Predictive Evaluation of Pharmaceutical Properties of Ulinastatin-Containing Vaginal Suppositories as a Hospital Preparation by Near-Infrared Spectroscopy.

A vaginal suppository containing ulinastatin (UTI) was developed as a hospital pharmacy product from UTI injection solution and Witepsol® S-55. After mixing at 50°C for 0-8 h, UTI suppositories were prepared, which had good UTI content uniformity. Because 2% surfactant was contained in S-55, the UTI injection solution formed a water-in-oil type emulsion as a suppository base. The measured residual moisture content (loss on drying (LOD)) in the prepared vaginal suppositories decreased as the mixing time increased, but their hardness (hardness test (HT)) increased. Near (N) IR spectra of UTI suppositories were measured after mixing for 0-8 h. The best calibration models to predict the HT and LOD of the suppositories were determined based on the NIR spectra by the leave-one-out method in a partial least-squares regression analysis (PLS). The validation result indicated that PLS models for HT and LOD were obtained based on the spectra treated by a combination of smoothing and normalized, respectively, and the model consisted of three latent variables. The plots between the predicted and measured pharmaceutical properties (HT and LOD) based on the calibration data were superimposed with those of the external validation data. The developed NIR spectroscopy method was applied to the preparation process monitoring for UTI vaginal suppositories. In the prepared vaginal suppositories, the predicted LOD decreased as the mixing time increased, and the measured LOD values superimposed well with the predicted values. In contrast, the predicted HT increased as the mixing time increased, and the measured values superimposed with the predicted values.

Rapid identification of oral solid dosage forms of counterfeit pharmaceuticals by discrimination using near-infrared spectroscopy.

BACKGROUND: Since it can take an enormous amount of time and cost to discriminate counterfeit medicines by using conventional methods, counterfeit medicines has been spread in the world markets. OBJECTIVE: The purpose of this study was to develop a rapid and simple analytical method to discriminate counterfeit drugs using near infrared (NIR) spectroscopy. METHODS: Seven types of brand name tablet and generic tablets containing atorvastatin calcium sesquihydrate (AT) preparations were used as simulated counterfeit medicines. NIR spectra of 35 AT tablet products were measured using a diffuse reflection method. RESULTS: The NIR spectral data were analyzed by principal component analysis (PCA). The PCA results suggested that the model had sufficient accuracy to discriminate the 7 types for AT tablets. The NIR spectral data were also analyzed using a soft independent modeling of class analogy (SIMCA) method. Predicting the classification of the AT tablet samples was performed based on all the validated AT tablet data using the SIMCA model, and the probability of classification of 7 types was 100%. The discrimination power spectrum of the SIMCA model indicated significant patterns based on diluents. CONCLUSIONS: The PCA and SIMCA classification of the AT tablets were depended on the major excipient combinations.

Therapeutic effects of transdermal systems containing zinc-related materials on thermal burn rats.

OBJECTIVE: The aim of the present study is to evaluate the efficacy of slow zinc (Zn) release from ß-tricalcium phosphate powder (ZnTCP) containing 10 mol% Zn on rats with thermal burns. METHODS: The first-aid tapes were contained zinc sulfate (ZnSO4) solution, ZnTCP suspensions or zinc oxide ointment. After thermal burn treatments were performed on Zn-deficient rats, the groups D1, D2 and D3 were treated with tapes containing ZnTCP, ZnSO4 and zinc oxide ointment. The effects of the tapes on wound area, plasma Zn levels and alkaline phosphatase activity (Alp) were investigated. RESULTS: The wound area profiles of all rat groups could be separated into before and after the scab formation at around day 6. The area under the curve (Aw-AUC) for wound area profiles, therefore, was evaluated as an index of therapeutic scores for the thermal wound. The order of Aw-AUC was D3>C>D2>D1. The degree of expansion at the initial stage by thermal burns of group D1 was the lowest and that of group D2 was the highest, and the order was D1

Non-destructive prediction of the drug content of an acetaminophen suppository by near-infrared spectroscopy and X-ray computed tomography.

The purpose of this study is to develop non-destructive methods to determine the drug content of suppositories using near-infrared (NIR) spectrometry and X-ray computed tomography (XCT). The suppository samples (acetaminophen content: 0, 100, 200, 300, 400 and 500 mg/suppository) consisted of acetaminophen powder and hard fat. NIR spectra of 18 standard suppository samples were recorded, and the data were divided into two wave number ranges, 4000-10 000 cm(-1) (LR), and 4280-6650 cm(-1) (SR). The best calibration model was determined to minimize the standard error of cross-validation (SECV) by the leave-one-out method in the partial least squares regression (PLS). Sliced XCT images of the suppositories were measured, and apparent density (AD) was evaluated using the image of the sample. The NIR models gave the best correlation coefficient constant (R) values, since the results for LR and SR gave straight lines with R of 0.9274 and 0.9707, respectively. The AD of the suppositories by XCT increased with increasing drug content, and the relationship between the AD and drug content had a straight line with R of 0.9958. Both NIR and X-ray CT performed accurate measurements of suppository samples through plastic packaging.

Quantitative analysis of α-mangostin in hydrophilic ointment using near-infrared spectroscopy.

The objective of this research was to quantify the α-mangostin content in mangosteen pericarp (MP) ointment as a colloidal dispersion using near-infrared (NIR) spectroscopy. Various concentrations of MP (IP and EP) ointments containing both internal and external pericarps were prepared and the NIR spectra of these ointments were measured. The NIR spectrum of each ointment was correlated with α-mangostin concentration by partial least square (PLS) regression. Validation of the models was performed and their predictive ability was also investigated. The equation and R(2) value for the prediction of α-mangostin concentration in IP ointment were y=0.9843x+0.4441 and 0.9730 and those in EP ointment were y=0.9569x+0.1142 and 0.9136, respectively. The biases of the IP and EP ointment models were 0.23 and 0.00, respectively. The results showed that NIR could be a useful tool for the quality control of herbal medicine in hydrophilic ointment without any sample preparation. It could predict α-mangostin content in hydrophilic ointment at very low concentration with sufficient accuracy.

Therapeutic effect of zinc-containing calcium phosphate suspension injection in thermal burn-rats.

The aim of this study was to evaluate the efficacy of suspensions of zinc-containing tricalcium phosphate (TCP) in the healing of thermal burns in rats. ß-ZnTCP containing 10 mol % zinc, α-ZnTCP containing 0.9 mol % zinc, and ZnSO4 ·(H2O)7 (ZnSO4) were used. The injections were prepared to suspend ZnSO4 , α-ZnTCP, and ß-ZnTCP powders in 2 mL of 1% sodium alginate saline solution containing 2 mg of Zn. In vitro Zn release rates were measured in simulated body fluid. The release of Zn from ZnSO4 was very fast, but that from α-ZnTCP and ß-ZnTCP was slowed by transformation to hydroxyapatite. The suspensions were injected into group C (control), D1 (ZnSO4), D2 (α-ZnTCP), and D3 (ß-ZnTCP) rats after thermal burns treatment for 3 h. The area under the curve for the plasma Zn for group D1 was the highest, and the order was groups D1 > D2 ≥ D3 ≥ C. The wounded area (Aw) of group D1 had almost the same profile as that of group C, and the Aw at 18 days was about 20%. In contrast, the Aw of group D2 and D3 decreased, and on day 15 was 8% and 37%, respectively. The results indicated that the healing process was shorter in the rats given α-ZnTCP and ß-ZnTCP than those given ZnSO4 or the control.

Application of NIR spectroscopy for the quality control of mangosteen pericarp powder: quantitative analysis of alpha-mangostin in mangosteen pericarp powder and capsule.

Near-infrared spectroscopy (NIR) was applied to the quantitative analysis of the concentration of alpha-mangostin (aM) in mangosteen pericarp powder (MP). The predicted results from the partial least squares chemometric method of various pretreatment data were compared to obtain the best calibration model. Two different types of containers (transparent capsules and glass vials) filled with the same samples were measured. For MP mixture in vials, the calibration model involving nine principal components (PC) could predict the amount of aM most accurately based on non-pretreatment spectral data. For MP mixture in capsules, the calibration model involving nine PC could predict the amount of aM most accurately based on first-derivative pretreatment spectra. The relationships of the calibration models for both samples had sufficiently linear plots. The standard error of cross-validation for the MP mixture in vials was lower and the R(2) values of validation were higher compared to the MP mixture in capsules. The equation for prediction of the concentration of aM in MP mixtures in vials is y = 0.9775x + 0.0425 with R(2) = 0.9950 and for those in capsules is y = 1.0264x + 0.0126 with R(2) = 0.9898. Both validation results indicated that the concentrations of aM in MP mixtures were predicted with sufficient accuracy and repeatability. NIR can be a useful tool for the quality control of herbal medicine in powder form without any sample preparation. The type and the shape of the container should be considered to obtain more accurate data.

Effect of geometrical structure on the in vivo quality change of a three-dimensionally perforated porous bone cell scaffold made of apatite/collagen composite.

Biodegradable artificial bone blocks with interconnective pores were prepared using a self-setting apatite/collagen composite cement as a cell scaffold for bone regenerative medicine. The biological behavior of the blocks was tested in rats, and the change in their properties after implantation was measured. One cubic block [10 mm X 10 mm X 10 mm; porous composite (PC)] was obtained from apatite cement (apatite/collagen cement; 80% of apatite:20% of collagen) with 60 interconnecting holes, 500 um in diameter. The other blocks (NC and NN) without holes were obtained from the apatite/collagen and plain apatite cements, respectively. All blocks were implanted in the rats for 56 days. Changes in the amount and density (block mineral mass and block mineral density) of the blocks were evaluated based on dual energy X-ray absorptiometry images, and the order of biodegradation was PC < NC < NN. After implantation, the blocks were removed, and subjected to an X-ray diffraction (XRD) analysis, Fourier-transformed infrared (FT-IR) spectroscopy and thermogravimetry (TG). The XRD peaks of all blocks increased significantly. TG revealed that the amount of carbonated apatite also increased with time. However, the organic component of PC depended on the implantation period, consistent with the FT-IR results. Because PC had interconnective macro- and micropores in the apatite/collagen matrices, the results indicated that soft tissue penetrated the block carbonated apatite was generated, bone remodeling was accelerated in the implant.

Quantitative evaluation of the disintegration of orally rapid disintegrating tablets by X-ray computed tomography.

To measure the rapid disintegration of Oral Disintegrating Tablets (ODT), a new test (XCT) was developed using X-ray computing tomography (X-ray CT). Placebo ODT, rapid disintegration candy (RDC) and Gaster®-D-Tablets (GAS) were used as model samples. All these ODTs were used to measure oral disintegration time (DT) in distilled water at 37±2°C by XCT. DTs were affected by the width of mesh screens, and degree to which the tablet holder vibrated from air bubbles. An in-vivo tablet disintegration test was performed for RDC using 11 volunteers. DT by the in-vivo method was significantly longer than that using the conventional tester. The experimental conditions for XCT such as the width of the mesh screen and degree of vibration were adjusted to be consistent with human DT values. Since DTs by the XCT method were almost the same as the human data, this method was able to quantitatively evaluate the rapid disintegration of ODT under the same conditions as inside the oral cavity. The DTs of four commercially available ODTs were comparatively evaluated by the XCT method, conventional tablet disintegration test and in-vivo method.

Efficacy of the injectable calcium phosphate ceramics suspensions containing magnesium, zinc and fluoride on the bone mineral deficiency in ovariectomized rats.

The purpose of this study was to evaluate the therapeutic efficacy of a new calcium phosphate (CaP)-based formulation in improving the bone mineral deficiency in ovariectomized (OVX) rats. The ions release experiments for CaP preparations (G2: 0.46% Mg, 5.78% Zn, and 2.5% F; G3:3.1% Mg, 0.03% Zn, and 3.01% F; G4: 1.25% Mg, 1.77% Zn, 1.35% F) and of a Zn-TCP (G1: 6.17% Zn) powders, the initial Mg and Zn ion release rates of MZF-CaPs were performed in acetate buffer at pH 4.5 (37 degrees C). Wistar rats were divided into six groups including a normal (not OVX) group (GN) and a control, OVX group (GC). Rats in groups GC, G1, G2, G3, G4 were OVX. Suspensions consisting of CaP preparations (G2, G3, G4) and of a Zn-TCP (G1) powders were injected in the right thighs of OVX rats in all groups except for GN and GC, once a week for 4 weeks. GN and GC rats were injected with saline solutions. Plasma was analyzed for Zn land alkaline phosphatase levels. The bone mineral density (BMD) was measured using DEXA and the bone (femur) strength determined using three-point-bending analysis. G1 and G2 groups showed high plasma Zn levels. The area under the curve of plasma Zn was significantly greater in the G1, G2, and GN groups than in the G3, G4, and GC groups (p < 0.05). The BMD and bone mechanical strength of the right femur were significantly higher in the G1, G2, G3, and G4 groups than GC group on day 28. The right femur had significantly greater BMD and bone mechanical strength than the left femur in G1, G2, G3, and G4 groups. However, there was no significant difference in the BMD of the right femur between the G1, G2, G3, and G4 groups. Results indicate that the new injectable CaP formulations are effective in improving bone properties of OVX rats and may be useful in osteoporosis therapy.

Toward freedom from cancer pain in Japan.

Life expectancy in Japan is highest in the world. Cancer is the leading cause of mortality in Japan, accounting for about 30 percent of all deaths. Many Japanese cancer patients experience severe pain although they and their families hope to be pain free at the end of their lives. Toward that end, the consumption of morphine in Japan has increased markedly since 1989. The amount of morphine hydrochloride and morphine sulfate consumed in 2001 was 6.1 times that used in Japan in 1989. However, the amount of morphine consumed in Japan is still less than in other developed nations, and was only one-sixth of the amount used in Australia in 2001. As a result, many Japanese cancer patients experience potentially manageable cancer pain, largely because the amount of the drug used by doctors is insufficient for pain control. An increasing number of Japanese doctors now understand that their patients' quality of life is most important in end-of-life care and how to use the three step analgesic ladder of the World Health Organization (WHO). However, other doctors do not understand these issues sufficiently causing some patients to die without good pain control. Both the general population and some medical professionals misunderstand and have prejudice against the use of morphine. Patients often do not participate in decision making about medical treatment because of remaining paternalism in the relationship between Japanese doctors and patients. Thus, cancer pain management in Japan is not as effective as it can be and not all Japanese cancer patients receive appropriate management for their cancer pain. To improve outcomes for Japanese patients, it is necessary for health professional and social work students and practicing professionals to receive contemporary education including an introduction to palliative care and ethics.

Theoretical analysis of tablet hardness prediction using chemoinformetric near-infrared spectroscopy.

In order to clarify the theoretical basis of the variability in the measurement of tablet hardness by compression pressure, NIR spectroscopic methods were used to predict tablet hardness of the formulations. Tablets (200 mg, 8 mm in diameter) consisting of berberine chloride, lactose, and potato starch were formed at various compression pressures (59, 78, 98, 127, 195 MPa). The hardness and the distribution of micropores were measured. The reflectance NIR spectra of various compressed tablets were used as a calibration set to establish a calibration model to predict tablet hardness by principal component regression (PCR) analysis. The distribution of micropores was shifted to a smaller pore size with increasing compression pressure. The total pore volume of tablets decreased as the compression pressure increased. The hardness increased as the compression pressure increased. The hardness could be predicted using a calibration model consisting of 7 principal components (PCs) obtained by PCR. The relationship between the predicted and the actual hardness values exhibited a straight line, an R(2) of 0.925. In order to understand the theoretical analysis (scientific background) of calibration models used to evaluate tablet hardness, the standard error of cross validation (SEV) values, the loading vectors of each PC and the regression vector were investigated. The result obtained with the calibration models for hardness suggested that the regression vector might involve physical and chemical factors. In contrast, the porosity could be predicted using a calibration model composed of 2 PCs. The relationship between the predicted and the actual total pore volume showed a straight line with R(2) = 0.801. The regression vector of the total pore volume might be due to physical factors.

Chemoinformetrical evaluation of dissolution property of indomethacin tablets by near-infrared spectroscopy.

PURPOSE: The purpose of this study was to use near-infrared spectrometry (NIR) with chemoinformetrics to predict the change of dissolution properties in indomethacin (IMC) tablets during the manufacturing process. A comparative evaluation of the dissolution properties of the tablets was performed by the diffused reflectance (DRNIR) and transmittance (TNIR) NIR spectroscopic methods. METHODS: Various kinds of IMC tablets (200 mg) were obtained from a powder (20 mg of IMC, 18 mg of microcrystalline cellulose, 160 mg of lactose, and 2 mg of magnesium stearate) under various compression pressures (60-398 MPa). Dissolution tests were performed in phosphate buffer, and the time required for 75% dissolution (T75) and mean dissolution time (MDT) were calculated. DRNIR and TNIR spectra were recorded, and the both NIR spectra used to establish a calibration model for predicting the dissolution properties by principal component regression analysis (PCR). RESULTS: The T75 and MDT increased as the compression pressure increased, since tablet porosity decreased with increasing pressure. Intensity of the DRNIR spectra of the compressed tablets decreased as the compression pressure increased. However, the intensity of TNIR spectra increased along with the pressure. The calibration models used to evaluate the dissolution properties of tablets were established by using PCR based on both DRNIR and TNIR spectra of the tablets. The multiple correlation coefficients of the relationship between the actual and predictive T75 by the DRNIR and TNIR methods were 0.831 and 0.962, respectively. CONCLUSION: It is possible to predict the dissolution properties of pharmaceutical preparations using both DRNIR and TNIR chemoinformetric methods. The TNIR method was more accurate for predictions of the dissolution behavior of tablets than the DRNIR method.

Comparative evaluation of bioactivity change of crystalline trypsin during compression by chemoinformatics and 2-D Fourier-transform infrared spectroscopy.

The purpose of this study is to develop a method of evaluating the enzymatic activity of trypsin in a solid-state based on Fourier transform infrared (FT-IR) spectra using chemoinformatics and two-dimensional (2-D) correlation spectroscopy. Crystalline trypsin powders are compressed at 0-4000 kg cm-2 by a compression/tension tester. The enzymatic activity of trypsin is assayed by the kinetic degradation method. Spectra of 10 calibration sample sets are recorded 3 times with a FT-IR spectrometer. The maximum intensity of FT-IR spectra and enzymatic activity of trypsin decrease as the compression pressure increases. The FT-IR spectra of trypsin samples are subjected to a principal component regression (PCR). A plot of the calibration data obtained is made between the actual and predicted trypsin activity based on a two-component model with gamma2=0.909 (n=30). The regression vector is almost the same as the loading vector for PC1. On the other hand, a generalized two-dimensional (2-D) correlation spectroscopic method is applied to FT-IR spectra of compressed trypsin. The result is consistent with that of the chemoinformatics method. The FT-IR chemoinformatics method allows for solid-state quantitative analysis of the bioactivity of the bulk powder of a polypeptide drug.

Effect of nanostructure on biodegradation behaviors of self-setting apatite/collagen composite cements containing vitamin K2 in rats.

Apatite cement and collagen were combined by a mechanochemical method to create a new self-setting apatite/collagen composite cement, and menatetrenone (VK2) was loaded into a drug-delivery system to test biocompatibility in rats. Powder X-ray diffraction analysis (XRD), scanning electron microscopy (SEM), and electron probe microanalyzer (EPMA) were performed to characterize the physicochemical properties of apatite/collagen composite cements. The XRD results suggested that ground apatite/collagen cement was completely transformed into bone-like hydroxyapatite, but that without grinding was incomplete. The SEM and EPMA results suggested that ground apatite/collagen cement was homogeneously dispersed of nanoapatite crystals in collagen matrices, similar to that in natural bone. In contrast, the cement without grinding was heterogeneously distributed. To evaluate in-vivo cement density (CMM), microradiograms were measured for 72 days after implanting apatite/collagen composite cements in intramuscular tissue on the backs of rats, and cross sections of the cements and surrounding soft tissues were observed by microscope. The CMM results of the apatite/collagen composite cements suggested that the biodegradation rate was dependent on the cement quality and nanogeometrical structure. The CMM result of VK2-loaded apatite/collagen cements suggested that the biodegradation rates of the cements were significantly dependent on their formulation. The CMM of ground apatite/collagen cement increased until 7 days and then decreased, and bone-like cells penetrated deeply in the center. The microphotograph and CMM results of apatite/collagen without grinding indicated that a lot of bone-like cells penetrated into the cement and the cement shape was totally deformed.

International harmonization of generic drugs: in vitro dissolution tests for Japanese and American generic tablets.

Ibuprofen tablets on the market in Japan and the USA were compared by manual- and automatic-dissolution tests according to USP24 criteria. Dissolution test were performed in 900 ml of phosphate buffer of pH 7.2 at 37.0+/-0.5 degrees C at 50 rpm for 60 min, and the time required for 70% dissolution (T70%) and 5% dissolution after 60 min (A60) were evaluated. The dissolution profiles of both Japanese and American tablets by the automatic-method showed almost the same profiles as those of the manual method. T70% of the American and Japanese tablets by the manual method were not significantly different (p>0.05) from the automatic-method at various sampling positions. The A60 of the American and Japanese tablets by the manual-method was not significantly different (p>0.05) except at one position. The results indicate that the automatic-method was more reproducible than the manual-method, and also that systematic error was negligible. The T70% and A60 of the American tablets were significantly different (p<0.05) from the Japanese tablets. The American tablets were a film-coated over-the-counter drug and the Japanese tablets were a sugar-coated prescription drug. There was a difference in dissolution behavior between the dosage forms of the two countries.

Time-controlled pulse-drug release from dry-coated wax matrix tablets for colon drug delivery.

This study aimed to prepare a colon drug delivery system using dry-coated time-controlled disintegration wax matrix tablets. Indomethacin was used as a model drug. Behenic acid and lactose were used as coating materials. The effects of lactose content and pH of the dissolution medium on drug release were investigated. The porosity and the tortuosity of the surface matrix layer were calculated. Four formulations of wax matrices containing different percentages of lactose in the surface layer, i.e. 70, 65, 60 and 55, were prepared. The lag times of indomethacin release from the matrices in 0.05 M phosphate buffer pH 7.4 were 50, 162, 294 and 539 minutes for formulations containing 70, 65, 60 and 55% lactose, respectively. The release of drug from formulations containing lactose in the range of 60-70% in different media, i.e. 0.05 M phosphate buffer pH 7.4, 0.05 M alkaline borate buffer pH 8.5 and in the case of pH changed media from pH 1.3 to pH 7.4, was not different (p=0.1). This implies that the different environment in the gastro-intestinal tract will not affect the release of this delivery device. The required lag time period can be met by varying the amount of lactose.

Effect of controlled zinc release on bone mineral density from injectable Zn-containing beta-tricalcium phosphate suspension in zinc-deficient diseased rats.

The purpose of this study was to evaluate the efficacy of zinc (Zn)-containing beta-tricalcium phosphate (Zn-TCP) in correcting the bone mineral deficiency noted in osteoporosis using ovariectomized rat model. Four rats were used for each of the four experimental groups: D0, D10, D20, and N10. The rats in D0, D10, and D20 groups were ovariectomized, and fed a vitamin D-, Ca-, and Zn-deficient diet, and induced Zn-deficient osteoporoses for 9 weeks. In contrast, the N10 group was the normal rats fed normal healthy diet for 9 weeks. D0 group was injected with pure beta-TCP suspension, D10 and D20 groups were injected with suspensions containing 10 mg of 10 mol % (6.17 wt % Zn) and 20 mol % (12.05 wt % Zn) Zn-TCP, respectively, and the healthy group, N10 were injected with 10 mol %. Zn-TCP suspensions. Injections were administered intramuscularly in the left thigh once a week in all rats, and fed a vitamin D- and Zn-deficient diet for 9 weeks. The plasma calcium (Ca) and Zn levels, plasma alkaline phosphatase activity (ALP) and bone mineral density (BMD) of the lumbar vertebra and femora were measured. The plasma Zn levels in all the rats were between 1.1 and 2.8 microg/mL. The areas under the curves for the Ca, Zn, and ALP (Ca-AUC, Zn-AUC, and ALP-AUC) levels between 0 and 63 days were calculated. Results for the AUCs were as follows: (1) the Zn-AUCs were in the order of N10 = D20 > D10 > D0; (2) the Ca-AUCs for D0, D10 groups were significantly lower than that for the N10 group; (3) the ALP-AUCs for the D10 and D20 groups were significantly higher than that for the N10 group, and that of the D0 group was in between those. The body weight of D10 and D20 groups significantly increased with time, that of the D0 group increased slightly, and that of the N10 group remained unchanged for the entire experimental period. The BMD of the lumbar vertebrae of the D10 and D20 groups (about 100 mg/cm(2)) was significantly higher than that of the D0 group but lower than that of the N10 group. The BMD of the left femur increased more than that of the right femur with the increase in the amount of Zn in the suspension. The results of this study suggest that the local effect on BMD was more pronounced than the effect on the whole body.