Is a treat-to-target strategy in osteoporosis applicable in clinical practice? Consensus among a panel of European experts.

A panel of European experts was convened to establish consensus on a treat-to-target strategy in osteoporosis. Panellists agreed that the ultimate goals of treating osteoporosis are recovering pre-fracture functional level and reducing subsequent fracture risk; there was consensus that total hip bone mineral density is currently the most appropriate treatment target in clinical practice. INTRODUCTION: A modified Delphi approach was convened to establish consensus among European experts on best practice management for patients with fragility fractures and whether a treat-to-target (T2T) strategy is applicable in osteoporosis. METHODS: A panel of 12 clinical experts (from eight European countries) voted on 13 final statements relating to a T2T strategy for osteoporosis across three rounds of blinded, remotely conducted electronic surveys (Likert scale: 'strongly disagree', 'disagree', 'unable to answer', 'agree', 'strongly agree'). When panellists disagreed, they were asked how the statement could be adjusted to allow for a positive response, which was used to refine the statement for the following round. Consensus was defined as ≥ 75% agreement with a statement. Panellists were selected by UCB Pharma, which provided financial and logistical support. RESULTS: Consensus was reached for 13/13 statements. Panellists agreed that the most important goals for fragility fracture patients are recovery of pre-fracture functional level and reduction of subsequent fracture risk. There was also consensus that a T2T strategy is applicable to osteoporosis and that bone mineral density (BMD) is currently the most clinically appropriate target. With regard to the definition of a specific BMD treatment target and timeframes applicable to T2T in osteoporosis, no clear consensus was reached; panellists emphasised that these would need to be individually determined. CONCLUSIONS: According to a panel of European experts, the main goals of fracture management are to recover pre-fracture functional level and reduce fracture risk. Total hip BMD seems to be the most clinically appropriate treatment target within a T2T strategy.

GRAND-4: the German retrospective analysis of long-term persistence in women with osteoporosis treated with bisphosphonates or denosumab.

UNLABELLED: This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5-2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab. INTRODUCTION: Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse. METHODS: From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan-Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use. RESULTS: Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7-17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96-2.02, respectively; all P < 0.0001). CONCLUSIONS: Two-year persistence with denosumab was 1.5-2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.

Thyrotropin serum levels are differentially associated with biochemical markers of bone turnover and stiffness in women and men: results from the SHIP cohorts.

UNLABELLED: In two large German population-based cohorts, we showed positive associations between serum thyrotropin (TSH) concentrations and the Fracture Risk Assessment score (FRAX) in men and positive associations between TSH concentrations and bone turnover markers in women. INTRODUCTION: The role of thyroid hormones on bone stiffness and turnover is poorly defined. Existing studies are confounded by differences in design and small sample size. We assessed the association between TSH serum concentrations and bone stiffness and turnover in the SHIP cohorts, which are two population-based cohorts from a region in Northern Germany comprising 2654 men and women and 3261 men and women, respectively. METHODS: We calculated the bone stiffness index using quantitative ultrasound (QUS) at the calcaneus, employed FRAX score for assessment of major osteoporotic fractures, and measured bone turnover markers, N-terminal propeptide of type I procollagen (P1NP), bone-specific alkaline phosphatase (BAP), osteocalcin, and type I collagen cross-linked C-telopeptide (CTX) in all subjects and sclerostin in a representative subgroup. RESULTS: There was no association between TSH concentrations and the stiffness index in both genders. In men, TSH correlated positively with the FRAX score both over the whole TSH range (p < 0.01) and within the reference TSH range (p < 0.01). There were positive associations between TSH concentrations and P1NP, BAP, osteocalcin, and CTX (p < 0.01) in women but not in men. There was no significant association between TSH and sclerostin levels. CONCLUSIONS: TSH serum concentrations are associated with gender-specific changes in bone turnover and stiffness.

[Bone metastases : New aspects of pathogenesis and systemic therapy]. / Knochenmetastasen : Neues zur Pathogenese und systemischen Therapie.

The occurrence of bone metastases, in particular secondary to breast and prostate cancer, represents a complex medical condition that is debilitating for affected patients. In order to provide an efficient and personalized therapy, an interdisciplinary treatment approach is mandatory; therefore, systemic pharmacological therapy represents a core element of the overall treatment concept. In terms of pathophysiology, the cancer cells cause a massive disturbance of the local bone microenvironment, which as a rule leads to activation of bone resorbing osteoclasts. In addition to bisphosphonates, which can be considered classical antiresorptive agents, the monoclonal receptor activator of nuclear factor-kappa B ligand (RANKL) antibody denosumab has been in use in clinical practice since 2011. The alpha-emitting radioisotope Alpharadin was also recently approved for the treatment of metastatic prostate cancer. This article provides a summary of the most recent knowledge on the pathogenesis of how cancer cells alter the bone microenvironment as well as a review of established and future systemic treatment options.

[Diagnostics in osteology]. / Diagnostik in der Osteologie.

Clinical diagnostics in metabolic bone diseases cover a broad spectrum of conventional and state of the art methods ranging from the medical history and clinical examination to molecular imaging. Patient treatment is carried out in an interdisciplinary team due to the multiple interactions of bone with other organ systems. Diagnosis of osteoporosis is supported by high level national guidelines. A paradigm shift concerning the clinical relevance of bone mineral density measurement renders this now to be a strong risk factor rather than a diagnostic parameter, while strengthening the value of other clinical factors for risk assessment. The impact of parameters for muscle mass, structure and function is steadily increasing in all age groups. In order to identify underlying diseases that influence bone metabolism a panel of general laboratory diagnostic parameters is recommended. Markers for bone formation and resorption and specific parameters for the regulation of calcium and phosphate metabolism should be evaluated by specialists because they require diligence in preanalytics and experience in interpretation. Genetic diagnosis is well established for rare bone diseases while diagnostic panels are not yet available for routine diagnostics in polygenetic diseases such as osteoporosis. Conventional radiology is still very important to identify, e. g. fractures, osteolytic and osteoblastic lesions and extraosseous calcifications; however tomography-based methods which combine, e. g. scintigraphy or positron emission technologies with anatomical imaging are of increasing significance. Clinical diagnostics in osteology require profound knowledge and are subject to a dynamic evolution.

Oncologic resection achieving r0 margins improves disease-free survival in parathyroid cancer.

BACKGROUND: Parathyroid cancer has a poor mid-term prognosis, often because of local recurrence, observed in half of all patients. Modern diagnostic workup increasingly enables a preoperative diagnosis of parathyroid cancer. There is limited evidence that more comprehensive oncologic surgery can reduce the risk of local recurrence. This study aims to identify the best specific surgical approach in parathyroid cancer. METHODS: This observational cohort study comprises 19 consecutive patients who had undergone oncologic or nononcologic resection for parathyroid cancer. Baseline parameters were compared by using univariate analysis; outcomes were assessed by χ (2) testing and Kaplan-Meier statistics. RESULTS: Fifteen of 19 patients were primarily operated on in our tertiary center between 1996 and 2013, and four were referred for follow-up because of their cancer diagnosis. Patient cohorts defined by histologic R-status were comparable for established risk factors: sex, calcium levels, low-risk/high-risk status, and presence of vascular invasion. Oncologic resections were performed in 13 of 15 patients primarily treated in the center and 0 of 4 treated elsewhere (χ (2) = 5.6; p < 0.01). R0 margins were achieved in 11 of 13 (85 %) undergoing oncologic resection and 1 of 6 (17 %) undergoing local excision (χ (2) = 8.1; p < 0.01). R0 margins and primary oncologic resection were associated with higher disease-free survival rates (χ (2) = 7.9; p = 0.005 and χ (2) = 4.7; p = 0.03, respectively). Revision surgery achieved R0 margins in only 2 of 4 (50 %) of patients. CONCLUSIONS: In parathyroid cancer, a more comprehensive surgery (primary oncologic resection) provides significantly better outcomes than local excision as a result of reduction of R1 margins and locoregional recurrence.

The non-interventional BonViva Intravenous Versus Alendronate (VIVA) study: real-world adherence and persistence to medication, efficacy, and safety, in patients with postmenopausal osteoporosis.

UNLABELLED: Adherence and persistence to oral bisphosphonates in women with postmenopausal osteoporosis is suboptimal. In this study, patients were treated with either oral or intravenous bisphosphonates. The increased adherence and persistence observed in patients receiving intravenous medication compared with those receiving oral medication may improve health outcomes. INTRODUCTION: Poor adherence and persistence to oral medication are often observed in women with postmenopausal osteoporosis (PMO). The purpose of the non-interventional BonViva Intravenous Versus Alendronate (VIVA) study was to determine whether, in a real-world setting, (1) increased adherence and persistence to medication would be observed in women with PMO receiving intravenous (i.v.) ibandronate versus oral alendronate, (2) a correlation exists between adherence and persistence to medication and drug efficacy, and (3) any unexpected adverse events/serious adverse events (AEs/SAEs) may occur. METHODS: The study was conducted in 632 centers in Germany. A total of 6,064 females with PMO were enrolled and recruited into one of two treatment arms: quarterly i.v. administration of 3 mg ibandronate or weekly oral medication of 70 mg alendronate, for 12 months. At the end of the study, adherence and persistence to medication, new osteoporotic fractures, mobility, use of analgesics, and AEs/SAEs were determined. RESULTS: Greater adherence and persistence to medication were observed in the ibandronate treatment arm compared with the alendronate treatment arm. Although there was no significant difference in the number of patients with new vertebral, hip, or forearm fractures between treatment arms, a significantly greater increase in mobility and decrease in the use of analgesics were reported in the ibandronate treatment arm. No unexpected AEs/SAEs occurred in either arm. CONCLUSIONS: Adherence and persistence to medication were greater in women with PMO receiving i.v. ibandronate compared with those receiving oral alendronate. This may have led to an increase in mobility and a decrease in pain in these patients.

A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis.

UNLABELLED: This paper provides a framework for the development of national guidelines for the management of glucocorticoid-induced osteoporosis in men and women aged 18 years and over in whom oral glucocorticoid therapy is considered for 3 months or longer. INTRODUCTION: The need for updated guidelines for Europe and other parts of the world was recognised by the International Osteoporosis Foundation and the European Calcified Tissue Society, which set up a joint Guideline Working Group at the end of 2010. METHODS AND RESULTS: The epidemiology of GIO is reviewed. Assessment of risk used a fracture probability-based approach, and intervention thresholds were based on 10-year probabilities using FRAX. The efficacy of intervention was assessed by a systematic review. CONCLUSIONS: Guidance for glucocorticoid-induced osteoporosis is updated in the light of new treatments and methods of assessment. National guidelines derived from this resource need to be tailored within the national healthcare framework of each country.

[Local and systemic bone effects of rheumatoid arthritis]. / Lokale und systemische Knocheneffekte bei rheumatoider Arthritis.

Rheumatoid arthritis (RA) is a bone-destructive disease that is a serious risk factor for the development of osteoporosis, which is defined by a loss in bone quality and an increased fracture risk. The proinflammatory cytokines tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and IL-17, in particular, contribute to local and systemic bone loss in RA. While effectively reducing inflammation, glucocorticoids add to the fracture risk. Therefore, an adequate supply of calcium and vitamin D is essential. For many patients with RA, bone density measurements are recommended.

Nuclear factor of activated T cells mediates oxidised LDL-induced calcification of vascular smooth muscle cells.

AIMS/HYPOTHESIS: Vascular calcification is a prominent feature of both atherosclerosis and diabetes, and is clinically associated with osteoporosis. The expression of bone-regulatory factors and the impact of oxidative stress in aortic calcification are well-documented. Recently, nuclear factor of activated T cells (NFAT) cytoplasmic, calcineurin-dependent 1 (NFATc1) was identified in calcified aortic valves and has been implicated in vascular calcification. Therefore, we assessed the mechanisms of osteogenic transdifferentiation of vascular smooth muscle cells induced by oxidised LDL (oxLDL) and evaluated the role of NFAT in this process. METHODS: Human coronary artery smooth muscle cells (HCASMCs) were cultured for 21 days in medium supplemented with oxLDL. NFAT was inhibited using the NFAT inhibitor VIVIT, or by knockdown with small interfering RNA (siRNA). Osteogenic transdifferentiation was assessed by gene expression, matrix mineralisation and alkaline phosphatase activity. RESULTS: Exposure to oxLDL caused the transformation of HCASMCs towards an osteoblast-like phenotype based on increased mineral matrix formation and RUNX2 expression. NFATc1 blockade completely prevented oxLDL-induced osteogenic transformation of HCASMCs as well as oxLDL-induced stimulation of osteoblast differentiation. In contrast, matrix mineralisation induced by osteogenic medium was independent of the NFAT pathway. Of note, oxLDL-conditioned medium from HCASMCs transferred to bone cells promoted osteoblast mineralisation. Consistent with these in vitro findings, diabetic rats with a twofold increase in oxidised lipid levels displayed higher aortic calcium concentrations and increased expression of osteogenic markers and production of NFATc1. CONCLUSIONS/INTERPRETATION: Our results identify the NFAT signalling pathway as a novel regulator of oxLDL-induced transdifferentiation of vascular smooth muscle cells towards an osteoblast-like phenotype.