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 Bone Mineral Density and Risk of Vertebral Fractures with Denosumab Treatment in Japanese Postmenopausal Women and Men with Osteoporosis.

In this post hoc analysis of the Denosumab Fracture Intervention Randomized Placebo-Controlled Trial (DIRECT) in Japanese postmenopausal women and men with osteoporosis, we evaluated the relationship between vertebral fracture risk and both bone mineral density (BMD) T-score and percent change after 24 months of denosumab treatment at total hip, femoral neck, and lumbar spine. Logistic regression analysis was performed and the proportion of treatment effect explained by BMD in vertebral fracture risk was estimated. The results demonstrate that both total hip BMD T-score and change can be strong predictors of subsequent fracture risk, and that total hip BMD change explained 73%, while T-score explained 23%, of the treatment effect. In contrast, neither femoral neck BMD change nor T-score can predict the effect of denosumab on vertebral fracture risk. Furthermore, although lumbar spine BMD T-score was associated with vertebral fracture incidence, lumbar spine BMD change was inversely related to vertebral fracture risk. Because there was no relationship between lumbar spine BMD change and T-score at 24 months of denosumab treatment, and because there can be small undetectable vertebral deformities that may increase BMD values, these results suggest that lumbar spine BMD change is not a good surrogate for vertebral fracture risk assessment. It is suggested that both total hip BMD change and T-score can be good surrogates for predicting vertebral fracture risk in Japanese patients with osteoporosis under denosumab treatment.ClinicalTrials.gov identifier: NCT00680953.

Efficacy of denosumab co-administered with vitamin D and Ca by baseline vitamin D status.

INTRODUCTION: In anti-osteoporosis drug trials, vitamin D and calcium (Ca) are common supplements; however, the optimal dose of each is unclear. Using data from the randomized, double-blind, placebo-controlled DIRECT trial, we assessed whether baseline serum 25-hydroxy vitamin D (25[OH]D) level influences the efficacy of denosumab co-administered with vitamin D and Ca. MATERIALS AND METHODS: In this prespecified sub-analysis, subjects with primary osteoporosis who received denosumab or placebo, plus vitamin D (≥ 400 IU/day) and Ca (≥ 600 mg/day), were classified as 25(OH)D deficient (< 20 ng/mL), insufficient (≥ 20 to < 30 ng/mL), and sufficient (≥ 30 ng/mL). Study endpoints included absolute serum 25(OH)D level at baseline, 12 months, and 24 months; change in serum 25(OH)D and bone mineral density (BMD) status from baseline; and incidence of new vertebral fractures at 24 months. RESULTS: In 475 denosumab-treated and 481 placebo-treated subjects, proportions with deficient/insufficient/sufficient 25(OH)D at baseline were 53.1%/37.1%/9.9% and 50.9%/42.0%/7.1%, respectively. Supplementation significantly increased mean serum 25(OH)D levels; at 24 months, mean levels were > 30 ng/mL (sufficient) in both treatment groups. Increase in BMD over time was higher in the denosumab group vs. placebo group in all three vitamin D status groups. At month 24, denosumab-treated subjects with deficient/insufficient baseline 25(OH)D had a significantly lower risk of new vertebral fracture vs. placebo-treated subjects. CONCLUSION: Among DIRECT trial subjects supplemented with ≥ 400 IU/day of vitamin D and ≥ 600 mg/day of Ca, baseline 25(OH)D sufficiency may not influence the efficacy of denosumab in increasing BMD or preventing vertebral fractures.

Assessment of eldecalcitol and alendronate effect on postural balance control in aged women with osteoporosis.

INTRODUCTION: Older people aged over 75 are more prone to falls because physical functions become deteriorated along with aging, and also fracture risk is strongly correlated with age. We evaluated the effects of anti-osteoporosis agents, eldecalcitol (ELD) and alendronate (ALN) on physical functions by assessing dynamic and static postural balance in aged patients with osteoporosis. MATERIALS AND METHODS: A randomized, open-label, controlled clinical trial has been conducted with 124 female patients aged 65 or over with osteoporosis. Patients were randomly assigned to receive either 0.75 µg of ELD once-a-day or 35 mg of ALN once-a-week for 24 weeks. The primary endpoint was the change in a postural balance index, adjusted composite equilibrium score (CES) of sensory organization test (SOT). The SOT equilibrium scores, leg muscle strength, and other physical functions were also evaluated. RESULTS: The Adjusted CES increased from baseline by 6.10% in the ELD group and 6.28% in the ALN group. There was no statistically significant difference between the two groups. The static postural balance at fixed platform were maintained in the ELD group, but declined in the ALN group. The dynamic postural balance at swaying platform and knee extension power increased from baseline in both groups. CONCLUSIONS: These results suggest that ELD and ALN treatments may each be beneficial to improve postural balance control in older patients with osteoporosis via different mechanisms of action.

Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03.

The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 ± 3.93 ng/mL to 2.59 ± 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 ± 4.36 ng/mL to 4.05 ± 3.40 ng/mL at 6 months) (p < 0.01). The treatment discontinuation rate was higher in the risedronate and vitamin K2 group than in the risedronate alone group (10.0 % vs 6.7 %). No unknown adverse drug reactions were reported. In conclusion, concurrent treatment with vitamin K2 and risedronate was not efficacious compared with monotherapy with risedronate in terms of fracture prevention.

Estrogen and cancers of the colorectum, breast, and lung in postmenopausal women.

As estrogens play an important role in maintaining physiological function in various organs, the estrogen decrease after menopause is thought to cause various diseases frequently observed in postmenopausal or elderly women. With the aging of society and a decrease in infectious or vascular diseases, neoplasms have now become the most frequent cause of death in Japan. Cancers of the colorectum, breast, and lung have been rapidly increasing both in incidence and death, especially among postmenopausal women. Interestingly, all three of these cancers are associated with estrogens. In premenopausal women, ovarian estrogens plays major roles in the female reproductive organs through the classic estrogen receptor, ER-α. In postmenopausal women, however, estrogens produced/activated by peripherally localized estrogen-metabolizing enzymes such as aromatase, which converts androgen into estrogens, are thought to play physiologically and pathobiologically important roles in various organs through second ER, namely ER-ß, distributing systemically. In this article, the association of estrogens with these cancers in postmenopausal or elderly women are reviewed, especially focusing on the role of ER-ß and peripheral estrogen metabolism. The possibility of prevention or treatment of these diseases through estrogenic control is also discussed.

[On "2015 Guidelines for Prevention and Treatment of Osteoporosis". Diagnostic criteria of primary osteoporosis and the criteria for pharmacological treatment].

Diagnosis of osteoporosis is based on the bone mineral density (BMD) measurement and differential diagnosis. The most important clinical determinant of bone strength is BMD in the conditions without previous fractures. It is indispensable to measure BMD to prevent first fractures. On the other hand, previous osteoporotic fractures are known to be the risk factors for other fractures. Particularly, osteoporotic vertebral fractures and hip fractures increase the risk of fractures even after the adjustment with BMD. These are the reasons why the information about previous osteoporotic fracures are important in the diagnosis of osteoporosis. In the current guideline, the patients who are given the diagnosis of primary osteoporosis are the candidates of pharmacological treatment. In addition, the patients of osteopenia one of whose parents has the history of hip fractures or those with the 10-year risk of major osteoporotic fractures of FRAX® are also considered to be the candidates of pharmacological treatment.

Design of a randomized clinical trial of concurrent treatment with vitamin K2 and risedronate compared to risedronate alone in osteoporotic patients: Japanese Osteoporosis Intervention Trial-03 (JOINT-03).

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.

[Treatment goals of osteoporosis].

Decision in starting and modulating the treatment of osteoporosis is being done by bone mineral density prevalent fractures, bone turnover markers, and other clinical indicators. However, the goal for the treatment of osteoporosis has not been established. Currently, treat-to-target is the most urgent issue to be discussed in the field of osteoporosis. In this article, the present status of this discussion is reviewed.

Diagnostic criteria for primary osteoporosis: year 2012 revision.

In 1995, the Japanese Society for Bone and Mineral Metabolism (now the Japanese Society for Bone and Mineral Research) established the Osteoporosis Diagnostic Criteria Review Committee. Following discussion held at the 13th scientific meeting of the Society in 1996, the Committee, with the consensus of its members, proposed diagnostic criteria for primary osteoporosis. The Committee revised those criteria in 1998 and again in 2000. The Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis aimed at obtaining international consistency and made a revised edition based on the new findings in 2012.

[Current approach to osteoporosis].

The aim of prevention and treatment of osteoporosis is to prevent osteoporotic fractures. In the process of revising the Japanese guideline for prevention and treatment of osteoporosis and the diagnostic criteria of primary osteoporosis, the clinical significance of prevalent fragile fractures was re-considered. Recent advances in the development of the drugs for osteoporosis should be followed by the new evidences, for example about appropriate selection of the drug and duration of drug therapy. Advices to collect life style are important for the effective drug therapy as well as for the prevention of osteoporosis.

Simultaneous total robotic right hemicolectomy and right partial nephrectomy.

The incidence of synchronous colorectal and renal cancers is reportedly as low as 0.33%. Simultaneous surgery for multi-organ cancers has been reported to have several advantages if tolerated by the patient. In addition, robotic surgery has gained wide application in various fields, but few reports exist on total robotic surgery involving multiple organ resections. We performed simultaneous total robotic surgery on a patient with combined colorectal and renal cancers. Before surgery, we examined the procedure with the surgical team, shared a portion of the trocar site without impairing the operability of the robotic surgery and performed the surgery safely. Further examinations are required to standardize the procedure for simultaneous robotic surgery for multi-organ cancers.

Association of CYP19 gene polymorphism with vertebral fractures in Japanese postmenopausal women.

This study investigates aromatase gene polymorphism, which might influence bone strength in terms of mineral density and quality. We explored the relationship between CYP19 polymorphisms and vertebral fractures in postmenopausal Japanese women. In addition, we compared estrogen and testosterone levels in Japanese postmenopausal women with and without fractures. Osteoporotic postmenopausal women showed higher incidences of vertebral fractures than osteopenic women or women with normal lumbar bone mineral density (L2-4 BMD). Estrogen concentrations in postmenopausal women were associated with BMD; however, no association was found between sex hormone levels and the presence of fractures. The C allele rs2470152 was significantly associated with increased risk of vertebral fractures (P = 0.04), whereas none of the CYP19 polymorphisms showed differences in sex steroid levels between subjects with and without fractures. Allelic variants of aromatase genes appear to interact to influence the risk of vertebral fractures in postmenopausal Japanese women.

[Clinical application of FRAX® in Japan].

FRAX® is a fracture risk assessment tool developed by WHO working groups. Ten-year risks for major osteoporotic fractures or hip fracture can be calculated with FRAX®. It has been discussed how to utilize FRAX® in the clinical settings in Japan. It was necessary to recognize the performance and limitation of this tool. In the Japanese guideline for prevention and treatment of osteoporosis 2011, a threshold of 10-year risk for major osteoporotic risk was proposed for the patients with osteopenia. It is emphasized that this is the proposal to use FRAX® in addition to the result of bone mineral density measurement and is not the proposal to use FRAX® as a screening tool. The way to utilize FRAX® as a screening tool should be investigated further.

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.

Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women.

Spinal osteoarthritis including disc degeneration is a very common condition in the axial skeletons of aged people. Recently, spinal osteoarthritis has been shown to be influenced by specific genetic risk factors. Vertebral osteophytes, endplate sclerosis, and intervertebral disc narrowing are recognized as radiographic features of spinal disc degeneration. HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the pathogenesis of cartilage-related diseases such as spinal degeneration. Here, we examine the association between an HAPLN1 gene polymorphism and the radiographic features of spinal degeneration. We evaluated the degree of endplate sclerosis, osteophyte formation, and disc space narrowing in 622 Japanese postmenopausal women. Four SNPs in the HAPLN1 gene-in the 5' flanking region, intron 1, intron 2, and intron 4-were analyzed using the TaqMan polymerase chain reaction method. We found that compared to subjects with the CC or CT genotype, those with the TT genotype for an SNP at intron 2 (rs179851) were significantly overrepresented among the subjects with higher scores for osteophyte formation (P = 0.0001; odds ratio 2.12; 95% confidence interval 1.45-3.11, as determined by logistic regression analysis) and disc space narrowing (P = 0.0057; odds ratio 1.83; 95% confidence interval 1.19-2.83). Consistent with the involvement of the HAPLN1 gene in cartilage metabolism, a variation in a specific HAPLN1 gene locus may be associated with spinal degeneration.

[Present situation of medical screening system for osteoporosis].

Medical screening system for osteoporosis is important method for detection of osteopenia or osteoporosis in the community. The medical screening for osteoporosis was done for female subjects at age 40, 45, 50, 55, 60, 65, 70 year-old people according to the Health Promotion Act in Japan. The number of females received the screening was 287,782 in 2008, and the number corresponded to 4.7% of the estimated numbers of subjects for the screening in the population. Sixty six percentages of institutions measured bone mass and/or bone mineral density with the purpose other than that proposed by Health Promotion Act at 2009. Calcaneus bone mass was measured in 81% of institutions by quantitative ultrasound(QUS). Because QUS is inexpensive, involves no radiation exposure, and is easily portable, this method should be suitable for medical screening for osteoporosis and its prevalent use in Japan supports this assumption.

A high-fat diet in the presence of vitamin D deficiency status is associated with a negative influence on calcaneal quantitative ultrasound parameters in young adults: a cross-sectional study.

Vitamin D deficiency and a high-fat diet are considered health problems worldwide. The aims of this study were to examine the prevalence of vitamin D deficiency/insufficiency in young adults, factors related to the vitamin D status, and the influence of vitamin D deficiency and/or a high-fat diet on bone parameters. Here, we investigated the hypothesis that a high-fat diet in the presence of a vitamin D-deficient status would have a more negative influence on bone parameters than a normal-fat diet with such a status. In the present study, we targeted young Japanese adults aged 21-23 (n = 175). We conducted a diet survey based on 3-day food records, biochemical examination of serum, and quantitative ultrasound measurements at the calcaneus. As a result, the rates of vitamin D deficiency {serum 25-hydroxyvitamin D3 [25(OH)D] concentration less than 20 ng/mL} and insufficiency [serum 25(OH)D concentration less than 30 ng/mL but not less than 20 ng/mL] were 60.6 and 30.9%, respectively. A positive correlation was observed between the serum 25(OH)D level and serum bone-specific alkaline phosphatase level, which is a serum marker of bone formation (r = 0.253, P< .01) or the speed of sound (SOS) as an index of bone density (r = 0.259, P< .01). A negative correlation was observed between the ratio of fat intake to total energy intake (%E) and serum 25(OH)D levels (r = -0.206, P< .01). Furthermore, we revealed that a high-fat diet in the presence of a vitamin D deficient status reduced the SOS parameter compared with a normal-fat diet with a vitamin D-deficient status (P< .05).

Usefulness of the mayo adhesive probability score as a predictive factor for renal function deterioration after partial nephrectomy: a retrospective case-control study.

PURPOSE: Whether the Mayo adhesive probability score, an index of the perinephric fat environment, could be a predictive factor for renal function deterioration after partial nephrectomy was investigated. METHODS: A retrospective case-control study of 78 patients who underwent laparoscopic partial nephrectomy was performed. An estimated glomerular filtration rate preservation rate at ≤ 90% at 3 months after surgery was defined as postoperative renal function deterioration. These patients were divided into two groups (non-deterioration and deterioration groups). Patient factors including Mayo adhesive probability scores (both tumor and unaffected sides) and surgical factors were evaluated to identify the predictors for postoperative renal function deterioration. The statistical analysis used univariate and multivariate logistic regression analyses. RESULTS: Thirty-seven (47.4%) patients had postoperative renal function deterioration after partial nephrectomy. Univariate analysis identified Mayo adhesive probability score on the unaffected side (p = 0.02), and warm ischemia time (p < 0.01) as predictors of postoperative renal function deterioration. On multivariate analyses, Mayo adhesive probability score on the unaffected side (odds ratio: 1.38 [1.05-1.79], p = 0.02) and warm ischemia time (odds ratio: 1.04 [1.01-1.07], p < 0.01) were significantly associated with postoperative renal function deterioration as same as univariate analysis. On receive operating characteristic curve analysis, Mayo adhesive probability score on the unaffected side (cutoff value 1.5; p = 0.02) and warm ischemia time (cutoff value 26.5 min; p = 0.01) were significant predictors of renal function deterioration 3 month after surgery. CONCLUSION: The Mayo adhesive probability score on the unaffected side and warm ischemia time are useful predictors for renal function deterioration after partial nephrectomy. TRIAL REGISTRATION NUMBER: 2019-249, January 21st, 2019, retrospectively registered.

Genetic aspects of osteoporosis.

The multiple factors contributing to the pathogenesis of osteoporosis include genetic and environmental factors. Because decrease in bone mineral density (BMD) is the major clinical indicator and a useful quantitative trait, many association and linkage studies of BMD have been conducted. Although the series of studies showed apparently significant associations, the genes have not been found that can be utilized in clinical practice. Several genes identified in robust genome-wide association studies will be the new cutting edge in genetic studies of osteoporosis. Our recent reports of functional single nucleotide polymorphism in the tissue-nonspecific alkaline phosphatase gene and gamma-carboxylase gene are presented in this review to discuss the future prospects in the genetic research of osteoporosis from the point of view of genome-nutrition interaction.