Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

Eficacia y seguridad de fulvestrant en pacientes con cáncer de mama metastásico con receptores hormonales positivos, no tributarios a quimioterapia, que ha progresado a inhibidores de aromatasa no esteroideos / Efficacy and safety of fulvestrant in patients with metastatic breast cancer with hormone receptor positive, non-tributary to chemotherapy, who has progressed to non-steroidal aromatase inhibitors

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación de eficacia y seguridad del uso de fulvestrant en el manejo de pacientes post-menopáusicas, con diagnóstico de cáncer de mama metastásico con receptores hormonales positivos, progresivo a inhibidores de aromatasa no esteroideos con control de enfermedad visceral y de partes blandas con quimioterapia basada en taxanos con toxicidad limitante (i.e., no tributarios a quimioterapia sistémica). Aspectos Generales: El cáncer de mama es el tipo de cáncer que se diagnostica con mayor frecuencia entre mujeres a nivel mundial. En el Perú, del total de cánceres reportados entre los años 2006 a 2011, el cáncer de mama fue el tercer tipo de cáncer más frecuente en toda la población (10.3%) y el segundo tipo de cáncer más frecuente entre mujeres (16.6%). Aproximadamente 34 de cada 100 mil mujeres al año es diagnosticada con cáncer de mama, con una tasa de mortalidad de 14 por cada 100 mil mujeres diagnosticadas. El cáncer de mama metastásico es la principal causa de muerte dentro de los pacientes con cáncer de mama. Más del 90% de pacientes con cáncer de mama muere por metástasis. Tecnologia Sanitaria de Interés: Fulvestrant (nombre comercial Faslodex), es una terapia antiestrogénica de tipo SERDs. Esta terapia está indicada para el tratamiento de cáncer de mama metastásico con receptores estrogénicos positivos en mujeres post-menopáusicas que han progresado luego de terapia antiestrogénica. Fulvestrant disminuye la actividad de los receptores de estrógeno, presenta actividad anti-proliferativa, induce apoptosis, no posee actividad agonista de estrógeno y carece de resistencia cruzada con otras terapias antiestrogénicas, tales como los SERMs. METODOLOGIA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de fulvestrant para el tratamiento de cáncer de mama con receptores estrogénicos positivos metastásico, en pacientes no tributarios a quimioterapia, que han progresado a inhibidores de aromatasa no esteroideos. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica hasta Junio 2016 para el sustento del uso de fulvestrant en el tratamiento de cáncer de mama positivo a receptores hormonales metastásico, en pacientes no tributarios a quimioterapia que han progresado a inhibidores de aromatasa no esteroideos. Se presenta la evidencia\r\ndisponible según el tipo de publicación priorizada en los criterios de inclusión (i.e., GP, ETS, RS y ECA fase III). CONCLUSIONES: El presente documento evaluó la evidencia científica publicada hasta Julio del 2016 para el uso fulvestrant en mujeres post-menopáusicas con cáncer de mama metastásico con receptores hormonales positivos que han progresado a tratamientos previos con inhibidores de aromatasa no esteroideos. Existen pacientes con cáncer de mama metastásico con receptores hormonales positivos que progresan a terapia hormonal estándar con inhibidores de aromatasa no esteroideos, en quienes la quimioterapia no está indicada, dejando limitadas alternativas para su tratamiento. En la actualidad, el Petitorio Farmacológico de EsSalud cuenta con exemestano, un inhibidor de aromatasa esteroideo, por lo tanto es necesario probar que fulvestrant es una alternativa superior a exemestano en relación a los desenlaces considerados en el presente dictamen. Fulvestrant, es una alternativa de terapia hormonal se segunda línea. Sin embargo, esta no ha probado ser mejor que exemestano para ninguno de los desenlaces de interés, a pesar de ello, el costo de este medicamento es considerablemente elevado en relación al que actualmente se encuentra en el petitorio farmacológico de EsSalud. El Instituto de evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso de fulvestrant para el tratamiento endocrino de cancer de mama con receptores hormonales positivos metastásico en mujeres post-menopaúsicas no tributarias a quimioterapia que han progresado a terapia con inhibidores de aromatasa no esteroideos.

Conjugated estrogens and bazedoxifene in minority populations: pooled analysis of four phase 3 trials.

OBJECTIVE: The aim of the study was to compare efficacy of conjugated estrogens (CE)/bazedoxifene (BZA) for treatment of menopausal symptoms and prevention of postmenopausal osteoporosis in minorities (black/Hispanic) versus whites. METHODS: In a post hoc analysis, data were pooled from 3,424 white or minority nonhysterectomized postmenopausal women randomized to CE 0.45 or 0.625 mg/BZA 20 mg or placebo in four double-blind, phase 3 Selective Estrogens, Menopause, and Response to Therapy (SMART) trials. Outcomes included hot flush frequency/severity (daily diary) in women with at least seven moderate-to-severe hot flushes per day (SMART-1, -2), vaginal cytology in women with at most 5% superficial cells (SMART-1, -3), lumbar spine and total hip bone mineral density (BMD) (SMART-1, -5), and the Menopause-Specific Quality of Life (MENQOL) questionnaire (SMART-1, -2, -3, -5). RESULTS: The analysis included 2,907 white (84.9%), 315 black (9.2%), and 202 Hispanic (5.9%) women. The reduction in hot flush frequency/severity versus placebo (P < 0.05; week 12) was similar in white and minority women. In both populations, both doses significantly (P < 0.05 vs placebo) improved MENQOL vasomotor function, sexual function, and total scores at 3 months; decreased the percentage of parabasal cells at 2 years; and increased the percentage of BMD responders at 12 and 24 months. Significant differential treatment effects by race/ethnicity were observed only for effects on vaginal superficial cells at month 24 and vaginal pH at month 3. CONCLUSIONS: Notwithstanding a limited sample size, CE/BZA had a similar and beneficial impact on hot flushes, MENQOL, and BMD in minorities and whites.

The selective estrogen receptor modulators in breast cancer prevention.

BACKGROUNDS: Persistently increased blood levels of estrogens are associated with an increased risk of breast cancer. Selective estrogen receptor modulators (SERMs) are a class of compounds that act on the estrogen receptor (ER). METHODS: Several clinical trials have demonstrated the effectiveness of its prophylactic administration. Incidence of invasive ER-positive breast cancer was reduced by SERMs treatment, especially for those women with high risk of developing breast cancer. In this study, we reviewed the clinical application of SERMs in breast cancer prevention. RESULTS: To date, four prospective randomized clinical trials had been performed to test the efficacy of tamoxifen for this purpose. Concerning on the benefit and cost of tamoxifen, various studies from different countries demonstrated that chemoprevention with tamoxifen seemed to be cost-effective for women with a high risk of invasive breast cancer. Based above, tamoxifen was approved for breast cancer prevention by the US Food and Drug Administration in 1998. Raloxifene was also approved for postmenopausal women in 2007 for breast cancer prevention which reduces the risk of invasive breast cancer with a lower risk of unwanted stimulation of endometrium. Thus, raloxifene is considered to have a better clinical possesses as prophylactic agent. Several other agents, such as arzoxifene and lasofoxifene, are currently being investigated in clinic. The American Society of Clinical Oncology and National Comprehensive Cancer Network had published guidelines on breast cancer chemoprevention by SERMs. However, use of tamoxifen and raloxifene for primary breast cancer prevention was still low. CONCLUSION: A broader educational effort is needed to alert women and primary care physicians that SERMs are available to reduce breast cancer risk.

Personalized assessment and management of women at risk for breast cancer in North America.

Many women at increased risk for breast cancer would benefit from referral for genetic testing, enhanced screening, preventive therapy or risk-reducing surgery. We present a visual model and a step-wise approach to assist with a personalized risk stratification and management of these women. We present current recommendations with respect to lifestyle behaviors and mammographic screening, and we review the current evidence regarding enhanced screening and risk-reducing therapies. We discuss the usefulness of three risk-assessment tools in determining whether a woman qualifies for genetic testing, enhanced screening or preventive therapy and present four cases to demonstrate the usefulness of this approach in the clinical setting.

Population pharmacokinetic/pharmacodynamic assessment of pharmacological effect of a selective estrogen receptor ß agonist on total testosterone in healthy men.

BACKGROUND: LY500307 is a highly selective estrogen receptor ß (ERß) agonist, which loses its selectivity at high dose and leads to undesirable suppression of total testosterone (TT) concentration. The objective of the present analysis was to define the LY500307 dose with minimal effect on TT METHODS: LY500307 and TT concentrations were obtained from a single ascending-dose study in a total of 30 healthy male subjects. LY500307 (in the range of 0.5 to 500 mg) or placebo was administered orally as a single dose on 2 occasions with a 3-week washout period. A population pharmacokinetics/pharmacodynamics (PK/PD) model that integrated Fourier series in an indirect response model was developed to describe the circadian rhythm of TT and the exposure-response relationship of LY500307 on TT. RESULTS: The maximum TT suppression (Emax ) was approximately 28.6%. The potency (EC50 ) of LY500307 on TT suppression was approximately 1.69 ng/mL with a 95%CI of 0.871 to 4.44 ng/mL. This model could provide inferences on LY500307 dose levels that would result in various magnitudes of TT suppression. CONCLUSIONS: Population PK/PD modeling is a highly sensitive tool to detect exposure-response relationships on top of the complicated and highly variable circadian rhythm of TT.

Assessment of ospemifene or lubricants on clinical signs of VVA.

INTRODUCTION: Ospemifene is a new oral estrogen receptor agonist/antagonist with tissue-selective effects approved for the treatment of moderate to severe dyspareunia, a symptom of postmenopausal vulvar and vaginal atrophy (VVA). AIM: The aim of the study is to assess ospemifene or lubricant use on the clinical signs of VVA. METHODS: Subjects in three double-blind, placebo-controlled clinical trials were randomized to ospemifene or placebo. In two of the trials, women were provided nonhormonal lubricants for use as needed, and a preplanned evaluation of the frequency of lubricant use was performed. Additionally, a post hoc placebo group analysis for impact of lubricant use or nonuse on physiologic effects of the percentage of superficial and parabasal cells (maturation index) and vaginal pH was conducted. A secondary preplanned end point included visual examination of the vagina (clinical signs of vaginal dryness, petechiae, pallor, friability, and redness of the mucosa) comparing change from baseline to end of treatment for the ospemifene 60-mg/day group and vs. placebo. MAIN OUTCOME MEASURES: The primary end points in the phase 3 clinical trials included the percentage of superficial cells, parabasal cells, vaginal pH, and most bothersome symptoms compared with placebo. RESULTS: There was no significant difference in physiologic effects between placebo lubricant users vs. nonusers in either 12-week study. Compared with baseline, substantially more subjects receiving ospemifene 60 mg/day than placebo showed complete resolution of clinical signs of VVA after 12 and 52 weeks of treatment. CONCLUSIONS: Ospemifene substantially improved clinical signs of VVA. Within the placebo group, there was no difference in physiologic effects in lubricant users vs. nonusers. Based on gynecologic evaluation of the vagina, benefits were apparent at 12 weeks and sustained for 52 weeks in the ospemifene-treated subjects with significant improvement over placebo. In these three clinical trials, in contrast to ospemifene-treated women, placebo subjects who utilized lubricants had no improvement in their underlying vaginal physiology.

Duration of treatment for osteoporosis.

Many treatments for postmenopausal osteoporosis with proven efficacy in lowering fracture risk had become available since many years now. In the last few years the issue about treatment duration has become a matter of importance. In this paper the pivotal trials for alendronate, risedronate, zoledronate and other anti reabsorptive drugs such as denosumab are revised with particular attention to the extension studies aimed to verify the effect of drug discontinuation. The results of the review highlight differences among the available drugs and the practical clinical consequences also in terms of cost-effectiveness.

[Osteoporosis and pharmaceutical care]. / Az oszteoporózis és a gyógyszerészi gondozás.

The increasing prevalence of osteoporosis is causing a substantial health burden. Compliance and adherence to osteoporosis management are of high priority, having a significant effect on the cost effectiveness of therapy. In this study, we aimed to summarize the literature on patient compliance in osteoporosis. Our findings indicate that 60% of the patients have some medication related problem, in particular, it is difficult to influence the patients to play an active role in their disease management and to keep a high level of persistence. Pharmaceutical care could help to reach optimal cooperation between patients and the heath care professional, as one of its main objective is to improve the rate of patient adherence in long-term drug therapy.

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up.

BACKGROUND: Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. METHODS: BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. FINDINGS: 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. INTERPRETATION: For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. FUNDING: Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

[Assessment of bone quality. Bone quality and osteoporosis treatment].

Anti-resorptive agents are useful for prevent osteoporotic fractures in postmenopausal women because they protect bone architecture. However, long duration of strong suppression of bone resorption may cause severe suppressed bone turnover, which results in reduced bone material properties such as homogenous distribution of mineralization or increased microdamage accumulation. Appropriate suppression of bone remodeling is a key for anti-resorptive treatments of osteoporosis to maintain or improve bone quality.

Improvements in tumor targeting, survivorship, and chemoprevention pioneered by tamoxifen. A personal perspective.

Twenty years ago, antiestrogen therapy with tamoxifen played only a secondary role in breast cancer care. All hopes to cure metastatic breast cancer were still pinned on either the discovery of new cytotoxic drugs or a dose-dense combination of available cytotoxic drugs with bone marrow transplantation. A similar strategy with combination chemotherapy was employed as an adjuvant for primary breast cancer. Simply stated, the goal was to kill the cancer with nonspecific cytotoxic drugs while keeping the patient alive with supportive care. However, medical research does not travel in straight lines, and an alternative approach emerged to solve the problem of controlling tumor growth with minimal side effects: targeted therapy. The approach of using long-term antihormone therapy to control early-stage breast cancer growth would revolutionize cancer care by targeting the tumor estrogen receptor (ER). The success of the strategy would contribute to a decrease in the national mortality figures for breast cancer. More importantly, translational research that targeted the tumor ER with a range of new antiestrogenic drugs would presage the current fashion of blocking survival pathways for the tumor by developing novel targeted treatments. But a surprise was in store when the pharmacology of "antiestrogens" was studied in detail: The nonsteroidal "antiestrogens" are selective ER modulators--ie, they are antiestrogens in the breast, estrogens in the bone--and they lower circulating cholesterol levels. This knowledge would establish a practical approach to breast cancer chemoprevention for women at high risk (tamoxifen) and low risk (raloxifene).

Model-based drug development: the road to quantitative pharmacology.

High development costs and low success rates in bringing new medicines to the market demand more efficient and effective approaches. Identified by the FDA as a valuable prognostic tool for fulfilling such a demand, model-based drug development is a mathematical and statistical approach that constructs, validates, and utilizes disease models, drug exposure-response models, and pharmacometric models to facilitate drug development. Quantitative pharmacology is a discipline that learns and confirms the key characteristics of new molecular entities in a quantitative manner, with goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans and enabling critical decision making. Model-based drug development serves as an integral part of quantitative pharmacology. This work reviews the general concept, basic elements, and evolving role of model-based drug development in quantitative pharmacology. Two case studies are presented to illustrate how the model-based drug development approach can facilitate knowledge management and decision making during drug development. The case studies also highlight the organizational learning that comes through implementation of quantitative pharmacology as a discipline. Finally, the prospects of quantitative pharmacology as an emerging discipline are discussed. Advances in this discipline will require continued collaboration between academia, industry and regulatory agencies.

[Postmenopausal osteoporosis]. / Osteoporosis a postmenopausában.

Due to its incidence and clinical consequences osteoporosis followed by vertebral, hip, and forearm fractures represents an outstanding problem of nowadays' health care. Because of its high mortality rate hip fractures are of special interest. The number of fractures caused by postmenopausal osteoporosis increases with age. Costs of examinations and treatment of women with postmenopausal osteoporosis and fractures are also increasing and represent a significant amount all over the world. Organization of Osteoporosis Centres in Hungary was founded in 1995 and has been since functioning, however, only the one-sixth of osteoporotic patients are treated. Several risk factors are known in the pathogenesis of osteoporosis, first of all the lack of sufficient calcium and vitamin D intake, age, genetic factors, and circumstances known to predispose falling. Estrogen deficiency is the most likely cause of postmenopausal osteoporosis. Osteodensitometry by DEXA is the most important method to evaluate osteoporosis, since decrease in bone mineral density strongly correlates with fracture incidence. Physical, radiologic, and laboratory examination are also required at the first visit and during follow-up. The quantity of bone can hardly be influenced after the 35th year of age, thus prevention of osteoporosis has special significance: appropriate calcium and vitamin D supplementation, weight-bearing sports and physical activity can prevent fractures. According to the results from studies fulfilling the criteria of evidence-based medicine, first choice treatment of osteoporosis involves hormone replacement therapy, bisphosphonates, the tissue specific tibolone, raloxifen and calcitonin. Calcium and vitamin D supplementation are always necessary to be added to any antiporotic treatment. Other combinations of different antiporotic drugs are useless and make the treatment more expensive. Other treatments like massage, physiotherapy, hip-protecting pants, etc. as well as rehabilitation have special clinical significance.

[Ovarian suppression in the adjuvant treatment of breast cancer: GnRh analogs, ovariectomy or radio-castration--"the philosopher's stone" instead of "chamber of horrors"]. / Ovarielle Suppression in der adjuvanten Therapie des Mammakarzinoms: GnRH-Analoga, Ovarektomie oder Radiomenolyse--"Stein der Weisen" statt "Kammer des Schreckens"?

BACKGROUND: Ovarian suppression in the adjuvant treatment of perimenopausal women with breast cancer is an important option. The therapeutic goal can be accomplished by administration of GnRH-analogues, ovarectomy or radiocastration. PATIENTS AND METHODS: We describe the advantages and the therapy related side effects and compare the different treatment modalities with each other. RESULTS: Because of its reversibility and patient's compliance GnRH-analogues seem to be advantageous especially in younger premenopausal women. When longer term side effects of artificially induced menopause are less important, therapeutic alternatives such as radiocastration or ovarectomy are effective without obvious superiority between these options. CONCLUSION: Even in the background of the increasing use of GnRH-analogues radiocastration remains still a therapeutic alternative because of its cost-effectiveness and feasibility. This accounts especially for peri- or premenopausal women above the age of 45.

Alendronic acid in primary prevention: new indication. No reduction in fracture risk.

(1) Alendronic acid at a dose of 5 mg/day is now licensed in France for primary prevention of postmenopausal fractures. (2) The clinical file is relatively bulky and methodologically adequate, but there are no comparisons with combined hormone replacement therapy or with raloxifen. (3) Three trials have shown that 5 mg/day alendronic acid slows postmenopausal bone loss. However, this effect disappears on treatment cessation, and mineral bone density is only one risk factor for postmenopausal fractures. (4) A placebo-controlled trial of primary prevention involving more than 4,000 patients showed no reduction in the risk of fracture after 4 years of treatment with alendronic acid (5 mg/day for 2 years, then 10 mg/day). (5) Alendronic acid increases the risk of oesophageal ulceration, necessitating strict precautions during ingestion.