Hideaki Sowa

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.

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

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.

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.

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.

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

Abstract 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 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 Fishers 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.

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.

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

Abstract 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.