Early adverse events after the first administration of zoledronic acid in Japanese patients with osteoporosis.

INTRODUCTION: The occurrence of early adverse events and the factors associated with these events in zoledronic acid-treated Japanese patients with osteoporosis were investigated. MATERIALS AND METHODS: All patients treated with zoledronic acid for the first time for primary osteoporosis were analyzed. Based on the history of bisphosphonate (BP) administration, the patients were divided into three groups: BP-switch, BP-washout, and naïve groups. The BP-washout and naive groups were combined into a non-BP group. RESULTS: A total of 184 patients with a mean age of 77.4 years were included. Acute phase reactions (APRs) occurred in 32 patients (17.4%). The significant risk factors were hospitalization (vs. outpatients), BP-switch (vs. non-BP), and age > 80 years (vs. ≤ 69 years), and the odds ratios were 5.63, 0.12, and 0.23, respectively. The serum calcium levels were significantly reduced in the non-BP group, regardless of the co-administration of active vitamin D3. However, the patients who were co-administered active vitamin D3 had significantly higher values than those who were not. In the BP-switch group, no significant reduction in serum calcium levels was observed; however, the reductions tended to be smaller in the patients who were co-administered active vitamin D3. CONCLUSION: Occurrence of APRs might be lesser in clinical practice than in phase 3 clinical trials. Although serum calcium levels decreased in many cases, the decrease could be suppressed by the co-administration of active vitamin D3.

Teriparatide rapidly improves pain-like behavior in ovariectomized mice in association with the downregulation of inflammatory cytokine expression.

Recent studies have indicated that teriparatide, an anti-osteoporosis agent, significantly improves back pain regardless of the presence of vertebral fracture in osteoporosis patients. The aims of this study were to examine whether teriparatide improves pain-like behavior in an ovariectomized (OVX) mouse model, and to evaluate changes in osteoclast marker levels and inflammatory cytokine expression levels induced by teriparatide treatment in bone tissue in association with improvements in pain-like behavior. OVX and sham operations were performed in 8-week-old mice, followed by teriparatide treatment for 2 weeks. Pain-like behavior tests (von Frey, paw flick and spontaneous pain test), and the measurement of serum tartrate-resistant acid phosphatase 5b (TRAP5b) level and inflammatory cytokine (interleukin [IL]-1ß, IL-6 and tumor necrosis factor [TNF]-α) expression levels in the bone tissue were conducted after teriparatide treatment in OVX mice. Pain-like behavior in the von Frey test was significantly improved by teriparatide treatment in OVX mice. With regard to the early phase (within the first 7 days of treatment), teriparatide significantly improved pain-like behavior in the von Frey test, the paw flick test and the spontaneous pain test. Teriparatide significantly inhibited the expression of IL-1ß, IL-6 and TNF-α in OVX mice in the early phase of the treatment, while the TRAP5b level in OVX mice was not significantly affected. We demonstrated that the teriparatide-induced rapid improvement effect on pain-like behavior in OVX mice was associated with the downregulation of inflammatory cytokine expression, including IL-1ß, IL-6 and TNF-α.

Improvement in the rate of inadequate pharmaceutical treatment by orthopaedic surgeons for the prevention of a second fracture over the last 10 years.

BACKGROUND: We have previously reported that the low rate of osteoporosis patients treated with anti-osteoporotic drugs following surgical treatment for the first fragility fractures by orthopaedic surgeons during 3 years from 2000 to 2003 was only 13.1%. Ten years have now passed our previous study, and we hypothesized that the rate of appropriate pharmacologic treatment for the prevention of secondary fractures has improved. METHODS: We studied 730 osteoporosis patients (102 men and 628 women; average age of 78 years, range 33-102 years) who underwent surgical treatment for fragility fractures, during 3-year period from 2010 to 2012. The 730 cases consisted of 489 hip fractures and 241 distal radius fractures. All patients were admitted and underwent surgical intervention in hospitals. Variables were examined to ascertain whether pharmaceutical treatment was performed after discharge. Based on these data, we compared results for patients in the present study with those from our previous study. RESULTS: The rate of treatment with anti-osteoporosis medication in the present (16.2%) was slightly but significantly improved from that in our previous study (13.1%). The rate of pharmaceutical treatment following hip fractures increased significantly, while that following distal radius fractures showed no significant change. Regarding the categories of anti-osteoporotic drugs prescribed to the patients, the rate of treatment with bisphosphonate as a higher evidenced drug for the prevention of fractures in the present study was significantly higher than that in our previous study. CONCLUSION: We demonstrated that the rate of pharmacologic treatment by orthopaedic surgeons and the rate of more effective anti-osteoporotic drugs prescribed to the patients following surgical intervention for the first fragility fracture in the present study were improved in comparison with those of 10 years ago.

Further significant effects of eldecalcitol on bone resorption markers and bone mineral density in postmenopausal osteoporosis patients having undergone long-term bisphosphonate treatment.

We investigated whether eldecalcitol has further significant effects on bone metabolic markers and bone mineral density (BMD) in osteoporosis patients having undergone long-term bisphosphonate treatment. Eldecalcitol treatment was initiated in 48 postmenopausal osteoporosis patients who had undergone bisphosphonate treatment with or without alfacalcidol treatment for more than 2 years (average period 6.3 years). Age, height, weight, total muscle volume, total fat volume, estimated glomerular filtration rate, and BMD at the lumbar spine, total hip, and distal third of the radius were measured as background data for each patient. Serum alkaline phosphatase, tartrate-resistant acid phosphatase 5b, calcium, and phosphate levels were measured at the baseline and 3 and 12 months after the initiation of eldecalcitol treatment, and BMD was measured at the baseline and 12 months after the initiation of eldecalcitol treatment. Tartrate-resistant acid phosphatase 5b level was significantly decreased at 3 and 12 months after the initiation of eldecalcitol treatment in comparison with the baseline level. There were no significant changes in alkaline phosphatase, calcium, or phosphate levels in comparison with the baseline levels. In addition, the lumbar spine BMD at 12 months after the initiation of treatment was significantly increased in comparison with the baseline level, although no significant changes in BMD at the total hip and distal third of the radius were observed. Eldecalcitol demonstrated significant effects in additionally decreasing the level of the bone resorption marker tartrate-resistant acid phosphatase 5b and increasing BMD at the lumbar spine, even in osteoporosis patients having undergone long-term bisphosphonate treatment.

Delayed fracture healing in tetranectin-deficient mice.

Tetranectin is a plasminogen-binding protein that enhances plasminogen activation, which has been suggested to play a role in tissue remodeling. Recently, we showed that tetranectin has a role in the wound-healing process. In this study, we investigated whether tetranectin plays a role in fracture healing. The fracture-healing process was studied using a femoral osteotomy model in tetranectin-null mice, previously generated by the authors. Radiographic imaging, micro-computed tomography (µCT), and histological analysis were used to evaluate osteotomy healing. In wild-type mice, a callus was apparent from 7 days, and most samples showed marked callus formation and rebridging of the cortices at the osteotomy site at 21 days. In contrast, in the tetranectin-null mice there was no callus formation at 7 days and much less callus formation and no bridging of cortices were observed at 21 days. At 35 days, all osteotomy sites showed clear rebridging, and secondary bone formation was achieved in wild-type mice by 42 days. In contrast, no clear rebridging or secondary bone formation was observed at 42 days in the tetranectin-null mice. Analysis using µCT at 21 days after osteotomy revealed that the callus area in tetranectin-null mice was smaller than that in wild-type mice. Histological analysis also showed that soft tissue and callus formation were smaller in the tetranectin-null mice at the early stage of the healing process after drill-hole injury. These results suggested that tetranectin could have a role in the positive regulation at the early stage of the fracture-healing process, which was reflected in the delayed fracture healing in tetranectin-deficient mice.

Antagonists to TRPV1, ASICs and P2X have a potential role to prevent the triggering of regional bone metabolic disorder and pain-like behavior in tail-suspended mice.

Our recent studies demonstrated that regional bone loss in the unloaded hind limbs of tail-suspended mice triggered pain-like behaviors due to the acidic environment in the bone induced by osteoclast activation. The aims of the present study were to examine whether TRPV1, ASIC and P2X (known as nociceptors) are expressed in bone, and whether the antagonists to those receptors affect the expression of osteoblast and osteoclast regulators, and prevent the triggering of not only pain-like behaviors but also high bone turnover conditions in tail-suspension model mice. The hind limb-unloaded mice were subjected to tail suspension with the hind limbs elevated for 14days. The effects of the TRPV1, ASIC3, P2X2/3 antagonists on pain-like behaviors as assessed by the von Frey test, paw flick test and spontaneous pain scale; the expressions of TRPV1, ASICs, and P2X2 in the bone; and the effects of those antagonists on osteoblast and osteoclast regulators were examined. In addition, we evaluated the preventive effect of continuous treatment with a TRPV1 antagonist on the trigger for pain-like behavior and bone loss in tail-suspended mice. Pain-like behaviors were significantly improved by the treatment with TRPV1, ASIC, P2X antagonists; TRPV1, ASICs and P2X were expressed in the bone tissues; and the antagonists to these receptors down-regulated the expression of osteoblast and osteoclast regulators in tail-suspended mice. In addition, continuous treatment with a TRPV1 antagonist during tail-suspension prevented the induction of pain-like behaviors and regional bone loss in the unloaded hind limbs. We, therefore, believe that those receptor antagonists have a potential role in preventing the triggering of skeletal pain with associated regional bone metabolic disorder.

Regional osteoporosis due to osteoclast activation as a trigger for the pain-like behaviors in tail-suspended mice.

Pathological conditions with refractory skeletal pain are often characterized by regional osteoporotic changes such as transient osteoporosis of the hip, regional migratory osteoporosis, or complex regional pain syndrome (CRPS). Our previous study demonstrated that the acidic microenvironment created by osteoclast activation under high bone turnover conditions induced pain-like behaviors in ovariectomized mice through the stimulation of acid-sensing nociceptors. The aim of the present study was to examine whether regional transient osteoporotic changes are related to pain-like behaviors in the hind limb using tail-suspended model mice. The hind limbs of tail-suspended mice were unloaded for 2 weeks, during which time the mice revealed significant regional osteoporotic changes in their hind limbs accompanied by osteoclast activation. In addition, these changes were significantly recovered by the resumption of weight bearing on the hind limbs for 4 weeks. Consistent with the pathological changes in the hind limbs, pain-like behaviors in the mice were induced by tail suspension and recovered by the resumption of weight bearing. Moreover, treatment with bisphosphonate significantly prevented the triggering of the regional osteoporosis and pain-like behaviors, and antagonists of the acid-sensing nociceptors, such as transient receptor potential channel vanilloid subfamily member 1 and acid-sensing ion channels, significantly improved the pain-like behaviors in the tail-suspended mice. We, therefore, believe that regional transient osteoporosis due to osteoclast activation might be a trigger for the pain-like behaviors in tail-suspended model mice. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1226-1236, 2017.

Combined use of ibandronate and eldecalcitol in postmenopausal Japanese women with osteoporosis.

PURPOSE: To evaluate the effect of combined use of ibandronate and eldecalcitol for 6 to 12 months on bone mineral density (BMD) and bone strength of the proximal femur in postmenopausal Japanese women with osteoporosis. METHODS: BMD and bone strength of the proximal femur were evaluated in 78 postmenopausal women (mean age, 73.6 years) who underwent treatment for osteoporosis with combined use of ibandronate and eldecalcitol for at least 6 months. BMD was measured at the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry (DXA) at baseline and every 6 months thereafter. Hip structure analysis of the narrow neck and intertrochanter was performed by a radiologist using DXA images. RESULTS: Respectively for the lumbar spine, femoral neck, and total hip, BMD significantly increased (from baseline) by 4.54%, 2.31%, and 1.56% at 6 months and by 5.92%, 3.02%, and 2.70% at 12 months. In hip structure analysis, most parameters improved significantly. Respectively for the narrow neck and intertrochanter, BMD significantly increased (from baseline) by 2.37% and 2.71% at 6 months and by 3.46% and 3.52% at 12 months; cross-sectional area significantly increased by 1.83% and 3.39% at 6 months and by 2.91% and 3.46% at 12 months; section modulus significantly increased by 2.42% and 4.11% at 6 months and by 4.84% and 3.26% at 12 months; cortical thickness significantly increased by 2.49% and 3.33% at 6 months and by 3.73% and 3.37% at 12 months; and buckling ratio significantly decreased by 2.97% and 2.57% at 6 months and by 3.86% and 2.99% at 12 months. CONCLUSION: Combined use of ibandronate and eldecalcitol for 6 months significantly improved bone strength of the proximal femur in postmenopausal Japanese women with osteoporosis.

Acid-sensing ion channel 3 or P2X2/3 is involved in the pain-like behavior under a high bone turnover state in ovariectomized mice.

We have recently demonstrated that pathological changes leading to increased bone resorption by osteoclast activation are related to the induction of pain-like behavior in ovariectomized (OVX) mice. In addition, bisphosphonate and the antagonist of transient receptor potential vanilloid type 1 (TRPV1), an acid-sensing nociceptor, improved the threshold value of pain-like behaviors accompanying an improvement in the acidic environment in the bone tissue based on osteoclast inactivation. The aim of this study was to evaluate the effect of (i) an inhibitor of vacuolar H(+) -ATPase, known as an proton pump, (ii) an antagonist of acid-sensing ion channel (ASIC) 3, as another acid-sensing nociceptor, and (iii) the P2X2/3 receptor, as an ATP-ligand nociceptor, on pain-like behavior in OVX mice. This inhibitor and antagonists were found to improve the threshold value of pain-like behavior in OVX mice. These results indicated that the skeletal pain accompanying osteoporosis is possibly associated with the acidic microenvironment and increased ATP level caused by osteoclast activation under a high bone turnover state.