Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study

Rheumatol Int (2006) 26: 427 431 DOI 10.1007/s00296-005-0004-4 ORIGINAL ARTICLE J. D. Ringe Æ H. Faber Æ P. Farahmand Æ A. Dorst Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study Received: 14 March 2005 / Accepted: 21 March 2005 / Published online: 7 July 2005 Ó Springer-Verlag 2005 Abstract Osteoporosis is prevalent in men with an estimated one in eight men older than 50 years suffering from osteoporotic fracture, and a higher mortality rate after fracture among men compared with women. There are few approved therapies for osteoporosis in men. This observational study assesses the efficacy and safety of risedronate in the treatment of men with primary and secondary osteoporosis. A single-center, open label, randomized, prospective 1-year study was conducted in men with primary or secondary osteoporosis. Patients were randomized to risedronate (risedronate 5 mg/day plus calcium 1,000 mg/day and vitamin D 800 IU/day) or control groups (alfacalcidol 1 lg/day plus calcium 500 mg/day or vitamin D 1,000 IU/day plus calcium 800 mg/day). Bone mineral density (BMD) measurements, X-rays of the spine, a medical history and physical exam, and patient self-assessments of back pain were performed at baseline and 12 months. Blinded semi-quantitative fracture assessment was conducted by a radiologist. A total of 316 men with osteoporosis were enrolled in the trial (risedronate, n=158; control, n=158). At 1 year lumbar spine BMD increased by 4.7% in the risedronate group versus an increase of 1.0% in the control group (P<0.001). Significant increases in BMD at the total hip and femoral neck were also observed with risedronate compared with the control group. The incidence of new vertebral fracture in the risedronate group was reduced by 60% versus the control group (P=0.028). Daily treatment with risedronate for 12 months significantly increased BMD at the lumbar spine, femoral neck and total hip and significantly reduced the incidence of new vertebral fractures. This is the first prospective, randomized, controlled trial to J. D. Ringe (&) Æ H. Faber Æ P. Farahmand Æ A. Dorst Medizinische Klinik 4, Allgemeine Innere (Rheumatology/Osteology), Klinikum Leverkusen, Akademisches Lehrkrankenhaus der Universita t zu Ko ln, 51375 Leverkusen, Germany E-mail: ringe@klinikum-lev.de demonstrate a significant reduction in vertebral fractures in 1 year in men with primary or secondary osteoporosis. Keywords Risedronate Æ Male Æ Osteoporosis Æ Bisphosphonates Æ Vertebral fracture Æ Non-vertebral fracture Introduction Osteoporosis is a common disease in postmenopausal women that manifests itself as fractures, most commonly at the spine, hip or wrist, and causes significant morbidity and mortality [1]. Although osteoporosis is less prevalent in men, it has been estimated that 30% of all hip fractures occur in males and that one in eight men older than 50 years will experience an osteoporotic fracture [2]. Moreover, studies have shown that the mortality rate after fracture in men is higher compared with that in women [3, 4]. There are few approved therapies for osteoporosis in men, and the disease remains largely under-diagnosed and under-treated [5, 6]. Androgen replacement therapy is effective in hypogonadal men [7], but they represent only a small proportion of men with osteoporosis. More recently, the bisphosphonate alendronate was shown to be effective for treatment of male osteoporosis [8 10]; and both alendronate and risedronate have been approved for treatment of glucorticoid-induced osteoporosis (GIO) in men in a variety of geographies [11]. Risedronate is a potent bisphosphonate that inhibits osteoclast activity and has been demonstrated to reduce both clinical vertebral and nonvertebral fractures in postmenopausal women within 6 months of treatment [12, 13] and to reduce hip fractures over a 3-year treatment period [14]. In men, risedronate has been shown to reduce vertebral fractures in patients with glucocorticoid-induced osteoporosis within 1 year [15, 16]. The aim of the present trial was to investigate the 1 year

428 therapeutic efficacy of risedronate in a pure male population with primary and secondary osteoporosis. Methods Study subjects This was a single-center, open label, randomized, prospective 1-year study, which enrolled men with primary or secondary osteoporosis. Osteoporosis was defined as a baseline lumbar spine bone mineral density (BMD) T-score of )2.5 SD and a baseline femoral neck BMD T-score of )2.0 relative to a healthy young adult male reference population. Men with or without pre-existing prevalent vertebral fractures were included in the study. The distinction primary or secondary osteoporosis was based on a thorough history of possible risk factors, medications or underlying diseases and complementary laboratory examinations. Patients with known hypersensitivity to bisphosphonates, severe impairment of renal function, hypocalcaemia and a history of bisphosphonate or fluoride pretreatment within the last 12 months were excluded from the study. Study design Eligible patients were randomized to risedronate or control groups, stratified by the presence of prevalent vertebral fractures at baseline. All patients in the risedronate treatment arm received risedronate (5 mg daily), elementary calcium (1,000 mg daily) and vitamin D (800 IU daily). Patients in the control group received one of two treatments dependent upon the presence of prevalent vertebral fractures: patients with prevalent vertebral fractures received alfacalcidol (1 lg daily) and calcium (500 mg daily); patients with no previous vertebral fractures received plain vitamin D (1,000 IU daily) and calcium (800 mg daily). Patient visits were performed at baseline and 12 months. Outcome measurements BMD was measured at baseline and observer blind at 12 months at the lumbar spine, femoral neck and hip by dual energy X-ray absorptiometry using the DEXA- Expert technique (Lunar Corp., Madison, WI, USA). Instrument and operator quality control measures were conducted and analyzed throughout the study. T-scores at baseline for the lumbar spine and femoral neck were calculated from a young male database provided by the manufacturer. Radiographic X-rays of the spine were obtained at baseline and 12 months. Assessment of vertebral fracture was performed using the semi-quantitative technique by a radiologist who was blinded to treatment allocation. Definitive fractures were determined by visual inspection. For equivocal vertebral fractures, vertebral heights were measured (anterior, median, posterior) and incident vertebral fractures were defined as a decrease in any vertebral height of at least 20%. A medical history and physical examination, including single height measurements, were obtained at all visits. Back pain was scored by patients at baseline and 12 months using a four-point self-assessment scale: 0=none, 1=mild, 2=moderate, 3=severe. Efficacy endpoints The primary efficacy endpoint was change in BMD at the lumbar spine. Secondary endpoints included assessment of the incidence of new vertebral fractures; change in BMD at the femoral neck and total hip; change in body height; course of back pain; and the incidence of non-vertebral fractures. Statistical analysis All analyses were performed within the intent-to-treat population, which included all patients who received at least one dose of study medication. Changes in BMD after 12 months were compared using analysis of covariance with the baseline BMD value as covariate. The Wilcoxon Mann Whitney U-test (continuous data) or Fisher s exact test (categorical data) was used to compare differences between treatment groups. All comparisons were two-sided and a P<0.05 was considered statistically significant. Results Patients and baseline characteristics From a screened population of 580 men sent to our outpatient department for diagnosis and/or treatment of osteoporosis a total of 316 men fulfilling the inclusion criteria and given the diagnosis of primary or secondary osteoporosis; were enrolled into the trial (risedronate, n=158; control, n=158). The number of patients with at least one prevalent vertebral fracture at baseline was similar in both treatment groups. A total of 84 (53.2%) and 81 (51.3%) patients had at least one prevalent fracture in the risedronate and control groups, respectively. Patient disposition is shown in Fig. 1. The baseline characteristics were similar and are summarized in Table 1. The mean lumbar spine and femoral neck BMD were approximately 3.3 and 2.5 SD, respectively, below the normal reference young adult mean. In the risedronate treatment group, a total of 94 patients had primary osteoporosis and 64 patients had secondary osteoporosis. In the control group a total of 92 and 66 patients had

429 Fig. 1 Patient disposition Table 1 Baseline patient characteristics primary and secondary osteoporosis, respectively. All 316 patients were re-examined at month 12. BMD changes Risedronate (n=158) Control a (n=158) Age (years) 55.8 (10.5) 58.0 (10.3) Weight (kg) 76.2 (13.5) 73.1 (9.6) Height (cm) 174.7 (7.0) 174.2 (6.2) Lumbar spine BMD T-score )3.34 )3.29 Femoral neck BMD T-score )2.45 )2.59 Total hip BMD T-score )2.63 )2.65 Prevalent vertebral fractures (%) 53.2 51.3 Data are given as mean (SD) unless otherwise specified a Received alfacalcidol/vitamin D and calcium The findings of the primary efficacy endpoint showed that treatment with risedronate resulted in a significant increase in lumbar spine BMD compared with the control group. At 1 year, there was an average 4.7% increase in the lumbar spine BMD in patients treated with risedronate compared with an increase of 1.0% in the control group (P<0.0001). Similarly, at the other BMD measurement sites total hip and femoral neck risedronate treatment produced a significant increase in BMD compared with the control group. The mean BMD percent changes after 12 months in patients treated with risedronate were +2.7% at the total hip and +1.8% at the femoral neck compared with +0.4% and +0.2% respectively, in the control group (P<0.0001) (Fig. 2). Fig. 2 Percent change in BMD from baseline to 12 months in men with osteoporosis in the risedronate and control groups Over 1 year, the incidence of new vertebral fractures in the risedronate group was reduced by 60% versus the control group (P=0.028) (Fig. 3). Over 1 year, 8 patients suffered new vertebral fractures (5.1%) in the risedronate treated group, compared with 20 patients with new vertebral fractures (12.7%) in the control group. Assessment of the incidence of nonvertebral fractures showed that there was a 42% reduction in the risedronate-treated group compared with control, although this difference did not reach statistical significance (P=0.227). Over 1 year, nonvertebral fractures occurred in 10 patients (6.3%) in the risedronate-treated group compared with 17 patients (10.8%) in the control group. Body height After 1 year of treatment, the average rate of height loss was significantly lower in the risedronate group compared with the control group (1.1 mm in the risedronate group versus )4.6 mm in the control group, P<0.001). Back pain Significant improvements in mean back pain score were observed for both treatment groups compared with baseline at 1 year (P<0.0001). Comparison of the mean Fracture incidence Fig. 3 Incidence of new vertebral fractures in patients treated with control or risedronate 5 mg

430 back pain scores between treatment groups showed that the improvement in back pain in patients treated with risedronate was significantly greater compared with the control group (P<0.0001). In patients treated with risedronate, 32% of the patients reported no back pain, and 45%, 20%, and 3% of patients reported mild, moderate and severe back pain, respectively. In contrast, in the control group, 7% had no back pain and 44%, 36% and 13% of patients had mild, moderate and severe back pain, respectively. Safety assessments In all patients laboratory examinations of blood (blood count, ygt, alk.phosph., LDH, Na, K, Ca, Pi, Fe, creat, uric acid, total protein, protein electropheresis) and 24- h-urine (creat., Ca, Pi) were performed at onset and after 12 months. There was no difference in number and quality of adverse events between the two groups. We did not observe any severe adverse event or withdrawal due to the antiosteoporotic medication. Discussion Despite the large number of men affected, osteoporosis in this population remains largely under-diagnosed and under-treated. We report here the first study to demonstrate early treatment effects in men with established osteoporosis. Daily treatment with risedronate 5 mg resulted in significant BMD increases of approximately 5% at the lumbar spine, 2% at the femoral neck and 3% at the hip in men at 1 year. Assessment of fracture showed a 60% reduction in the number of patients with new vertebral fractures compared with control patients (P=0.028), within 1 year of treatment. The current study also demonstrated significant reductions in height loss and back pain compared with control (P<0.001). Several studies have shown that there is a high risk for future fracture in patients with pre-existing or new incident vertebral fractures [17 19], exemplifying the need for rapid and effective fracture protection to prevent the fracture cascade from taking hold. The rapid reduction in the incidence of vertebral fractures observed in this study is consistent with the results of risedronate treatment for CIO in men reported by Reid et al. [15, 16], in which risedronate treatment resulted in an 82% reduction in the incidence of vertebral fractures at 1 year. Studies of risedronate treatment in postmenopausal women with osteoporosis have also shown reductions in the incidence of radiographically defined fracture by 65% at 1 year [20, 21]. In addition, a recent retrospective analysis by Roux et al. [12] examining the time course of fracture risk reduction in the risedronate VERT studies (MN and NA) showed that treatment with risedronate significantly reduced the incidence of clinical vertebral fractures within 6 months of treatment (P<0.05). Two studies have shown that alendronate increases BMD in men with osteoporosis [8, 10]; one of these studies showed a significant reduction of vertebral fractures after 2 years of treatment using a quantitative morphometric method, although these findings did not reach significance when a semiquantitative method was used [10]. At 1 year, the incidence of nonvertebral fractures in the risedronate group was reduced by 42% compared with control, although this did not reach statistical significance. Recently, a pooled analysis of four large randomized, double-blind, placebo-controlled studies in postmenopausal women [13] showed that risedronate significantly reduced the incidence of nonvertebral fractures after 1 year by 74% compared with control. Limitations of the study include the open label design, which could have introduced potential bias. To allow objective evaluation, especially of patient radiographs, the radiologist was not informed about the patient s treatment allocation. 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