[Bone marrow edema and atraumatic necrosis of the femoral head : Therapy]. / Knochenmarködem und atraumatische Femurkopfnekrose : Therapie.

BACKGROUND: An increase in interstitial bony fluid occurs in bone-marrow edema (BME). The exact pathogenetic processes still remain unknown. BME is an unspecific finding that can occur on its own or accompany multiple diseases and pathologies. GOAL: Literature review and presentation of new guidelines. MATERIAL AND METHODS: This is a narrative literature review followed by current advice for the therapy of atraumatic osteonecrosis of the hip, based on the recently published S3-guidelines for this disease. RESULTS AND DISCUSSION: The differentiation of at least 3 different etiologies is proposed (mechanic, reactive and ischemic). Difficult, but important, is the distinction between the mostly painful, but benign entities (BME syndrome, bone bruise) and the progressive pathologies (osteonecrosis, arthritis, CRPS, tumour). Treatment options are dependent on etiology and clinic and can often be symptomatic. Core decompression is the surgical gold standard, leading to immediate pressure relief and therefore reduction in pain. Recently, it was shown that intravenous administration of Iloprost and bisphosphonates are also effective in achieving a reduction of BME and pain, with considerable improvement in the accompanying symptoms. The combination of core decompression and infusion seems to be another possible optimization ofthe therapy, in particular in the treatment of osteonecrosis.

Nuclear magnetic resonance-based quantification of organic diphosphates.

Phosphorylated compounds are ubiquitous in life. Given their central role, many such substrates and analogs have been prepared for subsequent evaluation. Prior to biological experiments, it is typically necessary to determine the concentration of the target molecule in solution. Here we describe a method where concentrations of stock solutions of organic diphosphates and bisphosphonates are quantified using (31)P nuclear magnetic resonance (NMR) spectroscopy with standard instrumentation using a capillary tube with a secondary standard. The method is specific and is applicable down to a concentration of 200 µM. The capillary tube provides the reference peak for quantification and deuterated solvent for locking.

Effectiveness of bisphosphonates on bone mineral density in osteopenic postmenopausal women: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Various bisphosphonate agents have been proven to be effective in preventing bone loss and fracture in osteopenic postmenopausal women. This study was designed to compare the effectiveness of various BPs on preventing the loss of bone mineral density (BMD) for postmenopausal women with osteopenia. METHODS: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were screened up to identify randomized controlled trails comparing effectiveness of BPs or placebo on the BMD of postmenopausal women with osteopenia. Network meta-analysis and standard pair-wise meta-analyses were performed. The main outcomes include the percentage changes of 6-, 12-, 24-, and 36-month BMD at lumbar, total hip and femoral neck, and frequencies of new fractures and severe adverse events. RESULTS: Fourteen randomized controlled trials were eligible, involving 11,540 participants. No significant difference was presented among the available interventions for the 6-month BMD at 3 different sites, but the magnitudes of differences among the treatment regimens became gradually increased along with the extending of follow-up periods. Daily aledronate of more than 5 mg provided the maximal percentage increase on BMD of femoral neck and lumbar spine, while zoledronate provided maximal change on BMD of total hip, at different follow-up periods. This network meta-analysis also demonstrated similar frequencies of new clinical fractures and severe adverse events among different interventions. CONCLUSIONS: A ranking spectrum depicting the effectiveness on BMD percentage change following interventions with different bisphosphonate regimens was provided. Generally, regimens with zoledronate and aledronate were found to be the most effective interventions in the 3 sites at different end points.

UK clinical guideline for the prevention and treatment of osteoporosis.

INTRODUCTION: In 2008, the UK National Osteoporosis Guideline Group (NOGG) produced a guideline on the prevention and treatment of osteoporosis, with an update in 2013. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women and men age 50 years or over. METHODS: Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. RESULTS: Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment, lifestyle measures and pharmacological interventions, duration and monitoring of bisphosphonate therapy, glucocorticoid-induced osteoporosis, osteoporosis in men, postfracture care and intervention thresholds. CONCLUSION: The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals who are involved in its management.

Bone health and adherence to vitamin D and calcium therapy in early breast cancer patients on endocrine therapy with aromatase inhibitors.

OBJECTIVES: Randomized trials involving aromatase inhibitors (AIs) in the adjuvant treatment of breast cancer patients have reported increased osteoporosis risk. Bone loss can be reduced with appropriate life style, vitamin D and calcium supplements, and with bisphosphonate therapy. The aim of this analysis was to investigate adherence to vitamin D and calcium in postmenopausal breast cancer patients receiving adjuvant non-steroidal AIs, and oncologists' adherence to the bone health guidelines. MATERIAL AND METHODS: This prospective study included 438 newly diagnosed patients and those who have already been receiving non-steroidal AIs for up to 3.5 years. Median endocrine therapy duration before recruitment in the study was 10.5 months (interquartile 4.8-26.6). RESULTS: Densitometry was performed on 142 patients (32.4%) before initiation of endocrine therapy, and on additional 38 (8.6%) patients at second study visit. Densitometry was not performed on 258 (59%) patients. Vitamin D and calcium were prescribed to 329/438 (75.1%) patients at some point during the study. Patients who took more than 80% of the prescribed dose were considered adherent. Self-reported adherence was 88.4%. Osteoporosis was diagnosed in 24 patients (5.5%) of the total study population, bearing in mind that 258/438 (59%) patients did not have densitometry. Bisphosphonates were prescribed to 54/438 (12.3%) patients, whilst only 19 (35.2%) of those had osteoporosis. CONCLUSION: In this analysis, lack of oncologists' adherence to the bone health guidelines was observed. In addition, a significant proportion of the patients did not adhere to the vitamin D and calcium.

The role of bisphosphonates in the management of metastatic prostate cancer.

Most men with advanced prostate cancer have primarily skeletal metastases, which are responsible for most of the morbidity and mortality of prostate cancer. Although bone lesions are osteoblastic in radiographic appearance, recent evidence has demonstrated that anti-osteoclast therapy with bisphosphonates reduces skeletal-related complications in hormone-refractory prostate cancer. This observation may be explained by the demonstration that osteoclast activity is greatly upregulated even in osteoblastic metastases. Furthermore, androgen deprivation therapy, the mainstay of treatment for advanced prostate cancer, leads to increased bone resorption and reduces bone mineral density. These effects can be ameliorated, and potentially completely prevented, by coadministration of bisphosphonates. These findings may point to a role for bisphosphonates in men with prostate cancer even prior to the development of skeletal metastases. Determination of whether such early therapy ultimately results in delayed time to skeletal progression or in improved survival will require large randomized studies.

Evaluation of the efficacy and safety of oral tiludronate in Paget's disease of bone. A double-blind, multiple-dosage, placebo-controlled study.

OBJECTIVE: To assess the optimal dosage of oral tiludronate in Paget's disease of bone. METHODS: We studied 149 patients with Paget's disease, in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned to 1 of 5 therapeutic groups: a daily dose of 100 mg, 200 mg, 400 mg, or 800 mg of oral tiludronate, or a placebo. Treatment was for 3 months, followed by 3 months of placebo-controlled followup. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured monthly, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale and a global pain index. RESULTS: Statistical analysis revealed that beginning at a dosage of 200 mg/day, there was a direct dose-dependent effect on the reduction of SAP and OH/Cr levels. Reduction of SAP levels was clinically significant at a dosage of 400 mg (44.9 +/- 4.2% reduction at 90 days and 49.2 +/- 4.5% at 180 days, mean +/- SEM) and at 800 mg (53.4 +/- 5% at 90 days and 59.3 +/- 4.6% at 180 days). There was a significant reduction in pain in all groups, including the group taking placebo. In only those taking 800 mg/day of tiludronate was there a significant frequency of complete resolution of pain (versus placebo). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance of all 5 regimens was good. Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800-mg daily dose investigated. CONCLUSION: Because of its significantly better antiresorptive effects and greater analgesic properties (compared with lower dosages), combined with the excellent clinical and biochemical tolerance, the 800-mg daily dose of tiludronate appears to be optimal for the treatment of Paget's disease of bone.

Comparative quality control of 99mTc-Pyrophosphate and 99mTc-diphosphonate radiopharmaceuticals.

The results of analysis of 99mTc-Pyrophosphate (99mPyP), taken as a representative of the group of compounds having an organic P-O-P bond, and of the three diphosphonate compounds: methylene diphosphonate (MDP), 2,3-dicarboxy propane diphosphonate (DPD) and ethane-1-hydroxy-1, 1-diphosphonate (EHDP), which differ in their chemical structure, are shown. Also, some physicochemical parameters such as chloroform-water apparent partition coefficient, the osmotic pressure and pH values in final preparations were studied. The radiochemical purity of these radiopharmaceuticals was determined by the two methods: Sephadex chromatography for separation of 99mTc-hydrolysate and TLC on silica gel with 85% methanol for the determination of free 99mTcO-4. The yield of labelling for both methods was over 90%. Also, pharmacokinetic parameters such as binding to the plasma proteins and to erythrocytes were determined. 99mTc-PyP binding to plasma proteins was higher than the binding of diphosphonate compounds. The quantitative distribution of preparations was determined in experimental animals.

Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone.

OBJECTIVE: To compare the efficacy and safety of tiludronate and etidronate at the same dosage (400 mg/day) for the treatment of active Paget's disease of bone. METHODS: We studied 234 patients with radiologic lesions characteristic of Paget's disease of bone and serum alkaline phosphatase (AP) concentrations at least twice the upper limit of normal, in a prospective, randomized, double-blind, multicenter clinical trial lasting 6 months. Patients were randomly allocated into 1 of 3 treatment groups: tiludronate for 3 months followed by placebo for 3 months, tiludronate for 6 months, or etidronate for 6 months. Serum AP levels and urinary hydroxyproline excretion were measured at baseline and after 3 months and 6 months. Patients with a reduction of at least 50% in the serum AP concentration were considered to be responders. RESULTS: After 3 months, the proportion of responders was higher in the tiludronate group (57.4%) than in the etidronate group (13.9%) (P < 0.0001). In the etidronate group, this percentage was lower among patients who had received previous treatment with a bisphosphonate (2.3%) than among those who had not (28.6%) (P < 0.01). Previous bisphosphonate treatment was not associated with response in the tiludronate group. After 6 months, the proportion of responders did not differ between the 2 tiludronate groups (60.3% and 70.1%), but was lower in the etidronate group (25.3%) (P < 0.0001). There was a higher proportion of patients with treatment-resistant disease (< 25% reduction of serum AP) in the etidronate group (51.9%) than in the tiludronate 3-month group (17.9%) or the tiludronate 6-month group (19.5%) (P < 0.0001). Gastrointestinal disturbances were more common, and occurred earlier, with tiludronate, but they were mostly mild, requiring no treatment. CONCLUSION: Tiludronate at 400 mg/day for 3 months or 6 months is more effective than the same dosage of etidronate for 6 months in the treatment of Paget's disease.