Recent developments in bisphosphonate therapy

OBJECTIVE: To provide a review of current developments in bisphosphonates indicated for the treatment of several rheumatologic conditions, including postmenopausal and glucocorticoid-induced osteoporosis. METHODS: This review summarizes the pathology, diagnosis, and treatment of both postmenopausal and glucocorticoid-induced osteoporosis and examines the results of current clinical trials of the newest oral and intravenous formulations of nitrogen-containing bisphosphonates. We discuss important adverse events, including upper gastrointestinal symptoms and osteonecrosis of the jaw. Additionally, we explore methods that may improve patient adherence to bisphosphonate therapy, which is currently suboptimal. RESULTS: Clinical studies have shown that oral bisphosphonates are efficacious in increasing bone mineral density and reducing risk of fracture. Despite concerns of upper gastrointestinal irritation, most of the newer oral bisphosphonates display a safety profile similar to placebo. Many of the newest formulations offer patients a choice in both dosing frequency and method of administration (either oral or intravenous). CONCLUSIONS: Nitrogen-containing bisphosphonates are important therapeutic options for the prevention and treatment of osteoporosis.     

The role of zoledronic acid in the management of osteoporosis

Bisphosphonates are the current standard of care for treatment of osteoporosis. However, oral bisphosphonates are associated with complicated dosing regimens because of poor absorption and have the potential for upper gastrointestinal (GI) tract irritation, resulting in poor adherence and persistence. Zoledronic acid (ZOL) 5 mg, a once-yearly intravenous bisphosphonate, is approved for treatment and prevention of postmenopausal osteoporosis, increasing bone mass in men with osteoporosis, and treatment and prevention of glucocorticoid-induced osteoporosis. Because it is administered as an infusion, ZOL ensures adherence and persistence over the entire 12-month dosing interval and bypasses the GI absorption/irritation problems associated with oral bisphosphonates. The objective of this study was to review the safety and efficacy of 5 mg ZOL and its potential for improving patient compliance. Published reports dating back to 2001 were reviewed, with emphasis on osteoporosis treatment. In the HORIZON-Pivotal Fracture Trial, annual infusions of 5 mg ZOL produced significant reductions in risk of morphometric vertebral fractures (70%) and hip fractures (41%) vs placebo over 3 years in postmenopausal women with osteoporosis. In the HORIZON-Recurrent Fracture Trial, an annual infusion of 5 mg ZOL after repair of a recent low-trauma hip fracture was associated with significant reductions in risk for new clinical fractures (35%) vs placebo. In men with osteoporosis, an annual treatment of ZOL over 2 years increased lumbar spine bone mineral density (BMD) by 6% compared with baseline. In patients starting or continuing treatment with chronic glucocorticoids, ZOL resulted in significantly greater increases in lumbar spine BMD over 1 year than an oral bisphosphonate. In postmenopausal women with osteopenia, a single infusion of ZOL over a 2-year period produced significantly greater gains in lumbar spine and hip BMD than placebo. ZOL is generally safe and well tolerated. Five milligrams of ZOL has the potential to improve compliance with osteoporosis therapy and, consequently, to reduce fracture risk in clinical practice.     

Calcitonin

Calcitonin is a 32-amino acid polypeptide secreted by the parafollicular cells of the thyroid. Effects on bone include inhibition of osteoclasts, thus preventing bone resorption, as well as increased renal calcium excretion. Salmon calcitonin is often used therapeutically because it is more potent and has a longer duration of action compared with human calcitonin. Calcitonin also possesses analgesic properties. The mechanism of its analgesic effect is unknown but is thought to involve inhibition of prostaglandins and stimulation of β-endorphins. Most of the clinical data in postmenopausal osteoporosis involves the use of salmon calciton in nasal spray. Clinical trials have demonstrated a reduction in the risk of vertebral fractures and increased bone mineral density. Studies examining nonvertebral fractures have shown mixed results, some indicating a nonsignificant risk In general, calcitonin is inferior to bisphosphonates (BPs) in reducing fracture risk. Calcitonin is effective in the treatment of osteopathic pain. It has also been used in glucocorticoid-induced osteoporosis. Parenteral calcitonin is generally associated with more frequent side effects compared with intranasal calcitonin. Injectable administration can cause flushing, tingling, nausea, and injection site and allergic reactions. Side effects with intranasal use are usually limited to local effects (nasal congestion and irritation). Recent phase I trials with a new oral dosage form show promise in terms of efficacy and tolerability for treating patients who prefer this route of administration. This review of pertinent literature on calcitonin indicates that this remains a viable, though second-or third-line, agent for osteoporotic patients who refuse or cannot tolerate other treatments (e.g., BPs, raloxifene, and estrogen).     

Osteonecrosis of the jaw

Bisphosphonates are effective therapy for osteoporosis, Paget’s disease, and metastatic bone disease. Generally, the side effects of bisphosphonates are minimal. Recently, an uncommon adverse reaction affecting the maxilla or mandible, called osteonecrosis of the jaw, has been reported, especially in those patients receiving high doses of bisphosphonates in the oncology setting. Regarding doses used to treat osteoporosis, clinicians must keep the very small potential absolute risk of jaw osteonecrosis in perspective and consider it in relation to the demonstrated benefit of bisphosphonates. Still, in a very small number of patients taking bisphosphonates, intractable, painful, nonhealing exposed bone may occur following dental extractions or denture irritation.     

A review of bone pain relief with ibandronate and other bisphosphonates in disorders of increased bone turnover

Several disorders of increased bone turnover and low bone mineral density (BMD) are associated with severe pain that is refractory to treatment with conventional and even opioid analgesics. Because of their ability to effectively improve the underlying pathogenesis of these disorders (i.e., reduce bone resorption and increase BMD), bisphosphonates are considered part of the palliative care of malignant bone-related pain and also appear to have some analgesic efficacy in other, non-malignant conditions. Ibandronate, a potent, nitrogen-containing bisphosphonate that can be given orally and intravenously, has demonstrated robust effects in relieving the pain associated with several malignant disorders. Unlike other available intravenous (i.v.) bisphosphonates, i.v. ibandronate is not associated with renal side effects, even at high doses such as 6 mg every 3 weeks. In addition, oral ibandronate (50 mg daily) is currently the only oral bisphosphonate proven to reduce and maintain bone pain scores below baseline for 2 years in patients with metastatic bone disease. Lower dose, less intense dosing regimens of ibandronate relieve bone pain in non-malignant conditions: i.v. ibandronate (2 mg every 3 months with or without an initial 4 mg injection) provides pain relief for patients with corticosteroid-induced osteoporosis, localised transient osteoporosis (bone marrow oedema) and sternocostoclavicular hyperostosis. Both oral and i.v. ibandronate are well tolerated. In conclusion, ibandronate offers an effective and convenient choice for the relief of bone pain in a wide variety of underlying bone conditions.     

Management of osteoporosis in patients with gastrointestinal diseases

Osteoporosis is a frequent complication in the course of various gastrointestinal disorders. Since its pathogenesis is complex, and incompletely understood in comparison to the well-known pathomechanism of postmenopausal osteoporosis, adequate management is difficult. We first summarize those therapeutic options which have strong evidence in postmenopausal osteoporosis and, thereafter, we review those in the context of different gastrointestinal diseases. Treatment of the underlying intestinal disorder seems to be most important to normalise altered bone metabolism and to prevent osteoporosis in patients with coeliac disease. In patients with osteoporosis associated with Crohn's disease, various treatment strategies (such as vitamin D, sodium fluoride, bisphosphonates) are discussed. In contrast to postmenopausal osteoporosis, interventional studies in secondary osteoporosis are often limited by the small study population and data about the efficacy of any treatment in prevention of fractures are therefore lacking. Well-conducted, controlled studies with the endpoint of preventing fractures are therefore required to optimise the treatment of osteoporosis in these patients.     

Gastrointestinal Adverse Effects of Bisphosphonates

The bisphosphonate class of drugs are now utilized extensively in the treatment of patients with osteoporosis and Paget's disease. Gastrointestinal (GI) adverse effects, especially those associated with esophageal injury, have been of increasing concern to clinicians. Studies in humans and animals have shown that the mucosal erosion and ulceration seen with bisphosphonates is a result of direct contact with these agents. Numerous endoscopic studies in healthy volunteers and postmenopausal women have also demonstrated the potential of bisphosphonates to cause stomach and duodenal ulcers. However, serious GI adverse events have not been noted in several large efficacy trials. Esophageal injury has for the most part been avoided by appropriate administration instructions, and gastroduodenal injury appears to be an acute phenomenon not associated with significant complications, except in certain high-risk situations, for example in the presence of existing distal esophageal disease or motility disorders, or with concurrent use of nonsteroidal anti-inflammatory drugs or anticoagulants. From the standpoint of GI safety, the bisphosphonates are well tolerated and not associated with serious adverse events.     

Use of metabolic bone markers in clinical setting

It is useful to effectively measure metabolic bone markers for choice of pharmaceutical agents and early assessment of treatment efficacy in osteoporosis. The measurements of markers for bone resorption related to type I collagen crosslinks are recommended in evaluating treatment efficacy of bisphosphonates (BPs). Since the changes in free crosslinks during treatments with newer BPs containing amino residues is subtle, the advantage of measurement of N-telopeptide (NTX) has been reported elsewhere. When the change in bone markers exceed the magnitude of the least significant change, treatment efficacy is confirmed in individual patients.     

Bisphosphonates and osteonecrosis of the mandible/maxilla in osteoporosis: no reason to panic

Bisphosphonate (BP) therapy has modified the natural history of many bone metabolic diseases. Amino-bisphosphonates nowadays represent the primary therapeutic choice for the treatment of osteoporosis and for prevention of fractures. Osteonecrosis of the mandible and maxilla (ONJ) is a rare disease usually occurring in cancer patients with bone metastases treated with high doses of intravenous BPs. Some cases have been described in patients taking amino-BPs for osteoporosis, but the specific drug utilized, its dosage and use of the oral route have reduced that risk considerably (estimated at 1/100,000 subjects a year). Prevention of ONJ include good oral hygiene habits in all patients and, in a subject who has been treated for more than three years, conservative dental procedures when possible, an appropriate antibiotic therapy and a careful follow-up when invasive oral interventions are necessary, are recommended by dentists and bone metabolism experts alike.     

Bisphosphonate mechanism of action

The nitrogen-containing bisphosphonates (N-BPs), alendronate and risedronate, are the only pharmacologic agents shown to prevent spine and nonvertebral fractures associated with postmenopausal and glucocorticoid-induced osteoporosis. At the tissue level, this is achieved through osteoclast inhibition, which leads to reduced bone turnover, increased bone mass, and improved mineralization. The molecular targets of bisphosphonates (BPs) have recently been identified. This review will discuss the mechanism of action of BPs, focusing on alendronate and risedronate, which are the two agents most widely studied. They act on the cholesterol biosynthesis pathway enzyme, farnesyl diphosphate synthase. By inhibiting this enzyme in the osteoclast, they interfere with geranylgeranylation (attachment of the lipid to regulatory proteins), which causes osteoclast inactivation. This mechanism is responsible for N-BP suppression of osteoclastic bone resorption and reduction of bone turnover, which leads to fracture prevention.     

Bisphosphonate-associated osteonecrosis of the jaw in rheumatology: a systematic review

Osteonecrosis of the jaw (ONJ) is a well-known devastating side effect of parenteral bisphosphonate therapy for cancer. Several ONJ cases have been reported in patients taking oral bisphosphonates for osteoporosis or Paget's disease. Even if the number of cases of ONJ in patients taking oral bisphosphonates are still rare compared to the total exposure, rheumatologists treating bone diseases with bisphosphonates must be aware of this new complication, allowing for prevention and early diagnosis. The patients must be informed on the benefit/risk of bisphosphonate therapy and, when necessary and possible, alternative therapy for postmenopausal osteoporosis should be considered. The need for the patient to be dentally fit and to maintain this state forever should be part of the informed consent for bisphosphonate treatment. It is uncommon for rheumatologists to ask about dental problems but this new bisphosphonate- associated complication highlights the need for this to change. In this paper we review the literature available on this newly described bisphosphonate-induced complication with particular emphasis on ONJ cases related to the use of oral bisphosphonates.     

SERMs: an update for clinicians

With the successful manipulation by molecular pharmacological technology of the estrogenic properties of selective estrogen receptor modulators (SERMs) that are highly organ- and tissue-specific, SERMs have now become available for the management of osteoporosis, as they did for breast cancer earlier. This presentation focuses on raloxifene (RLX), a second-generation SERM and an agent of interest to clinicians engaged in the management of osteoporosis on a day-to-day basis. RLX is a unique agent, in that it exhibits similar but distinct effects on bone metabolism from those of estrogen. RLX also appears to exert milder inhibitory effects on bone resorption than bisphosphonates (BPs), another class of antiresorptive agents, while ample evidence suggests that RLX compares favorably with BPs in preventing a variety of non-traumatic fractures.     

Bisphosphonates

Osteoporosis is the result of bone loss due to an imbalance in bone turnover such that bone resorption exceeds bone formation. Bisphosphonates are potent inhibitors of osteoclast activity that reduce bone turnover and re-establish the balance between bone resorption and formation. In clinical studies, several bisphosphonates prevent bone loss, preserve bone structure, improve bone strength and, in patients with osteoporosis, substantially reduce fracture risk. They are effective in multiple clinical settings including postmenopausal osteoporosis, low bone mass in men and drug-induced bone loss. Intermittent oral dosing and intravenous administration are more convenient than the original daily dosing regimen. These drugs are generally well tolerated and have an excellent safety profile in that serious side effects are uncommon. Potent bisphosphonates are generally the preferred treatment option for most patients with or at risk for osteoporosis.     

Advances in the management of corticosteroid-induced osteoporosis with bisphosphonates

Corticosteroids are widely used as anti-inflammatory and immunosuppressive agents to treat a variety of chronic conditions. Long-term (>1 year) corticosteroid use can lead to bone loss, and therefore, osteopenia or osteoporosis. Corticosteroid-induced osteoporosis (CIO) leads to increased bone fragility and subsequently fractures, which, in turn, lead to a loss of physical, emotional and social health for the patient and increased costs for healthcare providers. A wealth of data exists demonstrating the efficacy of the oral bisphosphonates, etidronate, alendronate and risedronate in increasing bone mineral density in patients with CIO or preventing bone loss in patients commencing corticosteroid therapy. Data regarding fracture prevention are less clear, as statistically significant reductions in the incidence of fractures have only been reported for patient subgroups or meta-analyses. However, many treatment guidelines recommend the use of oral bisphosphonates for the prevention and treatment of CIO. These guidelines are, however, not reflected in prescribing practice, and the majority of patients do not receive adequate concomitant therapy. This review summarizes the available data for bisphosphonates in CIO. Therapeutic adherence with oral bisphosphonates is an issue, with approximately 50% of patients discontinuing therapy within the first year. The primary reasons for this are poor gastrointestinal tolerability and the frequency with which complex dosing requirements must be followed. The inconvenience of taking daily or weekly bisphosphonate therapy is of particular importance in patients with CIO who may be regularly taking several other medications. Data obtained in studies with ibandronate indicate that bisphosphonate administration by rapid intravenous injection provides an effective, well-tolerated and practical alternative to current oral regimens in the management of patients with CIO.     

Drug insight: Existing and emerging therapies for osteoporosis

Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1-34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.     

Intravenous pamidronate compared with oral alendronate for the treatment of postmenopausal osteoporosis

There are several options for the treatment of osteoporosis in postmenopausal women. One of the options is treatment with bisphosphonates, which are very potent inhibitors of osteoclast-mediated bone resorption in vitro and in vivo. The most potent bisphosphonates have a nitrogen side chain and can be given orally or intravenously (i.v.). In the present study we evaluated retrospectively the effect of intravenously administered pamidronate (60 mg monthly) in comparison with oral alendronate with regard to bone mineral density (BMD) and vertebral fractures. A total of 117 consecutive women aged 46 to 78 years were seen in the outpatient clinic because of postmenopausal osteoporosis. Three-year follow-up data were available for a total of 45 patients treated with pamidronate i.v. and 40 patients on alendronate for at least three years. In the pamidronate group mean T score of lumbar spine BMD increased from -3.49 +/- 0.72 to -2.81 +/- 0.74 SDs after three years of treatment (p < 0.001). In the 40 patients treated with alendronate we observed an increase in the T score from -2.95 +/- 0.67 to -2.33 +/- 0.74 SDs (p < 0.001) during the same observation period. X-rays of the lumbar and thoracic spine were analysed from 25 patients in each group who had been treated for at least three years. At baseline nine patients (36%) in the pamidronate group had one or more vertebral fractures compared with seven patients (28%) in the alendronate group. After three years of treatment no new fractures were observed, while only three women in the pamidronate group and two in the alendronate group showed a deterioration of one or more pre-existing vertebral fractures (p = ns between groups). This retrospective analysis demonstrates that monthly intravenous administration of pamidronate is at least as good as alendronate taken orally in the treatment of women with postmenopausal osteoporosis, with regard to improvement of bone mineral density of the lumbar spine. We conclude that it is a good alternative for the more widely used oral bisphosphonates as it is effective, well-tolerated and easy to administer.     

Comment on: Bisphosphonates and osteonecrosis of the jaw

SIR, We read the editorial by Shenker and Jawad [1] on bisphosphonates(BPs) and osteonecrosis of the jaw (ONJ) with great interest,and we would like to express our concern also regarding theyounger patients treated with BPs. Currently, both i.v. andoral BPs are increasingly also used for long-term treatmentin children and adolescents affected by conditions like osteogenesisimperfecta (OI), fibrous dysplasia or secondary osteoporosis     

Bisphosphonate and markers for bone metabolism

Bisphosphonates (BPs) are widely applied to clinical use as first lines of therapeutic agents for metabolic bone diseases such as osteoporosis and Paget's disease of bone. Data on changes in markers for bone metabolism and their abilities to predict treatment efficacy have been accumulated in these bone disease and recently a guideline for adequate use of markers for metabolism in osteoporosis has been proposed. In the use of BPs, particularly ones containing amino residuals in their structures of side chains, attention should be paid to the choice of markers for bone metabolism since their degrees of changes depends on markers selected.     

Bisphosphonates: potential therapeutic agents for disease modification in osteoarthritis

Current treatments for osteoarthritis (OA) are mainly targeted towards providing short-term symptom relief. The focus in the development of disease-modifying drugs has been on therapies that modify cartilage directly. Recent research has highlighted the importance of subchondral bone as a target for therapeutic intervention and disease modification. At the subchondral level, affected joints have decreased bone mineral content and quality. In addition, increased bone turnover has been observed at levels similar to those in patients with osteoporosis. Consequently, the potential benefits of drugs that alter bone metabolism are being examined in this disease, in particular, the antiresorptive agents, bisphosphonates. Results from pre-clinical studies have shown promising results for these compounds. Although the mechanism of action remains unclear, comparative studies indicate that this activity may be unique to the specific structure of the bisphosphonate, rather than representative of a class effect. Clinical studies are now under way to determine the efficacy and safety of bisphosphonates which may offer new therapeutic options in the treatment of OA.