Comparable Effects of Alendronate and Strontium Ranelate on Femur in Ovariectomized Rats

This study compared the effects of alendronate (ALN) and strontium ranelate (SR) on bone mineral density (BMD), bone histomorphometry, and biomechanics in ovariectomized (OVX) rats. We randomly assigned 48 3-month-old female Sprague–Dawley rats to four groups: sham, OVX, ALN, and SR. Rats in the OVX, ALN, and SR groups received bilateral OVX. Rats in the ALN and SR groups were orally administrated ALN (7 mg/kg/week) and SR (500 mg/kg/day). Rats in the sham and OVX groups were treated with saline. All treatments continued for 12 weeks. Femoral BMD examination, distal femoral bone histomorphometry analysis, and biomechanical tests at the femoral diaphysis and metaphysis were performed to evaluate the effects of treatments in OVX rats. Results showed that both ALN and SR significantly increased femoral BMD (total femur, diaphyseal BMD, and distal metaphyseal BMD), distal femoral bone histomorphometric parameters (BV/TV, Tb.N, and Tb.Th), and femoral biomechanical parameters (maximum load, failure load, stiffness) compared with the OVX group (P < 0.05). No differences were found between ALN and SR in increasing femoral BMD, distal femoral bone histomorphometric parameters (BV/TV, Tb.N, and Tb.Th), and femoral diaphysis biomechanical parameters (maximum load, failure load, stiffness) (P > 0.05). The SR group was inferior to the ALN group in femoral metaphysis biomechanical parameters (P < 0.05). In conclusion, ALN (7 mg/kg/week) and SR (500 mg/kg/day) have similar effects by increasing BMD, distal femoral bone histomorphometric parameters, and femoral metaphysis biomechanical properties. Although ALN has greater effects than SR on distal femoral metaphysis biomechanical properties, in general, ALN and SR have comparable effects on the femur in OVX rats.     

Effects of alendronate on lumbar intervertebral disc degeneration with bone loss in ovariectomized rats

Background Context

Osteoporosis adversely affects disc degeneration cascades, and prophylactic alendronate (ALN) helps delay intervertebral disc degeneration (IDD) in ovariectomized (OVX) rats. However, there remains no information regarding whether ALN affects IDD with bone loss.

Osseointegration of porous titanium implants with and without electrochemically deposited DCPD coating in an ovine model

Background

Alendronate (ALN) is the most common form of bisphosphonates used for the treatment of osteoporosis. Osteoprotegerin (OPG) has also been shown to reduce osteoporotic changes in both humans and experimental animals after systemic administration. The aim of this current study was to test if the anti-resorption effects of ALN may be enhanced when used in combination with OPG.

Objectives

To investigate the effects of ALN, OPG or combined on bone mass and bone mechanical properties in ovariectomized (OVX) rats.

Methods

OVX rats were treated with ALN, OPG-Fc, or OPG-Fc and ALN. Biochemical markers, trabecular bone mass, biomechanics, histomorphometry and RANKL expression in the bone tissues were examined following the treatments.

Results

The treatment of ALN, OPG-Fc and ALN+OPG-Fc all prevented bone loss in the OVX-rats, there was no statistical difference among the three treatment groups in terms of vertebrae BMD, mineralizing surfaces, mineral apposition rate, BFR/BS. The ALN+OPG-Fc treatment group had significantly increased the mechanical strength of lumber vertebral bodies and femoral shafts when compared to the ALN and OPG-Fc treatment groups. The RANKL protein expression in the vertebral bones was significantly decreased in the ALN and ALN+OPG-Fc treatment groups, suggesting the combined use of OPG-Fc and ALN might have amplified inhibition of bone resorption through inhibiting RANKL-dependent osteoclastogenesis.

Conclusion

The combined use of OPG-Fc and ALN may be a new treatment strategy for reversing bone loss and restoring bone quality in osteoprotic disorders.     

Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial

Summary

Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength.

Introduction

To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength.

Methods

In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated.

Results

Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p?<?0.01) and QCT (5.7%, p?<?0.0001). Between-treatment differences were significant for trabecular spine (p?=?0.0017) [non-parametric test], trabecular trochanter (10.7%, p?<?0.0001), total hip (10.8%, p?<?0.0001), and compressive strength indices at femoral neck (8.6%, p?=?0.0001), and trochanter (14.1%, p?<?0.0001).

Conclusions

Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength.     

Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice

Summary

This study evaluates the effect of hydrolyzed collagen (HC) on bone health of ovariectomized mice (OVX) at different ages. Twenty-six weeks after the OVX procedure, HC ingestion was still able to improve significantly bone mineral density (BMD) and some femur biomechanical parameters. Moreover, HC ingestion for 1?month before surgery prevented BMD decrease.

Introduction

HC can play an important role in preserving BMD before osteoporosis appears. The aim of this study was to evaluate the effect of HC on bone health of ovariectomized mice at different ages.

Methods

Female C3H mice were either OVX at 3 or 6?months and fed for 6?months (first experiment) or 3?months (second experiment) with diet including 0, 10, or 25?g/kg of HC. In the second experiment, one group received HC 1?month before surgery, and two groups received the supplementation immediately after surgery, one fed ad libitum and the other by gavage. Mice treated with raloxifene were used as a positive control. BMD, femur intrinsic and extrinsic biomechanical properties, and type I collagen C-terminal telopeptide were measured after 12 and 26?weeks. Food intake and spontaneous physical activity were also recorded.

Results

The OVX procedure increased body weight, while food intake decreased, thus suggesting that resting metabolism was decreased. Ingestion of 25?g/kg of HC for 3 or 6?months reduced bone loss significantly in, respectively, 3- and 6-month-old OVX mice. The lowest HC concentration was less efficient. HC ingestion for 3?months is as efficient as raloxifene to protect 3-month-old OVX mice from bone loss. Our results also demonstrated that HC ingestion before surgery prevented the BMD decreases.

Conclusion

This study confirms that dietary collagen reduces bone loss in OVX mice by increasing the diameter of the cortical areas of femurs and can have a preventive effect.     

Zoledronic acid in combination with alfacalcidol has additive effects on trabecular microarchitecture and mechanical properties in osteopenic ovariectomized rats

Background

We conducted the present study to investigate the therapeutic effects of the antiresorptive agent zoledronic acid (ZOL), alone and in combination with alfacalcidol (ALF), in a rat model of postmenopausal osteoporosis.

Methods

Female Wistar rats were ovariectomized (OVX) or sham-operated at 3 months of age. Twelve weeks post surgery, rats were randomized into six groups: (1) sham + vehicle, (2) OVX + vehicle, (3) OVX + ZOL (100 μg/kg, i.v. single dose), (4) OVX + ZOL (50 μg/kg, i.v. single dose), (5) OVX + ALF (0.5 μg/kg, oral gauge daily) and (6) OVX + ZOL (50 μg/kg, i.v. single dose) + ALF (0.5 μg/kg, oral gauge daily) for 12 weeks. After treatment, we evaluated the mechanical properties of the lumbar vertebra and femoral mid-shaft. Femurs were also tested for bone density, porosity and trabecular micro-architecture. Biochemical markers in serum and urine were also determined.

Results

With respect to improvement in the mechanical strength of the lumbar spine and the femoral mid-shaft, the combination treatment of ZOL and ALF was more effective than each administered as a monotherapy. Moreover, combination therapy using ZOL and ALF preserved the trabecular micro-architecture and cortical bone porosity. Furthermore, the combination treatment of ZOL and ALF corrected the decrease in serum calcium and increase in serum alkaline phosphatase and the tartarate-resistant acid phosphatase level better than single-drug therapy using ZOL or ALF in OVX rats. In addition, the combination treatment of ZOL and ALF corrected the increase in urine calcium, phosphorous and creatinine levels better than single-drug therapy using ZOL or ALF in OVX rats.

Conclusions

These data suggest that the combination treatment of ZOL and ALF has a therapeutic advantage over each monotherapy for the treatment of osteoporosis.     

A synergistic bone sparing effect of curcumin and alendronate in ovariectomized rat

Background

The purpose of this study was to evaluate the therapeutic effects of combination therapy with curcumin and alendronate on bone remodeling after ovariectomy in rats.

Methods

Eighty female Sprague-Dawley rats underwent either a sham operation (the sham group) or bilateral ovariectomy (OVX). The ovariectomized animals were randomly distributed amongst four groups: untreated OVX group, curcumin-administered group, alendronate-administered group, and the combination therapy group. At 8 and 12?weeks after surgery, rats from each of the groups were euthanized. Serum biochemical markers of bone turnover, including osteocalcin and alkaline phosphatase (ALP), and the telopeptide fragment of type I collagen C-terminus (CTX) were analyzed. Bone histomorphometric parameters of the 4th lumbar vertebrae were determined by micro-computed tomography (CT). In addition, mechanical strength was determined by a three-point bending test.

Results

Serum biochemical markers of bone turnover in the experiment groups (curcumin administered group, alendronate administered group, and the combination therapy group) were significantly lower than in the untreated OVX group (p?<?0.05). The combination therapy group had lower ALP and CTX-1 concentrations at 12?weeks, which were statistically significant compared with the curcumin only and the alendronate only group (p?<?0.05). The combination therapy group had a significant increase in BMD at 8?weeks and Cr.BMD at 12?weeks compared with the curcumin-only group (p?=?0.005 and p?=?0.013, respectively). The three point bending test showed that the 4th lumbar vertebrae of the combination therapy group had a significantly greater maximal load value compared to that of the curcumin only and the alendronate only group (p?<?0.05).

Conclusions

The present study demonstrated that combination therapy with a high dose of curcumin and a standard dose of alendronate has therapeutic advantages over curcumin or alendronate monotherapy, in terms of the synergistic antiresorptive effect on bone remodeling, and improving bone mechanical strength.     

Effects of zoledronic acid on bone mineral density in premenopausal women receiving neoadjuvant or adjuvant therapies for HR+ breast cancer: the ProBONE II study

Summary

The effects of bisphosphonates on altered bone turnover marker (BTM) levels associated with adjuvant endocrine or chemotherapy in early breast cancer have not been systematically investigated. In ProBONE II, zoledronic acid decreased these elevated BTM levels and increased bone mineral density (BMD) during adjuvant therapy, consistent with its antiresorptive effects.

Introduction

Adjuvant chemotherapy or endocrine therapy for early hormone receptor-positive breast cancer (HR⁺ BC) is associated with rapid BMD loss and altered BTM levels. Adjuvant bisphosphonate studies demonstrated BMD increases, but did not investigate BTM effects. The randomized, double-blind, ProBONE II study investigated the effect of adjuvant zoledronic acid (ZOL) on BMD and BTM in premenopausal women with early HR⁺ BC.

Methods

Seventy premenopausal women with early HR⁺ BC received adjuvant chemotherapy and/or endocrine therapy plus ZOL (4 mg IV every 3 months) or placebo for 24 months. Primary endpoint was change in lumbar spine BMD at 24 months versus baseline. Secondary endpoints included femoral neck and total femoral BMD changes, changes in BTM, and safety.

Results

Lumbar spine BMD increased 3.14 % from baseline to 24 months in ZOL-treated participants versus a 6.43 % decrease in placebo-treated participants (P?<?0.0001). Mean changes in T- and Z-scores, and femoral neck and total femoral BMD, showed similar results. Bone resorption marker levels decreased ～55 % in ZOL-treated participants versus increases up to 65 % in placebo-treated participants (P?<?0.0001 for between-group differences). Bone formation marker (procollagen I N-terminal propeptide) levels decreased ～57 % in ZOL-treated participants versus increases up to 45 % in placebo-treated participants (P?<?0.0001 for between-group differences). Adverse events were consistent with the established ZOL safety profile and included one case of osteonecrosis of the jaw after a tooth extraction.

Conclusions

Adding ZOL to adjuvant therapy improved BMD, reduced BTM levels, and was well tolerated in premenopausal women with early HR⁺ BC receiving adjuvant chemotherapy and/or endocrine therapy.     

Systemic treatment with strontium ranelate promotes tibial fracture healing in ovariectomized rats

Summary  

Systemic treatment with strontium ranelate (SR) was performed on ovariectomized (OVX) rats with fractured tibiae. Callus quality was assessed by radiographic, histological, micro-computerized tomography, and biomechanical examinations at 4 and 8 weeks after fracture. Results revealed that systemic applied SR promoted osteoporotic fracture healing.     

Effect of zoledronate acid treatment on osseointegration and fixation of implants in autologous iliac bone grafts in ovariectomized rabbits

One main problem associated with alveolar bone augmentation in implant dentistry is resorption of grafted bone, which may be further compromised by systemic skeletal disorders such as osteoporosis. Zoledronate acid (ZOL) is the most potent bisphosphonate to treat osteoporosis and therefore it is hypothesized to be able to invert the negative effect of osteoporosis on osseointegration and fixation of dental implants in autologous bone grafts. In this study, 56 rabbits received bilateral ovariectomy (OVX) (40 rabbits) or sham operation (16 rabbits). Three months later, 8 animals from each group were sacrificed for bone mineral density (BMD) examination. Then the remaining animals underwent bilateral autologous iliac bone grafting with simultaneous implantation of titanium implants in tibiae and were divided into 5 groups (n = 8): Sham, OVX, Loc-ZOL (local treatment), Sys-ZOL (systemic treatment) and Loc + Sys-ZOL (local plus systemic) group. At 3 months after implantation, all animals were sacrificed and specimens were harvested for examinations. Both BMD and histological examinations of femurs showed osteoporotic changes after ovariectomy, while systemic treatment with ZOL restored mineralized bone. Micro-CT examination demonstrated that OVX group showed significant decrease of mineralized bone and implant-bone contact when compared with sham control, whereas both systemic and local treatments of ZOL significantly increased mineralized bone and implant-bone contact in ovariectomized animals. However, the best effects were observed in Loc + Sys-ZOL group (combined use of ZOL) and most of bone indices were similar to (IBCR, p > 0.05) or higher than (BV/TV, Conn.D and Tb.N) (p < 0.01) those of the sham group, except Tb.Th, which was still significantly lower (p < 0.01), and Tb.Sp, which was further decreased (p < 0.01). The aforementioned effects were also confirmed by histomorphometric analysis of bone indices on implant-bone contact and mineralized bone. In addition, biomechanical testing further supported the beneficial effect of ZOL treatment and maximal removal torque of titanium implants was observed in Loc + Sys-ZOL group. In conclusion, our study suggests that both systemic and local treatments with ZOL can invert negative effect of osteoporosis and promote osseointegration and fixation of dental implants in autologous bone grafts under osteoporotic condition. Combined systemic and local use of ZOL exerts best effects when compared to their single use.     

Regional bone metabolism at the lumbar spine and hip following discontinuation of alendronate and risedronate treatment in postmenopausal women

Summary

The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using ¹⁸?F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1?year but increased in the hip in the alendronate group only.

Introduction

Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation.

Methods

Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN (n?=?11) or RIS (n?=?9) for a minimum of 3?years at screening (range 3–9?years, mean 5?years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12?months following treatment discontinuation. ¹⁸?F-fluoride plasma clearance (K_i) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed.

Results

With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12?months for both study groups. Measurements of K_i and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% (p?=?0.028) and 24.0% (p?=?0.013), respectively.

Conclusions

Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12?months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment.     

Long‐Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat

Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction : Once‐yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods : Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 μg/kg, alendronate 200 μg/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham‐operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4‐wk intervals for 32 wk. Bone architecture (μCT), bone formation dynamics (fluorochrome label‐based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results : Ovariectomy‐associated BMD loss was significantly attenuated for 32 wk by ZOL ≥4 μg/kg for total BMD, ZOL ≥20 μg/kg for cortical BMD, and ZOL ≥4 μg/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 μg/kg was of equivalent potency to ZOL 20 μg/kg. Ovariectomy‐associated decreases in trabecular architectural parameters were dose‐dependently attenuated by ZOL. Alendronate 200 μg/kg was equivalent to ZOL 20 μg/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX‐rats even at the lowest dose of 0.8 μg/kg, whereas at 100–500 μg/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 μg/kg but were significantly reduced by ZOL 100–500 μg/kg. Alendronate 200 μg/kg was equivalent to ZOL 100 μg/kg. ZOL produced dose‐related improvements in bone strength parameters after ovariectomy. Alendronate 200 μg/kg was of similar potency to ZOL 20 μg/kg. Conclusions : The duration and magnitude of the bone‐protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10‐fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis.     

Modulation of soy isoflavones bioavailability and subsequent effects on bone health in ovariectomized rats: the case for equol

Introduction

Soy products are of particular interest because of their potential health benefits in a range of hormonal conditions, such as osteoporosis, due to their high content in phytoestrogens. Because equol, the main metabolite from soy isoflavones, is thought to be powerful, the present study was designated to evaluate the bone-sparing effects of equol by either providing the molecule through the diet or by eliciting its endogenous production by modulating intestinal microflora by short-chain fructooligosaccharides (sc-FOS) or live microbial (Lactobacillus casei) together with daidzein, its precursor.

Methods

A comparison with daidzein and genistein was also performed. Rats (3 months old) were ovariectomised (OVX) or sham-operated (SH). Ovariectomised rats were randomly assigned to six experimental diets for 3 months: a control diet (OVX), the control diet supplemented with either genistein (G), or daidzein (D), or equol (E) at the level of 10 μg/g body weight/d. The remaining OVX rats were given daidzein at the dose of 10 μg/g body weight/d, simultaneously with short-chain FOS (Actilight®, Beghin-Meiji) (D+FOS) or Lactobacillus casei (Actimel, Danone) (D+L). The SH rats were given the same control diet as OVX.

Results

Genistein, daidzein or equol exhibited a bone sparing effect. Indeed, total femoral bone mineral density (BMD) was significantly enhanced (compared to that of OVX rats), as was the metaphyseal compartment. Bone strength was improved by E consumption, but not by genistein or daidzein given alone. As far as the FOS diet is concerned, the addition of prebiotics significantly raised efficiency of the daidzein protective effect on both femoral BMD and mechanical properties. The effects of lactobacillus were similar, except that the increase in metaphyseal-BMD was not significant.

Conclusion

In conclusion, long-term equol consumption, like genistein and daidzein, in the ovariectomized rat, provides bone sparing effects. Adding indigestible sugars, such as FOS or live microbial as L. casei, in the diet significantly improves daidzein protective effects on the skeleton.     

Protective effect of beta-glucan on contrast induced-nephropathy and a comparison of beta-glucan with nebivolol and N-acetylcysteine in rats

Background

It has been shown that beta-glucan (BG), which has antioxidant and immunomodulatory effects, attenuats renal ischemia–reperfusion injury. We aimed to investigate whether BG might have a preventive role against the development of contrast-induced nephropathy and to compare its effect with nebivolol (Nb) and N-acetylcysteine (NAC).

Methods

Thirty-six Wistar albino female rats were randomly divided into six groups (n?=?6 each): control, contrast media (CM), BG, BG?+?CM, Nb?+?CM, and NAC?+?CM. With the exception of control and CM groups, the others were given drugs orally once a day for 5?days. Kidney function parameters, inflammatory parameters, and serum and renal tissue oxidative stress markers were measured.

Results

Increases of serum creatinine and blood urea nitrogen levels were significantly higher (p?p?p?p?Conclusion This study suggests that BG protects or ameliorates against contrast-induced nephropathy. Its beneficial effects may be similar to or greater than those of Nb or NAC.     

Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON�CRecurrent Fracture Trial

Summary

This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON?CRFT. At month?24 and end of the study visit, ZOL significantly improved patients?? overall health state compared to placebo as assessed by the EQ-5D VAS.

Introduction

To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON?CRFT).

Methods

In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5?mg (n?=?1,065) or placebo (n?=?1,062) within 90?days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months?6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables.

Results

At baseline, patients (mean age 75?years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67?±?0.56 vs. 5.42?±?0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86?±?4.91 vs. ?1.69?±?3.42), non-vertebral fractures (5.03?±?2.48 vs. ?1.07?±?2.16), and clinical fractures (5.19?±?2.25 vs. ?0.72?±?1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p?=?0.6238), self-care (4.92% vs. 6.69%; p?=?0.1013), and usual activities (10.28% vs. 12.91%; p?=?0.0775).

Conclusion

ZOL significantly improves HRQoL in patients with low-trauma hip fracture.     

Estrogen alone or in combination with parathyroid hormone can decrease vertebral MEF2 and sclerostin expression and increase vertebral bone mass in ovariectomized rats

Summary

The study is about the regulatory effects of estrogen and parathyroid hormone (PTH) on sclerostin, a protein that inhibits the Wnt/β-catenin pathway. The results indicate that estrogen may down-regulate sclerostin expression and that estrogen displays synergistic action with PTH. These results provide a new perspective on the relationship between estrogen and bone.

Purpose

To investigate whether estrogen can down-regulate SOST and MEF2 (myocyte enhancer factor 2) expression and whether co-treatment with estrogen and PTH has a stronger effect on suppressing SOST than PTH applied alone in ovariectomized rats.

Methods

Forty-three-month-old virgin female Sprague–Dawley (SD) rats were ovariectomized and divided into four groups (n?=?10). Another ten age-matched rats received sham operations as controls. After allowing 8 weeks for the development of vertebral osteopenia, the rats were administered the drug intervention. For this intervention, the estrogen group was subcutaneously injected with 17β-estradiol at 25 μg/kg body weight, the PTH group was injected with 80 μg/kg synthetic human PTH (1–34), and the co-treatment group was concurrently treated with PTH and estrogen at the above dosage. The OVX group and sham group were treated with vehicle. The drug treatment was conducted for 12 weeks. After the lumbar spine bone mineral density (BMD) was measured, the rats were sacrificed, and the lumbar spine and blood were collected for qPCR, Western blot, immunohistochemistry and other tests.

Results

Estrogen can down-regulate MEF2 and sclerostin expression, and co-treatment with estrogen and PTH has a stronger effect on suppressing MEF2 and SOST mRNA than PTH alone. The co-treatment group displayed slightly higher bone mass and biomechanical properties than the PTH group, but the differences were not significant.

Conclusions

Estrogen appears to be a regulator of sclerostin, and the effect may involve suppressing MEF2s. Combined treatment with PTH and estrogen is not more beneficial for vertebral bone mass and strength than treatment with PTH alone in ovariectomized rats.     

Effects of the combination treatment of raloxifene and alendronate on the biomechanical properties of vertebral bone

Raloxifene (RAL) and alendronate (ALN) improve the biomechanical properties of bone by different mechanisms. The goal here was to investigate the effects of combination treatment of RAL and ALN on the biomechanical properties of vertebral bone. Six‐month‐old Sprague‐Dawley rats (n = 80) were randomized into five experimental groups (sham, OVX, OVX + RAL, OVX + ALN, and OVX + RAL + ALN; n = 16/group). Following euthanization, structural and derived material biomechanical properties of vertebral bodies were assessed. Density and dynamic histomorphometric measurements were made on cancellous bone. The results demonstrate that the structural biomechanical properties of vertebral bone are improved with the combination treatment. Stiffness and ultimate load of the OVX + RAL and OVX + ALN groups were significantly lower than those of sham animals, but the combination treatment with RAL + ALN was not significantly different from sham. Furthermore, the OVX + RAL + ALN group was the only agent‐treated group in which the ultimate load was significantly higher than that in OVX animals (p < .05). Cancellous bone fractional volume (BV/TV_canc) and bone mineral density (aBMD) also were improved with the combination treatment. BV/TV_canc of the OVX + RAL + ALN group was 6.7% and 8.7% greater than that of the OVX + RAL (p < .05) and OVX + ALN (p < .05) groups, respectively. Areal BMD of the OVX + RAL or OVX + ALN groups was not significantly different from that in OVX animals, but the value in animals undergoing combination treatment was significantly higher than that in OVX or OVX + RAL animals alone and not significantly different from that in sham‐operated animals. Turnover rates of both the RAL + ALN and ALN alone groups were lower than in the RAL‐treated alone group (p < .05). We conclude that the combination treatment of raloxifene and alendronate has beneficial effects on bone volume, resulting in improvement in the structural properties of vertebral bone. © 2011 American Society for Bone and Mineral Research.     

复合脉冲电磁场对去卵巢大鼠骨质疏松预防作用的研究

目的 观察复合脉冲电磁场（PEMFs)对去卵巢大鼠骨质疏松（OP）的预防作用,以寻求防治OP的新途径。方法 3月龄SD大鼠随机分为正常对照组（N）、去卵巢组（O）、去卵巢加苯甲酸雌二醇处理组（E）及去卵巢加PEMFs处理组（EM）,治疗8周后测定骨生物力学、骨密度、骨形态学。结果 生物力学性能测定显示,经PEMFs治疗后股骨最大抗拉强度和椎骨最大抗压强度明显提高,较O组分别增加39．2％、37．9％（P＜0．01）,并超过N组和E组（P＜0．01）;EM组骨密度（BMD）尽管未恢复至正常（P＜0．05）,但与0组相比仍有明显改善（P＜0．01）,且已基本达到E组水平;骨形态学分析发现EM组骨小梁增宽、致密,分布有序,结构优于O组和E组。结论 PEMFs能够增加骱密度,改善骨生物力学性能和骨结构。鉴于其对OP的预防作用主要是通过提高骨质量来实现的,我们认为在PEMFs一定程度上优于苯甲酸雌二醇,是颇具潜力的预防骨质疏松的方法。     

Cathepsin K inhibitors prevent bone loss in estrogen‐deficient rabbits

Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.8%) in lumbar vertebral bone mineral density (LV BMD) in rabbits at 13‐weeks after surgery, which was prevented by estrogen or ALN. A potent CatKI, L‐006235 (L‐235), dosed at 10 mg/kg per day for 27 weeks, significantly decreased LV BMD loss (p < .01) versus OVX‐vehicle control. ALN reduced spine cancellous mineralizing surface by 70%, whereas L‐235 had no effect. Similarly, endocortical bone‐formation rate and the number of double‐labeled Haversian canals in the femoral diaphysis were not affected by L‐235. To confirm the sparing effects of CatKI on bone formation, odanacatib (ODN) was dosed in food to achieve steady‐state exposures of 4 or 9 µM/day in OVX rabbits for 27 weeks. ODN at both doses prevented LV BMD loss (p < .05 and p < .001, respectively) versus OVX‐vehicle control to levels comparable with sham or ALN. ODN also dose‐dependently increased BMD at the proximal femur, femoral neck, and trochanter. Similar to L‐235, ODN did not reduce bone formation at any bone sites studied. The positive and highly correlative relationship of peak load to bone mineral content in the central femur and spine suggested that ODN treatment preserved normal biomechanical properties of relevant skeletal sites. Although CatKIs had similar efficacy to ALN in preventing bone loss in adult OVX rabbits, this novel class of antiresorptives differs from ALN by sparing bone formation, potentially via uncoupling bone formation from resorption. © 2011 American Society for Bone and Mineral Research.     

Influence of Early and Late Zoledronic Acid Administration on Vertebral Structure and Strength in Ovariectomized Rats

An annual infusion of zoledronic acid (ZOL) reduces fracture risk in osteoporotic patients. Previously, we showed that a single ZOL injection inhibited changes in bone microstructure and strength in rat tibiae after ovariectomy. Here, we determined the effects of a single ZOL injection as preventive and restorative treatment on the bone microstructure and strength in lumbar and caudal vertebrae of ovariectomized (OVX) rats. Twenty-nine female 35-week-old Wistar rats were divided into four groups: SHAM-OVX (n = 9), OVX (n = 5), OVX and early ZOL (n = 8), and OVX and late ZOL (n = 7). ZOL was given once (20 μg/kg body weight s.c.) at OVX in the early ZOL group and 8 weeks later in the late ZOL group; rats were killed 16 weeks after OVX. Trabecular and cortical bone microarchitecture were measured in lumbar (L3) and caudal (Cd6) vertebrae using micro-computed tomography, and compressive mechanical properties were determined in L3 vertebrae. Compared to SHAM-OVX, OVX rats had significantly lower BV/TV; SMI, Tb.N, Tb.Sp, and Conn.D tended to be deteriorated in lumbar vertebrae, while both ZOL groups did not differ from the SHAM-OVX group. Both ZOL groups had significantly higher BV/TV than OVX; the early ZOL group also had significantly lower SMI and higher Tb.Th. OVX tended to decrease mechanical properties, while early and late ZOL treatment inhibited OVX-induced degeneration. Neither OVX nor ZOL induced changes in the trabecular microarchitecture of caudal vertebrae. In summary, in adult rats a single ZOL injection inhibited OVX-induced changes in lumbar vertebral bone microarchitecture and strength.