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Cortical Bone Material Strength Index and Bone Microarchitecture in Postmenopausal Women With Atypical Femoral Fractures.
Popp, KL, Caksa, S, Martinez-Betancourt, A, Yuan, A, Tsai, J, Yu, EW, Bouxsein, ML
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019;(1):75-82
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Abstract
Atypical femoral fractures are rare fractures that occur in the subtrochanteric or diaphyseal region of the femur with minimal or no trauma. Though the association of atypical femoral fractures (AFFs) and bisphosphonate (BP) use is a growing concern in the management of osteoporosis, currently there is little knowledge about which patients may be at risk for an atypical femoral fracture. Given that these fractures initiate in the femoral cortex, we aimed to determine whether cortical bone tissue properties (bone material strength index; BMSi), as measured by in vivo impact microindentation, are altered in atypical fracture patients. We also aimed to identify factors associated with the BMSi measurements. We enrolled postmenopausal women with recent AFFs (n = 15) or hip fractures (Hip Fxs; n = 20), long-term (>5 years) BP users (n = 30), and treatment naïve controls (n = 88). We measured total hip and femoral neck BMD by DXA, cortical bone microstructure at the distal tibia by HR-pQCT, and BMSi at the midtibia by impact microindentation. BMSi values were similar in all groups, with no effects of long-term BP use or lower values in patients with AFFs or Hip Fxs, even after multivariable adjustment. BMSi measurements were independent of age, femoral BMD, duration of BP treatment, vitamin D level, and cortical bone microstructure, including cortical porosity and cortical tissue mineral density. In conclusion, impact microindentation values are not negatively affected by long-term BP use and do not appear to discriminate individuals who suffer AFFs. Thus, our results do not support clinical use of impact microindentation to identify those at risk for AFFs. This remains to be verified in larger studies. © 2018 American Society for Bone and Mineral Research.
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Hypermineralization and High Osteocyte Lacunar Density in Osteogenesis Imperfecta Type V Bone Indicate Exuberant Primary Bone Formation.
Blouin, S, Fratzl-Zelman, N, Glorieux, FH, Roschger, P, Klaushofer, K, Marini, JC, Rauch, F
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017;(9):1884-1892
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Abstract
In contrast to "classical" forms of osteogenesis imperfecta (OI) types I to IV, caused by a mutation in COL1A1/A2, OI type V is due to a gain-of-function mutation in the IFITM5 gene, encoding the interferon-induced transmembrane protein 5, or bone-restricted interferon-inducible transmembrane (IFITM)-like protein (BRIL). Its phenotype distinctly differs from OI types I to IV by absence of blue sclerae and dentinogenesis imperfecta, by the occurrence of ossification disorders such as hyperplastic callus and forearm interosseous membrane ossification. Little is known about the impact of the mutation on bone tissue/material level in untreated and bisphosphonate-treated patients. Therefore, investigations of transiliac bone biopsy samples from a cohort of OI type V children (n = 15, 8.7 ± 4 years old) untreated at baseline and a subset (n = 8) after pamidronate treatment (2.6 years in average) were performed. Quantitative backscattered electron imaging (qBEI) was used to determine bone mineralization density distribution (BMDD) as well as osteocyte lacunar density. The BMDD of type V OI bone was distinctly shifted toward a higher degree of mineralization. The most frequently occurring calcium concentration (CaPeak) in cortical (Ct) and cancellous (Cn) bone was markedly increased (+11.5%, +10.4%, respectively, p < 0.0001) compared to healthy reference values. Treatment with pamidronate resulted in only a slight enhancement of mineralization. The osteocyte lacunar density derived from sectioned bone area was elevated in OI type V Ct and Cn bone (+171%, p < 0.0001; +183.3%, p < 0.01; respectively) versus controls. The high osteocyte density was associated with an overall immature primary bone structure ("mesh-like") as visualized by polarized light microscopy. In summary, the bone material from OI type V patients is hypermineralized, similar to other forms of OI. The elevated osteocyte lacunar density in connection with lack of regular bone lamellation points to an exuberant primary bone formation and an alteration of the bone remodeling process in OI type V. © 2017 American Society for Bone and Mineral Research.
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Intravenous treatment with ibandronate normalizes bone matrix mineralization and reduces cortical porosity after two years in male osteoporosis: a paired biopsy study.
Misof, BM, Patsch, JM, Roschger, P, Muschitz, C, Gamsjaeger, S, Paschalis, EP, Prokop, E, Klaushofer, K, Pietschmann, P, Resch, H
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;(2):440-9
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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 -1.8%, p < 0.01). IBN treatment increased calcium concentrations versus baseline (Cn.CaMean +2.4%, Ct.CaMean, +3.0% both p < 0.01), and reduced heterogeneity of mineralization (Cn.CaWidth -14%, p = 0.044; Ct.CaWidth, -16%, p = 0.001), leading to cancellous BMDD within normal range. IBN treatment was associated with a decrease in porosity of mineralized cortical tissue (-25%, p = 0.01); increases in BMD at the lumbar spine, the femoral neck, and the total hip (+3.3%, +1.9%, and +5.6%, respectively, p ≤ 0.01); and reductions in CTX (-37.5%), P1NP (-44.4%), and OC (-36.3%, 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.
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Intermittent zoledronic Acid prevents bone loss in adults after allogeneic hematopoietic cell transplantation.
Hari, P, DeFor, TE, Vesole, DH, Bredeson, CN, Burns, LJ
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2013;(9):1361-7
Abstract
Bone mineral density (BMD) loss is common in survivors of allogeneic hematopoietic cell transplantation (alloHCT). We performed a multicenter, phase II, randomized open-label trial of intravenous zoledronic acid (ZA) to prevent BMD loss in adult recipients of alloHCT with osteopenia before HCT. The treatment group received ZA 4 mg intravenously within 28 days pre-HCT and at 3 and 6 months after HCT. Both treatment and control groups received calcium carbonate and vitamin D supplements. Of 61 patients, 32 were randomized to the ZA cohort and 29 to the control cohorts. More patients in the ZA group had an HCT comorbidity index high-risk score of ≥3 (50% versus 21%, P < .01). Baseline BMD, T-scores, serum osteocalcin, bone alkaline phosphatase, and urine N-telopeptide (UNTX) levels were similar in both cohorts. Thirty patients were evaluable for outcomes (11 from the treatment and 19 from the control group). At 12 months, subjects in the treatment group had an improvement in BMD at the femoral neck (mean change, .018 for ZA group versus -.054 for controls; P = .04) and a significant decline in levels of UNTX (-56 for ZA group versus -9 for control; P = .04) compared with baseline. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw or renal impairment. Lower survival observed in the ZA cohort was likely related to baseline imbalance in HCT-CI scores. Intermittent ZA is effective in preserving long-term bone health in adult alloHCT recipients at risk for osteoporosis.
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Bisphosphonate-induced osteonecrosis of the jaw: comparison of disease extent on contrast-enhanced MR imaging, [18F] fluoride PET/CT, and conebeam CT imaging.
Guggenberger, R, Fischer, DR, Metzler, P, Andreisek, G, Nanz, D, Jacobsen, C, Schmid, DT
AJNR. American journal of neuroradiology. 2013;(6):1242-7
Abstract
BACKGROUND AND PURPOSE Imaging of bisphosphonate-induced osteonecrosis of the jaw is essential for surgical planning. We compared the extent of BONJ on contrast-enhanced MR imaging, [(18)F] fluoride PET/CT, and panoramic views derived from standard conebeam CT with clinical pre- and intraoperative examinations. MATERIALS AND METHODS Between February 2011 and January 2012, ten subjects with written informed consent (9 women; mean, 69.6 years; range, 53-88 years) were included in this prospective ethics-board-approved study. Patients underwent CEMR imaging, [(18)F] fluoride PET/CT, and CBCT and were clinically examined pre- and intraoperatively. Surgery was performed, and BONJ was histologically confirmed in 9 patients. Location and extent of BONJ on different modalities/examinations were graphically compared (0 = no pathologic finding, 1 = smallest, 5 = largest extent of BONJ). Rank tests were used to assess overall and paired differences of ratings in 9 patients. A P value <.05 was considered statistically significant. RESULTS Significant differences in BONJ extent among different modalities and examinations were found (P < .001). The highest median rank was seen in PET/CT (4 ± 1.12) and CEMR imaging (4 ± 1.01), followed by intraoperative examinations (3 ± 0.71), CBCT (2 ± 0.33), and preoperative examinations (1 ± 0). No significant differences were found between PET/CT and CEMR imaging (P = .23), except when comparing PET/CT to either CBCT, pre- and intraoperative examinations (all P < .05). Preoperative examinations showed significantly less extensive disease than all other modalities/examinations (all P < .05). CONCLUSIONS [(18)F] fluoride PET/CT and CEMR imaging revealed more extensive involvement of BONJ compared with panoramic views from CBCT and clinical examinations.
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RTOG 0518: randomized phase III trial to evaluate zoledronic acid for prevention of osteoporosis and associated fractures in prostate cancer patients.
Kachnic, LA, Pugh, SL, Tai, P, Smith, M, Gore, E, Shah, AB, Martin, AG, Kim, HE, Nabid, A, Lawton, CA
Prostate cancer and prostatic diseases. 2013;(4):382-6
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Abstract
BACKGROUND RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). METHODS Eligible patients with T-scores of the hip (<-1.0, but >-2.5 vs >-1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. RESULTS Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm 1 and 34.8 months for Arm 2. Only two patients experienced a bone fracture (one in each arm) resulting in no difference in freedom from any bone fracture (P=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs -5%, P<0.0001), left total hip (1% vs -8%, P=0.0002), and left femoral neck (3% vs -8%, P=0.0007). CONCLUSIONS For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL.
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Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment.
Hu, MI, Glezerman, I, Leboulleux, S, Insogna, K, Gucalp, R, Misiorowski, W, Yu, B, Ying, W, Jain, RK
Journal of the National Cancer Institute. 2013;(18):1417-20
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Abstract
Hypercalcemia of malignancy (HCM), caused primarily by tumor-induced bone resorption, may lead to renal failure, coma, and death. Although HCM can be treated with intravenous bisphosphonates, patients may not respond or may relapse on therapy. Denosumab binds the bone resorption mediator RANKL. In this single-arm, open-label, proof-of-concept study, HCM patients with albumin-corrected serum calcium (CSC) levels greater than 12.5mg/dL (Common Terminology Criteria for Adverse Events grade ≥ 3) despite recent intravenous bisphosphonate treatment received subcutaneous denosumab on days 1, 8, 15, and 29, and then every 4 weeks. The primary endpoint was the proportion of patients with CSC 11.5mg/dL or less (grade ≤ 1) within 10 days of denosumab initiation. In a prespecified interim analysis, 15 patients received denosumab (median CSC = 13.6 mg/dL). Time to response and response duration were analyzed with Kaplan-Meier methods. All statistical tests were two-sided. By day 10, 12 patients (80%; 95% exact confidence interval [CI] = 52% to 96%) responded (CSC ≤ 11.5mg/dL); median response duration was 26 days. Ten patients (67%; 95% exact CI = 38% to 88%) had complete responses (CSC ≤ 10.8 mg/dL) by day 10. Denosumab may offer a new treatment option for HCM. Clinicaltrials.gov identifier: NCT00896454.
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Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study.
Scagliotti, GV, Kosmidis, P, de Marinis, F, Schreurs, AJM, Albert, I, Engel-Riedel, W, Schallier, D, Barbera, S, Kuo, HP, Sallo, V, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2012;(8):2082-2087
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Abstract
BACKGROUND Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes. PATIENTS AND METHODS This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS). RESULTS No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported. CONCLUSIONS ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course.
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Successful treatment of calcific uraemic arteriolopathy with bisphosphonates.
Torregrosa, JV, Durán, CE, Barros, X, Blasco, M, Arias, M, Cases, A, Campistol, JM
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2012;(3):329-34
Abstract
BACKGROUND AND OBJECTIVES Calcific uraemic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition that almost exclusively affects patients with chronic kidney disease. Several therapies have been employed to treat this disease but with irregular results. We report a prospective case series of eight patients diagnosed with CUA in our unit between 2002 and 2010. MATERIAL AND METHOD The series consisted of eight patients with CUA (including 4 men, 5 dialysis patients and 3 with functioning allografts) who were treated with bisphosphonates. The diagnosis was by clinical suspicion and a confirmatory biopsy. Five patients had a previous history of high calcium-phosphorus product, 6 had a history of high parathyroid hormone levels (>800pg/ml), 4 had undergone parathyroidectomy, 5 had a history of high cumulative doses of steroids, and 6 patients were under dicoumarin treatment. None of the patients were obese or had diabetes mellitus. RESULTS In all patients, progression of skin lesions stopped between 2 to 4 weeks after starting bisphosphonate therapy, with no changes in blood levels of calcium and phosphate. Improvement in pain and lesions was faster in patients receiving intravenous ibandronate. All of these patients remained on bisphosphonate treatment for at least 6 months until the wounds healed completely. No recurrences have been observed after follow-up periods between 1 and 9 years. Renal function remained stable in transplant recipients. The treatment was well tolerated and no adverse effects were observed. CONCLUSIONS Bisphosphonates could be a new and attractive alternative to treat CUA.
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Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation.
Mainra, R, Elder, GJ
Clinical journal of the American Society of Nephrology : CJASN. 2010;(1):117-24
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BACKGROUND AND OBJECTIVES Most patients who undergo kidney or kidney-pancreas transplantation have renal osteodystrophy, and immediately after transplantation bone mineral density (BMD) commonly falls. Together, these abnormalities predispose to an increased fracture incidence. Bisphosphonate or calcitriol therapy can preserve BMD after transplantation, but although bisphosphonates may be more effective, they pose potential risks for adynamic bone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 153 kidney (61%) and kidney-pancreas (39%) transplant recipients were allocated to bisphosphonate (62%) or calcitriol (38%) therapy using an algorithm that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment. Patients received cholecalciferol and calcium as appropriate and were followed for 12 mo. RESULTS Patients who were treated with bisphosphonates had lower BMD at the lumbar spine and femoral neck and longer time on dialysis. Age and gender were similar between the groups. At 12 mo, bisphosphonate-treated patients had significant BMD increases at the lumber spine and femoral neck and a negative trend at the wrist. Patients who were allocated to calcitriol, who were assessed to have lower baseline fracture risk, had no significant change in BMD at any site. At 1 yr, mean levels of bone turnover marker and intact parathyroid hormone normalized in both groups. Incident fracture rates did not differ significantly. CONCLUSIONS With targeted treatment, BMD levels were stable or improved and bone turnover markers normalized. This algorithm provides a guide to targeting therapy after transplantation that avoids BMD loss and may reduce suppression of bone turnover.