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The deception and fallacies of sponsored randomized prospective double-blinded clinical trials: the bisphosphonate research example.

The randomized prospective double-blinded clinical trial (RCT) is accepted as Level I evidence and is highly regarded. However, RCTs that gained FDA approval of drugs such as Vioxx, Fen-Phen, and oral and intravenous bisphosphonates have proven to generate misleading results and have not adequately identified serious adverse reactions. The development, research, and clinical marketing of the oral and intravenous bisphosphonates can serve as a representative example for the deteriorated value of many of today's RCTs. The expected high value of RCTs is jeopardized by: (1) sponsorship that incorp

Awareness and education of patients receiving bisphosphonates.

BACKGROUND: Bisphosphonates are used to fight osteoporosis and for treating malignancies. In 2003, the first case reports appeared that described bisphosphonate-induced osteonecrosis of the jaw (BONJ). The aim of this study was to assess patient awareness of the adverse effects of bisphosphonates in order to improve cooperation among doctors and between doctors and patients. METHODS: Patients with symptoms of osteoporosis, prostate cancer, or breast cancer were surveyed to determine their knowledge of bisphosphonates. The questionnaire comprised 12 questions that covered sociographic data, ki

Osteoporosis prevalence and characteristics of treated and untreated nursing home residents with osteoporosis.

OBJECTIVES: Our primary objective was to describe the prevalence of osteoporosis (OP) diagnosis in nursing home residents (NHRs). Secondary … ed to have OP. OP pharmacologic therapies were extracted from the pharmacy claims data and included alendronate, calcitonin salmon, denosumab, ibandronate, raloxifene, risedronate, and teriparatide. Using MDS items, cognitive impairment (Brief Instrument for Mental Status, Cognitive Performance Scale) and functional impairment (composite activities of daily l …

Declining trend in osteoporosis management and screening following vertebral compression fractures - a national analysis of commercial insurance and medicare advantage beneficiaries.

BACKGROUND CONTEXT: Despite the increasing national incidence, osteoporosis and its associated comanagement, often remain an overlooked issu … patient was $1,511. The most commonly prescribed treatment and associated average cost/patient was alendronate sodium (N=1,239; 66.6% to $120/patient). The most costly prescribed treatment was Forteo (N=177; 2.7%) with an average cost/patient of $12,074 and cost/injection being $2,373. Only 36.7% (N=2,371) received a dual-energy X-ray absorptiometry/bone den …

Bisphosphonates: the first 40 years.

The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timel … ntracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the cry …

Medical treatment of otosclerosis: rationale for use of bisphosphonates.

Otosclerosis is a bony dyscrasia characterized by histopathological findings of osteoclast production. Osteoclastogenesis explains the pathogenesis of otosclerosis. Basic science research in the experimental animal otic capsule has given insight into the process of evolution of otosclerosis. The normal otic capsule is preserved with very little bone turnover as a result of the production of osteoprotegerin (OPG) by the membranous inner ear that prevents the activation of osteoclasts. Animals genetically unable to produce OPG demonstrated the production of hearing loss and histopathology of the

Methionine down-regulates TLR4/MyD88/NF-κB signalling in osteoclast precursors to reduce bone loss during osteoporosis.

BACKGROUND AND PURPOSE: Studies have demonstrated that a moderate intake of amino acids is associated with development of bone health. Methionine, a sulphur-containing essential amino acid, has been largely implicated for improving cartilage formation, however its physiological significance on bone integrity and functionality have not been elucidated. We investigated whether methionine can prevent osteoporotic bone loss. EXPERIMENTAL APPROACH: The anti-resorptive effect of methionine, (250 mg kg(-1) body wt administered in drinking water for 10 weeks), was evaluated in ovariectomized (OVX) ra

Pharmacological interventions versus placebo, no treatment or usual care for osteoporosis in people with chronic kidney disease stages 3-5D.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than amo … atients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certai …

Management of osteoporosis in the aging male: focus on zoledronic acid.

Osteoporosis in the aging male remains an important yet under-recognized and undertreated disease. Current US estimates indicate that over 14 million men have osteoporosis or low bone mass, and men suffer approximately 500,000 osteoporotic fractures each year. Men experience fewer osteoporotic fractures than women but have higher mortality after fracture. Bisphosphonates are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivo markers of bone turnover, increase bone mineral density, decrease fractures, and improve survival in men with osteoporosis. Intravenous zoledr

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… Subjects were randomly assigned to receive alendronate 70 mg weekly or placebo at enrollment. At 12 months, all subjects in the placebo group crossed over to the alendronate group, and subjects in the alendronate group were re-randomized to continue alendronate or placebo. … decreased BMD at all skeletal sites compared to the alendronate–alendronate arm. …

Safety and tolerability of zoledronic acid and other bisphosphonates in osteoporosis management.

Bisphosphonates (BPs) are widely used in the treatment of postmenopausal osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively). The former inhibit farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine triphosphate. These mechanisms of action are associated with different antifracture efficacy, and NBPs show the most powerful action. Moreover, recent evi

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… The once-weekly alendronate-vitamin D tablet was shown to increase patient compliance, to provide an antiresorptive efficacy equivalent to once-weekly alendronate 70 mg without cholecalciferol, and to improve vitamin D status. … Schnitzer T Bone HG Crepaldi G Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group Aging 2000 12 1 1 12 10746426 41. …

Clinical role of bisphosphonate therapy.

Bisphosphonates (BPs) are synthetic analogues of pyrophosphate. They inhibit bone resorption and are therefore widely used in disorders where there are increases or disruptions in bone resorption. This includes postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, Paget's disease of bone, and malignancy-related bone loss. To best understand the clinical application of BPs, an understanding of their pharmacokinetics and pharmacodynamics is important. This review describes the structure, pharmacology and mode of action of BPs, focusing on their role in clinical practice. Controversie

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… Alendronate localization in rat bone and effects on osteoclast ultrastructure. … One study comparing the effects of alendronate and risedronate showed that alendronate was associated with greater gains in BMD and reductions in bone resorption, as shown in Figure 3 . 20 Another study compared the effects of weekly alendronate with a single dose of zoledronate, showing that suppression …

Progress in osteoporosis and fracture prevention: focus on postmenopausal women.

In the past decade, we have witnessed a revolution in osteoporosis diagnosis and therapeutics. This includes enhanced understanding of basic bone biology, recognizing the severe consequences of fractures in terms of morbidity and short-term re-fracture and mortality risk and case finding based on clinical risks, bone mineral density, new imaging approaches, and contributors to secondary osteoporosis. Medical interventions that reduce fracture risk include sufficient calcium and vitamin D together with a wide spectrum of drug therapies (with antiresorptive, anabolic, or mixed effects). Emerging

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… Some small studies suggest that GI side effects may be fewer with risedronate than alendronate [ 110 ]. The most common bisphosphonates licensed and used internationally are alendronate, risedronate, ibandronate, and zoledronic acid. … Increases in spinal BMD with alendronate continue for up to 7 years of daily therapy [ 119 ]. Daily alendronate has a similar benefit and adequate tolerability even among older female residents of long-term care facilities [ 120 ]. …

Bisphosphonates for Paget's disease of bone in adults.

BACKGROUND: Bisphosphonates are considered to be the treatment of choice for people with Paget's disease of bone. However, the effects of bi … icipants) compared bisphosphonates (etidronate, tiludronate, ibandronate, pamidronate, olpadronate, alendronate, risedronate, zoledronate) versus placebo, seven compared two bisphosphonates (992 participants), one trial compared a bisphosphonates with a bisphosphonate plus calcitonin (44 participants), and two studies, the largest trial (1331 participants) an …

Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility.

Denosumab is a breakthrough biological drug approved by the Food and Drug Administration and European Medicines Agency for the treatment of osteoporosis in 2010. It is a fully human monoclonal antireceptor activator of nuclear factor kappa-B ligand antibody, which inhibits the activity of osteoclasts, resulting in an antiresorptive effect with a significant increase in bone mineral density. The FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial, comparing denosumab with no treatment in 7868 women with postmenopausal osteoporosis, showed an important reduc

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… Open-label alendronate patients discontinued alendronate therapy after 24 months and received no additional drug therapy. The original placebo group was maintained for the entire 48 months. … denosumab 60 mg every 6 months or continuing oral alendronate 70 mg weekly. …

Bisphosphonate conjugation for bone specific drug targeting.

Bones provide essential functions and are sites of unique biochemistry and specialized cells, but can also be sites of disease. The treatment of bone disorders and neoplasia has presented difficulties in the past, and improved delivery of drugs to bone remains an important goal for achieving effective treatments. Drug targeting strategies have improved drug localization to bone by taking advantage of the high mineral concentration unique to the bone hydroxyapatite matrix, as well as tissue-specific cell types. The bisphosphonate molecule class binds specifically to hydroxyapatite and inhibits

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… In human OS cell lines, MMP-2 and invasion were reduced with alendronate treatment ( Cheng et al., 2004 ). … In a non-bone targeting antineoplastic application, a conjugate of alendronate and glucomannan was used for specific uptake by and elimination of highly endocytic tumor-associated macrophages, while alendronate alone did not show this effect ( Zhan et al., 2014 ). …

Intravenous zoledronic acid for the treatment of osteoporosis: The evidence of its therapeutic effect.

INTRODUCTION: Osteoporosis is a disease characterized by low bone mineral density and poor bone quality resulting in reduced bone strength and increased risk of fracture. Oral bisphosphonates, first-line therapy for most patients with osteoporosis, are associated with suboptimal adherence to therapy due to factors that include a complex dosing regimen and gastrointestinal intolerance in some patients. Intravenous bisphosphonates address these limitations through infrequent injectable dosing that assures 100% bioavailability. Intravenous zoledronic acid is the newest bisphosphonate to be approv

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… mg/week in postmenopausal women previously treated with alendronate. … Alendronate is the only generic bisphosphonate currently available. …

The Effect of Bisphosphonates on Fracture Healing Time and Changes in Bone Mass Density: A Meta-Analysis.

BackgroundOsteoporosis is a common complication of acute fracture, which can lead to fracture delayed union or other complications and resulting in poor fracture healing. Bisphosphate is a common anti-osteoporosis drug, but its application in fracture patients is still controversial because of its inhibitory effect on bone resorption.MethodStudies were acquired from literature databases in accordance with established inclusion criteria. Standard mean difference (SMD) and 95% confidence intervals (Cls) were calculated to evaluate the effectiveness of the bisphosphonates treatment in fracture pa

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… , C. ( 36 ) | 63 | 77.14 | 46.0% | 30.95 | OVCF | PKP surgery | Zoledronic acid | 2 years Uchiyama, S. ( 37 ) | 80 | 70.1 | 38% | – | Distal Radial Fractures | Surgery | alendronate | 6months van der P. ( 38 ) | 41 | 46.0 | 43.9% | 25.2 | Lower Leg fracture | Surgery | Alendronate | 1 year Zhang, J. … Alendronate in the Prevention of Bone Loss After a Fracture of the Lower Leg. J Bone Miner Res (2002) 17(12):2247–55. 10.1359/jbmr.2002.17.12.2247 39. Zhang J, Zhang T, Xu X, Cai Q, Zhao D. …

Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer.

Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is a combination of chemotherapy and surgery. However, anticancer drugs are still limited due to severe side effects, drug resistance, poor blood supply, and non-specific drug uptake, necessitating high toxic doses. Bisphosphonates are the main class of drugs utilized to inhibit metastatic bone cancer. It is

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… The IC 50 and IC 90 values of 5-Fluoro-2′-deoxyuridine, 5-fluorouracil, zoledronate, alendronate, and 5-Fluoro-2′-deoxyuridine-alendronate on the cell line tested are shown in Table 5 . … 64.7 | 8.2 | 62.5 Alendronate | 55.9 | 100.7 | 32.3 | 69.7 | 12.7 | 39.8 | 16.6 | 38.2 5-Fluoro-2′-deoxyuridine-alendronate-aledronate | 45.0 | 73.3 | 44.9 | 79.6 | 59.9 | 123.0 | 40.1 | 69.5 4.2. …

European guidance for the diagnosis and management of osteoporosis in postmenopausal women.

UnlabelledGuidance is provided in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis.IntroductionThe European Foundation for Osteoporosis and Bone disease (subsequently the International Osteoporosis Foundation) published guidelines for the diagnosis and management of osteoporosis in 1997. This manuscript updates these in a European setting.MethodsThe following areas are reviewed: the role of bone mineral density measurement for the diagnosis of osteoporosis and assessment of fracture risk; general and pharmacological management of oste

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… Thus, there was no evidence of synergy between PTH and alendronate [ 72 ]. … Alendronate was chosen because of the lower price of generic formulations currently available in Europe. Since the price of alendronate is very low in the UK and is unlikely to be sustained in Europe, the price of alendronate was set at 1 Euro daily. …

Role of zoledronic acid in the prevention and treatment of osteoporosis.

Taken once a year, intravenous zoledronic acid (Zol) (Reclast® or Aclasta®) is a third-generation nitrogen-containing bisphosphonate that is effective compared with placebo in reducing the risk of fractures in patients with postmenopausal osteoporosis and recent low-trauma hip fracture. In glucocorticoid-induced osteoporosis, there is no significant difference between Zol and risedronate for new fractures. Improvements in bone mineral density and early reduction of bone remodeling markers are observed in postmenopausal osteoporosis, recent low-trauma hip fracture, and glucocorticoid-induced os

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… The Zol infusion was shown to be noninferior to weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline (Zol 6.1% vs alendronate 6.2%). … Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma. 2008;22(5):346–350. doi: 10.1097/BOT.0b013e318172841c. 43. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. …