Safety and effects of calcifediol 0.266 milligrams soft capsules monthly and cholecalciferol 25000 international units monthly in osteoporotic women undergoing therapy with alendronate: a cross-sectional study.

BACKGROUND: The role of vitamin D in human physiology is a topic of great interest for the scientific community in the last decades. The common target for all clinicians is to improve its status in order to prevent several pathological conditions. METHODS: The aim of our study was to evaluate the safety and the efficacy of both calcifediol and cholecalciferol in combination with alendronate in osteoporotic women. A homogeneous population of 300 postmenopausal osteoporotic women was selected for this study. 150 women were administered with alendronate 70 mg combined with clacifediol 0.266 mg soft capsules monthly. The other half (other 150 women) were administered with alendronate 70 mg combined with cholecalciferol 25000 IU monthly. First follow-up was after 4 months and second follow-up after 12 months. RESULTS: No case of toxicity was detected throughout the study in any patient. In regards to increase of vitamin D serum level, after four months supplementation calcifediol is 1.29 fold more effective than cholecalciferol while after 12 months of supplementation calcifediol is 2.32 fold more effective compared to cholecalciferol. CONCLUSIONS: In our study calcifediol showed to be as safe as cholecalciferol and more effective than cholecalciferol in order to increase vitamin D serum level after four and 12 months of supplementation when supplementation is combined with alendronate 70 mg in osteoporotic women.

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.

Severe hypophosphataemia following oral bisphosphonate treatment in a patient with osteoporosis.

A 76-year-old woman was treated with oral bisphosphonate, alendronate, for osteoporosis in an outpatient clinic. Routine blood tests 4 months after alendronate prescription surprisingly revealed severe hypophosphataemia. The patient was hospitalised and treated with intravenous and oral phosphate supplements. Alendronate was later reintroduced as treatment for osteoporosis and the patient once again presented with severe hypophosphataemia in subsequent routine blood tests. The patient had only presented with lower extremity pain, muscle weakness and difficulty walking. Blood tests in the emergency department both times reconfirmed severe hypophosphataemia. Plasma (p-)ionised calcium levels were normal or slightly elevated and p-parathyroid hormone levels were normal or slightly suppressed. The p-25-hydroxyvitamin-D and p-creatine were in the normal range. Critical illness, malabsorption, nutritional issues and genetics were reviewed as potential causes but considered unlikely. Phosphate levels were quickly restored each time on replacement therapy and the case was interpreted as bisphosphonate-induced severe hypophosphataemia.

Comparison of the Efficacy and Renal Safety of Bisphosphonate Between Low-Dose/High-Frequency and High-Dose/Low-Frequency Regimens in a Late-Stage Chronic Kidney Disease Rat Model.

The efficacy and renal safety of low-dose/high-frequency (LDHF) dosing and high-dose/low-frequency (HDLF) dosing of bisphosphonates (BPs) are comparable in patients with normal kidney function but might be different in patients with late-stage chronic kidney disease (CKD). This study aimed to compare the efficacy and renal safety of two different dosage regimens of a BP, alendronate (ALN), in stage 4 CKD using a rat model. Male, 10-week-old Sprague-Dawley rats were subjected to either 5/6 nephrectomy or sham surgery. The animals received subcutaneous administration of vehicle (daily) or ALN in LDHF dosage regimen (LDHF-ALN: 0.05 mg/kg/day) or HDLF dosage regimen (HDLF-ALN: 0.70 mg/kg/2 weeks). Medications commenced at 20 weeks of age and continued for 10 weeks. Micro-computed tomography, histological analysis, infrared spectroscopic imaging, and serum and urine assays were performed to examine the efficacy and renal safety of the ALN regimens. Both LDHF-ALN and HDLF-ALN increased bone mass, improved micro-structure, and enhanced mechanical properties, without causing further renal impairment in CKD rats. Histologically, however, HDLF-ALN more efficiently suppressed bone turnover, leading to more mineralized trabecular bone, than LDHF-ALN in CKD rats, whereas such differences between LDHF-ALN and HDLF-ALN were not observed in sham rats. Both LDHF-ALN and HDLF-ALN showed therapeutic effects on high bone turnover osteoporosis in CKD stage 4 rats without causing further renal impairment. However, as HDLF-ALN more efficiently suppressed bone turnover than LDHF-ALN in late-stage CKD, HDLF-ALN might be more appropriate than LDHF-ALN for fracture prevention in high bone turnover osteoporosis patients with late-stage CKD.

Cost-effectiveness of denosumab for high-risk postmenopausal women with osteoporosis in Thailand.

Aims: This study assessed the cost-effectiveness of denosumab for treating postmenopausal women with osteoporosis (PMO) at high risk of fracture in Thailand.Materials and methods: A published Markov cohort cost-effectiveness model was populated with country-specific data as available and other published data as needed. The model used a societal perspective, lifetime horizon, efficacy data from network meta-analysis of trials, and included costs for direct medical and non-medical care, informal care, and osteoporosis treatments to compare denosumab to no pharmacologic treatment (calcium and vitamin D supplements only) and to oral weekly alendronate. The base case (high-risk population) included postmenopausal women with femoral neck T-score ≤-2.5, mean age 65 years at entry, and history of vertebral fracture.Results: High-risk women with osteoporosis using denosumab had the greatest number of life years and quality-adjusted life-years (QALYs) with higher reductions in hip and vertebral fracture incidence compared with patients with no pharmacologic treatment. The incremental cost-effectiveness ratio (ICER) was 119,575 Thai Baht (THB) per QALY for denosumab versus no pharmacologic treatment and 199,186 THB per QALY for denosumab versus alendronate. Among Thai postmenopausal women with high-risk of fractures, denosumab was cost-effective compared with no pharmacologic treatment at a willingness-to-pay threshold of 160,000 THB per QALY. One-way sensitivity analysis showed models were most sensitive to changes in denosumab pricing.Limitations: Data from other countries used when country-specific data were unavailable may not accurately reflect the true experience in Thailand. The model focused explicitly on hip, vertebral, and wrist fractures, and therefore provides a conservative estimate of the overall potential impact of osteoporosis-related fracture. The fracture risk was not adjusted to reflect potential changes in risk after denosumab treatment discontinuation.Conclusions: In Thailand, denosumab offers a cost-effective osteoporosis treatment option versus no pharmacologic treatment in postmenopausal women at high risk of fracture.

Evaluación de la Administración Infiltrativa de vitamina E y alendronato en la Reparación de Alvéolos Post Exodoncia de Ratas / Evaluation of the Infiltrative Administration of Vitamin E and Alendronate in the Repair of Alveoli Post-Extraction in Rats

RESUMEN: Los bisfosfonatos (BP) disminuyen la resorción ósea al frenar la actividad de los osteoclastos. La vitamina E es antioxidante y su efecto positivo en el hueso sería mediante la prevención del estrés oxidativo. Se estudió la administración infiltrativa de Alendronato y Vitamina E para determinar si favorecían la formación de hueso en la reparación ósea del alvéolo postexodoncia. Se utilizaron ratas machos Wistar (n=96), de 90 ± 15 g, se les realizó la exodoncia de los primeros molares inferiores. Fueron dividos en 4 grupos: Un grupo control (C) recibió solución salina. El grupo AL 0,5 mg/ Kg; grupo E recibió 20 mg/kg; y grupo con tratamiento combinado AL y E. Los animales se sacrificaron a los 0, 7, 15 y 30 días postextracción. Se realizó la resección de las mandíbulas; las muestras fueron descalcificadas con EDTA y luego se incluyeron en parafina. Se realizaron cortes histológicos y se colorearon con Hematoxilina/Eosina. Se realizó análisis histológico e histomorfométrico. Se utilizó análisis de Varianza (ANOVA). En el análisis histológico, a los 7 y 15 días el grupo E presentó mayor neoformación de tejido óseo que los otros grupos. A los 30 días se observó hueso maduro con presencia de osteonas en el grupo E. En el estudio histomorfométrico a los 15 y 30 días se evidencian diferencias significativas en el número de osteoblastos por mm lineal, entre el grupo AL + E y C (p<0,01) y a los 30 días se encontró diferencia entre el grupo E y C (p<0,01). Al medir espesor trabecular se observó a los 30 días diferencias significativas entre el grupo AL+E y C (p<0,01) y entre el grupo C y E (p<0,01). La Vitamina E demostró que administrada por vía infiltrativa favorece la remodelación ósea en los alvéolos post exodoncia.

ABSTRACT: Bisphosphonates (BP) decrease bone resorption to curb the activity of the osteoclasts. Vitamin E is an antioxidant and its positive effect on the bone would be by preventing oxidative stress. Infiltrative Alendronate and vitamin E administration wasstudied to determine if they favored the formation of bone in bone repair of the postextraction alveolus. Male Wistar rats were used (n = 96), 90 ± 15 g, underwent extraction of the lower first molars. They were divided into 4 groups: A control group (C) received saline. The Group at the 0.5 mg/Kg; Group E received 20 mg/kg; and combined treatment group to AL and E. The animals were sacrificed at days 0, 7, 15 and 30 post extraction. With the resection of the jaws; samples were decalcified with EDTA and then included in paraffin. Histological cuts were made and colored with Hematoxylin/ eosin. Histomorphometric and histological analysis was performed. We used analysis of variance (ANOVA). In the histological analysis, 7 to 15 days the Group E presented greater neoformation of bone tissue than other groups. At 30 days mature bone was observed, with presence of osteons in the Group E. Study shows significant differences in the number of osteoblast histomorphometric function to 15 to 30 days by linear mm, among the group to the + E and C (p < 0.01) and 30-day difference was found among the Group E and C (p < 0.01). When measuring thick trabecular, significant differences were observed at 30 days between the AL+E and C Group (p < 0.01) and between C and E (p < 0.01). Vitamin E showed that administered infiltrative favors the bone remodeling in post extraction sockets.

Cost-effectiveness Analysis of Sequential Treatment of Abaloparatide Followed by Alendronate Versus Teriparatide Followed by Alendronate in Postmenopausal Women With Osteoporosis in the United States.

BACKGROUND: The US Food and Drug Administration has recently approved abaloparatide (ABL) for treatment of women with postmenopausal osteoporosis (PMO) at high risk of fracture. With increasing health care spending and drug prices, it is important to quantify the value of newly available treatment options for PMO. OBJECTIVE: To determine cost-effectiveness of ABL compared with teriparatide (TPTD) for treatment of women with PMO in the United States. METHODS: A discrete-event simulation (DES) model was developed to assess cost-effectiveness of ABL from the US health care perspective. The model included three 18-month treatment strategies with either placebo (PBO), TPTD, or ABL, all followed by additional 5-year treatment with alendronate (ALN). High-risk patients were defined as women with PMO ⩾65 years old with a prior vertebral fracture. Baseline clinical event rates, risk reductions, and patient characteristics were based on the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. RESULTS: Over a 10-year period, the DES model yielded average total discounted per-patient costs of $10 212, $46 783, and $26 837 and quality-adjusted life-years (QALYs) of 6.742, 6.781, and 6.792 for PBO/ALN, TPTD/ALN, and ABL/ALN, respectively. Compared with TPTD/ALN, ABL/ALN accrued higher QALYs at lower cost and produced an incremental cost-effectiveness ratio (ICER) of $333 266/QALY relative to PBO/ALN. In high-risk women, ABL/ALN also had more QALYs and less cost over TPTD/ALN and yielded an ICER of $188 891/QALY relative to PBO/ALN. Conclusion and Relevance: ABL is a dominant treatment strategy over TPTD. In women with PMO at high risk of fracture, ABL is an alternative cost-effective treatment.

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.

Open-label study of treatment with alendronate sodium plus vitamin D in men and women with osteoporosis in Thailand.

BACKGROUND: It is generally believed that Thai people do not suffer from hypovitaminosis D because there is abundant sunlight throughout the year, and that taking vitamin D supplements could result in abnormally high levels of vitamin D. This is a Thai FDA-driven study to investigate this risk over a period of 26 weeks of taking alendronate sodium/vitamin D3 combination tablets. METHODS: Osteoporosis patients in Thailand were recruited to a multicenter, open-label, 6-month trial of oral alendronate sodium 70 mg/vitamin D3 5600 IU. Patients received study medication once a week for 26 weeks. Serum 25-hydroxyvitamin D (25(OH)D) and Beta-CrossLaps (ß-CTx) levels were measured at baseline and 26 weeks. The primary endpoint was the proportion of patients with 25(OH)D ≥ 50 ng/mL at week 26; it was hypothesized that 26 weeks' treatment would not result in 25(OH)D serum levels ≥ 50 ng/mL in > 7% of osteoporosis patients. RESULTS: One hundred ninety-eight patients were recruited. At baseline, 67.2% of the patients had 25(OH)D < 30 ng/mL; this declined to 34.4% by week 26. The mean 25(OH)D level improved from 27.8 ng/mL at baseline to 33.6 ng/mL at week 26. Five patients (2.69% of the full analysis set) had 25(OH)D levels ≥ 50 ng/mL at 26 weeks. The highest 25(OH)D level, 64.3 ng/mL, was observed in a patient whose baseline level was 102.2 ng/mL. The majority (62.9%) of the patients had optimal 25(OH)D levels (30-50 ng/mL). ß-CTx levels were reduced by 57.7% after 26 weeks' treatment. No clinically significant cases of hypercalcemia which could be associated with hypervitaminosis D were identified during physical examination, in vital signs, or in laboratory results. Overall, 73 patients (36.9%) reported at least one adverse event (AE), with 13 (6.6%) reporting drug-related AEs. Four patients discontinued due to AEs, two of which were drug-related. Serious AEs were reported for four patients, of which one was considered drug-related. CONCLUSIONS: Oral alendronate sodium 70 mg plus vitamin D3 5600 IU once weekly had an acceptable safety profile in this study, and increased serum 25(OH)D and reduced ß-CTx levels in osteoporosis patients. This treatment improved 25(OH)D levels, without causing abnormally high levels, after 26 weeks' treatment. TRIAL REGISTRATION: Clinical Trials.gov NCT01437111 , Registered September 19, 2011.

Clinical characteristics associated with bone mineral density improvement after 1-year alendronate/vitamin d3 or calcitriol treatment: Exploratory results from a phase 3, randomized, controlled trial on postmenopausal osteoporotic women in China.

Baseline and on-treatment characteristics, including age, obesity, calcium intake, and bone turnover markers, may predict the bone mineral density (BMD) response in women with postmenopausal osteoporosis (PMO) to 1 to 2 years of antiresorptive therapy and/or vitamin D supplementation. This study aimed to explore clinical characteristics associated with 12-month BMD improvement in Chinese women with postmenopausal osteoporosis (PMO).In this post hoc analysis of a previous phase 3 multicenter, randomized controlled trial, Chinese PMO women who were treated with once weekly alendronate 70 mg/vitamin D3 5600 IU (ALN/D5600) or once daily calcitriol 0.25 mcg, and had measurements of 1-year lumbar spine BMD (LS-BMD) and on-treatment bone turnover markers (BTMs) were included in the analysis.In Chinese PMO patients on ALN/D5600, 1-year LS-BMD change was negatively correlated with age (ß = -0.00084, P < .01), dietary calcium (ß = -0.0017, P = .07), and procollagen type 1 N-terminal propeptide (P1NP) change at month 6 (ß = -0.000469, P = .0016), but positively with body mass index (BMI) (ß = 0.00128, P = .08); baseline P1NP above the median was associated with a significantly greater BMD percentage change at the lumbar spine (P = .02) and the total hip (P = .0001). In the calcitriol group, a significant 1-year LS-BMD increase was associated with BMI (ß = 0.0023, P = .02), baseline P1NP (ß = 0.00035, P = .0067), history of prior vertebral fracture(s) (ß = 0.034, P < .0001) and baseline serum 25(OH)D level (ß = -0.00083, P = .02).The presented findings from Chinese postmenopausal osteoporotic women suggested clinically meaningful baseline and on-treatment characteristics predicting BMD improvement after 1 year of ALN/D5600 treatment, which differed from calcitriol treatment with baseline identifiable associations. The study remained exploratory and further accumulation of evidence is needed.

One percent alendronate and aloe vera gel local host modulating agents in chronic periodontitis patients with class II furcation defects: A randomized, controlled clinical trial.

AIM: Alendronate (ALN) has antiresorptive and osteostimulative properties. The major component of aloe vera (AV) gel is acemannan, which has been found to have osteogenic properties. The aim of the present study is to explore the effectiveness of 1% ALN and AV gel as an adjunct to scaling and root planing (SRP) in chronic periodontitis patients with class II furcation defects. METHODS: Ninety volunteers were randomly assigned to three treatment groups: (a) SRP plus placebo gel; (b) SRP plus 1% ALN gel; and (c) SRP plus AV gel. Clinical and radiographic parameters were recorded at baseline and at 6 and 12 months. RESULTS: The mean probing depth reduction and relative horizontal clinical attachment level (CAL) and relative vertical CAL gains were greater in the ALN group than in the AV and placebo groups at 6 and 12 months. Furthermore, a significantly greater mean percentage of defect depth reduction (DDR) was found in the ALN group (38.09 ± 9.53, 44.86 ± 6.29) than the AV groups (11.94 ± 15.10, 14.59 ± 25.49) at 6 and 12 months, respectively. CONCLUSION: ALN showed significant improvement in all clinical parameters, along with greater DDR, compared to AV in the treatment of class II furcation defects as an adjunct to SRP.

ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis.

Purpose: In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods: Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results: Five hundred fifty-eight women from ACTIVE's ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan-Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Conclusions: Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures.

[Catgut implantation at stellate ganglion for postmenopausal osteoporosis].

OBJECTIVE: To compare the efficacy differences between catgut implantation at stellate ganglion combined with oral administration of alendronate sodium and oral administration of alendronate sodium alone on postmenopausal osteoporosis (PO). METHODS: Sixty patients of PO were randomly divided into an observation group and a control group, 30 cases in each one. The patients in the control group were treated with oral administration of alendronate sodium. Based on the treatment of control group, the patients in the observation group were treated with catgut implantation at stellate ganglion. The treatment was given once a week in the two groups; the consecution treatment of four weeks constituted one session, and totally six sessions were given. The changes of total syndrome score, bone mineral density of lumbar vertebra (L1 to L4) and femeral neck (FN) and estradiol were observed before and after treatment; the clinical efficacy was compared between the two groups. RESULTS: Compared before treatment, the total syndrome score, bone mineral density of lumbar vertebra (L1 to L4) and FN and estradiol were significantly improved after treatment (all P<0.05); which were more significant in the observation group (all P<0.05). Compared before treatment, the level of estradiol in the control group was not significantly changed after treatment (P>0.05), while that in the observation group was significantly changed after treatment (P<0.05). After treatment, the level of estradiol in the observation group was higher than that in the control group (P<0.05). The total effective rate was 93.3% (28/30) in the observation group, which was significantly higher than 83.3% (25/30) in the control group (P<0.05). CONCLUSION: Catgut implantation at stellate ganglion combined with oral administration of alendronate sodium are superior to oral administration of alendronate sodium alone for postmenopausal osteoporosis, which improve the clinical symptoms, regulate the hormone level and increase bone mineral density.

Osteoprotective Effect of Radix Scutellariae in Female Hindlimb-Suspended Sprague-Dawley Rats and the Osteogenic Differentiation Effect of Its Major Constituent.

A number of medicinal herbs have demonstrated therapeutic effects for the prevention and treatment of disuse-induced osteoporosis. As a common ingredient in proprietary traditional Chinese medicines, the anti-osteoporosis effects of Radix Scutellariae extract (RSE, 50 mg/kg/day) were evaluated in a hindlimb suspended rat model. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry, and the micro-architecture observed by MicroCT assay with bone biomechanical properties evaluated by a three-point bending test. To elucidate potential mechanisms, the osteogenic differentiation effect of baicalin as the most abundant ingredient in RSE was investigated in rat bone marrow derived mesenchymal stem cells (rBMSC). After drug administration for 42 days, tibia-BMD was significantly increased to 0.176 ± 0.007 and 0.183 ± 0.011 g/cm² and f-BMD was enhanced to 0.200 ± 0.017 and 0.207 ± 0.021 g/cm² for RSE and ALE treatment, respectively, whereas tibia-BMD and femur-BMD of the HLS group were 0.157 ± 0.009 and 0.176 ± 0.008 g/cm². Deterioration of bone trabecula microstructure was improved by RSE and ALE with increased morphological parameters such as bone volume fraction, trabecular thickness, and trabecular number, as well as connectivity density compared to the HLS group (p < 0.01). A three-point bending test suggested that bone mechanical strength was also enhanced by RSE and ALE treatments with increased maximum stress, young's modulus, maximum load, and stiffness compared to those of the HLS group (p < 0.05). Besides, serum TRACP levels were significantly suppressed by RSE and ALE treatments. Furthermore, in vitro studies demonstrated that baicalin significantly increased ALP activities and the formation of mineralized nodules in rBMSC. Conclusively, supplementation of RSE could significantly prevent weightlessness induced osteoporosis, which might attribute to the osteogenic differentiation enhancement effect of baicalin.

Osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) in an osteoporotic patient chronically treated with bisphosphonates.

The aim of the study is to report the rare association of two complications of long-term treatment of osteoporosis with bisphosphonates in the same Caucasian elderly patient. A female patient of Italian descent, age 87 years, consulted in February 2013. She had a history of osteoporosis and had taken alendronate weekly for 7 years (1999-2006). Due to low back pain, an orthopedist had indicated i.v. zoledronic acid, 5 mg/year for 3 years (2006-2008). She received occasional supplements of ergocalciferol. In 2009, she suffered a fall and sustained a subtrochanteric fracture of the left femur. She was operated on and recovered uneventfully. In 2012, she consulted a dentist due to loose teeth. She underwent the removal of a molar and was given a denture. She had discomfort when using the prosthesis, and developed an ulceration in the gum of the mandible, which exposed the bone and did not heal for 2 months. After radiologic studies, the diagnosis was osteonecrosis of the jaw. She improved after surgical debridement and local and systemic antibiotics. In early 2013, laboratory tests were normal except for a slight elevation of serum PTH and CTX-I. Calcitriol 0.25 mcg/day was prescribed; after 3 months serum calcium, phosphate, PTH, and CTX-I showed no variation. Two years later, she experienced acute low back pain after a fall; MRI showed recent crushing of D12, and chronic deformities of D11 and L1. Bone densitometry of her right hip (DXA) showed a T-score of -2.3 at the femoral neck. An X-ray film of the right femur showed diffuse thickening of both cortices. She was treated with nasal calcitonin and analgesics. After the back pain subsided, she was treated with s.c. denosumab. Although the association of ONJ and AFF was known in cancer patients treated with high doses of bisphosphonates, it is very rare in patients with osteoporosis receiving these drugs at usual doses. Only three cases have been reported, all in oriental women. This appears to be the first reported case in a Caucasian woman.

Effects of raloxifene and alendronate on non-enzymatic collagen cross-links and bone strength in ovariectomized rabbits in sequential treatments after daily human parathyroid hormone (1-34) administration.

This study investigated the effects of raloxifene and alendronate to follow parathyroid hormone (PTH) on bone collagen and biomechanical properties in ovariectomized rabbits. Sequential treatments of raloxifene and alendronate after hPTH(1-34) treatment improved biomechanical properties with and without bone collagen improvement, respectively. INTRODUCTION: The standard sequential treatment to follow human parathyroid hormone (hPTH) (1-34) therapy for osteoporosis has yet to be determined. The objective of this study was to compare the effects of raloxifene and alendronate treatments to follow daily hPTH(1-34) treatment on non-enzymatic collagen cross-links, bone mass, and bone strength in ovariectomized (OVX) rabbits. METHODS: From 3 months after ovariectomy, seven month-old female New Zealand white rabbits were given either vehicle or hPTH(1-34) (8 µg/kg/day), once daily for 5 months. After hPTH(1-34) treatment, the hPTH(1-34)-treated animals were divided into two groups, and given raloxifene (10 mg/kg, daily) orally or alendronate (100 µg/kg, twice weekly) subcutaneously for 5 months. We evaluated bone mineral density (BMD), bone structural parameters, advanced glycation end product (AGE) content in collagen, and bone mechanical parameters including intrinsic parameters in the femur. RESULTS: Raloxifene (hPTH/RLX) and alendronate (hPTH/ALN) to follow hPTH(1-34) increased cortical thickness, maximum load, and maximum stress and decreased endocortical surface in the diaphysis, in addition to increasing total BMD in the distal metaphysis. Decreased trabecular AGE, pentosidine, and homocysteine contents and increased toughness and breaking energy were noted with hPTH/RLX treatment only. With hPTH/ALN treatment, no effects on non-enzymatic collagen cross-link AGEs were noted although increases in stiffness and elastic modulus were observed. CONCLUSION: These results suggest that sequential treatments with hPTH(1-34) and antiresorptive drugs (raloxifene and alendronate) have a beneficial effect on bone mass and biomechanical properties in OVX rabbits.

Metabolite Profiling Reveals the Effect of Dietary Rubus coreanus Vinegar on Ovariectomy-Induced Osteoporosis in a Rat Model.

The study was aimed at exploring the curative effects of Rubus coreanus (RC) vinegar against postmenopausal osteoporosis by using ovariectomized rats as a model. The investigations were performed in five groups: sham, ovariectomized (OVX) rats without treatment, low-dose RC vinegar (LRV)-treated OVX rats, high-dose RC vinegar (HRV)-treated OVX rats and alendronate (ALEN)-treated OVX rats. The efficacy of RC vinegar was evaluated using physical, biochemical, histological and metabolomic parameters. Compared to the OVX rats, the LRV and HRV groups showed positive effects on the aforementioned parameters, indicating estrogen regulation. Plasma metabolome analysis of the groups using gas chromatography-time of flight mass spectrometry (GC-TOF-MS) and ultra-performance liquid chromatography quadrupole-TOF-MS (UPLC-Q-TOF-MS) with multivariate analysis revealed 19 and 16 metabolites, respectively. Notably, the levels of butyric acid, phenylalanine, glucose, tryptophan and some lysophosphatidylcholines were marginally increased in RC vinegar-treated groups compared to OVX. However, the pattern of metabolite levels in RC vinegar-treated groups was found similar to ALEN, but differed significantly from that in sham group. The results highlight the prophylactic and curative potential of dietary vinegar against postmenopausal osteoporosis. RC vinegar could be an effective natural alternative for the prevention of postmenopausal osteoporosis.

Response of bone turnover markers to three oral bisphosphonate therapies in postmenopausal osteoporosis: the TRIO study.

UNLABELLED: We used bone turnover markers to identify women who responded to bisphosphonate treatment for osteoporosis. Response was more likely with alendronate and ibandronate than risedronate. There was a greater decrease in bone markers if baseline bone turnover markers were higher and if the patient took more than 80 % of her medication. INTRODUCTION: Biochemical response to bisphosphonate therapy can be assessed using either a decrease in bone turnover marker beyond the least significant change (LSC) or a reduction to within a reference interval (RI). We compared the performance of these target responses and determined whether response was related to the type of bisphosphonate, compliance and baseline bone turnover markers. METHODS: Biochemical responses to three oral bisphosphonates were assessed in an open, controlled trial comprising 172 postmenopausal osteoporotic women (age 53-84 years), randomised to alendronate, ibandronate or risedronate, plus calcium and vitamin D supplementation for 2 years. The LSC for each marker was derived within the study population, whereas RIs were obtained from a control group of healthy premenopausal women (age 35-40 years). RESULTS: Over 70 % of women achieved a target response for serum CTX and PINP, irrespective of the approach used. The percentage decrease at 12 weeks was greater for women with baseline PINP above the RI -63 % (difference 13 %, 95 % CI 0 to 27.1, P = 0.049) and good compliance -67 % (difference 15.9 %, 95 % CI 6.3 to 25.5, P = 0.001). Responders had a greater increase in spine bone density compared to nonresponders; for example 6.2 vs. 2.3 % (difference 3.9 %, 95 % CI 1.6 to 6.3, P = 0.0011) for PINP LSC. The magnitude of change in bone markers was greater with ibandronate and alendronate than risedronate. CONCLUSIONS: Both approaches to response identified similar proportions of women as responders. Nonresponders had smaller increases in BMD, and we suggest that biochemical assessment of response is a useful tool for the management of women with postmenopausal osteoporosis.

Analysis of bone metabolism during early stage and clinical benefits of early intervention with alendronate in patients with systemic rheumatic diseases treated with high-dose glucocorticoid: Early DIagnosis and Treatment of OsteopoRosis in Japan (EDITOR-J) study.

We conducted a prospective multicenter study to assess early changes in the dynamics of bone metabolism in patients with systemic connective tissue diseases following commencement of high-dose glucocorticoid therapy and the benefits of early treatment with bisphosphonate and vitamin D analogue. The subjects of this randomized controlled trial were 106 female patients with systemic connective tissue diseases treated for the first time with glucocorticoids at doses equivalent to prednisolone ≥20 mg/day (age ≥ 18 years). One week after initiation of glucocorticoid therapy, patients were randomly assigned to treatment with alfacalcidol at 1 µg/day (n = 33), alendronate 35 mg/week (n = 37), and alfacalcidol plus alendronate (n = 36). The primary endpoints were changes in lumbar spine bone density at 6 months of treatment and the frequency of bone fracture at 12 months. Commencement of glucocorticoid therapy was associated with a rapid and marked bone resorption within 1 week. The combination of alfacalcidol and alendronate administered after the first week of glucocorticoid therapy halted the pathological processes affecting bone metabolism, increased bone density, and reduced the incidence of bone fracture over a period of 12 months. Taken together, the use of the combination of alfacalcidol and alendronate improved bone metabolism, increased bone density, and significantly reduced the incidence of bone fracture during 1-year high-dose glucocorticoid therapy.

Vitamin D, osteoprotegerin/receptor activator of nuclear factor-kappaB ligand (OPG/RANKL) and inflammation with alendronate treatment in HIV-infected patients with reduced bone mineral density.

OBJECTIVES: The aim of the study was to determine the effect of alendronate (ALN) on inflammatory markers and osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL), and to explore the associations of baseline systemic inflammation and vitamin D status on the bone mineral density (BMD) response to ALN. METHODS: Eighty-two HIV-positive patients with lumbar spine T-score ≤ -1.5 were randomized to ALN 70 mg weekly or placebo for 48 weeks; all received calcium carbonate 500 mg/vitamin D3 200 IU twice daily. Serum C-telopeptide (CTx) and BMD were assessed at baseline and week 48. Stored plasma samples in 70 subjects were assayed for levels of 25-hydroxyvitamin D (25(OH)D), OPG, RANKL, interleukin (IL)-6 and soluble receptors for tumour necrosis factor (TNF)-α 1 and 2 (sTNFR 1 and 2). RESULTS: ALN increased BMD more than placebo at both the lumbar spine (difference ALN - placebo 2.64%; P = 0.011) and the total hip (difference 2.27%; P = 0.016). No within- or between-arm differences in OPG, RANKL or inflammatory markers were observed over 48 weeks. High baseline CTx and sTNFR2 were associated with a more robust BMD response to ALN over 48 weeks at the lumbar spine [difference 5.66%; 95% confidence interval (CI) 3.50, 7.82; P < 0.0001] and total hip (difference 4.99%; 95% CI 2.40, 7.57; P = 0.0002), respectively. Baseline 25(OH)D < 32 ng/mL was associated with larger increases in total hip BMD over 48 weeks, independent of ALN treatment (P = 0.014). CONCLUSIONS: Among HIV-positive patients, higher baseline bone resorption and TNF-α activity were associated with an increased BMD response to ALN. The greater BMD response in those with lower vitamin D reinforces the importance of vitamin D supplementation with bisphosphonate treatment.