Osteoporose: seleção de medicamentos e avanços no manejo clínico / Osteoporosis: medication selection and advances in the clinical management

Osteoporose é um problema de saúde pública importante que acomete mais de metade das mulheres com idade superior a 50 anos. Doença com um enorme impacto sobre a saúde pública, através da morbidade e mortalidade aumentadas, com custos econômicos associados resultantes das fraturas. O objetivo é avaliar e identificar as pessoas de risco para desenvolver fraturas osteoporóticas de fragilidade que necessitam ser tratadas. A abordagem de mulheres com baixa massa óssea e aumento do risco de fraturas deve ser multidisciplinar. A farmacoterapia é apenas uma Steiner ML, Strufaldi R, Fernandes CE das possíveis intervenções. Aspectos como a nutrição orientada, fortalecimento muscular, prevenção de quedas, suplementos vitamínicos e minerais devem ser considerados. O tratamento farmacológico permite a prevenção da perda óssea, a prevenção primária e secundária de fragilidade óssea e deve ser baseado na avaliação do risco de fratura do indivíduo e na relação custo-benefício do medicamento escolhido.

Osteoporosis is a significant public health problem that affects more than half of women aged over 50. This disease has a huge impact on public health through morbidity and increased mortality, and economic costs associated with the resulting fractures. The goal is to assess and identify risk people to develop osteoporotic fragility fractures that need to be addressed. The approach of women with low bone mass and increased risk of fractures should be multidisciplinary. Pharmacotherapy is just one of the possible interventions. Aspects such as the guidance nutrition, muscle strengthening, prevention of falls, mineral and vitamin supplements should be considered. Pharmacological treatment allows preventing bone loss and primary and secondary prevention of osteoporosis and should be based on risk factors and pharmaceutical cost benefit analysis.

Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747).

OBJECTIVE: To evaluate the cost-effectiveness of adding zoledronic acid or strontium-89 to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC). PATIENTS AND METHODS: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2 × 2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the National Health Service in the UK and included expenditures for trial treatments, concomitant medications, and use of related hospital and primary care services. Quality-adjusted life-years (QALYs) were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument, which evaluates health status. Results are expressed as incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. RESULTS: The per-patient cost for ZA was £12 667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group had on average 0.03 QALYs more than their counterparts in no ZA group. The ICER for this comparison was £8 005. Sr89 was associated with a cost of £13 230, £1365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16 884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively. CONCLUSIONS: The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources.

[The non-hormonal treatment of metastatic prostate cancer]. / Le traitement non hormonal de la maladie métastatique du cancer de la prostate.

AIM: To describe drugs used in the non-hormonal treatment of metastatic prostate cancer. MATERIAL: Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned. RESULTS: The metabolic radiotherapy although under-used for this indication, kept a place at the beginning of the disease. Radium-223 chloride seems to have to occupy an important place in the coming years. The chemotherapy, the only recourse until very recently in the castration-resistant prostate cancer, must redefine its place partially. The denosumab provide an interesting alternative to bisphosphonates. CONCLUSION: The non-hormonal treatment of the metastatic disease of the prostate cancer is changing rapidly with the emergence of new molecules. Urologist must know perfectly these new drugs.

(170)Tm-EDTMP: a potential cost-effective alternative to (89)SrCl(2) for bone pain palliation.

INTRODUCTION: Metastron ((89)SrCl(2)) is a radiopharmaceutical currently used for bone pain palliation in several countries since the long half-life of (89)Sr (50.5 days) favors wider distribution than other radioisotopes approved for this application, which have shorter half-lives. Strontium-89 is not ideal for bone pain palliation due to its high energy beta(-) particle emission [E(beta(max))=1.49 MeV] and is also difficult to produce in large quantities. A (170)Tm [T(1/2)=128.4 days, E(beta(max))=968 keV, E(gamma)=84 keV (3.26%)]-based radiopharmaceutical for bone pain palliation could offer significant advantages over that of (89)Sr. The present study constitutes the first report of the preparation of a (170)Tm-based agent, (170)Tm-ethylenediaminetetramethylene phosphonic acid (EDTMP), and its preliminary biological evaluation in animal models. METHODS: (170)Tm was produced by thermal neutron bombardment on natural Tm(2)O(3) target for a period of 60 days at a flux of 6x10(13) neutrons/cm(2).s. (170)Tm-EDTMP complex was prepared at room temperature. Biodistribution and scintigraphic imaging studies with (170)Tm-EDTMP complex were performed in normal Wistar rats. Preliminary dosimetric estimation was made using the data to adjudge the suitability of (170)Tm-EDTMP for bone pain palliation. RESULTS: (170)Tm was produced with a specific activity of 6.36 GBq/mg and radionuclidic purity of 100%. The (170)Tm-EDTMP was prepared with high radiochemical purity (>99%) and the complex exhibited satisfactory in vitro stability. Biodistribution and imaging studies showed good skeletal accumulation (50-55% of the injected activity) with insignificant uptake in any other vital organ/tissue. Activity was observed to be retained in skeleton until 60 days post-injection demonstrating that (170)Tm-EDTMP exhibits good bone-seeking properties with long retention. It is predicted that a dose of approximately 0.5 microGy/MBq is accrued to red bone marrow and 4.3 Gy/MBq is delivered to the skeleton. CONCLUSION: (170)Tm-EDTMP shows promising biodistribution features, encouraging dosimetric values and warrants further investigation in order to develop it as a bone pain palliative radiopharmaceutical. Despite the relatively long half-life (128.4 days) of (170)Tm, (170)Tm-EDTMP could be explored as a cost-effective alternative to (89)SrCl(2).

Radiopharmaceutical therapy of bone metastases with 89SrCl2, 186Re-HEDP and 153Sm-EDTMP: a dosimetric study using Monte Carlo simulation.

PURPOSE: The aim of the paper is to calculate the dose to bone surface and bone volume using a Monte Carlo particle transport model and to give quantitative arguments for activity prescription. METHODS: This study simulates the dose delivery process to skeletal metastases by bone surface- and bone volume-seeking radiopharmaceuticals. Dose distributions for three radiopharmaceuticals, 186Re-HEDP, 153Sm-EDTMP and 89SrCl2, frequently used for pain palliation therapies, were calculated using the EGSnrc Monte Carlo code. The model simulates a cylindrical geometry with regions of different constant density compositions and radioactivity distribution consistent with known biodistribution features of the three radiopharmaceuticals: superficial for phosphonates (186Re-HEDP and 153Sm-EDTMP) and volumetric for 89SrCl2. After 3D dose distribution calculation, dose-volume histogram reduction was carried out using the "preferred Lyman" method, which yields effective uniform dose (D(eff)) equivalent to the inhomogeneous dose distributions to the reference region (volume and surface). RESULTS: Our simulations showed that to obtain a delivered dose to bone surface equivalent to that obtained from 89SrCl2, the administered activities of 153Sm-EDTMP and 186Re-HEDP should be increased by 37% and 48%, respectively, in comparison with those usually administered. CONCLUSION: These results prove theoretically the empirical results from clinical observations and show that improvement in bone pain palliation by means of radiopharmaceutical therapy should be expected for dose-guided prescription.

Preclinical assessment of gastrooesophageal tolerance of the new antiosteoporotic drug strontium ranelate: an endoscopic study in monkeys.

This study was aimed at evaluating the digestive tolerance of the new antiosteoporotic drug, strontium ranelate, and to compare it to that of another strontium salt, strontium chloride (SrCl2). Strontium ranelate, SrCl2, or placebo were administered orally (capsules) to 3 groups of 2 male and 2 female cynomolgus monkeys (Macaca fascicularis) once a day for 7 days at a dose of 2 g/day, which is the recommended therapeutic dose in man. Endoscopic examination of the oesophagus, the stomach and the first part of the duodenum was performed on fasted animals approximately 3 hr after the first (Day 1) and last dosing (Day 7), and, on Day 8 and Day 14 in case of lesions on Day 7. Strontium ranelate did not induce any acute or subchronic toxic effect on the gastric mucosa, the oesophagus and the first part of the duodenum. On the contrary, acute and superficial damages were noted on all animals receiving SrCl2 such as haemorrhagic and erosive lesions (formation of an ulcer in one male and a marked congestive antritis in one female). These effects were reversible after cessation of treatment. The microscopic examination of biopsies sampled at the site of gastric lesions revealed moderate granulocyte infiltration, indicating a local irritating origin of the lesions. Strontium ranelate by oral route is safe for the gastric mucosa while SrCl2 induced superficial and reversible lesions.

Results of postoperative (90)Sr radiotherapy of keloids in view of patients' subjective assessment.

BACKGROUND AND PURPOSE: As treatment of keloids is mainly a cosmetic indication, the authors investigated, beyond the recurrence rate, the patients' satisfaction with the result and its correlation with objective medical findings. PATIENTS AND METHODS: 83 keloids of 66 patients had been irradiated after excision by a uniform protocol with 4 x 5 Gy (strontium- 90 [(90)Sr] surface applicator). A questionnaire was developed and sent out in which, above all, the satisfaction with the therapeutic and cosmetic outcome was obtained. These results were correlated with objective parameters and medical findings which were ascertained during an extra follow-up examination. RESULTS: Among 18 of the 41 patients (44%), who had answered the questionnaire, 19 of the 53 keloids treated (36%) had relapsed. 61% of the patients were extremely or mainly satisfied with the therapeutic outcome, 51% extremely or mainly satisfied with the cosmetic outcome. The relief from former keloid-caused symptoms (therapeutic outcome: p = 0.0005; cosmetic outcome: p = 0.0011), the ear as keloid localization (p = 0.0008 and p = 0.0197), and male gender (therapeutic outcome: p = 0.0423) were significantly associated with higher satisfaction. The recurrence rate as well as the extent of radiation side effects had no significant influence on patients' assessment. CONCLUSION: Cosmetic aspects like the dermal side effects and the patients' satisfaction should be taken into account when evaluating the results of radiotherapy in keloids.

Basic treatment planning parameters for a 90Sr / 90Y source train used in endovascular brachytherapy.

Working groups of the AAPM, DGMP, and ESTRO have published recommendations for endovascular brachytherapy, introducing concepts of relevant parameters for dose specification and treatment planning. However, the procedures for this treatment remain often mainly based on trial protocols and manufacturer instructions. Treatment planning requires the essential knowledge of the radial and longitudinal dose distribution, as well as information about geometrical uncertainties. The present study includes a whole data set for daily clinical practice using a commercially available device for endovascular brachytherapy (Novoste Betacath). The dose distribution around the 90Sr seed train was calculated with Monte-Carlo algorithms and verified by film dosimetry. The radial dose profile was determined starting from the surface of the delivery catheter Calculated dose profiles were in good agreement to measured values. The geometrical uncertainties were estimated with a retrospective analysis of 51 patient treatments. This shows the importance of using a safety margin of at least 10 mm between Intervention Length and Reference Isodose Length. Based on the longitudinal dose profile and the necessary safety margins, the maximum treatable intervention length is 25 mm and 45 mm for a 40 mm and 60 mm source train, respectively.

Green Or preparation in dentin hypersensitivity treatment.

The effectiveness of Green Or preparation in the treatment of cervical dental hypersensitivity was evaluated. This problem is difficult for patients and for dentists because of dual and unknown methods of treatment. The preparation was used in 30 patients between the ages of 20 and 70 years on 240 teeth with exposed and hypersensitive necks. The obtained results are acceptable, as total elimination of hypersensitivity was attained in 85% of cases, partial reduction of hypersensitivity in 15% cases.

The Collection of Indirect and Nonmedical Direct Costs (COIN) form: a new tool for collecting the invisible costs of androgen independent prostate carcinoma.

BACKGROUND: There are limited data available regarding the cost of care in patients with androgen independent prostate carcinoma (AIPC), and there are no data on the impact of direct nonmedical and indirect costs (DNM/IC). This lack of data, along with the feasibility of collecting DNM/IC, was examined in patients with AIPC who took part in a randomized trial using a newly developed questionnaire, the Collection of Indirect and Nonmedical Direct Costs (COIN) form. METHODS: Patients with AIPC were randomized to one of three treatment arms: 1) strontium only (strontium 4 Mci in Week 1 and Week 12) (STRONT); 2) vinblastine 4 mg/m(2) per week for 3 weeks then 1 week off and estramustine, 10 mg/kg per day (CHEMO); or 3) a combination of treatments outlined in the arms for CHEMO and STRONT (CHEMO/STRONT). Direct medical costs were collected through the hospital billing system. DNM/IC data were obtained prospectively using the COIN form. Cost data were analyzed for a period of 6 months. RESULTS: Twenty-nine patients were randomized, after which the protocol was closed because of poor accrual. The median survival of the patients was 22.3 months. The mean and median total costs for the 20 of 29 patients with complete cost information were $12,647 and $11,257 over 6 months, respectively. DNM/IC represented 11% of the total cost (range, from < 1% to 42%); in 20% of participating individuals, these costs accounted for 35-42% of total costs. Failure to collect complete cost information was due to early death, administrative difficulties, and loss to follow-up. CONCLUSIONS: In this pilot project, the collection of these cost data using the COIN form was feasible and practical and was limited primarily by logistic, not form specific, issues. DNM/IC were found to be a significant proportion of total costs (up to 42%) in selected patients, and this information proved to be a useful addition to the cost analysis. Approximately 98 patients would be required to detect a 20% difference in total costs between arms in a properly powered, randomized trial. Considering the potentially significant impact on total costs, DNM/IC data should be included in future cost-analysis studies of patients with AIPC and other diseases.

Dosimetric perturbations of linear array of beta-emitter seeds and metallic stent in intravascular brachytherapy.

The radiation treatment with catheter-based beta-emitter sources is under clinical trials to prevent restenosis following interventional coronary procedures. There are still large uncertainties in the dose calculation due to the complicated treatment geometry. We present the Monte Carlo simulations to account for the dosimetric perturbations due to neighboring trained seeds, proximal/distal gold markers, and a stainless steel stent. A catheter-based beta-emitter system is modeled using the Monte Carlo code, MCNP4B. Dose distributions and dose rates are calculated in voxels (0.64x0.64x0.5 mm3) around the long cylindrical trains of 90Sr/Y source with and without the stent (at 1.92 mm from the source axis). For the total activity of 70 mCi (2.59x10(9) Bq), the dose around most of the source length (except for edge seeds and gold markers) varies from 40 to 0.23 cGy/s as the radial distance from the source axis (r) increases from 0.64 to 6.4 mm. At the prescription range of r = 1.5-4.0 mm, the dose gradient is very steep and the contribution of neighboring seeds to the dose is significant. The dose enhancement due to neighboring seeds (the so-called "train effect") varies from 9% to 64% as r increases from 0.64 to 5.2 mm. The doses at r = 2 mm from the last edge seed and the gold marker are about 80% and 40% of that of the nonedge seed (8.7 cGy/s), respectively. The dose enhancement due to the secondary electrons and the primary electrons scattered with the stent is shown to be about 9.3% in the voxel including the stent. However, as r increases beyond the stent (r = 2.0-6.4 mm), the dose is slightly reduced by 4%-12%, compared to that without the stent.

Calculating lens dose and surface dose rates from 90Sr ophthalmic applicators using Monte Carlo modeling.

Using a 90Sr applicator for brachytherapy for the reduction of recurrence rates after pterygium excisions has been an effective therapeutic procedure. Accurate knowledge of the dose being applied to the affected area on the sclera has been lacking, and for decades inaccurate estimates for lens dose have thus been made. Small errors in the assumptions which are required to make these estimates lead to dose rates changing exponentially because of the attenuation of beta particles. Monte Carlo simulations have been used to evaluate the assumptions that are now being used for the calculation of the surface dose rate and the corresponding determination of lens dose. For an ideal 90Sr applicator, results from this study indicate dose rates to the most radiosensitive areas of the lens ranging from 8.8 to 15.5 cGy/s. This range is based on different eye dimensions that ultimately corresponds to a range in distance between the applicator surface and the germinative epithelium of the lens of 2-3 mm. Furthermore, the conventional 200 cGy threshold for whole lens cataractogenesis is questioned for predicting complications from scleral brachytherapy. The dose to the germinative epithelium should be used for studying radiocataractogenesis.

Strontium 89 therapy for the palliation of pain due to osseous metastases.

OBJECTIVE: To present the current state of systemic radiopharmaceutical therapy for the palliation of pain in individuals with metastatic cancer and to evaluate the palliative effect and degree of hemotoxicity of strontium chloride 89 (89Sr) in patients with painful osteoblastic metastases primarily from prostate and breast cancer. DATA SOURCES AND STUDY SELECTION: A MEDLINE search through December 1994 was performed to identify English-language studies that met the following criteria. All eligible studies reported treatment of patients with painful osteoblastic bony metastases primarily from prostate or breast cancer treated with intravenous 89Sr. For study eligibility, evaluation of clinical response as assessed by the Karnofsky index, need for pain medication, or changes in mobility or sleep patterns was required. Hemotoxicity data were a requirement. A minimum of 10 prostate cancer cases was necessary for study inclusion. Only those studies assessing clinical response following one injection of 89Sr were included. Preliminary reports of cooperative studies were not included. Doses of 89Sr ranged from 0.6 MBq/kg (16 microCi/kg) to 400 MBq (10.8 mCi) per patient. Evaluation of patients for at least 3 months following 89Sr treatment was required. In addition, two studies examining issues of cost with regard to 89Sr treatment were identified. DATA EXTRACTION: Baseline pain assessment and periodic pain estimates as measured by the Karnofsky index, medication diaries, changes in mobility, sleep patterns, and/or ability to work were the basis for assessment of response. Baseline and periodic complete blood cell counts were the basis for hemotoxicity evaluation. DATA SYNTHESIS: Palliation and hemotoxicity data were analyzed separately for each study. Some improvement occurred in as many as approximately 80% of patients. Several studies demonstrated complete relief of pain in at least 10% of patients The nadir of platelet and white blood cell counts appears at approximately 4 to 8 weeks following injection, with a partial return to baseline by 12 weeks. As many as 10 injections spaced 3 months apart have been given to some patients with repeated palliative effect and without serious hemotoxicity. Reinjection may be limited by a platelet count below 60 x 10(9)/L, a white blood cell count below 2.4 x 10(9)/L, or the absence of osteoblastic skeletal metastasis as seen on bone scan. Studies examining treatment costs suggest that 89Sr may decrease costs associated with palliation of pain due to metastatic disease. CONCLUSIONS: As many as 80% of selected patients with painful osteoblastic bony metastases from prostate or breast cancer may experience some pain relief following 89Sr administration. In addition, as many as 10% or more may become pain free. Duration of clinical response may average 3 to 6 months in some cases. Hemotoxicity is mild. A decrease in treatment costs with administration of 89Sr to patients with painful osteoblastic bony metastases from prostate cancer may occur. These observations reflect the preliminary nature of knowledge in this field and point to the need for larger clinical trials of the use of 89Sr palliation.

A retrospective analysis of the cost effectiveness of treatment with Metastron (89Sr-chloride) in patients with prostate cancer metastatic to bone.

The objectives of the study were to estimate the cost of medical care for patients recruited into the Trans Canada trial of Metastron (89Sr-chloride) as adjunct therapy in patients with prostate cancer metastatic to bone and to compare the costs of those receiving Metastron with those receiving placebo. Data from case report forms, hospital records and, where necessary, telephone follow-up were used. Twenty-nine patients, recruited into the trial at the Cross Cancer Institute, were followed from time of entry into the trial over the balance of their lifetime. Data were costed by reference to fee schedule, pharmacy and government and hospital defined costs as indirect (investigations, outpatient visits and total and tertiary hospital inpatient days) and direct (analgesics, hormones, radiotherapy and transfusions). Meaningful differences in analgesic, hormone and radiotherapy costs were seen between the two groups, with the group receiving Metastron showing a lifetime reduction of Can $1720 per person when compared with placebo. A reduction of Can $5696 per patient in the Metastron group was shown based upon requirements for admission for tertiary care; however, if total hospital stay costs are calculated there is no difference between the two groups. This retrospective study suggests that treatment with Metastron can bring about meaningful reductions in lifetime management costs in patients with advanced prostate cancer. These findings should be correlated with the significant improvement in quality of life reported in the Trans Canada study and appear to offer financial support to the clinical rationale for the use of Metastron in the palliative treatment of these patients.

A retrospective analysis of the cost effectiveness of treatment with Metastron in patients with prostate cancer metastatic to bone.

A retrospective study was performed on the cost-effectiveness of treatment for advanced prostate cancer metastatic to bone. Patients (n = 29) recruited into the trans Canada trial at the Cross Cancer Institute, Edmonton and randomized to treatment with Metastron (strontium-89 chloride) (n = 14) or placebo (n = 15) after local field irradiation therapy for pain palliation were studied over their entire survival time. Estimates were made of the direct costs of treatment, i.e. drugs (analgesics and hormonal agents) and external radiotherapy, and the indirect costs (investigations, outpatient visits and inpatient days, either total or for tertiary care) based on records from the referring hospital, the cancer clinic and any hospitals to which the patients may subsequently have been referred. Meaningful differences were apparent between the two groups in direct costs with the group receiving Metastron showing a reduction over the entire survival time of Can$ 1,720/person compared with placebo; it should be noted that in this analysis neither the costs of the Metastron, nor of the initial radiotherapy, have been included. The Metastron group also showed a reduction in costs of hospitalization for tertiary care of Can$ 5,696/person, though the total cost of hospitalization was similar in the two groups. These results suggest that treatment with Metastron can bring about reductions in management costs for patients with advanced prostate cancer and, coupled with the findings of the Trans Canada trial on the improvement in quality of life for patients given Metastron, they add financial support to the clinical rationale for the use of Metastron for the palliative treatment of patients with bone metastases resulting from prostate cancer.