Abstract
The rate of bone turnover increases around the time of menopause, and new bone may be remodeled before it is has been completely mineralized. If this is left untreated, osteoporosis often develops, leading to fractures, particularly of the spine and hip, which represent an enormous burden in terms of suffering, healthcare expenditure, disabilities and death. Bisphosphonates are potent inhibitors of bone resorption, which slow or arrest progressive bone loss. Continuous treatment with bisphosphonates reduces bone turnover, improves bone microarchitecture and increases bone mass, leading to greater mechanical strength and reduced fracture risk. Since osteoporosis is a chronic, progressive condition, treatment has to continue for many years. Therefore, the efficacy and safety of bisphosphonates, particularly alendronate and risedronate, have been evaluated in many thousands of patients for up to 10 years of continuous use. These drugs remain the cornerstone of osteoporosis treatment and appear to have favorable safety and efficacy profiles throughout long-term usage.
Background: bone remodeling & osteoporosis
Bone remodeling is a lifelong process in which collagenous matrix and mineral crystal are removed and replaced with new material. The role of bone remodeling is to remove damaged or old parts of bone, provide bone marrow with growth factors released from bone extracellular matrix and contribute to maintaining the homeostasis of extracellular calcium concentration. Bone resorption takes place at microscopic foci over a period of approximately 2 weeks, whereas subsequent formation of new bone at the site of resorption requires months, and the resulting matrix may require years to reach complete mineralization under normal conditions [1].
Around the time of the menopause, the average rate of bone turnover increases, reaching approximately three-times the rate of premenopausal women [2]. In this accelerated-turnover state, the amount of bone resorbed exceeds that formed, and new bone may be remodeled even before it has been completely mineralized. If this is left untreated, a progressive decline in bone mass, microarchitectural alterations and a decrease in bone strength will occur, leading to osteoporosis and an increased risk of fracture. Generally, there are no outward signs of these changes until fracture occurs. However, once a fragility fracture has occurred, it is an indication that bone strength has been compromised. Thus, patients who have experienced a fragility fracture have an increased risk of subsequent fractures, a risk that is particularly high during the year after the initial fracture [3–5,7].
Fractures related to postmenopausal osteoporosis, particularly hip fractures, represent an enormous burden in terms of suffering and healthcare expenditure. For example, nearly 25% of patients die within 1 year of sustaining a hip fracture, and approximately 25% of survivors require long-term nursing-home care [6]. Fragility fractures will occur in approximately 50% of women after menopause, as well as in approximately one in five men [8,9].
Bisphosphonate therapy: short- & long-term experience
Current pharmacological therapy for osteoporosis consists of reducing bone resorption with the use of antiresorptive (also known as anticatabolic) agents and/or increasing bone formation with the use of anabolic agents. Bisphosphonates are potent inhibitors of bone resorption that slow or arrest progressive bone loss. They have become the treatment of choice for the prevention and treatment of osteoporosis, as well as for other metabolic bone diseases, including Paget's disease of bone, hypercalcemia of malignancy and metastatic bone disease [10,11]. Two bisphosphonates in particular, alendronate and risedronate, have been extensively tested and shown to be effective in reducing the risk of both vertebral and nonvertebral fractures. Data for other bisphosphonates, such as etidronate, are much more limited; they have not convincingly shown reductions in nonvertebral fracture risk [12]. A newcomer in the field is ibandronate, which reduces the risk of vertebral fracture [29]. Certain other anticatabolics, such as calcitonin and raloxifene, have shown efficacy in reducing the risk of vertebral fractures, but do not reduce the risk of the more serious hip fractures and other nonvertebral fractures [12].
Due to their structure, bisphosphonates are poorly absorbed from the gastrointestinal (GI) tract (<1% of the administered dose) and their plasma half-life is very short. Approximately half of the absorbed dose of bisphosphonates is rapidly excreted in the urine, and the other half binds to active bone remodeling sites where the agent inhibits bone resorption by osteoclasts [1]. Thus, most soft tissues are not exposed to clinically significant amounts of bisphosphonates.
The inhibition of osteoclast cells by bisphosphonates decreases bone resorption, thereby allowing remodeling sites to be more completely filled and bone tissue to be fully mineralized [1]. Since osteoporosis is a chronic condition, bisphosphonates will probably be used by individual patients for years. Thus, therapy for osteoporosis has been studied in many thousands of patients for up to 5 years against placebo, and up to 10 years of continuous use [10,13–16]. Various dosing regimens have also been examined. At present, daily or weekly dosing is the customary schedule for administration of bisphosphonates, although once-monthly oral ibandronate has recently been approved in the USA, and annual intravenous administration of zoledronate is currently under investigation [13]. Daily and weekly dosing are considered to provide continuous treatment for osteoporosis. This is because the process of bone resorption requires approximately 2 weeks to complete; bisphosphonates bind to active sites of bone remodeling, where they interrupt the resorption process before it can be completed, when given at daily and weekly dosing at sufficient concentrations. Between 2-weekly dosings, there is no change in the rate of bone turnover. Continuous (daily or weekly) treatment with alendronate or risedronate improves bone microarchitecture and increases bone mass, leading to greater mechanical strength and reduced fracture risk [10].
Alendronate
Alendronate therapy for osteoporosis has been studied in clinical trials involving more than 20,000 patients with up to 10 years of continuous treatment [10,15,17]. The standard treatment dose of 10 mg/day (equivalent to 70 mg once-weekly, see below) reduces biochemical markers of bone turnover to within the premenopausal range within 3–6 months [18]. This dose also produced an increase of approximately 8% in bone mineral density (BMD) at the spine and 7% at the hip within 3 years [19]. Systematic reviews and meta-analyses have demonstrated that alendronate reduces the risk of all types of fractures (including hip fractures) by approximately 50% [20,21].
Long-term follow-up of patients in Phase III studies of alendronate showed that spinal BMD progressively increased throughout 10 years of continuous treatment [15]. Biochemical markers of bone turnover were reduced to premenopausal levels within months and remained stable for up to 10 years, with no evidence of progressive decline. Weekly dosing with alendronate at 70 mg has shown therapeutic equivalence to 10 mg/day, as assessed by bone turnover and BMD changes during 1–2 years of follow-up [22,23]. Alendronate has also demonstrated a significant effect on bone density in clinical trials in men with low bone mass [10].
Recently, a once-weekly tablet combining alendronate 70 mg and cholecalciferol (vitamin D3) 2800 IU has become available. Vitamin D plays a critical role in mineral homeostasis and also appears to be important for neuromuscular function, which may prevent falls (another risk factor for fractures) [24]. Thus, vitamin D is considered an essential component in managing osteoporosis. However, vitamin D is rare in foods and many osteoporotic patients do not take the recommended amounts of vitamin D-containing supplements. The combination tablet ensures that patients receive vitamin D supplements together with the proven effective dose of alendronate for reducing fracture risk.
Risedronate
The approved daily (5 mg) and weekly (35 mg) oral risedronate regimens are therapeutically equivalent to each other with regard to their effects on bone turnover and BMD [25]. Based on estimates derived from a meta-analysis of clinical trials up to 3 years in duration, daily risedronate reduces the relative risk of vertebral fractures by 36% and nonvertebral fractures by 27% [26]. In the Hip Intervention Program, risedronate significantly decreased hip-fracture risk in elderly women with osteoporosis. In addition, longer-term follow-up for up to 7 years has been reported [27]. Continued vertebral fracture efficacy was shown in an extension of the 3-year Vertebral Efficacy With Risedronate Therapy (VERT) multinational study; 265 participants continued treatment, with maintenance of blinding, for 5 years [27]. In an additional 2-year open-label extension of this study, in which all participants, including women previously randomized to placebo, received risedronate 5 mg/day, the incidence of vertebral fractures remained stable during the final 2 years of treatment among women who had received risedronate for all 7 years [28]. A sequential once-weekly risedronate and six-daily calcium treatment schedule is now available in some countries.
Ibandronate
In a 3-year clinical trial, both daily dosing of oral ibandronate (2.5 mg) and an intermittent dosing regimen of 20 mg every other day for 12 doses every 3 months, reduced the risk of vertebral fracture, but did not reduce the risk of nonvertebral fracture [29]. However, a
Etidronate
Etidronate is approved for the treatment of osteoporosis in Canada and some other countries, but not in the USA [10]. In early animal studies, continuous dosing of etidronate, a bisphosphonate with low potency that requires high doses to achieve the desired effect, appeared to inhibit mineralization (occasionally causing osteomalacia) and increase the risk of fractures, whereas a cyclic regimen of etidronate (400 mg/day for 2 weeks every 13 weeks) did not appear to have the same effect [1]. The more potent bisphosphonate compounds do not cause osteomalacia. In a meta-analysis of clinical trials of up to 4 years duration, the risk of vertebral fracture was estimated to be reduced by 27%; nonvertebral fracture risk was not significantly reduced [32].
Bisphosphonates for the prevention of osteoporosis
Bisphosphonates have been demonstrated to prevent bone loss and the development of osteoporosis in younger, at-risk postmenopausal women [10]. Hormone therapy had previously been used for this indication, but because recent randomized, controlled clinical trials have demonstrated associations with increased risk of breast and ovarian cancer, stroke, cardiovascular disease and dementia, current guidelines recommend its use only for short-term control of menopausal symptoms [10]. With alendronate 5 mg/day, bone density at critical sites was preserved after 6 years of continuous treatment in women aged 45–59 years [33]. During the first 2 years of the study, bone density responses with alendronate 5 mg were similar to those obtained with hormone (estrogen–progestin) treatment. Patients who continued through a further 4 years of treatment with alendronate (2.5 or 5 mg/day) or placebo gained significant BMD in the spine and hip. Bone turnover markers, indicators of bone resorption, were significantly decreased within 1 year in women receiving alendronate, and these decreases were sustained throughout the remaining 5 years of the study. The cost effectiveness of such a preventive strategy has recently been challenged [34]. A 3-year trial of risedronate 5 mg/day in an early post-menopausal population also reported that bone loss was prevented [35].
Comparisons between agents
Comparisons of fracture risk reductions would require impracticably large sample sizes, so head-to-head trials of osteoporosis treatments have compared effects on BMD and bone turnover. Alendronate 70 mg once-weekly had significantly greater effects on both BMD and turnover than risedronate 35 mg once-weekly [18,36]. These results are consistent with findings from studies in which alendronate was shown to be superior in terms of BMD changes to other bone resorption inhibitors, such as raloxifene and calcitonin [37,38]. There was no difference in nonvertebral fractures reported as adverse events. However, some further inferences regarding fracture efficacy can be drawn from systematic reviews and meta-analyses. In a series of meta-analyses, only alendronate and risedronate reduced the risk of nonvertebral fracture [39]. Subsequently, adjusted indirect comparison showed alendronate to have greater antinonvertebral fracture efficacy than each of the agents to which it was compared [40].
Safety & tolerability of long-term bisphosphonates
GI symptoms are the most frequently reported adverse event associated with the use of oral bisphosphonates. Esophageal irritation has been reported, and this risk is increased by incorrect dosing [10]. Following the standard administration by taking the dose with at least 2 dl of water and avoiding lying down for at least 30 min after taking the drug (60 min for ibandronate 150 mg) reduces the potential for this adverse effect. In large clinical trials, the incidence of upper GI irritation occurred with similar frequency in patients treated with placebo and those treated with either alendronate or risedronate [10]. The safety and tolerability profiles of alendronate and risedronate were also similar to each other in head-to-head trials [18,36]. The risk of these events does not increase with long-term administration [15,28]. Long-term use could be defined as treatment duration longer than the duration of placebo-controlled trials, in which safety and side effects are evaluated against placebo in an objective manner. Similar to other nitrogen-containing bisphosphonates given intravenously, intravenous ibandronate (2 mg) [41] and, sometimes, high-dose intermittent oral (50, 100 or 150 mg) [31] dosing regimens have been associated with the incidence of influenza-like symptoms, which has been as high as 14.3% with the intravenous dose. In analogy with other bisphosphonates given intravenously, these symptoms may be limited to the first few dosings.
The long-term safety of alendronate and risedronate administered continuously has been evaluated in large clinical studies of up to 10 years duration. There was speculation that the extended residence time of bisphosphonates in bone could overly suppress bone turnover, which would eventually increase the risk of fractures, but this hypothesis has not been supported by data from several studies [10,42–44]. For the potent oral bisphosphonates (risedronate and alendronate), little drug accumulates in the bone, and bone mineralization and quality are improved, not impaired [1]. Treatment of many thousands of patients for extended periods of time in randomized clinical trials has provided ample evidence that bone turnover remains relatively stable during long-term treatment [15,28,33]. In a 10-year study with alendronate in women with osteoporosis, levels of bone remodeling markers were reduced within weeks or months, then remained stable within the premenopausal range during the extended treatment time. Reductions in bone turnover, improved microarchitecture and increased BMD that were observed during the initial months of treatment with alendronate were sustained throughout 10 years of extended treatment [15]. Although there was no difference in nonvertebral fracture risk during the second 5-year period between alendronate-treated and untreated patients, a positive effect on clinical vertebral fracture was detected in the patients who were maintained on alendronate therapy [17].
In animal and human studies, there was no evidence of an increased risk of insufficiency fractures or delayed fracture healing in patients receiving alendronate or risedronate [1,15,19]. Fracture risk reduction benefits during treatment were not lost during extended treatment of up to 10 years [1,44]. Histomorphometric analysis of iliac crest bone biopsies has demonstrated normal bone quality and improvement in bone microarchitecture in women treated with alendronate for up to 10 years. Continued remodeling was observed in all samples and there was no evidence of oversuppression of turnover [43]. However, the offset of action of risedronate is likely to be faster than alendronate. Thus, resumption of bone loss may occur earlier after cessation of treatment with the former agent.
One recent report claimed that low or absent turnover was found in histomorphometric analysis of specimens from nine patients who had received long-term alendronate treatment and who presented with unusual fractures that exhibited delayed healing [45]. The authors speculated that unusually low turnover might have increased the susceptibility to nonspinal fractures, as well as delayed healing of these fractures [45]. Since biochemical markers of bone turnover in these patients were normal or elevated, it is more likely that other factors, such as normal variability among individuals, the presence of other clinical conditions, limitations of biopsy-processing techniques, or concurrent administration of estrogen or glucocorticoids, contributed to the findings reported. This case series has a much weaker level of evidence than the randomized trials discussed earlier.
With the use of large intravenous doses of bisphosphonates in the palliative treatment of bone metastases, a certain number of cases of osteonecrosis of the jaw have been reported [46]. Although the majority of the cases were cancer patients having undergone teeth extraction, a small number of them had received alendronate or risedronate for osteoporosis. The pathogenesis and prevalence of this side effect have still not been elucidated.
Several trials have addressed the pharmacodynamic responses following the cessation of bisphosphonate treatment after various periods of sustained usage. In a blinded, placebo-controlled trial, early postmenopausal women were treated with alendronate for 2, 4 or 6 years, and then given placebo during a total follow-up period of 6 years [14]. Discontinuation of alendronate did not markedly increase bone resorption and did not result in rapid bone loss, whereas a parallel group who received hormone replacement therapy for 4 years experienced large increases in bone resorption and rapid declines in BMD during the subsequent 2 years. Similarly, in patients with osteoporosis, discontinuation of alendronate did not result in rapid increases in turnover or decreases in BMD.
Conclusion
The bisphosphonates alendronate and risedronate have safety and tolerability profiles similar to placebo during both short- and long-term use. Progressive suppression of turnover has not been reported, and antifracture efficacy does not diminish with continuous treatment for as long as 10 years. These drugs are currently central to the management of osteoporosis and other disorders of skeletal metabolism.
Executive summary
Bone remodeling is a lifelong, ongoing process.
Around the time of the menopause, the rate of bone turnover increases.
Without treatment, bone mass and strength decline, potentially leading to osteoporosis and an increased risk of fractures.
Osteoporosis is chronic and progressive.
Bisphosphonates are potent antiresorptive agents that slow or arrest progressive bone loss.
Daily or weekly treatment regimens provide essentially continuous inhibition of bone resorption.
The efficacy and safety of the bisphosphonates alendronate and risedronate have been evaluated in many thousands of patients for up to 10 years of continuous use.
There is particularly strong evidence that alendronate and risedronate reduce the risk of all types of fractures, including hip fractures. Alendronate reduced fracture risk by approximately 50%; risedronate reduced fracture risk by approximately 27–36%.
Daily and intermittent oral dosing with ibandronate reduced the risk of vertebral fracture. A possible effect on nonvertebral fracture is only seen in a subgroup, using the daily regimen.
Vitamin D is an essential component of osteoporosis management, but most patients have low vitamin D levels and do not receive the recommended amounts. A once-weekly tablet combining alendronate and vitamin D3 has recently become available.
Bisphosphonates are also effective in younger, at-risk postmenopausal women to prevent bone loss and the development of osteoporosis. But the cost effectiveness of this therapy has recently been challenged.
In meta-analyses, only alendronate and risedronate reduced the risk of nonvertebral fracture.
Alendronate 70 mg once-weekly had significantly greater effects on bone mineral density and bone turnover than did risedronate 35 mg once-weekly
Safety and tolerability profiles of alendronate and risedronate are similar to placebo during both short- and long-term use.
Reductions in bone turnover remain stable during long-term use; progressive decreases have not been observed.
There is no evidence of an increased risk of insufficiency fractures or delayed fracture healing with the long-term use of alendronate or risedronate.
In short-term studies, high oral doses (50,100 or 150 mg) and intravenous ibandronate (2 mg) have been associated with influenza-like symptoms (incidence up to ~14% with the intravenous dose) at the beginning of treatment.
Alendronate and risedronate remain the cornerstone of osteoporosis treatment and appear to have favorable safety and efficacy profiles throughout long-term usage.
Future perspective
During the next 5–10 years, continuous (weekly regimens) dosing with oral bisphosphonates is likely to remain a prominent treatment option, and evidence from long-term studies will probably only be available for these regimens. A much longer 1-year treatment interval is being tested for intravenous zoledronate; long-term safety issues of intravenous dosing require further evaluation. Other treatments to inhibit bone resorption or increase formation via other mechanisms are currently under development and testing; some may be given orally and some by injection.