The role of i.v. ibandronate administration in osteoporosis therapy

Osteoporosis is a chronic disease of the osseous system characterised by decreased strength of bone tissue, which in turn leads to increased fracture risk. It has been demonstrated that osteoporosis affects more than 30% of women after the menopause (World Health Organization, 1994). However, the disease is also observed in men. The primary goals of osteoporosis therapy include prevention of low-energy fractures and general improvement of quality of life. Any patient with diagnosed osteoporosis requires, besides prevention, the application of proper treatment. Of the available therapeutic options, the best are bisphosphonates, medical agents with well identified properties, therapeutic efficacy, and safety which has been confirmed in many clinical studies. Therefore, they are recommended as first line drugs for osteoporosis. The efficacy of oral preparations may be limited, due to low bioavailability, complications and adverse effects from the gastrointestinal tract. So the parenteral administration of bisphosphonates is a valuable alternative. A fine example of such therapy is the intravenous administration of ibandronate. Short injection time periods and the relatively long, three-month intervals between administrations are unquestionable advantages of this therapy mode. In addition, the therapy does not constrain a patient's everyday activity, and simultaneously provides regular contact with doctors and the therapeutic centre. Additionally, a good tolerance of the drug and its high therapeutic efficacy, proven by appreciably reduced fracture risks, significantly improves the quality of life of patients suffering from osteoporosis. This paper is a thorough review of current knowledge on the efficacy and safety of i.v. ibandronate in osteoporosis therapy, as presented in the latest literature reports.     

Management of osteoporosis

Osteoporosis or osteopenia occurs in about 44 million Americans, resulting in 1.5 million fragility fractures per year. The consequences of these fractures include pain, disability, depression, loss of independence, and increased mortality. The burden to the healthcare system, in terms of cost and resources, is tremendous, with an estimated direct annual USA healthcare expenditure of about $17 billion. With longer life expectancy and the aging of the baby-boomer generation, the number of men and women with osteoporosis or low bone density is expected to rise to over 61 million by 2020. Osteoporosis is a silent disease that causes no symptoms until a fracture occurs. Any fragility fracture greatly increases the risk of future fractures. Most patients with osteoporosis are not being diagnosed or treated. Even those with previous fractures, who are at extremely high risk of future fractures, are often not being treated. It is preferable to diagnose osteoporosis by bone density testing of high risk individuals before the first fracture occurs. If osteoporosis or low bone density is identified, evaluation for contributing factors should be considered. Patients on long-term glucocorticoid therapy are at especially high risk for developing osteoporosis, and may sustain fractures at a lower bone density than those not taking glucocorticoids. All patients should be counseled on the importance of regular weight-bearing exercise and adequate daily intake of calcium and vitamin D. Exposure to medications that cause drowsiness or hypotension should be minimized. Non-pharmacologic therapy to reduce the non-skeletal risk factors for fracture should be considered. These include fall prevention through balance training and muscle strengthening, removal of fall hazards at home, and wearing hip protectors if the risk of falling remains high. Pharmacologic therapy can stabilize or increase bone density in most patients, and reduce fracture risk by about 50%. By selecting high risk patients for bone density testing it is possible to diagnose this disease before the first fracture occurs, and initiate appropriate treatment to reduce the risk of future fractures.     

The role of i.v. ibandronate administration in osteoporosis therapy

Osteoporosis is a chronic disease of the osseous system characterised by decreased strength of bone tissue, which in turn leads to increased fracture risk. It has been demonstrated that osteoporosis affects more than 30% of women after the menopause (WHO, 1994). However, the disease is also observed in men. The primary goals of osteoporosis therapy include prevention of low-energy fractures and general improvement of quality of life. Any patient with diagnosed osteoporosis requires, besides prevention, the application of proper treatment. Of the available therapeutic options, the best are bisphosphonates, medical agents with well identified properties, therapeutic efficacy, and safety which has been confirmed in many clinical studies. Therefore, they are recommended as first line drugs for osteoporosis. The efficacy of oral preparations may be limited, due to low bioavailability, complications and adverse effects from the gastrointestinal tract. So the parenteral administration of bisphosphonates is a valuable alternative. A fine example of such therapy is the intravenous administration of ibandronate. Short injection time periods and the relatively long, three-month intervals between administrations are unquestionable advantages of this therapy mode. In addition, the therapy does not constrain a patient's everyday activity, and simultaneously provides regular contact with doctors and the therapeutic centre. Additionally, a good tolerance of the drug and its high therapeutic efficacy, proven by appreciably reduced fracture risks, significantly improves the quality of life of patients suffering from osteoporosis. This paper is a thorough review of current knowledge on the efficacy and safety of i.v. ibandronate in osteoporosis therapy, as presented in the latest literature reports.     

Prospect of mesenchymal stem cells in therapy of osteoporosis: A review

Osteoporosis is a systemic skeletal disease associated with reduced bone strong point that results in raised fracture risk, with decreased bone strength, leading to reduced bone mineral density and poor bone quality. It is the most common in older females but some men are also at high risk. Although considered as a predictable result of aging, it is can be avoidable and treatable. The existing treatment of osteoporosis mainly contains antiresorptive and anabolic agents. In spite of these improvements, concerns around unusual side-effects of antiresorptive drugs, and the lack of perfect confirmation in maintenance of their long-standing effectiveness is bring about many patients not receiving these drugs. Over the years, the stem cell-based therapy has attained substantial clinical consideration because of its potential to treat numerous diseases. The stem cell therapy has been recommended as a probable therapeutic approach for patients with osteoporosis. Even though the concept of stem cell-based therapy for osteoporosis has caught substantial attention, no clinical trial has been published on humans. The cell studies based on osteoporosis are primarily focused on osteoclastic activity and bone resorption procedures. Earlier, it was on osteoblastogenesis and in recent times, on the differentiation probable of mesenchymal stem cells. In this review, we have summarized the therapeutic role of stem cell-based strategy in osteoporosis.     

Hormonal prevention and treatment of osteoporosis--state of the art 1990

Osteoporosis is a growing disease, and attention should be directed to possible means of preventing and treating this disease. Osteoporosis may be caused by a number of diseases (secondary osteoporosis), but it most often occurs in otherwise healthy persons. The major risk factors are a low bone mass at skeletal maturity, and a rapid bone loss. Postmenopausal bone loss may be prevented by hormone replacement therapy. All types of oestrogens and all administration forms are effective, as long as a sufficient serum concentration is obtained. The greatest benefit of hormone replacement therapy is obtained if instituted right after the menopause, when the bone loss is most rapid. But oestrogen will also arrest the bone loss when instituted much later in life.     

Polymorphism of VDR gene--the most effective molecular marker of osteoporotic bone fractures risk within postmenopausal women from Wielkopolska region of Poland

The major public health problem which will arise is a frequency of osteoporosis. The first manifestations of this disease are often bone fractures. Identification and evaluation of individual bone fracture risk will be the most effective way of solving the problem. Genetic determination of osteoporosis is unquestionable. The aim of this study is to detect which variants of genotypes lead to illness. We investigated 187 patients with osteoporosis (161 women, 26 men) and 19 healthy subjects. Polymorphisms of the following genes were investigated: OPG, VDR, ESR1, TGFB1 COL1A1, and BMP2. The statistically significant relationship between BMD value and T allele of Taq I VDR gene were found. Genotypes: aa, bb, TT of VDR gene occur more frequently in polish osteoporotic population in Wielkopolska region within patients with higher risk of bone fractures.     

降钙素与骨质疏松的治疗

骨质疏松症是常见的老年性疾病,日前尚无有效的预防和治疗手段。降钙素是一种多肽激素,能调节体内钙的代谢,对骨质疏松症有一定的疗效。本文简要阐述了降钙素用于治疗骨质疏松症的机理、方法、效果以及应用前景。     

The vacuolar ATPase in bone cells: a potential therapeutic target in osteoporosis

The vacuolar ATPase (V-ATPase) is a multisubunit enzyme that couples ATP hydrolysis to proton pumping across membranes. Recently, there is increasing evidence that V-ATPase may contribute to the pathogenesis of bone resorption disorders due to it is predominantly expressed in osteoclasts also function in bone resorption making it a good candidate in a therapeutic target for osteoporosis. Osteoclasts are capable of generating an acidic microenvironment necessary for bone resorption by utilizing V-ATPases to pump protons into the resorption lacuna. In addition, it has been shown that therapeutic interventions have been proposed that specifically target inhibition of the osteoclast proton pump. Modulation of osteoclastic V-ATPase activity has been considered to be a suitable therapy for the treatment of osteoporosis. All theses findings suggest that V-ATPase have important biological effects in bone resorption that might be a promising therapeutic target for osteoporosis. In this review, we will briefly discuss the biological features of osteoporosis and summarize recent advances on the role of V-ATPase in the pathogenesis and treatment of osteoporosis.     

Advances in mesenchymal stem cell transplantation for the treatment of osteoporosis

Osteoporosis is a systemic metabolic bone disease with characteristics of bone loss and microstructural degeneration. The personal and societal costs of osteoporosis are increasing year by year as the ageing of population, posing challenges to public health care. Homing disorders, impaired capability of osteogenic differentiation, senescence of mesenchymal stem cells (MSCs), an imbalanced microenvironment, and disordered immunoregulation play important roles during the pathogenesis of osteoporosis. The MSC transplantation promises to increase osteoblast differentiation and block osteoclast activation, and to rebalance bone formation and resorption. Preclinical investigations on MSC transplantation in the osteoporosis treatment provide evidences of enhancing osteogenic differentiation, increasing bone mineral density, and halting the deterioration of osteoporosis. Meanwhile, the latest techniques, such as gene modification, targeted modification and co‐transplantation, are promising approaches to enhance the therapeutic effect and efficacy of MSCs. In addition, clinical trials of MSC therapy to treat osteoporosis are underway, which will fill the gap of clinical data. Although MSCs tend to be effective to treat osteoporosis, the urgent issues of safety, transplant efficiency and standardization of the manufacturing process have to be settled. Moreover, a comprehensive evaluation of clinical trials, including safety and efficacy, is still needed as an important basis for clinical translation.     

Parathyroid hormone and its analogues - molecular mechanisms of action and efficacy of osteoporosis therapy

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.     

Osteoporosis and Dental Osteopenia in the Elderly1

Osteoporosis is a common, morbid, and expensive disease of the elderly skeleton, particularly in the postmenopausal female, resulting in fractures of the spine, hip, and wrist. Dental osteopenia (inadequate bone mass, particularly of the mandible) is also a condition of significant morbidity for the elderly, associated with loss of teeth and poorly fitting dentures. Questions of immediate concern regarding these disorders are: (1) Are techniques available for quantitating mandibular bone mass? (2) Is dental osteopenia a localized manifestation of a generalized skeletal osteoporosis, with similar etiologies and risk factors, or is it an entirely separate disease process, due primarily to periodontal disease with its associated causal factors? (3) Are therapeutic measures noted to be of benefit in osteoporosis also of benefit in dental osteopenia? Recent studies from our laboratories address these questions and indicate efficiency of the mandibular microdensitometry technique for measuring mandibular bone mass. Also, these studies suggest that dental osteopenia is part of a generalized skeletal osteoporosis of the elderly female, and that therapy for osteoporosis would possibly be of value in the treatment of dental osteopenia.     

Parathyroid hormone and its analogues--molecular mechanisms of action and efficacy in osteoporosis therapy

Most medical agents currently applied in osteoporosis therapy act by inhibiting bone resorption and reducing bone remodelling, i.e. they inhibit the process of bone mass loss by suppressing bone resorption processes. These drugs provide an ideal therapeutic option to prevent osteoporosis progression. They however have a rather limited usefulness when the disease has already reached its advanced stages with distinctive bone architecture lesions. The fracture risk reduction rate, achieved in the course of anti-resorptive therapy, is insufficient for patients with severe osteoporosis to stop the downward spiral of their quality of life (QoL) with a simultaneously increasing threat of premature death. The activity of the N-terminal fragment of 1-34 human parathormone (teriparatide - 1-34 rhPTH), a parathyroid hormone (PTH) analogue obtained via genetic engineering , is expressed by increased bone metabolism, while promoting new bone tissue formation by stimulating the activity of osteoblasts more than that of osteoclasts. The anabolic activity of PTH includes both its direct effect on the osteoblast cell line, and its indirect actions exerted via its regulatory effects on selected growth factors, e.g. IGF-1 or sclerostin. However, the molecular mechanisms responsible for the actual anabolic effects of PTH remain mostly still unclear. Clinical studies have demonstrated that therapeutic protocols with the application of PTH analogues provide an effective protection against all osteoporotic fracture types in post-menopausal women and in elderly men with advanced osteoporosis. Particular hopes are pinned on the possibility of applying PTH in the therapy of post-steroid osteoporosis, mainly to suppress bone formation, the most important pathological process in this regard. The relatively short therapy period with a PTH analogue (24 months) should then be replaced and continued by anti-resorptive treatment.     

Treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects middle age women. Most patients are diagnosed when asymptomatic. The disease is characterised by chronic, granulomatous inflammation of the small bile ducts, which leads to progressive ductopenia, cholestasis, fibrosis, cirrhosis and eventual liver failure. All PBC patients with abnormal liver biochemistry should be considered for therapy. Ursodeoxycholic acid (URSO) treatment reduces intracellular hydrophobic bile acid levels and thereby may have a cytoprotective effect on cell membranes. URSO may also act as an immunomodulating agent. Multicenter randomised controlled trials proved that the treatment is associated with a marked improvement in serum biochemical markers of cholestasis, i.e. bilirubin, ALP, GGT, including fall in serum cholesterol levels. Treatment does not seem to benefit the symptoms of fatigue, pruritus, and osteoporosis. UDCA has been shown when given in a dose of 15 mg/kg daily for up to 4 years to prolong the time to liver transplantation or death. Immunosuppressive therapy: based on the immunological abnormalities, several immunosuppressive drugs have been tested. Neither azathioprine nor cyclosporine was found in large enough trials to show beneficial effect on survival. D-penicillamine, cholchicin, methotrexát, prednisolone were found without significant long-term benefit. Combination therapy with URSO and budenoside appears to add some benefit to URSO monotherapy, but further studies are needed. Liver transplantation. The most crucial question is the timing. Serum bilirubin, Mayo risk score and some other factors such as uncontrollable pruritus and severe osteoporosis influence the decision. Recurrence of PBC in allograft is rare, the progress is slow, and is no reason for not recommending transplantation. Symptomatic treatment of pruritus, sicca syndrome and preventive treatment of osteoporosis, neuropathy and fat soluble vitamin deficiency is also important.     

Osteoporosis: the current status of mesenchymal stem cell-based therapy

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.     

Higher Levels of Osteoprotegerin and Immune Activation/Immunosenescence Markers Are Correlated with Concomitant Bone and Endovascular Damage in HIV-Suppressed Patients

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4⁺/CD8⁺ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9mm). Subjects with pathological c-IMT and BMD exhibited higher CD4⁺ and CD8⁺ activated, CD8⁺ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases.     

Genetic and environmental determinants of osteoporosis

Osteoporosis is a common, complex disease that is influenced by genetic and environmental factors. Although molecular genetic studies have identified several potential regions of linkage, underlying susceptibility gene(s) are largely unknown. Genetic susceptibility to osteoporosis may be both context dependent and developmentally regulated, and epigenetic mechanisms are the likely link between gene and environment. In this paper we will review the status of genetic research into osteoporosis, and present the evidence for gene-environment interaction in its pathogenesis. Finally, the current challenges and future directions of research will be briefly discussed.     

自噬与骨质疏松症的相关性

骨质疏松症是一种全身性骨骼疾病,其特征为低骨量和骨组织微结构退化。自噬是一个动态的、高度规律的自我消化过程,负责细胞存活和氧化应激反应,可以控制人体老化和骨质疏松症。尽管目前自噬对骨质疏松症的调控机制并没有完全解释清楚,但是随着对自噬研究的不断深入,其与骨质疏松症之间可能的联系和相互影响机制不断被揭示。本文回顾了近年来自噬与骨质疏松症的相关研究文献,探寻自噬与骨质疏松症相关的科学依据,发现对自噬与骨质疏松症共同影响的机制包括衰老、基因调控等。同时,自噬对糖皮质激素诱导的骨质疏松发病及药物治疗均有一定的影响。为进一步利用与自噬相关的调控体系来防治骨质疏松症提供证据。     

The Role of PINP in Diagnosis and Management of Metabolic Bone Disease

Serum procollagen type I N-propeptide (PINP) is designated the reference marker of bone formation in osteoporosis; the reference marker for resorption is C-terminal telopeptide of type I collagen (CTX). PINP has very low circadian and biological variation, is not affected by food intake, and is very stable in serum after venepuncture. The two automated commercial assays for PINP provide similar results in subjects with normal renal function, allowing reference intervals to be used interchangeably. Bone turnover markers (BTM) are currently not recommended for fracture risk assessment and therefore not included in fracture risk calculators. In the management of osteoporosis, the main utility of BTM including PINP is for monitoring therapy, both antiresorptive as well as anabolic agents; monitoring is thought to help improve adherence. PINP as well as CTX may also be used in assessing offset of drug action following a pause in bisphosphonate therapy, to help decide when to re-instate therapy, or following cessation of denosumab therapy to assess efficacy of follow-on bisphosphonate therapy. PINP may also be used in the diagnosis of Paget’s disease of bone as well as in monitoring response to therapy and for recurrence. Although BTM other than bone alkaline phosphatase are currently not recommended for use in metabolic bone disease of chronic kidney disease, PINP measured by assays specific to the intact molecule has potential in this condition. Further studies are needed to examine this area, as well as in malignant bone disease.     

Bisphosphonate-Associated Osteomyelitis of the Jaw: Guidelines for Practicing Clinicians

ObjectiveTo evaluate the literature and discuss the risk factors, mechanisms, pathophysiologic aspects, and recommended management of bisphosphonate-associated osteomyelitis of the jaw (BAOMJ).MethodsMore than 350 published articles, case reports mentioning BAOMJ, and independent histology slides from BAOMJ lesions were reviewed critically. The most pertinent publications are cited and discussed.ResultsThe incidence of BAOMJ increases after extraction of teeth, dentoalveolar surgical procedures, or recent oral trauma leading to exposed maxillary or mandibular bone. Contributory factors include poor oral hygiene, oral infections, periodontal disease; recent or ongoing corticosteroid administration or chemotherapy; compromised immune status; diabetes or vascular insufficiency; old age; chronic diseases; and malignancies. On average, 1 of every 100,000 patients treated with bisphosphonates orally for osteoporosis or Paget disease of bone may develop BAOMJ-like lesions. Patients with cancer often receive bisphosphonate doses 10 times or higher, and also more frequently, than those used in patients with osteoporosis or Paget disease of bone. Therefore, greater frequency of administration of bisphosphonates, higher dosages, and prolonged use (that is, for more than 2 years) are likely to be factors triggering BAOMJ.ConclusionThe association of bisphosphonate therapy with BAOMJ is rare in noncancer patients and is likely to be a class effect that may occur with use of any bisphosphonate. Whether patients with cancer require such a high frequency of intravenously administered bisphosphonates needs to be investigated. Following established guidelines can decrease the risks of BAOMJ in vulnerable patients. Rather than necrotic bone, current evidence supports an infectious and perhaps immunologic underlying cause for BAOMJ. The estimated incidence of BAOMJ among noncancer patients receiving bisphosphonates is about 0.001%, whereas among patients with cancer receiving intravenous bisphosphonate therapy the incidence is between 0.5% and 4%, depending on the dose, frequency, and duration of therapy (on average, ~ 2%). Nevertheless, the benefits of bisphosphonates far outweigh the risks. (Endocr Pract. 2008;14:1150-1168)