Effective Treatment For Osteoporosis Research Articles

Beneficial effects of sulfonamide‑based gallates on osteoblasts invitro.

Effective treatments for osteoporosis remain fairly elusive; however, studies have reported that antioxidants may aid in the maintenance of reactive oxygen species at a favorable level, in order to prevent osteoporosis. Gallic acid (GA) and its derivatives are potent antioxidative and anti-inflammatory agents that affect several biochemical and pharmacological pathways; however, GA is slightly cytotoxic and suppresses cell proliferation. The present study modified GA by the introduction of sulfonamide, in order to obtain a novel compound known as JEZ-C, and investigated its effects on osteoblasts by measuring cell proliferation, viability, morphology, alkaline phosphatase (ALP) activity, and the expression of relevant osteoblast markers. Results indicated that JEZ-C may effectively promote osteoblast growth. JEZ-C increased ALP activity, upregulated the expression of osteogenic-related genes, including runt-related transcription factor 2, bone sialoprotein, osteocalcin and alpha-1 type I collagen, thus indicating that JEZ-C enhances bone matrix production and mineralization. The recommended range of JEZ-C concentration is between 6.25×10−3 and 6.25×10−1 µg/ml, within which cell growth was promoted compared with the control. Specifically, treatment with 6.25×10−2 µg/ml JEZ-C is ideal. These findings may represent a novel approach to cell-based therapy for the treatment of osteoporosis.

Efficacy and Safety of Denosumab for the Treatment of Osteoporosis in Patients with Chronic Kidney Disease

Background: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and may lead to metabolic abnormalities that accelerate bone loss. Bisphosphonates, the most widely used treatment for osteoporosis, are contraindicated in patients with severe renal impairment. In the present study, we assessed whether denosumab is a safe and effective treatment for osteoporosis in patients with CKD. Methods and Findings: A total of 143 patients with osteoporosis who were treated with denosumab were analyzed retrospectively. Of these patients, 40 had been previously treated with bisphosphonates. All patients received supplemental vitamin D. Effectiveness was assessed by analyzing changes in bone mineral density (BMD) and serum tartrate-resistant acid phosphatase (TRACP)-5b as a marker for serum bone resorption. More than fifty percent of the patients treated with bisphosphonates showed low BMD at the time their therapy was changed to denosumab. Denosumab was associated with a larger increase in both lumbar and femur neck BMD than were bisphosphonates (+4.8% and +5.5%, respectively). Denosumab decreased serum TRACP-5b while increasing BMD (P<0.001), and was well tolerated. Serum calcium levels decreased shortly after the injection of denosumab, but recovered within 14 days. Supplemental vitamin D (0.5 to 1.0 μg/day) appeared to prevent hypocalcemia and to support efficacy of denosumab. Conclusions: Denosumab increases BMD in the lumbar vertebra and femur neck in patients with CKD. The effect of denosumab on BMD is greater than that of bisphosphonates in these patients.

Effects of abaloparatide-SC (BA058) on bone histology and histomorphometry: The ACTIVE phase 3 trial

There are a number of effective treatments for osteoporosis but most are in the antiresorptive class of compounds. Abaloparatide-SC is a new osteoanabolic agent, which increased bone mineral density and lowered the risk of osteoporosis-related fractures in the phase 3 ACTIVE trial. The objective of this report is to describe the effects of abaloparatide-SC 80μg on bone histology and histomorphometry in iliac crest bone biopsies from this trial in which participants were randomized to receive blinded daily subcutaneous injections of placebo or abaloparatide-SC 80μg/d or open-label teriparatide 20μg/d for 18months. Iliac crest bone biopsies were obtained between 12 and 18months. Qualitative histological analysis of biopsies from abaloparatide-SC-treated patients revealed normal bone microarchitecture without evidence of adverse effects on mineralization or on the formation of normal lamellar bone. There were no bone marrow abnormalities, marrow fibrosis nor was there presence of excess osteoid or woven bone. There were few significant differences among the three treatment groups in a standard panel of static and dynamic histomorphometric indices. The mineral apposition rate was higher in the teriparatide-treated group than in the placebo-treated group. The eroded surface was lower in the abaloparatide-SC-treated group than in the placebo-treated group. Cortical porosity was higher in both the abaloparatide-SC- and the teriparatide-treated groups than in the placebo-treated group. We conclude that histological and histomorphometric analysis of iliac crest bone biopsies from subjects who were treated for up to 18months with abaloparatide-SC showed no evidence of concern for bone safety.Trial registration: ClinicalTrials.gov number NCT01343004.

Teriparatide:benefit and safety for bone disease in CKD patients undergoing hemodialysis

Teriparatide, 1-34 parathyroid hormone, is one of effective treatments for osteoporosis. Teriparatide shows an anabolic effect for bone formation, as a result, increases bone mineral density as well as prevention of fractures in the general population. On the other hand, there are a few report about the effect of teriparatide on increase of bone mineral density in maintenance hemodialysis patients. In addition to CKD-MBD, osteoporosis is also an important pathological change in ESRD patients, therefore its safety and efficacy should be discussed in more detail.

Effects of Different Concentrations of Collagenous Peptide from Fish Scales on Osteoblast Proliferation and Osteoclast Resorption.

The incidence of osteoporosis has increased among the elderly population. Establishing a model of bone remodeling for screening new drugs is critical to identify safe and effective treatments for osteoporosis. In this study, we established a platform to investigate the therapeutic effects of collagenous peptides extracted from scales of two kinds of fish, namely, sparidae and chanos. These peptides were prepared using seven concentrations of collagenous peptide: 100, 80, 60, 40, 20, 10 and 1 mg/ml. Experimental results indicated that collagenous peptides promoted the proliferation of osteoblasts and inhibited the proliferation of mature osteoclasts; the effective concentration of collagenous peptide-sparidae was 10 mg/ml and that of collagenous peptide-chanos was 40 mg/ml. These findings demonstrate that, to a certain extent, collagenous peptides extracted from fish scales can be used to prevent osteoporosis to assist bone remodeling.

Sclerostin Antibody Therapy for the Treatment of Osteoporosis: Clinical Prospects and Challenges.

It is estimated that over 200 million adults worldwide have osteoporosis, a disease that has increasing socioeconomic impact reflected by unsustainable costs associated with disability, fracture management, hospital stays, and treatment. Existing therapeutic treatments for osteoporosis are associated with a variety of issues relating to use, clinical predictability, and health risks. Consequently, additional novel therapeutic targets are increasingly sought. A promising therapeutic candidate is sclerostin, a Wnt pathway antagonist and, as such, a negative regulator of bone formation. Sclerostin antibody treatment has demonstrated efficacy and superiority compared to other anabolic treatments for increasing bone formation in both preclinical and clinical settings. Accordingly, it has been suggested that sclerostin antibody treatment is set to achieve market approval by 2017 and aggressively compete as the gold standard for osteoporotic treatment by 2021. In anticipation of phase III trial results which may potentially signify a significant step in achieving market approval here, we review the preclinical and clinical emergence of sclerostin antibody therapies for both osteoporosis and alternative applications. Potential clinical challenges are also explored as well as ongoing developments that may impact on the eventual clinical application of sclerostin antibodies as an effective treatment of osteoporosis.

Utilization and Reporting of Bone Densitometry: What Can the Musculoskeletal Radiologist Do to Help, Rather Than to Hurt?

Osteoporosis is a highly prevalent disease that predisposes patients to fragility fractures. These fractures carry serious risks, including increased mortality and the potential loss of functional independence. Effective treatments for osteoporosis are available, but these should be initiated before a fragility fracture actually occurs; to do so, osteoporosis must be diagnosed while it is still asymptomatic. The gold standard screening test used to detect low bone mass is dual-energy x-ray absorptiometry (DXA). Despite its clinical importance, the DXA report is sometimes neglected by radiologists-as though it were somehow less significant in diagnosis than our other modalities. If musculoskeletal radiologists are to help, rather than to hurt, we must raise the profile of this critical test with evidence-based utilization and coherent reporting: detailed recommendations for doing so are available from professional organizations such as the International Society for Clinical Densitometry and the National Osteoporosis Foundation. This brief survey will seek to remind the radiologist that a good densitometry report requires more than just copying numbers from a scanner.

Can antiosteoporotic therapy reduce mortality in MRI-proved acute osteoporotic vertebral fractures?

Patients with MRI-proved acute painful vertebral fractures in whom conservative pain management fails are frequently referred for vertebroplasty. This study investigated the effects of treating osteoporosis on the mortality rate of patients with MRI-proved acute osteoporosis-related vertebral fractures who had undergone vertebroplasty. We retrospectively reviewed the cases of osteoporosis patients with MRI-proved acute vertebral fractures who had been treated with vertebroplasty from January 2001 to December 2007. The long-term outcomes of the patients who received antiosteoporotic therapy were compared with those of patients who received no therapy. A total of 304 patients (247 female patients and 57 male patients; mean age, 74.1±7.7years) were enrolled in the study. The patients who received antiosteoporotic therapy had a significantly lower mortality rate than did patients who did not receive antiosteoporotic therapy (P=0.001; hazard ratio,0.396, 95% confidence interval, 0.273-0.575). At the end of the study, 183 patients were alive, and 121 had died. Effective treatment for osteoporosis may improve survival in patients with osteoporosis-related vertebral fractures after vertebroplasty.

Hypocalcemia Post Denosumab in Patients with Chronic Kidney Disease Stage 4-5

Background: Denosumab, a RANK-ligand inhibitor, is an effective treatment for osteoporosis in postmenopausal women and men. Unlike the bisphosphonates, it is not excreted by the kidney. Little is known, however, about its efficacy and safety in patients with severe chronic kidney disease (CKD). Methods: A retrospective study was performed in CKD 4-5D patients from a tertiary referral hospital who were treated with denosumab between 1st January 2011 and 31st March 2014. Data collected included information about the following: CKD stage, fracture history, bone mineral density, serum calcium levels pre and post denosumab treatment, episodes of hypocalcemia, relevant medications and adverse events. Results: Eight patients with CKD-5 and 6 patients with CKD-4 were identified (all female, mean age 77.1 ± 9.9). The mean pre-denosumab calcium value was 2.42 ± 0.12 mmol/l, PTH 20.2 ± 14.7 pmol/l and 25-OH vitamin D 69.1 ± 30.1 nmol/l. After denosumab treatment, 6/8 patients with CKD-5/5D, and 2/5 patients with CKD-4 developed severe hypocalcemia. Two patients developed direct adverse complications of hypocalcemia (seizure, laryngospasm, prolonged QT_c). Among the patients who developed hypocalcemia, the median time to serum calcium nadir was 21 days and the median time to correction of hypocalcemia was 71 days. Treatment of hypocalcemia required large doses of oral calcium and calcitriol, and increases in dialysate calcium concentration. Conclusions: A high rate of severe hypocalcemia was observed in patients with advanced CKD treated with denosumab. If denosumab is used in patients with severe CKD, close monitoring and aggressive replacement of calcium and calcitriol is required to avoid the development of hypocalcemia.

Hormone replacement therapy and the prevention of postmenopausal osteoporosis.

Fracture prevention is one of the public health priorities worldwide. Estrogen deficiency is the major factor in the pathogenesis of postmenopausal osteoporosis, the most common metabolic bone disease. Different effective treatments for osteoporosis are available. Hormone replacement therapy (HRT) at different doses rapidly normalizes turnover, preserves bone mineral density (BMD) at all skeletal sites, leading to a significant, reduction in vertebral and non-vertebral fractures. Tibolone, a selective tissue estrogenic activity regulator (STEAR), is effective in the treatment of vasomotor symptoms, vaginal atrophy and prevention/treatment of osteoporosis with a clinical efficacy similar to that of conventional HRT. Selective estrogen receptor modulators (SERMs) such as raloxifene and bazedoxifene reduce turnover and maintain or increase vertebral and femoral BMD and reduce the risk of osteoporotic fractures. The combination of bazedoxifene and conjugated estrogens, defined as tissue selective estrogen complex (TSEC), is able to reduce climacteric symptoms, reduce bone turnover and preserve BMD. In conclusion, osteoporosis prevention can actually be considered as a major additional benefit in climacteric women who use HRT for treatment of climacteric symptoms. The use of a standard dose of HRT for osteoporosis prevention is based on biology, epidemiology, animal and preclinical data, observational studies and randomized, clinical trials. The antifracture effect of a lower dose HRT or TSEC is supported by the data on BMD and turnover, with compelling scientific evidence.

Controversies in Osteoporosis Management

Bisphosphonates are effective treatments for osteoporosis. The pharmacology and observance of atypical femoral fractures in patients on long-term therapy raise questions about the need for intermittent discontinuation of treatment, a "drug holiday." Fracture protection benefits of bisphosphonate therapy far outweigh the risk of atypical fractures for the first 10 years of therapy. However, because the fracture probability of therapy abates slowly after stopping the treatment while the risk of atypical fracture appears to decrease quickly, a "drug holiday" of 1 to 2 years should be considered after 3 to 5 years of bisphosphonate therapy except in those patients who remain at very high fracture risk.

Effective osteoporosis treatment with teriparatide is associated with enhanced quality of life in postmenopausal women with osteoporosis: the European Forsteo Observational Study

BackgroundTo describe changes in health-related quality of life (HRQoL) of postmenopausal women with osteoporosis treated with teriparatide for up to 18 months and followed-up for a further 18 months, and to assess the influence of recent prior and incident fractures.MethodsThe European Forsteo Observational Study (EFOS) is an observational, prospective, multinational study measuring HRQoL using the EQ-5D. The primary objective was to assess changes in HRQoL during 36 months in the whole study population. A secondary post-hoc analysis examined fracture impact on HRQoL in four subgroups classified based on recent prior fracture 12 months before baseline and incident clinical fractures during the study. Changes from baseline were analysed using a repeated measures model.ResultsOf the 1581 patients, 48.4% had a recent prior fracture and 15.6% of these patients had an incident fracture during follow-up. 10.9% of the 816 patients with no recent prior fracture had an incident fracture. Baseline mean EQ-VAS scores were similar across the subgroups. In the total study cohort (n = 1581), HRQoL (EQ-VAS and EQ-5D index scores) improved significantly from baseline to 18 months and this improvement was maintained over the 18-month post-teriparatide period. Improvements were seen across all five EQ-5D domains during teriparatide treatment that were maintained after teriparatide was discontinued. Subjects with incident clinical fractures had significantly less improvement in EQ-VAS than those without incident fractures. Recent prior fracture did not influence the change in EQ-VAS during treatment.ConclusionsEFOS is the first longitudinal study in women with severe postmenopausal osteoporosis in the real world setting to show a substantial improvement in HRQoL during teriparatide treatment that was sustained during subsequent treatment with other medications. The increase in HRQoL was lower in the subgroups with incident fracture but was not influenced by recent prior fracture. The results should be interpreted in the context of the design of an observational study.

Calcium induces pro-anabolic effects on human primary osteoblasts associated with acquisition of mature osteocyte markers

Calcium, in combination with vitamin D, is an effective treatment for osteoporosis. Since bone mineralisation occurs concurrently with osteoblast to osteocyte transition, we hypothesised that calcium would stimulate this process. The effect of calcium (1.8–11.8mM) was tested on human primary osteoblast (NHBC) differentiation in vitro. Cultures were assayed for cell-associated mineral and gene expression associated with osteoblast differentiation and mineralisation. Treatment with calcium resulted in a striking dose- and time-dependent increase in cell-associated mineralisation. Calcium appeared to promote osteoblast to osteocyte differentiation, as indicated by increased expression of osteocalcin (OCN), E11, dentin matrix protein 1 (DMP1) and SOST mRNA. The expression of the osteoclast inhibitor, osteoprotegerin, was dramatically enhanced by calcium. Calcium also increased the ratio of PHEX mRNA expression relative to that of MEPE, suggesting a mechanism for the pro-anabolic effect. Consistent with this, calcium-dependent mineralisation was reversed in the presence of MEPE–ASARM peptides. This study suggests that calcium promotes osteoblast to osteocyte transition and concurrent matrix mineralisation, at least in part through the PHEX–MEPE axis.

AB0602 Decreased serum CRP and MMP-3 levels in patients with rheumatoid arthritis treated with vitamin K2

BackgroundIt has been reported that Vitamin K2 (VitK2) is a key inducer of bone mineralization in human osteoblasts and also inhibits osteoclastogenesis by induction of the osteoclast apoptosis (1). Human...

THU0381 Up to Half of First Fragility Fractures (FF), and a Third of Recurrent FF, Occur in Patients with Low or Moderate Estimated Frax® 10-Year Fracture Risk: Results from the Optimus Initiative

BackgroundIdentification of patients who will sustain a fragility fracture (FF) is the main objective of the WHO Fracture Risk Assessment score (FRAX®).ObjectivesTo describe the FRAX scores at the time of...

Naringin promotes osteoblast differentiation and effectively reverses ovariectomy-associated osteoporosis

BackgroundOsteoporosis is a common pathological condition that influences 20% of women over 50years of age. This condition decreases bone strength and increases the risk of bone fracture. Naringin is a major flavonoid found in grapefruit and an active compound extracted from a Chinese herbal medicine (Rhizoma Drynariae). Studies have shown that naringin possesses many pharmacological effects. The current study evaluated the influence of naringin on osteoblastic cell differentiation and proliferation, and assessed its therapeutic effects on a rat osteoporosis model. MethodThe proliferation, differentiation, and function of rat bone marrow stromal cells (BMSCs) were determined following treatment with various concentrations of naringin. Ovariectomy (OVX)-induced osteoporotic rats were orally administered naringin daily at low, medium, and high dosages, while a control group received PBS for 2months. Femoral X-ray images and microCT scans were used for bone mineral density (BMD) and BV/TV (bone volume/total volume) analyses, and histological assessments of left tibiae were employed to check for changes in trabecular thickness (Tb.Th) and trabecular space (Tb.Sp) in the groups. ResultsNaringin was effective at enhancing the proliferation and osteogenic differentiation of BMSCs, and a concentration of 10μg/ml prompted the highest levels of osteocalcin expression among the in vitro study groups. There appeared to be a delayed response pattern of BMSCs to the naringin treatment. Naringin also effectively reversed OVX-induced bone loss via increasing BMD, bone volume, and trabecular thickness. The medium dose (300mg/kg) appeared to be the optimal dosage for delivering satisfactory therapeutic effects. ConclusionNaringin promotes the proliferation and differentiation of BMSCs, and increases osteocalcin expression. Naringin also effectively reverses ovariectomy-induced osteoporosis in rats. The study suggests that naringin administration may represent an effective treatment for osteoporosis.

Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor–Mediated Signaling Pathways

Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), acting through the osteoblast PTH1 receptor (PTH1R), play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation, whereas continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including G(s)/cAMP/protein kinase A, G(q)/calcium/protein kinase C, β-arrestin recruitment, and extracellular signal-related kinase (ERK)1/2 phosphorylation, as well as receptor internalization, but their role in promoting anabolic and catabolic actions of PTH(1-34) are unclear. In the present investigation, a collection of PTH(1-34) and PTHrP(1-34) peptide analogs were evaluated in orthogonal human PTH1R (hPTH1R) functional assays capturing G(s)- and G(q)-signaling, β-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization to further define the patterns of PTH1R signaling that they stimulate and further establish peptide domains contributing to agonist activity. Results indicate that both N- and C-terminal domains of PTH and PTHrP are critical for activation of signaling pathways. However, modifications of both regions lead to more substantial decreases in agonist potency and efficacy to stimulate G(q)-signaling, β-arrestin recruitment, ERK1/2 phosphorylation, and receptor internalization than to stimulate G(s)-signaling. The substantial contribution of the peptide C-terminal domain in activation of hPTH1R signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain. Several PTH and PTHrP peptides evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts. With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis.

An Optical Assay of the Transport Activity of CLC-7

Osteoporosis, characterized by excessive osteoclast mediated bone resorbtion, affects millions of people. ClC-7 is a chloride-proton exchanger member of the CLC protein family localized in lysosomes and in the ruffled border of osteoclasts. Loss of function of ClC-7 leads to osteopetrosis, neurodegeneration and lysosomal storage disease. The osteopetrotic phenotype is explained by the fact that the ion transport activity of ClC-7 is essential for the osteoclast mediated bone resorption. Thus, blocking ClC-7 can be expected to provide an effective treatment of osteoporosis. Here, we describe a purely optical assay of ClC-7 function employing the E2GFP-dsRed Cl−/pH sensor1 fused to the C-terminus of ClC-7, carrying in addition a mutation of a leucine motif at the N-terminus resulting in a partial redirection of ClC-7 to the plasma membrane2-3. For functional activity, ClC-7 associates with the beta-subunit Ostm14. To ensure the simultaneous and equivalent expression of ClC-7 and Ostm1, we constructed a plasmid in which the two cDNAs are linked by a self-cleavable 2AP peptide4. In addition, we introduced a mutation of the gating glutamate (E245A) which renders the transporter voltage-independent and abolishes proton transport3. The assay consists in lowering [Cl]ext and monitoring the resulting decrease in ClC-7 mediated decrease of [Cl]int by measuring the E2GFP/DSRed fluorescence ratio. This simple assay can be applied in HTS and may lead to the design of specific drugs modulating ClC-7 activity.Supported by IIT, Seed project1. Arosio D et al (2010) Nature Methods7, 516.2. Stauber T, Jentsch TJ (2010). J Biol Chem 285: 34537.3. Leisle L et al. (2011 EMBO J. 30, 2140.4. Trishas G et al (2008). BMC Biol. Sep 15;6.

Amphiregulin-EGFR Signaling Mediates the Migration of Bone Marrow Mesenchymal Progenitors toward PTH-Stimulated Osteoblasts and Osteocytes

Intermittent administration of parathyroid hormone (PTH) dramatically increases bone mass and currently is one of the most effective treatments for osteoporosis. However, the detailed mechanisms are still largely unknown. Here we demonstrate that conditioned media from PTH-treated osteoblastic and osteocytic cells contain soluble chemotactic factors for bone marrow mesenchymal progenitors, which express a low amount of PTH receptor (PTH1R) and do not respond to PTH stimulation by increasing cAMP production or migrating toward PTH alone. Conditioned media from PTH-treated osteoblasts elevated phosphorylated Akt and p38MAPK amounts in mesenchymal progenitors and inhibition of these pathways blocked the migration of these progenitors toward conditioned media. Our previous and current studies revealed that PTH stimulates the expression of amphiregulin, an epidermal growth factor (EGF)-like ligand that signals through the EGF receptor (EGFR), in both osteoblasts and osteocytes. Interestingly, conditioned media from PTH-treated osteoblasts increased EGFR phosphorylation in mesenchymal progenitors. Using several different approaches, including inhibitor, neutralizing antibody, and siRNA, we demonstrate that PTH increases the release of amphiregulin from osteoblastic cells, which acts on the EGFRs expressed on mesenchymal progenitors to stimulate the Akt and p38MAPK pathways and subsequently promote their migration in vitro. Furthermore, inactivation of EGFR signaling specifically in osteoprogenitors/osteoblasts attenuated the anabolic actions of PTH on bone formation. Taken together, these results suggest a novel mechanism for the therapeutic effect of PTH on osteoporosis and an important role of EGFR signaling in mediating PTH's anabolic actions on bone.

A multicenter randomized double-masked comparative study of different preparations of alendronate in osteoporosis – monthly (four weeks) intravenous versus once weekly oral administrations

Objective:The aim of this study was to evaluate the efficacy and safety of intravenous alendronate (ALN) 900 µg every 4 weeks compared to oral ALN 35 mg once weekly.Methods:A 52-week, multicenter, randomized, double-masked, active-controlled, parallel-group, non-inferiority study was conducted in a total of 325 Japanese patients aged 48–87 years with osteoporosis. Patients were randomly assigned to an intravenous ALN (iv, n = 162) group or oral ALN (po, n = 163) group. The efficacy of the both formulations was assessed primarily by bone mineral density (BMD) measurement.Results:The percentage BMD change from baseline in lumbar spine (L2–L4) after 52 weeks of treatment was 6.4 ± 0.3% in the iv group and 6.0 ± 0.3% in the po group (least-squares mean ± SE). The inter-group difference in least-squares mean of percentage change from baseline in BMD was 0.37%, and its 95% confidence interval was −0.47% to 1.20%. The non-inferiority of the iv group was established against the po group with a prespecified non-inferiority margin (Δ) of 1.5%. In addition, the four bone turnover markers were reduced to a similar level by either treatment throughout the treatment period. The safety profile was also similar between the two treatment groups. Because of the limitations presented in this study, the results of the iv group may not apply to non-Japanese patients with osteoporosis.Conclusions:The efficacy and safety of the intravenous ALN 900 µg once every 4 weeks were similar to those of the oral ALN 35 mg once weekly, indicating that intravenous administration of ALN is an effective treatment for osteoporosis and will provide a useful alternative to oral dosing.