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In clinical, various kinds of anti-bone-resorptive drugs have been used for the treatment of bone disorders such as osteoporosis. However, it remains elusive how they affect the osteoclast dynamics in living bone tissues. We recently succeeded in visualizing cellular dynamics of bone-resorbing osteoclasts and their precursors with intravital bone imaging techniques. We found that active vitamin D analogs could regulate the migratory behavior of circulating osteoclast precursors, whereas bisphosphonates could affect mature osteoclasts and inhibit bone resorption within a short period. Here we show the latest data of in vivo effects of anti-bone resorptive drugs currently developed in the world.

Teriparatide, recombinant human PTH(1-34), is the only anabolic agent widely used for osteoporosis. This drug is thought to promote bone formation by modulating bone remodeling system, although the detailed mechanism remains unclear. Recently, we developed a novel intravital imaging technique to visualize mature osteoclasts and mature osteoblasts simultaneously. By means of this system, we revealed the effect of teriparatide on three-dimensional distribution and cell-to-cell interactions between these cells. Advances in these imaging studies may lead to further understanding of the intercellular network in bone metabolism.

Postmenopausal osteoporosis is mainly caused by decreased estrogen levels, and progression of disease is associated with irreversible changes. It is therefore extremely important to maintain or improve healthy bone and calcium metabolism during and before the climacteric from a preventive medicine viewpoint. The specific preventive measures are appropriate calcium intake and regular physical exercise. In recent years, women in their twenties are considerably thinner and have a lower calcium intake than women in other age groups, which may lead to a further increase in the number of women with osteoporosis in the future. From the aspect of female hormone secretion, women are at higher risk for osteoporosis than men at any given age. Aggressive intervention should therefore be undertaken to prevent osteoporosis according to life stage in women.

Bone resorption inhibitors used in Japan are bisphosphonate, selective estrogen receptor modulators(SERMs), denosumab, eldecalcitol, and calcitonin. The structural and material properties of bone quality are important factors in osteoporosis treatment. In contrast to improvements in bone density, those in bone quality are difficult to clinically determine as no simple test is available and changes are difficult to detect. Numerous reports have been published on the mechanisms by which bone resorption inhibitors increase bone density and suppress bone fractures. This paper describes the effects of each bone resorption inhibitor and focusses on burr holes, trabeculae, microdamage, collagen cross-links, and microstructures.

Teriparatide(TPTD)products that can be used clinically in Japan include a daily subcutaneous injection form produced by genetic engineering and a weekly subcutaneous injectable TPTD acetate form produced by chemical synthesis. Published reports indicate that both forms exhibit excellent antifracture efficacy, and as the only anabolic agents that promote osteogenesis, TPTD products now occupy a prominent position. However, the two forms differ considerably, not only in frequency of administration, but also in mechanism of action. The daily form stimulates osteogenesis and accompanying resorption through more radical high bone turnover, and early in the course of treatment, intracortical porosity and apatite crystallization decrease, while immature collagen crosslinking increases. However, because daily formulations also produce an increase in cortical surface area or cortical thickness, the effects are counterbalanced, and bone strength is maintained. In contrast, the weekly form prioritizes osteogenesis, and by concurrently lowering turnover below pretreatment levels, improves trabecular bone mass and structure, and enhances strength without leading to cortical porosity and other undesirable phenomena. Abaloparatide, a PTHrP(1-34)analog that is homologous with the biologically active site of PTH drugs, is currently under development, and we eagerly anticipate further clarification of the mechanism of action of each formulation on bone.

Glucocorticoid(GC)is widely used to treat a variety of autoimmune, inflammatory and allergic diseases. GC causes a number of adverse effects and among them osteoporosis and degenerative bone fracture are major complications of GC therapy. GC inhibits differentiation of mesenchymal stem cells to osteoblasts, induces apoptosis of osteoblasts and osteocytes and prolongs lifespan of osteoclast, resulting in low bone mass and micro-architectural deterioration of bone tissue, which leads to severe osteoporosis, increased bone fragility and susceptibility to bone fracture. Physicians who prescribe GC have to manage patients according to guidelines on the management and treatment of GC-induced osteoporosis.

In the malignant tumors in women, uterine cervical cancer, endometrial cancer, ovarian cancer, and breast cancer are representative diseases. The cancer treatment is classified roughly into an operation, medical treatment, and radiation therapy and has an extremely big influence on ovarian function. With the improvement in survival of cancer patients, the importance of the health care for the cancer survivors increases. It is necessary to prevent the onset of the osteoporotic fractures to maintain QOL. This paper describes the action that the malignant tumors of the women affect bone metabolism mainly from the viewpoint of ovarian function.

Serum 25(OH)D level reflects bodily vitamin D store. Recently published "Assessment criteria for vitamin D deficiency/insufficiency in Japan" defines vitamin D sufficiency as 25(OH)D level of 30 ng/mL or more, vitamin D insufficiency as that of 20 to 30 ng/mL, vitamin D deficiency as that of less than 20 ng/mL. The lower the serum 25(OH)D level is, the higher the risks are, of secondary hyperparathyroidism, low bone mineral density, fall, fracture, rickets/osteomalacia, and hypocalcemia, as well as lower response to anti-osteoporosis medications. Beyond musculoskeletal disorders, vitamin D insufficiency/deficiency has been shown to be associated with various immunological, metabolic, and malignant disorders mainly by basic and epidemiological studies.

Teriparatide is a bone anabolic drug that is only available 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 but its effects on bone remodeling are pharmacological. Romosozumab, under clinical development as anti-osteoporosis drug, is a monoclonal antibody against sclerostin. Clinical data demonstrate that it temporally, but robustly activates bone formation as well as inhibits bone resorption. Thus, romosozumab is expected to have a strong anabolic action on bone remodeling.

Estrogens have a biphasic action on pubertal and/or adolescent skeletal growth. Low levels of estrogen may increase the periosteal expansion through the increase in the sensitivity of bone for mechanical stimuli and the secretion of IGF-1. On the other hand, high estrogen concentrations may inhibit periosteal bone formation. To use OC/LEP(oral contraceptive/low dose estrogen-progestin) during adolescence, meaning exposure to high levels of estrogen, may prevent the acquisition of physiologic peak of bone mass.

In osteoporosis, the risk of fracture is influenced by decrease of bone mineral density and deterioration of bone quality. The latter includes deterioration of the material and structural properties of bone. These changes arise from the influence of changes in hormonal balance, aging, changes in mechanical stress, lifestyle-related diseases, etc. on bone absorption and bone formation as the coupled functions of osteoclasts and osteoblasts. Deterioration of bone quality occurs at various levels ranging from the molecular to the tissue level, or even at the individual level, and leads to an increased fracture risk. In this chapter, bone quality evaluation using quantitative computed tomography is discussed among evaluation methods of various fracture risk.

Rheumatoid arthritis (RA) is an autoimmune diseases characterized by inflammation and destruction of bone and cartilage. Osteoclastogenesis induced by inflammatory cytokines contributes to focal and systemic bone and cartilage destruction including secondary osteoporosis. Recent progress in treatment enables us to prevent disease activity. Not only anti-inflammatory management but also therapies directly targeting bone metabolism can further prevent bone destruction in RA.

Zoledronic acid hydrate(zoledronic acid)is an osteoporosis therapeutic agent which shows the fracture suppression effect with once-yearly intravenous infusion. Although zoledronic acid is quickly disappeared from the blood after intravenous infusion, it is taken into the bone immediately and incorporated into the bone tissue. In addition, zoledronic acid shows the potent suppression effect on bone resorption by inhibiting farnesyl diphosphate synthase of the mevalonate pathway(FPPS)strongly. In vivo study, the single intravenous administration of zoledronic acid to the mature ovariectomized(OVX)rats demonstrated to suppress the decreasing bone strength dose-dependently in 32 weeks, corresponding to more than one year in human. Changes in bone resorption markers in the study of Japanese osteoporosis patients(ZONE Study)indicated that bone resorption inhibition action was maintained also over one year. The fracture suppression and increase of bone density with once-yealy administration was demonstrated in clinical trials in the osteoporosis patients in Japan and other countries, and zoledronic acid was currently approved for osteoporosis in September 2016 in Japan. Zoledronic acid is expected to contribute to the treatment of osteoporosis as a new bisphosphonate with once-yearly administration.

Teriparatide(recombinant human PTH1-34, 20 μg daily subcutaneous injection)has been approved for osteoporosis patients at high risk of fracture in many countries including Japan. Teriparatide daily injection therapy has been reported to increase BMD, improve microarchitecture of bone, and reduce the risk of new vertebral fractures and that of non-vertebral fractures. Pharmakokinetic(PK)study after a single Teriparatide injection of the daily dose in healthy Japanese postmenopausal women(n=18)revealed very rapid achievement of peak blood level(median of tmax=0.25 hr)followed by fast disappearance from the blood(mean t1/2=0.708 hr, n=17). Consistent with these PK characteristics, a rapid increase in bone formation marker and later increase in bone resorption marker has previously been observed, which was described as a bone anabolic window. More recently, once weekly subcutaneous injection of teriparatide acetate(56.5 μg)has been reported to reduce the risk of new vertebral fractures compared with placebo and has been approved in Japan. PK study after injection of the higher weekly dose in healthy Japanese postmenopausal women(n=10)revealed a relatively slow achievement of the peak blood level(mean tmax=0.875 hr)compared to daily injections, followed by relatively slow disappearance from the blood(mean t1/2=1.295 hr). Consistent with these PK characteristics, an initial(<24 hr)transient decrease of bone formation markers(serum osteocalcin and P1NP)and transient increase of bone resorption markers(serum NTX and urinary CTX)were observed. However, afterword, the bone formation and resorption markers were increased and decreased, respectively, for longer than 1 week from the baseline levels. The relationship of pharmacokinetics, changes of bone turnover markers and BMD/fractures efficacy during daily versus weekly teriparatide treatment needs to be clarified.

The objective of treating osteoporosis is to prevent fractures. Bisphosphonates inhibit bone resorption and increase bone density, thereby suppressing the occurrence of fractures. Bisphosphonates have a high affinity for hydroxyapatite. About 20-80%of bisphosphonates absorbed in vivo is adsorbed onto the bone surface. However, the absorption rates of orally ingested bisphosphonates are less than 1%. Bisphosphonates adhered to the bone surface are specifically incorporated into cells upon bone resorption by osteoclasts. Thus, the cytoskeleton of osteoclasts is destroyed, and apoptosis is induced to suppress bone resorption. This article overviews the mechanisms of action and pharmacokinetics of bisphosphonates.

Continuous exposure to parathyroid hormone (PTH) leads to hypercalcemia and a decrease in bone volume, which is referred to as its catabolic effect, while intermittent exogenously administered PTH leads to an anabolic effect on bone. Intermittent administration of PTH dramatically increases bone remodeling and modeling through their direct and indirect effects on the functional cells of bone remodeling units and their precursors. These effects on bone metabolism differ according to dosing frequency of PTH. Therefore, different dosing frequency of PTH shows different therapeutic effects on bone in terms of bone volume and bone quality in patients with osteoporosis.

Active vitamin D3 is used for the treatment for osteoporosis in Japan. Recently, data have accumulated that collagen cross-link formation in bone affect bone strength. In fact, impaired enzymatic cross-linking, over-hydroxylation of crosslinks, and an increase in non-enzymatic crosslinking advanced glycation end products (AGEs) such as pentosidine, in bone collagen have been proposed as a major cause of bone fragility in osteoporosis. We reported that alfacalcidol and eldecalcitol improves bone material properties such as collagen cross-link formation, microarchitecture, and microcrack resulting in the increase of bone strength (Saito M, Bone 2010;46:1170-1179, Calcif Tissue Int 2011;88:314-324, Bone, 2015;73:8-15). In this review, we described how active vitamin D3 improve bone collagen cross-link formation and mineral qualities.

Bone is constantly remodeled to maintain its volume, structural integrity and strength Currently available bone anabolic agent is teriparatide. Teriparatide increases bone mass and strength via both remodeling-dependent and -independent mechanisms, although remodeling-dependent mechanism overweighs the other. Canonical Wnt signal plays an important role in enhancing osteoblast differentiation and bone formation, and its osteocyte-derived inhibitor, sclerostin, regulates bone formation via the regulation of Wnt signaling. Anti-sclerostin antibody stimulates Wnt signaling and enhances bone formation. Phase II clinical trials with anti-sclerostin antibodies, romosozumab and blosozumab, demonstrated a marked increase in bone mineral density after one year of treatment. The new modality of anabolic agents via remodeling-independent stimulation of bone formation may open up a new avenue for the treatment of osteoporosis.

Vitamin D is a secosteroid, in which the B ring of the steroid structure is ruptured. The active form of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25 (OH) 2D3], regulates numerous physiological and pharmacological processes, including bone and calcium homeostasis, cellular growth and differentiation, immunity, and cardiovascular function, through binding to the vitamin D receptor (VDR), a member of the nuclear receptor superfamily. VDR ligands are promising in the treatment of bone and mineral disorders, cancer, autoimmune disease, and cardiovascular disease. However, the calcemic effect of vitamin D derivatives has limited their clinical application. Recently, nonsecosteroidal VDR modulators (VDRMs) have been developed. Several VDRMs have better therapeutic efficacy when compared to 1,25 (OH) 2D3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia. Analysis of crystal structures reveals that nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25 (OH) 2D3 and that hydrogen bond interactions between ligands and VDR are important for VDR transactivation. Pharmacokinetics of nonsecosteroidal VDRMs may be related to their less calcemic effect. Nonsecosteroidal VDRMs can induce VDR conformation distinct from that by 1,25 (OH) 2D3, likely leading to selective gene expression. Although the potential risk of unexpected adverse effects needs be considered, further development of nonsecosteroidal VDRMs should expand the possibility of VDR-targeted approaches.

Active forms of vitamin D3 have been widely used in the treatment of rickets, osteomalacia, and osteoporosis in order to stimulate bone mineralization and prevent bone loss. Meanwhile, the active form of vitamin D3, 1α, 25-dihydroxyvitamin D3 [1α, 25 (OH) 2D3], upregulates expression of receptor activator of nuclear factor-κB ligand (RANKL) in osteoblastic cells. Osteoclast formation requires RANKL and macrophage colony-stimulating factor (M-CSF), which are expressed in osteoblastic cells. Recently, IL-34 was discovered as a cytokine functionally overlapping M-CSF. We found that administration of 1α, 25 (OH) 2D3 into mice enhanced IL-34 expression in spleen and bone. These results suggest that 1α, 25 (OH) 2D3 is a bone resorption-stimulating factor. However, daily administration of an active vitamin D3 analog (eldecalcitol, an osteoporotic therapeutic drug) for a month suppressed RANKL expression in osteoblasts, resulting in suppression of bone resorption. Here we discuss new findings and hypotheses to explain this contradictory effect of active vitamin D3 on bone remodeling.

It has been revealed that various therapeutic agents for lifestyle-related diseases could affect bone metabolism. For example, thiazolidines, loop diuretics and warfarin would be possibly disadvantageous to bone metabolism. In many cases with lifestyle-related disease, it is necessary to take the medicine over a long term. Therefore, we should pay enough attention to bone metabolism during the selection of medicine, especially in the treatment of a high risk group for bone fracture. However, a majority of these drugs lack the evidence with randomized controlled trials for osteoporotic fracture. Further clinical research should be required to clarify the impact of each drug on osteoporosis with lifestyle-related diseases.

Teriparatide is a peptide with 34 amino acids that corresponds to N-terminal portion of parathyroid hormone (PTH) . Teriparatide is the only anabolic agent currently available and prevent fractures by increasing bone mass and improving bone architecture. PTH and bone turnover are reported to be low in some patients with type 2 diabetes and chronic kidney disease. For these patients, it seems to be theoretically reasonable to use teriparatide. However, it has not been shown that teriparatide is more effective for patients with low bone turnover than other subjects.

Sclerostin, a glycoprotein encoded by SOST gene and secreted from osteocyte, is known as an antagonist for bone formation induced in canonical Wnt/β-catenin signaling pathway by inhibiting receptor complex formation through binding to LDL receptor-related protein 5/6 (LRP 5/6) . From clinical symptoms observed in the patients with a loss-of-function mutation in LRP 6, disorder of that signal transduction pathway is considered as one of candidate molecular mechanism for the simultaneous occurrence of diabetes mellitus and osteoporosis. The serum sclerostin levels of diabetic patients as well as non-diabetic subjects are significantly and positively correlated with bone mineral density, which is the strongest determinant factor especially for diabetic patients. In addition, sclerostin concentrations are associated with prevalent vertebral fractures independent of bone mineral density as well as bone turnover, suggesting that elevated sclerostin levels reflect poor bone quality.

Most of the evidence for osteoporosis treatment comes from that in primary osteoporosis, with very little evidence available for that in secondary osteoporosis including lifestyle-related osteoporosis as a lifestyle-related disease despite the fact that secondary osteoporosis affects more patients than primary osteoporosis. This is in contrast to osteoporosis associated with type 2 diabetes and chronic kidney disease, where accumulating evidence demonstrates that osteoporosis is accounted for by decreases in bone strength associated with deterioration of bone quality due to accumulation of advanced glycation end products (AGEs) in collagen that results from elevated homocysteine and pentosidine levels. In this regard, given the ample evidence for their efficacy against deterioration of bone quality, selective estrogen receptor modulators (SERMs) are currently thought to represent the most efficacious of all available therapeutic agents for lifestyle-related osteoporosis.

A lifestyle-related disease and osteoporosis are diseases to increase with aging and a lifestyle-related disease has an influence on the bone metabolism. Because the number of patients with lifestyle-related disease is getting larger, it is necessary to prevent fracture in those. Unfortunately, substantial randomized control studies are yet to be done in patients with lifestyle-related disease to clarify if anti-osteoporotic drugs are effective to prevent fractures. It is suggested by the subanalysis in the existing clinical study with usefulness of bisphosphonates with evidence as an osteoporotic therapeutic drug in life-related disease. Here I will review about the effective and problem with bisphosphonate for the lifestyle-related disease with arteriosclerosis.

Intermittent PTH administration stimulates bone formation and counteracts the inhibition of bone formation by glucocorticoid excess. We have previously demonstrated that PTH enhances interleukin (IL) -11 gene transcription by a rapid induction of delta-fosB expression and Smad1/5 phosphorylation. On the other hand, glucocorticoid can suppress osteoblast differentiation and enhance apoptosis of osteoblast cells via down-regulation of IL-11 expression. PTH could reverse glucocorticoid-induced these damage of osteoblast via stimulation of IL-11 expression. Our data also suggested that IL-11 mediates stimulatory and inhibitory signals of osteoblast differentiation by affecting Wnt signaling. These data demonstrates that PTH and glucocorticoid may regulate osteoblast differentiation and apoptosis via their effect on IL-11 expression.

Bone fragility is one of the side effects of glucocorticoid (GC) use, even at low doses. An increase in fracture risk due to GC administration occurs immediately after beginning treatment. A number of GC-mediated effects are responsible for bone fragility. We demonstrated that GC administration deteriorates lysyl oxidase mediated collagen crosslink formation acting as a determinant of bone material properties (Saito M, et al., Calcified Tissue Int, 88 ; 314-424, 2011) . We reviewed the mechanism of low bone material quality by GC administration.

Glucocorticoids (GCs) were widely used for the treatment of various disorders. And Osteoporosis is one of the major complications of glucocorticoid therapy. An increased risk of both vertebral and nonvertebral fractures has been reported with dosages of prednisolone or equivalent as low as 2.5-7.5 mg daily. The skeletal effects of glucocorticoids include both direct and indirect actions on bone that result in an early, transient increase in bone resorption accompanied by a decrease in bone formation, which is maintained for the duration of glucocorticoid therapy. Bisphosphonates are the front-line choice for prevention of fracture in glucocorticoid-treated patients and are recommended renewal GIOP guideline from Japan.

Active vitamin D is a second line treatment followed by bisphosphonate in the Japanese guideline of glucocorticoid-induced osteoporosis (GIO) . Although it shows relatively mild but significant effect on BMD and fracture prevention, it is utilized as combination therapy with bisphosphonate. Vitamin D is recommended for GIO with gastrointestinal disease and hepatobiliary disorders. Vitamin D may be the first line treatment for younger GIO patients.

Receptor activator of nuclear factor-κB ligand (RANKL) stimulates osteoclast differentiation and activation via binding to its receptor RANK on the pre-osteoclast cells. RANKL is a transmembrane protein, but soluble form (soluble RANKL ; sRANKL) is also circulating in the blood. The origins of the sRANKL have been thought to be produced by cleavage of membrane RANKL or secreted by T-lymphocytes, however, it is recently reported that osteocytes were one of the major sources of sRANKL. However, the pathophysiological roles of serum sRANKL has not been clarified yet. We prospectively measured serum sRANKL and OPG levels before and after the initiation of glucocorticoid therapy in patients with systemic autoimmune diseases. It was suggested that serum sRANKL might be a useful marker of bone remodeling in these patients under glucocorticoid therapy. This paper reviewed significance of sRANKL measurement in various bone metabolic diseases including glucocorticoid-induced osteoporosis.

The American College of Rheumatology (ACR) developed recommendations for the prevention and treatment of glucocorticoid- induced osteoporosis (GIO) in 1996. As the beneficial effects of bisphosphonates on GIO were reported from 1997 to 1999, guidelines for the management of GIO were also published from the United Kingdom, Canada, and Australia. In Japan, the Japanese Society for Bone and Mineral Research released guidelines on the management and treatment of GIO in 2005. An approach trying to determine the pharmacological intervention threshold based on assessment of the absolute risk of fractures was initiated in the mid-2000s and FRAX®, a WHO-supported, computer-based, fracture risk assessment was published in 2007. Regarding pharmacological intervention, the efficacy of teriparatide for the treatment of GIO was reported from 2007 to 2009. Based on such new evidence regarding GIO, the ACR recommendation was updated to incorporate FRAX® as an assessment tool for fracture risk in the 2010 revision. The Joint GIO Guidelines Working Group of the International Osteoporosis Foundation and the European Calcified Tissue Society has also published a framework for the development of guidelines for the management of GIO.

Steroid-induced osteoporosis is known to remarkably induce bone fragility compared to their reduction of bone mineral density. The effect of glucocorticoid on bone structure appears greater on the trabecular than the cortical bone. Its major change is thinning of the trabeculae, and high dose of glucocorticoid induces the perforation of the trabeculae, which is thought to induce bone fragility. Furthermore, the deterioration of cortical bone, including increased cortical porosity as well as cortical thinning, has been reported to have stronger relationship with the reduction of bone strength than that of trabecular bone.

Glucocorticoid (GC) is widely used to treat a variety of inflammatory and allergic diseases and about one million people in Japan are known to take oral GC. GC causes a number of adverse effects and among them osteoporosis and degenerative bone fracture are major complications of GC therapy. GC induces apoptosis of osteoblasts and osteocytes and prolongs lifespan of osteoclast, resulting in low bone mass and microarchitectural deterioration of bone tissue, which leads to severe osteoporosis, increased bone fragility and susceptibility to bone fracture. Although GC-induced osteoporosis is the most common iatrogenic osteoporosis, few physicians fully manage it. Physicians who prescribe GC have to manage patients according to guidelines on the management and treatment of GC-induced osteoporosis, because recent multiple evidences strongly indicate that certain medication such as bisphosphonates is effective for treatment and prophylaxis of GC-induced osteoporosis.

Accumulating evidence indicates that several drugs for lifestyle-related diseases are involved in bone metabolism. Drugs that might reduce fracture incidence are statins, β-blockers and thiazide diuretics, and those that might increase fractures are thiazolidinediones and loop diuretics. It is yet controversial whether ACE inhibitors, angiotensin receptor- II blockers and aldosterone receptor antagonists in addition to incretin-related drugs are indeed involved in the increase or the decrease in fracture incidence.

Hypophosphatasia is caused by abnormal tissue-nonspecific alkaline phosphatase (ALP), leading to impaired calcification in bone. Patients with severe hypophosphatasia have difficulties in respiratory function from early days after birth and the rate of lethality is extremely high. Enzyme replacement therapy using bone-targeting recombinant ALP, which has 10 aspartic acids in the C-terminal tail has developed. The efficacy of ERT was firstly observed in model mice of hypophosphatasia. In clinical trial including perinatal and infantile types of hypophosphatasia, efficacy and safety have been reported. Expanded clinical trial is underway and the results of the clinical trial might be reported by the end of the next year.

This is the brief report on basic research at ASBMR 2013 held in Baltimore, MD, USA. I focused on the research about osteoarthritis and skeletal development and introduce a part of current topics referring to past reports.

This is a short report summarizing topics in 35(th) Annual meeting of ASBMR held at convention center in Baltimore on October 4-7(th). In this paper, I report some topics from the presentations of basic or clinical research in ASBMR 2013.

ASBMR2013 was held in Baltimore, MA, in October, 2013. Selected topics especially those on Wnt system will be reviewed.

The feature of atypical femoral fracture is stress induced cortical bone reaction. It was considered to be the accumulation of microdamage which come from increasing of mechanical stress by femoral lateral bowing, and the decreased of ability of microdamage repair system.

The incidence of non-vertebral fracture increases in old age, and the deterioration of cortical micro-structure is considered to be one of important reason to cause non-vertebral fracture. In this chapter, the age-related change of cortical microstructure, relationship with bone strength are discussed as well as the effect of anti-osteoporotic drugs on cortical bone ; bisphosphonate, teriparatide, active vitamin D3, and denosumab.

Recent progress in understanding molecular processes underlying osteoporosis has resulted in the development of several new anti-osteoporotic agents that are currently being explored in clinical trials. Denosumab, a monoclonal antibody directed against RANKL, has just approved in Japan and some additional new therapies are lining up for clinical approval in the coming years. Potential agents include cathepsin K inhibitor and sclerostin. Here, I will provide a short overview on these three agents focusing on their effect on structural properties and bone strength.

Osteoporotic drugs improve bone mechanical integrity by increasing bone mass and also by improving bone structure and quality, where controlling bone metabolism. Changes in trabecular microstructure can be detected since early period after starting drug treatment. Effects on bone metabolism of anti-resorptive agent of bisphosphonates are totally opposite from those of anabolic agent of teriparatide, however these different drug treatments results in the improvement of trabecular microstructure as well.

The changes in bone geometric parameters (hip structure analysis, HSA) by medication are reviewed. HSA parameters are strongly correlated with CT parameters. Raloxifene, bisphosphonate (alendronate, risedronate, minodronate) , and denosumab improved section modulus (index for bending force) more than bone mineral density, and the improvements in section modulus are superior in intertrochanter than in femoral neck. The tendency to change in femoral shaft is approximately similar in femoral neck and intertrochanter. On the other hand, the tendency to change in these parameters in teriparatide (20μg/day) is different from raloxifene, bisphosphonate, and denosumab. Teriparatide improved section modulus and bone mineral density in femoral neck and intertrochanter, but the improvement in section modulus was approximately similar in bone mineral density and the improvement in intertrochanter is not higher than femoral neck. The femoral shaft did not show significant change.

Intermittent administration of parathyroid hormone, PTH, appears to promote preosteoblastic proliferation and osteoblastic bone formation, giving rise to anabolic effect in bone. We investigated the behavior of osteoblastic cells after intermittent PTH treatment and attempted to elucidate the role of osteoclasts on the mediation of PTH-driven bone anabolism. As a consequence, bone formation was increased in PTH-treated wild-type mice, whereas in the osteoclast-deficient c-fos - / - mice, there was no significant increase in bone formation, despite the highly-increased population of preosteoblasts. It seems likely that the absence of osteoclasts might hinder PTH-driven bone anabolism, and also that osteoclastic presence may be necessary for full osteoblastic differentiation and enhanced bone formation seen after intermittent PTH administration. We will also discuss the pivotal role of osteocytes in PTH-mediated anabolic effect.

Glucocorticoid (GC) is widely used to treat a variety of inflammatory and allergic diseases and about one million people in Japan are known to take oral GC. GC causes a number of significant side effects and among them osteoporosis and degenerative bone fracture are major complications of GC therapy. GC induces apoptosis of osteoblasts and osteocytes and prolongs lifespan of osteoclast, resulting in severe osteoporosis. However, few physicians are aware of the increased risk of fracture caused by GC. Recent multiple evidence strongly indicates that bisphosphonate is effective for treatment and prophylaxis of GC-induced osteoporosis by improving both quantity and quality of bones, which results in reduction of the proportion of fractures. Recent findings regarding with anti-RANKL antibody and PTH (1-34) teriparatide for GC-induced osteoporosis will be also discussed.

Recently, atypical femoral fracture has emerged as potential complication of long-term bisphosphonate therapy. Before considering the potential harmful effects of oversupression of bone turnover, it has been supposed that suppressed bone turnover in postmenopausal skeleton has well documented beneficial effects on bone strength and fracture risk. However, the benefit of long-term use of bisphosphonate for the prevention of femoral fractures seems to be lower than previously speculated. There are several factors by which severely suppressed bone turnover may reduce bone mechanical properties. These include increased mineralization of bone and increased homogeneity of mineralization, changes in collagen cross linking and accumulation of bone microdamage.

Bisphosphonates such as alendronate and risedronate effectively reduce hip fracture risk, and thus are suitable for the elderly people in whom this fracture is most likely to happen. Bisphophonates should be administered when patients meet the guideline made by Japanese bone society, which picks up prevalent fractures, low bone mineral density, and established risk factors as features for starting osteoporosis treatment. Long-term alendronate administration may inhibit normal repair of microdamage arising from severe suppression of bone turnover (SSBT), which, in turn, results in accumulation of microdamage. This process would lead to brittle bone and the occurrence of unexpected stress fractures, characteristically at the subtrochanter of femur. A large-scale study suggests that for more women, discontinuation of alendronate after 5 years for up to 5 more years does not significantly increase fracture risk. Thus, alendronate treatment might be stopped for a while after 5 years to prevent SSBT and subsequent stress fractures.

It is unknown about beneficial or harmful effects of calcimimetic, which is a selective, allosteric agonist for calcium sensing receptor (CaSR) , on various organs, excluding parathyroid gland. While the distribution of CaSR is broad, in addition to hypocalcemia-induced symptoms, either nausea or vomiting is the only adverse symptoms by calcimimetics. In this review, the mechanism of nausea or vomiting, as well as the beneficial or harmful effects upon some organs (e.g. bone, kidney and vessel) , are extrapolated.