Catalpol attenuates osteoporosis in ovariectomized rats through promoting osteoclast apoptosis via the Sirt6-ERα-FasL axis.

BACKGROUND: Catalpol, a major active component of the Chinese herb Rehmannia glutinosa, possesses various pharmacological benefits, including anti-inflammatory, antidiabetic, and antitumor properties. Recent studies have reported that catalpol can attenuate bone loss and enhance bone formation. Nevertheless, the molecular mechanisms underlying its effects on osteoporosis pathogenesis remain unclear. PURPOSE: We investigated whether catalpol had a protective effect against postmenopausal osteoporosis (PMOP) and explored its exact mechanism of action. METHODS: Seventy-two rats were randomly divided into six groups: sham, model, low-dose catalpol (5 mg/kg/day), medium-dose catalpol (10 mg/kg/day), high-dose catalpol (20 mg/kg/day), and positive control (alendronate, 2.5 mg/kg). In this experiment, a ovariectomy was performed to establish a female rat model of PMOP. After 12 weeks of gavage, micro-computed tomography (micro-CT) and histochemical staining were performed to evaluate bone mass, bone microstructure and histological parameters. Furthermore, RAW 264.7 cells were induced by RANKL to form mature osteoclasts to investigate the effect of catalpol on osteoclast differentiation and apoptosis in vitro. Additionally, the osteoclast apoptosis-related proteins of Sirt6, ERα, FasL, NFATc1, cleaved-caspase 8, cleaved-caspase 3, and Bax were assessed using western blotting. The expressions of NFATc1, Ctsk, Oscar, and Trap were quantified using RT-qPCR. The apoptotic rate of the osteoclasts was determined using flow cytometry. Sirt6 knockdown was performed using siRNA gene silencing in experiments to investigate its role in catalpol-mediated osteoclast apoptosis. The deacetylation of ERα in osteoclasts was tested via co-immunoprecipitation. RESULTS: Catalpol (10 and 20 mg/kg) and alendronate (2.5 mg/kg) could significantly improve bone mineral density (BMD) and microstructure and decrease osteoclast density in ovariectomized (OVX) rats. In addition, catalpol (10 and 20 mg/kg) upregulated the expression of Sirt6, ERα, FasL, cleaved-caspase 8, cleaved-caspase 3, Bax, and downregulated the expression of NFATc1, Ctsk, Oscar, Trap both in vivo and in vitro. Catalpol also promoted ERα deacetylation and stabilized ERα protein to enhance the expression of FasL. In addition, Sirt6 knockdown by siRNA prevented ERα deacetylation and eliminated catalpol-mediated osteoclast apoptosis. CONCLUSIONS: The present study demonstrated that catalpol prevents estrogen deficiency-induced osteoporosis by promoting osteoclast apoptosis via the Sirt6-ERα-FasL axis. These findings revealed a novel molecular mechanism underpinning the impact of catalpol in the progression of osteoporosis and provided novel insights into the treatment of osteoporosis.

The role of bone modifying agents for secondary osteoporosis prevention and pain control in post-menopausal osteopenic breast cancer patients undergoing adjuvant aromatase inhibitors.

Introduction: Hormonal therapy (HT) blocks the hormone-mediated growth signal dramatically reducing estrogenic levels with aromatase inhibitors (AIs) becoming a crucial component of the treatment mainstay in patients with early breast cancer (BC). Postmenopausal BC patients receiving HT present with a significant risk of secondary osteoporosis with AIs further reducing estrogen levels and ultimately leading to an accelerated rate of bone resorption and thus decreased bone mineral density (BMD). This was an observational retrospective clinical study that consecutively enrolled early BC patients with osteopenia to compare the impact of alendronate versus denosumab on secondary osteoporosis prevention and pain control. Methods: We identified two groups of patients treated with denosumab 60 mg by subcutaneous injection once every six months or alendronate 70 mg orally once a week. All the patients underwent a baseline physiatric evaluation (T0) and underwent a follow-up visit after 18 months (T1) together with femoral and vertebral Dual-Energy X-ray Absorptiometry (DEXA) exam evaluating T-Score marks. From September 2015 to December 2019 a total of 50 early (stage I-III) BC patients were considered eligible and consecutively enrolled in our study if they met pre-specified inclusion criteria. Results: In the entire observed population, the addition of treatment with alendronate or denosumab led to a significant T-score improvement at the lumbar spine level (-1.92 vs -1.52, p=0.03), with a comparable contribution from alendronate (-1.60 vs -1.45, p=0.07) and denosumab (-2.26 vs -1.58, p=0.07). Regarding the femoral region, neither alendronate (-0.98 vs -1.07, p=0.23) nor denosumab (-1.39 vs -1.34, p=0.81) were able to produce any statistically relevant effect. However, concerning pain control, BMAs had a significant impact on reducing NRS scoresin the general population (T1 3.94 vs. baseline 4.32, p=0.007), with a likelyspecific contribution from alendronate (T1 3.52 vs. baseline 3.88, p=0.004) compared to denosumab (T1 4.36 vs baseline 4.76, p=0.12), without any differences in analgesic therapy assumption over time (p=0.93). Discussion: Both alendronate and denosumab significantly contributed to preventing secondary osteoporosis in early BC patients with low BMD undergoing AIs, mostly at the lumbar spine level. Moreover, alendronate seemed to significantly impact pain control in such patients further supporting alendronate as a cost-effective option in this frail setting, although BMAs particularities should be carefully considered on an individual basis according to specific clinical contexts.

Pharmacological agents for bone fracture healing: talking points from recent clinical trials.

INTRODUCTION: Pharmacological strategies might influence bone healing in terms of time to union or quality of mature bone. This expert opinion discussed the current level I evidence on the experimental pharmacological agents used to favor bone fracture healing. AREAS COVERED: This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the 2020 PRISMA statement. In April 2023, the following databases were accessed: PubMed, Web of Science, Google Scholar, Embase. All the randomized clinical trials investigating pharmacological agents for bone fracture healing were accessed. No time constraint was set for the search. The search was restricted to RCTs. No additional filters were used in the database search. Data from 19 RCTs (4067 patients) were collected. 78% (3160 of 4067) were women. The mean length of the follow-up was 9.3 months (range, 1-26 months). The mean age of the patients was 64.4 years (range, 8-84 years). EXPERT OPINION: Calcitonin could favor bone fracture healing. Bisphosphonates (alendronate, zoledronate, clodronate), monoclonal antibodies (denosumab, romosozumab), statins, vitamin D and calcium supplementation, strontium ranelate, and ibuprofen did not influence bony healing. Concerning the effect of parathormone, current level I evidence is controversial, and additional studies are required. LEVEL OF EVIDENCE: Level I, systematic review of RCTs.

Effects of genistein aglycone in glucocorticoid induced osteoporosis: A randomized clinical trial in comparison with alendronate.

Glucocorticoid-induced osteoporosis (GIO) complicates the clinical management of patients subjected to long-term glucocorticoid use. This study explored the effects of genistein on bone loss in a randomized double-blind alendronate-controlled trial in postmenopausal women with GIO. 200 postmenopausal women (taking at least 5 mg of prednisone equivalents) since 3 months, or more, and expected to continue for at least other 12 months, were randomized to receive genistein (54 mg/day daily) or alendronate (70 mg once a week) for 24 months. Both groups received also Calcium and Vitamin D3 supplementation. Median bone mineral density (BMD) at the antero-posterior lumbar spine significantly increased from 0.75 g/cm2 at baseline to 0.77 g/cm2 at 1 year and 0.79 g/cm2 at 2 years in alendronate-treated patients and from 0.77 g/cm2 at baseline to 0.79 g/cm2 at 12 months and to 0.80 g/cm2 at 24 months in genistein recipients. No difference was observed between the two treatments. Median BMD at the femoral neck increased from 0.67 g/cm2 at baseline to 0.68 g/cm2 at 1 year and 0.69 g/cm2 at 2 years in alendronate-treated patients and from 0.68 g/cm2 at baseline to 0.70 g/cm2 at 12 months and to 0.71 g/cm2 at 24 months in genistein recipients. No difference was observed between alendronate and genistein groups in BMD. Regarding bone markers genistein and alendronate statistically decreased c-terminal telopeptide, while osteocalcin, bone-ALP, and sclerostin showed greater changes in genistein treated patients. This randomized clinical trial suggests that genistein aglycone represents an additional therapeutic option for patients with GIO.

Local drug delivery in the treatment of furcation defects in periodontitis: a systematic review.

OBJECTIVES: To evaluate the effect of subgingival administration of various antimicrobials and host-modulating agents in furcation defects as an adjunct to scaling and root planing (SRP) compared to SRP alone or combined with placebo. METHODS: A systematic review was carried out using MEDLINE-PubMed, Embase, and Scopus for articles up to October 2022 in addition to hand searches. All longitudinal studies that evaluated the effect of subgingival application of antimicrobial and host-modulating agents in furcation defects as adjuncts to SRP compared to SRP alone or SRP + placebo with at least 3 months of follow-up were eligible for inclusion. RESULTS: A total of eight studies were included. Superior clinical treatment outcomes were shown when alendronate, rosuvastatin, boric acid, simvastatin, and tetracycline (only at 3 months) were utilized in furcation defects in conjunction with SRP alone or SRP + placebo. Significant improvement was reported in radiographic bone defect depth and defect depth reduction when SRP was supplemented with alendronate, rosuvastatin, boric acid, and simvastatin. CONCLUSIONS: Within the limitations of this review, the adjunctive subgingival administration of medications and host-modulating agents in furcation defects may confer additional clinical and radiographic benefits than non-surgical periodontal treatment alone. Future investigations are needed to confirm their long-term effectiveness. CLINICAL RELEVANCE: Local host modulators and antimicrobials may be used supplementary to enhance the clinical and radiographic treatment outcomes of conventional periodontal therapy in furcation defects.

Quercetin suppresses ovariectomy-induced osteoporosis in rat mandibles by regulating autophagy and the NLRP3 pathway.

With the aging population and the popularity of implant prostheses, an increasing number of postmenopausal osteoporosis (PMOP) patients require implant restorations; however, poor bone condition affects the long-term stability of implant prostheses. This study aimed to investigate the therapeutic effect of quercetin (QR) compared with alendronate (ALN), the primary treatment for PMOP, on mandibular osteoporosis (OP) induced by ovariectomy (OVX) in female rats. Adult female rats were treated with QR (50 mg/kg/day), ALN (6.25 mg/kg/week) by gavage for 8 weeks, chloroquine (CQ, 10 mg/kg/twice a week), and cytokine release inhibitory drug 3 (MCC950, 10 mg/kg/three times a week) by intraperitoneal injection for 8 weeks after bilateral OVX. Blood samples were collected prior to euthanasia; the mandibles were harvested and subjected to micro-computed tomography (micro-CT) and pathological analysis. QR administration controlled weight gain and significantly improved the bone microstructure in OVX rats, increasing bone mass, and bone mineral density (BMD), reducing bone trabecular spacing, and decreasing osteoclast numbers. Western blotting, real-time quantitative PCR (RT-qPCR), and serum markers confirmed that QR inhibited interleukin- 1ß (IL-1ß) and interleukin-18 (IL-18) on the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein 3 (NLRP3) pathway thereby inhibiting osteoclast differentiation, immunofluorescence and western blotting also confirmed that QR inhibited autophagy in OVX rats and suppressed the number of tartrate-resistant acid phosphatase (TRAP)-stained positive osteoclasts. The findings suggest that QR may protect the bone structure and prevent bone loss in osteoporotic rats by inhibiting the NLRP3 pathway and autophagy in osteoclasts with comparable effects to ALN, thus QR may have the potential to be a promising alternative supplement for the preventive and therapeutic treatment of PMOP.

Changes in osteoporosis therapy in postmenopausal women from the RAC­OST­POL study: a 10­year follow­up.

INTRODUCTION: Therapeutic regimens for osteoporosis are the key elements in the management of osteoporotic patients. OBJECTIVE: The aim of the study was to present data on changes in osteoporosis therapy in women during a 10­year follow­up. PATIENTS AND METHODS: We analyzed a population­based sample recruited in the RAC­OST­POL study. At baseline, the cohort included 978 women, of whom 541 remained in the follow­up. Mean (SD) age of the patients was 74.7 (6.6) years. RESULTS: The number of untreated women and those on alendronate decreased, while the number of patients receiving other forms of the antiresorptive therapy or calcium / vitamin D supplementation increased during the study. The percentage of untreated women in the rural areas and the urban areas was, respectively, 85% and 74.1% at baseline, and 74.3% and 63.3% at the end of the follow­up. The percentage of untreated women decreased significantly, both in rural and urban cohorts. It was accompanied by a significant increase in calcium / vitamin D supplementation in both subgroups. Regarding the antiresorptive therapy, there was a significant increase in the frequency of its use only in the rural cohort. The use of therapeutic strategies was determined by the level of education. The frequency of calcium and / or vitamin D supplementation increased significantly in all education-related categories during the follow­up. CONCLUSION: Changes in the therapy of postmenopausal women with osteoporosis, observed in a 10­year follow­up of the RAC­OST­POL study, indicated that the level of care did not improve in this group of patients.

Development of Atypical Ulnar Fracture is Associated with Bisphosphonate Therapy and Severe Spinal Deformity: A Case Report.

Atypical ulna fracture (AUF) is relatively rare and is known to be associated with prolonged bisphosphonate (BP) use. The developmental mechanism remains unclear. We report a patient with an AUF associated with BP and severe spinal deformity. The patient was an 85-year-old woman receiving oral alendronate for 8 years without vitamin D supplementation. During regular kitchen work, she needed left upper limb support. She presented with atraumatic pain over the ulna. Radiographs revealed a transverse fracture in the proximal ulna and ulna bowing deformity. Whole-spine standing radiographs showed severe degenerative kyphoscoliosis. The skin induration with pigmentation on her left elbow that suggested prolonged overload and during standing work, coincided exactly with fracture location. This report suggests that 'direct stress', with persistent local overload on the proximal ulna, is one of the developmental mechanisms of AUF, in addition to persistent suppression of bone remodelling by prolonged BP use and vitamin D deficiency. Level of Evidence: Level V (Therapeutic).

Vitamin D Boosts Alendronate Tail Effect on Bone Mineral Density in Postmenopausal Women with Osteoporosis.

Vitamin D modulates bisphosphonate (BP) efficacy, but its contribution to bone mineral density (BMD) after BP discontinuation is not known. To address this topic, we performed a retrospective analysis of postmenopausal women exposed to alendronate (ALN) to treat osteoporosis who regularly continued the supplementation of cholecalciferol or calcifediol at recommended doses. In the ninety-six recruited women (age 61.1 ± 6.9 years), ALN was administered for 31.2 ± 20.6 months and then discontinued for 33.3 ± 18.9 months. The modification of 25(OH)D serum levels over time was associated with a change of alkaline phosphatase (r = -0.22, p = 0.018) and C-terminal collagen type 1 telopeptide (r = -0.3, p = 0.06). Women in the tertile of the highest increase in 25(OH)D level showed a 5.7% BMD gain at lumbar spine, that was twice as great in comparison with participants with a lower 25(OH)D variation. At a multiple regression analysis, BMD change was associated with time since menopause (ß = 2.28, SE 0.44, p < 0.0001), FRAX score for major fracture (ß = -0.65, SE 0.29, p = 0.03), drug holiday duration (ß = -2.17, SE 0.27, p < 0.0001) and change of 25(OH)D levels (ß = 0.15, SE 0.03, p = 0.0007). After ALN discontinuation, improving the vitamin D status boosts the ALN tail effect on BMD.

Efficacy of alendronate for the treatment of ankylosing spondylitis: A protocol for systematic review and meta-analysis.

BACKGROUND: Ankylosing spondylitis (AS) is a very tricky orthopedic disorder. If such condition cannot be managed fairly well, it may significantly affect quality of life and even leads to disability among such population. A variety of studies have reported that alendronate is utilized for the treatment of AS. However, their results are still contrary, and no systematic review has addressed on this topic. Thus, this study will systematically assess the efficacy and safety of alendronate for the treatment of patients with AS. METHODS: A comprehensive literature search will be performed from the below electronic databases from their commencement to the January 31, 2020 without language and publication status limitations: PubMed, Embase, Cochrane Library, Web of Science, Allied and Complementary Medicine Database, WANGFANG, and China National Knowledge Infrastructure. Only randomized controlled trials focusing on the alendronate for the treatment of patients with AS will be considered for inclusion in this study. Two authors will independently select all identified records, extract essential data from all included studies, and appraise study quality for each eligible trial using Cochrane risk of bias. If any differences occur, another experienced author will be invited to solve them by discussion and a consensus decision will be made. We will implement RevMan 5.3 software to analyze the extracted data. RESULTS: This study will summarize high-quality randomized controlled trials to assess the efficacy and safety of alendronate for the treatment of patients with AS through primary outcome of bone densitometry; and secondary outcomes of pain intensity, quality of life, disease activity, functional status, and adverse events. CONCLUSION: This study will provide evidence to help determine whether alendronate is an effective and safe management for patient with AS or not. STUDY REGISTRATION: INPLASY202040153.

Preliminary study on the electromagnetic field treatment of osteoporosis in rats.

OBJECTIVE: In our study, the influence of PEMF on skeleton morphology and bone metabolism on rats with disuse osteoporosis was investigated, and the possibility of using it for the treatment of disuse osteoporosis was explored. METHODS: The rats in the ALN group were treated with alendronate, and the rats in the PEMF group were exposed to pulsed electromagnetic fields (3.82 mT, 10 Hz) for 40 mind-1. Rats were sacrificed by the end of 2, 4, 8 and 12 weeks, and serum and right leg bones were collected. Serum BMP-2, BGP concentrations and bone metabolism and biomechanical parameters were measured. RESULTS: The bone structural mechanical indices and material mechanical indices of the right femur in all groups of mice during weeks 2 and 4 were decreased. At week 8 the bone structural mechanical index and maximum stress of the right femur in the ALN group were markedly raised compared with the CON group (P< 0.01). Only maximum stress and strain were improved in the ALN group and had a significant difference (P< 0.05) at week 12. The serum BGP and BMP-2 concentration in the PEMF and ALN groups was increased (P< 0.05) at week 2, but this increase was not synchronized. After 8 weeks, BGP and BMP-2 level in the PEMF group was observably elevated (P<0.01) in contrast to the ALN group. CONCLUSION: From the experimental time interval analysis, PEMF can improve the mechanical stability of bone structure more gently and permanently than alendronate.

Alendronate Improves Bone Mineral Density in Children and Adolescents Perinatally Infected With Human Immunodeficiency Virus With Low Bone Mineral Density for Age.

BACKGROUND: Children and adolescents with perinatal human immunodeficiency virus (HIV) infection and with low bone mineral density (BMD) may be at higher risk of osteoporosis and fractures in later life than their uninfected peers. Bisphosphonate therapy has been shown to reduce fractures in adults with osteoporosis, but has not been formally studied in youths living with HIV. METHODS: Fifty-two children and adolescents (aged 11-24 years) perinatally infected with HIV with low lumbar spine (LS) BMD (Z score < -1.5) were randomized to receive once-weekly alendronate or placebo in a double-blind cross-over study designed to assess the safety and efficacy of 48 and 96 weeks of alendronate in the United States and Brazil. All participants received daily calcium carbonate and vitamin D supplementation and were asked to engage in regular weight-bearing exercise. Safety and efficacy are summarized for the initial 48 weeks of the trial. RESULTS: Grade 3 or higher abnormal laboratory values, signs, or symptoms developed in 5 of 32 (16%) participants on alendronate and 2 of 18 (11%) on placebo (P > .99). No cases of jaw osteonecrosis, atrial fibrillation, or nonhealing fractures were reported. Mean increases (95% confidence interval) in LS BMD over 48 weeks were significantly larger on alendronate (20% [14%-25%]) than placebo (7% [5%-9%]) (P < .001). Similar improvements were seen for whole body BMD. CONCLUSIONS: In this small study in children and adolescents perinatally infected with HIV with low LS BMD, 48 weeks of alendronate was well-tolerated, showed no safety concerns, and significantly improved LS and whole body BMD compared to participants on vitamin D/calcium supplementation and exercise alone. CLINICAL TRIALS REGISTRATION: NCT00921557.

Effect of continuous long-term treatment for 10 years with bisphosphonate on Japanese osteoporosis patients.

INTRODUCTION: In terms of the balance between benefits and risks of long-term treatment with bisphosphonate, uncertainties remain regarding the optimal treatment duration. We investigated effects of continuous long-term treatment for 10 years with bisphosphonate in postmenopausal osteoporosis patients. MATERIALS AND METHODS: Fifty five patients in the outpatient clinic of our hospital have been continuously treated with alendronate or risedronate for 10 years. All data were retrospectively collected. The age, height, weight, total muscle volume, total fat volume, and BMD at the lumbar spine, total hip and distal 1/3 radius, alkaline phosphatase (ALP), urinary type I collagen cross-linked N-telopeptide (uNTX) and tartrate-resistant acid phosphatase-5b (TRAP5b), calcium (Ca) and phosphate (P) levels were measured pre- and after the start of 10-year continuous treatment. RESULTS: BMD at the lumbar spine increased continuously over the 10-year period, while BMD at the total hip slightly but significantly decreased, and that at the 1/3 radius did not show any significant change over the 10 years. Serum Ca value was significantly decreased after the start of treatment, and became stable within the reference range from the second year. Bone resorption markers such as uNTX and TRAP5b significantly decreased from the second year after the start of treatment and no significant changes were observed thereafter. There were no serious medical adverse events including atypical femoral fractures and osteonecrosis of the jaw. CONCLUSION: We believe that the continuous use of alendronate and risedronate for 10 years could be an option for the treatment of postmenopausal osteoporosis patients.

Eficácia e segurança do ácido zoledrônico comparado aos bifosfonados orais para prevenção de fraturas na osteoporose: revisão rápida de evidências / Effectiveness and safety of zoledronic acid compared to oral bifosfonates for fracture prevention in osteoporosis: rapid review of evidence

Tecnologia: Ácido zoledrônico e bifosfonados orais (alendronato e risedronato de sódio). Indicação: Prevenção de fraturas em pessoas com osteoporose. Pergunta: Em pessoas com osteoporose, o ácido zoledrônico é mais eficaz e seguro que os bifosfonados orais para prevenção de fraturas e outros desfechos de interesse? Métodos: Levantamento bibliográfico foi realizado nas bases eletrônicas Pubmed e BVS usando estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta Assessing the Methodological Quality of Systematic Reviews (AMSTAR). Resultados: Foram selecionadas e incluídas 5 revisões sistemáticas. Conclusão: O ácido zoledrônico é similar aos bifosfonados orais para prevenir fraturas em mulheres com osteoporose. Seu efeito sobre a densidade mineral óssea femoral é similar ao do alendronato e superior ao do risedronato. Um tratamento por 3 anos com ácido zoledrônico ou por 5 anos com alendronato de sódio é suficiente para prevenir fraturas vertebrais e não vertebrais. Bifosfonados têm similar risco de eventos adversos que o placebo, incluindo transtornos cardiovasculares e taxa de abandono do tratamento devido a distúrbios gastrointestinais. O ácido zoledrônico tem maior incidência de sintomas influenza-like que o placebo. O ácido zoledrônico não provoca eventos adversos do tipo esofágicos, gastrointestinais sérios ou do trato gastrointestinal superior, mas tem maior risco de náuseas, que pode estar relacionada à infusão intravenosa de grandes doses

Technology: Zoledronic acid and oral bisphosphonates. Indication: Prevention of osteoporotic fractures. Question: In people with osteoporosis, is zoledronic acid more effective and safer than oral bisphosphonates for preventing fractures and other outcomes? Methods: Bibliographic search was performed on PUBMED and BVS, using predefined search strategies. Evaluation of the methodological quality of systematic reviews was done by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool. Results: 5 systematic reviews were selected and included. Conclusion: Zoledronic acid is similar to bisphosphonates for preventing fractures in women with osteoporosis and his effect on femoral bone mineral density is similar to that of alendronate and superior to risedronate. A 3 years treatment with zoledronic acid or for 5 years with sodium alendronate is sufficient to prevent vertebral and non-vertebral fractures. Bisphosphonates have a similar risk of adverse events than placebo, including cardiovascular disorders and risk of attrition due to gastrointestinal events. Zoledronic acid has a higher incidence of influenza-like symptoms (myalgia and arthralgia) than placebo, limited to the first dose and lasting a few days. Zoledronic acid does not cause esophageal, serious gastrointestinal or upper gastrointestinal tract adverse events, but has a higher risk of nausea, which can be caused by large doses of intravenous infusion

Predictors and Outcomes Associated With Adherence to Weekly Alendronate in US Military Veterans: Clinical Research Study.

Background: Poor adherence to oral bisphosphonates is a challenge to treatment and prevention of osteoporosis. The Veterans Health Administration (VA) operates the largest integrated health care system in the United States and offers certain advantages to possibly improve medication adherence. We aimed to determine adherence to weekly alendronate for osteoporosis in Veterans, and investigate predictors and outcomes related to adherence. Methods: A retrospective study cohort was generated from VA databases selecting Veterans who were treated with weekly alendronate. Adherence was measured by medication possession ratio (MPR) and persistence. Two groups were defined as low and high adherence based on MPR <80% or ≥80%, respectively. Regression models were used to investigate predictors of adherence and included clinically relevant covariates. Further regressions were used to investigate the impact of adherence on change in bone mineral density measured by dual energy X-ray absorptiometry and incident fracture. Results: In a cohort of 913 (female/male, 207/706) Veterans, 48% had high adherence in year 1. Distribution for gender, race, and age were similar between the 2 groups, MPR <80% or MPR ≥80%. Baseline fracture [odds ratio OR: 0.64, 95%CI: (0.41, 0.98)], alcohol abuse [0.40 (0.21, 0.74)] and tobacco use [0.44 (0.31, 0.63)] were associated with low adherence in the unadjusted analyses, but only tobacco use [0.45 (0.30, 0.67)] was associated with low adherence after adjustment. Among males, tobacco use was associated with low adherence while prostate cancer predicted high adherence in adjusted models. High adherence was associated with a 30% [hazard ratio HR: 0.70, 95% CI: (0.47, 1.03)] decreased risk of incident fracture in the whole cohort, and a 40% [0.60 (0.38, 0.95)] decrease risk in males. Conclusion: Year one adherence to weekly alendronate was a relevant determinant to long-term clinical outcomes including changes in bone mineral density and incident fracture in Veterans.

Dual targeting curcumin loaded alendronate-hyaluronan- octadecanoic acid micelles for improving osteosarcoma therapy.

INTRODUCTION: Curcumin (CUR) is a general ingredient of traditional Chinese medicine, which has potential antitumor effects. However, its use clinically has been limited due to its low aqueous solubility and bioavailability. In order to improve the therapeutic effect of CUR on osteosarcoma (i.e., bone cancer), a multifunctional micelle was developed here by combining active bone accumulating ability with tumor CD44 targeting capacity. METHODS: The CUR loaded micelles were self-assembled by using alendronate-hyaluronic acid-octadecanoic acid (ALN-HA-C18) as an amphiphilic material. The obtained micelles were characterized for size and drug loading. In addition, the in vitro release behavior of CUR was investigated under PBS (pH 5.7) medium containing 1% Tween 80 at 37℃. Furthermore, an hydroxyapatite (the major inorganic component of bone) affinity experiment was studied. In vitro antitumor activity was evaluated. Finally, the anti-tumor efficiency was studied. RESULTS: The size and drug loading of the CUR loaded ALN-HA-C18 micelles were about 118 ± 3.6 nm and 6 ± 1.2%, respectively. CUR was released from the ALN-HA-C18 micelles in a sustained manner after 12 h. The hydroxyapatite affinity experiment indicated that CUR loaded ALN-HA-C18 micelles exhibited a high affinity to bone. CUR loaded ALN-HA-C18 micelles exhibited much higher cytotoxic activity against MG-63 cells compared to free CUR. Finally, CUR loaded ALN-HA-C18 micelles effectively delayed anti-tumor growth properties in osteosarcoma bearing mice as compared with free CUR. CONCLUSION: The present study suggested that ALN-HA-C18 is a novel promising micelle for osteosarcoma targeting and delivery of the hydrophobic anticancer drug CUR.

[Comparison of the clinical effects between Dihuang Decoction and alendronate sodium in the treatment of primary osteoporosis].

OBJECTIVE: To study and compare the clinical effects of Rehmannia Decoction and alendronate sodium for the treatment of primary osteoporosis. METHODS: From January 2016 to December 2017, 72 patients with primary osteoporosis who took Dihuang Decoction(DHD) orally and alendronate regularly for more than one year were randomly divided into 2 groups:experimental group and control group. The experimental group consisted of 14 males and 22 females, with an average age of(63.97±3.70) years old. The patients in the experimental group took Chinese medicine DHD, one dose each time, one time in the morning and one time in the evening, twice a week. The control group consisted of 16 males and 20 females with an average age of(63.36±3.07) years old. Patients in the control group were given alendronate 70 mg orally once a week. The basic treatment for osteoporosis remained unchanged in both groups(600 mg of calcium carbonate D3 and 0.5 µg of calcitriol capsules were taken daily). Bone mineral density (BMD) of femoral neck and lumbar vertebrae was measured by dual energy X-ray absorptiometry before and after treatment for one year. The levels of serum collagen type I C-terminal peptide (beta-CTX) and serum osteoclast (SOST) were measured before and after treatment for two groups. RESULTS: The age, bone mineral density, SOST and beta-CTX baseline values between the two groups before and after anti-osteoporosis treatment were compared. The difference was not statistically significant(P>0.05). Compared with the two groups, the BMD of femoral neck and lumbar vertebrae were increased after 1 year of anti-osteoporosis treatment. The differences were statistically significant (P<0.001). The value of serum beta-CTX was significantly lower than before. The t values were 52.002 and 50.071 respectively. The value of serum SOST was increased than that before treatment. The t values were -29.242 and -30.807 respectively. The differences were statistically significant (P<0.001). BMD of the femoral neck and lumbar spine was compared between the two groups after treatment. The P values were 0.294 and 0.478 respectively. The difference was not statistically significant (P>0.05). The serum beta-CTX values were compared between the two groups after treatment. The P value was 0.908. The serum SOST values were compared between the two groups after treatment. The P value was 0.888. The difference was not statistically significant (P>0.05). CONCLUSIONS: In this study, traditional Chinese medicine DHD is used to treat osteoporosis. It is found that DHD and alendronate have a good effect. The DHD can be used as a choice of Chinese medicine in the treatment of primary osteoporosis.

Effects of alendronate and calcifediol compared to alendronate and cholecalciferol in osteoporotic patients.

BACKGROUND: Several formulations of vitamin D and alendronate are available for the treatment of osteoporosis. The objective of this study was to examine efficacy and safety of calcifediol (25(OH)D) compared to cholecalciferol (vitamin D3) and also the relationship between different formulations of alendronate and adverse reactions. METHODS: We observed a population of women diagnosed with postmenopausal osteoporosis or osteopenia treated with alendronate 70 mg weekly associated to vitamin D3 or 25(OH)D at monthly total dose of 625 µg. Data collected both at baseline (T0) and at follow-up after at least 12 months of therapy (T1) were: demographic characteristics, BMI, full medical history, lumbar T-score, femur T-score, calcium, osteocalcin, alkaline phosphatase, PTH and vitamin D blood level. RESULTS: A total of 362 patients were enrolled in the study. Alendronate 70 mg + calcifediol (A+25(OH)D) group consisted of 202 patients while 160 patients were treated with alendronate 70 mg + cholecalciferol (A+D3). In the A+25(OH)D group, we observed a significant increase in lumbar T-score value (0.26±0.35 vs. 0.13±0.3) and serum vitamin D (20.64±20.71 vs. 6.07±7.61 ng/mL) levels compared to the A+D3 group (P<0.05). The lowest incidence of gastrointestinal adverse reactions was observed among patients taking alendronate 70 mg in drinkable solution form (P<0.05). CONCLUSIONS: Alendronate 70 mg with calcifediol gives a better outcome in the treatment of osteoporosis according to lumbar T-score and vitamin D serum level observed at one-year follow-up compared to alendronate 70 mg with cholecalciferol. Both vitamin D formulations did not show to cause hypercalcemia in this study. Alendronate 70 mg in drinkable solution form is also associated with lowest incidence of gastrointestinal adverse reactions.

Efficacy and safety of recombinant human parathyroid hormone (1-34) are similar to those of alendronate in the treatment of postmenopausal osteoporosis.

The study evaluates efficacy and safety of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] and alendronate (ALN) in the treatment of postmenopausal osteoporosis.Totally 65 postmenopausal women with osteoporosis were divided into 2 groups. PTH group received daily subcutaneous injection of rhPTH (1-34), and ALN group were treated orally with ALN per week. Bone mineral density (BMD) of lumbar spine (1-4), femoral neck, and total hip, serum levels of calcium, phosphorus, total cholesterol, triglyceride, alkaline phosphatase (ALP), N-terminal propeptide of type I collagen (PINP), and C-telopeptide of type I collagen (CTX) were tested before treatment and at week 24 and 48 after treatment. Serum levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB) were measured before treatment and at week 48 after treatment.The rhPTH (1-34) increased BMD of lumbar spine (1-4), but decreased BMD of femoral neck and total hip at week 48 after treatment. By contrast, ALN enhanced BMD of lumbar spine (1-4) and femoral neck, but reduced BMD of total hip at week 48 after treatment. In PTH group, serum levels of PINP, ALP, and ß-CTX were significantly elevated above baseline at week 24 and 48 after treatment. Treatment with ALN decreased levels of PINP, ALP, and ß-CTX compared with baseline at week 24 and 48 after treatment. rhPTH (1-34) and ALN significantly decreased levels of PDGF-BB, but not levels of VEGF. rhPTH (1-34) increased levels of calcium, phosphorus and triglyceride, but decreased levels of total cholesterol. ALN increased levels of calcium and triglyceride, but reduced levels of phosphorus and total cholesterol. rhPTH (1-34) and ALN were safe in the treatment of postmenopausal osteoporosis.The study demonstrates that efficacy of rhPTH (1-34) on BMD of lumbar spine (1-4) is similar to that of alendronate in the treatment of postmenopausal osteoporosis. The effect of rhPTH (1-34) on BMD of femoral neck or total hip is weaker than that of ALN. In addition, rhPTH (1-34) increases BMD of lumbar spine (1-4) maybe by raising serum levels of VEGF, but reduces BMD of femoral neck and total hip maybe by decreasing serum levels of PDGF-BB.

The Beneficial Effect of Proanthocyanidins and Icariin on Biochemical Markers of Bone Turnover in Rats.

Nutrition is an important factor that influences bone metabolism, the endocrine and/or paracrine system, and bone-active mineral elements homeostasis. We studied antiosteoporotic effects of grape seed proanthocyanidins extract, icariin or alendronate (ALN) in retinoic acid-induced (13cRA) bone loss in rats. Proanthocyanidins and icariin have beneficial effects on bone health; they have improved the bone weight reduction, the length and the diameter of the bone, calcium, and phosphorus content in bone ash, bone mineral density (BMD), the biochemical markers of bone turnover and uterus atrophy induced by 13cRA. All results suggest that proanthocyanidins and icariin reverse osteoporosis in 13cRA rats by stimulating bone formation or regulating bone resorption by their antioxidative and estrogenic-like activity without toxic side-effects observed in ALN treatment.