Predictors of discontinuation of osteoporosis treatment: sub-analysis of the Japanese osteoporosis intervention trial-05 (JOINT-05).

INTRODUCTION: To identify predictors of discontinuing treatment with teriparatide (TPTD) and alendronate (ALN), data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high risk of fracture were re-analyzed. MATERIALS AND METHODS: Participants received sequential therapy with once-weekly TPTD for 72 weeks followed by ALN for 48 weeks (TPTD-ALN group) or monotherapy with ALN for 120 weeks (ALN group). Background data including comorbidities, fracture prevalence, cognitive function, quality of life, activities of daily living, bone metabolism parameters, and nutrient intake were collected. The endpoints were 3 types of discontinuations by the reason: a poor compliance, adverse events (AEs), or any reason including those unrelated to AEs or poor compliance. Odds ratios (ORs) of baseline predictors of discontinuation were evaluated by single or multiple regression analysis. RESULTS: A total of 234 (49.0%) patients in the TPTD-ALN group and 167 (34.2%) patients in the ALN group discontinued. In the TPTD-ALN group, a lower serum calcium level was a significant predictor of compliance-related discontinuation. Serum 25-hydroxyvitamin D levels were lower in patients with lower serum calcium levels than with higher serum calcium levels. In the ALN group, poor cognitive function was significantly associated with compliance-related discontinuation, and higher body mass index and alcohol intake were predictors of AE-related discontinuation. Predictors of discontinuation were drug-specific. Lower serum calcium levels and poor cognitive function were predictors of discontinuing once-weekly TPTD and ALN, respectively. CONCLUSION: When starting TPTD and ALN treatment, careful attention to patients with lower serum calcium levels and poor cognitive function, respectively, may be needed for better treatment continuity.

Serum branched-chain amino acid levels are associated with fracture risk in Japanese women.

AIM: Branched-chain amino acids (BCAAs) have been shown to exert beneficial effects on muscle and bone metabolism; however, no studies to date have investigated whether BCAAs have beneficial effects on bone fractures. Herein, we aim to prospectively investigate the relationship between serum BCAA concentrations and the occurrence of vertebral fractures (VFs) in Japanese women. METHODS: During the observation period (7.5 ± 6.1 years), 188 of 983 participants experienced VF. Kaplan-Meier analyses were conducted to examine time-dependent variations in the vertebral compression fracture occurrence rate. Patients were stratified into quartiles based on serum BCAA concentration for this analysis. RESULTS: The analysis results indicated that the group with the lowest BCAA level developed VFs significantly earlier and with a higher frequency than the other groups (P < 0.001). A Cox proportional hazards model showed that BCAA concentration was a significant risk factor for incident fracture, even after adjusting for possible confounding factors. A series of multiple regression analyses were performed to identify factors related to serum BCAA concentration, with the results identifying levels of glycated hemoglobin (P < 0.001), adiponectin (P < 0.001), and NOx (P = 0.011) as significant factors associated with serum BCAA. CONCLUSIONS: Overall, the present study revealed that a lower serum BCAA level was an independent risk factor for incident VF in postmenopausal women. Geriatr Gerontol Int 2024; 24: 603-608.

Achieving osteoporosis treat-to-target goals with teriparatide or alendronate: sub-analysis of Japanese Osteoporosis Intervention Trial-05 (JOINT-05).

INTRODUCTION: The purpose of this study was to evaluate whether bone mineral density (BMD) ≥ -2.5 SD could be used as the treat-to-target (T2T) goal when treating osteoporosis with teriparatide (TPTD) and alendronate (ALN), and to investigate the relationship with incident vertebral fracture by re-analyzing data from a randomized, controlled trial (JOINT-05) involving postmenopausal Japanese women at high fracture risk. MATERIALS AND METHODS: Participants received sequential therapy with once-weekly TPTD for 72 weeks, followed by ALN for 48 weeks (TPTD-ALN group) or ALN monotherapy for 120 weeks (ALN group). BMDs were measured at the lumbar spine (L2-4), total hip, and femoral neck at 0, 24, 48, 72, and 120 weeks by dual-energy X-ray absorptiometry. The T2T goal was BMD ≥ -2.5 SD, and the endpoint was the proportion of participants with baseline BMD < -2.5 SD in three measurement sites achieving BMD ≥ -2.5 SD. RESULTS: A total of 559 participants were selected. BMD ≥ -2.5 SD at 120 weeks in the L2-4, total hip, and femoral neck sites was achieved in 20.5%, 23.1%, and 5.9%, respectively, in the TPTD-ALN group and 22.2%, 11.7%, and 7.3%, respectively, in the ALN group. Incident vertebral fractures occurred in areas of both lower and high BMD. CONCLUSION: During the 1.5-year treatment period, more than 20% of participants achieved BMD ≥ -2.5 SD as a T2T goal at L2-4. Since the achievement level differed depending on the BMD measurement site, the appropriate site should be selected according to the baseline BMD level.

Nutritional and inflammation factors associated with current frailty level and effect of co-morbidities on the progression of frailty.

AIM: Frailty is defined as extreme vulnerability, a syndrome that exposes the individual to a higher risk of disability. While risk factors for frailty have been gradually uncovered, the full identification of biochemical factors and co-morbidities influencing frailty remains incomplete. METHODS: Cross-sectional and longitudinal analyses were performed to elucidate the risk factors for the prevalence and progression of frailty. The study included 1035 Japanese female outpatients. At baseline, biochemical markers were measured. Co-morbidities included diabetes mellitus, dyslipidemia, hypertension, vertebral osteoarthritis, and osteoporosis. Frailty levels were assessed using frailty scores ranging from 0 to 5. Prevalence of frailty was judged by a score of 3 or above, and progression was judged by an increase in the frailty score during the observation period. Multiple regression analysis was used for the cross-sectional analysis, and the Cox hazard model was used for the longitudinal analysis. RESULTS: Of the 1035 selected participants, 212 were diagnosed with frailty. Advanced age and log IL-6 and branched-chain amino acids (BCAA) levels were significant independent risk factors for frailty. Subjects were followed for 7.7 ± 5.9 years and progression was observed in 130 subjects. Older age, the absence of hyperlipidemia, the presence of osteoporosis, and lower frailty scores were identified as significant risk factors for frailty progression. CONCLUSIONS: Inflammatory and nutritional markers exhibited significant associations with the current frailty status, whereas co-morbidities such as osteoporosis or hyperlipidemia emerged as independent risk or protective factors of future frailty progression. Geriatr Gerontol Int 2024; 24: 523-528.

Spinal osteoarthritis is a risk of vertebral fractures in postmenopausal women.

Recent studies have revealed that despite high bone mineral density (BMD), osteoarthritis (OA) is a risk factor for osteoporotic fractures. However, the relationship between spinal OA and vertebral fractures has not yet been fully investigated. This longitudinal analysis used a subset of ongoing cohort study consist with Japanese postmenopausal women. The prevalence of spinal OA was determined using Kellgren-Lawrence grading method. The incidence of vertebral fractures were determined by semiquantitative analysis of spinal X-ray films. The relationship between the presence of spinal OA and incidence of vertebral fractures was evaluated using the Cox regression analysis. In total, 1480 women were followed up for 8.1 ± 6.4 years. Among them, 923 were diagnosed with spinal OA, and incident vertebral fractures were observed in 473 participants. After adjusting for confounding variables, the spinal OA (≥ grade 2) was a significant predictor of incident vertebral fractures (hazard ratio, 1.52; 95% confidence interval: 1.19-1.93, p = 0.001). Using ROC analysis, the thresholds of lumbar BMD for incident vertebral fractures were 0.952 g/cm2 for patients with spinal OA and 0.753 g/cm2 for patients without spinal OA. The presence of spinal OA is a risk factor for incident vertebral fractures despite high lumbar BMD.

Nitric oxide is associated with fracture risk in Japanese women.

Although nitric oxide (NO) is a known factor that regulates the bone physiology, few and discordant results have been obtained in human studies evaluating the effect of nitrates on bone health. We investigated for the relationship between serum NOx level and incident osteoporotic fracture rate prospectively in a cohort consisting of Japanese women. A total of 871 subjects (67.5 ± 10.8 y/o) were analyzed. During the observation period (8.8 ± 7.2 yrs), incident osteoporotic fractures occurred in 267 participants (209 vertebral fractures, 57 long-bone fractures, and 1 both types). Hazard ratio, by the Cox proportional hazards model, of serum NOx for incident fracture was 0.64 (95% confidence interval 0.53-0.78, p < 0.001) after adjustment for baseline age (1.13, 1.06-1.21, p < 0.001), lumbar bone mineral density (L-BMD; 0.85, 0.78-0.92, p < 0.001), presence of prevalent fracture (3.27, 2.49-4.32, p < 0.001), and treatment of osteoporosis (0.70, 0.53-0.92, p = 0.010). The relationships between serum level of NOx and bone-related parameters were examined by multiple regression analysis; body mass index (p < 0.001) and L-BMD (p = 0.011) were significantly associated with serum NOx level. These results suggest that the low circulating NOx is one of the independent predictors for osteoporotic fracture occurrence in postmenopausal women.

Antiresorptive Drugs and the Risk of Femoral Shaft Fracture in Men and Women With Osteoporosis: A Cohort Study Using the National Database of Health Insurance Claims of Japan.

BACKGROUND: This cohort study aimed to estimate incidence rates of femoral shaft fracture in patients who were treated with antiresorptive drugs. METHODS: We used data from the National Database of Health Insurance Claims of Japan from April 2009 and October 2016. All patients with new use of an antiresorptive drug, prescription-free period of ≥3 months, and no prior femoral fractures were included. Femoral shaft fractures were identified using a validated definition based on International Classification of Diseases, 10th revision (ICD-10) codes. Incidence rate ratios were estimated using Poisson regression, with adjustment for sex, age, and the Charlson Comorbidity Index. RESULTS: We identified 7,958,655 patients (women: 88.4%; age ≥75 years: 51.2%). Femoral shaft fractures were identified in 22,604 patients. Incidence rates per 100,000 person-years were 74.8 for women, 30.1 for men, 30.1 for patients aged ≤64 years, 47.7 for patients aged 65-74 years, and 99.0 for patients aged ≥75 years. Adjusted incidence rate ratios in patients taking versus not taking each type of antiresorptive drug were 1.00 (95% confidence interval [CI], 0.98-1.03) for bisphosphonates, 0.46 (95% CI, 0.44-0.48) for selective estrogen receptor modulators, 0.24 (95% CI, 0.18-0.32) for estrogens, 0.75 (95% CI, 0.71-0.79) for calcitonins, and 0.93 (95% CI, 0.84-1.03) for denosumab. The adjusted incidence rate ratio for alendronate was 1.18 (95% CI, 1.14-1.22). CONCLUSION: The incidence rates of femoral shaft fracture varied across patients treated with different antiresorptive drugs. Further research on a specific antiresorptive drug can increase understanding of the risk of femoral shaft fracture.

Relationship Between Changes in Serum Levels of Intact Parathyroid Hormone and Sclerostin After a Single Dose of Zoledronic Acid: Results of a Phase 1 Pharmacokinetic Study.

Although changes in serum sclerostin levels at 12 months after infusion of zoledronic acid have been reported, the changes in sclerostin levels at earlier time points are poorly understood. We reanalyzed the study data of a previous phase 1 pharmacokinetic study and investigated the correlation between changes in sclerostin levels and relevant factors in calcium metabolism. A total of 24 Japanese female subjects with primary postmenopausal osteoporosis were administered a single 4- or 5-mg dose of zoledronic acid. Serum and urine samples were collected on days 15, 29, 90, 180, and 365 after administration. Serum levels of calcium, phosphate, intact parathyroid hormone (iPTH), and sclerostin were measured. Levels of serum sclerostin were unchanged from baseline on days 15 and 29, but increased significantly on day 90, subsequently decreased significantly on day 180, and returned to baseline levels on day 365. A significant negative correlation was observed between changes in iPTH levels at early time points and sclerostin levels at later time points. This suggests that sclerostin was negatively regulated by iPTH, and the decrease in sclerostin may indicate the start of bone formation during later time points after zoledronic acid injection.

Cardiac acoustic biomarkers as surrogate markers to diagnose the phenotypes of pulmonary hypertension: an exploratory study.

Pulmonary hypertension (PH) is commonly associated with left heart disease. In this retrospective study, using the database of a clinical study conducted between January 2008 and July 2008, the phenotypes of PH were classified using non-invasive cardiac acoustic biomarkers (CABs) and compared with classification by echocardiography. Records with same-day measurement of acoustic cardiography and right heart catheterization (RHC) parameters were included; cases with congenital heart disease were excluded. Using the RHC measurements, PH was classified as pre-capillary PH (Prec-PH), isolated post-capillary PH (Ipc-PH), and combined pre-capillary and post-capillary PH (Cpc-PH). The first, second, third, and fourth heart sounds (S1, S2, S3, and S4) were quantified as CABs (intensity, complexity, and strength). Forty subjects were selected: 5 had Prec-PH, 5 had Ipc-PH, 8 had Cpc-PH, and 22 had No-PH. CABs were significantly correlated with RHC measurements, with significant differences among phenotypes. Phenotype classification was performed using various CABs, and the diagnostic performance as assessed by the area under the receiver operating characteristic curve was 0.674-0.720 for Prec-PH, 0.657-0.807 for Ipc-PH, and 0.742 for Cpc-PH. High negative and low positive predictive values for phenotype identification were observed. CABs may provide an ambulatory measurement method with home-monitoring friendliness which is more convenient than standard examinations to identify presence of PH and its phenotypes.

Acute Phase Reactions After Intravenous Infusion of Zoledronic Acid in Japanese Patients with Osteoporosis: Sub-analyses of the Phase III ZONE Study.

In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

Association of advanced glycation end-products levels with vascular events in postmenopausal women.

AIM: Advanced glycation end-products (AGEs) are a known factor that accelerates vascular complications. AGEs (e.g. pentosidine or N-ε-carboxy-methyl-lysine [CML]) have been particularly investigated in patients with diabetes or chronic kidney disease and have been associated not only with arteriosclerosis, but also with novel vascular events. On the contrary, the correlation of vascular events with AGEs has not been sufficiently investigated in groups excluding those with diabetes or chronic kidney disease. The present study aimed to evaluate the impact of AGEs on the history of vascular events in postmenopausal women excluding those with diabetes or renal insufficiency. METHODS: Japanese postmenopausal women were registered to the study after obtaining informed consent. Patients with critical illness, including diabetes mellitus and renal insufficiency, were excluded from the study. Participants were asked about their medical histories during the registration for the Nagano Cohort Study. Non-fasting serum and urine samples were collected to measure biochemical markers, including urinary pentosidine and serum CML levels. RESULTS: Among 357 postmenopausal women, 32 had a history of vascular events. After adjusting age and other variables known to be associated with the presence of vascular event history, positive correlations between AGEs and vascular event history were observed (standardized odds ratio of log[pentosidine] 1.38, 95% CI 0.96-2.00, P = 0.086; standardized odds ratio of log[CML] 1.73, 95% CI 1.10-2.74, P = 0.019). DISCUSSION: The present results showed a significant association between serum CML and the presence of vascular event history, suggesting that serum CML might play a role in vascular events. Geriatr Gerontol Int 2021; 21: 651-656.

Low serum osteocalcin concentration is associated with incident type 2 diabetes mellitus in Japanese women.

Increasing evidence suggests that osteocalcin is involved in the regulation of glucose homeostasis. However, the relationship between serum osteocalcin levels and risk of incident type 2 diabetes mellitus is not clear. The objective of this study is to investigate whether serum osteocalcin levels are associated with the risk of incident type 2 diabetes mellitus. This study included 1691 Japanese postmenopausal women, 61 incident diabetes cases, and 1630 non-diabetic control subjects in the observation period. Baseline concentrations of intact osteocalcin, HbA1c, bone-specific alkaline phosphatase, adiponectin, leptin, urinary N-telopeptides were assessed. Serum osteocalcin levels were significantly correlated with HbA1c levels among 1691 Japanese postmenopausal women (R = -0.12, P < 0.0001). In receiver operating characteristic curve analysis, the optimal cut-off levels for serum osteocalcin to predict the development of type 2 diabetes mellitus was 6.1 ng/mL. The group with baseline osteocalcin levels <6.1 ng/mL showed a significantly higher risk for developing diabetes than the group with baseline osteocalcin levels >6.1 ng/mL (log-rank test, P  <  0.0001) during the mean observation period (7.6 ± 6.1 years; mean ± SD). In multiple Cox proportional hazard analysis, osteocalcin levels were significantly associated with development of type 2 diabetes mellitus during the observation period. Our results indicate that a decrease in serum osteocalcin levels is associated with future development of type 2 diabetes mellitus independent of conventional risk factors in Japanese postmenopausal women.

Bisphosphonates prevent age-related weight loss in Japanese postmenopausal women.

Decline of body weight with aging is a major risk factor for frailty, osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. Recently, we have shown that 5-year treatment with raloxifene prevented age-related weight loss, suggesting some other drugs for osteoporosis may also prevent a decrease in body weight with aging. The present study aimed to identify the relationship between bisphosphonate treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 551 Japanese postmenopausal women with bisphosphonate treatment, which included risedronate or alendronate treatment (BP-treatment group; N = 193) and without treatment by any osteoporosis drug (no-treatment group; N = 358) for 4-7 years (mean observation periods; 5.5 years) and analyzed the relationship of these with BMD, body mass index (BMI), body weight, and biochemical markers. The mean (SD) age of the participants was 68.6 (9.8) years in the BP-treatment group and 63.7 (10.6) years in the no-treatment group. Percent changes in body weight and BMI were significantly different between the BP-treatment and no-treatment groups (P < 0.01 and P < 0.01, respectively). In multiple linear regression analysis, bisphosphonate treatment was a significant independent determinant of percent changes in body weight and BMI (P < 0.01 and P = 0.01, respectively). Long-term use of bisphosphonates prevented reductions in BMI and body weight, usually observed in elderly women. Our results suggest that bisphosphonate treatment not only reduces the risk for incident osteoporotic fractures but also for frailty in the elderly.

Optimal vitamin D intake for preventing serum 25-hydroxyvitamin D insufficiency in young Japanese women.

Populations of East Asian countries have been known to have low calcium intakes and low serum 25(OH)D concentrations, suggesting that Ca and vitamin D (VitD)-deficiencies are commonly observed. These nutritional imbalances may lead to low peak bone mass (PBM). The low PBM seen in Ca/VitD-deficient individuals may lead to osteoporosis, as well as an increased risk of fracture. A survey was conducted in young Japanese women (n = 296, 21.2 ± 2.3 years old) on their Ca/VitD intakes and serum 25(OH)D levels, which demonstrated a significant positive correlation between VitD intake and serum 25(OH)D levels (R 2 = 0.020, P = 0.016), and the proportion with serum 25(OH)D over 20 ng/mL was significantly increased with VitD intake (P = 0.013). Serum 25(OH)D was negatively correlated to serum intact parathyroid hormone (R 2 = 0.053, P < 0.001). On receiver operating characteristic curve analysis, the VitD intake threshold for maintaining 25(OH)D levels at 20 ng/mL or higher was 11.6 µg/day or greater. It was suggested that the recommended VitD intake allowance, defined in the Adequate Intakes as 5.5 µg/day, may not be sufficient to maintain serum 25(OH)D levels for bone health.

Preventive effects of raloxifene treatment on agerelated weight loss in postmenopausal women.

Decline of body weight and body mass index (BMI) with aging is a major risk factor for osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. However, the effects of treatment for osteoporosis on body composition are not well known. The present study aimed to identify the relationship between raloxifene treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 236 Japanese postmenopausal women with raloxifene treatment (N = 50) and without treatment by any osteoporosis drug (N = 186) for 5 years and analyzed the relationship of these with BMD, BMI, body weight, and biochemical markers. The mean (SD) age of the participants was 65.5 (9.3) years. Percent-changes in body weight and BMI were significantly different between women taking raloxifene and those not taking any osteoporosis drugs (P = 0.03 and 0.048, respectively). Raloxifene treatment was a significant independent determinant of body weight and BMI. Long-term treatment with raloxifene prevents age-related weight loss.

Decreased rate of hip fracture and consequent reduction in estimated medical costs in Japan.

The frequency of hip fractures associated with aging of the population is declining in many countries. Even in Japan, where this frequency has been increasing continually, a shift to decreasing frequency has been noted in recent reports. The objective of this study was to investigate the effects of this decrease and to estimate the number of hip fracture patients and the resulting reduction in national medical care expenditures. The differences in the number of patients were estimated by multiplying the population for each sex and each age group by the fracture rates before the decrease (2007) and after the decrease (2012). Total reduced cost was calculated by multiplying the treatment cost required for hip fracture and the annual medical cost of nursing care. The estimated number of hip fracture patients decreased by approximately 4000 in the elderly female population, and the resulting reduction in medical costs was approximately US$280 million. The number of patients with hip fractures has decreased in elderly Japanese women; as a result, the medical costs for treatment and nursing care might decrease.

Renal Phosphate Reabsorption is Correlated with the Increase in Lumbar Bone Mineral Density in Patients Receiving Once-Weekly Teriparatide.

In order to assess the changes in serum calcium and phosphate and the changes in renal tubular phosphate reabsorption (TmP/GFR) and to evaluate the association between these indices and the increase in bone mineral density (BMD) with once-weekly intermittent administration of teriparatide (TPTD), the results from the teriparatide once-weekly efficacy research (TOWER) trial were re-analyzed. The TOWER trial studied postmenopausal women and older men with osteoporosis. Patients were randomly assigned to receive TPTD 56.5 µg or placebo for 72 weeks. Of these patients, the present study investigated those whose calcium and phosphate levels and lumbar BMD (L-BMD) were measured (TPTD group, n = 153 and Placebo group, n = 137). The TPTD group had significantly lower serum phosphate, calcium-phosphate product, and TmP/GFR at weeks 4, 24, 48, and 72 and urinary fractional calcium excretion (FECa) at weeks 12, 48, and 72 (p < 0.05). In the TPTD group, the serum phosphate and TmP/GFR during early treatment (4, and 12 weeks) showed a significant positive correlation with the percent change in L-BMD at weeks 48 and 72. Based on multivariate analysis corrected for age, BMI, and L-BMD at the start of treatment, serum phosphate and TmP/GFR at week 4 showed a significant correlation with the percent change in L-BMD. This study suggests that the L-BMD response to once-weekly long-term TPTD treatment is associated with circulating phosphate or with the status of its renal reabsorption. Preventing decrease in serum phosphate levels may be important in acquiring greater L-BMD with once-weekly TPTD.

Induction and antagonism of pica induced by teriparatide in rats.

Intermittent subcutaneous injection of teriparatide, an active fragment of human parathyroid hormone, is clinically used for the treatment of osteoporosis. Patients suffer from nausea, which is one of the side effects teriparatide induces; however, the etiology of teriparatide-induced nausea remains unknown. We have reported pica, kaolin ingestion behavior, can be used as an assessment of nausea-related response in rats. In this study, we investigated the characteristics of teriparatide-induced pica and the abilities of anti-emetic drugs to inhibit teriparatide-induced pica. Male and female adolescent (4-week-old), young (8-week-old), and adult (30-week-old) naive rats, and ovariectomized (OVX: 17-week-old) and sham-operated (17-week-old) rats subcutaneously received teriparatide (0.4 mg/kg, n=4), and their kaolin and food intakes were monitored for 24 h after the injection. Among the tested rats, we found that OVX rats, rather than male, female, and sham-operated rats, showed marked teriparatide-induced pica (0 mg/kg: 0.17±0.07 g, 0.4 mg/kg: 6.18±0.91 g). Teriparatide-induced pica in OVX rats was inhibited by intraperitoneal pretreatment with serotonin 5-HT3 (granisetron 0.5 mg/kg), dopamine D2 (prochlorperazine 0.5 mg/kg), neurokinin NK1 (fosaprepitant 1 mg/kg), and histamine H1 (diphenhydramine 10 mg/kg) receptor antagonists to 70%, 11%, 19%, and 59% of that in vehicle-treated control, respectively. These results suggest that teriparatide-induced pica in OVX rats has the potential to reflect teriparatide-induced nausea; 5-HT3, D2, NK1, and H1 receptor activation is involved in the development of this behavior; antagonists of these receptors have the potential to be medical candidates used as treatments for teriparatide-induced nausea in human patients.

Once-weekly teriparatide increases bone mineral density in the distal 1/10 radius, but not in the distal 1/3 radius.

Teriparatide significantly increases bone mineral density (BMD) of the lumbar vertebrae and femur and has a strong effect in reducing the risk of bone fractures. However, few detailed investigations with dual-energy X-ray absorptiometry (DXA) of the effects of teriparatide on the radius have been reported; specifically, there are no reports of the use of once-weekly teriparatide. In this study, the effect of once-weekly teriparatide in increasing BMD was examined in the distal 1/10 of the radius and the distal 1/3 of the radius using a DXA system for the radius. In addition, the effect of radius positioning, especially accurate correction of rotation and inclination before and after administration of teriparatide, was evaluated in an assessment of its efficacy. It was found that when positioning was corrected, a significant increase in BMD in the distal 1/10 of the radius was observed after 6 months of once-weekly teriparatide. In the distal 1/3 of the radius, no significant increase of BMD was observed. This suggests that when DXA scans of the radius are analyzed with appropriate positioning, weekly teriparatide significantly increases BMD in the distal 1/10 of the radius, which is rich in cancellous bone.