Combination Of Alendronate Research Articles

Effects of bisphosphonates and treadmill exercise on bone and kidney in adenine-induced chronic kidney disease rats.

The increasing prevalence of osteoporosis and chronic kidney disease (CKD) due to the aging of society has highlighted the need for development of effective treatments for elderly patients. This study examined whether the combination of treadmill exercise therapy and alendronate (ALN) can improve bone mineral density (BMD) and bone strength without worsening renal function in adenine-induced CKD model rats. 8-week-old male Wistar rats (n = 70) were divided into experimental groups based on the treatment protocol, i.e., non-CKD (control), vehicle only (CKD), ALN only, exercise only, and combined ALN plus exercise. A 0.75% adenine diet was used to induce CKD. Groups were killed at either 20 or 30weeks of age. Comprehensive assessments included serum and urine biochemistry tests, renal histology, bone histomorphometry, BMD measurement, micro-computed tomography examinations, and biomechanical testing. Blood biochemistry tests, urine analyses and histological evaluations of the kidney demonstrated that ALN treatment did not worsen renal function or kidney fibrosis in moderate-stage CKD model rats. Both ALN and treadmill exercise significantly suppressed bone resorption (p < 0.05-p < 0.01). Moreover, ALN monotherapy and combined ALN and treadmill exercise significantly improved BMD of the lumbar spine and femur, bone microstructure, and trabecular bone strength (p < 0.05-p < 0.01). Treadmill exercise was also shown to decrease cortical porosity at the mid-diaphysis of the femur and improve kidney fibrosis. The combination of ALN and treadmill exercise is effective in improving BMD, the microstructure of trabecular and cortical bone, and bone strength, without compromising renal function in adenine-induced CKD model rats.

Clinical, CT profile of wistar rats receiving therapeutic doses of alendronate alone and in combination with cyclophosphamide and dexamethasone

IntroductionThe exact pathogenesis of drug-induced osteonecrosis of the jaw is still unknown. The aim of this study is to develop a reliable rat model of alendronate-related osteonecrosis of the jaw and to determine the CT profile of bisphosphonate-induced osteonecrosis of the jaw. Materials and methods98 Wistar rats were divided into 4 groups. Rats in the test groups received, in addition to 0.05 mg/kg alendronic acid orally (twice a week for 8 consecutive weeks), 1 mg/kg/day subcutaneously of dexamethasone for 2 weeks and 150 mg/kg cyclophosphamide orally twice and once a week before and after dental avulsion. ResultsFrom week 4 to week 8 after drug administration, the frequency of stage 3 osteonecrotic lesions increased in the test groups from (G1 = 5 (18.5%); G2 = 11 (39.2%); G3 = 6 (21.4%)) to (G1 = 8 (32%); G2 = 12 (42.8%); G3 = 13 (46.4%)) respectively. However, healing was not impaired in the control group (p = 0.003).Scannographic analysis showed that the difference in bone mineral density was greater in rats exposed (G2 = 486.22 ± 94.76; G3 = 584.9 ± 42.47) to the drug combinations than in rats exposed (G1 = 421.61 ± 125.81) to alendronate alone. ConclusionBased on this study, the rat treated with alendronate in combination or not with dexamethasone and cyclophosphamide and dental extraction can be considered as a new, reliable and reproducible model to better understand the pathophysiology of osteonecrosis of the jaws in the context of osteoporosis and prostate cancer. Furthermore, bone mineral density has been shown to be an important diagnostic criterion.

Comparative effects of Venlafaxine and Alendronate on Biochemical, Bone mechanical and Anti-inflammatory properties in ovariectomized rats

The drug of choice in the treatment of postmenopausal osteoporosis is alendronate. Antidepressive agents are currently used in combination with alendronate to protect against depression and may affect the condition of osteoporosis. The aim is to study the comparative effects of venlafaxine and alendronate on biochemical, bone mechanical and anti-inflammatory properties in osteoporotic induced rats. 36 female Wistar albino rats were included (6 rats/group). Treated groups were ovariectomized bilaterally to induce osteoporosis. Rats were treated orally with alendronate (3mg/kg/day) and venlafaxine (20mg/kg/day) and combined alendronate and venlafaxine for 28 days. Body weight, serum alkaline phosphates, serum calcium, three point bending test, bone mineral mass and inflammatory cytokines The induction of osteoporosis showed significant elevated serum alkaline phosphatase, decreased serum calcium, body weight, bone mineral mass and inflammatory cytokines. Venlafaxine treatment did not ameliorate the changes in tested parameters, where at end of the experiment alendronate has significant improved with serum alkaline phosphatase, serum calcium, bone mineral mass, bone mineral density. The improvement was not affected by combining venlafaxine with alendronate whereas the venlafaxine treatment alone caused a significant deterioration of tested parameters. Venlafaxine is an anti-depressive agent that inhibits brain serotonin which leads to decrease in bone formation. Hence, from the above findings the combination of alendronate and venlafaxine showed worsen the condition of osteoporosis rats.

Use of Bisphosphonates, Calcium and Vitamin D for Bone Demineralization in Patients with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome: A Systematic Review and Meta-Analysis of Clinical Trials.

Background The present study performed a systematic review and meta-analysis of clinical trials using bisphosphonates for bone demineralization in human immunodeficiency virus (HIV) patients.Methods A comprehensive literature search was performed from January 2004 to January 2020 considering the bone mineral density (BMD) of the lumbar spine (LS) as the main outcome. Out of 214 titles that met criteria, 9 studies fulfilled the selection criteria.Results A total of 394 patients were identified, and they were allocated into 2 groups: the intervention group (200 patients), to whom a combination of alendronate or zoledronate with calcium and vitamin D was administered; and control group (194 patients), to whom only calcium and vitamin D was administered. Clinical profile and indicators of bone metabolism of the participants were evaluated regarding effect size, homogeneity, and consistency. No substantial heterogeneity between the groups was found for the baseline variables, and there was high consistency to the main outcome. The meta-analysis shows a significant difference in post-treatment BMD, favoring the intervention over the control treatment. The intervention improved LS density up to 0.227 g/cm², raising the average to the levels of general population. Adverse effects related to intervention were fever immediately after zoledronate administration and gastrointestinal complaints during alendronate usage. Other adverse effects were barely reported and poorly connected to intervention by studies’ authors, despite all of them have been successfully resolved.ConclusionsThis study provides evidence that BMD post-treatment is better in HIV patients who used bisphosphonates combined with calcium and vitamin D.

Effect of co-administration of alendronate and allan sodium phosphate for the management of osteoporosis

Purpose: To study the therapeutic effect of combination of alendronate and allan sodium phosphate on osteoporosis.Methods: Patients diagnosed with osteoporosis (100) were randomly assigned to control and study groups (50 subjects/group). The control group received conventional calcium treatment (calcium carbonate D3) after surgery. They consisted of 21 males and 29 females aged 62 to 78 years. The observation group consisted of 22 males and 28 females aged 63 to 77 years (mean age = 68.90 ± 6.43 years), and were treated with sodium alendronate and allan sodium phosphate. Bone mineral density (BMD), bone pain score, clinical effectiveness and levels of calcium, phosphorus, osteocalcin, collagen N-terminal peptide (NTX) and urinary calcium/creatinine were determined using ELISA kits.Results: After 1 year of treatment, lumbar vertebral and femoral neck BMD significantly increased in both groups. The study group had significantly higher BMD than the controls (p &lt; 0.05). Blood calcium levels increased significantly after 1 year in both groups. The treatment led to a higher level of osteocalcin in the study group than in the control group (p &lt; 0.05). However, the treatment brought about significantly lower NTX level in the study group than in controls.Conclusion: The results indicate that combined administration of sodium alendronate and allan sodium phosphate is effective for the treatment of osteoporosis.Keywords: Osteoporosis, Allan sodium phosphate, Alendronate, Apoptosis-related factors, Calcium

Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of glucocorticoid-induced osteopenia rats

ObjectivesGlucocorticoid (GC) treatment inhibits activation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation from stem cells. As a result, GC treatment results in bone loss, GC-induced osteoporosis (GIO), elevated fracture risk, and delayed bone healing. Bisphosphonates such as alendronate (ALN) are recommended for treating or preventing GIO, and low-intensity pulsed ultrasound (LIPUS) facilitates fracture healing and maturation of regenerated bone. Combined therapy with ALN and LIPUS may stimulate cancellous bone healing in GIO rats. Here, we examined the effect of ALN and LIPUS on cancellous bone osteotomy repair in the proximal tibia of GIO rats. MethodsPrednisolone (10 mg/kg body weight/day) was administered for 4 weeks to induce GIO in 6-month-old female Sprague-Dawley rats. Tibial osteotomy was then performed and daily subcutaneous injection of ALN (1-μg/kg body weight) was subsequently administered alone or in combination with LIPUS (20 min/day) for 2 or 4 weeks. ResultsALN significantly increased bone mineral density (BMD) at 2 and 4 weeks, and ALN + LIPUS significantly increased BMD at 4 weeks. Bone union rates were significantly increased after 2 and 4 weeks ALN and ALN + LIPUS treatment. Lastly, ALN and ALN + LIPUS significantly increased the proportion of Runx2 positive cells at 4 weeks. ConclusionsALN monotherapy and combined ALN and LUPUS treatment augmented BMD and stimulated cancellous bone repair with increased Runx2 expression at the osteotomy site in GIO rats. However, the combined treatment had no additional effect on cancellous bone healing compared to ALN monotherapy.

A Novel H2S-releasing Amino-Bisphosphonate which combines bone anti-catabolic and anabolic functions

Bisphosphonates (BPs) are the first-line treatment of bone loss resulting from various pathological conditions. Due to their high affinity to bone they have been used to develop conjugates with pro-anabolic or anti-catabolic drugs. We recently demontrated that hydrogen sulfide (H2S), promotes osteogenesis and inhibits osteoclast differentiation. Here we developed an innovative molecule, named DM-22, obtained from the combination of alendronate (AL) and the H2S-releasing moiety aryl-isothiocyanate. DM-22 and AL were assayed in vitro in the concentration range 1-33 μM for effects on viability and function of human osteoclasts (h-OCs) and mesenchymal stromal cells (h-MSCs) undergoing osteogenic differentiation. Amperometric measures revealed that DM-22 releases H2S at a slow rate with a thiol-dependent mechanism. DM-22 significantly inhibited h-OCs differentiation and function, maintaining a residual h-OCs viability even at the high dose of 33 μM. Contrary to AL, in h-MSCs DM-22 did not induce cytotoxicity as revealed by LDH assay, significantly stimulated mineralization as measured by Alizarin Red staining and increased mRNA expression of Collagen I as compared to control cultures. In conclusion, DM-22 is a new BP which inhibits h-OCs function and stimulate osteogenic differentiation of h-MSCs, without cytotoxicity. DM-22 is an ideal candidate for a novel family of osteoanabolic drugs.

Do acid suppressive drugs (pantoprazole and ranitidine) attenuate the protective effect of alendronate in estrogen-deficient osteoporotic rats?

BackgroundAlendronate is a drug of choice in the treatment of postmenopausal osteoporosis. Acid suppressive drugs are recently used in combination with alendronate to protect against stomach ulceration and oesophagitis occurring as serious problems in patients under this treatment. Aim of the workTo study the effect of pantoprazole and ranitidine on the anti-resorptive effect of alendronate in a rat model of osteoporosis. Material and methods64 female Wister albino rats were included (8 rats/group). Treated groups were Ovariectomized bilaterally to induce osteoporosis. Rats were treated orally with alendronate (3mg/kg/day), ranitidine (20mg/kg/day), pantoprazole (3mg/kg/day), combined alendronate and ranitidine or alendronate and pantoprazole for 4weeks. Bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry scan. Serum bone-specific alkaline phosphatase (BSALP), serum calcium, cortical thickness and histopathological examination were assessed. ResultsInduction of osteoporosis significantly elevated serum BSALP, decreased serum calcium, bone mineral density and cortical thickness and significantly increased the histopathological score. Ranitidine treatment resulted in insignificant changes in tested parameters. Pantoprazole given alone, significantly decreased serum calcium and increased serum BSALP. At the end of the experiment, alendronate significantly improved BSALP level, serum calcium, BMD, cortical thickness and histopathological score. This improvement was not affected by combining ranitidine with alendronate. Meanwhile, pantoprazole with alendronate caused a significant deterioration of tested parameters. ConclusionRanitidine proved safer than pantoprazole for patients with high risk of osteoporosis and in alendronate-treated patients. Clinicians should carefully judge the indication of use of acid suppressing medications in osteoporotic patients.

Effects of combination treatment with alendronate and raloxifene on skeletal properties in a beagle dog model.

A growing number of studies have investigated combination treatment as an approach to treat bone disease. The goal of this study was to investigate the combination of alendronate and raloxifene with a particular focus on mechanical properties. To achieve this goal we utilized a large animal model, the beagle dog, used previously by our laboratory to study both alendronate and raloxifene monotherapies. Forty-eight skeletally mature female beagles (1–2 years old) received daily oral treatment: saline vehicle (VEH), alendronate (ALN), raloxifene (RAL) or both ALN and RAL. After 6 and 12 months of treatment, all animals underwent assessment of bone material properties using in vivo reference point indentation (RPI) and skeletal hydration using ultra-short echo magnetic resonance imaging (UTE-MRI). End point measures include imaging, histomorphometry, and mechanical properties. Bone formation rate was significantly lower in iliac crest trabecular bone of animals treated with ALN (-71%) and ALN+RAL (-81%) compared to VEH. In vivo assessment of properties by RPI yielded minimal differences between groups while UTE-MRI showed a RAL and RAL+ALN treatment regimens resulted in significantly higher bound water compared to VEH (+23 and +18%, respectively). There was no significant difference among groups for DXA- or CT-based measures lumbar vertebra, or femoral diaphysis. Ribs of RAL-treated animals were smaller and less dense compared to VEH and although mechanical properties were lower the material-level properties were equivalent to normal. In conclusion, we present a suite of data in a beagle dog model treated for one year with clinically-relevant doses of alendronate and raloxifene monotherapies or combination treatment with both agents. Despite the expected effects on bone remodeling, our study did not find the expected benefit of ALN to BMD or structural mechanical properties, and thus the viability of the combination therapy remains unclear.

Combination of alendronate and genistein synergistically suppresses osteoclastic differentiation of RAW267.4 cells in vitro.

Bone is a dynamic tissue that undergoes constant remodeling, with removal by osteoclastic bone resorption and replacement via osteoblastic bone formation and mineralization. Deterioration of bone mass with aging leads to osteoporosis. Bisphosphonates are potent inhibitors of osteoclastic bone resorption. Genistein, an isoflavone, exerts a bone anabolic effect by suppressing osteoclastic bone resorption and stimulating osteoblastic bone formation. The present study was undertaken to investigate the anabolic effects of a combination of alendronate and genistein on osteoclastic differentiation. Preosteoclastic RAW267.4 cells were cultured with alendronate (0.1-100 µM) and/or genistein (0.1-100 µM) in vitro. Alendronate or genistein alone had no significant effect on the proliferation and death of RAW267.4 cells. Notably, the combination of the two agents was found to potently and synergistically repress the proliferation and death of RAW267.4 cells. Moreover, alendronate or genistein used separately at higher concentrations suppressed the osteoclastic differentiation of RAW267.4 cells induced by receptor activator of nuclear factor-κB ligand (RANKL) in vitro. However, combinations of the two agents (0.1-100 µM) synergistically suppressed the RANKL-induced osteoclastic differentiation. In conclusion, bisphosphonate and genistein combination therapy may provide a novel strategy for the prevention and treatment of osteoclastic bone resorption.

Effects of Combination Therapy of Alendronate and Hormonal Therapy on Bone Mineral Density in Postmenopausal Korean Women: Multicenter, Randomized Controlled Clinical Trial.

This study evaluated the effects of combination treatment with alendronate (ALEN) and hormone therapy (HT) on bone mineral density (BMD) in postmenopausal Korean women. This multicenter, randomized, controlled clinical trial enrolled 344 postmenopausal women with low BMD. The women received HT (0.625 mg/day of conjugated equine estrogen and 2.5 mg/day of medroxyprogesterone acetate) alone or in combination with ALEN (10 mg/day) for 1 year. Changes in BMD and biochemical markers of bone turnover were evaluated. Data from 203 women (HT alone, 99; combination treatment, 104) who completed this study were analyzed. BMD at the lumbar spine and total hip increased significantly in both treatment groups after 1 year. There were no significant differences between HT alone vs. the combination of ALEN and HT in mean BMD increase at the lumbar spine (6.9% vs. 7.9%) and total hip (3.7% vs. 3.8%). Combined therapy suppressed serum osteocalcin and urinary deoxypyridinoline to a greater extent than HT alone. In conclusion, compared to HT alone, combination treatment with ALEN and HT for 1 year did not offer a benefit in BMD in postmenopausal Korean women with low BMD.

In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice

Nitrogen-containing bisphosphonates (N-BP), including zoledronic acid (ZOL) and alendronate (ALD), have been proposed as sensitisers in γδ T cell immunotherapy in pre-clinical and clinical studies. Therapeutic efficacy of N-BPs is hampered by their rapid renal excretion and high affinity for bone. Liposomal formulations of N-BP have been proposed to improve accumulation in solid tumours. Liposomal ALD (L-ALD) has been suggested as a suitable alternative to liposomal ZOL (L-ZOL), due to unexpected mice death experienced in pre-clinical studies with the latter. Only one study so far has proven the therapeutic efficacy of L-ALD, in combination with γδ T cell immunotherapy, after intraperitoneal administration of γδ T cell resulting in delayed growth of ovarian cancer in mice. This study aims to assess the in vitro efficacy of L-ALD, in combination with γδ T cell immunotherapy, in a range of cancerous cell lines, using L-ZOL as a comparator. The therapeutic efficacy was tested in a pseudo-metastatic lung mouse model, following intravenous injection of γδ T cell, L-ALD or the combination. In vivo biocompatibility and organ biodistribution studies of L-N-BPs were undertaken simultaneously. Higher concentrations of L-ALD (40–60μM) than L-ZOL (3–10μM) were required to produce a comparative reduction in cell viability in vitro, when used in combination with γδ T cells. Significant inhibition of tumour growth was observed after treatment with both L-ALD and γδ T cells in pseudo-metastatic lung melanoma tumour-bearing mice after tail vein injection of both treatments, suggesting that therapeutically relevant concentrations of L-ALD and γδ T cell could be achieved in the tumour sites, resulting in significant delay in tumour growth.

Effect of Vitamin K and Alendronate Combination Treatment on Bone Mineral Density of Postmenopausal Osteoporosis Patients: A Pilot Study

Introduction: Osteoporosis is a common problem in postmenopausal women. Numerous studies investigated the effects of vitamin K on bone health, which yielded conflicting results. In this study, we aimed to compare the effect of vitamin K and alendronate combination with alendronate alone on Bone Mineral Density (BMD) of women with postmenopausal osteoporosis. Materials and Methods: This study was performed in Imam Reza Hospital of Mashhad, Iran, during 14 months (January 1, 2014-February 29, 2015). Our patients (n=28) were randomly divided into two groups of receiving calcium, vitamin D, and alendronate (n=13) and receiving the same combination + vitamin K1 supplement (10 mg daily) (n=15). BMD was measured pre- and post-intervention by the same bone scanner. Results: The baseline characteristics of the two groups did not differ significantly. The mean variation in femoral neck BMD of the alendronate and alendronate + vitamin K groups were -4.20±11.91% and 0.39±11.80%, respectively. There was no significant difference between the two groups in terms of mean change in femoral neck BMD (P=0.32). The mean variations in lumbar spine BMD of the alendronate and alendronate + vitamin K groups were 0.71±0.06% and 0.76±0.11%, respectively. There was no significant difference between the two groups in terms of mean change in lumbar spine BMD (P=0.24). Conclusion: It was found that combined treatment with vitamin K and alendronate was not more effective than alendronate alone in increasing BMD of postmenopausal osteoporosis patients.

Changing patterns of prescription in vitamin D supplementation in adults: analysis of a regional dataset.

Scientific interest in vitamin D has greatly risen during the last 10 years. The analysis of the changes in vitamin D prescriptions and related costs in a regional prescription dataset has revealed a profound increase in the period 2006-2013. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed. The aim of this study was to analyze the changes in population-based prescription patterns of vitamin D supplements in the general population in an Italian regional setting during an 8-year period (2006-2013). Data have been retrieved from the database of reimbursed prescriptions of the Region of Tuscany containing all of the medical reimbursements for the whole regional population (total of 3,619,872 and 3,692,828 inhabitants in 2006 and 2013, respectively). Data referring to adult population (age 20-90+ years) have been considered for this analysis (3,033,530 in 2006 and 3,066,741 in 2013). Two different flows (pharmaceutical distribution dataset and general data flow) were taken into account, using the ATC5 coding system for vitamin D supplements alone or in combination with calcium or alendronate. The number of boxes dispensed was retrieved, the number of patients receiving a specific treatment was calculated, and a cost analysis was performed. An upsurge in the prescriptions of vitamin D compounds was disclosed, mainly sustained by a 75.3-fold increase in cholecalciferol, in all age groups and both sexes. This occurred in parallel to a 4.3-fold rise in prescriptions of oral alendronate in combination with cholecalciferol, a slight decrease in dispensed alendronate alone, and a modest increase in the prescription of the combination of calcium salts and cholecalciferol, and calcium alone. The total cost for reimbursement by the Regional Health System for vitamin D-related compounds rose from €3,242,100 euros in 2006 to €8,155,778 in 2013. The huge increase in vitamin D prescriptions and related costs in the last decade, as revealed by the analysis of a regional pharmaceutical dataset, reflects the increased awareness of the possible consequences of a poor vitamin D status. Further studies on cost-effectiveness of such increase in vitamin D supplementation are needed.

Mechanical competence of ovariectomy-induced compromised bone after single or combined treatment with high-frequency loading and bisphosphonates.

Osteoporosis leads to increased bone fragility, thus effective approaches enhancing bone strength are needed. Hence, this study investigated the effect of single or combined application of high-frequency (HF) loading through whole body vibration (WBV) and alendronate (ALN) on the mechanical competence of ovariectomy-induced osteoporotic bone. Thirty-four female Wistar rats were ovariectomized (OVX) or sham-operated (shOVX) and divided into five groups: shOVX, OVX-shWBV, OVX-WBV, ALN-shWBV and ALN-WBV. (Sham)WBV loading was applied for 10 min/day (130 to 150 Hz at 0.3g) for 14 days and ALN at 2 mg/kg/dose was administered 3x/week. Finite element analysis based on micro-CT was employed to assess bone biomechanical properties, relative to bone micro-structural parameters. HF loading application to OVX resulted in an enlarged cortex, but it was not able to improve the biomechanical properties. ALN prevented trabecular bone deterioration and increased bone stiffness and bone strength of OVX bone. Finally, the combination of ALN with HF resulted in an increased cortical thickness in OVX rats when compared to single treatments. Compared to HF loading, ALN treatment is preferred for improving the compromised mechanical competence of OVX bone. In addition, the association of ALN with HF loading results in an additive effect on the cortical thickness.

μCT-based, in vivo dynamic bone histomorphometry allows 3D evaluation of the early responses of bone resorption and formation to PTH and alendronate combination therapy

Current osteoporosis treatments improve bone mass by increasing net bone formation: anti-resorptive drugs such as bisphosphonates block osteoclast activity, while anabolic agents such as parathyroid hormone (PTH) increase bone remodeling, with a greater effect on formation. Although these drugs are widely used, their role in modulating formation and resorption is not fully understood, due in part to technical limitations in the ability to longitudinally assess bone remodeling. Importantly, it is not known whether or not PTH-induced bone formation is independent of resorption, resulting in controversy over the effectiveness of combination therapies that use both PTH and an anti-resorptive. In this study, we developed a μCT-based, in vivo dynamic bone histomorphometry technique for rat tibiae, and applied this method to longitudinally track changes in bone resorption and formation as a result of treatment with alendronate (ALN), PTH, or combination therapy of both PTH and ALN (PTH+ALN). Correlations between our μCT-based measures of bone formation and measures of bone formation based on calcein-labeled histology (r=0.72–0.83) confirm the accuracy of this method. Bone remodeling parameters measured through μCT-based in vivo dynamic bone histomorphometry indicate an increased rate of bone formation in rats treated with PTH and PTH+ALN, together with a decrease in bone resorption measures in rats treated with ALN and PTH+ALN. These results were further supported by traditional histology-based measurements, suggesting that PTH was able to induce bone formation while bone resorption was suppressed.

Vitamin K₂ therapy for postmenopausal osteoporosis.

Vitamin K may play an important role in the prevention of fractures in postmenopausal women with osteoporosis. Menatetrenone is the brand name of a synthetic vitamin K2 that is chemically identical to menaquinone-4. The present review study aimed to clarify the effect of menatetrenone on the skeleton in postmenopausal women with osteoporosis, by reviewing the results of randomized controlled trials (RCTs) in the literature. RCTs that investigated the effect of menatetrenone on bone mineral density (BMD), measured by dual-energy X-ray absorptiometry and fracture incidence in postmenopausal women with osteoporosis, were identified by a PubMed search for literature published in English. Eight studies met the criteria for RCTs. Small RCTs showed that menatetrenone monotherapy decreased serum undercarboxylated osteocalcin (ucOC) concentrations, modestly increased lumbar spine BMD, and reduced the incidence of fractures (mainly vertebral fracture), and that combined alendronate and menatetrenone therapy enhanced the decrease in serum ucOC concentrations and further increased femoral neck BMD. This review of the literature revealed positive evidence for the effects of menatetrenone monotherapy on fracture incidence in postmenopausal women with osteoporosis. Further studies are required to clarify the efficacy of menatetrenone in combination with bisphosphonates against fractures in postmenopausal women with osteoporosis.

Efficacy of alendronate for preventing collapse of femoral head in adult patients with nontraumatic osteonecrosis.

The purpose of the current review was to determine the efficacy of alendronate for preventing collapse of femoral head in adult patients with nontraumatic avascular osteonecrosis of femoral head (ANFH). Five randomized controlled trials (RCTs) involving 305 hips were included in this review, of which 3 studies investigated alendronate versus control/placebo and the other 2 studies compared the combination of alendronate and extracorporeal shockwave therapy (ESWT) with ESWT alone. Our results suggested that even the patients with extensive necrosis encountered much less collapse in the alendronate group than control group. In these RCTs, their data also indicated a positive short- and middle-term efficacy of alendronate treatment in joint function improvement and hip pain diminishment. With the presence of the outlier study, only insignificant overall efficacy of alendronate could be observed with substantial heterogeneities. In addition, we did not find any additive benefits of alendronate in combination with ESWT for preventing collapse compared to ESWT alone. In conclusion, there is still lack of strong evidence for supporting application of alendronate in adult patients with nontraumatic ANFH, which justified that large scale, randomized, and double-blind studies should be developed to demonstrate the confirmed efficacies, detailed indication, and optimized strategy of alendronate treatment.

EFFECT OF ALENDRONATE COMBINED WITH ALFACALCIDOL ON THE BIOLOGICAL STABILITY OF HIP JOINT ENDOPROSTHESIS IN PATIENTS WITH SYSTEMIC OSTEOPOROSIS

In a comparative study we investigated the influence of a combination of alendronate and alfacalcidol on the dynamics of bone mass density (BMD) at the site attached to the femoral component of endoprosthesis in total hip replacement in patients with systemic osteoporosis. Evaluation of performance of pharmacotherapy in the postoperative period on osteoporosis, systemic osteoporosis, sustained BMD deficit at Gruen regions confirmed that the essential component of osteointegration at the «implant-bone» site during the period of physiological adaptive remodeling after arthroplasty in women suffering from systemic osteoporosis is the pharmacological correction of the intensity of bone resorption in post-operative period.

Comparative effectiveness of combination osteoanabolic and antiresorptive therapy for osteoporosis: an update

The combination of an osteoanabolic and antiresorptive agent for the treatment of osteoporosis has been a topic of interest for at least a decade. When used together, in theory, bone formation would be stimulated by the action of the osteoanabolic drug, while bone resorption would be reduced by the action of the antiresorptive agent. Based upon these two different mechanisms, combination therapy, at least in concept, would be expected to be more efficacious than monotherapy with either agent alone. The earliest studies used alendronate in combination with teriparatide [PTH(1–34)] or PTH(1–84) [1,2]. With regard to bone mineral density (BMD) of the lumbar spine as assessed by dual-energy x-ray absorptiometry (DXA), combination therapy was similarly effective as PTH monotherapy, with these two arms of the trials showing densitometric advantages over alendronate alone. When BMD was measured by quantitative computed tomography, teriparatide monotherapy gave even greater improvement in BMD than either combination therapy or alendronate alone. At the hip, by DXA, gains in BMD at 1 year were greater with combination therapy than teriparatide alone, but similar to alendronate monotherapy. When carried out to 2 years, however, there was no longer an advantage to combination therapy over PTH alone. At the distal 1/3 radius site, combination therapy helped to mitigate reductions in BMD seen when teriparatide was used alone, but again provided results similar to alendronate alone. These studies in men and women did not provide support for the idea that combination therapy provides greater densitometric advantages over monotherapy with either an osteoanabolic or antiresorptive agent [1,2]. A clue to these results could be seen in the bone turnover markers influenced by combination therapy. Both formation and resorption markers were reduced, mirroring the effect of alendronate, not PTH. It was expected, on the contrary, that combination therapy would reveal the dominating effects of osteoanabolic therapy on skeletal dynamics, leading to an increase in bone turnover markers. The results of these studies led to the idea that an antiresorptive agent with a smaller effect on bone resorption might enhance – or at the very least not impair – the osteoanabolic actions of PTH to increase bone formation. Encouraging results were noted in a short-term study using raloxifene [3], a selective estrogen receptor modulator that is indeed less potent than alendronate in reducing bone turnover. More recently, Walker et al. studied the combination of teriparatide with risedronate, a bisphosphonate that does not reduce bone resorption to the same extent as alendronate or zoledronic acid [4]. The study randomized 29 men with low BMD to risedronate or teriparatide alone or in combination. Lumbar spine BMD, the primary end point, was significantly increased in all three treatment groups with out any advantage gained by combination therapy. At the total hip, however, BMD increased to a greater extent in the combination group (+3.9%) versus teriparatide alone (+0.3%) or risedronate alone (+0.8%; p < 0.05 for both comparisons). Femoral neck BMD also increased to a greater extent in the combination group 1