Junichi Takada

Guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis (2012 edition)

Recently the clinical application of bone metabolic markers has achieved significant progress and the measurements of these indices give us a better understanding of the pathogenesis of osteoporosis. Bone metabolic markers were adapted to select drug treatment for osteoporosis and to evaluate drug efficacy. Therefore, the proper application and assessment of bone metabolic markers in clinical practice is very important. To achieve these aims, the committee on the guidelines for the use of biochemical markers of bone turnover in osteoporosis authorized by the Japan Osteoporosis Society has summarized recent progress in bone markers and proposed the proper utilization of bone markers. Although the use of bone metabolic markers now has an important role in the daily management of osteoporosis, their use in Japan is still insufficient because of insurance coverage limitations. Since the Japan Osteoporosis Society first created the 2001 guidelines, new bone metabolic markers have been introduced into clinical practice. The availability of new osteoporosis treatments that promote bone formation has changed the clinical application of bone metabolic markers in current practice. Therefore, revisions to the current clinical practice are needed which led to the proposal to create these new 2012 guidelines.

Stimulation by low concentrations of fluoride of the proliferation and alkaline phosphatase activity of human dental pulp cells in vitro

Fluoride has been used for decades, either systemically or topically, to prevent dental caries. The purpose of this study was to clarify the effects of low concentrations of fluoride on proliferation, differentiation and extracellular-matrix synthesis in normal human dental pulp cells (DP-1 and DP-2) in vitro. The effects were compared with those on a human osteoblastic osteosarcoma cell line, TE-85. Fluoride at micromolar concentrations significantly and dose-dependently stimulated [3H]thymidine incorporation into DNA in DP-1, DP-2 and TE-85 cells, with optimal effects around 50 microM, by 127 +/- 7%, 124 +/- 0.6% and 152 +/- 13.4%, respectively. To assess the potential influence of fluoride on cell differentiation, the effects of mitogenic concentrations on alkaline phosphatase activity were measured. Fluoride significantly increased the enzymes activity in DP-1 and TE-85 by 177 +/- 12% and 144 +/- 12.3%. To evaluate the effect on extracellular-matrix synthesis, the synthesis of type I collagen was indirectly determined by an assay of procollagen type I c-peptide production. Fluoride significantly increased that production by 150 +/- 8.7% in TE-85, but not in either DP-1 or DP-2. These observations suggest that fluoride, if used at low concentrations, could be a useful therapeutic agent where increased regeneration of dentine is desired, such as after pulp amputation, by stimulating the proliferation and differentiation of the dental pulp cells.

The serum level of bone-specific alkaline phosphatase activity is associated with aortic calcification in osteoporosis patients.

It has been suggested that there are several possible linkages between vascular calcification and osteoporosis. In addition, the processes of vascular calcification may have a common etiology with bone formation. Thus, we hypothesized that the serum levels of bone metabolic markers would be different between osteoporosis patients with and without vascular calcification. In this study, we showed that the serum level of bone-specific alkaline phosphatase activity in osteoporosis patients with abdominal aortic calcification had a higher value than in those without the calcification. On the other hand, there were no significant differences in the urine levels of type I collagen cross-linked N-telopeptides (a bone resorption marker), or in the serum levels of intact osteocalcin, Ca, and P. Bone-specific alkaline phosphatase is the most important marker for osteoblast differentiation; furthermore, the serum level of its activity may reflect the process of calcification of the aorta in osteoporosis patients.

Vertebral body ischemia in the posterior spinal artery syndrome: case report and review of the literature.

Study Design. A case of posterior spinal cord syndrome in which magnetic resonance images showed predominant T2 hyperintense signal in the adjacent vertebral body is reported. Objectives. To present the case for abnormal bone marrow magnetic resonance signal in the radiologic diagnosis of posterior spinal cord syndrome and to review its significance. Summary of Background Data. Infarction in the region of posterior spinal arteries has been rarely described. This is attributable not only to the infrequent occurrence of infarction of posterior spinal arteries, but also to a lack of well-established diagnostic procedures. It is of clinical value to define diagnostic images of posterior spinal cord syndrome, especially early in the course of the disease. Methods. The subject was a 52-year-old man who was presented with acute nontraumatic myelopathy. Magnetic resonance imaging, performed serially after onset of the disorder from 5 hours to 11 months, was evaluated in comparison with neurologic findings. The literature was reviewed to discuss the magnetic resonance images of spinal cord infarction. Results. The neurologic findings were consistent with posterior spinal cord syndrome. A magnetic resonance image taken at 5 hours after onset of the syndrome showed T2 hyperintense signal in the T12 vertebral body. At 3 days after onset, T2 hyperintense signal became obvious in the posterior portion of the spinal cord at T9–T12 vertebral levels. Follow-up magnetic resonance imaging at 41 days, 8 months, and 11 months showed a decrease in the size and intensity of the T2 signal change in the spinal cord and T12 vertebral body. In the literature, T2 hyperintense bone marrow signal was defined in one case of posterior spinal cord syndrome and seven cases of anterior spinal cord syndrome. Conclusions. Associated bone marrow abnormalities likely reflect the underlying pathology of the blood supply to the vertebral body, and may be an additional key sign for radiologic diagnosis of posterior spinal cord syndrome.

Improvement of pain and regional osteoporotic changes in the foot and ankle by low-dose bisphosphonate therapy for complex regional pain syndrome type I: a case series

IntroductionComplex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, signs of vasomotor instability, movement disorders, joint stiffness, and regional osteopenia. It is recognized to be difficult to treat, despite various methods of treatment, including physiotherapy, calcitonin, corticosteroids, sympathetic blockade, and nonsteroidal anti-inflammatory drugs. Pathophysiologically, complex regional pain syndrome reveals enhanced regional bone resorption and high bone turnover, and so bisphosphonates, which have a potent inhibitory effect on bone resorption, were proposed for the treatment of complex regional pain syndrome.Case presentationA 48-year-old Japanese man with complex regional pain syndrome type I had severe right ankle pain with a visual analog scale score of 59 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for five months. Radiographs showed marked regional osteoporotic changes and bone scintigraphy revealed a marked increase in radioactivity in his ankle. One month after the start of oral administration of risedronate (2.5 mg per day), his bone pain had fallen from a VAS score of 59 out of 100 to 18 out of 100. Bone scintigraphy at 12 months showed a marked reduction in radioactivity to a level comparable to that in his normal, left ankle. On the basis of these results, the treatment was discontinued at 15 months. At 32 months, our patient had almost no pain and radiographic findings revealed that the regional osteoporotic change had returned to normal.A second 48-year-old Japanese man with complex regional pain syndrome type I had severe right foot pain with a visual analog scale score of 83 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for nine months. Radiographs showed regional osteoporotic change in his phalanges, metatarsals, and tarsals, and bone scintigraphy revealed a marked increase in radioactivity in his foot. One month after the start of oral administration of alendronate (35 mg per week), his bone pain had fallen from a visual analog scale score of 83 out of 100 to 30 out of 100 and, at nine months, was further reduced to 3 out of 100. The treatment was discontinued at 15 months because of successful pain reduction. At 30 months, our patient had no pain and the radiographic findings revealed marked improvement in regional osteoporotic changes.ConclusionsWe believe low-dose oral administration of bisphosphonate is worth considering for the treatment of idiopathic complex regional pain syndrome type I accompanied by regional osteoporotic change.

Long‐Term Treatment of Indomethacin Reduces Vertebral Bone Mass and Strength in Ovariectomized Rats

We investigated the effect of the long‐term treatment of indomethacin, on lumbar spinal bone mineral density (LSBMD), cancellous bone mass, structure, and strength of vertebral body in old ovariectomized (OVX) rats. Ten‐month‐old female Wistar rats were divided into five groups: the sham operated + vehicle (sham+VEH) group, the OVX + vehicle (OVX+VEH) group, the OVX + indomethacin (IN) 1.5 mg/kg/week (OVX+IN1.5) group, the OVX + IN 6.0 mg/kg/week (OVX+IN6.0) group, and the OVX + IN 15.0 mg/kg/week (OVX+IN15.0) group. IN or vehicle were given by subcutaneous injection (sc) three times per week. The treatments were started at 1 week after operation and continued for 24 weeks. LSBMD(L2–L5) was measured at 0, 12, and 24 weeks after the beginning of treatment. At the end of the experimental period, the animals were sacrificed, and bone histomorphometrical and biomechanical analysis of lumbar vertebral body were done. LSBMD, trabecular bone volume (BV/TV), and trabecular thickness (Tb.Th) decreased significantly in a dose‐related manner with IN. In the OVX+IN15.0 group, LSBMD decreased by 12.7%, BV/TV decreased by 65.5%, and Tb.Th decreased by 32.8%, compared with the OVX+VEH group. In addition, the maximum stress in a compressive mechanical test of L4 vertebral body in OVX groups was also decreased in a dose‐related manner with IN, and this value in the OVX+IN15.0 group was 31.3% lower than in the OVX+VEH group. We conclude that long‐term treatment with IN accentuated the OVX‐related decrease in trabecular bone mass and the compressive strength of lumbar vertebrae.

A significant improvement in lower limb pain after treatment with alendronate in two cases of Camurati–Engelmann disease

Camurati–Engelmann disease, also known as progressive diaphyseal dysplasia, is a rare osteosclerotic dysplasia of bone that is characterized by endosteal and periosteal thickening of the diaphysis of the long bones. The most common symptoms are severe, bilateral, and symmetrical bone pain in the limbs, waddling gait, muscle weakness, and easy fatigability [1,2]. Camurati–Engelmann disease is inherited in an autosomic dominant manner, and alterations in the sequence in the transforming growth factor-β1 (TGF-β1) gene in the chromosomal region 19q13.1 have been found to be associated with the disorder [3]. Radiographically, symmetrical osteosclerosis is observed in the diaphyses and metaphyses of the long bones [4], and bone scintigraphy reveals a marked increase in radioactivity at the affected regions [5]. These radiologic fi ndings provide a meaningful assessment of disease extent and activity. A few previous reports showed that biochemical markers of bone turnover were useful to evaluate the disease activity of Camurati–Engelmann disease [6]. Concerning the treatment of Camurati–Engelmann disease, corticosteroids have been reported to be effective in reducing the symptoms in some cases [7], whereas there were no defi nitive data on the effectiveness of corticosteroids on disease activity in a previous report [8]. Recently, several reports showed that bisphosphonates have been used in Camurati–Engelmann disease because of the experience of treatment with these drugs in Paget’s disease. However, most of the studies indicated that the administration of bisphosphonates was ineffective for treating Camurati–Engelmann disease [8–10]. In this study, treatment of two cases of Camurati–Engelmann disease was attempted with alendronate. The drug markedly improved bone pain, and a correlative decrease in cross-linked Ntelopeptides of type I collagen (NTX), a bone resorption marker, was noted.

Changes in urinary NTX levels in patients with primary osteoporosis undergoing long-term bisphosphonate treatment

BackgroundBisphosphonates, antiresorptive drugs, are widely used to treat osteoporosis patients. However, recent reports indicated that several osteoporosis patients who underwent long-term bisphosphonate therapy subsequently developed severe suppression of bone turnover. We investigated whether urinary crosslinked N-telopeptide of type I collagen (NTX), a bone resorption marker, in osteoporosis patients was highly suppressed during long-term treatment with alendronate or risedronate.MethodsWe investigated 87 primary osteoporosis outpatients who were treated with alendronate or risedronate for more than 2 years. All patients were women, with an average age of 72.6 years. Altogether, 49 patients were treated with alendronate and 38 with risedronate, and the average administration period was 3.5 years. We defined high suppression as NTX being reduced <9.3 nmol bone collagen equivalent/mmol·Cr and a 35% decrease from baseline.ResultsIn total, 11 of 87 patients (12.6%) had high NTX suppression based on the above criteria. The incidences of high suppression of NTX at 1,2,3,and 4 years after starting the treatment were 0%, 1.1%, 11.9%, and 4.7%, respectively. The average age, bone mineral density, and NTX values at baseline and the administration period were not associated with high suppression of NTX during alendronate or risedronate treatment. Regarding suppression of NTX during long-term treatment, there was no significant difference between alendronate and risedronate.ConclusionsThe results suggested that long-term treatment with bisphosphonates necessitates careful follow-up of the patients.

Usefulness of a novel monoclonal antibody against human osteocalcin in immunohistochemical diagnosis.

A novel monoclonal antibody against human osteocalcin, recently established in our laboratory, was shown by immunoblotting and immunohistochemistry to react specifically with human osteoblasts. In the present study, the antibody was applied to the immunohistochemical diagnosis of human bone tumours, especially osteoblastic tumours. The antibody reacted with all 27 osteosarcomas. No positive reaction was found either in chondrosarcoma, giant cell tumours of bone, soft tissue tumours or epithelial tumours. A positive reaction was found preferentially in the cytoplasm of most of the osteosarcoma cells, but not in the extracellular matrix. Since the antibody reacted with formalin-fixed and paraffin-embedded tissues, it will be a useful tool for routine immunohistochemical diagnosis of osteoblastic lesions.

Changes in bone resorption markers among Japanese patients with postmenopausal osteoporosis treated with alendronate and risedronate.

We compared the abilities of alendronate and risedronate to reduce levels of urinary cross-1inked N-telopeptides of type I collagen (NTX) in Japanese postmenopausal women. The patients were randomly divided into two groups (alendronate, 5 mg/day, n = 61; risedronate, 2.5 mg/day, n = 60). All patients had taken all medication prescribed for the first month and at least 90% of that prescribed for each of the following 6 months. Urinary NTX was measured at baseline, as well as at 1 and 6 months after starting treatment. According to the guidelines of the Japan Osteoporosis Society, the minimum significant change (MSC) for urinary NTX is defined as a 35% decrease from baseline and the cutoff level for a high risk of future fracture is 54.3 nmol bone collagen equivalent (BCE)/mmol·Cr. The NTX reduction rates at 1 and 6 months were greater with alendronate than with risedronate, but the difference was not significant. The rate of patients with a reduction in the MSC at 1 month was greater with alendronate than with risedronate, but the difference did not reach significance. Alendronate reduced NTX at 1 month significantly more in patients with a high risk of fracture than risedronate, but the difference was no longer significant at 6 months. The rate of MSC did not significantly differ between the two groups. In conclusion, alendronate decreases bone resorption markers more obviously and rapidly than risedronate, especially in high risk for fracture, but not significantly according to the guidelines of the Japan Osteoporosis Society.