The Performance of Secondary Nasal Alar Base Revision for Unilateral Cleft Lip by Single YV-Plasty (the Importance of Overcorrection During Surgery).

Although primary surgery for cleft lip has improved over time, the degree of secondary cleft or nasal deformity reportedly varies from a minimum degree to a remarkable degree. Patients with cleft often worry about residual nose deformity, such as a displaced columella, a broad nasal floor, and a deviation of the alar base on the cleft side. Some of the factors that occur in association with secondary cleft or nasal deformity include a deviation of the anterior nasal spine, a deflected septum, a deficiency of the orbicularis muscle, and a lack of bone underlying the nose. Secondary cleft and nasal deformity can result from incomplete muscle repair at the primary cleft operation. Therefore, surgeons should manage patients individually and deal with various deformities by performing appropriate surgery on a case-by-case basis. In this report, we applied the simple method of single VY-plasty on the nasal floor to a patient with unilateral cleft to revise the alar base on the cleft side. We adopted this approach to achieve overcorrection on the cleft side during surgery, which helped maintain the appropriate position of the alar base and ultimately balanced the nose foramen at 13 months after the operation. It was also possible to complement the height of the nasal floor without a bone graft. We believe that this approach will prove useful for managing cases with a broad and low nasal floor, thereby enabling the reconstruction of a well-balanced nose.

Phase II/III, randomized, double-blind, parallel-group study of monthly delayed-release versus daily immediate-release risedronate tablets in Japanese patients with involutional osteoporosis.

Absorption of oral immediate-release (IR) risedronate tablets is reduced by food intake, thus a delayed-release (DR) tablet has been developed to overcome the necessity of taking IR tablets under fasting conditions. This randomized, double-blind, phase II/III study compared efficacy and safety of risedronate IR once-daily (QD) and DR once-monthly (QM) tablets in Japanese patients with involutional osteoporosis. Patients received 2.5 mg IR on awakening QD, or 25 or 37.5 mg DR on awakening, following breakfast, or 30 min after breakfast, QM for 12 months. Primary endpoint was non-inferiority in mean percent change from baseline to end of study (month 12, last observation carried forward [M12, LOCF]) in mean lumbar spine (L2-L4) bone mineral density (BMD) between risedronate IR on awakening and DR following breakfast. Mean percent changes in (L2-L4) BMD at M12, LOCF were 5.07% (IR at awakening, n = 190), 3.36% (25 mg DR following breakfast, n = 194), and 4.11% (37.5 mg DR following breakfast, n = 181). Mean percent change in (L2-L4) BMD was numerically lower in the DR following breakfast groups versus the respective on awakening and 30 min after breakfast DR groups. Overall incidences of treatment-emergent adverse events (TEAEs) were comparable between groups. In the DR groups, 1.5-4.0% of patients reported TEAEs potentially associated with acute-phase reactions versus 0% in the IR group. In this study, non-inferiority could not be declared for 37.5 or 25 mg DR following breakfast QM (p = 0.1346 or p = 0.6711, respectively) versus 2.5 mg IR on awakening QD.

A randomized, double-blind, placebo-controlled study of once weekly elcatonin in primary postmenopausal osteoporosis.

OBJECTIVE: Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period. METHODS: This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs). RESULTS: No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified. CONCLUSIONS: Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated.

Erratum to: Attempt at standardization of bone quantitative ultrasound in Japan.

In the original version of the article, the third author name was incorrectly published. The correct name is Kosei Yoh.

Attempt at standardization of bone quantitative ultrasound in Japan.

Dual X-ray absorptiometry (DXA) is used to diagnose osteoporosis. On the other hand, quantitative ultrasound (QUS) is widely used to assess bone density as part of medical screening as it is relatively inexpensive and easy to perform. Current QUS devices do not share precise ultrasound-related parameters, such as frequency, waveform, beam pattern, transient response, definition of propagation time, definition of degree of attenuation, and precise measurement site, resulting in different measurements across models. The Japan Osteoporosis Society established a QUS Standardization Committee in 2007 to investigate standardization of speed of sound (SOS) and broadband ultrasonic attenuation (BUA) measurements to resolve this issue. The committee came up with a formula to convert SOS and BUA values yielded by each model available in Japan. This has made it possible to convert QUS measurements from different models into standardized values, greatly improving the effectiveness of QUS measurements.

24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk.

INTRODUCTION: To clarify the additional efficacy and safety benefits of 24 months' treatment with the once-weekly formulation of teriparatide, which is currently used for 72 weeks. METHODS: This was a multicenter, open-label, single-arm study conducted in Japan. Subjects who were 65 years or older with prevalent vertebral fractures received once-weekly subcutaneous injection of 56.5 µg teriparatide for 24 months. The main outcome measure was percentage change from baseline in lumbar (L2-L4) BMD measured by dual-energy X-ray absorptiometry. RESULTS: A total of 189 subjects received at least one dose of the once-weekly formulation of teriparatide. Lumbar, femoral neck, and total hip BMD increased significantly compared with baseline at Weeks 24, 48, 72, and 104. In addition, significant increases in lumbar (+1.5%) and femoral neck (+0.8%) BMD were noted at Week 104 compared with Week 72. Significant increases from baseline in BMD for radius 1/10 were noted at Weeks 24 and 104. No substantial increases were noted in the cumulative incidences of new vertebral fracture and other types of fracture after Week 72. The safety profile seen in the first 72 weeks remained unchanged until 104 weeks. CONCLUSION: The once-weekly formulation of teriparatide is effective and safe for the treatment of osteoporosis over 24 months. The limitation of this study is that this was an open-label, single-arm study. FUNDING: Asahi Kasei Pharma Corporation. CLINICAL TRIAL REGISTRATION: JapicCTI-132276.

The Lesser Palatine Nerve Innervates the Levator Veli Palatini Muscle.

When the lesser palatine nerve (LPN) is supposed to be a branch of the trigeminal nerve and innervate sensation of the soft palate, whether the LPN contains motor fibers is unclear. In this study, we monitored the electromyogram of the levator veli palatini (LVP) muscle on stimulating the LPN during palatoplasty in 3 patients. The electromyogram of the muscles showed the myogenic potential induced by electrostimulation of the LPN. Taken together with the finding from our previous anatomical study that the motor fibers come from the facial nerve, this result supports the double innervation theory of the LVP, which posits that both the pharyngeal plexus and the facial nerve innervate it. Identifying and preserving the LPN during palatoplasty might improve postoperative speech results.

[Effects of antiresorptive therapy on the structural and material properties of bone strength].

Bone strength depends on its structural and material properties. Structural properties are determined by the size and shape of bone and also the microarchitecture. Material properties are determined by mineral crystallinity, collagen structure and microdamage in bone. The strength of bone is adapted to the needs of physical activities by biologic mechanisms, bone modeling and remodeling. The deterioration of bone strength in postmenopausal women is characterized by a trabecular bone deficit with poor trabecular connectivity and followed by a cortical bone deficit with trabeculation of endocortical bone and intracortical porosity due to accelerated bone remodeling. In high turnover osteoporosis antiresorptive therapy is effective in preventing the structural deficit and in increasing the stiffness and the toughness(bone strength)by increasing the mean degree of mineralization of bone tissue through the prolongation of secondary mineralization. But the long-term use of strong antiresorber, i.e. bisphosphonate or denosumab, would result in highly mineralized bone and disturbed repair of microcracks by inhibition of bone remodeling. Intermittent use or discontinuation of strong antiresorber after about 3-5 years of administration could be recommended to avoid the deterioration of bone strength.

Three-dimensional imaging of palatal muscles in the human embryo and fetus: Development of levator veli palatini and clinical importance of the lesser palatine nerve.

BACKGROUND: After palatoplasty, incomplete velopharyngeal closure in speech articulation sometimes persists, despite restoration of deglutition function. The levator veli palatini (LVP) is believed to be significantly involved with velopharyngeal function in articulation; however, the development and innervation of LVP remain obscure. The development of LVP in human embryos and fetuses has not been systematically analyzed using the Carnegie stage (CS) to standardize documentation of development. RESULTS: The anlage of LVP starts to develop at CS 21 beneath the aperture of the auditory tube (AT) to the pharynx. At CS 23, LVP runs along AT over its full length, as evidenced by three-dimensional image reconstruction. In the fetal stage, the lesser palatine nerve (LPN) is in contact with LVP. CONCLUSIONS: The positional relationship between LVP and AT three-dimensionally, suggesting that LVP might be derived from the second branchial arch. Based on histological evidence, we hypothesize that motor components from the facial nerve may run along LPN, believed to be purely sensory. The multiple innervation of LVP by LPN and pharyngeal plexus may explain the postpalatoplasty discrepancy between the partial impairment in articulation vs. the functional restoration of deglutition. That is, the contribution of LPN is greater in articulation than in deglutition.

Compliance and persistence with daily, weekly, and monthly bisphosphonates for osteoporosis in Japan: analysis of data from the CISA.

UNLABELLED: Compliance and persistence with daily, weekly, and monthly bisphosphonates (BPs) for osteoporosis were assessed using data from the Platform for Clinical Information Statistical Analysis (CISA) database that contains data of prescriptions in 13 university hospitals in Japan. The analysis revealed compliance and persistence improved as the dosing interval increases. PURPOSE: BPs are an effective first-line therapy for osteoporosis, but adherence is low. Compliance (medication possession ratio, MPR) and persistence (time to discontinuation) with daily, weekly, and monthly BPs were compared to ensure better adherence. METHODS: Using data from the CISA database containing prescription data in 13 university hospitals in Japan, adherence to oral BPs of osteoporotic patients was investigated. Daily and weekly BPs were compared for compliance and persistence over 5 and 8 years, and daily, weekly, and monthly BPs for those over 1 and 2 years. RESULTS: MPR over 5 years was 20.8 and 60.9 % for daily and weekly BPs (p < 0.001), respectively. MPR over 1 year was 38.6, 70.6, and 77.7 % for daily, weekly, and monthly BPs (P < 0.001), respectively. Persistence over 8 years was significantly higher in weekly than daily BPs (p < 0.001), and that over 5 years was highest in patients receiving BPs monthly (p < 0.01). CONCLUSION: The present analysis indicates that a monthly regimen has better adherence to treatment as compared with weekly and daily regimens.

Efficacy, tolerability and safety of once-monthly administration of 75mg risedronate in Japanese patients with involutional osteoporosis: a comparison with a 2.5mg once-daily dosage regimen.

Oral risedronate has been shown to be effective in the treatment of osteoporosis when administered once-daily or once-weekly in Japan. This randomized, double-blind, multicenter 12-month study was conducted to compare the efficacy and tolerability of oral risedronate 75mg once-monthly with 2.5mg once-daily in Japanese patients with involutional osteoporosis. Bone mineral density (BMD), biochemical markers of bone metabolism, fractures, and adverse events (AEs) were evaluated. At the end of the study (Month 12, last observation carried forward [M12, LOCF]), mean percent change (SD) from baseline in lumbar spine (L2-L4) BMD, measured by dual energy X-ray absorptiometry (primary endpoint), was increased by 5.69 (4.00)% in the 2.5mg once-daily group (n=428), and 5.98 (4.54)% in the 75mg once-monthly group (n=422). In the non-inferiority t-test (non-inferiority margin Δ=1.5%), the 75mg once-monthly group was non-inferior to the 2.5mg once-daily group (p<0.0001). The difference between treatment groups was 0.28% (95% CI, -0.31% to 0.88%). Changes in biochemical markers of bone metabolism were generally comparable in the two groups, although decreases in the percent change from baseline in urinary NTX/CRN and CTX/CRN were statistically greater in the 2.5mg once-daily group than the 75mg once-monthly group. The frequency of new vertebral fractures (including aggravation of prevalent fractures) at the end of the study (M12, LOCF) was also similar in the two groups: 1.2% in the 2.5mg once-daily group and 1.3% in the 75mg once-monthly group. The incidence of mild/moderate/severe AEs was 75.5%/6.3%/0.5% in the 2.5mg once-daily group and 77.7%/8.1%/0.7% in the 75mg once-monthly group. AEs associated with gastrointestinal symptoms occurred in approximately 30% of subjects in each group but with no severe cases. AEs potentially associated with acute phase reaction (including symptoms of influenza-like illness or pyrexia starting within 3days of the first dose of the study drug and with a duration of 7days or less) only occurred in the 75mg once-monthly group (2.1%, 9/422 subjects; influenza-like symptoms in 1 subject and pyrexia in 8 subjects), although the incidence was low without any severe cases. In conclusion, risedronate 75mg once-monthly (a dosage which is 30 times higher than risedronate 2.5mg once-daily) had non-inferior efficacy in terms of BMD and was similarly well tolerated compared to the once-daily regimen in Japanese patients with involutional osteoporosis. Consistent with the once-daily and once-weekly dosage, the once-monthly dosage of risedronate 75mg was half that used outside Japan (150mg).

Once-weekly teriparatide reduces the risk of vertebral fracture in patients with various fracture risks: subgroup analysis of the Teriparatide Once-Weekly Efficacy Research (TOWER) trial.

Once-weekly teriparatide (human parathyroid hormone [1-34]) (56.5 µg for 72 weeks) injections provided a vertebral fracture risk reduction in Japanese osteoporotic patients evaluated in the Teriparatide Once-Weekly Efficacy Research (TOWER) trial. Using data from the TOWER trial, a subgroup analysis was performed to study the efficacy of once-weekly teriparatide for a variety of baseline clinical risk factors in placebo (n = 281) and teriparatide (n = 261) groups. Significant fracture risk reductions were observed in the subgroups of individuals aged <75 years [relative risk (RR) 0.06, p = 0.007] and ≥75 years (RR 0.32, p = 0.015). A significant risk reduction was observed among patients with prevalent vertebral fracture in the subgroup with 1 (RR 0.08, p = 0.015) or ≥2 (RR 0.29, p = 0.009) prevalent vertebral fractures, and in those with grade 3 deformity (RR 0.26, p = 0.003). Significant risk reduction was observed in the subgroup with lumbar bone mineral density (BMD) < -2.5 SD (RR 0.25, p = 0.035). In the teriparatide group, no incident fracture was observed in the subgroups with a prevalent vertebral fracture number of 0, with grade 0-2 vertebral deformity, or with lumbar BMD ≥2.5 SD. Significant risk reduction was observed in all of the bone turnover marker and estimated glomerular filtration rate subgroups. In conclusion, once-weekly 56.5 µg teriparatide injection reduced the vertebral fracture risk in patients with varying degrees of fracture risk, age, vertebral fracture number and grade, bone turnover level, and renal function.

[Effects of aging and therapy on the structural properties and strength of vertebral body].

Bone strength depends on its structure and its material properties. Structural properties are determined by the size and shape of bone and also the microarchitecture. Material properties are determined by mineral crystallinity, collagen structure and microdamage in bone. The strength of bone is adapted to the needs of physical activities by biologic mechanisms, bone modeling and remodeling. The deterioration of bone strength in postmenopausal women is characterized by a trabecular bone deficit with poor trabecular connectivity and followed by a cortical bone deficit with trabeculation of endocortical bone and intracortical porosity due to accelerated bone remodeling. Trabecular bone is getting more fragile with age by poor adaptation to mechanical load by modeling. As a consequence, the endplate collapses and vertebral body fracture occurs. The deterioration of bone strength could be improved by osteoporosis treatment using antiresorber or teriparatide, and these drugs would decrease the risk of vertebral fracture consequently.

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.

Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk.

CONTEXT: Weekly teriparatide injection at a dose of 56.5 µg has been shown to increase bone mineral density. OBJECTIVE: A phase 3 study was conducted to determine the efficacy of once-weekly teriparatide injection for reducing the incidence of vertebral fractures in patients with osteoporosis. DESIGN AND SETTING: In this randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan, the incidence of morphological vertebral fractures by radiographs was assessed. PATIENTS: Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture. INTERVENTION: Subjects were randomly assigned to receive once-weekly s.c. injections of teriparatide (56.5 µg) or placebo for 72 wk. MAIN OUTCOME MEASURE: The primary endpoint was the incidence of new vertebral fracture. RESULTS: Once-weekly injections of teriparatide reduced the risk of new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5% in the placebo group (P < 0.01), and a relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). At 72 wk, teriparatide administration increased bone mineral density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P < 0.01). Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable. CONCLUSION: Weekly s.c. administration of teriparatide at a dose of 56.5 µg may provide another option of anabolic treatments in patients with osteoporosis at higher fracture risk.

[Calcium Pros and Cons--Which method is useful for diagnosis of vertebral body fracture; radiograph or MRI?--Vertebral radiograph is the useful method for diagnosis and monitoring of vertebral body fractures].

Vertebral radiograph is very useful to assess the vertebral body fracture and the severity of deformity due to fracture. To decrease the severity of vertebral body fracture deformity, treatment should be started as soon as possible after diagnosis. We can diagnose the early stage of vertebral body fracture to get the special findings on radiographs. Furthermore, the process of fracture healing could be monitored by X-ray radiograph of vertebrae. Vertebral radiograph could be the best method for assessing and monitoring the vertebral body fracture, especially for clinical use.

Design of a pragmatic approach to evaluate the effectiveness of concurrent treatment for the prevention of osteoporotic fractures: rationale, aims and organization of a Japanese Osteoporosis Intervention Trial (JOINT) initiated by the Research Group of Adequate Treatment of Osteoporosis (A-TOP).

The aim of osteoporosis treatment is to prevent future fractures. Although concurrent treatment has been used very frequently for osteoporosis in clinical practice, there are no data on accurate and verified effectiveness of concurrent treatment for fracture prevention in patients with osteoporosis. To clarify the clinical usefulness of concurrent treatment, the Japan Osteoporosis Society has authorized the establishment of the A-TOP (Adequate Treatment of Osteoporosis) research group. The objective of this research is to establish a design for a clinical trial to prove whether concurrent treatment using both alfacalcidol (1-alpha-hydroxycholecalciferol) and alendronate is more effective as compared to treatment using alendronate alone in terms of fracture prevention. The present study was named JOINT (Japanese Osteoporosis Intervention Trial) and is based on a method using national, prospective, randomized, open-labeled, blinded endpoints focusing on postmenopausal osteoporosis with a high risk for fracture. The patients were mainly selected by practitioners and allocated randomly by a central registration system into two groups, of which one received 5 mg/day of alendronate alone, and the other received 1 µg/day of 1-alpha-hydroxycholecalciferol (alfacalcidol) in addition to the alendronate. The endpoints focused primarily on fracture prevention, and the patients' quality of life (QOL) and change in body height, as well as adherence and the adverse events of the treatments were evaluated secondarily. To obtain sufficient statistical power in the events during a 2-year observation period, the patients who are expected to have higher risk were selected to participate in this study, and it was decided that the final plan would involve 890 patients per group (two-sided alpha = 0.05, power = 0.8). Data collection began in November 2003. Correspondence regarding the registration of the investigator and the progress of the study was conducted through a web system from the Public Health Research Foundation to practitioners.

[Combination therapy for osteoporosis].

Combination therapy of the two agents for osteoporosis has not been determined to be more effective or not than the use of either one alone. Bisphosphonates are now the most widely used drugs for osteoporosis. Concurrent administration of bisphosphonate and vitamin D could increase bone mineral density (BMD) more than the use of bisphosphonate alone especially in the patients with vitamin D deficiency. Bisphosphonates increased BMD, but the increment of BMD was reached to plateau after two or three years. After stopping bisphosphonates, PTH administration was effective to gain more BMD. Sequential administration of antiresorber (bisphosphonate or raloxifene) and PTH could be more effective than the use of bisphosphonate alone. But there would be some differential effects of sequential treatment on BMD among antiresorbers. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy. Further studies are necessary to fully ascertain the clinical significance of combination therapy in postmenopausal osteoporosis.

[Bone fracture and the healing mechanisms. Pathophysiology and classification of osteoporotic fractures].

Bone provides momentary strength and fatigue strength, and bone strength decreases with age. In elderly men and women with fragile bones osteoporotic fractures frequently occur. Fragility fracture occurs as a consequence of the decrease in momentary strength, and fragility fracture is one of the pathological fractures. In patients with the decrease in fatigue strength, insufficiency fractures frequently occurs. Insufficiency fracture is the same term as stress or fatigue fracture.