Safety of daily teriparatide treatment: a post hoc analysis of a Phase III study to investigate the possible association of teriparatide treatment with calcium homeostasis in patients with serum procollagen type I N-terminal propeptide elevation.

OBJECTIVE: Serum procollagen type I N-terminal propeptide (PINP), a representative marker of bone anabolic action, is strongly related to bone mineral density during teriparatide therapy. This post hoc study analyzed data from a Phase III study (ClinicalTrials.gov identifier NCT00433160) to determine if there was an association between serum PINP elevation and serum calcium concentration or calcium metabolism-related disorders. RESEARCH DESIGN AND METHODS: Japanese subjects with osteoporosis at high risk of fracture were randomized 2:1 to teriparatide 20 µg/day (n=137) or placebo (n=70) for a 12-month double-blind treatment period, followed by 12 months of open-label teriparatide treatment of all subjects. MAIN OUTCOME MEASURES: Serum PINP levels were measured at baseline, and after 1, 3, 6, 12, 18, and 24 months of treatment. Serum calcium levels were measured at baseline, and after 1, 3, 6, 9, 12, 15, 18, 21, and 24 months of treatment. RESULTS: Serum PINP increased from baseline to 1 month of treatment and then remained high through 24 months. Twenty-eight of 195 subjects experienced PINP elevations >200 µg/L during teriparatide treatment. Serum calcium concentration in both the teriparatide and placebo groups remained within the normal range. There was no clinically relevant difference in serum calcium concentration between subjects with PINP >200 µg/L and subjects with PINP ≤200 µg/L. Two subjects experienced hypercalcemia and recovered without altering teriparatide treatment. Adverse events possibly related to calcium metabolism disorders included periarthritis calcarea (one subject) and chondrocalcinosis pyrophosphate (two subjects), but neither was accompanied with a significant increase in PINP or serum calcium concentration. CONCLUSION: Although the moderate size of this study prevented statistical analysis of any potential association between calcium metabolism-related disorders and elevated PINP, this analysis suggests that there was no association between serum PINP elevation during daily teriparatide treatment and serum calcium concentration or calcium metabolism-related disorders in Japanese subjects.

Safety of 3-year raloxifene treatment in Japanese postmenopausal women aged 75 years or older with osteoporosis: a postmarketing surveillance study.

OBJECTIVE: Long-term safety of medication is a concern for older persons because they may have several comorbidities that can influence drug metabolism, efficacy, and safety. In Japan, raloxifene is an effective and well-tolerated medication for the treatment of osteoporosis in postmenopausal women, but there is little available evidence on whether raloxifene has an acceptable safety profile in older women. The objective of this post hoc analysis was to investigate the safety of raloxifene as a long-term treatment of osteoporosis in Japanese postmenopausal women aged 75 years or older. METHODS: We report a post hoc analysis of a safety dataset (6,960 participants) from a published postmarketing surveillance study (postmenopausal women treated with raloxifene 60 mg/d for ≤3 y). The safety dataset was divided into two groups: (1) women younger than 75 years at baseline (4,522 participants) and (2) women aged 75 years or older at baseline (2,438 participants). Incidence of adverse drug reactions and reactions of note in each age group were compared using Fisher's exact test. RESULTS: Approximately 10% of women in each group reported at least one adverse drug reaction. This analysis did not identify any clinically important differences in the incidence or type of adverse drug reactions reported or in reactions of note between women aged 75 years or older and younger women. CONCLUSIONS: There were no obvious additional safety concerns for women aged 75 years or older who were treated with raloxifene. The findings in this post hoc evaluation suggest no differences in adverse events in the age groups evaluated.

The Effect of Discontinuing Treatment With Blosozumab: Follow-up Results of a Phase 2 Randomized Clinical Trial in Postmenopausal Women With Low Bone Mineral Density.

Administration of blosozumab, a humanized monoclonal antibody that binds sclerostin, increases bone formation and bone mineral density (BMD) in postmenopausal women with low BMD. To evaluate the effect of discontinuing blosozumab, we studied women enrolled in a 1-year randomized, placebo-controlled phase 2 trial for an additional year after they completed treatment. Of the 120 women initially enrolled in the study, 106 women completed treatment and continued into follow-up; 88 women completed 1 year of follow-up. At the beginning of follow-up, groups remained balanced for age, race, and body mass index, but lumbar spine and total hip BMD were increased in prior blosozumab groups, reflecting an anabolic treatment effect. At the end of follow-up, 1 year after discontinuing treatment, lumbar spine BMD remained significantly greater than placebo in women initially treated with blosozumab 270 mg every 2 weeks (Q2W) and blosozumab 180 mg Q2W (6.9% and 3.6% above baseline, respectively). Total hip BMD also declined after discontinuation of treatment but at 1 year after treatment remained significantly greater than placebo in women initially treated with blosozumab 270 mg Q2W and blosozumab 180 mg Q2W (3.9% and 2.6% above baseline, respectively). During follow-up, median serum P1NP was not consistently different between the prior blosozumab groups and placebo. A similar pattern was apparent for median serum C-terminal telopeptide of type 1 collagen (CTx) levels, with more variability. Mean serum total sclerostin concentration increased with blosozumab, indicating target engagement, and declined to baseline after discontinuation. There were no adverse events considered related to prior treatment with blosozumab. Anti-drug antibodies generally declined in patients who had detectable levels during prior treatment. These findings support the continued study of blosozumab as an anabolic therapy for treatment of osteoporosis.

A randomized, double-blind phase 2 clinical trial of blosozumab, a sclerostin antibody, in postmenopausal women with low bone mineral density.

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.

Quality of life in Japanese women with postmenopausal osteoporosis treated with raloxifene and vitamin D: post hoc analysis of a postmarketing study.

OBJECTIVES: To assess the effect of active vitamin D3 on quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis. RESEARCH DESIGN AND METHODS: This is a post hoc analysis of a previous prospective postmarketing observational study conducted without a comparator group. This study was conducted in 60 Japanese hospitals from September 2007 to February 2009. We compared changes from baseline in QOL and pain in patients receiving raloxifene plus active vitamin D3 with those in patients receiving raloxifene monotherapy at 8 and 24 weeks after treatment. CLINICAL TRIAL REGISTRATION: Japan Pharmaceutical Information Center (JapicCTI-070465). MAIN OUTCOME MEASURES: QOL and pain were assessed using Short Form-8 (SF-8), European Quality of Life Instrument 5 Dimensions (EQ-5D), Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), visual analogue pain scales (VAS pain), and pain frequency scores. RESULTS: A total of 506 patients were included in the post hoc analysis. Both raloxifene monotherapy (RLX, n = 354) and active vitamin D3 cotreatment (COMBI, n = 152) significantly improved QOL and reduced pain from the baseline at Week 8 and Week 24. The COMBI group had significantly greater improvements in JOQOL total score and activity of daily living (total) domain at Week 24 and last observation carried forward (LOCF) than the RLX group. The COMBI group also had significantly greater improvements in SF-8 domains of general health (at Week 8, Week 24, and LOCF), role physical (at Week 24 and LOCF), and mental health (at LOCF) than the RLX group. The COMBI group also had significantly greater reduction in VAS pain at LOCF than the RLX group (mean [SD]: RLX = -0.99 [2.72], COMBI = -1.54 [2.21], P = 0.042). CONCLUSIONS: Active vitamin D3 supplementation to raloxifene treatment for 24 weeks may have additional benefits in improving QOL and relieving pain in Japanese women with postmenopausal osteoporosis.

The safety and effectiveness profile of daily teriparatide in a prospective observational study in Japanese patients with osteoporosis at high risk for fracture: interim report.

This postmarketing surveillance study assessed the safety and effectiveness of daily teriparatide treatment in patients with osteoporosis in a Japanese clinical setting. In this prospective, multicenter, observational study, patients with osteoporosis at high risk for fracture received subcutaneous injections of teriparatide (20 µg/day) for a maximum of 24 months. For this interim report, data from 1,671 patients were eligible for analysis at the cutoff date. The mean age was 75.3 years; 93% of patients (1,552/1,671 patients) were women. There were 117 adverse drug reactions (ADRs) reported in 101 of 1,671 patients (6.04%); the most common reported ADRs were nausea, dizziness, headache, and palpitations. No clinically significant safety issues were identified, although 5 serious ADRs were reported in 4/1,671 (0.24 %) patients. At 12 months, 71.9% of patients remained on teriparatide treatment. From 1 month, there were rapid increases in the biomarkers of bone formation P1NP and, to a lesser extent, BAP. In contrast, increases in the biomarkers of bone resorption, serum NTX, urinary NTX, and TRACP5b, were smaller. After 12 months of treatment, there was an increase in bone mineral density at the lumbar spine, femoral neck, and total hip, and a decrease in the Visual Analog Scale score for back pain. The incidence of new vertebral and nonvertebral fractures was 1.21% and 3.18%, respectively. In conclusion, the favorable safety profile and effectiveness of teriparatide observed in this population of Japanese patients with osteoporosis were accompanied by relatively high persistence with treatment, which is a key factor in the success of osteoporosis treatment.

Osteoporosis and treatments in Japan: management for preventing subsequent fractures.

Prevalent fractures are major contributors to an increased risk of subsequent fractures, particularly in people with osteoporosis. While many studies have been conducted to assess the incidence of fracture in Japanese people with osteoporosis, far fewer have been conducted to assess the risk of subsequent fractures. This article reviews the morbidity, mortality, and risk of fracture in patients who are at high risk of subsequent fracture in Japan and the current treatment options available for these patients. Osteoporotic fractures in Japan are associated with high morbidity and mortality that result in significant financial and social costs. The rise in the proportion of elderly women in the Japanese population is contributing to a greater proportion of people with osteoporotic fractures and the high cost of osteoporosis. Although hip fractures have a significant effect on costs, a greater proportion of the Japanese population experience vertebral fractures. An increase in the incidence of vertebral fractures is concerning because preexisting vertebral fractures in older patients are associated with an increased risk of subsequent fractures. Hence, there is a clear rationale for pharmacological treatment of patients with prevalent vertebral fractures, or for those who are hospitalized or undergo surgery for osteoporotic fractures. Several pharmacological therapies are now available in Japan for the treatment of patients with osteoporosis. Understanding the consequences of subsequent fractures and the treatment options available for patients at high risk of subsequent fractures may contribute to clinical decision-making and improved outcomes for patients with osteoporosis.

Assessing the effect of baseline status of serum bone turnover markers and vitamin D levels on efficacy of teriparatide 20 µg/day administered subcutaneously in Japanese patients with osteoporosis.

In this previously reported multicenter study, teriparatide 20 µg/day was administered to elderly Japanese subjects (93 % female; median age 70 years) with osteoporosis and at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled period, which was followed by a 12 month treatment period in which all subjects received open-label teriparatide. Subjects were randomized 2:1 to teriparatide versus placebo (teriparatide n = 137, placebo-teriparatide n = 70). This was an exploratory analysis to determine whether the baseline status of serum bone turnover markers (BTMs) and vitamin D levels affect the efficacy of teriparatide at 20 µg/day. The BTMs included were type I procollagen N-terminal pro-peptide (P1NP) and type I collagen cross-linked C-telopeptide (CTX). Changes in BMD were analyzed by subgroups: (1) tertile subgroups of BTM; (2) BTM determined by the upper limit of normal; and (3) level of vitamin D. Teriparatide increased lumbar spine BMD in all subgroups by 10 % or more through 24 months. Subgroups with higher baseline BTM levels had greater mean percent changes of lumbar spine BMD through 24 months. The baseline status of vitamin D sufficiency did not impact the mean percent change of lumbar spine BMD through 24 months. Results of this study suggest that clinically significant increases in BMD can be achieved in patients receiving teriparatide regardless of baseline BTM or vitamin D levels. Additionally, when vitamin D is coadministered, vitamin D insufficiency would not be expected to affect the overall efficacy of teriparatide.

Quality of life in raloxifene-treated Japanese women with postmenopausal osteoporosis: a prospective, postmarketing observational study.

OBJECTIVE: To assess changes in quality of life (QOL) and pain in raloxifene-treated Japanese women with postmenopausal osteoporosis. RESEARCH DESIGN AND METHODS: This prospective, postmarketing observational study was conducted at 60 Japanese hospitals from September 2007 to February 2009 and included Japanese women with postmenopausal osteoporosis who were new to standard treatment with raloxifene (60 mg/day). Primary outcome measures (QOL and pain) were assessed using the Short Form-8 (SF-8), European Quality of Life Instrument (EQ-5D), osteoporosis-specific Japanese Osteoporosis Quality of Life Questionnaire (JOQOL), a visual analogue scale (VAS-pain), and a pain frequency survey. Assessments were performed at baseline and 8 (except JOQOL) and 24 weeks after first administration of raloxifene. Adverse drug reactions were recorded. Japan Pharmaceutical Information Center registration number: JapicCTI-070465. RESULTS: A total of 506 participants, mean (±standard deviation [SD]) age = 70.7 ± 8.7 years, completed ≥1 follow-up assessment and were included in the analyses. All QOL scores increased from baseline during follow-up. All SF-8 domain scores increased significantly from baseline after 8 and 24 weeks (P < 0.001). Mean (±SD) EQ-5D scores increased significantly from baseline (0.70 ± 0.17) by 0.05 ± 0.15 after 8 weeks and 0.07 ± 0.17 after 24 weeks (P < 0.001). The mean (±SD) total JOQOL score increased significantly from baseline (66.8 ± 16.5) by 3.8 ± 11.3 after 24 weeks (P < 0.001). The percentage of participants with a ≥20 mm reduction in VAS-pain was 32.6% (120/368) and 39.5% (115/291) after 8 and 24 weeks, respectively. The frequency of pain reported by participants decreased after 8 and 24 weeks. Forty adverse drug reactions were reported by 34 participants. LIMITATIONS: Limitations include the lack of a control group, the possibility of the changes being due to the natural disease course, and potential selection bias. CONCLUSIONS: Our findings suggest that standard treatment with raloxifene improves QOL and relieves pain in Japanese women with postmenopausal osteoporosis in a real-world clinical setting.

Safety and effectiveness profile of raloxifene in long-term, prospective, postmarketing surveillance.

This large-scale postmarketing surveillance of raloxifene (60 mg/day) was conducted to assess the safety and effectiveness of raloxifene for long-term use in postmenopausal Japanese women with osteoporosis. The baseline examination included 6,967 women (mean age, 70.4 years). Participants completed observation after 6, 12, 24, and 36 months of therapy. Adverse drug reactions (ADR) were reported in 776 participants (11.14 %), with a total of 87 serious ADR cases occurring in 76 participants (1.09 %). The most frequently reported ADRs were edema peripheral (45/6,967, 0.65 %) and venous thromboembolism (11/6,967, 0.16 %). Of the 6,967 participants, 2,784 were included in the effectiveness analysis. Lumbar spine bone mineral density (BMD) increased significantly (p < 0.001, paired t test) compared with baseline at 6, 12, 24, and 36 months (2.51 %, 2.85 %, 4.76 %, and 3.51 %, respectively). Significant decreases in serum and urinary cross-linked amino-terminal telopeptide of type I collagen (NTX) and urinary deoxypyridinoline levels from baseline were observed at 3 months, followed by a significant decrease of serum bone alkaline phosphatase at 6 months [p < 0.001 for all comparisons except serum NTX (p = 0.011), Wilcoxon signed-rank test]. Early reductions in the biochemical markers of bone turnover (BTM) observed at 3 months with raloxifene treatment correlated negatively with subsequent increases in lumbar spine BMD at 1 year (r = -0.347, p = 0.008). The incidence of any new clinical fractures within 3 years was 1.18 % (82/6,967 participants). In summary, no new signals in safety were observed in the daily use of raloxifene. Moreover, the effectiveness profile of raloxifene was confirmed in practical use by this large-scale, long-term, postmarketing surveillance.

[Evidence for osteoporosis treatment using PTH (1-34) daily subcutaneous injection].

PTH (1-34) daily subcutaneous injection is a bone anabolic agent. It has already been approved in more than 80 countries over the world (including Europe and United States) and in Japan on Jul 2010. The number of patients treated with this agent is more than 20 thousand in Japan and about one million over the world. In nonclinical studies, teriparatide was shown to have a unique bone formation-stimulating effect not seen in existing drugs. In domestic and overseas clinical studies, teriparatide was shown to have strong effects in increasing BMD, promoting remodeling of bone microstructure and suppressing the onset of fracture. Furthermore, it can increase BMD through stimulation of bone formation regardless of the nature of prior treatment or the presence/absence of responses to prior treatment. With these features, teriparatide is expected to serve as a first-line drug for management of patients with osteoporosis at high risk for fracture.

Effects of teriparatide in Japanese and non-Japanese populations: bridging findings on pharmacokinetics and efficacy.

Teriparatide is an anabolic therapy for osteoporosis approved in the United States since 2002 and European Union since 2003; however, approval in Japan lagged significantly. This report describes analyses based on International Conference on Harmonisation (ICH) E-5 guidelines that support bridging between Japanese studies and the large Fracture Prevention Trial (FPT). We analyzed data from single teriparatide doses in healthy Japanese and Caucasian postmenopausal women (J-PK) and from studies of 6 months [Phase 2, dose ranging (J-Ph2)] and 12 months [Phase 3, efficacy and safety (J-Ph3)] of randomized, placebo-controlled, once-daily treatment in Japanese subjects with osteoporosis. In J-PK, apparent teriparatide area-under-the-curve (AUC) and peak concentration (C (max)) were up to 40% higher in Japanese versus Caucasian women; however, body weight-adjusted values were comparable between populations; these findings were supported by population pharmacokinetic analyses. Between the FPT and Japanese studies, baseline demographic characteristics were similar but bone mineral density (BMD) at lumbar spine (L1-L4) and body weight were lower for Japanese subjects. With teriparatide 20 µg/day, significant increases in BMD were observed compared to placebo at 12 months in both the FPT and J-Ph3 study, and percent change and actual change in BMD were comparable between studies. Dose response at 6 months was also comparable across populations. No novel safety signals were identified in Japanese subjects. These analyses show that teriparatide clinical data met ICH E-5 criteria for bridging. Findings from foreign trials such as the FPT can thus be extrapolated to Japanese subjects treated with teriparatide 20 µg/day.

Consistency of fracture risk reduction in Japanese and Caucasian osteoporosis patients treated with teriparatide: a meta-analysis.

In the global Fracture Prevention Trial, teriparatide reduced the risk of vertebral and non-vertebral fractures and significantly increased BMD. Recently, a 12-month, phase 3, randomized, multicenter, double-blind, placebo-controlled trial with BMD as a primary endpoint was conducted to assess the effects of teriparatide in Japanese subjects at high risk of fracture. Although BMD was significantly increased in the Japanese study, the study was not statistically powered to assess the anti-fracture efficacy with teriparatide treatment. A meta-analysis was carried out testing whether teriparatide had consistent anti-fracture efficacy in Japanese patients compared to that observed in the global fracture trial. Three studies in which fracture data were available from prospectively scheduled spinal radiographs were included in the analysis. A systematic review of the literature (Medline, Embase) confirmed that no studies with teriparatide had been excluded from this analysis. There was no significant heterogeneity for vertebral and non-vertebral fractures among the studies included in the meta-analysis. Odds ratio estimates (95% CI) were 0.29 (0.20, 0.43) for vertebral fracture and 0.53 (0.32, 0.86) for non-vertebral fracture. There was also a consistent effect of teriparatide to increase BMD across all studies. Furthermore, our analysis demonstrated that teriparatide-mediated increases in spine BMD accounted for 25-32% of the reduction in vertebral fracture risk in the combined population including Caucasian and Japanese patients, which was similar to that derived from Caucasian patients. These results provide evidence for the consistency of anti-fracture efficacy with teriparatide treatment in Japanese patients compared to those observed in Caucasian patients.

Improved glycemic control and reduced bodyweight with exenatide: A double-blind, randomized, phase 3 study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks.

UNLABELLED: Aims/Introduction: To evaluate the efficacy and safety of the glucagon-like peptide-1 receptor agonist, exenatide, in Japanese patients with type 2 diabetes mellitus suboptimally controlled despite therapeutic doses of a sulfonylurea alone or combined with a biguanide or thiazolidinedione. MATERIALS AND METHODS: Patients were randomized to a placebo or exenatide, either 5 or 10 µg, given subcutaneously b.i.d. in addition to oral therapy. Patients randomized to 10 µg exenatide received 5 µg b.i.d. for the first 4 weeks, followed by 10 µg b.i.d. for the last 20 weeks. RESULTS: A total of 179 patients received the study drug and composed the full analysis set (n = 35, placebo; n = 72, exenatide 5 µg; n = 72, exenatide 10 µg; 68% male; 58 ± 10 years; body mass index 25.5 ± 4.1 kg/m(2); HbA1c 8.2 ± 0.9%; means ± standard deviations). Baseline to end-point (least-squares means ± standard errors) HbA1c changes (%) were -0.28 ± 0.15 (placebo), -1.34 ± 0.11 (exenatide 5 µg) and -1.62 ± 0.11 (exenatide 10 µg) (both P < 0.001, exenatide vs placebo). Baseline to end-point bodyweight changes (kg) were -0.47 ± 0.39 (placebo), -0.39 ± 0.28 (exenatide 5 µg) and -1.54 ± 0.27 (exenatide 10 µg; P = 0.026, exenatide 10 µg vs placebo). Nausea, generally mild to moderate, was reported in 8.6% (placebo), 25.0% (exenatide 5 µg) and 36.1% (exenatide 10 µg) of patients. Mild to moderate hypoglycemia was reported in 22.9% (placebo), 51.4% (exenatide 5 µg) and 58.3% (exenatide 10 µg) of patients. CONCLUSIONS: Over 24 weeks, exenatide vs the placebo improved glycemic control, reduced bodyweight (10 µg) and was well tolerated in Japanese patients with type 2 diabetes mellitus suboptimally controlled, despite oral therapy including a sulfonylurea. This trial was registered with ClinicalTrials.gov (no. NCT00577824). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00084.x, 2011).

PINP as an aid for monitoring patients treated with teriparatide.

Biochemical markers of bone turnover may be useful aids for managing patients with osteoporosis. A 12-month, phase 3, multicenter trial of Japanese patients at high risk of fracture was conducted to assess the effects of teriparatide 20 µg/day on BMD, serum markers of bone turnover, and safety. Two-hundred and seven subjects (93% female; median age 70 years) were randomized in double-blind fashion 2:1 to teriparatide versus placebo. Bone turnover markers including procollagen type I N-terminal propeptide (PINP), bone-specific alkaline phosphatase (bone ALP) and type I collagen cross-linked C-telopeptide (CTX) were collected at baseline, 1, 3, 6, and 12 months. Lumbar spine, femoral neck, and total hip BMD were measured at baseline, 3, 6, and 12 months. Increases in PINP at 1 month correlated best with increases in lumbar spine BMD at 12 months (r=0.76; P<0.01). The proportions of patients with an increase from baseline in PINP >10 µg/L at 1, 3, and 6 months were 3%, 0%, and 2% in the placebo, and 93%, 87%, and 83% in the teriparatide group. The proportions of patients with an increase in PINP >10 µg/L at either 1 or 3 months were 3% in the placebo and 95% in the teriparatide group (P<0.001). The proportions of patients with a significant increase in lumbar spine BMD (increase from baseline ≥3%) at 12 months were 20% in the placebo and 94% in the teriparatide group. The proportions of patients with an increase in PINP >10 µg/L at 1 or 3 months and an increase in lumbar spine BMD ≥3% at 12 months was 0% of placebo group patients and 92% of teriparatide group patients (P<0.001). These data confirm a strong relationship between early change in PINP and later change in lumbar spine BMD during teriparatide therapy. Also, these results suggest that monitoring with PINP and lumbar spine BMD successfully identifies positive responses in most patients taking teriparatide and negative responses in most patients not taking teriparatide. PINP monitoring may be a useful aid in the management of patients with osteoporosis during teriparatide treatment.

[Teriparatide: human recombinant parathyroid hormone (1-34) as a daily subcutaneous injection].

Teriparatide is a preparation of human parathyroid hormone (PTH) (1-34). It has been approved as an agent for stimulating bone formation in many foreign countries, including Europe and the United States. In Japan, it was approved in July this year. In nonclinical studies, teriparatide was shown to have a unique bone formation-stimulating effect not seen in existing drugs. In domestic and overseas clinical studies, teriparatide was shown to have strong effects in increasing BMD, promoting remodeling of bone microstructure and suppressing the onset of fracture. Furthermore, teriparatide can increase BMD through stimulation of bone formation regardless of the nature of prior treatment or the presence/absence of responses to prior treatment. With these features, teriparatide is expected to serve as a first-line drug for management of patients with osteoporosis at elevated risk for fracture.

Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes.

This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 microg (N = 38), 5 microg (N = 37), or 10 microg (N = 38) exenatide administered subcutaneously twice daily (BID). Patients randomly assigned to 10 microg exenatide received 5 microg BID for the first 4 weeks, with the dose escalated to 10 microg BID for the final 8 weeks. Patients were 60.3 +/- 9.7 years old, with body mass index 25.3 +/- 4.3 kg/m(2) and hemoglobin A1c (HbA1c) 8.0 +/- 0.8%. Baseline-to-endpoint HbA1c changes (%) were +0.02 +/- 0.1 (placebo), -0.9 +/- 0.1 (2.5 microg), -1.2 +/- 0.1 (5 microg), and -1.4 +/- 0.1 (10 microg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c -7%, 5.1% (placebo), 50.0% (2.5 microg), 71.4% (5 microg), and 79.4% (10 microg) achieved HbA1c <7% at endpoint (p < 0.001, trend test). Baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 +/- 4.8 (placebo), -18.6 +/- 5.7 (2.5 microg), -25.0 +/- 7.0 (5 microg), and -28.9 +/- 5.9 (10 microg) (all p < or = 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p < or = 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

[Regulation of energy metabolism by bone].

In terms of feedback regulation in Endocrinology, one question was arisen from the evidences that energy metabolism regulates bone metabolism. "Does bone metabolism regulates energy metabolism?" To address this question, Dr. Gerard Karsenty and his colleagues studied energy metabolism in the mice lacking Osteocalcin, an osteoblast-specific gene. The mutant mice exhibited abnormal energy metabolism phenotypes, diabetes and obesity. Here I would like to remind you his previous and recent works so that we can discuss how to apply bone metabolism information to therapeutic strategy for metabolic syndrome.

Endocrine regulation of energy metabolism by the skeleton.

The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.