Intravenous Treatment With Ibandronate Normalizes Bone Matrix Mineralization and Reduces Cortical Porosity After Two Years in Male Osteoporosis: A Paired Biopsy Study

Abstract

The spectrum of therapeutic options and the amount of clinical trials for male osteoporosis (mOP) is lower than those for postmenopausal osteoporosis. Therefore, we examined the effects of 24 months of ibandronate (IBN) treatment (3 mg/3 mL intravenously every 3 months) on bone material quality in 19 subjects with mOP within an open-label, single-center, prospective phase III study (Eudract number 2006-006692-20). Patients (median age [25th, 75th percentiles] 53.0 [44.5; 57.0] years) were included if they had low bone mineral density (BMD) and/or at least one low trauma fracture and no secondary cause of osteoporosis. The primary endpoint was to evaluate IBN effects on cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) of paired transiliacal bone biopsies (baseline, 24 months). Secondary endpoints included changes in areal bone mineral density (BMD by dual-energy X-ray absorptiometry [DXA]) and serum markers of bone turnover including type I collagen peptides CrossLaps (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and osteocalcin (OC). At baseline, cancellous bone matrix mineralization from mOP was lower than published reference data (mean degree of mineralization Cn.CaMean À1.8%, p < 0.01). IBN treatment increased calcium concentrations versus baseline (Cn.CaMean þ2.4%, Ct.CaMean, þ3.0% both p < 0.01), and reduced heterogeneity of mineralization (Cn.CaWidth À14%, p ¼ 0.044; Ct.CaWidth, À16%, p ¼ 0.001), leading to cancellous BMDD within normal range. IBN treatment was associated with a decrease in porosity of mineralized cortical tissue (À25%, p ¼ 0.01); increases in BMD at the lumbar spine, the femoral neck, and the total hip (þ3.3%, þ1.9%, and þ5.6%, respectively, p 0.01); and reductions in CTX (À37.5%), P1NP (À44.4%), and OC (À36.3%, all p < 0.01). Our BMDD findings are in line with the reduction of bone turnover markers and the increase in BMD by IBN in our patients and suggest that the latter mainly reflects the increase in matrix mineralization and the reduction of cortical porosity in this cohort with mOP.

Ibandronate Increases Sclerostin Levels and Bone Strength in Male Patients with Idiopathic Osteoporosis

“…Using paired biopsies, we recently demonstrated in the same cohort of MIO patients that mineralization improved within 24 months of IBN therapy [11].…”

“…Paired biopsy micro-CT data were previously reported [3,11]. Inclusion criteria were adapted from major interventional trials in male osteoporosis and consisted of either (1) a femoral neck T-score of -2.0 or less and a lumbar spine Tscore of -1.0 or less or (2) a femoral neck T-score of -1.0 or less and at least one prevalent osteoporotic fracture (i.e., at least one vertebral fracture grade I according to the Genant criteria or one low-trauma peripheral fracture).…”

“…Inclusion criteria were adapted from major interventional trials in male osteoporosis and consisted of either (1) a femoral neck T-score of -2.0 or less and a lumbar spine Tscore of -1.0 or less or (2) a femoral neck T-score of -1.0 or less and at least one prevalent osteoporotic fracture (i.e., at least one vertebral fracture grade I according to the Genant criteria or one low-trauma peripheral fracture). [3,11,16]. Patients were not included if they had at least one concomitant known disease which negatively affects bone metabolism: any systemic or local inflammatory or autoimmune disease, any type acute or chronic liver disease, type 1 or type 2 diabetes mellitus, hypo-or hyperthyroidism, depression, alcohol intake [2 IU/day, smoking [10 cigarettes/day, coronary heart disease, cardiomyopathy, ankylosing spondylitis, osteogenesis imperfecta, depression, eating disorders, chronic malnutrition or malabsorption, hemochromatosis, chronic obstructive pulmonary disease, Cushing's disease, hypogonadism, body mass index B20 kg/m 2 , any stage of hyperparathyroidism, hypoparathyroidism, serum calcium or phosphate levels outside range of normal, any stage of chronic kidney disease, immunosuppression, any medical history of malignoma, and/or chemotherapy/radiation therapy.…”

“…Recently, in elderly MIO patients, extensive microstructural changes in the subcortical region of the femoral neck as well as decreased trabecular and cortical bone volume were reported with prevalent hip fractures compared to male patients with osteoarthritis. These changes were caused by altered gene expression of RUNX2 and Osterix in the osteoblast cell lineage and decreased mineralization [10,11].…”

Long-term safety of antiresorptive treatment: bone material, matrix and mineralization aspects

“…72 It is difficult to speculate on general differences between antiresorptive treatment effects in material properties (in particular tissue mineralization) in cancellous versus cortical bone compartments, as few comparative data are available. Considering the mineralization pattern, cortical bone was found to be affected by bisphosphonate in a similar manner as cancellous bone, 73 whereas others report an increase in the mineral-to-matrix ratio of cortical bone only. 74 These works analyzed bone from short-term bisphosphonate treatment.…”