A comparative effectiveness pilot study of teriparatide for medication-related osteonecrosis of the jaw: daily versus weekly administration.

We studied the effectiveness of teriparatide (TPTD) for treating medication-related osteonecrosis of the jaw (MRONJ) in patients with osteoporosis and examined differences in the clinical outcomes following daily versus weekly TPTD. The outcomes were significantly improved in the entire patient series and the daily group. PURPOSE: Teriparatide (TPTD) treatment for Stage II-III medication-related osteonecrosis of the jaw (MRONJ) in osteoporotic patients has yielded promising results in uncontrolled studies. The daily administration and the weekly administration of TPTD have been reported to improve outcomes in MRONJ. Herein, we sought to identify differences in the clinical outcomes of MRONJ patients treated with daily TPTD versus weekly TPTD. METHODS: We enrolled 13 patients and randomly assigned them to receive either of two treatments: 1×/week 56.5-µg TPTD injection for 6 months (weekly group; n = 6 patients after 1 dropout), or 20-µg TPTD injection daily for 6 months (daily group; n = 6 patients). Patients in both groups received conventional therapy plus intensive antibiotic therapy as necessary. We compared the changes in the patients' clinical stage of MRONJ, bone metabolism, percentage of bone formation, and bone turnover markers between the weekly and daily groups. RESULTS: TPTD treatment with MRONJ led to partial remission or complete remission in 5 daily-group patients and 3 weekly-group patients. The MRONJ stage was significantly improved from baseline to 6 months of treatment in the entire series of 12 patients (p = 0.008); the weekly group did not show significant improvement, but the daily group did (p = 0.01). CONCLUSIONS: This study provides the first comparison of clinical outcomes between MRONJ patients who received daily or weekly TPTD injections. Six months of treatment with TPTD realized a significant improvement of MRONJ stage in both the entire patient series and the daily group.

Mineral and bone disorder is temporary in patients treated with early rapid corticosteroid reduction after kidney transplantation: a single-center experience.

BACKGROUND: Mineral and bone disorder (MBD) is a major complication of chronic kidney disease and remains a major problem even after kidney transplantation. Although early steroid withdrawal protocols have beneficial effects on mineral and bone metabolism, they are also associated with significantly increased rates of acute allograft rejection (AR). Recently, patients have been treated with early rapid corticosteroid reduction protocols, but it is still unclear whether these protocols reduce the rate of MBD. The aim of this study was to evaluate the effects of early rapid corticosteroid reduction on MBD after kidney transplantation. METHODS: We retrospectively evaluated 34 adult kidney transplant recipients who were treated with an early rapid corticosteroid reduction protocol. Glucocorticoid treatment was reduced to methylprednisolone 4 mg/d at 1 month after transplantation. RESULTS: The AR rate at 3 years after transplantation was 15%. Bone mineral density was slightly decreased in the femur at 4 months after transplantation but returned to the preoperative level by 24 months after transplantation. There was no significant decrease in the bone mineral density of the lumbar spine during the first year after transplantation. Urinary deoxypyridinoline levels and plasma osteocalcin levels returned to the normal range during the follow-up period. Bone mineral density tended to be lower in female patients than male patients and in patients who underwent long-term pretransplant dialysis than those who did not undergo long-term pretransplant dialysis. CONCLUSION: The present study found that MBD was temporary in kidney transplant recipients who were treated with an early rapid corticosteroid reduction protocol and that these patients did not have an increased AR rate.

Collagen maturity, glycation induced-pentosidine, and mineralization are increased following 3-year treatment with incadronate in dogs.

UNLABELLED: Collagen cross-linking is a determinant of bone quality. A three-year treatment of bisphosphonate-incadronate disodium-in beagles increased degree of mineralization, collagen maturity, and pentosidine, a compound with advanced glycation end products. The treatment had no effect on the total amount of enzymatic cross-link formation. INTRODUCTION: Collagen cross-linking is a determinant of bone quality. Recently, we reported that long-term treatment with bisphosphonate increased microdamage accumulation. The aim of this study was to clarify the effect of a three-year treatment with bisphosphonate on degree of mineralization and immature and mature enzymatic cross-links and non-enzymatic collagen cross-link, pentosidine, in cortical bone in the same dogs. METHODS: Twenty-nine 1-year-old beagles (15 males, 14 females) were divided into three groups that daily were given vehicle or incadronate at doses of 0.3 or 0.6 mg/kg/day orally for three years. A cortex of a rib was fractionated into low- and high-density portions. The contents of calcium, phosphorus, enzymatic immature and mature cross-links, and the non-enzymatic glycation product pentosidine were determined in each fraction. RESULTS: Calcium, phosphorus, and pentosidine contents and the ratio of mature to immature cross-links increased significantly with incadronate in a dose-dependent manner, but the total amount of enzymatic cross-links was unchanged. The pentosidine content correlated inversely with cortical activation frequency (p < 0.01). CONCLUSION: Long-term suppression of bone remodeling by bisphosphonate increases degree of mineralization, collagen maturity, and non-enzymatic cross-linking.

Bone remodeling at the iliac crest can predict the changes in remodeling dynamics, microdamage accumulation, and mechanical properties in the lumbar vertebrae of dogs.

We previously demonstrated that suppression of bone remodeling allows microdamage to accumulate, thereby leading to reduced bone toughness in dog bone. In this study we evaluated the relationships between bone remodeling at the iliac crest and skeletal activation frequency, microdamage accumulation, or biomechanical properties of lumbar vertebrae using the same dogs to determine whether bone remodeling at the iliac crest can predict damage accumulation and mechanical parameters of the lumbar spine following treatment with antiresorptive agents. Thirty-six female beagles, 1 to 2 years old, were divided into three groups. The control group was treated daily for 12 months with saline vehicle. The remaining two groups were treated daily with oral risedronate at a dose of 0.5 mg/kg/day, or alendronate at 1.0 mg/kg/day orally. The doses of these bisphosphonates were 5 to 6 times the clinical doses approved for treatment of osteoporosis in humans. After sacrifice, the right ilium and L2 vertebra were assigned to histomorphometry. The left ilium and L3 vertebra were used for microdamage analysis. The L4 vertebra was mechanically tested to failure in compression, and bone toughness calculated from the stress-strain curve. There was a strong positive relationship for activation frequency (Ac.f) between ilium and lumbar vertebrae (r2 = 0.82; P < 0.0001). Iliac crest Ac.f underestimates Ac.f in L2, but L2 Ac.f reaches a minimum threshold and does not decline further when iliac crest Ac.f is below 0.10/yr. Microdamage (Cr.S.Dn) accumulation at the ilium was significantly associated with increased microdamage accumulation in the L3 lumbar vertebra (r2 = 0.43, P < 0.0001). The data also show that bisphosphonate treatment increased Cr.S.Dn at a faster rate in L3 than in the iliac crest. Although bisphosphonate treatment decreased bone toughness in L4, this decrease demonstrated no relationship to decreased Ac.f in the ilium. These results clearly indicate that bone remodeling data obtained from iliac crest biopsy could be used to estimate the activation frequency and microdamage burden in the vertebral column.

Bisphosphonate treatment affects trabecular bone apparent modulus through micro-architecture rather than matrix properties.

Bisphosphonates are emerging as an important treatment for osteoporosis. But whether the reduced fracture risk associated with bisphosphonate treatment is due to increased bone mass, improved trabecular architecture and/or increased secondary mineralization of the calcified matrix remains unclear. We examined the effects of bisphosphonates on both the trabecular architecture and matrix properties of canine trabecular bone. Thirty-six beagles were divided into a control group and two treatment groups, one receiving risedronate and the other alendronate at 5-6 times the clinical dose for osteoporosis treatment. After one year, the dogs were killed, and samples from the first lumbar vertebrae were examined using a combination of micro-computed tomography, finite element modeling, and mechanical testing. By combining these methods, we examined the treatment effects on the calcified matrix and trabecular architecture independently. Conventional histomorphometry and microdamage data were obtained from the second and third lumbar vertebrae of the same dogs [Bone 28 (2001) 524]. Bisphosphonate treatment resulted in an increased apparent Young's modulus, decreased bone turnover, increased calcified matrix density, and increased microdamage. We could not detect any change in the effective Young's modulus of the calcified matrix in the bisphosphonate treated groups. The observed increase in apparent Young's modulus was due to increased bone mass and altered trabecular architecture rather than changes in the calcified matrix modulus. We hypothesize that the expected increase in the Young's modulus of the calcified matrix due to the increased calcified matrix density was counteracted by the accumulation of microdamage.

Canine cancellous bone microarchitecture after one year of high-dose bisphosphonates.

We examined the effects of one-year high-dose bisphosphonates (risedronate 0.5 mg/kg/day or alendronate 1.0 mg/kg/day) on the three-dimensional (3-D) microstructural and mechanical properties of canine cancellous bone. A high-resolution micro-CT scanner was used to scan cubic specimens produced from the first lumbar vertebrae. Microstructural properties of the specimens were calculated directly from the 3-D datasets and the mechanical properties of the specimens were determined. Our data demonstrate significant microarchitectural changes in the bisphosphonate-treated cancellous bone that was typically plate-like, denser, with thicker and more trabeculae compared with those of the controls. Consistent with architectural changes, the Young's moduli of cancellous bone increased in all three directions with the greatest increase in primary axial loading (cephalo-caudal) direction after treatment. Our results suggest a bone remodeling-adaptation mechanism stimulated by bisphosphonates that increases bone volume fraction, thickens trabeculae, changes trabeculae towards more plate-like, and increases mechanical properties. The secondary degree of anisotropy contributed significantly to the explained variance in bone strength, and the primary or tertiary degree of anisotropy improved the explanation of variances for Young's moduli, i.e., 79% of strength variances or 74-83% of modulus variances could be explained by the combined anisotropy and bone volume fraction. These significant improvements of cancellous bone architecture provide a rationale for the clinical observation that fracture risk decreased by 50% in the first year of bisphosphonate therapy with only a 5% increase in bone mineral density. We conclude that bisphosphonates enhance mechanical properties and reduce fracture risk by improving architectural anisotropy of cancellous bone 3-D microarchitecture.

Effects of high-dose etidronate treatment on microdamage accumulation and biomechanical properties in beagle bone before occurrence of spontaneous fractures.

We recently demonstrated that suppressed bone remodeling allows microdamage to accumulate and causes reductions in some mechanical properties. However, in our previous study, 1 year treatment with high-dose etidronate (EHDP) did not increase microdamage accumulation in most skeletal sites of dogs in spite of complete remodeling suppression and the occurrence of spontaneous fractures of ribs and/or thoracic spinous processes. This study evaluates the effects of EHDP on microdamage accumulation and biomechanical properties before fractures occur. Thirty-six female beagles, 1-2 years old, were treated daily for 7 months with subcutaneous injections of saline vehicle (CNT) or EHDP at 0.5 (E-low) or 5 mg/kg per day (E-high). After killing, bone mineral measurement, histomorphometry, microdamage analysis, and biomechanical testing were performed. EHDP treatment suppressed intracortical and trabecular remodeling by 60%-75% at the lower dose, and by 100% at the higher dose. Osteoid accumulation caused by a mineralization deficit occurred only in the E-high group, and this led to a reduction of mineralized bone mass. Microdamage accumulation increased significantly by two- to fivefold in the rib, lumbar vertebra, ilium, and thoracic spinous process in E-low, and by twofold in the lumbar vertebra and ilium in E-high. However, no significant increase in damage accumulation was observed in ribs or thoracic spinous processes in E-high where fractures occur following 12 months of treatment. Mechanical properties of lumbar vertebrae and thoracic spinous processes were reduced significantly in both E-low and E-high. These findings suggest that suppression of bone remodeling by EHDP allows microdamage accumulation, but that osteoid accumulation reduces production of microdamage.

Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles.

We recently demonstrated that suppression of bone remodeling allows microdamage to accumulate, leading to reduced bone toughness in the rib cortex of dogs. This study evaluates the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties at clinically relevant skeletal sites in the same dogs. Thirty-six female beagles, 1-2 years old, were divided into three groups. The control group was treated daily for 12 months with saline vehicle (CNT). The remaining two groups were treated daily with risedronate at a dose of 0.5 mg/kg per day (RIS), or alendronate at 1.0 mg/kg per day (ALN) orally. The doses of these bisphosphonates were six times the clinical doses approved for treatment of osteoporosis in humans. After killing, the L-1 vertebra was scanned by dual-energy X-ray absorptiometry (DXA), and the L-2 vertebra and right ilium were assigned to histomorphometry. The L-3 vertebra, left ilium, Th-2 spinous process, and right femoral neck were used for microdamage analysis. The L-4 vertebra and Th-1 spinous process were mechanically tested to failure in compression and shear, respectively. One year treatment with risedronate or alendronate significantly suppressed trabecular remodeling in vertebrae (RIS 90%, ALN 95%) and ilium (RIS 76%, ALN 90%) without impairment of mineralization, and significantly increased microdamage accumulation in all skeletal sites measured. Trabecular bone volume and vertebral strength increased significantly following 12 month treatment. However, normalized toughness of the L-4 vertebra was reduced by 21% in both RIS (p = 0.06) and ALN (p = 0.05) groups. When the two bisphosphonate groups were pooled in a post hoc fashion for analysis, this reduction in toughness reached statistical significance (p = 0.02). This study demonstrates that suppression of trabecular bone turnover by high doses of bisphosphonates is associated with increased vertebral strength, even though there is significant microdamage accumulation and a reduction in the intrinsic energy absorption capacity of trabecular bone.

Effects of human parathyroid hormone (1-34), LY333334, on bone mass, remodeling, and mechanical properties of cortical bone during the first remodeling cycle in rabbits.

We have previously shown that parathyroid hormone (PTH) increases cortical bone mass and mechanical strength of female rabbits after 140 days of treatment. However, cortical porosity was also shown to increase. If cortical porosity increases prior to the change in geometry, there may be a transient decrease in cortical bone strength that could make the bone more susceptible to fracture in the early phase of treatment. The purpose of this study is to examine the effects of PTH on the remodeling dynamics and mechanical properties of cortical bone in rabbits, which exhibit haversian remodeling, during the first remodeling cycle after the initiation of treatment. Fifty 9-month-old intact female New Zealand white rabbits were randomized into five groups. A baseline control group was killed at the start of the experiment. The two PTH-treated groups were given human PTH(1-34) at 10 microg/kg daily subcutaneously for 35 (P35) or 70 (P70) days. Two respective age-matched control groups (V35, V70) were injected with vehicle. Histomorphometry of the cortical bone in the tibial midshaft showed that, although intracortical activation frequency was significantly increased by PTH at 35 days, there was no significant increase of cortical porosity in the first remodeling cycle (70 days). Moreover, stimulation of cortical surface bone formation in the treated animals led to significantly greater cortical area and greater bone strength in both P35 and P70. We conclude that, although intracortical remodeling increases within the first remodeling period (70 days) in animals treated with 10 microg/kg PTH, the greater cortical area due to acceleration of bone formation on cortical surfaces increases cortical bone strength. There is no mechanical risk during the first remodeling cycle associated with intermittent PTH treatment in animals with normal bone mass.

Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage.

Two kinds of remodeling, stochastic and targeted, have been proposed based on the observation that microdamage in bone can initiate the remodeling process. Bisphosphonates are known to suppress stochastic bone remodeling. It has been hypothesized that bisphosphonates allow microdamage to accumulate, suggesting that they also suppress targeted remodeling. This study investigated whether suppression of remodeling using bisphosphonates inhibits remodeling targeted to repair microdamage, or whether the suppression of stochastic remodeling alone can account for the observed increase in damage accumulation. Beagle dogs were divided into three groups: control (CNT), risedronate-treated (RIS), and alendronate (ALN)-treated groups. The doses of both bisphosphonates were 6 times higher than the clinical doses. After 1-year treatment, animals were sacrificed and the right 9th rib was assigned to microdamage analysis. There were 3.06 times more associations between cracks and resorption spaces in CNT than expected (P < 0.005), indicating that remodeling normally targets cracks for repair, i.e., cracks can initiate a new remodeling event. However, although there was increased microdamage accumulation in RIS and ALN compared with CNT, fewer cracks than expected were associated with resorption spaces. The observation in RIS and ALN that there were fewer associations between cracks and resorption spaces than expected indicates that both targeted and non-targeted remodeling are suppressed in these groups. These data further suggest that the complete suppression of targeted remodeling could account for the increased microdamage burden.

Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib.

It has been hypothesized that suppression of bone remodeling allows microdamage to accumulate, leading to increased bone fragility. This study evaluated the effects of reduced bone turnover produced by bisphosphonates on microdamage accumulation and biomechanical properties of cortical bone in the dog rib. Thirty-six female beagles, 1-2 years old, were divided into three groups. The control group (CNT) was treated daily for 12 months with saline vehicle. The remaining two groups were treated daily with risedronate (RIS) at a dose of 0.5 mg/kg per day or alendronate (ALN) at 1.0 mg/kg per day orally. After sacrifice, the right ninth rib was assigned to cortical histomorphometry or microdamage analysis. The left ninth rib was tested to failure in three-point bending. Total cross-sectional bone area was significantly increased in both RIS and ALN compared with CNT, whereas cortical area did not differ significantly among groups. One-year treatment with RIS or ALN significantly suppressed intracortical remodeling (RIS, 53%; ALN, 68%) without impairment of mineralization and significantly increased microdamage accumulation in both RIS (155%) and ALN (322%) compared with CNT. Although bone strength and stiffness were not significantly affected by the treatments, bone toughness declined significantly in ALN (20%). Regression analysis showed a significant nonlinear relationship between suppressed intracortical bone remodeling and microdamage accumulation as well as a significant linear relationship between microdamage accumulation and reduced toughness. This study showed that suppression of bone turnover by high doses of bisphosphonates is associated with microdamage accumulation and reduced some mechanical properties of bone.

Effect of bisphosphonate (incadronate) on fracture healing of long bones in rats.

This study was designed to test whether bisphosphonates disturb the process of fracture healing. Female Sprague-Dawley rats were injected with either two doses of bisphosphonate (incadronate) (10 microg/kg and 100 microg/kg) or vehicle three times a week for 2 weeks. Right femora were then fractured and fixed with intramedullary wires. Incadronate treatment was stopped in pretreatment groups (P-10 and P-100 groups), while the treatment was continued in continuous treatment groups (C-10 and C-100 groups). Animals were sacrificed at 6 and 16 weeks after surgery. Soft X-ray of all fractured femora was taken. After mechanical testing, fractured femora were stained in Villanueva bone stain and embedded in methyl methacrylate. Cross-sections near fracture line were analyzed by microradiography and histomorphometry. Radiographic study showed that bony callus was present in all the fractures and incadronate treatment led to a larger callus, especially in C-100 group at both 6 and 16 weeks. Histologic study showed that the process of fracture healing in pretreatment groups was delayed at 6 weeks, but reached control level thereafter and showed same characteristics as in control at 16 weeks. Woven bony callus could still be seen in continuous treatment groups at 16 weeks. Mechanical study indicated that the ultimate load of C-100 group was slightly higher than the other treatment groups and control. The results suggest that pretreatment with incadronate did not affect fracture healing at 16 weeks after fracture. However, continuous incadronate treatment could lead to larger callus, but it delayed remodeling process during fracture healing, especially with high-dose treatment.

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

UNLABELLED: 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 11,377 women for a 3-year period. Of these, 1208 osteoporotic patients were treated with either 1,25-(OH)2D3 or 1 alpha-(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 10,169 women were the 'non-treatment group'. Fractures in the non-treatment group occurred at a rate of 39.8 fractures/10,000 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.

Preadministration of incadronate disodium can prevent bone loss in rat proximal tibial metaphysis when induced by hindlimb immobilization by bandage.

The purpose of this study is to determine whether short-term preadministration of bisphosphonates prevents bone loss in rat proximal tibial metaphysis when induced by hindlimb immobilization by bandage. Six-month-old female Sprague Dawley rats were injected with incadronate disodium (YM-175, 10 micrograms/kg) or vehicle, three times per week for 2 weeks (YM or V groups). Then, the left hindlimb was fixed to the abdomen with a bandage (V-B, YM-B groups), or only the abdomen was bandaged as control (V-SHM, YM-SHM groups), for 4 weeks. The animals were subsequently killed and left proximal tibiae were processed undecalcified for quantitative histomorphometric evaluation. Immobilization-induced cancellous bone loss resulted not only from increased percent eroded surface area but also from decreased percent labeling surface and bone formation rate in V-B compared with V-SHM animals. In contrast, preadministration of YM-175 decreased percent eroded surface significantly and prevented the loss of cancellous bone mass in YM-B compared with V-B animals. Cancellous bone mass was neither increased nor decreased by preadministration of YM-175 in YM-SHM animals. Our results suggest that preadministration of bisphosphonates is effective in prevention of bone loss at the tibial metaphysis when induced by hindlimb immobilization in rats.

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.

Maintaining bone mass by bisphosphonate incadronate disodium (YM175) sequential treatment after discontinuation of intermittent human parathyroid hormone (1-34) administration in ovariectomized rats.

Intermittent treatment with human parathyroid hormone (1-34) [hPTH(1-34)] stimulates bone formation and increases cancellous bone mass in ovariectomized (OVX) rats. But PTH-induced cancellous bone rapidly disappears upon cessation of treatment. The fate of cortical bone treated by PTH has not been well characterized. Incadronate disodium (disodium cycloheptylaminomethylenedisphosphonate monohydrate, YM175) was expected to be antiresorptive without inhibiting bone formation. The purposes of this study were to determine (1) whether PTH treatment increases new cancellous and cortical bone mass and bone formation, (2) whether the new bone could be maintained by YM175 sequential treatment, and (3) whether the maintenance effect is persistent after YM175 withdrawal. Eighty-eight 11-week-old Sprague-Dawley rats were divided into sham operation and OVX groups. The OVX rats were treated for 8 weeks with the subcutaneous intermittent injection of 30 micrograms/kg of hPTH(1-34) three times a week beginning 4 weeks after surgery, then PTH treatment was withdrawn and YM175 (10 micrograms/kg) was injected subcutaneously three times a week for 4 weeks. YM175 treatment was withdrawn for the last 8 weeks of the protocol. The results of microstructural assessment in proximal tibial metaphysis and bone mineral density in distal and proximal femur demonstrated that PTH treatment for 8 weeks restored bone mass to the sham control level. However, after cessation of PTH treatment, the PTH-induced tibial cancellous bone mass showed a decrease at 4 weeks and almost totally disappeared after 12 weeks. Conversely, YM175 treatment maintained the PTH-induced tibial cancellous bone mass, and the bone continued to be maintained after 8 weeks of withdrawal of the YM175. Cortical bone was not lost during PTH treatment. YM175 maintained the PTH-induced new tibial cancellous bone in OVX rats by suppressing remodeling.

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.

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)