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Fragility fractures associated with osteoporosis can have a major impact on a person's "activities of daily living" (ADL) and life span. Therefore, osteoporosis and its complications must be addressed by early screening and prompt intervention. A Fracture Risk Assessment Tool (FRAX) has been developed by the WHO. FRAX allows the calculation/estimation of absolute fracture risk over a 10-year period. The FRAX can be completed using a free application form, accessible online. The relationship between FRAX and the young adult mean (YAM) was investigated in order to calculate the cut-off value of FRAX for each age group. FRAX can be used by both physicians and other healthcare professionals to pre-screen patients for more detailed subsequent work-ups. Using FRAX in clinical practice has proven to be simple, inexpensive and useful.

FGF23-related hypophosphatemic rickets is basically treated with active vitamin D and phosphorus. The treatment goals are to minimize bone deformity and improve adult height in children, and to relieve pain and decrease osteomalacia in adult. However, since they do not target the underlying molecular defect, bone deformity can worsen during growth and adult height is suboptimal restricted. Many adult patients suffer from enthesopathy leading to symptoms such as spinal cord compression and debilitating pain. At present, no treatment is effective in preventing or revenging this complication. The recently developed anti-FGF23 antibody may potentially be a more fundamental treatment.

Vitamin D insufficiency is one of the risk factors of osteoporosis. To know the vitamin D intake for the prevention of bone loss and fracture, it is necessary to evaluate the appropriate serum 25-hydroxyvitamin D (25-D) concentration for bone health, and the vitamin D intake to maintain its concentration. Although vitamin D intake 15 and 20 μg/d have been set as RDA (Recommended Dietary Allowance) in USA/Canada DRIs (Dietary reference intakes), 5.5 μg/d has been set as AI (adequate intake) in Japanese DRIs (2015). While reference values in Japan and USA/Canada were quite different, both DRIs are common in that it aim to maintain the serum 25-D concentration to more than 50 nmol/L. In the present review, vitamin D intakes and bone health, vitamin D status in Japanese people, DRIs for vitamin D and improvement of vitamin D insufficiency are reviewed.

The association of vitamin K with bone mineral density has been reported in some previous cohort studies and intervention studies. In cohort studies, higher vitamin K1 intake was associated with lower fracture incidence. Some intervention studies have described that vitamin K1 and vitamin K2 (menaquinone-4 : MK-4) supplementation were modestly efficacious in preventing fracture, but not in preserving bone mass. Although dietary reference intake (adequate intake : AI) for vitamin K was increased from previous value, current AI was determined as the dose sufficient to maintain normal blood coagulation with little mentioning to bone. Vitamin K intake greater than the current AI would be required for the bone health.

Osteoporosis is a common and under-diagnosed disease characterized by the systemic impairment and structural deterioration of bone tissue, leading to bone fragility and an increased risk of fractures of the hip, spine, and wrist. Recent progress in osteoporosis revealed new information on its pathogenesis, the relative risks of fragility fractures, and new treatment measures. In the wake of progress in osteoporosis research, the Japanese Society for Bone and Mineral Research (JSBMR) and Japan Osteoporosis Society Joint Review Committee revised the diagnostic criteria for primary osteoporosis, aimed at obtaining international consensus on the new findings, in 2012. The JSBMR also published guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis in that year. Then, the JSBMR revised the guidelines on the management and treatment of glucocorticoid-induced osteoporosis in 2014. This article focuses on the diagnosis and pharmacological treatment of osteoporosis, with an overview of the Japanese guidelines.

Teriparatide is an only available bone anabolic drug in practice. It is a N-terminal fragment of parathyroid hormone (PTH) . Mode of actions of teriparatide is pharmacological but not physiological as it is administered to patients with osteoporosis. Physicians need to understand the fact that treatment with teriparatide is not just like a hormone replacement. They also should administer teriparatide to their patients after rigorous evaluation of its clinical superiority to other anti-osteoprosis drugs, because it is not classified as a first-line drug.

The goals of osteoporosis treatment are prevention of fracture. If the patients with higher risk of fragility fractures are treated, the larger effect on reduction of the risk of fragility fractures is expected. Criteria for initiating pharmacological treatment in U.S.A or Europe are based on cost-effectiveness. In Japan, the criteria for initiating pharmacological treatment to prevent fragility fracture were established in the revised version of 2011 guidelines for prevention and treatment of osteoporosis. In these criteria, postmenopausal women and men age 50 and older with vertebral fracture are considered for treatment regardless of bone density. FRAX® was newly introduced to consider whether or not to initiate pharmacological treatment in persons without a fragility fracture who have a low bone mass.

Accumulating evidence shows that type 2 diabetes and chronic kidney disease (CKD) enhance fracture risk mainly by deteriorating bone quality. Vertebral fracture on X-ray films and hip fracture in past history in subjects of 50 years old or more are hallmarks to start medication for osteoporosis. Patients with diabetes or CKD who have no fracture could undergo drug treatments if their bone mineral density is osteopenic, considering the established link between these disorders and fracture risk.

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.

While prevention forms part of the armamentarium for osteoporosis which is no less important than treatment, there is as yet a paucity of evidence that provides the rationale for prevention compared to that for treatment in osteoporosis. While preventive measures against osteoporosis vary depending on the life stage of the patient being targeted (i.e., young, perimenopausal or elderly) , prevention is being addressed in this article from a different perspective with a focus on the following three areas : prevention of onset of osteoporosis, prevention of osteoporotic fracture, and prevention of falls. The biggest challenge in preventing the onset of osteoporosis has to do with how best to alert the patient to the risk of osteoporosis which remains nearly asymptomatic, then to encourage her to seek medical consultation, and finally to prevent osteoporosis from happening in the patient. Again, while the importance of preventing primary osteoporotic fracture is beginning to be widely recognized, how to keep a chain reaction of fracture events from happening in osteoporotic patients remains a major challenge to be addressed. Lastly, as fracture events go hand in hand with falls, how to minimize the impact of falls in such a way that they do not lead to fractures remains yet another challenge calling for attention.

The importance of measurement of bone metabolic markers has been increasingly recognized in the treatment of osteoporosis. Bone is a dynamic organ in which bone formation and resorption continuously occurs. Biochemical marker for bone metabolism is an non-invasive measure to assess bone metabolic state. Although the purpose of its measurement was initially hypothesized to predict rate of bone loss, the increase of bone marker by itself provides a clinically relevant marker for bone fragility. Furthermore, measurement of bone marker is known to help improve drug compliance. Recent sophistication of bone marker measurement and the increasing kinds of bone markers increase the importance of its measurement to improve osteoporosis treatment.

The aim of osteoporosis treatment is to reduce fracture risk. Many kinds of anti-osteoporosis drugs are available in these days, and most of them increase bone mineral density and reduce the risk of fractures. Japanese 2011 guidelines for prevention and treatment of osteoporosis documents the recommendation level of each osteoporosis drugs. It is important to select drugs appropriate for each osteoporosis patient considering the mechanisms of drug action and their clinical efficiency.

The number of patients with lifestyle-related diseases is rapidly increasing in Japan. Metabolic syndrome caused by abdominal fat accumulation induces diabetes mellitus, dyslipidemia, and hypertension, resulting in an increase in cardiovascular diseases. On the other hand, recent studies have shown that the lifestyle-related diseases are risk factors of osteoporotic fractures. Although it remains still unclear how metabolic disorders affect bone tissue, oxidative stress and/or glycation stress might directly have negative impacts on bone tissue and increase the risk of fractures. In this review, we describe the association of diabetes mellitus and dyslipidemia with the fracture risk through oxidative stress and glycation stress.

Osteoporosis, as well as renal osteodystrophy, is a skeletal disorder predisposing to an increased risk of fracture. Although some medications to CKD-MBD prevent fragility fracture, the incidence of the fracture will increase according to the aging of the patients on maintenance hemodialysis.

Teriparatide, a treatment formula of parathyroid hormone (PTH) , is a powerful anabolic agent on bone, improving its mass, geometry and microarchitecture. It can decrease the occurrence of fracture in the subjects with increased fracture risks. Teriparatide can provide good protection against fracture using as monotherapy, and possibly as combination with an antiresorptive agent such as zoledronate. Teriparatide should be considered in patients with osteoporosis who sustained the reduction of BMD or fracture on established bisphosphonates or SERMs. Treatment period of teriparatide is 1.5-2 years and consecutive use of antiresorptive agents is greatly recommended to secure long-term protection against fracture after teriparatide treatment.

Quantitative ultrasound (QUS) is a convenient method for bone mass measurement and provides an index of bone strength reflecting bone structure as well as bone density. It applies to the peripheral skeleton such as calcaneus and is not applicable to vertebra and hip. The sensitivity for interval change is not so high. Thus, QUS is preferred for assessing fracture risk, and has not been established as a method for diagnosing osteoporosis and monitoring the effectiveness of therapy.

The large prospective studies of osteoporotic fracture in Europe and the United States have confirmed the utility of calcaneal QUS to predict fracture risk in elderly people. The other side, QUS has unfortunately only a few evidence concerning about usefulness as osteoporosis diagnostic tool in recent reports. For the present, QUS should be used as risk assessment tool of osteoporotic fracture. Because various ultrasound parameters depending on the manufacture are defined, the standardization of these values should be achieved. A large number of normative data have been collect to re-calculate to standardize SOS by the committee of Japan Osteoporosis Society, and age-related change of the standardized Speed of Sound (S-SOS) has been already reported. In this report, the peak value of S-SOS is seen in teenager, and mean of S-SOS in each age are gradually decrease in life. This age related change indicates that fracture risk would be gradually increase in life.

The outline of Japanese Guideline for the prevention and treatment of Osteoporosis (up dated 2011) was introduced. Descriptions were made on the identification of risk factors for fracture, prevention of osteoporosis, criteria for initiating pharmacotherapy to prevent fracture. Grading of recommendation for medication based on evidence, introduction of bone turnover markers in the treatment and secondary osteoporosis.

In the past several decades, the method of bone mineral measurement has been establised and contributed to the advancement of clinical practice of osteoporosis. The microfocus X-ray CT has been applied to the analysis of bome microarchitecture, and recently it is possible to analyse trabecular architecture in distal radius using clinical CT. On the other hand, as to the aplication of plain radiography, standarization of vertebral fracture assessment has been progressed in parallel to the recognition of prevalent vertebral fracture as fracture risk.

Eldecalcitol, a new active vitamin D compound, has revealed to have its superiority to alfacalcidol in preventing vertebral fractures in osteoporotic subjects, as well as in preventing major non-vertebral fracture. Several animal studies demonstrated the greater efficacy in bone metabolism comparing the traditional active vitamin D, partly in relation to improvement of trabecular bone microstructure ; increase in BV/TV, Tb.N and Tb.Th, and decrease in Tb.Sp. Furthermore, three years longitudinal observation of hip geometry and biomechanical properties using clinical CT (multi-detector row CT) has disclosed an unexpected potential of eldecalcitol to improve biomechanical parameters by the increase in cortical cross-sectional area, cortical bone mass, and cortical perimeter, and by maintaining clinical thickness, probably through a more potent effect of eldecalcitol in mitigating endocortical bone resorption compared to alfacalcidol.

We conducted a post-hoc analysis of the phase III clinical trial of eldecalcitol (in comparison with alfacalcidol) . Enrolled subjects were divided into subgroups according to age, vitamin D levels, prevalent vertebral fractures, and baseline lumbar bone mineral density (LBMD) . In the eldecalcitol group, LBMD increased more than 3% in 3 years, which was significantly higher than that in the alfacalcidol group in all 4 subgroups. Incidence of new vertebral fractures was lower in the eldecalcitol group than in the alfacalcidol group in each of the first 3 subgroups, and the difference between eldecalcitol and alfacalcidol was significant in the age group of 70 years and over. When we compared the fracture risk with the placebo group reported in the minodronic acid phase III fracture prevention trial, the reductions in relative risk in the alfacalcidol and eldecalcitol group were about 30% and 50%, respectively (not direct comparisons) . Eldecalcitol is beneficial for a wide range of patients with osteoporosis, since its effects of increasing BMD and preventing fractures were not impaired by age, vitamin D levels, prevalent vertebral fractures, or baseline BMD.

Although active vitamin D₃ only slightly increases bone mineral density (BMD) , it prevents fractures to a greater extent than is predicted, based on measurements of BMD. This effect is partly attributed to enhanced muscle strength and increased physical capabilities by vitamin D, which, in turn, decreases the risk of falls and fractures. In addition, active vitamin D₃ has been reported in animal studies to improve bone quality by enhancing trabecular bone microarchitecture and increasing enzymatic collagen cross-links in bone. A (large scale of) randomized controlled trial in Japanese postmenopausal women verified that the combination therapy of bisphosphonate (alendronate) plus active vitamin D₃ was more effective than monotherapy in terms of fracture prevention in high fracture risk group.

Eldecalcitol is a new active vitamin D₃ compound, bearing a hydroxypropyloxy residue at the 2β-position of 1α, 25 (OH) ₂D₃. In ovariectomized rats, eldecalcitol increased vertebral bone mass and bone strength by inhibiting bone resorption and maintaining bone formation. In randomized, placebo-controlled, double-blinded clinical trial for osteoporotic subjects, eldecalcitol increased lumber vertebral and hip bone mineral density independent of vitamin D status. Furthermore, in patients with osteoporosis, eldecalcitol treatment was associated with a lower risk of vertebral and wrist fractures, with greater decrease in bone turnover markers compared with alfacalcidol. The incidence of adverse events was similar between the two treatments. Therefore, eldecalcitol can become a new treatment of choice for osteoporosis.

Only bisphosphonates have evidence that show to reduce the risk of vertebral, nonvertebral, and hip fractures in postmenopausal osteoporosis. From the viewpoint of risk benefit, it may be said that a utility is far superior to problems of the long-term use. Long-term use of bisphosphonates is necessary for the patients at elevated risk for the hip fracture.

In Japan, where the society is fast aging at an unprecedented pace, osteoporosis is estimated to affect more than 15 million individuals, thus representing a "common" disease, which exactly meets the definition of a lifestyle-related disease. As osteoporosis has a predominantly female prevalence and bone accounts for the most marked gender difference all organs commonly affected in males and females alike, to have an understanding of the development and aging of bone in women represents an urgent task toward gaining a better understanding of the pathophysiology of osteoporosis affecting them as well as its clinical stages. In this context, the benefit of ensuring bone health has been identified as maintenance of ADL/QOL in the elderly as well as prevention of osteoporotic fractures which lead to affected individuals becoming bed-ridden and requiring nursing care.

Minodronic acid has been developed and approved for the treatment of osteoporosis in Japan. It was reported that daily 1 mg minodronate for 24 months reduced the risk of vertebral fractures. It was also reported that minodronic acid suppressed the risk of vertebral fractures in patients aged 75 years or older in the same way as in patients aged less than 75 years. Monthly 50 mg minodronate is now under development for the treatment of osteoporosis in Japan. It is expected that monthly administration would improve medication adherence and, as a result, incidence of fragility fractures will be reduced with the improvement of quality of life in the elderly.

A monitoring period in osteoporosis treatment should be considered in accordance with the efficacy of medicine as well as the precision of monitoring tool, because a significant bone gain should be larger than the precision error of the measurement. Regarding bisphosphonate treatment in osteoporosis, 2-5 years'period is required to detect a significant change in bone mineral density (BMD) using dual-energy x-ray absorptiometry. Furthermore, the degree of increase in BMD by bisphosphonate treatment cannot account for the degree of reduction in the risk of fracture. It therefore makes no sense to determine how much BMD increases during the treatment.

The treatment efficacy of antiresorptive therapy, including bisphosphonates, is not fully accounted for by change in bone mineral density (BMD). The 1-year increases in hip BMD were reported to be associated with a reduction in spine fracture by using the data from FIT trial, but the changes in spine BMD that was greater than hip BMD were not associated with the risk of spine, non-spine, or hip fracture. On the other hand, the diagnosis of osteoporosis is made mainly by measurement of BMD. In this sense, BMD measurement is thought to be useful in will improvement for the treatment of the patients.

We introduced the relationship between bone change and neurological disturbance in the patients with cerebrovascular disease (CVD) , Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) . High incidence of osteoporosis and right/left difference in osteopenia are found in the diseases. CVD and PD patients with asymmetrical osteopenia show an association between clinical symptoms, peripheral circulatory symptoms, and predominant osteopenia. Although the muscle strength of PD patients was normal, the more severely affected side for PD symptoms and autonomic symptoms coincided with predominant osteopenia in the body. Increased bone resorption was detected in ALS patients. We speculated that neurological disturbances affect the remodeling of local sites of the bone. We have to start treatment from an early stage of the neurological disease to prevent a fracture.

A 76-year-old woman with multiple bone metastases from lung adenocarcinoma was admitted due to a pathological femoral fracture. On the night after admission, her consciousness deteriorated rapidly and she developed progressive respiratory failure. Computed tomography of the chest revealed diffuse ground glass opacities in both lungs, and magnetic resonance imaging of the brain showed multiple acute infarctions. Her condition improved after several days of supportive treatment with oxygen, corticosteroids and diuretics. Fat embolism syndrome should be considered as a differential diagnosis if consciousness disturbance and respiratory failure occur in patients with metastatic bone carcinoma and pathological long bone fractures.

Bone strength is determined not only by BMD, but also by many other bone quality relating factors such as bone structure etc.. Hip fractures are the most serious fragile fractures, considering that controlling their risk factors will successfully prevent these fractures. Recently Hip structure (strength) analyses have become available during standard DXA measurements. Bending strength and stability of the bone can be determined by their obtained parameters such as section modulus, cross sectional area and buckling ratio. These parameters shift towards fragile by aging, especially remarkably reduce after 70 years. It has been reported that both anti-resorptive agents and anabolic PTH increase bone strength in different manner. Further progressed 3 dimensional femoral neck strength analysis using CT scanning are now under development.

Calcium transfer from the mother to the infant during pregnancy and lactation plays an extremely important role in the bone health of the mother and neonate. Calcium aids in bone health through all ages but is especially crucial during pregnancy and lactation. Changes in the structure and metabolism of bone during pregnancy and the early stage of postpartum are evaluated by investigating bone mineral density (BMD), bone histomorphometry and bone markers of human or animal models. The bone resorption increased at the end of pregnancy and lactation, and the bone formation increases and the bone structure is almost recovered after cessation of lactating in postpartum. Puerperal BMD remained static over the subsequent 5-10 years. If the women have a low BMD at this stage of their reproductive life, it tends not to improve over this time. Perhaps identification of this at-risk group may lead to effective interventions to reduce fracture risk in later life.

Osteoporosis is known to increase in prevalence with age. With aging of population in the recent years, the number of male osteoporosis patients is increasing. Osteoporosis can progress without symptoms. Diagnosis and treatment of osteoporosis are often delayed especially in men, because the concept of male osteoporosis has not been fully penetrated. Even after fragile fracture caused by osteoporosis, it is frequent that an appropriate treatment for osteoporosis has not been provided in men. Furthermore, it has been reported that about half of male osteoporosis patients have secondary causes. In management of osteoporosis patients, we have to pay attention to background diseases and life style of the patients.

Patients with cancers such as breast or prostate cancer who have been treated with hormone deprivation therapies or anti-cancer agents for certain periods of time frequently manifest reduced bone mass or pathological fractures during their clinical course. These are likely due to an imbalance between osteoblastic bone formation and osteoclastic bone resorption resulting from hypogonadism. Bone should be carefully monitored in cancer patients who are going to continually receive adjuvant hormonal or anti-cancer therapies. Administration of anti-bone resorption agents such as bisphosphonates may be necessary to maintain bone mineral density and protect pathological fractures in these cancer patients.

Secondary osteoporosis is caused by various disorders, metabolic derangements, and drug administration, whose elimination as a cause for osteoporosis is necessary before establishing the diagnosis of primary osteoporosis. The underlying diseases or conditions are diversified, including those related to endocrine, nutrition, rheumatism, immobility, medicine, hematology, and congenital one. Among them, osteoporosis induced by steroid administration and that accompanied by diabetes mellitus are most frequently observed. They exhibit high fracture risks based on deteriorated bone quality rather than reduced bone mass.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is considered to be a systemic disorder that associated with fracture, cardiovascular disease, and mortality. Because the early initiation of appropriate therapy may prevent or ameliorate the mineral and bone disorder that developed in late CKD, the ability to define the pathophysiologic process underling abnormality is important. In patients with earlier stage of CKD with osteoporosis or high risk of fracture, management similar to the general population is recommended. There are few data on the treatment for fragility fractures in patients with later stage of CKD.

Recently, much of the attention given to bone-mineral disorder as the prognostic factor for mortality has focused on their links to chronic kidney disease (CKD-MBD; chronic kidney disease-mineral bone disease), especially in dialysis patients. Bone disease in dialysis patients showed heterogeneity caused by multiple factors other than postmenopausal osteoporosis. Evaluation of the bone mineral density with DEXA and the bone metabolic markers becomes useless for the assessment of bone fragility in dialysis patients. Prevalence of bone fracture in end-stage renal disease patients is 3-4 times higher than that in general population. The skeletal fracture in ESRD patients is suggested to be related with malnutrition. Guidelines of the therapy for bone-mineral disorder in dialysis patients is centered on the prevention of cardio-vascular disease and the mortality. Physicians should carefully understand these effects in the daily clinical practices.

The 2000 NIH definition of osteoporosis may now call for revision in light of evidence accumulated through clinical studies in the last decade. Of note, as bone quality is now becoming available for evaluation, it is becoming clear that bone quality contributes to bone strength to a far greater degree than was previously assumed and the myth of bone mineral density is now quickly losing ground. Against this background, the role of the selective estrogen receptor modulator raloxifene (RLX) is undergoing a reevaluation. No doubt RLX fills an important role as a therapeutic for osteoporosis given its mechanisms of action which are distinct from those of the bisphosphonates, and is expected to have an increasingly larger role in osteoporosis management.

The umbrella concept chronic kidney disease-mineral bone and disorders (CKD-MBD) has been developed these days, which includes vascular calcification, laboratory abnormalities, and bone abnormalities. Given the high prevalence of CKD stage 3 in the patients with osteoporosis and the high risk of fracture in osteoporosis with CKD, the role of raloxifene, one of SERM, in the care of CKD-MBD should not be overlooked. In the post-hoc analysis of the MORE trial, the effect of raloxifene to reduce vertebral fracture was confirmed as well as a positive effect on bone mineral densities in patients with moderate renal failure and normal parathyroid hormone (PTH). However, there is a possibility of this drug increasing PTH level just like other antiresorbing medications. Therefore, concomitant prescription of active vitamin D might be a good solution. From the viewpoint of pharmacokinetics, it is better to reduce the dose of raloxifene in patients with severe CKD. Moreover, it should be remembered not to prescribe this drug in nephrotic syndrome, which is associated with high risk of thrombosis.

Since the aim of the treatment of osteoporosis is to prevent fractures, the first-line drugs must be chosen according to their antifracture efficacies. In postmenopausal women with osteoporosis, alendronate, risedronate, minodronate, and raloxifene are effective in preventing vertebral fractures, and alendronate and risedronate significantly prevent hip fractures. Because the antifracture efficacy of raloxifene against vertebral fractures is considered similar to that of bisphosphonates, the discrimination of raloxifene from bisphosphonates depends on the strategy of doctors (internal medicine, gynecology, and orthopaedics) for preventing vertebral fractures according to the possible side effects of drugs including upper gastrointestinal events, hot flash, and deep vein thromboembolism. Recent reports suggest that patients could be identified who are more responsive to raloxifene than bisphosphonates by evaluating collagen cross-links markers such as homocysteine. Because the incidence of vertebral fractures is higher in Japanese patients, raloxifene plays an important role in the prevention of vertebral fractures in postmenopausal Japanese women with osteoporosis.

It is generally considered that drugs with different pharmacological actions are prescribed when combination therapy is undertaken. Vitamin D insufficiency or deficiency is prevalent in osteopenic and osteoporotic postmenopausal women. Combination therapy of raloxifene with other agents including vitamin D has been reported and its effect on fracture prevention remains to be elucidated.

Osteoporosis is closely associated with lifestyle-related diseases, such as diabetes mellitus, hypertension, and hyperlipidemia. The meta-analysis data reveals that risk of hip fracture is higher in the patients with diabetes mellitus or hypertension compared with those without it. Bone quality more markedly contributes to bone strength in osteoporosis associated with diabetes mellitus than without it. The reduction rate of vertebral fractures by raloxifene in the osteoporotic women with diabetes mellitus is higher than or equal to those without it. Raloxifene more markedly reduces vertebral fractures in the osteoporotic women with high value of serum triglyceride. Raloxifene improves hyperlipidemia in the postmenopausal osteoporotic women and increases the value of serum adiponection in the postmenopausal osteoporotic women without diabetes mellitus.

Recently, prostate cancer is one of the common cancer in Japanese men, with a high incidence of bone metastasis. Bone metastasis is incurable and contributes significantly to disease-specific morbidity and mortality. And more, there are many opportunity to perform androgen deprivation therapy in prostate cancer patients, but worsen osteoporosis and raise a risk of bone fracture. Thus, the management of bone metabolism in patients is a clinically significant issue. The bisphosphonates are targeted to osteoclasts and are considered to be standard management in the care of bone metastasis patients in combination with chemotherapy and hormone therapy. In this review, we summarized the current understanding and therapy of bone metastasis in prostate cancer in mainly respect to Zoredronic acid use.

The incidence of prostate cancer is increasing and the patients are generally of relatively advanced age. There has been an increase in the use of hormonal therapy in such cases. However, hormonal therapy for prostate cancer increases the risk of fracture. Bisphosphonates have been reported to prevent the bone loss caused by hormonal therapy. Therefore, oral bisphosphonates will play an important role in preventing bone loss in prostate cancer patients undergoing hormonal therapy.

Insufficient vitamin K nutrition is one of the risks for bone fracture. Vitamin K is clinically applied to osteoporosis treatment in Japan and Asian countries, as the administration has preventive effects on bone fracture. Recent studies have revealed that vitamin K functions as a ligand for Steroid and Xenobiotic Receptor (SXR), as well as a cofactor for gamma-carboxylase. In osteoblastic cells, several SXR responsive genes have been identified, including tsukushi, matrilin-2, CD14, and Msx2. Working together with gamma-carboxylated bone proteins, these SXR targets will function in the vitamin K-mediated bone protection. It has been also suggested that vitamin K could prevent or treat the hepatocellular carcinoma (HCC) in some clinical studies. SXR may also contribute to the vitamin K-dependent reduction of HCC.

The objective of the present review of the literature was to evaluate the effect of vitamin K supplementation on the skeleton of postmenopausal women. PubMed was used to search the reliable literature for randomized controlled trials (RCTs) by using the inclusion criteria: >or= approximately 50 subjects per group and study period of >or= 2 years. The results of 7 RCTs that met the inclusion criteria showed that vitamin K (K(1) and K(2)) supplementation reduced serum undercarboxylated osteocalcin levels regardless of dose, but that it had inconsistent effects on serum total osteocalcin levels and no effect on bone resorption. Despite the lack of a significant change or the occurrence of only a modest increase in bone mineral density, high-dose vitamin K supplementation improved indices of bone strength in the femoral neck and reduced the incidence of clinical fractures. Furthermore, a post hoc analysis in a large RCT in Japan showed that high-dose vitamin K(2) supplementation decreased the subsequent incidence of vertebral fractures in osteoporotic postmenopausal women with a history of at least 5 vertebral fractures. The review of the reliable literature showed the effect of high-dose vitamin K supplementation on the skeleton of postmenopausal women mediated by mechanisms other than bone mineral density and bone turnover.

With the recent development of diverse therapeutic modalities for osteoporosis, there is an increasingly recognized need to develop cost-effective strategies to determine which patients will benefit most from pharmacologic treatment. The World Health Organization (WHO) has developed a 10-year osteoporotic fracture risk assessment tool (FRAX) based on clinical risk factors combined with bone mineral density measured at the femoral neck. In postmenopausal women, age and prior history of fragility fracture were found to be major contributing factors to osteoporotic fracture risk as assessed by FRAX. In the US, the National Osteoporosis Foundation (NOF) guidelines recommend treatment in patients with osteopenia when the 10-year probability of major osteoporotic fracture is = 20% or the hip fracture is = 3%. On the other hand, in the UK, the National Osteoporosis Guideline Group (NOGG) has developed a case finding approach for individuals whose 10-year probability of major osteoporotic fracture exceeds age-specific thresholds. The FRAX algorithms may be worth incorporating in a cost-effectiveness model for socioeconomic analyses to determine the pharmacological intervention threshold for osteoporosis treatment. FRAX represents a significant advance for practitioners in women's health as an easy-to-use calculator of osteoporotic fracture probability. However, it should be noted that FRAX is intended as a guideline for clinical decision making only and does not force the decision to treat on physicians.

FRAX is developed based on the use of clinical risk factor with or without bone mineral density. It would be expected in diagnosis of osteoporosis that FRAX(R) would be used in a group examination, in medical institution which does not have DEXA, and at home. However, results of FRAX are expressed as percentage indication which is not familiar to Japanese. We did questionnaire survey to the osteoporosis patient about the results of FRAX. As a result, fracture risk is thought of seriously by the initial diagnosis patient, the younger patient, and the patient with interest in osteoporosis. It is necessary to explain fracture risk of FRAX on the basis of patient background in clinical use.