Selective estrogen receptor modulator (SERM) for the treatment of osteoporosis in postmenopausal women: focus on lasofoxifene

Selective estrogen receptor modulators (SERMs) represent a class with a growing number of compounds that act as either estrogen receptor agonists or antagonists in a tissue-specific manner. This article reviews lasofoxifene, a new-generation SERM that has completed phase III development for the prevention and treatment of osteoporosis in postmenopausal women. Consistent with preclinical observations, this new SERM demonstrated improved skeletal efficacy over raloxifene and at an oral dose of 0.5 mg/day was effective in the prevention of both vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. At the same dosage, lasofoxifene treatment also reduced estrogen receptor-positive breast cancer risk and the occurrence of vaginal atrophy, but, like the other SERMs, was associated with hot flushes and an increased risk of venous thromboembolic events. With its increased efficacy on the prevention of nonvertebral fractures than current available SERMs and its positive effects on the vagina, this new compound may represent an alternative and cost-effective therapy for osteoporosis in postmenopausal women

Aromatase Activity and Bone Loss in Men

Aromatase is a specific component of the cytochrome P450 enzyme system responsible for the transformation of androgen precursors into estrogens. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is, expressed in ovary and testis, but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The activity of aromatase regulates the concentrations of estrogens with endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen in men. Clinical and experimental evidences clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, the attainment of peak bone mass, pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity may significantly affect bone loss and fracture risk in men

Lasofoxifene: Evidence of its therapeutic value in osteoporosis

Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain. Aims: The purpose of this article is to review the clinical trials of lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis. The medical literature was reviewed for appropriate articles containing the terms “lasofoxifene” and SERMs”. Evidence review: There are three (phase II or phase III) clinical trials that clearly demonstrate efficacy and safety of this new SERM in the suppression of bone loss and the prevention of vertebral and nonvertebral fractures. Moreover, lasofoxifene treatment also reduced breast cancer risk and the occurrence of vaginal atrophy. Place in therapy: With its increased potency and efficacy on the prevention of nonvertebral fractures lasofoxifene may be an alternative and cost-effective therapy for osteoporosis in postmenopausal women

Bazedoxifene for the prevention of postmenopausal osteoporosis

Bazedoxifene acetate is a novel, chemically distinct selective estrogen receptor modulator (SERM) that has been specifically developed after a stringent preclinical screening in order to obtain favorable effects on the skeleton and lipid metabolism with the additional improvement of a neutral effect on hot flushes and without stimulating the uterus or the breast. In both preclinical and clinical studies this SERM was shown to maintain BMD, prevent fractures, and reduce total cholesterol. Moreover, bazedoxifene also showed an improved uterine profile and demonstrated estrogen antagonistic activity on the endometrium. Importantly, this latter capacity has led to the development of a novel class of menopausal therapy called tissue selective estrogen complex (TSEC), in which bazedoxifene is combined with conjugated estrogen. The rationale for selecting bazedoxifene as the SERM in this TSEC combination is that it may offset estrogen stimulation of endometrial and breast tissue, without the necessity of using a progestin in women with an intact uterus, without aggravating menopausal vasomotor symptoms, but with an additive effect on bone. Preliminary data from phase 3 clinical trials appear to confirm this hypothesis, showing a greater effect of bazedoxifene on BMD with respect to raloxifene, coupled with efficacy on menopausal vasomotor symptoms not achieved by SERM alone. These properties and the safety profile of this combination, if confirmed long-term in ongoing phase 3 trials, might significantly affect the way women and physicians approach menopause and its related disorders

The effect of zoledronic acid on serum osteoprotegerin in early stage multiple myeloma

We evaluated the effect of zoledronic acid (ZA) on serum levels of osteoprotegerin (OPG) and the ligand for receptor activator of nuclear factor kappaB (RANKL) in patients with smoldering myeloma. In treated subjects we found an increase of OPG accounting for an effect of ZA on osteoblast and/or bone marrow stromal cells together with the direct effect on osteoclasts

Beyond Glycemic Control in Diabetes Mellitus: Effects of Incretin-Based Therapies on Bone Metabolism

Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients

Management of Osteoporosis in Men: A Narrative Review

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women

Insulin-like Growth Factor-1 Receptor (IGF-1R) expression on Circulating Tumor Cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial

Purpose To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients. Methods CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses. Results Seventy-two out of 126 randomized patients were evaluated: 57% had >= 1 IGF-1R positive CTC and 37.5% >= 4 IGF-1R negative cells; 42% had CTC count >= 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found. Conclusion Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies. Clinical trial registration: Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26)