Etanercept Promotes Bone Formation via Suppression of Dickkopf-1 Expression in Rats with Collagen-Induced Arthritis.

BACKGROUND: Various clinical reports suggest etanercept (ETN) has some efficacy in bone formation in rheumatoid arthritis (RA). To examine this effect, we investigated the gene expression of cytokines relevant to osteoblast/osteoclast differentiation, and evaluated histomorphometric findings in mature rats with collagen-induced arthritis (CIA). METHODS: Total RNA was extracted from knee joints with CIA after ETN or placebo administration. Subsequently, realtime-PCR was carried out to quantify the mRNAs encoding Wnt-1, Dickkopf-1 (DKK-1), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegelin (OPG) and TNF (tumor necrosis factor)-alpha. In histomorphometric analysis, the infiltrating pannus volume and pannus surface, and the following items in contact with pannus surface were measured: osteoclast number, osteoid surface, osteoid volume and labeling surface. These were evaluated in the distal femur with CIA with or without ETN administration. RESULTS: TNF-alpha, RANKL and OPG mRNA expressions, linked to osteoclastogenesis, were not significantly different with or without ETN administration. ETN administration significantly increased Wnt-1 mRNA expression, the osteoblast promoter, and decreased DKK-1 mRNA expression, the Wnt signal inhibitor. In histomorphometric analysis, pannus volume, pannus surface and osteoclast number, parameters of bone destruction, were not significantly different among groups. Osteoid volume, osteoid surface and labeling surface, parameters of bone formation, increased significantly with ETN administration. CONCLUSION: Our results suggest that ETN suppresses DDK-1 expression, and, as a result, Wnt expression is promoted and osteoblastogenesis becomes more active, independent of the regulation of osteoclast activity. Marked bone formation is attributed to the fact that ETN directly promotes osteoblastogenesis, not as a result of suppressing osteoclastogenesis.

Morphological and volumetric analysis of the development of atlantoaxial vertical subluxation in rheumatoid arthritis.

BACKGROUND: Cervical disorders in rheumatoid arthritis (RA) patients have been an important problem for a long time. Although the recent progression of the treatment strategies for RA might change the progression of atlantoaxial vertical subluxation (VS) in RA patients, to reveal the risk factors for VS progression should be important at present. Osteoporosis (OP) and RA share the same risk factors. The purposes of this study were to identify the progression of VS in RA, and to evaluate the relationship between the VS development and OP. METHODS: Eighty female patients with RA and 18 female patients with OP were retrospectively analyzed. The RA patients were divided into VS (10 patients) and non-VS groups (70 patients). Morphological parameters on coronal reconstructed computed tomography images were evaluated. Three-dimensional analysis was used to measure volumes and volumetric bone mineral densities (vBMDs) at the upper cervical spine (UCS). RESULTS: The VS group had higher age, longer RA symptom duration, and lower BMD at the lumbar spine compared to the non-VS group. Volumes and vBMDs at the UCS in RA group were greater than those in the OP group. In accordance with VS development, the lateral masses at the UCS became shorter, the C1 facet angle became sharper, and the volumes at the UCS decreased. However, there was no statistically significant relationship between vBMDs at the UCS and the VS development. CONCLUSION: The C1 facet angle became sharper with VS progression. Although 3-dimensional analysis revealed that decreases in the volumes at the UCS were associated with VS development, no significant relationship between OP and the VS development was observed.

Recent trends in adult-onset septic arthritis of the knee and hip: retrospective analysis of patients treated during the past 50 years.

This study was a retrospective analysis of 53 adult patients with septic arthritis (SA) of the knee or hip treated during the years from 1955 to 2005 in Tottori University Hospital in Japan. Patients with postoperative infection, infection caused by trauma, and periprosthetic infection were excluded. The 50-year period between 1955 and 2005 was divided into five periods: there were 5 patients in the first decade, 9 in the second decade, 11 in the third decade, 10 in the fourth decade, and 18 in the fifth decade. All SA occurred in the knee until the fourth decade. Five cases of septic arthritis in the hip occurred in the fifth decade. In contrast to the decrease in direct infections (post intraarticular injection), hematogenous infections were observed to increase after 1986. The rate of SA caused by Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus, MRSA) had been highest during the 50 years. Infections caused by MRSA, comprising 22% of all staphylococcal infection, occurred in the fifth decade. The numbers of patients with comorbid conditions such as diabetes increased during the 50-year period. This study indicated that patients with SA have been increasing in number. Furthermore, hematogenous SA has been increasing. The increase in occurrence of SA could result from increase in opportunistic infection, occurrence of SA of the hip, and increase in MRSA infection.

Effect of raloxifene on arthritis and bone mineral density in rats with collagen-induced arthritis.

We studied the effect of raloxifene (RAL) on arthritis and bone mineral density (BMD) in rats with collagen-induced arthritis (CIA). Seven-month-old female Sprague-Dawley rats were divided into five groups: rats without CIA (CNT), CIA rats that underwent ovariectomy (OVX) and were treated with RAL (CIA + OVX + RAL), CIA rats that underwent OVX and were treated with vehicle (CIA + OVX + Veh), CIA rats that had sham surgery and were treated with RAL (CIA + sham + RAL), and CIA rats that had sham surgery and were treated with vehicle (CIA + sham + Veh). RAL was orally administered at 10 mg/kg every day for 3 weeks, beginning 1 week after initial sensitization until death at 4 weeks. Every week until death, we evaluated hind paw thickness and arthritis score. BMD was measured by peripheral quantitative computed tomography at the distal metaphysis and the diaphysis of the femur; we also performed histomorphometry of the proximal tibia and histological evaluation of arthritis. RAL administration suppressed hind paw thickness and arthritis score and prevented decreases in BMD and cortical thickness. In the histomorphometric analysis, bone-resorption parameters were significantly lower in the RAL groups than in the Veh groups. RAL significantly inhibited synovial proliferation in CIA rats. RAL effects on arthritis and bone were apparent regardless of whether an animal had undergone OVX. RAL could suppress arthritis and bone loss in estrogen-replete or -depleted rats. These findings, using an animal model, indicate the potential usefulness of RAL as an effective treatment for premenopausal RA patients as well as postmenopausal ones.

[Daily practice using the guidelines for prevention and treatment of osteoporosis. Evolution of bisphosphonate therapy. Intravenous injection].

Injectable formulation of bisphosphonate (pamidronate, alendronate, incadronate, and zoledronate) is available only for therapy of malignancy in Japan. Ibandronate and zoledronate are permitted to use by injection in the treatment of osteoporosis in US and Europe and have shown a significant effect in fracture prevention. Recently, it was reported that an annual infusion of zoledronate was associated with improved survival in addition to a reduction in the rate of new fractures. Injectable formulation of ibandronate is now in the 3rd phase of clinical trial for fracture prevention in Japan. It is expected that patients with a high fracture risk who could not take bisphosphonate orally receive the benefit of bisphosphonate through injection.

Influence of glucocorticoid on bone in 3-, 6-, and 12-month-old rats as determined by bone mass and histomorphometry.

The influence of glucocorticoid (GC) on bone in rats at different ages was investigated in order to provide insight into human glucocorticoid induced osteoporosis (GCOP). Three-, 6-, and 12-month-old female Wistar rats were divided into four groups: Zero-time control (ZT), vehicle (Cont), prednisolone (PSL) 2 mg/kg (P-L), PSL 20 mg/kg (P-H). PSL was subcutaneously administered every day for 4 weeks. Bone mineral density (BMD) at the proximal metaphysis and diaphysis of the tibia was measured by peripheral quantitative computed tomography. Histomorphometry of the tibia was performed for 3- and 6-month-old rats. GC increased trabecular and cortical BMD at the metaphysis in all 3-month-old rats with time. Trabecular BMD at the metaphysis in the P-L and P-H groups was significantly higher than in the control group. Histomorphometric parameters for both bone formation and resorption were also increased by GC treatment. In the 6-month-old rats, the metaphyseal trabecular BMD did not significantly change in any group, but the diaphyseal trabecular BMD significantly increased in the control group with time. The trabecular BMD of the metaphysis and diaphysis was significantly lower in the P-L and P-H groups than in the control group at week 4. Histomorphometric parameters for bone formation and resorption were both reduced by GC treatment. The BMD remained unchanged in all 12-month-old rats. Six-month-old rats treated with 20 mg/kg GC are suitable models for GC-induced osteoporosis with dominant cancellous bone decrease and reduced bone turnover. The pathology induced by 20 mg/kg prednisolone in 6-month-old female rats seems to be most similar to glucocorticoid-induced osteoporosis in humans.

Knee deformity in rheumatoid arthritis is closely correlated with generalized osteoporosis.

To examine the relationship between knee deformity and osteoporosis in women with rheumatoid arthritis (RA), bone mineral density (BMD) in the lumbar spine and distal radius was measured using dual X-ray absorptiometry, and knee deformity (valgus or varus deformity) was measured using plain radiograms in 55 women with RA. Associations between knee deformity and BMD, disease related variables, including RA stage, RA duration, age, cumulative doses of administered glucocorticosteroids, body mass index, or postmenopausal period were evaluated. Cut-off values of the BMD defining RA patients with knee deformity were very close to the BMD value corresponding to 70% of young adult mean in the lumbar spine and distal radius. The femorotibial alignment was significantly correlated with age and deformity of the proximal tibia. Deformity of the proximal tibia was negatively correlated with the radial BMD and lumbar BMD. Deformity of the proximal tibia showed a significant difference between the groups of less than 5 years after menopause and the group of 5-10 years after menopause. We concluded that knee deformity in RA derived from deformity of the proximal tibia, and it was closely correlated with generalized osteoporosis.

Effect of estrogen replacement therapy on arthritis and bone mineral density in estrogen-replete rats with collagen-induced arthritis.

The influence of estrogen therapy on changes in arthritis and bone mineral density (BMD) was evaluated using an estrogen-replete collagen-induced arthritis (CIA) rat model. Seven-month-old female Sprague-Dawley rats (n = 30) were divided into the three groups; control (CONT), collagen sensitization (CIA), and CIA + 17beta-estradiol administration for 7 weeks (CIA + E). BMD was measured by peripheral quantitative computed tomography in the proximal tibia every 2 weeks. Eight weeks after the initial sensitization the rats were killed and histomorphometry of tibia was performed. The hind paw thickness increased with time in CIA rats and there was a significant difference between CONT and CIA at 8 weeks after the initial sensitization. Estrogen tended to make the development of arthritis milder. In CIA, BMD at metaphyseal cancellous bone began to decrease with the onset of arthritis and became significantly lower than in CONT after 8 weeks. Compared with the CIA, the deterioration in BMD was inhibited in CIA + E. Histomorphometrical parameters of bone resorption were increased in CIA compared with CONT, and those elevations were reduced by estrogen treatment, but estrogen had no effect on bone formation parameters. In conclusion, estrogen could partially suppress arthritis and bone loss in estrogen-replete rats as well as estrogen-deplete ones.

Role of subchondral bone in osteoarthritis development: a comparative study of two strains of guinea pigs with and without spontaneously occurring osteoarthritis.

OBJECTIVE: To evaluate the relationships among cartilage and subchondral bone before and after the onset of cartilage degeneration in the Hartley guinea pig model of spontaneous osteoarthritis (OA) as compared with those in Weiser-Maple guinea pigs, which do not develop OA. METHODS: Mice from each strain were used at ages 2, 3, 5, and 8 months (n = 7 at each time point). The region observed was the medial tibial plateau. Cartilage degeneration was evaluated histologically. Subchondral bone structure was evaluated based on subchondral bone plate thickness and subchondral cancellous bone trabecular parameters calculated from the microfocal computed tomography 3-dimensional reconstruction image. The bone mineral density (BMD) of the subchondral cancellous bone as well as levels of urinary N-telopeptide of type I collagen (NTX) and serum osteocalcin (OC) were measured. RESULTS: In Hartley guinea pigs, the number of chondrocytes in the surface layer started to decrease at 3 months. At 8 months, fibrillation expanded to the radial zone. In Weiser-Maple guinea pigs, no cartilage degeneration was noted even at 8 months. Subchondral bone plate thickness was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The subchondral bone had a rod-like and convex structure at 2 months in Hartley guinea pigs. BMD was significantly lower in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months. The serum OC level was significantly higher in Hartley guinea pigs than in Weiser-Maple guinea pigs at 2 months and 3 months, whereas the urinary NTX level was significantly lower in Hartley guinea pigs at 3 months. CONCLUSION: Subchondral bone is fragile, and bone formation may be promoted in subchondral bone before the onset of cartilage degeneration in Hartley guinea pigs. Subchondral bone may be involved in the development of OA.

[Treatment and management of severe osteoporosis].

Because there is an extremely high probability of new fractures occurring in cases in which there are pre-existing fractures, it is easy for such patients to develop severe osteoporosis. We therefore must correctly ascertain any existence of either vertebral or hip fractures. High values of bone resorption markers reflect the existence of microfractures, so it is necessary to be careful due to the high risk of new fractures. Kinesitherapy for severe osteoporosis focuses on therapeutic exercise, walking, balance drills, and so forth with the aim of maintaining muscular strength and thus preventing falls. For severe osteoporosis such as senile osteoporosis and glucocorticoid-induced osteoporosis, bisphosphonates are currently the only medication that has been proven to be effective for preventing fractures. For the treatment of disuse osteoporosis stemming from paralysis, etc., the intravenous injection of bisphosphonates is able to suppress the decline in bone mass, but there is still very little evidence of its fracture prevention effect.

Increasing incidence of hip fracture in Tottori Prefecture, Japan: trend from 1986 to 2001.

We conducted a survey of all hip fractures in patients 35 years old and over during 1998-2001 in Tottori Prefecture, Japan, and compared them with those reported previously. The survey found 604, 671, 710, 729 patients, in 1998, 1999, 2000, and 2001, respectively. The mean age- and gender-specific incidences (per 100,000 person-years) for men were 108.0, 209.0, 449.1, and 780.0 in the age groups of 70-74, 75-79, 80-84 and over 84, respectively, and those for women were 249.1, 505.8, 1,115.4, and 2,066.4, respectively. The expected numbers of patients in 1998 were 1.23 and 1.42 times those in 1986, and those in 2001 were 1.61 and 1.48 times those in 1986, for men and women, respectively, and the increases with time for both genders were significant. It was concluded that there was a significant increase in the incidence rates of hip fracture from 1986 to 2001.

Effect of intermittent administration of human parathyroid hormone on bone mineral density and arthritis in rats with collagen-induced arthritis.

OBJECTIVE: To investigate the effect of intermittent administration of human parathyroid hormone (PTH) on bone mineral density (BMD) and arthritis in rats with collagen-induced arthritis (CIA). METHODS: Seven-month-old female Sprague-Dawley rats were divided into 4 groups: rats without CIA (control), rats with CIA treated with vehicle, rats with CIA treated with PTH for 4 weeks, and rats with CIA treated with PTH for 6 weeks. PTH (20 mug/kg) was injected subcutaneously 3 times per week. BMD in the proximal metaphysis and the diaphysis of the tibia was measured by peripheral quantitative computed tomography every 2 weeks until week 8. Eight weeks after initial sensitization, the animals were killed, and the BMD and mechanical properties of excised limbs were evaluated. Histomorphometric analysis of tibiae and histologic evaluation of arthritis were also performed. RESULTS: In the PTH-treated rats with CIA, the incidence and severity of arthritis were macroscopically and histologically similar to the findings in the vehicle-treated rats with CIA. The decrease of BMD caused by CIA was suppressed by treatment with human PTH, in a manner that was dependent on the duration of administration. In the histomorphometric analysis, bone formation parameters were higher and bone resorption parameters were lower in the PTH-treated arthritic rats compared with vehicle-treated arthritic rats. Mechanical properties were also maintained in the PTH-treated rats. CONCLUSION: Our findings indicate that, in an animal model of arthritis, intermittent PTH administration activates bone formation, resulting in increased BMD and preventing deterioration of mechanical properties. However, PTH has no effect on the arthritis itself.

Bone response to mechanical loading in adult rats with collagen-induced arthritis.

To elucidate the effects of inflammation on the response of bone to mechanical stress, we performed experiments using a rat with collagen-induced arthritis (CIA) model. Six-month-old female Wistar rats were used in the experiment. Bovine type II collagen sensitization and additional sensitization after 1 week were preformed in all CIA groups. Loads were applied using a four-point bending device. The right tibia was loaded in both CIA and control (CONT) groups at 35 N (low groups), 40 N (medium groups), or 47 N (high groups) for 36 cycles at 2 Hz three times per week for 3 weeks. Histomorphometrical data were collected from the periosteal and endosteal surfaces of the tibia in all rats. The tibia periosteal surface was subdivided into lateral and medial surfaces. Formation surface (FS), mineral apposition rate (MAR) and bone formation rate (BFR) were calculated. At lateral surface of periosteal surface, all three parameters showed significant differences between the loaded and nonloaded tibiae. All these parameters were significantly lower in CIA groups than in CONT groups, and interaction was seen between applied loading and CIA. There was a significant correlation between peak strain and the right-left difference of FS in the CONT groups. At medial surface of periosteal surface, there were force-related increase in FS, MAR, and BFR on the loaded side in both CIA and CONT groups, except MAR in the CONT group. All three parameters showed significant differences between the loaded and nonloaded tibiae. At endocortical surface, force-related increase was observed only in FS on the loaded side in CONT groups, and FS was significantly higher on the loaded side than the nonloaded side. CIA lowered all three parameters significantly. We examined the response to mechanical loading on the tibia in untreated CONT rats and rats with CIA by bone histomorphometry, and found that arthritis suppressed bone formation induced by mechanical loading.

Effect of minodronic acid (ONO-5920) on bone mineral density and arthritis in adult rats with collagen-induced arthritis.

OBJECTIVE: To study the effect of minodronic acid (ONO-5920) on bone loss and arthritis in rats with collagen-induced arthritis (CIA) treated according to 2 different schedules. METHODS: Four groups of female Sprague-Dawley rats (7 months old) were studied: rats without CIA treated with vehicle (controls), CIA rats treated with vehicle (CIA-V), CIA rats treated therapeutically with minodronic acid (CIA-T), and CIA rats treated prophylactically with minodronic acid (CIA-P). Minodronic acid was administered orally at 0.2 mg/kg 3 times a week, beginning 2 weeks after initial sensitization in the CIA-T rats and beginning the day after initial sensitization in the CIA-P rats. Bone mineral density (BMD) was measured by peripheral quantitative computed tomography in the proximal metaphysis and diaphysis of the tibia every 2 weeks until week 8, when the rats were killed. The BMD and bone microstructure of the excised femur were evaluated by dual x-ray absorptiometry and microfocal computed tomography, respectively. Histomorphometry of the proximal tibia was also performed. RESULTS: In CIA-P rats, the incidence of arthritis and the severity of posterior limb swelling were reduced early after sensitization, and the decrease in BMD was prevented throughout the observation period. Bone and joint destruction evaluated by radiography of the foot was reduced in CIA-P rats. The eroded surface was reduced and the microstructure was maintained in CIA-P rats compared with CIA-V rats. The mineral apposition and bone formation rates were not reduced in the CIA-P rats. In CIA-T rats, however, the inflammation was not suppressed and the inhibitory effect on bone loss was smaller than that in CIA-P rats. CONCLUSION: Minodronic acid suppressed the decrease in BMD and the deterioration of the bone microstructure caused by arthritis. Prophylactic administration of minodronic acid had a preventive effect on arthritis at the early stage, although not throughout the observation period.

[Clinical trials of alendronate].

A number of large scale double-blind controlled studies with alendronate were carried out to evaluate therapeutic efficacy for osteoporotics. Alendronate administered orally at 5 mg per day for 7 years induced an average 8.2% increase of bone mineral density in the spine and 2.6% in the hip. Alendronate given orally for 4 years decreased significantly by 44% the occurrence of vertebral and non-vertebral fractures in patients with low bone mineral density and at least one fracture. In patients without any fracture, the results were significant for non-vertebral fractures when initial BMD was low. In histomorphometry with iliac bone biopsies, mineralization was normal, and trabecular bone turnover markedly decreased in patients receiving long-term dosing with alendronate. Alendronate is expected to have a potency to inhibit bone fracture occurrence in Japanese osteoporotics safely.