The effects of teriparatide on acceleration of bone healing following atypical femoral fracture: comparison between daily and weekly administration.

We compared the effectiveness of promoting bone healing between two teriparatide preparations for atypical femoral fracture (AFF). A total of 45 AFFs were included in this study, and we compared the duration of bone union. Teriparatide administered by daily injection enhanced bone union more than weekly administration in complete AFFs. INTRODUCTION: The efficacy of teriparatide for atypical femoral fracture (AFF) has been recently reported. Although two different teriparatide preparations can be used to treat osteoporosis in Japan, daily or weekly injection, all previous reports on the effectiveness of teriparatide for AFF only examined daily injection formulations. Therefore, we compared the promotion of bone healing between the two teriparatide preparations for AFF. METHODS: A total of 45 consecutive AFFs in 43 Japanese patients were included in this study. They received either a daily 20-µg teriparatide injection (daily group; n = 32) or a once-a-week 56.5-µg teriparatide injection (weekly group; n = 13). We compared the clinical background and duration of bone union between these two groups. RESULTS: When all patents were included, the fracture healing time was not significantly different between the two groups. Only patients with complete AFFs had significantly fewer daily bisphosphonate or denosumab injections than the weekly group (P < 0.05). The fracture healing time in the daily group (6.1 ± 4.1 months) was significantly shorter than that in the weekly group (10.1 ± 4.2 months) (P < 0.05). Even if the influence of bisphosphonate or denosumab usage was excluded, a similar significant difference was observed in the fracture healing time (P < 0.05). There was no significant difference between the two groups among patients with incomplete AFFs. CONCLUSIONS: Daily teriparatide injections enhance bone union more than weekly injections in complete AFF patients.

Comparison of spinal alignment, muscular strength, and quality of life between women with postmenopausal osteoporosis and healthy volunteers.

This study compared spinal alignment, muscular strength, and quality of life (QOL) between women with postmenopausal osteoporosis and healthy volunteers. The results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness. INTRODUCTION: Increased spinal kyphosis is common in patients with osteoporosis and negatively impacts quality of life (QOL). Muscular strength is also important for QOL in patients with osteoporosis. However, spinal kyphosis and muscle weakness also occur in healthy individuals with advancing age. The purposes of this study were thus to compare spinal alignment, muscular strength, and QOL between women with postmenopausal osteoporosis and healthy volunteers. METHODS: Participants comprised 236 female patients with postmenopausal osteoporosis (mean age, 68.7 years) and 93 healthy volunteer women (mean age, 71.0 years). Body mass index (BMI), angles of spinal kyphosis, back extensor strength, grip strength, and QOL were compared between groups. RESULTS: BMI, back extensor strength, and grip strength were significantly higher in the volunteer group than in the osteoporosis group (p < 0.01). Both thoracic kyphosis and lumbar lordosis were significantly greater in the osteoporosis group than in the volunteer group (p < 0.01). With regard to QOL, the 36-Item Short-Form Health Survey (SF-36) subscale scores of role physical, bodily pain, general health, and role emotional were all significantly lower in the osteoporosis group than in the volunteer group (p < 0.05 each). SF-36 physical component summary (PCS) score was significantly lower in the osteoporosis group than in the volunteer group (p < 0.001). SF-36 PCS score correlated positively with thoracic kyphosis and negatively with BMI only in the osteoporosis group (p < 0.05 each). CONCLUSIONS: These results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness.

Improvement of spinal alignment and quality of life after corrective surgery for spinal kyphosis in patients with osteoporosis: a comparative study with non-operated patients.

UNLABELLED: This study evaluated changes in spinal alignment and quality of life (QOL) after corrective spinal surgery for patients with postmenopausal osteoporosis and spinal kyphosis. Spinal global alignment and QOL were significantly improved after corrective spinal surgery but did not reach the level of non-operated controls. INTRODUCTION: With the increased aging of society, the demand for corrective spinal instrumentation for spinal kyphosis in osteoporotic patients is increasing. However, previous studies have not focused on the improvement of quality of life (QOL) after corrective spinal surgery in patients with osteoporosis, compared to non-operated control patients. The purposes of this study were thus to evaluate changes in spinal alignment and QOL after corrective spinal instrumentation for patients with osteoporosis and spinal kyphosis and to compare these results with non-operated patients. METHODS: Participants comprised 39 patients with postmenopausal osteoporosis ≥50 years old who underwent corrective spinal surgery using multilevel posterior lumbar interbody fusion (PLIF) for symptomatic thoracolumbar or lumbar kyphosis, and 82 age-matched patients with postmenopausal osteoporosis without prevalent vertebral fractures. Spinopelvic parameters were evaluated with standing lateral spine radiography, and QOL was evaluated with the Japanese Osteoporosis QOL Questionnaire (JOQOL), SF-36, and Roland-Morris Disability Questionnaire (RDQ). RESULTS: Lumbar kyphosis angle, sagittal vertical axis, and pelvic tilt were significantly improved postoperatively. QOL evaluated with all three questionnaires also significantly improved after 6 months postoperatively, particularly in domain and subscale scores for pain and general/mental health. However, these radiographic parameters, total JOQOL score, SF-36 physical component summary score, and RDQ score were significantly inferior compared with non-operated controls. CONCLUSIONS: The results indicate that spinal global alignment and QOL were significantly improved after corrective spinal surgery using multilevel PLIF for patients with osteoporosis and spinal kyphosis but did not reach the level of non-operated controls.

Association of spinal curve deformity and back extensor strength in elderly women with osteoporosis in Japan and the United States.

UNLABELLED: The difference in the shape of sagittal spinal curvature and distribution of vertebral fractures in women of comparable age with osteoporosis from Japan and the United States with different cultures and lifestyles was identified. Back extensor strength was significantly associated with lumbar lordosis in Akita group, indicating the potential importance of strengthening the back extensor. INTRODUCTION: The purpose of the study was to assess the association of osteoporotic spinal deformities with back strength in elderly women in Japan and the United States. METHODS: Subjects diagnosed with osteoporosis were selected to participate prospectively. In both groups, we measured the angles of thoracic kyphosis and lumbar lordosis with plain lateral radiographs and back extensor strength. The number of vertebral fractures and the ratio of lumbar fractures to thoracic fractures are also evaluated. The level of participants' daily activities was assessed with use of comparable tests in Akita (quality-of-life score) and Minnesota (physical activity score). RESULTS: A total of 102 Japanese women residing in Akita, Japan (Akita group), and 104 white women evaluated in Rochester, MN, USA (Minnesota group), participated in this study. The angle of thoracic kyphosis and lumbar lordosis was higher in the Minnesota group than in the Akita group. The ratio of lumbar fractures to thoracic fractures was higher in the Akita group than in the Minnesota group. In the Akita group, multiple regression analysis revealed that the angle of lumbar lordosis correlated significantly with back extensor strength. CONCLUSIONS: We identified the difference in the shape of sagittal spinal curvature and distribution of vertebral fractures in women of comparable age with osteoporosis from two geographic areas of the world with different cultures and lifestyles. Back extensor strength was significantly associated with lumbar lordosis in Akita group, indicating the potential importance of strengthening the back extensor for improving or maintaining lumbar lordosis.

Combined treatment of alendronate and low-intensity pulsed ultrasound (LIPUS) increases bone mineral density at the cancellous bone osteotomy site in aged rats: a preliminary study.

INTRODUCTION: During fracture healing, alendronate encourages callus volume by inhibiting bone resorption, whereas low-intensity pulsed ultrasound (LIPUS) enhances bone regeneration by promoting an anabolic response. METHODS: In the present study, 9-month-old Sprague-Dawley rats, with a unilateral proximal tibial osteotomy, were treated with alendronate (daily, 1 µg/kg) plus sham-LIPUS (n = 14), saline plus LIPUS (20 min/day) (n = 18), alendronate plus LIPUS (n = 16), or saline plus sham-LIPUS as a control (n = 13) for 4 weeks. The rats were then examined for changes in bone mineral density (BMD) during metaphyseal bone repair. RESULTS: The combined therapy significantly increased BMD at the osteotomy site at 4 weeks (p < 0.001) compared with the control, without affecting the contralateral, non-osteotomized tibia. Both alendronate and LIPUS alone also exerted a positive, albeit less, effect on BMD in the affected limb (p < 0.001 and p = 0.006, respectively). CONCLUSION: Alendronate and LIPUS cooperate to enhance BMD during metaphyseal bone healing.

Spinal curvature and postural balance in patients with osteoporosis.

SUMMARY: Postural deformity might represent another risk factor for postural instability and falls. Relation between spinal curvatures and postural sway were evaluated. Lumbar (not thoracic) kyphosis and spinal inclination have a statistical correlation with postural sway. Postural deformity with lumber kyphosis may represent as a risk factor for falls. INTRODUCTION: Postural instability has been considered as a risk factor for falls and osteoporotic fractures. Previous studies have demonstrated that several factors display significant relationships with postural instability. Postural deformity might represent another risk factor for postural instability and falls. This study evaluates the influence of spinal curvature on postural instability in patients with osteoporosis. METHODS: Subjects comprised 93 patients with a mean age of 70 years. Angles of thoracic and lumbar kyphosis and spinal inclination that reflected a forward stooped posture were evaluated using a computer-assisted device. Sway and postural instability were evaluated using a computerized stabilometer showing seven parameters. Relationships among parameters of postural deformity and postural balance were analyzed using Pearson's correlation coefficients. RESULTS: No significant correlations were observed between any parameters of postural balance and angle of thoracic kyphosis. However, all parameters showed significant positive correlations with angle of lumbar kyphosis (r = 0.251-0.334; p < 0.05-0.001). Moreover, lumbar kyphosis, but not thoracic kyphosis, showed a positive correlation with spinal inclination (r = 0.692, p < 0.001), and all parameters of postural balance showed significant positive correlations with spinal inclination (r = 0.417-0.551, p < 0.001). CONCLUSION: Lumbar kyphosis, but not thoracic kyphosis, affecting spinal inclination and postural balance may represent a risk factor for falls.

Impact of spinal kyphosis on gastroesophageal reflux disease symptoms in patients with osteoporosis.

SUMMARY: Spinal kyphosis has been speculated to participate in the increased frequency of gastroesophageal reflux disease (GERD) in patients with osteoporosis. The present study provides further evidence that increases in lumbar kyphosis and number of vertebral fractures represent very important risk factors for GERD in patients with osteoporosis. INTRODUCTION: Osteoporosis and spinal kyphosis have been speculated to participate in the increased frequency of gastroesophageal reflux disease (GERD). The present study examined whether GERD in patients with osteoporosis is affected by spinal factors including spinal kyphosis in the presence of oral pharmacotherapies. METHODS: Subjects comprised 112 patients with osteoporosis (mean age, 78 years) who responded to the Frequency Scale for Symptoms of GERD (FSSG) questionnaire, regardless of complaints. Relationships between total FSSG score and number of vertebral fractures, angles of kyphosis, use of bisphosphonates and nonsteroidal anti-inflammatory drugs (NSAIDs), and total number of oral medicines per day were evaluated. Logistic regression identified factors associated with GERD. RESULTS: Bisphosphonates and NSAIDs did not affect total FSSG score. Total FSSG score showed significant positive correlations with total number of medicines (r = 0.283, p = 0.0025), angle of lumbar kyphosis (r = 0.576, p = 0.0001), and numbers of thoracic vertebral fractures (r = 0.214, p = 0.0232) and lumbar vertebral fractures (r = 0.471, p < 0.0001). Angle of lumbar kyphosis and number of lumbar vertebral fractures were identified by multivariate analysis as indices affecting the presence of GERD. CONCLUSION: Increases in angle of lumbar kyphosis and number of lumbar vertebral fractures may represent very important risk factors for GERD in osteoporotic patients.

Characterization of the mechanism of zidovudine uptake by rat conditionally immortalized syncytiotrophoblast cell line TR-TBT.

PURPOSE: To characterize the uptake mechanism of zidovudine (AZT), a nucleoside reverse transcriptase inhibitor, in syncytiotrophoblast cells using the TR-TBT 18d-1 cell line previously established by our group. MATERIALS AND METHODS: The effects of several transporter inhibitors on the initial and steady-state apical uptake of AZT by TR-TBT 18d-1 were characterized, in order to identify the transporter(s) involved. RESULTS: Initial uptake of AZT was sodium-independent and saturable; the K(m) value was about 16 microM. Nitrobenzylthioinosine (NBMPR), probenecid and cimetidine each had little effect on the saturable AZT uptake, indicating that well characterized transporters, such as organic anion transporters (OATs and OATPs), organic cation transporters (OCTs) and equilibrative nucleoside transporters (ENTs), are not involved. However, thymidine and 2'-deoxyuridine strongly inhibited AZT uptake. These results suggest that an unidentified nucleoside uptake transporter is responsible for the uptake of AZT. Cyclosporin A, Ko143 and probenecid had little effect on AZT accumulation by TR-TBT 18d-1 cells, suggesting that transporter-mediated efflux of AZT is not substantial. CONCLUSION: Our results indicate that saturable AZT uptake into TR-TBT 18d-1 is mediated by a so-far-unidentified transporter.

Effect of low-intensity back exercise on quality of life and back extensor strength in patients with osteoporosis: a randomized controlled trial.

UNLABELLED: Randomized controlled study in 80 postmenopausal women with osteoporosis was conducted to investigate the effect of a home-based, simple, low-intensity exercise. Low-intensity back-strengthening exercise was effective in improving the quality of life and back extensor strength. INTRODUCTION AND HYPOTHESIS: Back-strengthening exercise is effective in increasing back extensor strength and decreasing risk of vertebral fractures. We hypothesized that a home-based, simple, low-intensity exercise could enhance back extensor strength and improve the quality of life and/or spinal range of motion in postmenopausal women in a short-term follow-up. METHODS: Eighty postmenopausal women with osteoporosis were randomly assigned to a control group (n = 38) or an exercise group (n = 42). Subjects were instructed to lift their upper trunk from a prone position antigravity and maintain the neutral position. Isometric back extensor strength, spinal range of motion, and scores for quality of life were evaluated at baseline and 4 months. RESULTS: Back extensor strength significantly increased both in the exercise group (26%) and in the control group (11%). Scores for quality of life increased in the exercise group (7%), whereas it remained unchanged in the control group (0%). There was a significant difference in quality of life score between the groups (p = 0.012). CONCLUSIONS: Low-intensity back-strengthening exercise was effective in improving the quality of life and back extensor strength in patients with osteoporosis.

Back extensor strength and lumbar spinal mobility are predictors of quality of life in patients with postmenopausal osteoporosis.

UNLABELLED: To assess the effect of multiple factors on quality of life (QOL) in osteoporosis, relationships between the QOL and possible spinal factors were analyzed in 174 postmenopausal women with osteoporosis. Back extensor strength and lumbar spinal mobility were the most important factors for QOL in these patients. INTRODUCTION: Quality of life (QOL) in patients with osteoporosis and vertebral fractures is impaired by the decline of total spinal mobility, although it is not clear to what extent. This study aimed to assess the effect of multiple factors on QOL in patients with osteoporosis. METHODS: QOL of 174 postmenopausal women with osteoporosis (mean, 68 years old) was evaluated using the Japanese Osteoporosis QOL Questionnaire (JOQOL). Correlations between the JOQOL score, bone mineral density (BMD) of the lumbar spine/proximal femur/whole body, the kyphosis angle and mobility of thoracic and lumbar spine, the number of vertebral fractures, grip strengths of dominant and non-dominant hands, and isometric back extensor strength (BES) were analyzed. RESULTS: JOQOL showed significant correlation (p < 0.05) with age (r = -0.303), BES (r = 0.455), dominant and non-dominant grip strengths (r = 0.273 and r = 0.255, respectively), number of vertebral fractures (r = -0.282), BMDs of proximal femur and whole body (r = 0.200 and r = 0.157, respectively), lumbar kyphosis angle (r = -0.296), and lumbar spinal mobility (r = 0.345). Multiple regression analysis revealed that the BES and lumbar spinal mobility were the significant contributors to the JOQOL (p < 0.05). CONCLUSION: BES and lumbar spinal mobility are the important factors for QOL in patients with postmenopausal osteoporosis.

Effects of h-PTH on cancellous bone mass, connectivity, and bone strength in ovariectomized rats with and without sciatic-neurectomy.

The purpose of this study was to determine whether h-PTH (1-34) treatment would recover cancellous bone connectivity and bone strength in ovariectomized (OVX) or ovariectomized and sciatic-neurectomized (OVX+NX) rats. Seven-month-old female Wistar rats were treated with h-PTH or vehicle (6.0 microg/kg, six times a week, subcutaneously) for four weeks beginning 4, 8, or 12 weeks after OVX or OVX+NX. These were compared to age-matched baseline and sham-operated groups. Right tibiae were used for bone histomorphometry and node-strut analysis, and left tibiae were used for mechanical testing. The bone formation rates in the OVX and OVX+NX rats treated with h-PTH were significantly higher than those in their baseline controls. h-PTH treatment increased the node numbers and failure energies in the OVX rats, compared to their baseline controls, at all time points. However, in the OVX+NX rats, the effects of h-PTH treatment on the node number and failure energy were observed only at four weeks after surgery, but not at eight weeks or 12 weeks after surgery. These results suggest that the lowest limit, at which trabecular connectivity and bone strength are able to be restored by h-PTH, occurred between four and eight weeks in OVX+NX rats, but not in OVX rats. h-PTH cannot recover trabecular connectivity and bone strength in advanced osteopenia.

Impact of postural deformities and spinal mobility on quality of life in postmenopausal osteoporosis.

The objective of the study was to evaluate the impact of postural deformities and spinal mobility on quality of life (QOL) in patients with spinal osteoporosis. A total of 157 postmenopausal women aged over 60 years with osteoporosis were divided into five groups according to their postural deformities: round back (RB, n=41), hollow round back (HRB, n=33), whole kyphosis (WK, n=40), lower acute kyphosis (LAK, n=18), and normal posture (NP, n=25). QOL was evaluated using the Japanese Osteoporosis QOL Questionnaire (JOQOL) proposed by the Japanese Society for Bone and Mineral Research. This questionnaire contains six domains, with higher scores indicating higher levels of QOL. The number of vertebral fractures, thoracic kyphosis and lumbar lordosis angles, and spinal range of motion (ROM) during maximum flexion and extension were also measured with radiographs. Total QOL scores in RB, HRB, WK, and LAK groups were significantly lower than those in the NP group, and those in WK group were even lower compared with the other groups ( P<0.05). All the groups with postural deformities, but not the NP group, showed significant positive correlations between total QOL score and spinal ROM (0.521

Effects of combined treatment of insulin and human parathyroid hormone(1-34) on cancellous bone mass and structure in streptozotocin-induced diabetic rats.

The purpose of this study was to test the hypothesis that combined treatment with insulin and human parathyroid hormone (hPTH) is more effective than treatment with insulin or hPTH alone in improving cancellous bone mass, connectivity, and strength in insulin-dependent diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) in 7-month-old female Wistar rats. The diabetic rats received insulin, hPTH, insulin and hPTH, or hPTH vehicle for 4 weeks, starting 8 weeks after STZ injection. They were compared with baseline controls and normal controls that received STZ alone and STZ vehicle alone, respectively. The rats' proximal right tibias were processed to serve as undecalcified Villanueva-stained bone sections for histomorphometry. Changes in trabecular connectivity were determined through node-strut analysis. The decreased cancellous bone volume (BV/TV) and bone formation in diabetic rats improved in all the drug-treated groups compared with baseline controls. Furthermore, recovery of BV/TV was greater in rats that received the combination of insulin and hPTH than in those that received insulin or hPTH alone. In node-strut analysis, the node-related parameter (N.Nd/TV) significantly increased in rats that received the combination of insulin and hPTH, but did not increase in those that received insulin or hPTH alone. In addition to these results, the combination treatment significantly increased bone mineral density of the femur and bone strength in the femoral metaphysis compared with treatment with insulin or hPTH alone. These results indicate that the doses of insulin and hPTH employed in the combination treatment were more effective in improving not only bone mass but also trabecular connectivity and bone strength than treatment with insulin or hPTH alone in insulin-dependent diabetic rats.

Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats.

In order to develop a successful gene therapy system for the healing of bone defects, we developed a murine leukemia virus (MLV)-based retroviral system expressing the human bone morphogenetic protein (BMP) 4 transgene with high transduction efficiency. The bone formation potential of BMP4 transduced cells was tested by embedding 2.5 x 10(6) transduced stromal cells in a gelatin matrix that was then placed in a critical size defect in calvariae of syngenic rats. Gelatin matrix without cells or with untransduced stromal cells were the two control groups. The defect area was completely filled with new bone in experimental rats after 4 weeks, while limited bone formation occurred in either control group. Bone mineral density (BMD) of the defect in the gene therapy group was 67.8 +/- 5.7 mg/cm(2) (mean +/- s.d., n = 4), which was 119 +/- 10% of the control BMD of bone surrounding the defect (57.2 +/- 1.5 mg/cm(2)). In contrast, BMD of rats implanted with untransduced stromal cells was five-fold lower (13.8 +/- 7.4 mg/cm(2), P < 0.001). Time course studies revealed that there was a linear increase in BMD between 2-4 weeks after inoculation of the critical size defect with 2.5 x 10(6) implanted BMP4 cells. In conclusion, the retroviral-based BMP4 gene therapy system that we have developed has the potential for regeneration of large skeletal defects.

Restoring effect of human parathyroid hormone (1-34) on trabecular connectivity in ovariectomized rats.

The purpose of this study was to determine if the loss of the trabecular connectivities can be recovered by human parathyroid hormone-(1-34) therapy in ovariectomized (OVX) rats. Seven-month old female Wistar rats underwent ovariectomy or sham-operation at the beginning of the experiment. All sham operated groups (sham groups) were sacrificed after 0 (initial-BL group), 4, 8, 12, and 16 weeks, and one-third of the OVX rats were sacrificed as the baseline controls (OVX-BL groups) at 4, 8, and 12 weeks after OVX. Four weeks PTH or its vehicle treatment for residual OVX rats was started at 4, 8, or 12 weeks after OVX (OVX+PTH groups, OVX+vehicle groups). h-PTH (6.0 microg/kg) was injected subcutaneously six times a week for 4 weeks for each group. Their proximal right tibiae were processed for undecalcified Villanueva bone staining sections for bone histomorphometry. Furthermore, changes in trabecular connectivities were determined by node-strut analysis. h-PTH completely restored OVX-induced cancellous bone loss by stimulating bone formation. In node-strut analysis, node number in the OVX-BL-4, -8, and -12 groups was decreased to 53%, 49% and 44% of the initial-BL value respectively, and that in the OVX-4, -8, -12 + PTH groups recovered to 80%, 66%, 56% of the initial-BL value respectively. However, they were lower than those in their corresponding sham groups. The findings of this study suggested that decreased trabecular connectivity by OVX was recovered by intermittent h-PTH administration. However, delayed treatment blunted the restoration of trabecular connectivity.

Evidence that anabolic effects of PTH on bone require IGF-I in growing mice.

Although it has been established that PTH exerts potent anabolic effects on bone in animals and humans, the mechanism of PTH action on bone remains controversial. Based on the previous findings that PTH treatment increased production of IGF-I in bone cells and that PTH effects on bone cells in vitro were blocked by IGF-I-blocking antibodies, we proposed that IGF-I action is required for the stimulatory effects of PTH on bone formation. To test this hypothesis, we evaluated the effects of PTH on bone formation parameters in growing mice lacking functional IGF-I genes. Five-week-old IGF-I(-/-) mice and wild-type littermates were given daily sc injections of 160 microg/kg body weight of PTH (1-34) or vehicle for 10 d. In wild-type animals, PTH caused a significant increase in serum osteocalcin levels (113%), serum alkaline phosphatase activity (48%), and alkaline phosphatase activity in femoral bone extracts (>80%), compared with the vehicle-treated control group. In contrast, in IGF-I(-/-) mice, there was no significant effect of PTH on any bone formation parameters. PTH treatment increased total bone mineral density, as evaluated by peripheral quantitative computer tomography, at the distal metaphysis of the femur by 40% in wild-type mice, but it had no effect on bone mineral density in mice lacking functional IGF-I genes. In vitro studies using osteoblasts derived from control and IGF-I(-/-) mice revealed that PTH treatment increased cell number in osteoblasts derived from IGF-I knockout mice in the presence of exogenously added IGF-I but not without IGF-I. These data to our knowledge provide the first direct evidence that the anabolic effects of PTH on bone formation in vivo require IGF-I action in growing mice.

Evaluation of long-term sequential changes in bone mass and strength following withdrawal of incadronate disodium (YM175) in ovariectomized rats.

We evaluated the long-term effects of withdrawal of a newer third-generation bisphosphonate, incadronate disodium (YM175), on both cancellous and cortical bone mass and strength in ovariectomized (OVX) rats. One hundred and sixty female SD rats at 13 weeks of age were randomized into four groups: sham-operated, OVX, and low- and high- YM (0.01 or 0.1 mg/kg s.c., three times a week after OVX). After 4 weeks of treatment with vehicle or incadronate disodium, rats from each group (n = 8) were killed at 0 (baseline), 3, 6, 9, and 12 months after the withdrawal of YM175. Histomorphometric studies of the proximal tibia revealed a dose-dependent decrease in OVX-induced bone turnover; cancellous bone volume was significantly higher in the YM groups compared with the OVX control group up to 6 months after withdrawal at low dose and up to 12 months after withdrawal at high dose. The low-dose group showed little effect on tibial diaphyseal cortical bone volume and width, while the high-dose group preserved both cortical parameters 12 months after withdrawal. Mechanical testing of femurs revealed that both metaphyseal and diaphyseal strengths were significantly higher at high dose compared with the OVX group until 12 months after withdrawal. These observations demonstrated that high-dose incadronate disodium preserved both cancellous and cortical bone mass and strength in OVX rats for 12 months after withdrawal of the agent.

First total synthesis of (-)-ichthyothereol and its acetate.

The first and stereoselective total syntheses of (-)-ichthyothereol (1) and its acetate ((+)-2) were achieved by incorporation of the two chiral centers of diethyl L-tartrate. The starting diethyl L-tartrate was converted into trans-2-ethynyl-3-hydroxytetrahydropyran 14 in a stereoselective manner via the endo mode cyclization of the epoxy-alkyne derivative 12. The alcohol 12 was then transformed into (E)-iodoolefin derivative 15, which was exposed to a coupling reaction with 1-tributylstannyl-1,3,5-heptyne (19), derived from the corresponding 1-trimethylsilyl-1,3,5-heptyne (18), under Stille conditions to produce the all-carbon framework of the target natural products. Chemical modification of the coupled product 20 under conventional conditions completed the first total synthesis of (-)-ichthyothereol (1) and its acetate ((+)-2).

Systemic administration of insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) increases bone formation parameters in mice by increasing IGF bioavailability via an IGFBP-4 protease-dependent mechanism.

Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) is a potent inhibitor of IGF actions in vitro. However, we found that systemic administration of IGFBP-4 at pharmacological doses caused a significant increase in bone formation parameters in mice by a mechanism that may involve increased IGF bioavailability via proteolysis of IGFBP-4. To evaluate the hypothesis that proteolysis of IGFBP-4 is essential for the stimulatory effects of systemically administered IGFBP-4, we produced wild-type, protease-resistant, and IGFBP-4 proteolytic fragments and evaluated their effects using biochemical markers. Protease-resistant IGFBP-4 was more potent than wild-type IGFBP-4 in inhibiting IGF-I-induced mouse osteoblast cell proliferation in vitro and in inhibiting IGF-I-induced increase in alkaline phosphatase (ALP) activity in bone extract after local administration in vivo. Systemic administration of wild-type IGFBP-4, but not protease-resistant IGFBP-4, increased serum osteocalcin, serum ALP, and ALP in skeletal extracts in a dose-dependent manner, with a maximal effect of 40% (P < 0.05) at 1.25 nmol/mouse. Systemic administration of wild-type, but not protease-resistant, IGFBP-4 increased free IGF-I levels in serum in normal mice. IGF-I, but not wild-type IGFBP-4, increased bone formation parameters in IGF-I-deficient mice. This study demonstrates that systemic administration of IGFBP-4 increases bone formation parameters in mice by increasing IGF bioavailability in the circulation via an IGFBP-4 protease-dependent mechanism.

Long-term effects of withdrawal of bisphosphonate incadronate disodium (YM175) on bone mineral density, mass, structure, and turnover in the lumbar vertebrae of ovariectomized rats.

This study was designed to evaluate the long-term effects of incadronate disodium (YM175) after its withdrawal on cancellous bone mass in ovariectomized (OVX) rats. Thirteen-week-old female SD rats were randomized into four groups: sham-operated, OVX, low-YM, and high-YM (0.01 mg/kg or 0.1 mg/kg subcutaneously [sc], three times a week after OVX) groups. After 4 weeks of treatment with vehicle or YM175, rats from each group were killed at time points of 0 (baseline), 3, 6, 9, and 12 months after withdrawal of the agent. Bone mineral density (BMD) of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry (DXA). Bone volume (BV/TV), trabecular number and trabecular separation (Tb.N and Tb.Sp), eroded surface (ES/BS), osteoclast number and osteoclast surface (N.Oc/BS and Oc.S/BS), osteoid surface (OS/BS), and bone formation rate (BFR/BS) were measured as histomorphometric parameters of the fifth lumbar vertebra. BMD, BV/TV, Tb.N, and Tb.Sp in YM175-treated groups were maintained at the same level as in the sham group until 12 months after withdrawal in the high-YM group and until 3 months after withdrawal in the low-YM group. YM175 decreased both bone formative and resorptive parameters in histomorphometry. Serum bone-specific alkaline phosphatase (ALP) and urinary deoxypyridinoline at both doses of YM175 also showed a suppressive effect of this agent on bone turnover. These results indicate that YM175, after withdrawal, still maintains bone volume dose dependently by depressing bone resorption and formation in OVX rats. Intermittent YM175 treatment with a long interval may be sufficient to maintain the bone volume and structure in OVX rats.