Epimedium-derived phytoestrogen exert beneficial effect on preventing steroid-associated osteonecrosis in rabbits with inhibition of both thrombosis and lipid-deposition

OBJECTIVES: This study tested the effect of Epimedium-derived phytoestrogen (PE) on preventing steroid-associated osteonecrosis (ON) in rabbit model. METHODS: Thirty 28-week-old male New-Zealand white rabbits were divided into control group (CON; n=14) and PE group (PE; n=16; 5 mg/kg body weight/day) after receiving an established inductive protocol for inducing steroid-associated ON. Before and after inductive protocol, Dynamic-MRI was employed on bilateral femora for local intra-osseous perfusion, blood samples were examined for coagulation, fibrinolysis and lipid-transportation, and marrow samples were quantified for adipogenesis-gene mRNA expression. Six weeks later, bilateral femora were dissected for Micro-CT-based micro-angiography, and then ON lesion, intravascular thrombosis and extravascular fat-cell-size were examined histopathologically. RESULTS: The incidence of ON in the PE group (31%) was significantly lower than that in the CON group (93%). Compared to the CON group, local intra-osseous perfusion was maintained in the PE group. Blocked trunk vessels were seldom found in micro-angiography of the PE-treated rabbits. Thrombosis incidence and fat-cell-size were both significantly lower in the PE group than those in the CON group. During the early period after induction, indicator of coagulation, fibrinolysis, lipid-transportation and adipogenesis-gene expression were found with significantly changing pattern in the PE group compared to the CON group. CONCLUSION: PE was able to exert beneficial effect on preventing steroid-associated ON in rabbits with inhibition of both thrombosis and lipid deposition.     

Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study.

The natural isoflavone phytoestrogen genistein has been shown to stimulate osteoblastic bone formation, inhibit osteoclastic bone resorption, and prevent bone loss in ovariectomized rats. However, no controlled clinical trial has been performed so far to evaluate the effects of the phytoestrogen on bone loss in postmenopausal women. We performed a randomized double-blind placebo-controlled study to evaluate and compare with hormone-replacement therapy (HRT) the effect of the phytoestrogen genistein on bone metabolism and bone mineral density (BMD) in postmenopausal women. Participants were 90 healthy ambulatory women who were 47-57 years of age, with a BMD at the femoral neck of <0.795 g/cm2. After a 4-week stabilization on a standard fat-reduced diet, participants of the study were randomly assigned to receive continuous HRT for 1 year (n = 30; 1 mg of 17beta-estradiol [E2] combined with 0.5 mg of norethisterone acetate), the phytoestrogen genistein (n = 30; 54 mg/day), or placebo (n = 30). Urinary excretion of pyridinoline (PYR) and deoxypyridinoline (DPYR) was not significantly modified by placebo administration either at 6 months or at 12 months. Genistein treatment significantly reduced the excretion of pyridinium cross-links at 6 months (PYR = -54 +/- 10%; DPYR = -55 +/- 13%; p < 0.001) and 12 months (PYR = -42 +/- 12%; DPYR = -44 +/- 16%; p < 0.001). A similar and not statistically different decrease in excretion of pyridinium cross-links was also observed in the postmenopausal women randomized to receive HRT. Placebo administration did not change the serum levels of the bone-specific ALP (B-ALP) and osteocalcin (bone Gla protein [BGP]). In contrast, administration of genistein markedly increased serum B-ALP and BGP either at 6 months (B-ALP = 23 +/- 4%; BGP = 29 +/- 11%; p < 0.005) or at 12 months (B-ALP = 25 +/- 7%; BGP = 37 +/- 16%; p < 0.05). Postmenopausal women treated with HRT had, in contrast, decreased serum B-ALP and BGP levels either at 6 months (B-ALP = -17 +/- 6%; BGP = -20 +/- 9%; p < 0.001) or 12 months (B-ALP = -20 +/- 5%; BGP = -22 +/- 10%; p < 0.001). Furthermore, at the end of the experimental period, genistein and HRT significantly increased BMD in the femur (femoral neck: genistein = 3.6 +/- 3%, HRT = 2.4 +/- 2%, placebo = -0.65 +/- 0.1%, and p < 0.001) and lumbar spine (genistein = 3 +/- 2%, HRT = 3.8 +/- 2.7%, placebo = -1.6 +/- 0.3%, and p < 0.001). This study confirms the genistein-positive effects on bone loss already observed in the experimental models of osteoporosis and indicates that the phytoestrogen reduces bone resorption and increases bone formation in postmenopausal women.     

The effect of soy isoflavone on bone mineral density in postmenopausal Taiwanese women with bone loss: a 2-year randomized double-blind placebo-controlled study

Summary  

The treatment of 300-mg/day isoflavones (aglycone equivalents) (172.5 mg genistein + 127.5 mg daidzein) for 2 years failed to prevent lumbar spine and total proximal femur bone mineral density (BMD) from declining as compared with the placebo group in a randomized, double-blind, two-arm designed study enrolling 431 postmenopausal women 45–65 years old.     

Effect of green tea and Tai Chi on bone health in postmenopausal osteopenic women: a 6-month randomized placebo-controlled trial

Summary  

Postmenopausal women with osteopenia received green tea polyphenols (GTP) supplement and/or Tai Chi exercise for 6 months. Bone turnover biomarkers, calcium metabolism, and muscle strength were measured. This study showed that GTP supplementation and Tai Chi exercise increased bone formation biomarkers and improved bone turnover rate. Tai Chi exercise increased serum parathyroid hormone. GTP supplementation, Tai Chi exercise, and the combination of the two all improved muscle strength in postmenopausal women with osteopenia.     

The effect of weight training on bone mineral density and bone turnover in postmenopausal breast cancer survivors with bone loss: a 24-month randomized controlled trial

Summary  

This study examined whether 24 months of weight training exercises enhanced the effectiveness of risedronate, calcium, and vitamin D in maintaining or improving bone mineral density (BMD) in 223 postmenopausal breast cancer survivors. Subjects who were ≥50% adherent to exercise had no improvement in BMD but were less likely to lose BMD.     

Dexamethasone in preventing post-dural puncture headache: a randomized, double-blind, placebo-controlled trial

Spinal anesthesia is major complication is Post-Dural Puncture Headache (PDPH) which is an intense and debilitating event. We decided to assess if intravenous administration of dexamethasone can decrease the incidence and/or intensity of this kind of headache. For this purpose 178 patients, who were supposed to undergo lower extremity orthopedic surgery, were enrolled in the study . Before spinal anesthesia was initiated, the first group (DXM-group) received 2 mL intravenous (i.v) dexamethasone whereas the second group (PCB-group) received 2 mL i.v. normal saline. After termination of surgery, a 7 days follow-up started to observe the possible occurrence and intensity of PDPH. There was no statistically significant difference between DMX and PCB groups regarding the incidence of PDPH. However, the intensity of headache differed between the two groups being less severe if IV dexamethasone had been given prophylactically. Dexamethasone can be used to decrease the severity of PDPH in patients who receive spinal anesthesia.     

The effect of solifenacin on postvoid dribbling in women: results of a randomized,double-blind placebo-controlled trial

Introduction and hypothesis

To determine the effectiveness of the muscarinic receptor antagonist solifenacin (VESIcare®) in the treatment of postvoid dribbling (PVD).

Methods

We carried out a multicenter, 12-week, double-blind, randomized, placebo-controlled, parallel design study. Between 2012 and 2015, a total of 118 women (age 18–89 years) with PVD at least twice/weekly, were randomized to receive solifenacin (5 mg; n?=?58) or placebo (n?=?60) once daily. The primary outcome was the percentage reduction in PVD episodes. Secondary outcomes included the percentage of patients with ≥50% reduction in PVD episodes and changes in quality of life.

Results

There were no differences in either the primary or secondary outcome variables. Subgroup analysis, based on those with more severe disease (>10 PVD episodes/week), showed a greater and significant percentage reduction in the frequency of PVD episodes per day (60.3% vs 32.1%; p =?0.035) and a higher percentage of patients showing ≥50% reduction in the frequency of PVD episodes with solifenacin (68.1% vs 45.8%; p =?0.0476). A significant solifenacin effect occurred at week 2 and continued through week 12 for the subgroup. For solifenacin, PVD reduction was the same for the entire cohort and subgroup, whereas for placebo, it was 10% lower in the subgroup, declining from 42% to 32%.

Conclusion

There were no differences in PVD outcomes between the solifenacin and placebo groups. Solifenacin may play a role in treating women with the most severe symptoms. Because of the powerful placebo response seen in this study, behavior-based interventions may be useful for treating PVD.

     

A randomized,double-masked,placebo-controlled trial of chlorthalidone and bone loss in elderly women

Employing a double-masked, prospective design, bone loss at three skeletal sites has been monitored among 113 postmenopausal women participating in a placebo-controlled trial of the thiazide-like diuretic chlorthalidone for treatment of systolic hypertension. The mean duration of chlorthalidone use was 2.6 years, at doses of 12.5–25 mg/day. Compared with placebo use, chlorthalidone use was associated with significant reductions in annual bone loss rates. Non-use of chlorthalidone was associated with bone loss at the calcaneus (–0.56% per year) and the proximal radius (–0.91% per year); borderline bone gain was observed at the distal radius (+0.39%). In contrast, chlorthalidone use was associated with bone gain at the calcaneus (+0.44% per year) and the distal radius (+1.51% per year); proximal radius bone loss was significantly reduced to –0.32% per year. The average increment for three appendicular sites was +0.9% per year. These data support a causal relationship between chlorthalidone use and reduced bone loss.     

Effect of pamidronate in preventing local bone loss after total hip arthroplasty: a randomized, double-blind, controlled trial.

Acute periprosthetic bone loss occurs after total hip arthroplasty. Bone loss undermines the support of the implant and may contribute to prosthetic failure. At present, there is no established prophylaxis for this process. We studied the effect of a single-dose infusion of 90 mg of pamidronate on early periprosthetic bone mineral density (BMD), biochemical markers of bone turnover, radiological, and clinical outcome in a 26-week, prospective, randomized, double-blinded study of 47 men and women undergoing total hip arthroplasty. Pamidronate therapy led to a significant reduction in bone loss compared with placebo for both the proximal femur and the pelvis (repeated measures analysis of variance [ANOVA]); p = 0.001 and p = 0.01, respectively). Pamidronate therapy was associated with suppression of all biochemical markers of bone turnover compared with placebo (repeated measures ANOVA; p < 0.05 for all comparisons), with the exception of urinary free deoxypyridinoline. Pamidronate did not interfere with the clinical improvement in symptoms after total hip arthroplasty, or radiological outcome, and was not associated with an increase in adverse events. This study provides clinical data on the efficacy and safety of bisphosphonates for the prevention of bone loss after total hip arthroplasty and supports the establishment of larger-scale clinical trials to determine the long-term clinical efficacy of this intervention using implant failure as the primary endpoint.     

Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial.

We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6-month double-blind, placebo-controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline. INTRODUCTION: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide [rhPTH(1-34)] monotherapy with combination teriparatide and raloxifene therapy. MATERIALS AND METHODS: A 6-month randomized, double-blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis. RESULTS: Bone formation (N-terminal propeptide of type 1 collagen [PINP]) increased similarly in both treatment groups. However, the increase in bone resorption (serum C-terminal telopeptide of type I collagen [CTx]) in the combination group was significantly smaller than in the teriparatide-alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 +/- 0.67% from baseline in the teriparatide-alone group. In the combination group, lumbar spine (6.19 +/- 0.65%), femoral neck (2.23 +/- 0.64%), and total hip (2.31 +/- 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide-alone group (p = 0.04). In the teriparatide-alone group, mean serum calcium levels increased from baseline to endpoint (0.30 +/- 0.06 mg/dl, p < 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (-0.20 +/- 0.06 mg/dl, p < 0.001) from baseline to endpoint. Changes in serum calcium (p < 0.001) and phosphate (p < 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone. CONCLUSIONS: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.     

Growth hormone increases bone mineral content in postmenopausal osteoporosis: a randomized placebo-controlled trial.

Eighty osteoporotic, postmenopausal women, 50-70 years of age, with ongoing estrogen therapy (HRT), were randomized to recombinant human growth hormone (GH), 1.0 U or 2.5 U/day, subcutaneous, versus placebo. This study was double-blinded and lasted for 18 months. The placebo group then stopped the injections, but both GH groups continued for a total of 3 years with GH and followed for 5 years. Calcium (750 mg) and vitamin D (400 U) were given to all patients. Bone mineral density and bone mineral content were measured with DXA. At 18 months, when the double-blind phase was terminated, total body bone mineral content was highest in the GH 2.5 U group (p = 0.04 vs. placebo). At 3 years, when GH was discontinued, total body and femoral neck bone mineral content had increased in both GH-treated groups (NS between groups). At 4-year follow-up, total body and lumbar spine bone mineral content increased 5% and 14%, respectively, for GH 2.5 U (p = 0.01 and p = 0.0006 vs. placebo). Femoral neck bone mineral density increased 5% and bone mineral content 13% for GH 2.5 U (p = 0.01 vs. GH 1.0 U). At 5-year follow-up, no differences in bone mineral density or bone mineral content were seen between groups. Bone markers showed increased turnover. Three fractures occurred in the GH 1.0 U group. No subjects dropped out. Side effects were rare. In conclusion, bone mineral content increased to 14% with GH treatment on top of HRT and calcium/vitamin D in postmenopausal women with osteoporosis. There seems to be a delayed, extended, and dose-dependent effect of GH on bone. Thus, GH could be used as an anabolic agent in osteoporosis.     

Risedronate for prevention of bone mineral density loss in patients receiving high-dose glucocorticoids: a randomized double-blind placebo-controlled trial

Summary This 6-month randomized double-blind placebo-controlled trial shows that risedronate is well tolerated and effective in improving lumbar spine BMD and reducing loss of BMD at the hips in patients receiving high-dose prednisolone. Introduction Bisphosphonates have proven benefits in patients receiving chronic low-dose glucocorticoids. However, whether they are effective in preventing bone mineral density (BMD) loss during periods of high-dose glucocorticoid treatment is unclear. The objective of this paper is to study the efficacy of risedronate in preventing bone mineral density (BMD) loss in users of high-dose glucocorticoids. Methods Adult patients with medical diseases treated with high-dose prednisolone (>0.5 mg/kg/day) were randomized to receive risedronate (5 mg/day) or placebo for 6 months in a double-blind manner, along with elemental calcium (1,000 mg/day). Changes in BMD were studied. Results One hundred and twenty patients were recruited (82 women, age 42.8 ± 14.3 years, 63% corticosteroid-naive, 30% women postmenopausal) and 103 completed the study. Baseline clinical characteristics and BMD were similar in the risedronate and placebo groups. At 6 months, a significant gain in spinal BMD was observed in the risedronate group (+0.7 ± 0.3%; p = 0.03) but a drop was detected in the placebo group (−0.7 ± 0.4%; p = 0.12). After adjustment for baseline BMD, age, gender, body mass index and cumulative prednisolone dosages, the inter-group difference in spinal BMD remained significant (1.4%; p = 0.006). Both groups had a significant drop in hip BMD, but the magnitude was greater in the placebo arm (−0.8 ± 0.4% in risedronate versus −1.3 ± 0.5% the in placebo). No new fractures developed. Subgroup analysis of corticosteroid-naive patients yielded similar results. Upper gastrointestinal adverse events were numerically more frequent in the risedronate group. Conclusions Risedronate improves spinal BMD in users of high-dose glucocorticoids.     

Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial.

NO regulates bone remodeling in cellular and animal models. We examined the effect of administering ISMO, a NO donor, on bone turnover in 144 postmenopausal women. After 3 months, women randomized to ISMO had a greater decrease in bone resorption and a greater increase in bone formation compared with placebo. NO donors may prevent postmenopausal bone loss. INTRODUCTION: NO both stimulates bone formation and inhibits bone resorption in vitro. NO donors (nitrates) are inexpensive and widely available, but their value for postmenopausal osteoporosis has never been evaluated in a randomized trial. MATERIALS AND METHODS: We randomly assigned 144 healthy postmenopausal women with a hip BMD T score between 0 and -2.5 to 5 or 20 mg/day of isosorbide mononitrate (ISMO) or placebo for 12 weeks. We measured urine N-telopeptide (NTx), a marker of bone resorption, and serum bone-specific alkaline phosphatase (BSALP), a marker of bone formation. Markers were measured immediately before randomization and after 12 weeks of treatment. We calculated the percent change in NTx and BSALP for each of the treatment groups (placebo, 5 mg ISMO, and 20 mg ISMO). Our primary outcome was the percent change in NTx and BSALP in the 5- and 20-mg ISMO groups compared with placebo. RESULTS AND CONCLUSIONS: Compared with women randomized to placebo, women randomized to 20 mg of ISMO had a 45.4% decrease in NTx (95% CI, 25.8-64.9) and a 23.3% increase (95% CI, 8.9-37.8) in BSALP. Women randomized to 5 mg of ISMO had a 36.3% decrease in NTx (95% CI, 14.8-57.8) and a 15.9% increase in BSALP (95% CI, 1.1-30.7). ISMO decreases bone resorption and increases bone formation. These findings suggest that nitrates may be useful for the prevention of postmenopausal osteoporosis.     

Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial

Summary  

Vitamin K2 may preserve bone strength and reduce fracture risk. In this randomised double-blind placebo-controlled trial among healthy postmenopausal Norwegian women, 1 year supplementation of vitamin K2 in the form of Natto capsules had no effect on bone loss rates.     

Effects of a combined alendronate and calcitriol agent (Maxmarvil®) on bone metabolism in Korean postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study

Introduction A randomized, double-blind, prospective, 24-week clinical trial was performed to evaluate the effects of a combinative agent, Maxmarvil, of calcitriol (0.5 μg) and alendronate (5 mg) on bone metabolism in postmenopausal women.Methods A total of 217 postmenopausal women with osteoporosis were enrolled; 199 patients were randomly assigned to one of two treatment groups (Maxmarvil group or alfacalcidol group). None of the patients were vitamin-D-deficient, as assessed by serum 25-hydroxyvitamin D (25(OH)D), nor had they received any drugs affecting bone metabolism before enrollment. Bone mineral densities (BMD) of L1–L4 and the femur were measured by dual-energy X-ray absorptiometry (DXA) at the initial assessment and after 6 months of treatment. Serum biochemical assays, including serum calcium, 24-h urinary calcium excretion, and bone turnover markers (both bone-specific alkaline phosphatase [bsALP] and urine N-telopeptide [NTx]), were performed at the baseline and after 3 and 6 months of treatment.Results In the Maxmarvil group, the BMD of the lumbar spine increased up to 2.42±0.5% from the baseline after 6 months (p<0.05). On the other hand, the change in BMD in the alfacalcidol group was 0.28±0.5% after 6 months. There was no significant difference in femoral BMD between the two groups. The levels of bsALP and NTx were significantly lower in the Maxmarvil group than in the alfacalcidol group (−22.04±3.9% vs. −11.42±2.8% [p<0.05] and −25.46±5.2% vs. 1.24±6.2% [p<0.001], respectively). Interestingly, there was a significantly smaller amount of 24-h urinary calcium in the Maxmarvil group (p<0.05).Conclusions Our study demonstrates that a combination of calcitriol and alendronate is quite effective in preventing bone loss, with the advantage of lesser hypercalciuric effect of calcitriol in the postmenopausal osteoporotic women.