 20]. Finally, it is widely accepted that a 70–80 % of compliance is needed to obtain the effect of the drug therapies for osteoporosis [21]. However, even when these conditions are excluded, some patients do not respond to bisphosphonate treatment and should be considered the “true” inadequate responders to osteoporosis treatment [15]. The possible additional factors associated with an inadequate response to the bisphosphonate therapy in patients without secondary osteoporosis and/or hypovitaminosis D and with an adequate adherence to the therapy are unknown. This is an important lack of knowledge, since the individuation of the possible risk factors of an inadequate response to osteoporosis therapy could consent to act on these factors or to choose the most suitable drug for a given patient [14]. Therefore, the aim of our study was to evaluate the true prevalence of the bisphosphonate treatment failure and its possible associated factors in a homogenous sample of postmenopausal women with primary osteoporosis and adequate calcium and vitamin D supplementation, treated for 36 months with bisphosphonates and who were compliant to the therapy.

Patients and methods Study design, population, inclusion/exclusion criteria The present study is the continuation of a protocol aimed to evaluate the prevalence of subclinical causes of secondary osteoporosis [22]. Briefly, 1,095 patients consecutively admitted to our Osteoporosis and Metabolic Bone Diseases Outpatients Clinic from September 2009 to December 2011 and referred by their primary care physician for reduced BMD and/or a history of an adult fragility fracture, underwent an accurate workup, designed to find out the prevalence of

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secondary osteoporosis after the normalization of vitamin D levels. Among these subjects, 602 patients were affected with an apparent primary osteoporosis. In these subjects, a general chemistry profile, serum phosphate, serum cortisol after 1-mg overnight dexamethasone suppression test, antitissue transglutaminase and endomysial antibodies, testosterone (in males), 25-hydroxyvitamin D (25OHVitD), serum and urinary calcium and PTH levels (before and after 25OHVitD levels normalization), and the creatinine clearance estimated by Cockcroft–Gault equation (normal values >60 mL/min) were assessed. In order to normalize 25OHVitD levels, all patients with 25OHVitD concentration below 75 nmol/L received cholecalciferol supplementation. An oral bolus of 100,000 IU or 300,000 IU of cholecalciferol was administered in patients with 25OHVitD levels between 25 and 75 nmol/L and below 25 nmol/L, respectively. Eventually, after the exclusion of subjects with a secondary form of osteoporosis, including those taking drugs known to affect bone metabolism, 331 patients (309 females) were found to be affected with primary osteoporosis. The complete protocol and the inclusion and exclusion criteria have been described elsewhere [22]. All patients with primary osteoporosis (n=331) were evaluated for the need of an antiresorptive therapy with bisphosphonates. Among these, all previously untreated postmenopausal women with a fragility fracture and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥7.5 % (n=154) were enrolled in the present 3-year prospective observational study [23]. All patients were treated with alendronate 70 mg/weekly or risedronate 35 mg/weekly. During the 3-year follow-up, in all patients, a cholecalciferol supplementation of 50,000 IU monthly and 400 IU daily was administered [24] and in those with a calcium intake