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.

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.

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.

Evidence that IGF-binding protein-5 functions as a growth factor.

Recent studies support the concept that IGF-binding protein-5 (IGFBP-5) stimulates bone formation, at least in part, via IGF-independent mechanisms. To evaluate this hypothesis further, we evaluated in vitro and in vivo effects of IGFBP-5 on bone formation parameters using the IGF-I knockout (KO) mouse. Treatment of serum-free cultures of osteoblast clones derived from IGF-I KO mice with recombinant human IGFBP-5 increased both proliferation and alkaline phosphatase (ALP) activity in a dose-dependent manner, an effect comparable to that seen with IGF-I. IGF-II levels from media conditioned by osteoblasts derived from IGF-I KO mouse were below those detectable by RIA. To eliminate possible actions of IGF-II, if any was produced by osteoblasts derived from IGF-I knockout mice, the IGFBP-5 effect was studied in the presence of exogenously added IGFBP-4, a potent inhibitor of IGF-II actions in bone cells. Addition of IGFBP-4 blocked IGF-I- but not IGFBP-5-induced cell proliferation in osteoblasts derived from IGF-I knockout mice. Consistent with in vitro results, a single local injection of IGFBP-5 to the outer periosteum of the parietal bone of IGF-I KO mice increased ALP activity and osteocalcin levels of calvarial bone extracts. The magnitudes of IGFBP-5-induced increases in ALP and osteocalcin in parietal bone extracts of IGF-I KO mice were comparable to those seen in C3H mice. In contrast to IGFBP-5, local administration of IGFBP-4 had no significant effect on bone formation in C3H and IGF-I KO mice. These results provide the first direct evidence to our knowledge that IGFBP-5 functions as a growth factor that stimulates its actions in part via an IGF-independent mechanism.

Differential protein profile in the ear-punched tissue of regeneration and non-regeneration strains of mice: a novel approach to explore the candidate genes for soft-tissue regeneration.

Wound repair/regeneration is a genetically controlled, complex process. In order to identify candidate genes regulating fast wound repair/regeneration in soft-tissue, the temporal protein profile of the soft-tissue healing process was analyzed in the ear-punched tissue of regeneration strain MRL/MpJ-Fas(lpr) (MRL) mice and non-regeneration strain C57BL/6J(B6) mice using surface-enhanced laser desorption and ionization (SELDI) ProteinChip technology. Five candidate proteins were identified in which responses of MRL to the ear punch were 2-4-fold different compared to that of B6. Their corresponding genes were predicted using an antigen-antibody assay validated mass-based approach. Most of the predicted genes are known to play a role or are likely to play a role in the wound repair/regeneration. Of the five candidate proteins, the amount of the 23560 Da protein in the ear-punched tissue was significantly correlated with the rate of ear healing in six representative strains of mice, making it a good candidate for fast wound repair/regeneration. We speculate that the increased concentration of the 23560 Da protein in the wound tissue could stimulate the expression of various growth-promoting proteins and consequently speed up the wound repair/regeneration processes. Here, we have shown that examination of protein expression profile using SELDI technology, coupled with database search, is an alternative approach to search for candidate genes for wound repair/regeneration. This novel approach can be implemented in a variety of biological applications.

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.

Postnatal and pubertal skeletal changes contribute predominantly to the differences in peak bone density between C3H/HeJ and C57BL/6J mice.

Previous studies have shown that 60-70% of variance in peak bone density is determined genetically. The higher the peak bone density, the less likely an individual is to eventually develop osteoporosis. Therefore, the amount of bone accrued during postnatal and pubertal growth is an important determining factor in the development of osteoporosis. We evaluated the contribution of skeletal changes before, during, and after puberty to the development of peak bone density in C3H/HeJ (C3H) and C57BL/6J (B6) mice. Volumetric bone density and geometric parameters at the middiaphysis of femora were measured by peripheral quantitative computed tomography (pQCT) from days 7 to 56. Additionally, biochemical markers of bone remodeling in serum and bone extracts were quantified. Both B6 and C3H mice showed similar body and femoral weights. B6 mice had greater middiaphyseal total bone area and thinner cortices than did C3H mice. Within strains, males had thicker cortices than did females. C3H mice accumulated more minerals throughout the study, with the most rapid accumulation occurring postnatally (days 7-23) and during pubertal maturation (days 23-31). C3H mice had higher volumetric bone density as early as day 7, compared with B6 mice. Higher serum insulin-like growth factor I (IGF-I) was present in C3H mice postnatally at day 7 and day 14. Until day 31, B6 male and female mice had significantly higher serum osteocalcin than C3H male and female mice, respectively. Alkaline phosphatase (ALP) was found to be significantly higher in the bone extract of C3H mice compared with B6 mice at day 14. These data are consistent with and support the hypothesis that the greater amount of bone accrued during postnatal and pubertal growth in C3H mice compared with B6 mice may be caused by increased cortical thickness, increased endosteal bone formation, and decreased endosteal bone resorption.

Effects of recombinant insulin-like growth factor-binding protein-4 on bone formation parameters in mice.

Insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4), one of the most abundant IGFBPs produced by bone cells, is a potent inhibitor of IGF actions in vitro. To evaluate the modulation of IGF actions on bone formation in vivo by IGFBP-4, we produced intact and fragment (50- to 100-fold reduced IGF affinity) forms of BP-4 and examined their local and systemic effects using biochemical markers. Local administration of IGF-I over the right parietal bone significantly increased bone extract alkaline phosphatase activity; this was completely blocked by an equimolar dose of intact IGFBP-4, but not IGFBP-4 fragment. A single sc administration of IGF-I (2 microg/g BW) significantly increased bone formation markers in both serum and skeletal extracts; surprisingly, so did intact IGFBP-4, but not fragment IGFBP-4. Subcutaneous administration of an equimolar dose of IGFBP-4 along with IGF-I did not significantly block the IGF-I effect. Administration of intact IGFBP-4 significantly increased the serum 50-kDa IGF pool and decreased the 150-kDa IGF pool without significantly changing total IGF-I. We postulate that the increase in the 50-kDa IGF pool might enhance IGFs bioavailability via a mechanism involving IGFBP-4-specific protease. This study demonstrates for the first time that a single local administration of IGFBP-4 inhibits IGF-I-induced increases in bone formation, whereas systemic administration of IGFBP-4 alone increases serum levels of bone formation markers.

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.

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.

Development and evaluation of C-telopeptide enzyme-linked immunoassay for measurement of bone resorption in mouse serum.

The mouse is increasingly being used as an animal model for the study of skeletal phenotypes in humans, mainly because of the ease of genetic manipulation. Biochemical markers of bone metabolism provide a valuable parameter for the assessment of skeletal metabolism. In the mouse model, assays for bone formation have been available for a long time; however, little is known about bone resorption markers. The present study describes the development of a serum C-telopeptide enzyme-linked immunoassay (ELISA), which measures degradation products of type I collagen that are generated by osteoclastic bone resorption. The C-telopeptide ELISA uses affinity-purified antibodies generated against human sequence DFSFLPQPPQEKAHDGGR. The epitope involves an amino acid sequence, which is identical in the mouse and human C-terminal peptide of type I collagen (alpha1 chain). Sensitivity of the ELISA used was <0.1 ng/mL. The average intra- (n = 10) and interassay (n = 8) coefficient of variation for two controls was <12%. The average dilution and spike recovery rates were 98% and 97%, respectively. Application of the ELISA to measure C-telopeptide in 3-4-week postovariectomized (ovx) C57BL/6J (B6) mice (n = 9 or 10) showed a 45% higher C-telopeptide concentration than the sham-operated mice. Treatment of ovx mice with estradiol (400 microg/kg body weight) or alendronate (1.0 mg/kg body weight) resulted in a 20%-50% decrease in C-telopeptide levels compared to the vehicle-treated ovx group. In addition, B6 mice fed a calcium-deficient diet (0.01% calcium) showed a 50% higher C-telopeptide concentration compared to the B6 mice receiving a normal diet (0.6% calcium). In conclusion, the C-telopeptide ELISA exhibited acceptable analytical performance and sufficient discriminatory power to show expected directional changes in the rate of bone resorption following ovariectomy, ovx plus estradiol or alendronate treatment, and administration of a calcium-deficient diet. Therefore, the ELISA developed in this study could be used for measuring bone resorption in the mouse model.

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.

Trabecular remodeling processes in the ovariectomized rat: modified node-strut analysis.

The purpose of this study was to evaluate the trabecular bone remodeling processes in ovariectomized rats, focusing on diminishing trabecular connectivity. We used modified node-strut analysis defining three areas in the trabecular surfaces for the three-dimensional understanding of trabecular resorption derived from two-dimensional conventional sections, in addition to conventional bone histomorphometry and node-strut analysis. Seven-month-old female Wistar rats were used and treated with bilateral ovariectomy (ovx) and sham operation. Six rats in each group were examined at 4 and 8 weeks. We prepared undecalcified sections from the left tibiae with Villanueva bone and Goldner stains. We divided the trabecular bone surfaces (BS) into three areas: node (Nd), terminus (Tm), and strut (St), and measured the bone resorption and formation parameters, including eroded surface (ES), osteoclast surface (Oc.S), osteoid surface (OS), and double-labeled surface (dLS) in each defined area. In conventional bone histomorphometry, the ovx group showed high turnover osteopenia compared with the sham operation group. In node-strut analysis, the ovx group showed significantly lower values for node-related parameters than did the sham operation group. In the modified node-strut analysis, bone resorption parameters in the ovx group showed significantly higher values, particularly for strut and terminus-eroded surfaces (StES/BS, TmES/BS), and for each area of osteoclast surface (NdOc.S/BS, TmOc.S/BS, and StOc.S/BS) compared with the sham operation group. Bone formation parameters in the ovx group also showed significantly higher values, particularly for strut and terminus osteoid surfaces (TmOS/BS, StOS/BS), and for each area of double-labeled surface (NddLS/BS, TmdLS/BS, and StdLS/BS) compared with the sham operation group at 4 weeks. At 8 weeks, each area of bone formation parameter in the ovx group showed significantly higher values than that in the sham operation group. These results suggest that in the ovx group, the trabecular plates became perforated and the perforative cavities progressively enlarged, and/or the edges of plates were eroded regardless of elevated bone formation, resulting in diminished trabecular connectivity, and the node area might not be influenced relatively by bone remodeling in the early resorption.

Effects of dietary calcium depletion and repletion on dynamic determinants of tibial bone volume in two inbred strains of mice.

As an adjunct to our efforts to identify the genes that determine peak bone density, we examined phenotypic differences between two inbred strains of mice, C3H/HeJ (C3H) and C57BL/6J (B6), which are of similar size but differ with respect to peak bone density (e.g., C3H mice have 53% higher femoral bone density than B6 mice). The current studies were intended to compare the skeletal responses of C3H and B6 mice to 2 weeks of dietary calcium (Ca) depletion, followed by 2 weeks of Ca repletion. Initial studies showed that: (a) femur dry weight decreased during Ca depletion in both C3H and B6 mice (by 25% and 19%, respectively, p < 0.001) and most of this loss was recovered during Ca repletion; and (b) serum alkaline phosphatase (ALP) activity increased during Ca depletion, in both strains of mice (p < 0.001), and returned to normal after Ca repletion. Histological analyses of ground cross sections prepared at the tibiofibular junction showed that Ca-depletion increased medullary area in both C3H and B6 mice (indicating endosteal bone loss, p < 0.01), with reversal during Ca repletion. There were no effects of Ca depletion or repletion on periosteal bone growth. Endosteal bone forming surface and endosteal mineral apposition decreased during Ca depletion and increased during repletion in both C3H and B6 mice (p < 0.05). Net bone formation decreased during Ca depletion in C3H mice, but not B6 mice (p < 0.01), and was normal during Ca repletion in both strains. Endosteal bone resorbing surface and net bone resorption increased during Ca depletion and decreased during repletion in both strains (p < 0.01). A supplemental study (of Ca depletion without repletion) confirmed the effects of Ca depletion on femoral dry weight and serum ALP activity (p < 0.001 for each). This supplemental study also showed that Ca deficiency increased serum parathyroid hormone (PTH) (p < 0.05) and decreased (tibial) cortical bone area and cortical mineral content (p < 0.05 to p < 0.001) in both strains of mice. Together, these data demonstrate that the skeletal responses to Ca depletion and repletion are, qualitatively, similar in C3H and B6 mice.

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.

Outcome of one-level posterior lumbar interbody fusion for spondylolisthesis and postoperative intervertebral disc degeneration adjacent to the fusion.

STUDY DESIGN: Review of the clinical and radiologic records of patients who underwent one-level posterior lumbar interbody fusion (PLIF) at L4-L5. OBJECTIVE: To determine whether adjacent intervertebral disc degeneration after PLIF affects the clinical results, and whether preoperative caudal disc (L5-S1) degeneration affects postoperative clinical results. SUMMARY OF BACKGROUND DATA: There is little reliable information in the literature regarding clinical results and adjacent disc degeneration after PLIF. METHODS: Forty-five patients who underwent L4-L5 PLIF for spondylolisthesis with more than 5 years of postoperative observation were included in this study. PLIF was performed in conjunction with posterior instrumentation. The posterior lumbar intervertebral grafting was performed using both autograft and a ceramic spacer. Intervertebral disc heights at L2-L3, L3-L4, and L5-S1 were measured before and after surgery. The patients were divided into two groups based on the presence or absence of the preoperative L5-S1 narrowing. Correlation between clinical status evaluated by the recovery rate of the Japanese Orthopedic Association (JOA) score and disc heights were determined. RESULTS: All intervertebral disc heights adjacent to the fusion decreased after surgery (P < 0.05). However, no significant correlation was seen between clinical results estimated by the recovery rate and postoperative disc narrowing. There was also no significant difference in clinical results between patients with or without preoperative L5-S1 narrowing. CONCLUSIONS: There is no evidence from the results that postoperative narrowing of the adjacent disc and preoperative narrowing of the L5-S1 disc affects the clinical outcome of L4-L5 PLIF.

Anterior decompression with single segmental spinal interbody fusion for lumbar burst fracture.

STUDY DESIGN: The clinical and radiologic records for seven patients with lumbar burst fracture who underwent anterior decompression with single segmental interbody fusion were reviewed. OBJECTIVE: To determine the clinical results obtained with this method and its influence on the intervertebral disc degeneration inferior to the fusion. SUMMARY OF BACKGROUND DATA: Some patients with Denis' type B fracture can tolerate one-segment anterior fusion. However, there is no reliable information in the literature regarding the juxtafusional disc degeneration after one-segment fusion. METHODS: Seven patients with type B lumbar burst fractures, including four with cleavage fracture of the lower endplate, underwent anterior single segmental fusion; three patients underwent surgery with no instrumentation, and four underwent surgery with Kaneda instrumentation. The mean follow-up period lasted 85 months. The kyphosis angle and inferior intervertebral disc height adjacent to the fusion were measured before and after surgery. Pain and working status were evaluated using the scales proposed by Denis et al. RESULTS: Significant correction loss was obtained 1 year after surgery in the patients in whom no instrumentation was used (7.3 +/- 0.6 degrees), compared with the correction loss in patients whose surgery included the use of instrumentation (0.3 +/- 0.5 degree; P = 0.00001). No further correction losses were seen in either group at the final follow-up examination. No marked reduction in disc height was observed in any patient, including the four patients with cleavage fracture of the lower endplate. All patients returned to their previous occupation; five patients were rated as P1 (no pain) and W1 (returned to heavy labor), and two patients were rated as P2 (minimal pain) and W2 (return to heavy labor with lifting restrictions) at the final follow-up examination. CONCLUSIONS: There was slight correction loss within 1 year when no instrumentation was used, but this deformity did not affect the clinical results. The results provided no evidence that cleavage fracture of the lower endplate accelerates degeneration of the adjacent intervertebral disc.