Role of bisphosphonates in the management of postmenopausal osteoporosis: an update on recent safety anxieties

Abstract

Following their introduction in the 1990s, bisphosphonates have become the mainstay of treatment in the management of postmenopausal osteoporosis, and their use continues to rise. Commonly noted adverse effects in clinical practice include gastrointestinal side-effects, acute phase reactions (predominately seen with intravenous preparations) cutaneous reactions and more rarely, ocular side-effects. However, recent reports of potentially serious adverse effects of bisphosphonate therapy, including atypical subtrochanteric and femoral shaft fractures, atrial fibrillation, oesophageal carcinoma and osteonecrosis of the jaw, have prompted concerns regarding the long-term safety of this class of drugs. This review summarizes the benefits and potential adverse effects of bisphosphonates used in the treatment of postmenopausal osteoporosis. Although evidence of a definitive casual relationship between bisphosphonate therapy and serious adverse effects is lacking, concern remains particularly in relation to atypical subtrochanteric and femoral shaft fractures. This has important consequences in terms of determining optimum duration of therapy and how best to target therapy at those most at risk. Recently, attention has focused on individual fracture risk assessment in order to optimize the risk–benefit ratio of treatment for individual patients. A review of the role of hormone replacement therapy in younger women with significant risk of osteoporotic fractures may be timely in these circumstances.

Keywords

Postmenopausal osteoporosis bisphosphonates adverse effects fracture prediction hormone replacement therapy

Introduction

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture, notably at the hip, spine and wrist.¹ It is estimated that there are 180,000 osteoporosis-related symptomatic fractures each year in England and Wales, with hip fractures accounting for 70,000 of these.² Around 85% of all osteoporotic fractures occur in women, partly because women have lower peak bone mass compared with men and partly because of the hormonal changes that occur at the menopause. For women over the age of 50 years, the lifetime risk is one in five for hip fracture and one in three for vertebral fracture.² This has substantial economic as well as clinical implications, with the cost of treating osteoporotic fractures in postmenopausal women in the UK predicted to rise to over £2 billion by 2020.³ Following their introduction in the 1990s, bisphosphonates have become the mainstay of treatment in the management of postmenopausal osteoporosis and their use in the UK continues to rise.⁴ Commonly noted adverse effects include gastrointestinal (GI) side-effects, acute phase reactions (predominately seen with intravenous preparations) cutaneous reactions and more rarely ocular side-effects. However, recent reports of potentially serious adverse effects, including atypical subtrochanteric and femoral shaft fractures, atrial fibrillation (AF), oesophageal carcinoma and osteonecrosis of the jaw (ONJ), have prompted concerns regarding the long-term safety of bisphosphonates, which is important in determining how long the treatments should be prescribed. This review summarizes the benefits and potential adverse effects of bisphosphonates used in the treatment of postmenopausal osteoporosis. It also examines the need for individualized fracture risk assessment and targeting of treatment to those patients at highest risk of fracture, the optimum duration of bisphosphonate therapy and the role of hormone replacement therapy (HRT) in the treatment of postmenopausal osteoporosis.

Antifracture efficacy of bisphosphonates

Randomized controlled trials (RCTs) and meta-analyses have shown that alendronate and risedronate reduce the incidence of vertebral, non-vertebral and hip fractures. Etidronate and ibandronate (both oral and intravenous) reduce the incidence of vertebral fractures; however, their impact on non-vertebral fractures is less clear.⁵ Zoledronic acid is the latest third-generation bisphosphonate to be licensed for the treatment of postmenopausal osteoporosis as a once-yearly intravenous infusion. It has been shown to significantly reduce the risk of vertebral, non-vertebral and hip fractures in osteoporotic-postmenopausal women⁶ and reduce vertebral, non-vertebral fractures and mortality in women following surgical repair of hip fracture.⁷ A recent meta-analysis by Bolland⁸ concluded that treatments for osteoporosis with established vertebral and non-vertebral fracture efficacy reduce mortality in older, frailer individuals with osteoporosis who are at high risk of fracture.

Atypical subtrochanteric and femoral shaft fractures

The overall incidence of subtrochanteric and femoral shaft fractures is very low, accounting for less than 10% of all femoral fractures.⁹ The majority of these fractures occur as a result of high-energy trauma, although a significant minority occur in patients following low-energy trauma thus sharing some features of typical osteoporotic fractures.^9–11 However, recent case reports have highlighted subtrochanteric and femoral fractures with atypical clinical and radiographic features in patients on long-term bisphosphonate therapy, raising concern about a possible causal relationship. Biologically this is plausible since bisphosphonates inhibit bone resorption and formation, leading to accumulation of microdamage and stress fractures.¹² Reduced bone remodelling and impaired angiogenesis attributed to bisphosphonates may also delay stress fracture healing, contributing to the development of atypical fractures.¹⁰

Case reports

The American Society for Bone and Mineral Research appointed a task force to address this issue and identified almost 300 case series and reports of subtrochanteric/femoral shaft fractures occurring in patients treated with long-term bisphosphonate therapy for osteoporosis (median duration 7 years; range 1.3–17 years), although they did record that atypical fractures have also been reported in bisphosphonate-naive patients. All individual case reports of atypical femoral fractures illustrate one or more distinctive features, including lack of precipitating trauma, bilaterality, transverse fractures, cortical thickening, stress reaction and poor fracture healing. Prodromal thigh/groin pain was reported in more than 50% of cases and concurrent use of glucocorticoids or proton pump inhibitors noted in a number of cases. Surprisingly, markers of bone turnover were often not suppressed.¹⁰

Clinical trial data

No cases of subtrochanteric fractures were reported in preclinical studies or placebo-controlled registration trials of oral bisphosphonates involving more than 17,000 patients; however, the duration of exposure was less than four years for most patients.¹⁰ Black et al. ¹³ in a secondary analysis of the Fracture Intervention Trial (FIT) of alendronate, the FIT Long-Term Extension Trial (FLEX) and the HORIZON Pivotal Fracture Trial (PFT) of zolendronate, found no significant increased risk, even in women treated for as long as 10 years in the FLEX trial, although confidence intervals were wide due to the small number of events. Atypical features could not be assessed as radiographs were generally unavailable.

Registry-based studies

Data from register-based studies have so far produced conflicting results. In a US study, Neives et al. ⁹ found a significant decline in age-specific incidence rates of typical osteoporotic hip fracture following the introduction of bisphosphonates, but no change in the incidence of subtrochanteric or femoral shaft fractures. A cross-sectional nationwide register study in Denmark by Abrahamsen et al. ¹¹ similarly concluded that patients receiving alendronate were at no greater risk of subtrochanteric/femoral shaft fracture than for an osteoporotic fracture of any part of the femur, and that this risk was reduced by high adherence to alendronate. However, a recent Canadian population-based, nested case-control study concluded that treatment with a bisphosphonate for more than five years was associated with an increased risk of subtrochanteric/femoral shaft fracture, although absolute fracture risk was very low (0.13% during subsequent year and 0.22% within 2 years of surpassing 5 years treatment).¹⁴ These studies have limitations, however, in terms of reliance on diagnostic codes, which can misclassify fracture location, and lack of X-ray adjudication.

A recent study by Dell et al examined the incidence of atypical femoral fractures in a large Californian Health Maintenance Organization. Six hundred subtrochanteric and femoral shaft fractures were identified out of 15,000 hip and femoral shaft fractures in patients over the age of 45, after exclusion of typical hip, peri-prosthetic, pathological and high-energy trauma fractures. All X-rays of subjects with subtrochanteric and femoral shaft fractures were reviewed for atypical features, which were present in 102 (17%) of such patients, 97 of whom were taking oral bisphosphonates for an average duration of 5.5 years. Preliminary estimates of atypical femoral fracture incidence progressively increased from two per 100,000 per year to 78 per 100,000 per year as duration of bisphosphonate therapy increased from two to eight years, suggesting that atypical femoral fractures are more common in patients receiving long-term bisphosphonates.¹⁵ However, there were no age-matched controls, so the baseline incidence in the study population is unknown.

In summary, current evidence is conflicting, although concern remains that long-term bisphosphonate therapy may be associated with an increasing risk of atypical subtrochanteric/femoral shaft fractures. However, the overall risk is likely to be very low and far more femoral neck fractures are likely to be prevented by bisphosphonate use compared with atypical fractures that may be caused by therapy.

Atrial fibrillation

Clinical trial data

A potential association between bisphosphonate therapy and AF was first identified in the HORIZON PFT, which found an increased risk of AF reported as a serious adverse event in the zolendronate group compared with placebo (1.3% versus 0.5%, P < 0.001). The majority of events occurred more than 30 days post infusion.⁶ This prompted re-analysis of the alendronate FIT data, which showed a non-significant increased risk of serious AF in alendronate users (1.5% versus 1.0%, P = 0.07).¹⁶ Subsequent review of risedronate trial data found no increased risk of AF among risedronate users.¹⁷ Interestingly, a subsequent trial of zolendronate in patients following hip fracture found no excess risk of AF, with a reduction in all-cause mortality in the zolendronate-treated group. Only 8% of the mortality reduction was attributed to a reduction in secondary fractures and zolendronate surprisingly appeared to have beneficial effects in terms of cardiac arrhythmias.⁷ The US Food and Drug Administration (FDA) obtained data from drug sponsors of the placebo-controlled clinical trials of bisphosphonates that included 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients. No clear association between overall bisphosphonate exposure and the rate of serious or non-serious AF was observed.¹⁸ A meta-analysis of RCTs and observational studies found a non-significantly higher risk of AF in bisphosphonate users.¹⁹

Registry-based studies

A Danish population-based case-control study by Sorensen et al. ²⁰ found no increased risk of AF/flutter in 2393 current users of alendronate or etidronate. Using the General Practice Research Database (GPRD) in the UK, Grosso et al. ²¹ performed a self-controlled case-series analysis of 2195 patients with AF/flutter and exposure to either alendronate or risedronate. There was no evidence of an increased risk of AF/flutter in bisphosphonate-exposed patients; however, a post hoc time-to-event analysis suggested an increased incidence during the first few months of therapy with alendronate.

Another Danish register-based study by Abrahamsen et al. ²² compared incident rates of AF between 15,795 patients beginning bisphosphonates after fracture, and matched controls. Incident rates were slightly higher in the bisphosphonate group compared with controls; however, effect size was reduced after adjustment for co-morbidity and co-medications and became insignificant (HR 1.18; CI 1.08–1.24). The risk was increased even in patients who stopped bisphosphonates after one prescription and inversely proportional to bisphosphonate adherence. They concluded that the increased occurrence of AF in fracture patients receiving bisphosphonate therapy reflected an elevated baseline risk. This is supported by data from the USA, which demonstrated that patients receiving bisphosphonates have a greater burden of cardiovascular disease.²³ Similarly, postmenopausal women with osteoporosis have been demonstrated to have an increased risk of cardiovascular events proportional to the severity of osteoporosis at the time of diagnosis.²⁴ Postulated mechanisms by which bisphosphonates could directly alter atrial conduction and induce AF include altered electrolyte homeostasis, pro-inflammatory, pro-fibrotic and antiangiogenesis mechanisms, although clinical evidence for this is lacking.²⁵

In summary, studies suggest little or no increased risk of AF in bisphosphonate users; however, these patients appear to have an elevated baseline risk of cardiovascular disease compared with the background population.

Gastrointestinal side-effects

In clinical trials of alendronate, the incidence of upper GI adverse events was similar to placebo. However, post-marketing experience demonstrated that GI side-effects were more common than anticipated and included nausea, dyspepsia, diarrhoea, oesophageal and gastric irritation, erosions and ulceration.^26,27 GI side-effects are a major cause of poor compliance and discontinuation of therapy,²⁸ and are more common in patients with a history of upper GI disorders and those taking concomitant non-steroidal anti-inflammatory drugs, proton-pump inhibitors or histamine-receptor blockers.²⁶ The anatomical distribution of oesophageal and gastric damage is consistent with a topical irritant effect.²⁷ Potential reasons for the discrepancy between trial data and post-marketing experience include poor adherence to dosing instructions in clinical practice and the high background incidence of GI disorders²⁹ and poly-pharmacy in the elderly population most often prescribed bisphosphonates who would otherwise have been excluded from the original clinical trials.²⁷ Intravenous dosing is a means of circumventing the topical irritant effects of oral bisphosphonates.

Oesophageal cancer

In 2009, the FDA reported on 23 cases in the USA and 31 cases in Europe and Japan of oesophageal cancer in patients receiving oral bisphosphonates, with alendronate the most commonly identified suspect drug. Median time from drug use to diagnosis was just over two years.³⁰ A subsequent register study from Denmark found a decreased risk of oesophageal cancer in fracture patients receiving oral bisphosphonates compared with controls.³¹ Similarly a US-based study found no increased incidence among oral bisphosphonate users compared with those receiving other osteoporosis medications.³¹ However, due to the low cancer rate, confidence intervals were wide in both studies and neither study adjusted for potential confounders.

Two subsequent studies using data from the UK GPRD have produced conflicting results. Cardwell et al. ³² found no significant association between bisphosphonate use and oesophageal or gastric cancer. In contrast, Green et al. ³³ using the same database reported a doubling of the risk of oesophageal cancer in patients receiving oral bisphosphonates over five or more years. However, both studies had a number of limitations and it is difficult to draw definitive conclusions from the current evidence available. Current advice from the MRHA lays emphasis on the importance of adhering to dosage instructions and suggest caution when prescribing oral bisphosphonates to patients with known Barretts's oesophagus and other active or recent upper GI disorders.³⁴ However, patients with osteoporosis have been shown to have an increased risk of GI events prior to commencing treatment²⁹ and the risk−benefit ratio in the majority of patients’ remains in favour of bisphosphonate therapy.

Osteonecrosis of the jaw

ONJ, defined by the presence of exposed bone in the mouth that fails to heal after appropriate intervention over a period of six to eight weeks, has increasingly been reported in patients treated with bisphosphonates, mainly those receiving high-dose intravenous bisphosphonates for bone metastases or myeloma.³⁵ It is likely that ONJ results from direct toxicity to cells of the bone and soft tissue from high-potency bisphosphonates, probably acting through their effects on the mevalonate pathway.³⁵ Studying the incidence of ONJ in osteoporosis patients treated with bisphosphonates has proven difficult as ONJ is rare and quantifying the incidence of ONJ from clinical trials and registry data has a number of limitations.¹² However, based on current evidence, the risk of ONJ in osteoporosis appears to be comparable to that of the general population,³⁵ although patients receiving intravenous bisphosphonates are at increased risk,¹² as are those with recent dental extractions and poor oral hygiene.³⁶ When commencing bisphosphonates, in particular intravenous therapy, it is prudent to ensure any major dental work such as extractions are performed prior to commencing treatment. Patients should also be advised to maintain good oral hygiene and receive regular dental check-ups.³⁴

Other adverse effects

Intravenous bisphosphonates are associated with an ‘acute phase reaction’ (APR), occurring to a variable degree in 10–50% of patients, comprising fever, myalgia, arthralgia and flu-like symptoms 1–3 days post infusion.³⁷ Aminobisphosphonates have been shown to stimulate the production of γ/δ T-cells and the associated cytokine release may contribute to the APR seen.³⁸ It is much less likely to occur with second and subsequent infusions and usually responds to simple analgesia such as paracetamol.³⁷ Theoretically, the reaction should be inhibited by co-administration of a statin but a recent randomized controlled trial, while demonstrating the pattern of cytokine release following intravenous zoledronic acid, failed to demonstrate any symptomatic or cytokine benefit in the groups receiving a statin.³⁹ Myalgia, arthalgias and flu-like symptoms have also been reported following administration of oral bisphosphonates¹² and more rarely, generalized musculoskeletal pain.³⁶

Zoledronic acid has been associated with reports of renal failure and impairment following its use, especially in patients with pre-existing renal impairment or other risk factors such as concomitant use of nephrotoxic drugs. The MRHA now recommend that renal function should be monitored before and after each dose, and that patients are adequately hydrated prior to treatment. Zolendronate should not be used in patients with a creatinine clearance <35 mL/minute.³⁴

Bisphosphonates have also been associated with ocular disturbances such as conjunctivitis, blurred vision, eye pain and uveitis, and although rare, patients should be encouraged to immediately report any new eye symptoms while on bisphosphonate therapy.⁴⁰ Cutaneous adverse reactions are not uncommon and range from benign reactions such as maculopapular eruptions, photosensitivity and urticaria to the much rarer and more severe, life-threatening reactions such as angioedema, Stevens Johnson Syndrome and toxic epidermal necrolysis.⁴¹ Treatment is supportive, along with cessation of bisphosphonate therapy.

Assessment of fracture risk

The emerging concern regarding potential adverse effects of bisphosphonates has focused attention on the careful assessment of fracture risk in order to optimize the risk–benefit ratio of treatment for individual patients. Intervention thresholds based on bone mineral density (BMD) alone lack sensitivity, as for any given BMD, the risk of fracture increases exponentially with increasing age and is much greater than can be explained on the basis of BMD alone. Assessment can be improved by the integration of clinical risk factors with or without BMD and the 10-year probability of hip and major osteoporotic fracture in UK men and women aged between 40 and 90 years can be estimated using the WHO Fracture Risk Assessment Tool (FRAX), available at http://www.shef.ac.uk/FRAX.⁴² Output from FRAX has recently been incorporated into guidelines for the diagnosis and management of osteoporosis produced by the National Osteoporosis Guideline Group.⁴³

Duration of bisphosphonate therapy

The antifracture efficacy of alendronate appears to be sustained for up to 10 years.⁴⁴ Similarly, after seven years of continuous risedronate treatment, no loss of antifracture efficacy or adverse safety concerns were reported.⁴⁵ The FLEX trial demonstrated that women who discontinued alendronate after five years had no higher fracture risk over the following five years, other than for clinical vertebral fractures, compared with women who continued alendronate, although the trial was underpowered to detect modest differences in fracture rates.⁴⁶ Similarly, one year after discontinuation of three year's treatment with risedronate, vertebral fracture risk remained reduced, despite an apparent resolution of effects on BMD and bone turnover markers.⁴⁷ The recent suggestion that long-term bisphosphonate therapy may lead to an increase in atypical subtrochanteric and femoral shaft fractures may encourage prescribers to consider a drug holiday after five or more likely 10 years of treatment.

Role of hormone replacement therapy

HRT was considered the first-line therapy for the treatment of postmenopausal osteoporosis up until 2003. Meta-analysis of RCTs demonstrated that HRT produces a significant reduction in vertebral and non-vertebral fractures, including hip fracture, although this effect may be attenuated in women over 60 years.⁴⁸ However, subsequent data from the Women's Health Initiative (WHI) trial in the USA⁴⁹ and the Million Women Study in the UK⁵⁰ demonstrated significant increases in the risk of breast cancer in women taking combined estrogen and progestin compared with placebo. HRT has also been associated with an increased risk of venous thromboembolism and ischaemic stroke.⁵¹ Following the publication of the WHI trial and the Million Women Study, data from the UK GPRD indicated a dramatic drop in the number of prescriptions of HRT in the UK from 2003 to 2005 in women aged below 65 years, along with a steady rise in the number of bisphosphonate prescriptions, predominately in women over 70 years.⁴

HRT remains indicated for the prevention of osteoporosis in postmenopausal women at high risk of fractures who are intolerant of, or in whom other therapies are contraindicated, but is no longer recommended as first-line therapy.⁵² However, recent guidance from the National Osteoporosis Society suggests HRT still has a role to play in younger women aged below 60. In peri-menopausal women with significant osteoporosis, with or without fracture, and no risk factors for breast cancer, heart disease, stroke or venous thromboembolism, the risks associated with HRT are low and the benefits of reduced fracture risk may outweigh the risks associated with HRT in these individuals.⁵³ HRT helps to prevent the dramatic bone loss seen at the menopause for as long as treatment is continued and initial treatment with HRT may be followed by bisphosphonate therapy in those patients with an ongoing high risk of fracture for whom lifelong antifracture treatment may be required, thereby decreasing the duration of exposure to bisphosphonate therapy.

Conclusions

Bisphosphonates are currently the first-line therapy for the prevention and treatment of postmenopausal women based on their efficacy and low cost. Emerging reports of potentially serious adverse effects associated with bisphosphonate use has focused attention on the careful assessment of individual fracture risk, so that treatment can be targeted to those patients at highest risk of fracture. Perhaps of greatest concern currently is the emerging association between long-term bisphosphonate therapy and atypical subtrochanteric and femoral shaft fractures. Physicians and patients should be aware of this rare complication and alert to the prodrome of thigh and/or groin pain that has been reported in more than 50% of patients presenting with atypical subtrochanteric/femoral shaft fractures. The risk of ONJ has been widely publicized, but remains rare in patients treated with bisphosphonates for osteoporosis. Risk can be minimized by attention to good dental hygiene, especially in those patients receiving intravenous bisphosphonates. Given the rarity of both atypical femoral fractures and ONJ, definitive conclusions regarding causality are difficult without further carefully adjudicated large-scale clinical case-control studies. Conclusive evidence for a casual association between AF and oesophageal cancer and bisphosphonate use is lacking and changes in clinical practice are not indicated on the basis of current evidence. However, treatment of women with postmenopausal osteoporosis should include consideration of cardiovascular risk factors, and caution exercised when prescribing bisphosphonates to patients with upper GI disorders.

Ongoing need for treatment should be re-assessed after five years with a view to continuing therapy in those at highest risk of fracture. After 10 years of treatment, good clinical practice would suggest a ‘drug holiday’ of one to two years, before resuming treatment in patients whom ongoing fracture risk remains high. Although there is some evidence that antifracture efficacy does persist for alendronate and risedronate following cessation of treatment, there is no evidence that a ‘drug holiday’ reduces the risk of potential complications such as atypical fractures and the risks and benefits of stopping bisphosphonate therapy need to be considered on an individual basis. HRT may have a role to play in women aged below 60 with significant osteoporosis and no contraindications to its use.

Competing interests: Professor Reid has received recent trial funding from Amgen, Novartis and Roche, and research support from Merck and Pfizer. He has served on advisory boards for Eli Lilly, Amgen, Merck, Novartis and Servier, and is a shareholder in Astra Zeneca and GlaxoSmithKline. He has also received speaker fees from Amgen and Novartis in the past year. Dr Hollick has received speaker fees from Eli Lilly.

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