Solomon Epstein, MD, FRCP, FACP, is Professor of Medicine and Geriatrics at Mount Sinai University School of Medicine in New York, and Director of the Clinical Research Department at Doylestown Hospital, in Doylestown, PA. Dr Epstein has established many academic initiatives in bone and mineral research and is continuing basic research studies at Mount Sinai. He has also developed an osteoporosis program and center at Doylestown Hospital. He has authored numerous book chapters and over 250 peerreviewed publications, has served worldwide as a visiting professor, sits on many editorial boards, and is President of the International Society for Post-transplant Bone Disease. Dr Epstein received his MD with honors at the University of Cape Town Medical School, where he also completed an internship in general medicine and general surgery. He completed his postgraduate training in internal medicine and endocrinology at Tufts University in Boston and the Royal Postgraduate school of Medicine in London.
Fractures related to untreated osteoporosis greatly contribute to increased morbidity and mortality in the older population. In the US, an estimated 10 million people over the age of 50 suffer from osteoporosis and an additional 34 million people are at risk for developing this condition. As a result, osteoporosis has become widely recognized as a startlingly prevalent bone disease and a foremost healthcare concern. Osteoporosis is a chronic and progressive skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture. Consequent bone fragility predisposes the individual to an increased risk of fracture. Due to the progressive nature of the bone mass reduction, this condition can be initially silent, without presenting symptoms even where fractures are present. While age-related osteoporosis can occur in both women and men, women are at the highest risk for developing osteoporosis due to the decrease in estrogen that results from the menopause and the consequent accelerated reduction in bone mass. Until recently, a clinical diagnosis of osteoporosis, as defined by the World Health Organization in 1994, has primarily included a bone mineral density (BMD) reading, measured by dual-energy X-ray absorptiometer, that is 2.5 standard deviations below the young adult mean. This value is reported as a T-score of <-2.5. However, the inclusion of risk factors (i.e. age, history of fracture, lifestyle, and medications) has become increasingly important in assessing fracture risk. Bisphosphonates (BPs), a class of drugs with a high affinity for bone mineral, have been shown to reduce bone resorption and increase BMD.They have become the most commonly prescribed therapy for the prevention and treatment of post-menopausal osteoporosis (PMO) and have been associated with anti-fracture efficacy. Despite ample short-term and long-term data demonstrating that BPs are an effective treatment for osteoporosis, patient adherence to therapy has emerged as an immense challenge for the healthcare industry. The stringent dosing requirements and
potential for exacerbations of upper gastrointestinal (GI) ailments with BP treatment are often cited as likely reasons for low compliance among patients. In an effort to minimize inconvenience and reduce the potential for adverse events, formulations have been developed that enable progressively simpler and less frequent dosing (i.e. weekly oral, monthly oral, or quarterly intravenous (IV)). This article reviews the newer nitrogencontaining BPs and highlights characteristics that enable extended between-dose intervals. Special focus is given to ibandronate, as it is the only BP currently approved by the Food and Drug Administration (FDA) for monthly oral or quarterly (every three months) IV dosing regimens for the treatment of PMO.
Biology of Bone Remodelling
In the healthy adult skeleton, the removal and formation of bone are highly balanced and coupled processes. The basic multicellular unit (BMU) is responsible for the dynamic nature of bone tissue and its continual regeneration, encompassing both bone repair and maintenance.The BMU comprises two types of highly specialized and juxtaposed cells: a team of osteoclasts in the front and a team of osteoblasts in the back. Osteoclasts, derived from hematopoietic cells of the monocyte/macrophage lineage, are responsible for the removal of old bone, while osteoblasts, derived from mesenchymal stem cells, create new bone. The bone resorption process is dependent on the differentiation of osteoclast precursor cells and the activation of mature osteoclasts.While bone remodeling is regulated by several cellular and hormonal factors, including parathyroid hormone, estrogens, and cytokines, recently identified members of the tumor necrosis factor ligand family have been found to play a crucial role. Receptor activator of nuclear factor-_B (RANK) is expressed in osteoclast progenitor cells, and its corresponding ligand, RANK ligand (RANKL), is expressed in osteoblasts/stromal cells. It has been shown that the RANK/RANKL interaction is essential for osteoclast differentiation. The formation of the RANK/RANKL complex stimulates osteoclast formation and commences the bone resorption process.
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mechanisms. The lengthening of the alkyl chain and the introduction of a nitrogen as a primary (alendronate and pamidronate), tertiary (ibandronate), or heterocyclic ring (risedronate and zoledronate) at the R2 position have increased the anti-resorptive potency of the newest BPs. This is advantageous as it translates to significant therapeutic efficacy with lower concentrations of these newer agents.The PCP backbone and negative charge at physiological pH (polarity) make them resistant to metabolic degradation.
Mechanisms of Osteoclast Inhibition and Apoptosis
BPs are highly stable synthetic compounds that bind to the calcium in bone and possess bone-specific, antiresorptive properties. All BPs share a characteristic phosphorus-carbon-phosphorus (PCP) backbone, comprising two phosphonate groups linked by phosphoether bonds to a central carbon atom. The three-dimensional structure of BPs allows for chelation of divalent metal ions, hence their strong affinity for the Ca2+ in hydroxyapatite. Additionally, the central carbon atom can bind two side chains, designated R1 and R2. It is these side chains that govern the binding affinity of the particular BP for bone mineral, a characteristic that is correlated to anti-resorptive potency; modification of these side chains allows for pharmacologic diversity within the BP class of anti-resorptive drugs. The greatest affinity for bone mineral appears to be conferred by a hydroxyl [OH] group at the R1 position. All of the newer and more potent BPs (alendronate, risedronate, ibandronate, zoledronate) possess this OH group and preferentially bind to exposed areas of active bone resorption.The chemical group at the R2 position contributes to the pharmacological properties and intracellular
Some of the mechanisms underlying impairment of osteoclast activity and reductions in bone resorption via BP treatment have been elucidated in the past few years. The local acidic environment created by the enzyme-secreting osteoclast as it dissolves bone matrix lowers the ability of BPs to chelate Ca2+. Previously bound BP molecules are released from bone mineral and internalized by osteoclasts; inside the cell, they inhibit vital cellular processes and eventually induce apoptosis. BPs have been found to interfere with the creation of farnesyl diphosphate (FPP) synthase, which consequently inhibits the production of the lipid FPP, part of the biosynthetic mevalonate pathway. FPP is important for the post-translational modification or prenylation of small GTPase proteins (including Ras, Rho, Rab, and Rac), which are responsible for membrane ruffling, trafficking of intracellular vesicles, arrangement of the cytoskeleton, and the survival of the cell. Results of a recent in vitro study by Dunford et al., suggest that GTP-bound, Rho-family GTPases accumulate following BP treatment, and this accumulation of unprenylated small GTPases (rather than the loss of prenylated GTPases) and inappropriate activation of downstream signaling pathways are related to the ability of BPs to cause osteoclast apoptosis.
Pharmacokinetics
The amount of BPs that is retained by the skeleton is dependent on several factors, including bone turnover rate, renal function, and the binding properties of the specific BP. Inhibition of bone resorption is a function of the amount of BP bound to the skeleton and the antiresorptive activity of the particular BP. Intestinal absorption of all oral BPs is poor, averaging only 0.6% to 0.7% of the ingested dose. Since food can further decrease absorption, dosing instructions require that BPs are administered only with water and after an overnight fast. After absorption, BPs reach mean peak plasma concentrations approximately one hour after ingestion and plasma concentrations reach 10% of maximum after three to eight hours. Within 24 hours, approximately
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Post-menopausal Osteoporosis
50% of the absorbed dose is excreted unmetabolized in the urine and the remainder is retained on actively resorbing bone surfaces. For ibandronate, the mean terminal serum half-life was estimated to be between 10 and 60 hours.The estimated mean terminal elimination half-life of alendronate (30mg given intravenously over four days) was found to be greater than 10 years, indicating prolonged retention in the skeleton.
Bisphosphonates and Intermittent Dosing
Osteoporosis is a chronic condition that requires long-term therapy.While BPs have been shown to be an effective option for reversing this bone disease, the inconvenient dosing regimen and potential for upper GI irritation have been obstacles to achieving consistent patient adherence to daily therapy. In addition, bone mineralization was found to be defective with continuous treatment of some of the older BPs such as etidronate. In response to these challenges, weekly formulations for alendronate and risedronate were investigated and found to be therapeutically equivalent to daily therapy on the basis of BMD increases while also providing a more convenient dosing schedule. Adherence to weekly BP therapy was found to be better than adherence to daily BP therapy; however, overall adherence remains suboptimal. Considering these behaviors, the development of a BP formulation that allows dosing intervals greater than one week may offer a more convenient schedule for patients. Certain molecular characteristics are necessary for intermittent administration; the BP should demonstrate potent bone resorption properties, high binding affinity for bone mineral, and a favorable clinical safety and tolerability profile. Intermittent dosing was initially explored in two studies, which administered 400mg of etidronate to women with PMO in various dosing regimens. Vertebral bone mineral content was significantly increased in each trial. In a meta-analysis of trials administering intermittent etidronate therapy, it was determined that treatment with etidronate was effective in reducing the relative risk of vertebral fractures, but there was no impact on non-vertebral fractures. Cyclical treatment with etidronate has been associated with rare cases of osteomalacia.
Pre-Clinical Animal Models
with ibandronate is as effective as daily dosing in reducing bone loss and increasing bone strength. An in vivo study reported that ibandronate is 2-, 10-, 50-, and 500-fold more potent than risedronate, alendronate, pamidronate, and clodronate, respectively, as found by inhibition of arotinoid-stimulated bone resorption in a rat model. Studies conducted in rats with ovariectomy-induced bone loss examined the effects of ibandronate on bone mass, bone strength, and bone architecture.These studies found that the prevention of bone loss was related to the total dose of ibandronate, independent of treatment schedule.The safety and efficacy of IV ibandronate (bolus injection) given at 30-day intervals was examined in cynomolgus monkeys; this study confirmed that ibandronate IV injection had potential use in humans. Histomorphology studies of bone conducted during these pre-clinical trials verified that bone quality was maintained with the use of intermittent ibandronate.
Intermittent Oral Dosing
The optimal dose of oral daily ibandronate was found to be 2.5mg when examined in a phase II dose-finding trial. Another phase II trial compared 2.5mg daily with intermittent oral dosing (20mg of ibandronate every other day for the first 24 days, followed by nine weeks without active drug).This study found that increases in BMD and decreases in bone turnover in the intermittent dosing group were equivalent to those from the oral daily dosing group, thus confirming the results of pre-clinical trials. Both phase II trials described above found ibandronate to be well-tolerated at the dosages studied. The first trial to examine the safety, pharmacodynamics, and pharmacokinetics of ibandronate used in a monthly dosing paradigm was the phase I Monthly Oral Pilot Study (MOPS). Post-menopausal women were given once-monthly placebo or oral ibandronate at three dosing strengths (50mg, 100mg, or 150mg). All of the once-monthly ibandronate dosages were associated with a safety profile that was similar to placebo and were effective in suppressing bone resorption, as indicated by reductions in bone turnover markers (BTMs). While this preliminary study had limitations, i.e. a small number of patients (n=144) and lack of calcium and vitamin D supplementation, findings clearly indicated that once-monthly dosing was a feasible option. The pivotal phase III oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) investigated daily as well as intermittent oral dosing (20mg every other day for 12 doses every three months) among women with PMO and examined the rate of new morphometric vertebral fractures over three
The emergence of newer and more efficacious BPs has driven the development of dosing intervals that are greater than one week. Pre-clinical trials with rats, dogs, and monkeys have suggested that intermittent dosing
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Intermittent IV ibandronate (1mg or 2mg every three months) was further examined in the one-year, phase III Intermittent Regimen intravenous Ibandronate Study (IRIS). Increases in lumbar spine and total hip BMD were significantly different from placebo and found to be dose-dependent. The 2mg dose was significantly more effective in comparison with the 1mg dose. Reductions in bone turnover (serum C-telopeptide crosslinks of type l collagen [sCTX] and CTX creatinine) provided evidence of significantly reduced bone resorption. Both IV regimens were well-tolerated and there were no reports of renal toxicity. The first fracture efficacy trial of quarterly IV ibandronate found that due to insufficient increases in lumbar spine BMD and reductions in BTMs, the administered doses (0.5mg and 1.0mg) appeared to be too low to result in significant fracture reduction. Subsequently, the Dosing IntraVenous Administration (DIVA) study, a two-year randomized, double-blind, double-dummy, phase III, non-inferiority study, examined gains in BMD and safety profiles for IV doses of 2mg every two months and 3mg every three months. After one year, both IV doses were well-tolerated and were statistically superior to the daily oral regimen in increasing lumbar spine BMD (p <0.001).
Conclusions
Intravenously delivered BPs may be useful in patients who are unable to take oral BPs because of contraindications, upper GI conditions, and/or polypharmacy. The high potency of ibandronate and its effectiveness at lower doses compared with the older BPs, such as etidronate and clodronate, identify it as an excellent candidate for administration as a 10- to 20-second IV bolus injection. While other BPs can be delivered intravenously, slow infusion is required to prevent renal side effects, which have occurred with the use of some intravenously delivered BPs (including etidronate, clodronate, tiludronate, and zoledronate). The efficacy and safety of various doses of a bolus IV ibandronate injection was first explored in a one-year, partly double-blind, placebo-controlled, randomized, parallel group multi-center study of women with PMO (n=126). Doses of ibandronate (0.25mg, 0.5mg, 1.0mg, and 2.0mg) were given as quarterly IV injections. After one year, investigators reported significant dosedependent increases in lumbar spine BMD in the 0.5, 1.0, and 2.0mg groups compared with baseline. The occurrence of adverse events was similar between the quarterly IV groups and placebo.
Clinical trials consistently have shown that BPs are an efficacious therapy for the prevention and treatment of osteoporosis. Suboptimal adherence to daily and weekly therapies has provided motivation for the development of treatment regimens that are simpler and more convenient. The bone-binding properties (affinity and persistence) and the greater anti-resorptive activities of the newer BPs allow for extended between-dose intervals. In particular, clinical trials have demonstrated that intermittent regimens of ibandronate are efficacious in increasing BMD and reducing bone turnover. It is the hope of healthcare providers that monthly oral or quarterly IV dosing options will improve patient adherence, reduce probability of fractures, and improve the long-term medical outcomes and quality of life for osteoporosis sufferers.
Acknowledgements
The author acknowledges the assistance of Rebecca Jarvis, PhD, of Envision Pharma, in the preparation of this manuscript. A version of this article containing references can be found in the Reference Section on the website supporting this briefing (www.touchbriefings.com).
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