Tasuku Mashiba

Increased bone formation by intermittent parathyroid hormone administration is due to the stimulation of proliferation and differentiation of osteoprogenitor cells in bone marrow

In order to examine the mechanism of the anabolic effect of parathyroid hormone (PTH) on bone formation, human PTH(1-34) [hPTH(1-34)] (30 micrograms/kg) was injected subcutaneously to 9-week-old rats 5 times a week for 1 or 3 weeks. Trabecular bone volume (BV/TV) in the tibial metaphysis was not significantly different between the PTH- and vehicle-treated groups, but the parameters related to bone formation, including osteoid surface (OS/BS), mineralizing surface (MS/BS), mineral apposition rate (MAR), and bone formation rate (BFR/BS), were significantly increased as early as 1 week after PTH treatment. And the parameters related to bone resorption including eroded surface (ES/BS) and osteoclast number (N.Oc/BS) were also significantly increased as early as 1 week after PTH treatment. Treatment with PTH for 1 week induced no significant increase in bone mineral density at the femoral metaphysis, whereas the same treatment for 3 weeks induced a significant increase. When bone marrow cells isolated from femora and tibiae of either PTH- or vehicle-treated rats were cultured at a high density (2 x 10(7) cells/one well of 24-multiwell plate), cellular alkaline phosphatase (ALP) activity was significantly increased in the cells isolated from PTH-treated rats compared with vehicle-treated rats. When bone marrow cells were cultured at a low density (4 x 10(6) cells/a one well of 6-multiwell plate) to generate colonies (colony forming unit-fibroblastic, CFU-F), PTH induced apparent increases in both the total number of CFU-F and the number of ALP-positive CFU-F.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment with active vitamin D metabolites and concurrent treatments in the prevention of hip fractures: a retrospective study.

Abstract: The purpose of this study was to determine the effect of treatment with active vitamin D metabolites and other concurrent medication on the prevention of hip fractures in elderly women. We inspected the medical records of the entire female population over 65 years of age on Sado Island, and followed a total of 11377 women for a 3-year period. Of these, 1208 osteoporotic patients were treated with either 1,25-(OH)2D3 or 1α-(OH)D3. The 765 patients who received the minimum effective dosage for more than 6 months made up the ‘treatment group’. Nearly half these patients were also treated with either calcitonin or calcium. The 443 patients who received treatment with active vitamin D metabolites, but at a dosage or for a duration that did not meet the criteria for the treatment group, were deemed the ‘ineffective group’. The remaining 10169 women were the ‘non-treatment group’. Fractures in the non-treatment group occurred at a rate of 39.8 fractures/10000 person-years. The rate in the treatment group was 10.8, which was significantly lower (p= 0.039). Interestingly, the fracture rate after ceasing treatment was 52.1, which was significantly higher (p= 0.002) than the rate in patients receiving treatment. No statistical differences in the fracture rate were found between the ineffective, non-treatment and post-treatment groups. A reduction in the fracture rate was observed only in the treatment subgroup that did not also receive calcitonin (p= 0.042), and not in the subgroup that also received calcitonin therapy (p= 0.333). However, there was no statistical difference in the hip fracture rates between these two subgroups (p= 0.157) and the actual number of fractures was minimal (0 vs 2). Therefore, in this study, the advantage of treatment with active vitamin D alone over combined treatment with calcitonin seems to be marginal. In conclusion: (1) treatment with active vitamin D metabolites and with combined therapy may be marginally effective in preventing hip fractures, and (2) stopping the treatment clearly increases the risk of hip fractures.

A histomorphometric study on effects of single and concurrent intermittent administration of human PTH (1-34) and bisphosphonate cimadronate on tibial metaphysis in ovariectomized rats

This study compared the single administration of hPTH(1-34), bisphosphonate cimadronate (YM-175), and concurrent therapy of these two for restoration of lost bone mass in ovariectomized (OVX) rats. Animals were untreated for 4 weeks after surgery, and then injected s.c. with vehicle (OVX+V), hPTH(1-34) (30 micrograms/kg) (OVX+P), YM-175 (5 micrograms/kg) (OVX+Y), or a combination of these two (OVX+P+Y), 3 days a week, for 8 weeks, and sacrificed. Their proximal tibia were processed undecalcified for quantitative bone histomorphometry. Although OVX+Y showed a reduction of bone turnover compared to OVX+V, it failed to restore lost bone mass in OVX rats. In contrast, OVX+P exhibited a stimulation of bone formation and restored cancellous osteopenia due to OVX. OVX+P+Y also resulted a recovery of osteopenia, however, stimulation of bone formation by PTH was suppressed by YM-175.

Effects of human PTH(1-34) and bisphosphonate on the osteopenic rat model

It has been demonstrated that the intermittent administration of human parathyroid hormone (hPTH) is beneficial for restoration of bone mass in osteoporotic patients. The mechanisms of anabolic effects of hPTH have been determined by ovariectomized rat models and other larger remodeling animals. However, treatment with hPTH may increase the cancellous bone mass at the expense of cortical bone mass and cessation of the treatment results in rapid bone loss. Efforts have been made to maintain newly formed bone mass after withdrawal of the hPTH treatment. These issues are not well understood. In this article, the authors would like to represent previous studies of their own and others concerning these issues.

Effects of single and concurrent intermittent administration of human parathyroid hormone and bisphosphonate cimadronate on bone mineral densities of femur in ovariectomized rats

This study compared the single administration of human parathyroid hormone [hPTH(1-34)] or bisphosphonate cimadronate (YM-175), and concurrent therapy with both of these agents for restoration of lost bone mineral density (BMD) in ovariectomized (OVX) rats. Animals were untreated for 4 weeks after surgery, and then injected s.c. with vehicle (OVX+V), hPTH(l-34) (30μg/kg) (OVX+P), YM-175 (5μg/kg) (OVX+Y), or a combination of these two (OVX+P+Y), 3 days a week, for 8 weeks, and killed. BMD of distal, middle, and total femur were determined by dual-energy X-ray absorptiometry (DXA). BMD of distal and total femur, but not of midfemur, decreased at both 4 weeks and 12 weeks after ovariectomy. In the distal femoral BMD, although OVX+Y failed to restore lost BMD in OVX rats, either OVX+P or OVX+P+Y could reverse BMD lost due to OVX. Midfemoral BMD was unchanged through OVX or both single treatments, whereas this parameter was increased only in OVX+P+Y. These results suggest that concurrent treatment with PTH and YM-175 results in a bone anabolic effect not only in cancellous bone but also in cortical bone.

Histomorphometric and Node-Strut Analysis of Effects of Exercise or Incadronate Disodium on hPTH (1–34)-Induced Bone Mass in Ovariectomized Rats

Intermittent administration of human parathyroid hormone (hPTH) (1–34) activates bone formation and increases cancellous bone mass in ovariectomized (OVX) rats. However, PTH-induced increases in cancellous bone volume rapidly decrease to the original levels after withdrawal of hPTH(l-34). Besides confirming that intermittent PTH administration increases cancellous bone mass, this study determined whether PTH-induced cancellous bone mass could be maintained by running exercise after PTH treatment was discontinued, whether a bisphosphonate, incadronate disodium (YM-175), could also maintain that bone, and, if so, whether that maintenance effect persisted after YM-175 withdrawal. Eleven-week-old Sprague-Dawley rats were OVX and hPTH (1–34), 30 μg/kg, was injected subcutaneously three times per week for 12 weeks, beginning 1 week after OVX in experiment 1, and for 8 weeks beginning 4 weeks after OVX in experiment 2. After withdrawal of PTH, treadmill exercise was done for the next 8 weeks (15.7m/min, 1h/day, 5 days/week), or YM-175, 10 μg/kg, was injected subcutaneously three times per week for 4 weeks. In the proximal tibial metaphysis, histomorphometric analysis with standard bone histomorphometry and node-strut analyses revealed that hPTH administration partially prevented OVX-induced cancellous bone loss. Eight weeks after PTH administration stopped, PTH-induced increases in cancellous bone mass had returned to the OVX/V (vehicle injection) level. Treadmill exercise helped to maintain the PTH-induced bone mass but did not increase bone mass in OVX control rats. YM-175 administration maintained the PTH-induced additions to tibial cancellous bone mass after PTH treatment stopped and even for 8 weeks after treatment with YM-175 had also stopped.