Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy.

BACKGROUND: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. AIM: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. MATERIAL/SUBJECTS AND METHODS: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia®) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. RESULTS: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was -2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was -2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. CONCLUSIONS: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures.

Physical exercise for late-life major depression.

BACKGROUND: Interventions including physical exercise may help improve the outcomes of late-life major depression, but few studies are available. AIMS: To investigate whether augmenting sertraline therapy with physical exercise leads to better outcomes of late-life major depression. METHOD: Primary care patients (465 years) with major depression were randomised to 24 weeks of higher-intensity, progressive aerobic exercise plus sertraline (S+PAE), lower-intensity, non-progressive exercise plus sertraline (S+NPE) and sertraline alone. The primary outcome was remission (a score of ≤10 on the Hamilton Rating Scale for Depression). RESULTS: A total of 121 patients were included. At study end, 45% of participants in the sertraline group, 73% of those in the S+NPE group and 81% of those in the S+PAE group achieved remission (P = 0.001). A shorter time to remission was observed in the S+PAE group than in the sertraline-only group. CONCLUSIONS: Physical exercise may be a safe and effective augmentation to antidepressant therapy in late-life major depression.

Fragility fractures: clinical and therapeutic aspects.

Osteoporosis is the most important bone metabolic disorder characterized by reduction of bone mass and micro-architectural deterioration associated to an increased risk for fragility fractures. It involves millions of worldwide-dispersed individuals of both sexes and, consequently, the elevated morbidity and mortality of fractured subjects and the increased socio-economic costs suggest it must be faced as a major health problem. Thus, there is a need for either a precocious identification of subjects with fragile “bones” or the institution of specific diagnostic-therapeutical strategies. Improvement in bone pathophysiology knowledge, together with progress in pharmaceutical development has led to an opportunity for early identification and therapy of subjects at high risk of fragility fractures. In this review, we briefly describe the recent acquisitions in bone pathophysiology as well as in the anti-fracture drug development with a brief excursus on those already well established.

Fast and multiscale formation of isogeometric matrices of microstructured geometric models.

The matrix formation associated to high-order discretizations is known to be numerically demanding. Based on the existing procedure of interpolation and lookup, we design a multiscale assembly procedure to reduce the exorbitant assembly time in the context of isogeometric linear elasticity of complex microstructured geometries modeled via spline compositions. The developed isogeometric approach involves a polynomial approximation occurring at the macro-scale and the use of lookup tables with pre-computed integrals incorporating the micro-scale information. We provide theoretical insights and numerical examples to investigate the performance of the procedure. The strategy turns out to be of great interest not only to form finite element operators but also to compute other quantities in a fast manner as for instance sensitivity analyses commonly used in design optimization.

Role of calcium-sensing receptor in bone biology.

Extracellular calcium concentration changes are recognized by Ca++ sensing receptor (CaR), a member of the G-protein-coupled receptor family. Recently, progress has been made in the understanding of CaR functional role in bone cells, notwithstanding a lack of detailed knowledge about the identity of the cation receptors. It is generally agreed that a high extracellular calcium induces osteoblast proliferation and osteoclastogenesis inhibition. Potential implications that may be considered include a role for CaR in osteogenesis, in serum calcium homeostasis regulation, and as a factor coupling bone formation to resorption in bone remodeling. The localization of CaR in bone cells provides further knowledge of the mechanisms operating in the bone remodeling model; in fact, increased calcium gradient in the site of bone resorption favors osteoblast precursors chemotaxis and inhibits osteoclasts through the increase of [Ca++]e. In vitro data indicate that CaR is a physiological regulator of bone cells, regulating the recruitment, differentiation and survival of osteoblasts and osteoclasts. This leads to the concept that the CaR present in bone cells may be targeted by agonists or antagonists to control bone cell metabolism and bone remodeling.

Physical Exercise for Late-Life Major Depression.

(Reprinted with permission from Br J Psychiatry 2005; 207: 235-242).

Hyperphosphatemia: effects on bone metabolism and cardiovascular risk.

Hyperphosphatemia indicates a plasma inorganic phosphate (Pi) concentration greater than 5 mg/dl in the adult and 7 mg/dl in adolescent subjects. Pi homeostasis is maintained by several mechanisms (intestinal absorption, renal excretion, balance of Pi exchanges in and out of the cells, hormonal regulation). Most of the Pi, after intestinal absorption, undergoes urinary excretion suggesting that the kidney plays a major role in the maintenance of homeostasis and plasma concentration of the Pi, modifying its reabsorption in the proximal tubule where 3 types of sodium/ phosphate cotransporters have been identified (NPT). NPT2 is crucial for the Pi reabsorption and is modulated by several hormones (PTH and vitamin D3, phosphatonins) and non-hormonal factors. The hyperphospatemia is usually due to a decrease in renal function or a PTH absence (primary or secondary hypoparathyroidism) or phosphatonin deficiency. A correct serum Pi concentration is a critical condition for maintaining the calcium-phosphate (CaxPi) product within a safe range ensuring the physiological processes of bone mineralization; an increase of CaxPi product in extracellular fluids over a critical threshold, may promote processes of extraskeletal calcification. In the last few years several studies have shown that the pathogenetic mechanisms of vascular calcification do not imply a simple deposition of calcium phosphate crystals in the wall of the vessels affected by atherosclerotic lesions, but an active process making vascular smooth cells assume functional characteristics of osteoblasts. The consequences on bone are heterogeneous according to the pathogenetic mechanisms responsible for hyperphosphatemia.

Uselessness of a questionnaire for osteoporosis and role of bone mass measurements in predicting tooth loss.

AIM: We evaluated whether the number of teeth lost is associated with risk factors for osteoporosis and whether bone mass measurements can add further information. METHODS: A total of 455 healthy women were enrolled. All the subjects filled in a questionnaire on risk factors for osteoporosis. The bone mineral density (BMD) was measured both by dual X-ray absorptiometry (DXA) and quantitative ultrasound measurements (QUS). RESULTS: On the basis of the questionnaire score 65.1% of the subjects were in the low risk category, 11% in the moderate risk category, 19.3% in the fairly high risk category and 4.6% in the high risk category. Close relationships (P<0.001) were observed between bone mass loss and the questionnaire risk categories. The number of teeth lost significantly increased from normal to osteoporosis groups. High correlations were also found between osteosonographic parameters and the number of teeth lost. Among questionnaire items a significant positive correlation was found only between the number of teeth lost and both age class (P<0.001) and years since menopause (P<0.001). A multiple regression showed that only age class (P<0.001) and ultrasound bone profile index (UBPI) (P=0.041) were independently linked to tooth loss. CONCLUSIONS: The results obtained showed that age is the main determinant of tooth loss and that QUS adds further information in identifying patients at a higher risk of tooth loss.

Palladium-103 versus iodine-125 for ophthalmic plaque radiotherapy.

PURPOSE: A dosimetry study comparing the use of I-125 vs. Pd-103 radioactive seeds for ophthalmic plaque brachytherapy. METHODS AND MATERIALS: Palladium-103 (Pd-103) seeds in ophthalmic plaques were used to treat 15 patients with intraocular malignant melanoma. Computer-aided simulations were performed to evaluate the intraocular dose distribution of I-125 versus Pd-103 ophthalmic plaques (delivering equivalent apex doses). Seven target points were selected. Starting at the outer scleral surface, four were located along the central axis of the plaque: the 1 mm point (the inner sclera), the 6 mm point, the tumors apex, and the opposite eye wall. We also evaluated the fovea, optic nerve, and the lens because they were considered to be critical structures. RESULTS: These studies demonstrated that the lower energy photons generated by Pd-103 seeds (average 21 KeV) in ophthalmic plaques were more rapidly absorbed in tissue than photons generated by I-125 (average 28 KeV). Therefore, during ophthalmic plaque radiotherapy, Pd-103 photons were found to be more rapidly absorbed within the tumor and less likely to reach most normal ocular structures. On average, the use of Pd-103 decreased the dose to the fovea by 5.7%, to the optic nerve by 8.4%, to the lens by 26%, and to the opposite eye wall by 38.4%. CONCLUSION: Palladium-103 ophthalmic plaque brachytherapy resulted in slightly more irradiation of the tumor and less radiation to most normal ocular structures.

Distinct chemotactic and angiogenic activities of peptides derived from Kaposi's sarcoma virus encoded chemokines.

The vMIPs are chemokine-like proteins expressed by the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) during the lytic phase of viral infection. vMIP-I activates CCR8, a chemokine receptor expressed by Th2 lymphocytes and cultured monocytes. vMIP-II is an agonist for CCR3, a receptor expressed by eosinophils, and an antagonist for several other chemokine receptors. Both are highly angiogenic in the chick chorio-allantoic membrane. We designed and tested three 26-mer peptides, derived from vMIP-I (pK-I), from vMIP-II (pK-II) and from the control MIP-1alpha (pM), spanning key residues of chemokines. pK-I, pK-II and pM all were able to activate a strong chemotactic response in monocytes, higher than parental vMIP-I and II. This corresponded to induction of calcium fluxes in these cells, typical of chemokines. Interestingly, pK-II and pM were also active on PMN neutrophils. In vivo studies (matrigel sponge and rabbit cornea models) showed that pK-I retains the strong angiogenic potential exerted by vMIP-I, while pK-II and pM induced an inflammatory response, probably mediated by PMN recruitment. Our observations indicate that chemokine-derived peptides can show biological activity at pharmacological concentrations. pK-I, in particular, displays the angiogenic activity of full-length vMIP-I, while all peptides appear to have acquired additional properties, stimulating new cellular targets.

Quasi-single-helicity reversed-field-pinch plasmas

The reversed field pinch (RFP) is a configuration for plasma magnetic confinement. It has been traditionally viewed as dominated by a bath of MHD instabilities producing magnetic chaos and high energy transport. We report experimental results which go beyond this view. They show a decrease of magnetic chaos and the formation of a coherent helical structure in the plasma, whose imaging and temperature profile are provided for the first time. These quasi-single-helicity states are observed both transiently and in stationary conditions. The last case is consistent with a theoretically predicted bifurcation. Our results set a new frame for improving confinement in high current nonchaotic RFP's.

Electron backscatter corrections for parallel-plate chambers.

The wall of an ionization chamber is commonly assumed to have a negligible effect on chamber response in electron beams. For cylindrical chambers with thin walls this assumption is valid. However, parallel-plate chambers commonly possess large mechanical supports which may affect chamber response in a manner not accounted for in current dosimetry protocols. This is due to changes with energy in the relative backscattered electron fluence between chamber support and phantom materials. To investigate this effect, electron backscatter from low atomic number materials has been measured with electrons from 6 to 20 MeV. The effect of the diameter and thickness of the backscattering material has also been studied. Based on these data, Lucite and polystyrene chambers in water phantoms are expected to underrespond by 1% and 2% at 6 MeV. The expected underresponse decreases to 0.8% and 0.4% for polystyrene and Lucite at 12 MeV and is insignificant above 16 MeV. Two commercially available parallel-plate chambers were compared with a cylindrical chamber in electron beams from 6 to 20 MeV. Using the 20-MeV intercomparison, the expected chamber responses at the lower energies were calculated and compared with measurements. Both parallel-plate chambers underresponded by approximately 1% at 6 MeV and 0.5% at 9 MeV which is qualitatively consistent with the electron backscatter data. Recommendations for minimizing electron backscatter effects through chamber design are discussed.

Range spectra in electron penetration problems.

The theory of electron penetration as predicted by the Fokker-Planck equation is first reviewed within a restricted context that considers the multiple scattering and transport of charged particles. We then broaden the context and show that range straggling effects also fit successfully into this framework, which completes an electron model initiated by Yang. We introduce those effects with a superposition of Fokker-Planck solutions, i.e., by using an incident beam that contains a spectrum of initial energies, or equivalently, a set of csda ranges. Straggling effects appear to be a beam property in this approach but are returned to the material when we use it. All the information needed to construct the spectrum is obtained from a measurement of the electron rest charge distribution in polystyrene. To illustrate the correctness of this procedure, we consider the case of a 20 MeV electron beam incident on water. We predict the absorbed dose distribution as a function of depth and also measure it with an ionization chamber in a water tank. We find nearly perfect agreement between calculation and experiment in this case where all the results derive and apply to a clinically operational machine.

Examination of the factors Ac and Aeq for cylindrical ion chambers used in cobalt-60 beams.

The calibration of a cobalt-60 beam in a phantom with an ion chamber, which has been calibrated with respect to exposure, requires the use of a displacement correction factor which essentially corrects the photon fluence for the attenuation and scatter when the chamber with buildup cap is removed and replaced by phantom material. To determine the displacement factor, Ac, a special set of cylindrical ionization chambers with various volumes were constructed out of polystyrene. Tissue-air ratios were measured with these chambers for cobalt-60 gamma rays in a polystyrene phantom, and the ratio Ac/Aeq was experimentally determined. In order to calculate Ac from this ratio, Aeq was determined also. It was found that Ac depended on chamber diameter only, and not on field size or depth. A value of 0.990 for Aeq is recommended and a table of Ac for chambers of different outer diameters is included.

N,N-dicarboxymethyl chitosan as delivery agent for bone morphogenetic protein in the repair of articular cartilage.

Bone morphogenetic protein (BMP), associated with N,N-dicarboxymethyl chitosan, is used to induce or facilitate the repair of articular cartilage lesions. This association is intended for the synergistic potentiation of the respective biological effects. Data show that BMP-7 enhances the in vivo proliferation of cells with chondrocytes phenotype in the articular environment, leading to partial healing of the articular surface of the lesions. N,N-dicarboxymethyl chitosan is found to be useful as a molecular carrier or drug delivery agent.

Does bone mineral density predict fractures comparably in women and men?

Osteoporosis (OP) is a very common disease associated with increased morbidity, mortality and costs. For a 50-yr-old woman the lifetime risk of an osteoporotic fracture is 40%, while for a man of the same age the risk is 13%. Good evidence exists as to the correlation between bone mineral density (BMD) and fracture risk in post-menopausal women. The diagnosis of OP can be made when BMD is more >2.5 SD below the mean of normal young women (T-score < or = -2.5). In men it has not been possible, until now, to identify a definite T-score under which the diagnosis of OP can be made. Several studies produced conflicting results when they tried to answer the question as to whether males and females fracture at the same absolute BMD value. Men have a greater bone size than women even when this parameter is corrected for weight and body mass. As densitometric devices measure areal density, men appear to have a higher BMD than women. Some studies have shown that, for a given BMD, males and females have the same fracture risk, while other papers have demonstrated that fractured men have a higher BMD than fractured women. Another problem concerns the diagnosis of osteoporosis. In fact, when the T-score is calculated in men on the basis of a young female reference range the prevalence of osteoporosis can be underestimated. The official position of International Society for Clinical Densitometry (ISCD) may represent an "interim" answer in order to identify men at risk of fracture.

Long-term potassium citrate therapy and bone mineral density in idiopathic calcium stone formers.

Several authors have described an association between idiopathic calcium (Ca) stone disease and bone mass reduction. Hypocitraturia is a frequent feature of urolithiasis, and alkaline citrate has been recommended as one of the choice treatments in this disease. Some evidence exists as to the positive effect of potassium (K) citrate therapy on bone mass. The aim of this work was the longitudinal evaluation of bone mineral density (BMD) changes in a group of Ca oxalate stone formers treated with K citrate for two years. Enrolled patients were 120; 109 subjects completed the study (51 males and 58 females). A metabolic study and distal radius BMD measurements were conducted both at baseline (BAS) and at the end of the study (END). BMD (0.451 +/- 0.081 vs 0.490 +/- 0.080 g/cm2), T-score (-1.43 +/- 1.02 vs -0.90 +/- 1.04), net gastrointestinal alkali absorption (40.37 +/- 50.57 vs 61.26 +/- 42.26 mEq/day), urinary citrate (2.53 +/- 1.15 vs 3.10 +/- 1.44 mmol/day) and K (58.93 +/- 22.28 vs 65.45 +/- 23.97 mmol/day) excretion significantly increased from BAS to END. Urinary Ca excretion remained unchanged from BAS to END (5.16 +/- 2.74 vs 5.57 +/- 2.85 mmol/ day). Our results indicate that long-term treatment with K citrate increases forearm BMD in idiopathic Ca stone formers. It seems probable that the alkali load provided by this drug reduces bone resorption by a buffering of the endogenous acid production. K citrate appears to be a further therapeutic opportunity for the management of osteoporosis in Ca stone formers.

Palladium 103 plaque radiotherapy for uveal melanoma. Clinical experience.

PURPOSE: To evaluate the effect of palladium 103(103Pd) ophthalmic plaque brachytherapy on patients with uveal melanoma. BACKGROUND: Radioactive 103Pd seeds have become available for plaque brachytherapy, and computer-aided simulations have compared the intraocular dose distribution of 103Pd versus iodine 125 (125I) plaques in patients with uveal melanoma. The use of the lower-energy radionuclide 103Pd increased the radiation to the tumors and decreases irradiation of most normal ocular structures. METHODS: The authors have begun a phase 1 clinical trial evaluating the effect of 103Pd ophthalmic plaque radiotherapy on intraocular tumors. Uveal melanoma was diagnosed, and the patients were found to be negative for metastatic disease. All patients were given one 103Pd radioactive plaque treatment, and six patients also were given adjuvant microwave hyperthermia. RESULTS: Palladium 103 ophthalmic plaque radiotherapy was used to treat 23 patients with uveal melanoma. Patients were followed for up to 27 months (mean, 13.5 months). One eye was enucleated for progressive tumor enlargement (4 months after treatment). One patient died (of metastatic melanoma). Eight patients have lost greater than two lines of visual acuity, one has gained more than two lines. Fifteen patients (65%) were within two lines or had better than their preoperative visual acuity. Relating to the effect of treatment on visual acuity, 15 (65%) tumors were located equal to or less than 2 mm from the fovea. CONCLUSION: Palladium 103 ophthalmic plaque radiotherapy was noted to control the growth of uveal melanomas. Compared with other forms of plaque radiotherapy at this follow-up interval, the authors have noted no new complications, no difference in local control, and/or changes in tumor response to treatment. More long-term follow-up will be required to demonstrate differences between 125I and 103Pd ophthalmic plaque brachytherapy.

Osteoporosis and urolithiasis.

Several studies have indicated that up to 60% of idiopathic calcium stone formers present hypercalciuria. Many authors have described reduced bone mineral density (BMD) in stoneformers with hypercalciuria, but osteopenia has also been found in normocalciuric patients. Moreover, Jaeger's group found that bone mass was reduced in all patients with calcium stone disease, independently of hypercalciuria. Many factors may contribute to the pathogenesis of osteopenia in stone formers. A predominant role has been given to the low-calcium diet that is still prescribed in nephrolithiasis. Also slight metabolic acidosis, which is frequently present in stone formers eating a diet rich in animal protein, can contribute to bone loss. Finally, some authors described a pathogenetic role for cytokines, prostaglandins and vitamin D receptor gene polymorphisms.