miR-101-3p/Rap1b signal pathway plays a key role in osteoclast differentiation after treatment with bisphosphonates

( Jie Li ),( You Li ),( Shengjie Wang ),( Hui Che ),( Jun Wu ),( Yongxin Ren ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.9

Bisphosphonates are the mainstay of therapy worldwide for osteoporosis. However, bisphosphonates also have limitations. The objective of this study was to determine the role of miR-101-3p/Rap1b signal pathway in osteoclast differentiation after treatment with bisphosphonates. Our results revealed that miR-101-3p was an important regulator in bisphosphonates treated-osteoclasts. When miR-101-3p was down-regulated in bone marrow-derived macrophage-like cells (BMMs), the development of mature osteoclasts was promoted, and vice versa. However, alendronate decreased multinucleated cell number regardless of whether miR-101-3p was knocked down or over-expressed. TRAP activity assay confirmed the above results. Luciferase assay indicated that miR-101-3p was a negative regulator of Rap1b. Western blot analysis revealed that protein expression level of Rap1b in BMMs transfected with OV-miR-101-3p was lower than that in BMMs transfected with an empty vector. Rap1b overexpression increased TRAP-positive multinucleated cells, while Rap1b inhibition decreased the cell numbers. In vivo data showed that miR-101-3p inhibited osteoclast differentiation in ovariectomized mice while overexpressed of Rap1b blocked the differentiation. Taken together, our data demonstrate that miR-101-3p/Rap1b signal pathway plays a key role in osteoclast differentiation after treatment with bisphosphonates. [BMB Reports 2019; 52(9): 572-576]

The Effects of Low-Dose Bisphosphonate Treatment on Bone Mineral Density and Bone Turnover Markers in Elderly Patients With Osteoporosis

이서영,김경민,공성혜,오태정,문재훈,최성희,임수,장학철 대한노인병학회 2016 Annals of geriatric medicine and research Vol.20 No.3

Background: Osteoporosis is commonly treated with bisphosphonates. These drugs promote osteoclast apoptosis, which suppresses bone resorption. However, the probability of side effects increases with long-term use of bisphosphonates. There are several reports in Asia that show comparable effects between low and conventional doses of bisphosphonates; however, such reports are lacking in Korea. Here, we report a case series of 7 patients with osteoporosis —all women aged over 70 years — who were treated with bisphosphonates administered every other week. Methods: Patients who had been diagnosed with osteoporosis and treated with a less frequent dose of bisphosphonates at a tertiary university hospital from January 2010 to May 2016 were included in this study. Bone mineral density (BMD) was assessed at the baseline and at a 12-month interval after the first administration of low-dose bisphosphonates by using dual-energy X-ray absorptiometry. The bone turnover marker C-terminal telopeptide (CTX) was evaluated at 3, 6, and 12 months after the first administration. Results: After 12 months of treatment with a lower dose of bisphosphonates, BMD increased and CTX levels were suppressed. The mean change in BMD was 4.0% at the lumbar spine, 3.1% at the femur neck, and 1.5% at the total hip; CTX was suppressed by 34% at 3 months, 42% at 6 months, and 44% at the end of the treatment. Conclusion: We found that low-dose bisphosphonate therapy improved BMD and suppressed bone turnover rates in elderly Korean women.

비스포스포네이트 관련 악골괴사의 진단 및 치료에 대한 임상적 연구

김경욱(Kyung-Wook Kim),김범진(Beom-Jin Kim),이충현(Chung-Hyun Lee) 대한구강악안면외과학회 2011 대한구강악안면외과학회지 Vol.37 No.1

Introduction: Bisphosphonates is used widely for the treatment of the Paget’s disease, multiple myeloma, bone metastases of malignant tumors with the prevention of pain and their pathological fracture. However, it was recently suggested that bisphosphonates related osteonecrosis of the jaw (BRONJ) is a side effect of bisphosphonate use. Materials and Methods: Twenty-four individuals, who were referred to the Department of Oral and Maxillofacial surgery, Dankook University Dental Hospital, were selected from those who had exposed bone associated with bisphosphonates from January, 2005 to December, 2009 according to the criteria of American Association of Oral and Maxillofacial Surgeons (AAOMS) for BRONJ. The patients group consisted of 7 males and 17 females between the age of 46 to 78 years (average 61.8 years). Each patient had panoramic imaging, computed tomography (CT), whole body bone scanning performed for a diagnosis and biopsy sampling from the necrotizing tissue. C-terminal cross-linking telopeptide of type I collagen (CTX) level of patients who had undergone surgical intervention was measured 7 days before surgery. Results: The main cause of bone exposure was post-extraction (15), chronic periodontitis (4), persistent irritation of the denture (3). Twenty people had undergone BRONJ treatment for two to eight months except for 4 people who had to maintain the bisphosphonates treatment to prevent a metastasis and bone trabecular pain with medical treatment. When the bisphosphonate treatment was suspended at least for 3 months and followed up according to the AAOMS protocols, the exposed necrotizing bones were found to be covered by soft tissue. Conclusion: Prevention therapy, interruption of bisphophonates for at least 3 months and cooperation with the physician for conservative treatment are the essential for treating BRONJ patient with high risk factors. The CTX level of BRONJ patients should be checked before undergoing surgical intervention. Surgical treatments should be delayed in the case of a CTX level <150 pg/mL.

Altered VEGF Regulation in Ovariectomized Rat Alveolar Bone Sockets by Bisphosphonate

Dong-Wook Yang,Geum-Dong Han,Sun-Hun Kim 대한구강해부학회 2018 대한구강해부학회지 Vol.39 No.1

Bisphosphonates reduce bone loss by suppressing osteoclast activity and are currently used for the treatment of osteoporosis. As a side effect of bisphosphonates treatment, the emergence of osteonecrosis of the jaw (ONJ) has stimulated interest in elucidating how bisphosphonates affect the bone, but far less understanding exists as to the ONJ mechanism. In the present study, it was hypothesized that bisphosphonates may affect the healing of the alveolar socket by altering VEFG regulation. In vivo osteoporosis rat models were made by bilateral surgical ovariectomy. Pamidronate (3.5 mg/kg/wk) was IP injected for 8 wks and the maxillary 1st molars were bilaterally extracted. For in vitro test, periodontal ligament cells were treated with pamidronate. Unexpectedly, VEFG-A and -B mRNA and protein levels were increased in in vivo and in vitro by the high concentration treatment of bisphosphonates. However, VEGF-C level was not changed. In the socket at day 7 after the molar extraction, the socket was filled with infiltration of neutrophils which showed strong immunoreactivity against VEGF. VEGF-B mRNA was in particular upregulated by the pamidronate treatment. This result suggest that high dose pamidronate may alter VEGF expression that may serve as another mechanism of ONJ.

Bisphosphonate’s and Intermittent Parathyroid Hormone’s Effect on Human Spinal Fusion: A Systematic Review of the Literature

Michael A. Stone,Andre M. Jakoi,Justin A. Iorio,Martin H. Pham,Neil N. Patel,Patrick C. Hsieh,John C. Liu,Frank L. Acosta,Raymond Hah,Jeffrey C. Wang 대한척추외과학회 2017 Asian Spine Journal Vol.11 No.3

There has been a conscious effort to address osteoporosis in the aging population. As bisphosphonate and intermittent parathyroid hormone (PTH) therapy become more widely prescribed to treat osteoporosis, it is important to understand their effects on other physiologic processes, particularly the impact on spinal fusion. Despite early animal model studies and more recent clinical studies, the impact of these medications on spinal fusion is not fully understood. Previous animal studies suggest that bisphosphonate therapy resulted in inhibition of fusion mass with impeded maturity and an unknown effect on biomechanical strength. Prior animal studies demonstrate an improved fusion rate and fusion mass microstructure with the use of intermittent PTH. The purpose of this study was to determine if bisphosphonates and intermittent PTH treatment have impact on human spinal fusion. A systematic review of the literature published between 1980 and 2015 was conducted using major electronic databases. Studies reporting outcomes of human subjects undergoing 1, 2, or 3-level spinal fusion while receiving bisphosphonates and/or intermittent PTH treatment were included. The results of relevant human studies were analyzed for consensus on the effects of these medications in regards to spinal fusion. There were nine human studies evaluating the impact of these medications on spinal fusion. Improved fusion rates were noted in patients receiving bisphosphonates compared to control groups, and greater fusion rates in patients receiving PTH compared to control groups. Prior studies involving animal models found an improved fusion rate and fusion mass microstructure with the use of intermittent PTH. No significant complications were demonstrated in any study included in the analysis. Bisphosphonate use in humans may not be a deterrent to spinal fusion. Intermittent parathyroid use has shown early promise to increase fusion mass in both animal and human studies but further studies are needed to support routine use.

Physicians’ Attitudes on Management of Osteopenia in South Korea

Joo Hyung Ha,Hong Seok Kim,Samuel Jaeyoon Won,이영균,구경회 대한골대사학회 2020 대한골대사학회지 Vol.27 No.3

Background: Osteopenia patients have a risk of fracture and may develop osteoporosis. We investigated physicians’ management of osteopenia patients in South Korea. Methods: A survey was conducted using a questionnaire including 6 items: (1) do you think anti-osteoporosis medications are necessary in osteopenia patients?; (2) what is your preference to manage osteopenia patients, except for anti-osteoporosis medications?; (3) what is your indication for the anti-osteoporosis medication in osteopenia patients?; (4) what kind of anti-osteoporosis medication do you prefer to treat osteopenia patients?; (5) do you use bisphosphonates?; and (6) if not, what is the reason for not using?. Results: Among the 173 participants, 150 (86.7%) replied that anti-osteoporosis medications were necessary in osteopenia patients. Indications for the medication were (1) past medical history of pathologic fracture in 85 (49.1%); (2) T-score <-2.5 on dual energy X-ray absorptiometry in 73 (42.2%); (3) previous history of osteoporosis in 44 (25.4%); (4) risk of fracture according to fracture risk assessment tool in 34 (19.7%); and (5) progressive bone loss in 31 (17.9%). One hundred and sixteen (67.1%) favored bisphosphonates, 93 (53.8%) selective estrogen-receptor modulator, and 24 (13.9%) hormone replacement therapy. Thirty-one (17.9%) replied that they do not use bisphosphonates due to (1) restricted reimbursement by the health insurance in 24 (77.4%); and (2) bisphosphonate-related complications in 19 (61.3%). Conclusions: Most respondents (86.7%) thought anti-osteoporosis medications were necessary in osteopenia patients, but 17.9% of the respondents did not use bisphosphonates. Restricted reimbursement by the national health insurance was the major obstacle against the use of bisphosphonates.

Bisphosphonates for Osteoporosis in Nonmetastatic Prostate Cancer Patients Receiving Androgen-deprivation Therapy: A Systematic Review and Meta-analysis

Ding, Hui,Yang, Li,Du, Wan,Teng, Yang,Fu, Sheng-Jun,Tao, Yan,Lu, Jian-Zhong,Wang, Zhi-Ping Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.5

This systematic review was conducted to assess the efficacy and safety of bisphosphonates for prevention and treatment of osteopenia or osteoporosis in men with non-metastatic prostate cancer receiving androgendeprivation therapy. We searched for randomised controlled trials (RCTs) of bisphosphonates compared with placebo from Pubmed, Embase, the Cochrane Library, and ISI - Science Citation Index. Meta-analyses of prespecified outcomes (bone mineral density, fractures, and adverse events) were performed using Review Manager. Ten RCTs with a total patient population of 1,017 were identified. There was generally more improvement in bone mineral density of the lumbar spine for patients who received bisphosphonate treatment than placebo or other medical treatment at 12 months (WMD 6.02,95%CI 5.39 to 6.65). Similar effects were also observed for total hip, trochanter or femoral neck bone mineral density. However, there was no significant reduction in fractures. Fever and gastrointestinal symptoms were the most common adverse events (10.4% vs. 1.2%; 0.10% vs. 0.03%). Currently, our meta-analysis suggested that oral and intravenous bisphosphonates caused a rapid increase in spine and hip or femoral BMD in non-metastatic prostate cancer patients receiving androgen-deprivation therapy. Fever and gastrointestinal symptoms were common with the use of bisphosphonates. These short-term trials (maximum of 12 months) did not show fracture reduction. In future, more efficient performance of higher quality, more rigorous, large sample, long-term randomised controlled trials (>12 months) are needed where outcomes are detailed.

Development of animal model for Bisphosphonates-related osteonecrosis of the jaw (BRONJ)

Jang, Hyo-Won,Kim, Jin-Woo,Cha, In-Ho Korean Association of Maxillofacial Plastic and Re 2015 Maxillofacial Plastic Reconstructive Surgery Vol.37 No.-

Background: The aim of this study is to develop a rat model of bisphosphonates-related osteonecrosis of the jaw (BRONJ) that would be verified with clinical, radiological and histological examination, and to confirm the influence of concurrent bisphosphonates and steroids use upon the occurrence and aggravation of BRONJ. Methods: Twenty seven rats were divided into 3 groups; Saline group (I), Zoledronate group (II), Zoledronate and Dexamethasone group (III). Rats got weekly intraperitoneal injection for 4 times and extraction of left maxillary and mandibular 1st, 2nd molars were followed. Consecutive injections were performed, and blood sampling for measurements of C-terminal crosslinked telopeptide of type I collagen and tartrate-resistant acid phosphate 5b rats were performed at the time of 2, 4 and 8 weeks. And then, rats were sacrificed and evaluated clinically, radiologically and histologically. Results: 12/18 (66.6 %) of experimental group were diagnosed as BRONJ. There was no significant difference in incidence between zoledronate alone group (ll) and concurrent use of zoledronate and dexamethasone group (lll). Conclusions: Concurrent use of bisphosphonates and steroids increase incidence of BRONJ compared to saline group (l). Zoledronate alone group (ll) and concurrent use of zoledronate and dexamethasone group (lll) shows same incidence of BRONJ. Based on this study, the rat treated with bisphosphonates and steroids can be considered a novel, reliable and reproducible model to understand pathology of BRONJ.

Review on the comparison of effectiveness between denosumab and bisphosphonates in post-menopausal osteoporosis

Biju Benjamin,Mridula Ambwani Benjamin,Myint Swe,Sandheep Sugathan 대한골다공증학회 2016 Osteoporosis and Sarcopenia Vol.2 No.2

Objective: Osteoporosis is a rapidly rising cause of concern for elderly patients. Various classes of drugs are available in the market. Bisphosphonates are considered as a first-line therapy for the prevention and treatment. Denosumab is an antiresorptive agent which is a RANK ligand inhibitor. There is a scarcity of comparison between these two classes of drugs. The aim of this study is to compare efficacy of Bisphosphonates and Denosumab in various parameters. Materials and methods: Literature search was done for randomized controlled trials (RCTs) comparing bisphosphonates with denosumab. RCTs with a treatment period of at least one year with a baseline bone mineral density (BMD) and bone turnover markers (BTM) and follow up values at one year were included in the study. All included studies were also analysed for complications. The study has also been registered in PROSPERO International prospective register of systematic reviews. Results: A total of five RCTs were identified providing data on 3751 participants. In all five studies, the BMD changes at both hip and spine were statistically significant in favour of denosumab. Result was similar in three studies that studied BMD changes at the wrist. Denosumab also produced significant reduction in BTM as early as one month, but at one year there was no difference compared to the bisphosphonates. There was no statistically significant differences in the complication rates. Conclusion: Though both bisphosphonates and denosumab were effective with similar side effects, the latter was statistically superior in increasing the BMD and reducing the BTM. © 2016 The Korean Society of Osteoporosis. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Can denosumab be a substitute, competitor, or complement to bisphosphonates?

( Su Young Kim ),( Hwoe Gyeong Ok ),( Christof Birkenmaier ),( Kyung Hoon Kim ) 대한통증학회 2017 The Korean Journal of Pain Vol.30 No.2

Osteoblasts, originating from mesenchymal cells, make the receptor activator of the nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in order to control differentiation of activated osteoclasts, originating from hematopoietic stem cells. When the RANKL binds to the RANK of the pre-osteoclasts or mature osteoclasts, bone resorption increases. On the contrary, when OPG binds to the RANK, bone resorption decreases. Denosumab (AMG 162), like OPG (a decoy receptor), binds to the RANKL, and reduces binding between the RANK and the RANKL resulting in inhibition of osteoclastogenesis and reduction of bone resorption. Bisphosphonates (BPs), which bind to the bone mineral and occupy the site of resorption performed by activated osteoclasts, are still the drugs of choice to prevent and treat osteoporosis. The merits of denosumab are reversibility targeting the RANKL, lack of adverse gastrointestinal events, improved adherence due to convenient biannual subcutaneous administration, and potential use with impaired renal function. The known adverse reactions are musculoskeletal pain, increased infections with adverse dermatologic reactions, osteonecrosis of the jaw, hypersensitivity reaction, and hypocalcemia. Treatment with 60 mg of denosumab reduces the bone resorption marker, serum type 1 C-telopeptide, by 3 days, with maximum reduction occurring by 1 month. The mean time to maximum denosumab concentration is 10 days with a mean half-life of 25.4 days. In conclusion, the convenient biannual subcutaneous administration of 60 mg of denosumab can be considered as a first-line treatment for osteoporosis in cases of low compliance with BPs due to gastrointestinal trouble and impaired renal function. (Korean J Pain 2017; 30: 86-92)