Akiko Iida-Klein

Helen Hayes Hospital, West Haverstraw, New York, United States

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Publications (8)34.73 Total impact

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    ABSTRACT: A cyclic PTH regimen is as effective as a daily regimen on bone density gain in humans and in improving bone quality in mice. Our previous murine study evaluated the effects of a cyclic PTH regimen in the absence of a bisphosphonate, whereas our human study addressed the effects of a cyclic PTH regimen in the presence of ongoing alendronate (ALN) treatment. Accordingly, the current study examined the effects of cyclic or daily PTH regimens in combination with ALN on bone quality and bone density in mice. Twenty-week-old, female C57BL/6J mice were treated with the following sc injections (n = 10): 1) vehicle for 5 d/wk (control); 2) ALN (20 microg/kg x d) 3 d/wk (ALN); 3) human PTH(1-34) (40 microg/kg x d) 5 d/wk (daily PTH); 4) daily PTH in addition to ALN (daily PTH plus ALN); 5) PTH 5 d/wk and vehicle 5 d/wk alternating weekly (cyclic PTH); 6) cyclic PTH in addition to ALN (cyclic PTH plus ALN); and 7) PTH and ALN alternating weekly (alt PTH and ALN). Bone mineral density was measured weekly by dual-energy x-ray absorptiometry, and at 7 wk, bone markers, bone structure, and bone strength were evaluated by biochemical assays, peripheral quantitative computed tomography and mechanical testing, respectively. At 7 wk, all treatments significantly increased femoral and vertebral bone mineral density. ALN slightly decreased endosteal circumference, whereas PTH increased periosteal circumference, resulting in significant increases in femoral cortical thickness in all groups. PTH and ALN enhanced bone strength synergistically in the lumbar vertebrae and additively in the femur. Combined therapy, however, had no effects on bone markers. The results show that combinations of ALN and PTH, in both daily and cyclic regimens, produce more beneficial effects than treatment with either agent alone, suggesting that the mechanisms of actions of ALN and PTH on bone quality may be complementary.
    Endocrinology 10/2007; 148(9):4466-74. · 4.72 Impact Factor
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    ABSTRACT: Previously, we demonstrated that the human parathyroid hormone (1-34) fragment (hPTH(1-34)) increased bone strength in proportion to its effects on BMD and cortical bone structure in the murine femur by comparing cyclic vs. daily administration of hPTH(1-34). Both cyclic and daily regimens increased vertebral BMD similarly at 7 weeks. Here, we have examined the effects of daily and cyclic PTH regimens on bone structure and cellular activity by static and dynamic histomorphometry. Twenty-week-old, intact female C57BL/J6 mice were treated with the following regimens (n=7 for each group): daily injection with vehicle for 7 weeks [control]; daily injection with hPTH(1-34) (40 microg/kg/day) for 7 weeks [daily PTH]; and daily injection with hPTH(1-34) (40 microg/kg/day) and vehicle alternating weekly for 7 weeks [cyclic PTH]. At days 9 and 10, and 2 and 3 prior to euthanasia, calcein (10 mg/kg) was injected subcutaneously. At the end of study, the lumbar vertebrae 1-3 and the left femora were excised, cleaned, and processed for histomorphometry. In the lumbar vertebrae, daily and cyclic PTH regimens significantly increased cancellous bone volume (BV/TV), trabecular number, trabecular osteoclast and osteoblast perimeters, trabecular mineral apposition rate (MAR) and bone formation rate (BFR), and periosteal MAR and BFR compared to control, with no significant difference between the two PTH-treated groups. Increased trabecular tunneling was observed in both PTH-treated groups. Both regimens tended to increase vertebral cortical bone formation parameters with the effects at the periosteum site being more marked than those at the endosteum site, resulting in a significant increase in cortical width. In the femur, the effects of cyclic PTH on BV/TV, trabecular width and number, trabecular and endocortical osteoblast and osteoclast perimeters, cortical width, and trabecular and periosteal BFR were less marked than those of daily PTH. A cyclic PTH regimen was as effective as a daily regimen in improving cancellous and cortical bone microarchitecture and cellular activity in the murine vertebra.
    Bone 03/2007; 40(2):391-8. · 4.46 Impact Factor
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    ABSTRACT: We developed a cyclic PTH regimen with repeated cycles of 1-week on and off daily PTH injection and explored its effects on bone strength, BMD, bone markers, and bone structure in mice. Cyclic protocols produced 60-85% of the effects achieved by daily protocols with 57% of the total PTH given, indicating more economic use of PTH. The study supports further exploration of cyclic PTH regimens for the treatment of osteoporosis. To minimize the cost and the catabolic action of hPTH(1-34), a cyclic PTH regimen with repeated 3-month cycles of on-and-off daily injection of hPTH(1-34) was developed in humans and shown to be as effective as a daily regimen in increasing vertebral BMD. However, changes in BMD may not adequately predict changes in bone strength. A murine model was developed to explore the efficacy of a cyclic PTH regimen on bone strength in association with other bone variables. Twenty-week-old, intact, female C57BL/J6 mice (n = 7/group) were treated with (1) daily injection with vehicle for 7 weeks (control); (2) daily injection with hPTH(1-34) (40 microg/kg/day) for 7 weeks (daily PTH); and (3) daily injection with hPTH(1-34) and vehicle alternating weekly for 7 weeks (cyclic PTH). BMD was measured weekly by DXA, and serum bone markers, bone structure, and strength were measured at 7 weeks. Daily and cyclic PTH regimens increased BMD at all sites by 16-17% and 9-12%, respectively (all p < 0.01). The most dramatic effect of cyclic PTH occurred during the second week of treatment when PTH was off, with femoral and tibial BMD continuing to increase to the same extent as that produced by daily PTH. Both daily and cyclic PTH regimens significantly increased osteocalcin (daily, 330%; cyclic, 260%), mTRACP (daily, 145%; cyclic, 70%), femoral cortical width (daily, 23%; cyclic, 13%), periosteal circumference (daily, 5%; cyclic, 3.5%), and bone strength (max load: daily, 48%; cyclic, 28%; energy absorbed: daily, 103%; cyclic, 61%), respectively. Femoral bone strength was positively correlated with BMD, bone markers, and cortical structure. Neither regimen had an effect on vertebral bone strength. Although actual effects of cyclic PTH were 60-85% of those produced by daily PTH, the effects of cyclic PTH per unit amount administered were slightly greater than those of daily PTH for most measures. PTH-enhanced femoral bone strength is positively correlated with its effects on femoral BMD, bone markers, and bone structure. Cyclic PTH regimens represent a potential economic use of PTH and warrant further study.
    Journal of Bone and Mineral Research 03/2006; 21(2):274-82. · 6.13 Impact Factor
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    ABSTRACT: Parathyroid hormone (PTH) stimulates bone resorption as well as bone formation in vivo and in organ culture. The catabolic actions of PTH have been recognized in patients with hyperparathyroidism, or with acute infusion of the N-terminal 1-34 fragment of human PTH (hPTH1-34). Whereas the anabolic actions of daily injection with PTH have been well studied in both humans and mice, the catabolic actions of PTH on murine bone remain to be defined. To do this we sought to create a model with short-term, sustained hyperparathyroidism using osmotic infusion pumps. We treated 10-week-old female C57BL/J6 mice with continuous infusion of hPTH1-34 (8.1 pmol/0.25 microl per h, equivalent to 40 microg/kg per day) or vehicle for 2 weeks, using Alzet osmotic pumps. Bone mineral density (BMD), serum total calcium, hPTH1-34, mouse intact PTH (mPTH1-84), osteocalcin and mouse tartrate-resistant acid phosphatase (mTRAP) activity, and microarchitectural variables of the distal femur were measured. Separately, we compared the effects of intermittent daily injection of hPTH1-34 (40 microg/kg per day) with continuous infusion of hPTH1-34 on BMD and bone markers. Exogenous hPTH1-34 was detected only in the PTH-infused mice. Both intermittent and continuous treatment with hPTH1-34 markedly suppressed endogenous mPTH1-84, but only the latter induced hypercalcemia. Daily PTH injection significantly increased both serum osteocalcin and mTRAP, while continuous PTH infusion showed a strong trend to stimulate mTRAP, with a slight but non-significant increase in osteocalcin. There were significant differences in BMD at all sites between animals treated with the same daily dose of intermittent and continuous hPTH1-34. Micro-computed tomography (muCT) analysis of the distal femurs revealed that hPTH1-34 infusion significantly decreased trabecular connectivity density (P<0.05). Thus, the murine bone response to continuous PTH infusion was quite different from that seen with daily PTH injection. Short-term infusion of hPTH1-34 appears to be a good model to study the mechanisms underlying the catabolic action of PTH in mice.
    Journal of Endocrinology 10/2005; 186(3):549-57. · 4.06 Impact Factor
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    ABSTRACT: The prevailing view for many years has been that osteoclasts do not express parathyroid hormone (PTH) receptors and that PTH's effects on osteoclasts are mediated indirectly via osteoblasts. However, several recent reports suggest that osteoclasts express PTH receptors. In this study, we tested the hypothesis that human osteoclasts formed in vitro express functional PTH type 1 receptors (PTH1R). Peripheral blood monocytes (PBMC) were cultured on bone slices or plastic culture dishes with human recombinant RANK ligand (RANKL) and recombinant human macrophage colony-stimulating factor (M-CSF) for 16-21 days. This resulted in a mixed population of mono- and multi-nucleated cells, all of which stained positively for the human calcitonin receptor. The cells actively resorbed bone, as assessed by release of C-terminal telopeptide of type I collagen and the formation of abundant resorption pits. We obtained evidence for the presence of PTH1R in these cells by four independent techniques. First, using immunocytochemistry, positive staining for PTH1R was observed in both mono- and multi-nucleated cells intimately associated with resorption cavities. Second, PTH1R protein expression was demonstrated by Western blot analysis. Third, the cells expressed PTH1R mRNA at 21 days and treatment with 10(-7) M hPTH (1-34) reduced PTH1R mRNA expression by 35%. Finally, bone resorption was reproducibly increased by two to threefold when PTH (1-34) was added to the cultures. These findings provide strong support for a direct stimulatory action of PTH on human osteoclasts mediated by PTH1R. This suggests a dual regulatory mechanism, whereby PTH acts both directly on osteoclasts and also, indirectly, via osteoblasts.
    Journal of Cellular Biochemistry 06/2005; 95(1):139-48. · 3.06 Impact Factor
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    ABSTRACT: The mouse is being increasingly used to study the anabolic action of parathyroid hormone (PTH) on the skeleton. The efficacy of intermittent PTH treatment on bone varies widely among tested strains of mice with differences in peak bone mass and structure. We have therefore examined the responses of skeletal sites with high or low cancellous bone mass to PTH treatment in a single strain with genetically low bone mass. Mature C57BL/6 mice were ovariectomized (ovx) or sham operated and, after 4 weeks, treated with PTH(1-34) (40 microg/kg/day, 5 days/week sc) or vehicle for 3 or 7 weeks. Two doses of fluorescent labels were given to the animals 9 and 3 days before euthanasia. Histomorphometry was performed on sections of the proximal tibia, tibial diaphysis, and vertebral body. The results indicate that 4 to 11 weeks of ovx induced a approximately 44% loss of cancellous bone in the proximal tibia and a approximately 25% loss of cancellous bone in the vertebra with impaired trabecular architecture and high bone turnover. In the intact animals, PTH increased cancellous bone volume to a greater extent in the vertebral body than in the proximal tibia, a site with lower cancellous bone volume at the outset. In the ovx mice, PTH increased cancellous bone volume to a greater extent in the vertebral body, a site displaying moderate cancellous bone loss, than in the proximal tibia, a site with severe cancellous bone loss. Conversely, the treatment added a little cortical bone to the tibia, a highly loaded site, but did not significantly increase cortical width of the vertebral body, a less loaded site. We conclude that, for intermittent PTH treatment to be maximally effective, there must be an adequate number of trabeculae present at the beginning of treatment, regardless of estrogen status. Our results also support an interaction between PTH anabolic action and mechanical loading.
    Bone 06/2003; 32(5):513-20. · 4.46 Impact Factor
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    ABSTRACT: Dual X-ray absorptiometry (DXA) has currently become a clinical standard for the assessment of bone mass and bone mineral density (BMD) at multiple sites for the diagnosis and follow-up assessment of osteoporosis in humans. The precision of DXA measurement in human studies has been well documented during the last two decades. However, there have been no systematic reports on the precision and accuracy of BMD measurements in mice using DXA, although mice have proven to be useful models for the study of osteoporosis. Accordingly, BMD of total body as well as regions of interest (ROIs) was measured twice in mice in vivo after a short (10-min) and long (16-hr) interval between scans by DXA, and scanning variations were calculated. Inter- and intra-analyzer variations from the same scans were also determined. The percent coefficients (%CVs) of short-interval scanning variation and inter- and intra-analyzer variations for total body and regional BMDs were less than 2% at sites, demonstrating high precision of in vivo BMD measurements in mice. Moreover, the BMD values comparing in vivo and ex vivo samples from the same animals were of %CV less than 10% at all sites. The correlation of bone mineral content (BMC) to bone ash was further examined, and the correlation between ROI BMC and bone ash was relatively high at all sites both in vivo and ex vivo, with the latter higher. We conclude that in vivo DXA BMD measurements in mice are very reliable with high precision and acceptable accuracy, and therefore useful for longitudinal studies of the mouse skeleton.
    Journal of Clinical Densitometry 02/2003; 6(1):25-33. · 1.71 Impact Factor
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    ABSTRACT: The cellular and molecular events triggering the anabolic response of the skeleton to exogenous parathyroid hormone (PTH) are not well understood. Despite the numerous bone mass studies in rats, few data are available for mice. Therefore, we treated 10-week-old female intact C57BL/6J mice with human PTH(1-34) delivered subcutaneously at a dose of 40 microg/kg per day 5 days a week for 3 weeks and 7 weeks. Bone mineral density (BMD) of total bone, femur, tibia, and lumbar vertebrae was measured weekly by PIXImus. Bone turnover was examined by histomorphometry, and gene expression of bone formation and resorption markers and osteoclastogenesis regulators in the excised femur and tibia was assessed by reverse-transcription polymerase chain reaction (RT-PCR) at 3 weeks and 7 weeks. The PTH-stimulated increase in BMD was more prominent in the tibia and femur than in the lumbar vertebrae, with an anabolic effect detected within 1-2 weeks and BMD continuing to increase. The appearance of a detectable PTH-stimulated increase in BMD was slower in the lumbar vertebrae where the increase was only significant after 7 weeks of treatment. Histomorphometric analysis of the proximal tibia at both 3 weeks and 7 weeks indicated significant time-dependent increases in trabecular area, trabecular number, trabecular and cortical widths, and osteoblast and osteoid perimeters. In the lumbar vertebrae, these stimulatory effects of PTH on trabecular area, trabecular number, and cortical width were smaller and not detected until 7 weeks. PTH-stimulated increases in bone turnover were evident by increased gene expression of osteocalcin (OC), tartrate-resistant acid phosphatase (TRAP), and receptor of activator nuclear factor kappaB (NF-kappaB) ligand (RANKL) in the tibia and femur. No significant difference in gene expression was observed between the two long bone sites. In conclusion, PTH exerts an anabolic action at the tissue and cellular levels in intact mice and the magnitude and temporal pattern of this anabolic action, as assessed by densitometry and histomorphometry, are skeletal site specific.
    Journal of Bone and Mineral Research 06/2002; 17(5):808-16. · 6.13 Impact Factor