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The MOVEMENT study was designed to assess the effectiveness of monthly intravenous ibandronate on bone mineral density (BMD) in daily clinical practice in Japanese patients with primary osteoporosis whose lumbar spine BMD did not increase despite oral bisphosphonate therapy. This study was a multicenter, prospective, interventional study (52 sites; August 2015 to March 2018). Patients aged ≥ 50 years with primary osteoporosis, evaluated as low responders to oral bisphosphonate treatment for 1-3 years, continued on their existing oral bisphosphonate or switched to monthly intravenous ibandronate (1 mg) for 12 months. The primary endpoint was change in lumbar spine BMD from baseline to 12 months in the intravenous ibandronate group (IV IBN). A total of 240 and 141 patients were enrolled in the IV IBN and oral bisphosphonate groups (OBP), respectively. At 12 months, a significant increase in mean percent change from baseline in lumbar spine BMD was observed in the IV IBN (2.70%). This change was also significant at 6 months (1.92%). Similarly, the change in total hip BMD showed a significant increase at 12 months (0.78%). In the IV IBN, the responder rate, percentage of patient whose change from baseline of lumbar spine BMD has greater than 0%, for lumbar spine BMD was high at both 6 (72.3%, 141/195 patients) and 12 (78.0%, 145/186 patients) months. No new safety concerns were observed in either treatment group. Treatment with intravenous ibandronate significantly increased lumbar spine BMD without any new safety concerns in Japanese patients with osteoporosis who showed low response to existing oral bisphosphonates.

Background and aims Clinical data regarding alendronate jelly are limited. We compared the efficacy and safety of once‐weekly alendronate oral jelly with once‐weekly alendronate tablet formulations in the context of primary osteoporosis. Methods In this 6‐month, open‐label, prospective, observational study, Japanese patients aged ≥60 years with primary osteoporosis were included from 14 primary care centres in Japan. The effects of once‐weekly alendronate oral jelly and tablet formulations on bone mineral density (BMD), bone turnover markers, and quality of life related to gastrointestinal symptoms were assessed at baseline and 6 months. Treatment was allocated by patient preference. This potentially confounding factor was adjusted for statistically. Results In total, 170 patients were enrolled (jelly, n = 97; tablet, n = 73). Mean percent changes in radius, lumbar spine, femoral neck, and hip BMD were similar in both treatment groups at 6 months. Both formulations decreased tartrate‐resistant acid phosphatase 5b (TRACP‐5b) and procollagen 1 N‐terminal peptide (P1NP) between baseline and 6 months (by about 50% and 60%, respectively); no significant differences in mean changes were noted in these markers between groups. At 6 months, no significant differences were noted in visual analogue scale or EuroQOL five‐dimension questionnaire scores between groups. The jelly group had significantly lower scores than the tablet group in the Izumo scale domains of heartburn (−0.81, P = 0.0040), epigastralgia (−0.94, P = 0.0003), and epigastric fullness (−0.49, P = 0.044). During treatment, more patients discontinued for upper gastrointestinal symptoms in the tablet group (n = 4) than the jelly group (n = 1). Conclusions Once‐weekly alendronate oral jelly 35 mg may be a suitable alternative therapeutic agent for primary osteoporosis in Japan.

In the original publication of the article, the Figures 2 and 3 were published incorrectly. The corrected figures are given below.

Summary Combined treatment with alendronate and eldecalcitol was found to be more effective in reducing the bone turnover markers and increasing bone mineral density than alendronate treatment with vitamin D3 and calcium supplementation in the osteoporotic patients. Introduction We compared the clinical efficacy and safety of combined treatment with alendronate plus eldecalcitol (ALN + ELD) with those of treatment with ALN plus vitamin D and calcium (ALN + VitD). Methods Osteoporotic 219 patients were randomly assigned to the ALN + ELD, or the ALN + VitD group. Primary endpoint was the inter-group differences in lumbar spine BMD (L-BMD) at patient’s last visit. Secondary endpoints included the differences in BMD at other sites and the bone turnover marker (BTM) levels. Results L-BMD, total hip BMD and femoral neck (FN-BMD) increased from baseline by 7.30, 2.41, and 2.70 % in the ALN + ELD group, and by 6.52, 2.27, and 1.18 % in the ALN + VitD group, respectively. Inter-group differences of the L-BMD and total hip BMD values were not significant. The increase of the FN-BMD was larger in the ALN + ELD group than the ALN + VitD group. Reductions of the BTMs were greater in the ALN + ELD group than the ALN + VitD group. Interaction of the percent increase of the L-BMD with the baseline values of the BTMs was observed in the ALN + VitD group only. The increases of the FN-BMD in patients with lower baseline values of type-I-collagen C-telopeptide (sCTX) and serum 25(OH) D levels

Bisphosphonates are effective in decreasing bone resorption, the incidence of fragility fracure, and pain from bone metastases. Although relatively well tolerated, the initial dose(s)of intravenous or oral monthly aminobisphosphonates can be associated with an acute phase response, a nonspecific physiologic reaction associated with increased levels of inflammatory cytokines, fever, and flu like symptoms including fatigue, nausea, and myalgia within 3 days of dosing and lasting 7 days or less. Nitrogen-BPs(N-BPs)inhibit osteoclast function by acting as potent inhibitors of the enzyme farnesyl diphosphate(FPP)synthase in the mevalonate biosynthetic pathway. Following an intravenous infusion or oral monthly BPs, transient uptake of N-BP into peripheral blood monocytes results in intracellular accumulation of isopentenyl diphosphate(IPP)due to FPP synthase inhibition. Recognition of IPP by γδT cells triggers their activation and expansion, resulting in the release of pro-inflammatory cytokines that cause the flulike symptoms of the acute phase reaction. There is trial evidence that its severity can be reduced by more than half with coadministration of acetaminophen, so the short-term use of these drugs to lessen the APR is advisable in patients receiving their first dosing of N-BPs. Levels of 25(OH)D were negatively correlated with the incidence and severity of APR. Vitamin D reduces the intensity of musculoskeletal pain after dosing of N-BPs for postmenopausal osteoporosis. APR has minimal impact on long-term adherence to therapy. It is less common in subjects who have previously used bisphosphonates. Information of APR to a patient is important before administration.

To evaluate the effects of tiludronate on the mass, structure, and turnover of cancellous bone regions in immobilized rat tibiae, we performed a 4 week dosing experiment. The right hindlimbs of 84 Sprague-Dawley rats (5 weeks old) wee neurectomized or sham operated. Animals were assigned to seven groups (n = 12 each); group 1 was sham operated, and groups 2-7 were neurectomized. Groups 1 and 2 were given vehicle only (distilled water), and groups 3, 4, and 5 were given tiludronate orally at doses of 25, 50, and 100 mg/kg body weight (BW)/day, respectively, throughout the experimental period. Group 6 was given 100 mg/kg BW/day of the agent for the first 2 weeks only, and group 7 received vehicle only for the first 2 weeks and then 100 mg/kg BW/day of the agent for the last 2 weeks. After tetracycline labeling was performed, the right tibiae were removed from the animals and processed to yield undecalcified sections. Histomorphometry was performed in the epiphyseal, primary, and secondary spongiosa of the proximal tibia. In group 2, trabecular bone volume (BV/TV) and trabecular number (Tb.N) were significantly decreased in the primary and secondary spongiosae, but this did not occur in the epiphyseal spongiosa. Osteoid surface (OS/BS) was decreased and osteoclast surface (Oc.S/BS) was increased in the secondary spongiosa. Tiludronate increased BV/TV and Tb.N in the primary spongiosa by reducing the values for the parameters of osteoclast surface (Oc.S/BS) and osteoclast number (Oc.N/BS). Osteoid surface in this region was not decreased by the agent. In groups 4 and 5, tiludronate prevented bone loss in the secondary spongiosa by reducing both OS/BS and Oc.S/BS. In group 6, BV/TV in the primary spongiosa was maintained at the level of group 1, but Oc.S/BS and Oc.N/BS were elevated. In the secondary spongiosa, bone mass was preserved and the reduction in these parameters was maintained. In group 7, however, BV/TV was increased in the primary spongiosa as a result of a reduction in osteoclastic resorption; in the secondary spongiosa, however, BV/TV was decreased and trabecular turnover was not reduced at the end of the experiment in these growing animals. Mineral apposition rates were not reduced by tiludronate. This study clearly demonstrated that this agent prevented immobilization bone loss by inhibiting resorption.(ABSTRACT TRUNCATED AT 400 WORDS)

We report four cases of femoral shaft fracture after operative treatment for femoral neck fracture. All cases were women aged 68 to 91 years. They were studied from January 1999 to June 2001. Three femoral shaft fractures occurred three months after operation for femoral neck fracture and were treated using the long gamma nail. One femoral shaft fracture occurred four months after operation and was treated using the intramedullary nail. Two cases were treated using the gamma nail without distal locking screw for the femoral neck fracture, one using the gamma nail with distal locking screw, and the remaining one using the compression hip screw and canulated cancellous hip screw.In all cases, postoperative femur shaft fracture occurred in an early stage. Treatment for this fracture needs to be selected in consideration of union of the femur neck fracture. The long gamma nail and intramedullary nail were found to be useful for secondary femoral shaft fracture.

To clarify the effects of 1 alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) on bone growth, strength, and turnover in growing rats with liver cirrhosis induced by carbon tetrachloride (CCl(4)) injection, groups of 4-week-old male Wistar rats (n = 10, each) were injected intraperitoneally with CCl(4) twice weekly for 7 weeks. One group was treated with the vehicle alone (Group 1). Three CCl(4)-injected groups were orally administered 1,25(OH)(2)D(3) at doses of 0, 0.05, and 0.1 micro g/kg, respectively (Groups 2, 3, and 4). At the end, serum levels of 1,25(OH)(2)D(3), IGF-I, and osteocalcin were reduced in Group 2 compared to Group 1, and the corresponding values in Group 4 were larger than those in Group 2. Urinary deoxypyridinoline levels increased in Group 2 compared to Group 1, and did not significantly differ in Groups 2-4. The values for bone sizes, mineral content (BMC) in the lumbar vertebra and femur, and ultimate bending load in the femur were reduced in Group 2 compared to Group 1, and lumbar BMC in Group 3 and bone sizes in Group 4 were larger than those in Group 2. The values for lumbar trabecular bone volume in Group 2 were reduced compared to Group 1, and the corresponding values in Group 4 were larger than those in Group 2. Bone formation rates, reduced in Group 2 compared to Group 1, did not differ in Groups 2-4. Parameters for trabecular osteoclasts did not differ among all groups. In the proximal tibia, the value of activation frequency (Ac.f) in Group 2 significantly decreased compared to Group 1. Ac.f values in Groups 3 and 4 were larger than that in Group 2. These data demonstrated that retardation of bone growth in CCl(4)-injected rats was associated with reduced serum 1,25(OH)(2)D(3) and IGF-I levels. The trabecular bone in the rats exhibited low turnover osteopenia. 1,25(OH)(2)D(3) administration partially prevented the growth disturbance, but did not substantially affect bone turnover. Factors other than 1,25(OH)(2)D(3) and IGF-I appeared to be critical in the low turnover osteopenia evident in liver cirrhosis.

To test the hypothesis that the effect of trabecular microarchitecture on bone strength varies with the duration of estrogen loss, we evaluated the relationship between three-dimensional (3D) parameters for trabecular microarchitecture and bone minerals with the compressive load of the lumbar vertebra in rats. Female Sprague-Dawley rats (n = 190) were divided into 19 groups. Ten rats were killed at day 0. Half of the remaining rats underwent bilateral ovariectomy (ovx), and the others were subjected to sham surgery. Ten rats from each group were killed at 3, 7, 11, 14, 28, 42, 56, 70, and 84 days postsurgery. Urinary deoxypyridinoline and serum osteocalcin increased significantly in the ovx group from days 28 and 11, respectively, compared with the sham group. Bone mineral content (BMC) and bone mineral density (BMD) of the fifth lumbar body diminished from days 42 and 84, respectively, compared with the sham group. In ovx rats, trabecular bone volume (BV/TV), measured using 3D images of microcomputed tomography, diminished from day 28 compared with both baseline control and sham. The trabecular bone pattern factor (TBPf) and structure model index (SMI) increased from day 28 in the ovx group compared with both baseline control and sham. Ultimate compression loads diminished at day 28 compared with baseline control and decreased progressively thereafter. Neither of these parameters changed in the sham group during the same period. Within 4 weeks post-ovx, TBPf, SMI, and BV/TV correlated with load (p < 0.01). BMC and BMD correlated with load from 6 weeks post-ovx (p < 0.01). Stepwise regression analysis showed that TBPf was the most significant determinant of load within 4 weeks post-ovx (coefficient of determination [R(2)] = 0.669; p < 0.01). SMI correlated with TBPf (R(2) = 0.968; p < 0.01). Moreover, R(2) for ultimate load indicated higher values of 0.975 with TBPf and SMI. However, BMC was the most significant determinant of load from 6 weeks post-ovx (R(2) = 0.511; p < 0.01), as it was in the sham group. These data suggest that changes in trabecular bone contour with increased bone turnover are critical for reducing lumbar bone strength during the early post-ovx period in rats.

Deficiency of vitamin D, which is required for calcium homeostasis, causes rickets with hypocalcemia and hypophosphatemia, resulting in growth retardation and impaired bone formation. Mice lacking the vitamin D receptor (VDR) develop the typical features of rickets, establishing that VDR plays a role in controlling the actions of vitamin D. Normalization of impaired mineral homeostasis in VDR KO mice fed a diet supplemented with high concentrations of calcium (2%) and phosphorus (1.25%) is reported to reverse the malformation of bone and the growth retardation as well. However, the relationship between mobilization of phosphorus and calcium and nuclear control of vitamin D actions remains unclear. The present study was undertaken to determine the effect of dietary phosphorus on mineral mobilization and bone mineralization. We report here that feeding a diet supplemented with a restricted amount of phosphorus (0.25%) and a normal amount of calcium (0.5%) for 4 weeks reverses the growth retardation and the impaired mineralization in VDR KO mice, as does a high-calcium and high-phosphorus diet (Ca: 2%; P: 1.25%). Thus, the present study suggests that mobilization of calcium and mobilization of phosphorus are differentially regulated through vitamin D-dependent and -independent systems, and that intake of calcium and phosphorus in the proper ratio is important for mineral homeostasis and bone mineralization.

Although it is well established that estrogen deficiency causes osteoporosis among the postmenopausal women, the involvement of estrogen receptor (ER) in its pathogenesis still remains uncertain. In the present study, we have generated rats harboring a dominant negative ERalpha, which inhibits the actions of not only ERalpha but also recently identified ERbeta. Contrary to our expectation, the bone mineral density (BMD) of the resulting transgenic female rats was maintained at the same level with that of the wild-type littermates when sham-operated. In addition, ovariectomy-induced bone loss was observed almost equally in both groups. Strikingly, however, the BMD of the transgenic female rats, after ovariectomized, remained decreased even if 17beta-estradiol (E(2)) was administrated, whereas, in contrast, the decrease of littermate BMD was completely prevented by E(2). Moreover, bone histomorphometrical analysis of ovariectomized transgenic rats revealed that the higher rates of bone turnover still remained after treatment with E(2). These results demonstrate that the prevention from the ovariectomy-induced bone loss by estrogen is mediated by ER pathways and that the maintenance of BMD before ovariectomy might be compensated by other mechanisms distinct from ERalpha and ERbeta pathways.

Trabecular bone turnover and bone marrow capacity for the development of bone cells in the tibia were assessed after sciatic neurectomy (NX) in mice. The right hindlimbs of 6-week-old DDY mice were neurectomized and left hindlimbs were sham-operated and served as NX controls. Histomorphometrical analyses of the trabecular bone of the proximal tibia demonstrated the initial decrease in bone formation rate for the first 14 days and the subsequent increase in osteoclast surface for the next 14 days. The number of adherent stromal cells per tibia obtained for the NX limbs was reduced on days 7 and 10 postsurgically, and then recovered on day 12. However, the alkaline phosphatase activity of the cells was persistently depressed. The formation of osteoclast-like multinucleated cells in the marrow cultures obtained from NX limbs at days 10, 12, and 14 showed a significant increase in the medium containing parathyroid hormone (PTH). The number of colonies cultured for colony forming units-fibroblastic (CFU-f) that developed from the marrow cells did not differ in the NX and the contralateral limbs at any time during the period. On the other hand, the number of colonies cultured of colony forming units for granulocytes and macrophages (CFU-GM) was markedly increased for both the NX and the contralateral tibiae at days 12 and 14. This study clearly demonstrates that there are two stages in the development of osteopenia after NX. During the first 14 days, trabecular bone formation and number of marrow stromal cells are reduced. In the second 14 day period, the trabecular osteoclast number is increased and osteoclast formation from the bone marrow cells is enhanced in the presence of PTH. However, neither the CFU-f nor the CFU-GM assay could identify the changes in osteogenic or osteoclastogenic potential of the bone marrow. These in vitro assays provide limited information on the shifts in bone marrow cell lineages and the local environment producing osteopenia in the immobilized limb in vivo.

To clarify the local changes in bone formation and resorption during the early period after ovariectomy (OVX), 200 SD rats, 4 months of age, underwent OVX or sham surgeries and seven to nine rats from each group were terminated at 1, 3, 7, 11, 15, 19, 23, 28, 35, 63, and 91 days postsurgery after tetracycline labeling. Serum intact osteocalcin levels were measured. Undecalcified sections of the 5th lumbar body (L5) and the right proximal tibia were measured for trabecular bone area, the labeled perimeters and the interlabeling distances after Villanueva's staining. On the 4th lumbar body (L4) and the left proximal tibia, undecalcified sections were measured for the trabecular osteoclast by tartrate-resistant acid phosphatase staining. The uterine horns were atrophied on the 3rd postovariectomy day (day 3). Serum osteocalcin levels increased on day 7 and reached the highest value on day 23. In either L5 or the metaphysis of the proximal tibia, trabecular bone volume (BV/TV) significantly decreased on day 15. The trabecular bone loss on day 28 was approximately 50% in the tibia and 15% in the L5. In either the lumbar or the tibia, osteoclast numbers significantly increased at day 3, and peaked between days 15 and 23. In the tibia, however, the bone formation rates (BFR/BS) were significantly reduced on the 3rd and 7th post-surgical days compared with the start value for both the OVX and sham groups. The BFR/BS values in L5 did not decrease during the first 7 days in either group. The BFR/BS values were then increased for both L5 and the tibia after day 7. These data clearly demonstrated that the local bone turnover 7 days post-OVX was identical in the proximal tibia and the lumbar vertebra. In the proximal tibia, however, it may be suggested that the increased bone resorption and reduced formation within 7 days after OVX due to the combined effects of both an estrogen deficiency and the surgical intervention would possibly play a critical role in the greater magnitude of the trabecular bone loss.

This study compared radiological and clinical results of Mallory-Head (Biomet, Warsaw, Indiana) cementless total hip arthroplasty (THA) by anatomical (AP group) or high cup placement (HP group) for Crowe I to III developmental dysplasia of the hip. Of the 68 hips studied, 43 hips were available for 15.3-year follow-up. Ten cups were placed at anatomical center with bulk bone grafting, and 33 cups were at high hip center without bulk bone grafting. No acetabular or femoral components showed loosening in either group. One standard polyethylene liner in a highly placed cup was revised due to excessive wear after 11 years. The average rate of polyethylene wear was 0.128 mm/year in the AP group and 0.148 mm/year in the HP group (except for the revision case). The extent of grafted bone coverage was 34.6% in the AP group. Hip center height was 24.5 mm from the inter-teardrop line in the HP group. The center of the hip horizontal location in the AP group (24.5 mm) and HP group (26.4 mm) was significantly shorter than in normal hips (35.6 mm). Postoperative center-edge angle was 11° (except grafted bone) in the AP group and 25° in the HP group. Mean Harris Hip Score in the AP group improved from 38 points preoperatively to 82 points postoperatively and in the HP group improved from 40 points preoperatively to 88 points postoperatively. Survivorship was 100% in the AP group and 97% in the HP group. Our results indicate that moderate high cup placement without bulk bone grafting at a horizontal locus more medial than that of a normal hip is an alternative durable solution.

Poly-L-Lactic acid screws were applied for internal fixation when performing a Rotation Acetabular Osteotomy in 6 Hip joints (PLLA group). A comparison group had a K-wire applied in 21 Hip joints (K-wire group). We reviewed the surgical time, bleeding volume during and after surgery, and could not find any significant difference between the PLLA and K-wire groups. Strength and complications such as bone resorption and inflammation around the screws were abo similar.

Paget's disease is a localized and progressive disorder of bone, characterized by increased bone remodeling. The increase of bone turnover changed bone quality in Paget's disease. The assessment of bone quality is consisted on two properties of structure and material. Bone quality is evaluated clinically by the bone turnover. Treatment of bisphosphonate in Paget's disease controlled bone turnover. There's a possibility that treatment of bisphosphonate improve not only the property of structure but also that of material. It's hoped that the newer and stronger bisphosphonates play an increasingly important role in the treatment for bone quality of Paget's disease.

Patients with rheumatoid arthritis (RA) develop both generalized and periarticular osteoporosis. Osteoporosis in RA causes by increase of bone resorption, however the decrease of bone formation has been concerned in development of osteoporosis. Drug therapy have to bigin as early as osteopenia, and a potent inhibitor of bone resorption will be effective to suppress the increse of bone resorption in RA patients. RA-associated osteoporosis including grucocorticoid induced osteoporosis decreases bone formation, vitamin D and parathyroid hormon would become the useful drug for promoting the bone formation by examination of new agents, method and dosage of treatment for osteoporosis in RA patients.

From 1991 to 1994, we performed 31 cementless total hip arthroplasties in 30 patients. Of these we were able to follow 15 joints in 15 patients for more than one year. From these 15 total hip arthroplasties, we assessed roentgenologic criteria on the stem side. According to the assessment, there were two “unstable” stems and it seemed important to get cancellous condensation in the proximal femur.

A-fifty-four year old man was admitted to our hospital on June 12, 1986. He was unable to walk and had 96 degrees of kyphosis. He had suffered from tuberculosis of the spine when he was nine years old. From that time he had had no complaints although retained a level of kyphosis. Forty years later he had weakness in the lower limbs and eventually became unable to walk. Surgery for anterior debridement and spinal fusion with strut bone grafts was carried out with Halo-Pelvic traction, and followed by treatment with INH, RF, SM, EB. He was able to walk again and worked regularly after discharge. Eight years later the spine remained fused and the degree of kyphosis was 83°. Anterior decompression and fusion with strut bone grafts is a good treatment for Pott's Palsy with severe kyphosis.

To clarify the role of nitric oxide (NO) in regulation of bone metabolism in response to skeletal loading, we examined inducible NO synthase (iNOS) gene knockout mice in the tail-suspension model. Histomorphometric analyses of proximal tibias revealed that 7 days of tail suspension decreased the bone volume (BV/TV) and bone formation rate (BFR/BS) and increased the osteoclast surface (Oc.S/BS) in mice with all iNOS genotypes. Both iNOS+/+ and iNOS+/- mice responded to subsequent 14-day reloading, with increases in BV/TV and BFR/BS and a decrease in Oc.S/BS, whereas these responses were abolished in iNOS-/- mice. The osteoblasts flattened after tail suspension appeared cuboidal during subsequent reloading. Immunoreactivity for iNOS was detected in these osteoblasts and osteocytes by immunohistochemistry. These defective responses after reloading were rescued in iNOS-/- mice by treatment with an NO donor nitroglycerine (NG). Conversely, the responses in iNOS+/+ mice were inhibited by treatment with an NOS inhibitor aminoguanidine (AG). In bone marrow cell cultures, mineralized nodules derived from iNOS-/- mice after reloading were significantly reduced. Taken together, our results suggest that NO generated by iNOS in osteoblasts plays a critical role in adjusting bone turnover and increasing osteogenic activity in response to the acute increase in mechanical loading after tail suspension.

Rheumatoid arthritis (RA) is a disease characterized by inflammatory polyarthritis leading to destruction of the joints and reduction in bone mass. However, the relationship between bone mass and turnover is not yet clear in RA patients. To clarify the effect of bone turnover and marrow osteogenic capacity on mass and structure during the development of arthritis, we examined DBA1/J mice for 8 weeks after the first immunization with bovine type II collagen at the age of 9 weeks. Localized arthritis developed at 4 weeks and advanced arthritis at 6 weeks postimmunization. Urinary deoxypyridinoline levels in arthritic mice were significantly higher at 4 weeks, and levels were maintained thereafter. Their serum osteocalcin levels were significantly reduced compared with controls at 2 and 6 weeks, but did not differ significantly from those in the control group at 4 and 8 weeks. Three-dimensional (3D) trabecular bone volume of the proximal tibia measured by 3D microcomputed tomography (micro-CT) in the arthritic mice became significantly lower at 4 weeks and decreased further at 6 weeks compared with controls. Parameters of 3D trabecular bone structure, such as structure model index and trabecular bone pattern factor, were increased at 4 and 6 weeks, respectively. Trabecular osteoclast number increased and bone formation rates decreased at 8 weeks. The number of total bone marrow cells (BMCs), adherent stromal cells, and area of mineralized nodule formation in the tibia of arthritic mice were significantly reduced compared with controls at 6 weeks. Numbers of total fibroblastic colony-forming units (CFU-f) and alkaline phosphatase (ALP)-positive CFU-f colonies also decreased. However, the values of these osteogenic parameters corrected for the total BMCs and/or adherent stromal cells did not differ significantly between the arthritic and control groups. These data indicate that an increase in bone resorption led to the reduction in trabecular bone mass and deterioration of 3D structure during the localized arthritic stage. The reduction in bone marrow osteogenic potential in the advanced arthritic stage was due to the reduction in the number of total bone marrow cells, and differentiation of osteogenic cells was apparently unaffected. The reduction in bone formation may not be substantial in this arthritic model.

Basic fibroblast growth factor (FGF-2), an important modulator of cartilage and bone growth and differentiation, is expressed and regulated in osteoblastic cells. To investigate the role of FGF-2 in bone, we examined mice with a disruption of the Fgf2 gene. Measurement of trabecular bone architecture of the femoral metaphysis of Fgf2(+/+) and Fgf2(-/-) adult mice by micro-CT revealed that the platelike trabecular structures were markedly reduced and many of the connecting rods of trabecular bone were lost in the Fgf2(-/-) mice. Dynamic histomorphometry confirmed a significant decrease in trabecular bone volume, mineral apposition, and bone formation rates. In addition, there was a profound decreased mineralization of bone marrow stromal cultures from Fgf2(-/-) mice. This study provides strong evidence that FGF-2 helps determine bone mass as well as bone formation.

To delineate the influence of mechanical unloading on the osteogenic potential, the effects of mechanical unloading on the trabecular bone formation and the development of osteoblastic cells from bone marrow cells were examined using neurectomized mice. The trabecular osteoclasts and the osteoclastogenic potential of the bone marrow cells were also assessed. In 14 days after sciatic neurectomy, trabecular bone volume in the proximal tibial metaphysis was significantly reduced. The double-labeled surface and bone formation rate (BFR/BS) were significantly reduced. While the numbers of the total bone marrow cells and the nonadherent cells in the neurectomized limbs were not signficantly smaller than that of the sham-operated loaded limbs, the number of the adherent cells in the unloaded limbs was significantly reduced. The number of CFU-f colonies did not differ, but the number of bone nodules developed from bone marrow cells was significantly reduced in the unloaded limbs. The osteoclast-like cell development was increased when the bone marrow cells were incubated with parathyroid hormone. But, the number of CFU-GM colonies did not increase in the unloaded limbs. These data confirmed that the reduction in trabecular bone formation was associated with the reduction in the adherent stromal cells and bone nodule formation of bone marrow cells in the mice tibia after neurectomy. However, in vitro assays including CFU-f and CFU-GM did not identify the changes by unloading. The mechanical unloading affects the development of the bone cells, but may not greatly enhance the capacity for osteoclastogenesis in the bone marrow.

We examined the effects of prednisolone (PSL) administration in normal female Sprague Dawley rats and adjuvant-induced arthritic rats at the age of 6 weeks. Rats were intramuscularly injected with PSL twice a week at doses of 0 (control), 10, 30, 90, or 270 mg/kg body weight (b.w.). In the normal rats, serum osteocalcin level at 14 days and serum carboxyterminal pyridinoline cross-linked telopeptide of type 1 collagen (1CTP) level at 28 days in the 270 mg/kg dose group was lower than the respective value in control animals. The BMC and the trabecular bone formation rate (BFR/BS) of the lumbar body (L-4) in the 270 mg/kg dose group at 14 and 28 days were significantly lower than the values in the control rats. In the arthritic rats, however, serum osteocalcin levels in the PSL-treated groups did not differ compared with arthritic controls. The serum 1CTP levels in all of the PSL-treated groups were significantly reduced at 28 days. The age-dependent increases in the L-4 BMC, BMD, and L-3 ultimate compressive load values were maintained. The BFR/BS values in the 90 mg/kg and 270 mg/kg dose groups were significantly higher than those in the arthritic control rats. The trabecular osteoclast number and surface values in all of the PSL-treated groups were significantly lower than the values in arthritic controls. These data demonstrate that PSL administration prevented reduction in bone mass and strength of the lumbar trabecular bone in adjuvant-induced arthritic rats by reducing the increase in bone resorption and the decrease in bone formation at both the local and systemic levels.

One hundred fifteen Wistar rats, 7 months of age, were ovariectomized (ovx) or sham-operated to evaluate the effects of a weekly injection of human parathyroid hormone (hPTH) and withdrawal on the bone mass, strength, and turnover in mature ovariectomized rats. At 3 months, ovx rats were given a weekly injection of hPTH(1-34) at the respective doses of 0 (vehicle), 10, and 90 microg/kg body weight (BW) for 3 months. Then, hPTH-treated rats were divided into two groups each: continuously treated groups, and the groups treated with vehicle only for another 3 months. Weekly hPTH injections at doses of 10 or 90 microg/kg BW maintained the lumbar BMD values and increased the values of the femoral cortical bone, increasing the bone formation rates in the trabecular, endocortical, and periosteal envelopes. Trabecular osteoclasts were increased in the 90 microg/kg dose group. Trabecular bone surface relative to the volume was decreased by hPTH. The compressive load of the lumbar bone and the bending moment of the midfemur were increased. The lumbar compressive load values, corrected for BMD and volume, and the moment of inertia of the midfemur were also increased. The intracortical porosity values were not increased by the treatment. After withdrawal of hPTH treatment, the BMD values in both the lumbar and the midfemur were reduced to ovx control levels. The bone mass stimulated by the 90 microg/kg dose was reduced faster than that by the 10 microg/kg dose. However, the parameters of bone strength were still larger than those of the ovx controls after cessation of the hPTH treatment. Thus, a weekly hPTH injection effectively stimulated the bone formation in both the trabecular and cortical bone, leading to positive effects on mass and structure of the bone. These data suggest the possibility of benefits of both a lower frequency of hPTH injections as well as high-frequency injections for human osteoporotics.

Twelve-week-old female rats were ovariectomized (OVX) and compared with sham-operated control rats at 3, 5, 7, 10, 14, 30, and 60 days postoperation with respect to the expression of type I collagen and osteopontin mRNAs, as well as bone structure and the number of osteoclasts. The trabecular number and separation were significantly decreased and increased, respectively, in the metaphyseal trabecular bones of OVX rat femurs. The number of osteoclasts was significantly increased in the same region of OVX rats at 3 and 5 days postoperation. Type I collagen mRNA was expressed in osteoblasts, and osteopontin mRNA was expressed in some osteoclasts, in mononuclear cells on the bone resorption surface, and in osteocytes near the resorption surface. In the metaphyseal trabecular bone, type I collagen and osteopontin mRNA expression levels in individual cells was initially increased in OVX rats from 7 to 10 days postoperation, and this was sustained for 60 days. The number of osteopontin mRNA-expressing osteocytes was also significantly increased at 10 days postoperation, which lasted until 60 days. In the epiphysis, an increase in type I collagen mRNA expression was initially observed in OVX rats at 14 days postoperation, which lasted until 60 days. The number of osteopontin mRNA-expressing osteocytes was virtually identical until 30 days postoperation in the epiphysis. These findings indicated that the biological activities of osteoblasts and osteocytes are stimulated in bones of the OVX rat and that the response for OVX differs between the metaphysis and epiphysis. Furthermore, the number of osteopontin mRNA-expressing osteocytes was increased only in bones that tended to be resorbed after OVX. This indicates that some osteocytes were stimulated to express osteopontin mRNA by estrogen deficiency and suggests that these osteopontin mRNA-expressing osteocytes may be involved in regulation of bone metabolism.

We performed dosing experiments to evaluate the bone mass increasing action of a novel, synthetic vitamin D derivative, 2 beta-(3-hydroxypropoxy)-1 alpha,25(OH)2D3 (ED-71), in normal and estrogen-deficient rats. The first experiment consisted of 31 Sprague-Dawley rats, 28 weeks of age. The second experiment consisted of 44 animals who were ovariectomized (OVX) or sham operated at the age of 12 weeks. ED-71 was given twice a week for the duration of 12 weeks. At the end of the experiments, serum chemistries were examined and lumbar vertebrae were assessed histomorphometrically. Serum alkaline-phosphatase levels tended to decrease by ED-71 administration in the first experiment and their elevated values after ovariectomy were also depressed by ED-71 in the second experiment. Serum osteocalcin levels, however, increased by the agent. In the first experiment, cancellous bone volume (BV/TV) increased dose dependently. Bone formation rates (BFR/BS) also increased. In the second experiment, BV/TV significantly decreased by ovariectomy and it increased in ED-71-treated groups, but not in 1 alpha-(OH)D3-treated group. BFR/BS increased by ED-71. Activation frequency did not decrease by ED-71 in either experiment. These data clearly demonstrated that ED-71 administration was capable of increasing the bone mass by stimulating bone formation in normal and estrogen-deficient rats.

We reviewed 8 patients in whom the Cervical Spine Locking Plate was aplied for degenerative cervical spine disease. Morscher introduced a system to prevent migration and loosening of screws by using a cross-split screw head that can be locked into the plate. The secondary advantage of this system is that it eliminates the need for posterior cortex purchase and there by decreases the risk of spinal cord injury. Subjects comprised 5 men and 3 women with a mean age of 56 years. Five were cervical spondylosis and 3 ossification of the posterior longitudinal ligament. Hardware lossening occurred in one Rheumatoid Arthritis Patent but a fusions healed in a good position. CSLA provides immediate stable fixation with minimal complications. Its use should be considered in the surgical treatment of patients requiring multilevel anterior cervical arthrodesis of degenerative cervical spine disease.

Calcifying aponeurotic fibroma is a rarely seen benign soft part tumor. Throughout the world, from 70 to 80 cases have been reported and in Japan there have been only 6 cases since Keasbey reported the first one in 1953.Recently we experienced such a case which is reported here.A 5 -year-old girl visited our hospital with the complaint of a tumor in the area of the left ankle joint after learning of calcification of the area by X-ray at a hospital in her neighborhood.She had an elastic hard tumor, the size of the head of the little finger, in the anterior distal lateral malleolus of her left foot. The surface was smooth, the margin unclear, and adhesion to skin, mobility, redness and local heat was not found.In the operative findings, the tumor was about 4.0×2.0×1.5cm in size, yellow-white, elastic soft and adhered tightly to the periosteum of fibula, anterior talo-fibular ligament, anterior tibio-fibular ligament and the capsule of ankle joint. These adhesions were invasive.In the pathological findings, the tumor mainly consisted of spindle cells like fibroblasts, and these cells were of an interlaced pattern. Focal calcification was present and pathological diagnosis was calcifying aponeurotic fibroma.

Although the repairments of the peripheral nerve have been developed in cases recently, there are some controversies over the timing of the secondary repairment. We have experienced 14 cases (18 nerves) of secondary repairment of divided peripheral nerve injuries. There are 5 nerves of the ulnar nerve, 3 of the median nerve, 2 of the radial nerve and 8 of the digital nerve. All cases were sutured with epineural suture microscopically, and these postoperative results were evaluated by using Heighet's criterion and the static two-point discrimination method. No significant differences were observed between the timing before and after 3 month from the initial injuries. However, neuromas and relative big scars at the nerve stumps were observed in the cases which repair was performed after 3 months. We suggest that the large gap should be avoided, so the timing of secondary repairment is better within 3 months after injuries.

Summary This multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products. Introduction The purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates. Methods Study patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients’ treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain. Results In total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being “less frequent dosing more convenient.” Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use. Conclusions MIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence.