Effects of glucosamine in patients with osteoarthritis of the knee: a systematic review and meta-analysis.

Osteoarthritis (OA) of the knee is one of the main causes of mobility decline in the elderly. Non-surgical treatments such as administration of supplements to strengthen the joint cartilage matrix have become popular not only for pain relief but also for joint preservation. Glucosamine has been used in many countries based on the increasing evidence of its effectiveness for OA. Although there are many previous studies and systematic reviews, the findings vary and different conclusions have been drawn. We aimed to review recent randomized controlled trials on glucosamine for knee OA to reveal up-to-date findings about this supplement. We also performed a meta-analysis of some of the outcomes to overcome the unsolved bias in each study. Eighteen articles written between 2003 and 2016 were analyzed. Many used visual analogue scale (VAS) pain scores and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), which were assessed in our meta-analysis. We found a marginally favorable effect of glucosamine on VAS pain scores. The effect on knee function, as measured by the WOMAC, was small and not significant. A newly established knee OA scale, the Japanese Knee Osteoarthritis Measure (JKOM), is commonly used in Japan. Although the number of subjects was small, the JKOM meta-analysis indicated that glucosamine is superior to a placebo in alleviating knee OA symptoms. Given this, we concluded that glucosamine has the potential to alleviate knee OA pain. Further studies are needed to evaluate the effect of glucosamine on knee function and joint preservation, as well as to evaluate the combined effect with other components, such as chondroitin.

The effect of balneotherapy on pain relief, stiffness, and physical function in patients with osteoarthritis of the knee: a meta-analysis.

This meta-analysis was performed to determine the effect of balneotherapy on relieving pain and stiffness and improving physical function, compared to controls, among patients with knee osteoarthritis. We searched electronic databases for eligible studies published from 2004 to December 31, 2016, with language restrictions of English or Japanese. We screened publications in Medline, Embase, Cochrane library, and the Japan Medical Abstracts Society Database using two approaches, MeSH terms and free words. Studies that examined the effect of balneotherapy for treating knee osteoarthritis of a ≥2-week duration were included. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were used as the outcome measure. A total of 102 publications were assessed according to the exclusion criteria of the study; eight clinical trial studies, which comprised a total of 359 cases and 375 controls, were included in this meta-analysis. The meta-analysis analyzed improvement in WOMAC score at the final follow-up visit, which varied from 2 to 12 months post-intervention. Our meta-analysis indicates that balneotherapy was clinically effective in relieving pain and stiffness, and improving function, as assessed by WOMAC score, compared to controls. However, there was high heterogeneity (88 to 93%). It is possible that balneotherapy may reduce pain and stiffness, and improve function, in individuals with knee osteoarthritis, although the quality of current publications contributes to the heterogeneity observed in this meta-analysis.

Effects of eldecalcitol on cortical bone response to mechanical loading in rats.

BACKGROUND: Mechanical loading of bones activates modeling and suppresses remodeling by promoting bone formation. Eldecalcitol is approved for the treatment of osteoporosis in Japan and is often used in patients undergoing exercise therapy. However, the effects of eldecalcitol on bone formation during mechanical loading are unknown. The aim of this study was to clarify the influence of eldecalcitol administration on bone response to mechanical loading using a four-point bending device. METHODS: Forty six-month-old female Wistar rats were randomized into four groups based on eldecalcitol dose (vehicle administration (VEH), low dose (ED-L), medium dose (ED-M), and high dose (ED-H)). Loads of 38 N were applied in vivo to the right tibia for 36 cycles at 2 Hz, by four-point bending, 3 days per week for 3 weeks. After calcein double-labeling, rats were sacrificed and tibial cross sections were prepared from the region with maximal bending at the central diaphysis. Histomorphometry was performed on the entire periosteal and endocortical surface of the tibiae, dividing the periosteum into lateral and medial surfaces. RESULTS: The effects of external loading on bone formation parameters were significant at all three surfaces. Bone formation parameters were highest in the ED-H group, and the effects of eldecalcitol on bone formation rate were significant at the endocortical surface. In addition, the interaction between loading and eldecalcitol dose significantly affected bone formation rate at the endocortical surface. CONCLUSIONS: Eldecalcitol enhanced the cortical bone response to mechanical loading and a synergistic effect was observed in a rat model.

Vitamin D3 analogs for the treatment of osteoporosis.

Vitamin D supplementation is recommended whenever patients are given therapeutic drugs for osteoporosis, to make their calcium (Ca) balance positive. Vitamin D is converted to 25-hydroxyvitamin D in the liver, and then activated to become 1α,25-dihydroxyvitamin D in the kidneys. The active vitamin D acts in the intestine to stimulate Ca absorption and maintain the Ca balance. 2ß-(3-Hydroxypropyloxy)-1α,25-dihydroxyvitamin D3 (eldecalcitol) and 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 (2MD) are newly developed vitamin D analogs, with a substitution at the 2 position of 1α,25-dihydroxyvitamin D3 (calcitriol). Eldecalcitol and 2MD share common structural and biological characteristics. Both compounds increase serum Ca levels more markedly than calcitriol, increase bone mineral density (BMD), and improve bone strength in ovariectomized (OVX) rats. In a randomized, placebo-controlled, double-blind, 1 year clinical trial, eldecalcitol dose-dependently increased lumbar and hip BMD and suppressed bone turnover markers in patients with osteoporosis. Whereas, 2MD markedly increased the bone turnover markers, but it did not change the BMD of postmenopausal women with osteopenia in a 1 year clinical trial. After a randomized, double-blind, 3 year fracture-prevention trial comparing it with alfacalcidol, eldecalcitol was approved for the treatment of osteoporosis in Japan. On the other hand, the manufacturer discontinued the clinical development of 2MD. In this review, we discuss the similarities and differences between these 2 compounds, and the reasons why different outcomes resulted from their clinical trials.

Vertebral fracture risk after once-weekly teriparatide injections: follow-up study of Teriparatide Once-Weekly Efficacy Research (TOWER) trial.

OBJECTIVE: To evaluate fracture risk and bone mineral density (BMD) in patients with primary osteoporosis, 1 year after completing 72 weeks of weekly teriparatide injections. RESEARCH DESIGN AND METHODS: After 72 weeks of teriparatide injections or placebo (original trial), treatment was unblinded and subjects were subsequently treated with bisphosphonates or other therapeutic regimens at the discretion of their physicians and followed for 1 year. Spine radiographs and BMD measurements at the lumbar spine, femoral neck, and total hip by dual energy X-ray absorptiometry were performed. MAIN OUTCOME MEASURE: Incident vertebral fracture rate. RESULTS: A total of 465 patients were enrolled and 447 (96.1%) completed the study. In the 1 year follow-up period, new morphometric vertebral fractures occurred in 7/203 (3.4%) in the post-teriparatide group and 33/241 (13.7%) in the post-placebo group (relative risk [RR]: 0.23, 95% confidence interval [CI]: 0.10 to 0.52, P < 0.05). The cumulative incidences from the start of the original trial were 4.9% and 22.8%, respectively (RR: 0.18, 95% CI: 0.09 to 0.36, P < 0.05). There were no significant differences in incidences of vertebral fractures between subsequent therapeutic regimens in the post-teriparatide group. In subjects treated with bisphosphonates, mean BMD values further significantly increased by 9.6%, 2.9%, and 4.1% at the lumbar spine, femoral neck, and total hip, respectively (P < 0.05). CONCLUSIONS: The reduced risk of vertebral fracture was sustained for 1 year after completion of 72 weeks of weekly teriparatide injections. The effects did not differ between subsequent therapeutic regimens. BMD gains continued with sequential bisphosphonate treatment, but not with the other sequential therapeutic regimens. Bisphosphonates seem to be a useful choice as a subsequent treatment to weekly teriparatide. LIMITATION: This study was an observational follow-up study and the regimens of subsequent medication after discontinuation of the original TOWER trial were not randomly allocated.

Effects of minodronate on cortical bone response to mechanical loading in rats.

The effects of BPs on bone formation during mechanical loading are still unknown. In this study, we evaluated the effect of minodronate on the cortical bone response to mechanical loading applied using a 4-point bending device. We used six-month old female Wistar rats and randomized into five groups (N=10/group): Vehicle administration (VEH), low dose minodronate administration (MIN-L, 0.01 mg/kg BW), middle dose minodronate administration (MIN-M, 0.1mg/kg BW), high-dose minodronate administration (MIN-H 1mg/kg BW), and very high-dose minodronate administration (MIN-VH, 10mg/kg BW). Minodronate or vehicle was administered orally using the feeding needle at a dosage 3 times/week for 3 weeks. Loads on the right tibia at 38 N for 36 cycles at 2 Hz were applied in vivo by 4-point bending on the same day for 3 weeks. After calcein double labeling the rats were sacrificed and tibial cross sections were prepared from the region with maximal bending at the central diaphysis. Histomorphometry was performed at the entire periosteal and endocortical surface of the tibiae, dividing the periosteum into lateral and medial surfaces. The formation surface was reduced significantly in MIN-H and MIN-VH groups at the medial surface, and in MIN-VH group at the endocortical surface of the loaded tibia (p<0.01 vs. VEH). The mineral appositional rate was reduced significantly in MIN-H and MIN-VH groups at the endocortical surface of the loaded tibia (p<0.01 vs. VEH). The bone formation rate was significantly reduced in MIN-H group at the medial surface, and in MIN-H and MIN-VH groups at the endocortical surface of the loaded tibia (p<0.01 vs. VEH). However, no significant differences were observed in any parameters between the VEH group and either the MIN-L or MIN-M groups for both the loaded and non-loaded tibiae. Based on previous preventive studies in OVX rats, the optimal dose of minodronate for the treatment of osteoporosis would be 0.03 mg/kg (0.21 mg/kg/week). Therefore, we used 0.1mg/kg of minodronate 3 times/week (0.30 mg/kg/week) that was close to 0.21 mg/kg/week. In conclusion, minodronate does not reduce the cortical bone response to mechanical loading at the optimal dose for the treatment of osteoporosis in rat model.

Three years of treatment with minodronate in patients with postmenopausal osteoporosis.

The objective of this study was to determine the safety and efficacy of long-term minodronate treatment in women with postmenopausal osteoporosis based on re-analysis of a phase III 2-year clinical trial with a 1-year extension. Women aged 55-80 years old with fragility fractures were enrolled and randomized to take 1 mg minodronate or placebo once a day in the original 2-year study. The subjects who completed the 2-year study were invited to participate in an additional 1-year extension in which all subjects were to receive minodronate. Finally, a total 380 subjects completed the extension study (186 from the placebo group and 194 from the minodronate group). Fracture results observed in the extension study were consistent with those observed in the first 2 years in minodronate group. In contrast, the placebo/minodronate group showed a decreased incidence of new vertebral fractures during year 3 compared to that in year 2. In the patients who received minodronate in the original 2-year study, lumbar bone mineral density (BMD) increased consistently during year 3 and bone turnover markers decreased within the first 6 months and remained constant thereafter over 3 years. Similar positive effects of minodronate on BMD and bone turnover markers occurred when therapy was initiated in the placebo/minodronate group. No new safety concerns observed during the extension period compared to the safety observations made during the 2-year study. It was concluded that daily administration of 1 mg oral minodronate is safe and well tolerated, and that the efficacy of this dose in reducing vertebral fracture risk in postmenopausal women over 2 years is sustained with continuing treatment.

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.

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.

A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial.

CONTEXT: ED-71 has been shown to increase lumbar bone mineral density (BMD) in osteoporotic subjects. However, vitamin D insufficiency might have influenced the effect of ED-71 on BMD. OBJECTIVE: Our objective was to examine whether ED-71 can increase BMD in osteoporotic patients under vitamin D supplementation. DESIGN, SETTING, AND PATIENTS: We conducted a randomized, double-blind, placebo-controlled clinical trial of 219 osteoporotic patients (49-87 yr of age). INTERVENTIONS: Subjects were randomly assigned to receive placebo or 0.5, 0.75, or 1.0 microg/d ED-71 for 12 months. All the subjects received 200 or 400 IU/d vitamin D(3). MAIN OUTCOME MEASURES: We assessed changes in lumbar and hip BMD and bone turnover markers from baseline. RESULTS: Lumbar BMD increased with ED-71 treatment for 12 months (2.2, 2.6, and 3.1% from baseline and 2.9, 3.4, and 3.8% vs. placebo group in subjects receiving 0.5, 0.75, and 1.0 microg ED-71, respectively). Total hip BMD also increased with 0.75 and 1.0 microg ED-71 (-0.8, 0.6, and 0.9% from baseline and 0.1, 1.5, and 1.8% vs. placebo group in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively). Bone formation and resorption markers were suppressed by approximately 20% after 12 months of 0.75 and 1.0 microg ED-71 treatment. Transient hypercalcemia over 2.6 mmol/liter occurred in 7, 5, and 23% of subjects in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively, but none of them developed sustained hypercalcemia. CONCLUSIONS: These results demonstrate that ED-71 treatment at around 0.75 microg/d can effectively and safely increase lumbar and hip BMD in osteoporotic patients with vitamin D supplementation.

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.

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.