Available Treatments For Osteoporosis Research Articles

Osteocyte-mediated mechanical response controls osteoblast differentiation and function.

Low bone mass is a pervasive global health concern, with implications for osteoporosis, frailty, disability, and mortality. Lifestyle factors, including sedentary habits, metabolic dysfunction, and an aging population, contribute to the escalating prevalence of osteopenia and osteoporosis. The application of mechanical load to bone through physical activity and exercise prevents bone loss, while sufficient mechanical load stimulates new bone mass acquisition. Osteocytes, cells embedded within the bone, receive mechanical signals and translate these mechanical cues into biological signals, termed mechano-transduction. Mechano-transduction signals regulate other bone resident cells, such as osteoblasts and osteoclasts, to orchestrate changes in bone mass. This review explores the mechanisms through which osteocyte-mediated response to mechanical loading regulates osteoblast differentiation and bone formation. An overview of bone cell biology and the impact of mechanical load will be provided, with emphasis on the mechanical cues, mechano-transduction pathways, and factors that direct progenitor cells toward the osteoblast lineage. While there are a wide range of clinically available treatments for osteoporosis, the majority act through manipulation of the osteoclast and may have significant disadvantages. Despite the central role of osteoblasts to the deposition of new bone, few therapies directly target osteoblasts for the preservation of bone mass. Improved understanding of the mechanisms leading to osteoblastogenesis may reveal novel targets for translational investigation.

Osteoporosis and bone metabolism in patients with Klinefelter syndrome.

Low bone mass is common in men with Klinefelter syndrome (KS), with a prevalence of 6-15% of osteoporosis and of 25-48% of osteopenia. Reduced bone mass has been described since adolescence and it might be related to both reduced bone formation and higher bone resorption. Although reduced testosterone levels are clearly involved in the pathogenesis, this relation is not always evident. Importantly, fracture risk is increased independently from bone mineral density (BMD) and testosterone levels. Here we discuss the pathogenesis of osteoporosis in patients with KS, with a particular focus on the role of testosterone and testis function. In fact, other hormonal mechanisms, such as global Leydig cell dysfunction, causing reduced insulin-like factor 3 and 25-OH vitamin D levels, and high follicle-stimulating hormone and estradiol levels, might be involved. Furthermore, genetic aspects related to the supernumerary X chromosome might be involved, as well as androgen receptor expression and function. Notably, body composition, skeletal mass and strength, and age at diagnosis are other important aspects. Although dual-energy x-ray absorptiometry is recommended in the clinical workflow for patients with KS to measure BMD, recent evidence suggests that alterations in the microarchitecture of the bones and vertebral fractures might be present even in subjects with normal BMD. Therefore, analysis of trabecular bone score, high-resolution peripheral quantitative computed tomography and vertebral morphometry seem promising tools to better estimate the fracture risk of patients with KS. This review also summarizes the evidence on the best available treatments for osteoporosis in men with KS, with or without hypogonadism.

Sphingosylphosphorylcholine blocks ovariectomy-induced bone loss by suppressing Ca2+ /calmodulin-mediated osteoclast differentiation.

Osteoporosis is a disease in which bone mineral density decreases due to abnormal activity of osteoclasts, and is commonly found in post‐menopausal women who have decreased levels of female hormones. Sphingosylphosphorylcholine (SPC) is an important biological lipid that can be converted to sphingosine‐1‐phosphate (S1P) by autotaxin. S1P is known to be involved in osteoclast activation by stimulating osteoblasts, but bone regulation by SPC is not well understood. In this study, we found that SPC strongly inhibits RANKL‐induced osteoclast differentiation. SPC‐induced inhibitory effects on osteoclast differentiation were not affected by several antagonists of S1P receptors or pertussis toxin, suggesting cell surface receptor independency. However, SPC inhibited RANKL‐induced calcineurin activation and subsequent NFATc1 activity, leading to decrease of the expression of Trap and Ctsk. Moreover, we found that bone loss in an experimental osteoporosis mouse model was recovered by SPC injection. SPC also blocked ovariectomy‐induced body weight increase and Nfatc1 gene expression in mice. We also found that SPC inhibits RANKL‐induced osteoclast differentiation in human macrophages. Since currently available treatments for osteoporosis, such as administration of female hormones or hormone receptor modulators, show serious side effects, SPC has potential as a new agent for osteoporosis treatment.

Pharmacological agents and natural compounds: available treatments for osteoporosis.

Osteoporosis, a systemic skeletal disease characterized by a decrease in bone mass and deterioration of bone structure leading to an increased risk of fragility fractures, represents one of the major health problems worldwide. Currently, there are numerous pharmacological products used for the treatment of osteoporosis. Anti-resorptive drugs include bisphosphonates, hormone therapy, selective estrogen-receptor modulators, calcitonin, denosumab, calcium and vitamin D supplementation. Anabolic drugs such as teriparatide, strontium ranelate, romosozumab have recently become available based on advanced clinical trials. In recent years, combination therapy of anabolic and anti-resorptive agents is expected to be ideal anti-osteoporosis option. The adverse side effects caused by the long-term administration of pharmacological drugs have prompted researchers to study natural therapeutic compounds to find an alternative and effective way for osteoporosis treatment. Natural compounds including phytoestrogens with estrogenic effects (e.g. genistein, daidzein, icariin, dioscin, Ginkgo biloba), antioxidant and anti-inflammatory agents (e.g. acteoside, curcumin, resveratrol, Camellia sinensis), treatments that exert their effects by multiple actions (e.g. kinsenoside, berberine, Olea europaea, Prunus domestica, Allium cepa) could provide a safer alternative to primary pharmacological strategies. In this review, both pharmacological agents and natural compounds as available treatments for osteoporosis are characterized. In addition, possible mechanisms of action of all aforementioned treatments associated with bone remodelling, osteoclastogenesis, osteoblastogenesis, bone cell activity, death, and oxidative stress are presented. Nevertheless, more high-quality clinical studies with natural compounds are needed to provide greater evidence of the beneficial and safer antiosteoporotic application for the candidate.

OSTEOPROTECTIVE MEDICINAL PLANTS - PART 1 (A HUMAN CLINICAL EVIDENCE-BASED REVIEW)

Background. Osteoporosis is a bone metabolic disease affecting a large percentage of aging population, which leads to an increased risk of fractures and has a negative impact on life quality. The available treatments for osteoporosis are effective, but are associated with several severe adverse reactions, hence the interest for alternative treatments devoid of such redoubtable side effects. Medicinal plants represent a viable resource for new therapeutic agents.
 The purpose of this review is to provide an overview about the medicinal plants that have been reported to have anti-osteoporotic effects in human clinical studies.
 Materials and Methods. Relevant studies found in PubMed database, pertaining to efficacy in humans, mechanism of action, osteoactive phytochemicals and safety, were selected. For the inquiry, keywords such as “medicinal plant”, “osteoporosis”, “bone”, “fracture”, “osteoclast” and “osteoblast” were used in various combinations. The information extracted was integrated with the traditional knowledge on the correspondent medicinal plants. Results. Eight medicinal plants (Cimicifuga racemosa, Cissus quadrangularis, Eleutherococcus senticosus, Epimedium spp., Glycine max, Pueraria spp., Panax notoginseng, Salvia milthiorriza) were selected. Mechanisms involved include the activation of osteoblasts, inhibition of osteoclastogenesis, estrogen-like activity, anti-inflammatory activity, inhibition of collagen degradation by cathepsin K.
 Conclusion. Several medicinal plants have been included in clinical studies successfully targeting osteoporosis, thus showing the potential to modulate bone resorption and bone formation.

The effects of organic nitrates on osteoporosis: a systematic review

Current treatments for osteoporosis are limited by lack of effect on cortical bone, side effects, and, in some cases, cost. Organic nitrates, which act as nitric oxide donors, may be a potential alternative. This systematic review summarizes the clinical data that reports on the effects of organic nitrates and bone. Organic nitrates, which act as nitric oxide donors, are novel agents that have several advantages over the currently available treatments for osteoporosis. This systematic review summarizes the clinical data that reports on the effects of organic nitrates on bone. We searched Medline (1966 to November 2012), EMBASE (1980 to November 2012), and the Cochrane Central Register of Controlled Trials (Issue 11, 2012). Keywords included nitrates, osteoporosis, bone mineral density (BMD), and fractures. We identified 200 citations. Of these, a total of 29 were retrieved for more detailed evaluation and we excluded 19 manuscripts: 15 because they did not present original data and four because they did not provide data on the intervention or outcome of interest. As such, we included ten studies in literature review. Of these ten studies two were observational cohort studies reporting nitrate use was associated with increased BMD; two were case control studies reporting that use of nitrates were associated with lower risk of hip fracture; two were randomized controlled trials (RCT) comparing alendronate to organic nitrates for treatment of postmenopausal women and demonstrating that both agents increased lumbar spine BMD. The two largest RCT with the longest follow-up, both of which compared effects of organic nitrates to placebo on BMD in women without osteoporosis, reported conflicting results. Headaches were the most common adverse event among women taking nitrates. No studies have reported on fracture efficacy. Further research is needed before recommending organic nitrates for the treatment of postmenopausal osteoporosis.

Essential Role of Nuclear Factor of Activated T Cells (NFAT)-mediated Wnt Signaling in Osteoblast Differentiation Induced by Strontium Ranelate

The antiosteoporotic treatment strontium ranelate (SrRan) was shown to increase bone mass and strength by dissociating bone resorption and bone formation. To identify the molecular mechanisms of action of SrRan on osteoblasts, we investigated its effects on calcineurin-NFAT (nuclear factor of activated T cells) signaling, an important calcium sensitive pathway controlling bone formation. Using murine MC3T3-E1 and primary murine osteoblasts, we demonstrate that SrRan induces NFATc1 nuclear translocation, as shown by immunocytochemical and Western blot analyses. Molecular analysis showed that SrRan increased NFATc1 transactivation in osteoblasts, an effect that was fully abrogated by the calcineurin inhibitors cyclosporin A or FK506, confirming that SrRan activates NFATc1 signaling in osteoblasts. This has functional implications because calcineurin inhibitors blunted the enhanced osteoblast replication and expression of the osteoblast phenotypic markers Runx2, alkaline phosphatase, and type I collagen induced by SrRan. We further found that SrRan increased the expression of Wnt3a and Wnt5a as well as beta-catenin transcriptional activity in osteoblasts, and these effects were abolished by calcineurin inhibitors. The Wnt inhibitors sFRP1 and DKK1 abolished SrRan-induced osteoblast gene expression. Furthermore, blunting the Wnt5a receptor Ryk or RhoA that acts downstream of Ryk abrogated cell proliferation and osteoblast gene expression induced by SrRan. These results indicate that activation of NFATc1 and downstream canonical and non-canonical Wnt signaling pathways mediate SrRan-induced osteoblastic cell replication and differentiation, which provides novel insights into the mechanisms of action of this antiosteoporotic agent in osteoblastogenesis.

Dual effect of strontium ranelate: Stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro

Strontium ranelate is a newly developed drug that has been shown to significantly reduce the risk of vertebral and non-vertebral fractures, including those of the hip, in postmenopausal women with osteoporosis. In contrast to other available treatments for osteoporosis, strontium ranelate increases bone formation and decreases resorption. In this study, the dual mode of action of strontium ranelate in bone was tested in vitro, on primary murine osteoblasts and osteoclasts derived from calvaria and spleen cells, respectively. We show that strontium ranelate treatment, either continuously or during proliferation or differentiation phases of mouse calvaria cells, stimulates osteoblast formation. Indeed after 22 days of continuous treatment with strontium ranelate, the expression of the osteoblast markers ALP, BSP and OCN was increased, and was combined with an increase in bone nodule numbers. On the other hand, the number of mature osteoclasts strongly decreased after strontium ranelate treatment. Similarly to previous studies, we confirm that osteoclasts resorbing activity was also reduced but we found that strontium ranelate treatment was associated with a disruption of the osteoclast actin-containing sealing zone. Therefore, our in vitro assays performed on primary murine bone cells confirmed the dual action of strontium ranelate in vivo as an anabolic agent on bone remodeling. It stimulates bone formation through its positive action on osteoblast differentiation and function, and decreases osteoclast differentiation as well as function by disrupting actin cytoskeleton organization.

Strontium ranelate: New insights into its dual mode of action

Strontium ranelate is a newly developed drug that acts as an effective antiosteoporotic therapy in postmenopausal women with osteoporosis. In contrast to other available treatments for osteoporosis, strontium ranelate induces opposite effects on bone resorption and formation. Preclinical studies showed that this dual effect results in increased bone mass and improved bone microarchitecture and strength in intact rodents, and in prevention of bone loss in osteopenic animals. Histomorphometric analysis of unpaired iliac crest bone biopsies in postmenopausal osteoporotic patients treated with strontium ranelate for 3 years showed that the drug increased bone formation, assessed by both the mineralization rate and osteoblast surface, and tended to decrease the osteoclast surface, compared with the placebo group. Three-dimensional micro-computed tomography analysis of the bone biopsies consistently showed a higher number of trabeculae, decreased trabecular separation, and an increase in cortical thickness, which provides evidence for a better trabecular and cortical bone microarchitecture in treated patients compared with the placebo group. Some mechanisms that underlie the beneficial effects of strontium ranelate on bone metabolism and strength have now been identified. In vitro analyses showed that strontium activates the calcium-sensing receptor. We, however, showed that strontium ranelate activates cell replication and downstream ERK1/2 signaling in osteoblasts from calcium-sensing receptor-null mice, indicating that, in addition to the calcium-sensing receptor, another receptor could mediate the effect of strontium ranelate on osteoblastic cell replication. Other in vitro studies showed that strontium ranelate can activate the osteogenic differentiation of bone marrow stromal cells by activating cyclo-oxygenase 2 (COX-2)-mediated prostaglandin E 2 production. Finally, recent data indicate that strontium ranelate can upregulate osteoprotegerin (OPG) and decrease receptor activator of nuclear factor kappa B (RANK) ligand expression in human osteoblastic cells, suggesting that strontium ranelate may reduce bone resorption by modulating the RANK/RANK-ligand/OPG system, which is essential for osteoclastogenesis. These recent data provide new insights into the mechanism of action of strontium ranelate and give biochemical support to cell physiology which explain the opposite effects of strontium ranelate on bone formation and resorption.

Treatment of postmenopausal osteoporosis.

POSTMENOPAUSAL OSTEOPOROSIS IS a common and serious clinical problem. As both individuals and society have come to recognize the importance of preventing and treating osteoporosis, several new medications have been developed that have been shown to reduce fracture rates in women with osteoporosis. This article will review recent studies and evaluate the currently available treatments for osteoporosis. All women with low bone mineral density (BMD) should ingest 1200 to 1500 mg of calcium and 400 to 800 IU of vitamin D daily. The National Osteoporosis Foundation recommends pharmacological treatment of all postmenopausal women with T scores (the number of SDs below peak young adult bone mass) below −2.0, and those with T scores below −1.5 and risk factors for osteoporosis. However, for the same level of BMD, the fracture risk is much greater in older than in younger subjects. Furthermore, the greatest benefit in fracture reduction occurs in patients with preexisting vertebral fractures or T scores below −2.5. While older women with low BMD and a history of an osteoporotic fracture should be treated pharmacologically, the decision is less clear for other patients.