Bisphosphonates (BPs) are chemically characterized by a P-C-P bond with two lateral side chains on the carbon atom, and have been widely used as anti-resorptive agents in various metabolic bone diseases. 4-[(methylthio) phenylthio] methanebisphosphonate (MPMBP) is a novel non-nitrogen-containing BP with an antioxidant side chain that possesses anti-inflammatory properties. Since inflammation is known to be a cause of the pathological bone resorption, we investigated the effects of MPMBP on bone metabolism both in vitro and in vivo. The results showed that: i) MPMBP dose-dependently increased alkaline-phosphatase activity in a culture of osteoblastic MC3T3-E1 cells, ii) MPMBP increased the synthesis of collagen (type-I) in an organ culture of mouse calvaria, iii) local injection of MPMBP to alveolar bone induced prominent increases in both the bone mass and thickness of alveolar bone at the local site of injection in rabbits, iv) MPMBP increased the mRNA expression of alkaline-phosphatase, type-I collagen, osteocalcin, and bone sialoprotein in MC3T3-E1 cells, v) MPMBP inhibited the translocation of NF-κB/p65 to the nuclei in osteoblasts of cultured mouse calvaria. Taken together, these findings suggest that MPMBP is a promising agent to prevent bone loss, or even accelerate new bone formation, through inducing an uncoupling between bone resorption and bone formation, which is preferable to maintain bone mass and quality.
Discovery of RANKL (receptor activator of NF-κB ligand) gave a great impact on identification of the mechanisms regulating osteoclast differentiation and function, establishment of research field bridging bone and mineral research and immunology (osteoimmunology), and development of a fully human anti-RANKL monoclonal neutralizing antibody (denosumab). Denosumab has been clinically available for treatment of osteoporosis and cancer-induced bone diseases in the US, Europe and many countries including Japan. Denosumab is a so-called blockbuster of which sales amount was 3.9 billion US dollars in 2017. Because RANKL is the absolute factor for osteoclast differentiation, anti-RANKL antibody is very effective and its application is good news for many patients. Recent topics are the identification of importance of RANKL on osteoblasts in regulation of osteogenesis and the demonstration of RANKL-RANK (the receptor of RANKL) dual signaling in coupling between bone resorption and bone formation. RANKL reverse signaling that we had hypothesized was demonstrated at last. In this review I describe the mechanism of anti-RANKL antibody in the treatment of metabolic bone diseases including osteoporosis. I also suggest possible applications of anti-RANKL antibody to the treatment of cancer patients.
Intermittent administration of human parathyroid hormone (PTH) [1-34], or teriparatide, has been used for osteoporotic treatment, which is available for daily and weekly administration for the osteoporotic patients in Japan, increasing bone mass and reduce bone fracture risk. In general, continuous PTH infusion shows catabolic effects in bone, while the intermittent administration of PTH results in anabolic action in osteoporotic patients. Intermittent PTH administration promotes preosteoblastic proliferation, as well as stimulates osteoblastic bone formation dependent on cell coupling with osteoclasts. Dosing frequency of PTH administration may affect resultant bone mass, and therefore, we have examined the anabolic effects of the high and low frequency of PTH administration using a mouse model. As a consequence, the high frequency of PTH administration accelerated the preosteoblastic proliferation with forming thick preosteoblastic network, osteoclastogenesis inside the preosteoblastic network, as well as osteoblastic bone formation. In contrast, the low frequency of PTH administration promoted osteoblastic bone formation, but, did not stimulate preosteoblastic proliferation and osteoclastogenesis. In addition, the high or low frequency of PTH administration demonstrated bone formation by manners of accelerated bone remodeling or bone remodeling/mini-modeling, respectively. Thus, the different dosing frequency of PTH administration may induce the different cellular mechanism of anabolic effects in bone.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ), which is characterized by refractory bone exposure, has recently emerged as a serious side effect of bisphosphonate (BP) treatment. BRONJ was first thought to be due to administration of high doses of intravenous BP to treat metastatic bone lesions or multiple myeloma. However, more recent studies have indicated that BRONJ also frequently occurs in patients receiving low doses of BP for the treatment of osteoporosis. In addition, patients treated with denosumab, a human monoclonal antibody against receptor activator of nuclear factor-kappa B ligand (RANKL) whose antiresorptive effects differ from those of BP, may develop osteonecrosis of the jaw. Since both BP and denosumab are associated with osteonecrosis of the jaw (ONJ), antiresorptive agent-related ONJ (ARONJ) has been suggested as a comprehensive term. Although the pathophysiology of BRONJ remains unclear and the number of affected patients is increasing in Japan, significant improvements have been made with respect to risk reduction strategies and treatment. Despite the publication of the first position paper on BRONJ in Japan in 2010, an increase of the number of patients of BRONJ is hypothesized to result from an increase in the long-term use of BP. Previous findings have suggested that inadequate preventive measures including restriction of tooth extraction may be responsible for increases in BRONJ incidence.
The drug discovery activities for novel compounds with the superior efficacies to current drugs have been largely unsuccessful in the psychiatric field. One of the main reasons is the lack of appropriate behavioral assays and animal models for psychiatric disorders. Since the prefrontal cortex has great roles in their pathophysiology, non-human primate common marmosets with the well-developed prefrontal cortex would be useful as experimental animals in the future translational research. To measure objectively and quantitatively the psychiatric symptoms like motivational deficits, negative affective bias and cognitive impairments in patients with schizophrenia or major depressive disorder, the clinical laboratory tasks have been developed. The development of marmoset behavioral paradigms, which may correspond to the clinical laboratory tasks, have been progressed for the translational research. On the other hand, there are still limitations to develop the marmoset models resembling the pathophysiology of psychiatric disorders. We review the current state and future perspective of translational behavioral research using marmosets.
Herpes zoster is a viral infectious disease caused by reactivation of varicella zoster virus (VZV) in a latently infected ganglion, and is characterized by blistering and pain developing in a zonal region innervated from the ganglion. Amenamevir is an antiherpes agent that does not have a nucleic acid-like structure, and exerts antiviral action by inhibiting the enzymatic activity of a virus-derived helicase-primase complex, which is considered essential for viral DNA replication. Amenamevir is mainly metabolized by CYP3A, and excreted into feces. In in vitro antiviral testing, amenamevir demonstrated higher antiviral activity against ZV than aciclovir, and its antiviral activity did not diminish even against acyclovir-resistant VZV. In a phase III clinical study in patients with herpes zoster in Japan, cessation of new rash formation by the 4th day of administration, the primary endpoint of the study, was observed in 81.1% of the patients given oral administration of amenamevir 400 mg once daily after meal, verifying its non-inferiority to valaciclovir hydrochloride (P<0.0001 by non-inferiority test using Farrington-Manning test extended to Mantel-Haenszel type adjustment). Adverse reactions were observed in 10.0% (25/249 patients), and were mainly abnormal clinical laboratory tests results. Based on the above results, the efficacy and safety of amenamevir tablet 400 mg once daily administration in herpes zoster treatment have been confirmed, and amenamevir can be a novel treatment option in Japan.