Dr Frances Barnett, The Ludwig Institute for Cancer Research, Post Office Box 2008, Royal Melbourne Hospital, Parkville, Vic. 3050, Australia. Email: email@example.com
Cancer treatment-induced bone loss (CTIBL) is the phenomenon of loss of bone mass directly due to the effects of treatment for cancer. There are many causes of CTIBL. This article focuses on CTIBL in the hormone-dependent cancers (breast and prostate) and reviews the mechanisms, the extent of the problem and the management strategies.
WHAT IS ‘CANCER TREATMENT-INDUCED BONE LOSS’ AND HOW IS IT MEASURED?
The term ‘cancer treatment-induced bone loss’ (CTIBL) refers to a reduction in bone mass and bone mineral density (BMD) as a direct result of cancer treatment. It occurs due to a disruption in the normal process of bone remodelling.
Bone remodelling is a continuous process, consisting of simultaneous breakdown and rebuilding of bone in order to mobilise calcium from the skeleton and to optimise bone structure for mechanical support. Remodelling is carried out by the bone multicellular unit,1 which consists of osteoclasts, mononuclear cells, osteoblasts, and relevant precursor cells. In response to mechanical processes, hormones or cytokines, osteocytes are believed to initiate remodelling by sending a signal to bone lining cells. This signal begins a process that results in osteoclast formation and bone resorption.2 Resorption is followed by the phase of bone formation, which involves osteoblasts. Osteoblasts synthesise the matrix that is then mineralized and which replaces or reshapes the bone that has been resorbed.2
Many factors are essential for osteoclast differentiation and function. The critical factor is believed to be receptor activator of nuclear factor κB (RANK)-ligand.2 Binding of RANK-ligand to its receptor (RANK) on osteoclasts induces various signaling cascades, resulting in stimulation of osteoclasts and subsequent bone resorption (Fig. 1). Expression of RANK-ligand is influenced by a number of competing processes. Factors such as interleukin-1 (IL-1), IL-11, IL-6, prostaglandin E2, glucocorticoids, parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) can stimulate the expression of RANK-ligand in osteoblast lineage cells.3,4 RANK-ligand expression is inversely correlated with serum levels of estrogen.5 The key inhibitor of the system is osteoprotegerin (OPG). OPG is produced by pre-osteoblast/stromal cells in response to a number of cytokines and hormones, including estrogen.6,7 OPG production is inhibited by glucocorticoids, PTH and prostaglandin E2. It is a soluble decoy receptor of RANK-ligand, and is named for its role in protecting against bone loss. OPG specifically binds to RANK-ligand and prevents the ligand binding to its receptor8 (Fig. 2). In doing this, OPG inhibits osteoclastogenesis and bone resorption.
The control of osteoblast differentiation is an area of ongoing research, but appears to involve the core binding protein from the runt family (CBF-A1)9 and osterix (OSX).10 Osteoblast lineage cells can be divided into two groups: regulatory cells and worker cells. In response to osteoclast-stimulating signals and other signals that regulate bone remodelling, the regulatory osteoblast lineage cells express RANK-ligand leading to osteoclast formation and activation. Worker pre-osteoblasts/osteoblasts are actively involved in bone formation by producing and laying down bone matrix.2
During periods of childhood skeletal growth, bone mass increases due to increased bone formation. In early adulthood (20–40 years), bone formation and resorption are in balance, and bone mass is maintained. Estrogen is the primary hormone responsible for maintaining bone mass in adult women, and may serve a similar role along with androgen in men. The exact mechanisms through which estrogen regulates bone remodelling are not currently completely understood. It is believed that estrogen acts directly on osteoblast differentiation and gene expression, which leads to regulation of osteoclast activity11 and inhibition of bone resorption. When estrogen levels drop substantially, such as at the female menopause, the inhibition of osteoclastogenesis is lost, and bone resorption is greater than bone formation. This can lead to osteopenia and osteoporosis.
In pre-menopausal women estradiol, produced by the ovaries, is the primary estrogen. When estradiol production ceases at menopause, androgens (from the adrenal gland and, in part, from the stroma of the ovary) are converted into estrone by the aromatase enzyme complex.12 Although estrone is a weaker estrogen than estradiol, it does help to maintain bone mass.13
With regard to androgens and their effects on bone physiology, there is evidence that testicular androgens inhibit bone resorption. Thus orchidectomy, like oophorectomy, is associated with increased bone resorption and loss of bone mass.14 The role of progesterone and adrenal androgens in bone biology remains unclear.
How is CTIBL measured?
Dual energy X-ray absorptiometry (DEXA) scanning is the gold-standard for measurement of bone density. BMD measurements are reported as standard deviations (SD) from the mean. In relation to the bone mass of 30 year-old subjects of the same sex, this SD value is expressed as a T-score. In relation to an age-matched population, the SD value is expressed as a Z-score. A T-score of between −1 and −2.5 is defined as osteopenia and osteoporosis is defined operationally as a T-score of <−2.5.15 For every decrease in BMD by 1 standard deviation, there is a 1.5–2.5 fold increase in the relative risk of fracture.16
Other methods to measure skeletal mass or density include quantitative computed tomography (CT) and ultrasound; these are not routinely used at present for this indication.
Causes of CTIBL
CTIBL may be due to:
1Hypogonadism induced by chemotherapy, hormonal manipulation or cerebral radiotherapy.
2Direct effects of individual drugs on bone metabolism (e.g. methotrexate, ifosfamide, glucocorticoids).
3Other causes, including malnutrition/malabsorption (e.g. following gastric surgery), growth-hormone deficiency (e.g. following cerebral radiotherapy), thyroid-stimulating hormone-suppressive doses of thyroxine in patients with thyroid carcinomas, and post-transplantation osteopathy following some hematological malignancies.
The following review will focus on CTIBL due to hypogonadism in hormone-dependent cancers.
HYPOGONADISM AND CTIBL
As discussed earlier, sex hormones play a vital role in development of peak bone mass and maintenance of bone mass during life. Both osteoclasts and osteoblasts have receptors for estrogen17,18 and androgen.14 Progesterone receptors have been identified on osteoblasts.14
Hypogonadism leads to decreased levels of estrogen and/or progesterone and/or testicular androgens. It may be a desired or undesired effect of treatment, depending on whether the tumor is hormone dependent or not. In patients with cancers that are not hormone dependent, CTIBL may be effectively prevented and/or managed, at least in the short term, with age-appropriate hormone replacement therapy (HRT). This is a common situation in diseases such as acute leukemia and the lymphomas, where curative myeloablative therapy leads to premature gonadal failure, and HRT is a safe and effective replacement. The situation is quite different in patients who develop the hormone-dependant cancers, breast cancer and prostate cancer. In these patients the use of HRT is contra-indicated due to its potential impact on disease relapse.
Hypogonadism in breast cancer patients due to chemotherapy
Permanent ovarian failure is a frequent side-effect of cytotoxic therapy for pre-menopausal women with breast cancer. The incidence ranges from 63 to 85% of women treated with cyclophosphamide, methotrexate and 5-fluorouracil, and 50% or more of women treated with anthracycline-containing regimens.19,20 The use of adjuvant taxanes can further increase the frequency of premature menopause.21 The risk of ovarian failure also relates to the age at time of treatment22 (with a higher likelihood the closer the woman is to the natural menopause), the cumulative dose of drug administered, and the duration of treatment.23 Premature ovarian failure causes a significant drop in serum estradiol levels, resulting in an increase in osteoclast activity and bone resorption. Decreases in BMD have been observed in women with ovarian failure related to chemotherapy,24–26 similar to the bone loss that follows natural menopause (Table 1). There is no data concerning actual fracture rates as BMD is used as a surrogate for fracture risk.
Table 1. Changes in BMD after chemotherapy-induced ovarian failure
Many women with estrogen and/or progesterone receptor positive tumors are treated with tamoxifen as adjuvant therapy (either alone or following chemotherapy). In post-menopausal women, tamoxifen has been shown to maintain, or even increase, BMD.28,29 This is believed to result from tamoxifen’s estrogen-agonist properties on bone cells. However, in pre-menopausal women tamoxifen use has been associated with a significant loss of BMD.28,29 A possible explanation is that when estrogen levels are high, tamoxifen has an estrogen-antagonist (rather than agonist) effect on bone cells.
There are three third-generation aromatase inhibitors (AI) currently used in clinical practice. Anastrazole and letrozole are non-steroidal AI, and exemestane is a steroidal AI. AI reduce circulating estrogen to near undetectable levels. The average estradiol level in a post-menopausal patient is 17.2 pmol/L; treatment with anastrazole and letrozole decreases this to 2.6 pmol/L and 2.1 pmol/L, respectively.30 Estrone was also dramatically reduced by both anastrazole and letrozole. With the critical role that estrogen plays in maintenance of bone mass, this reduction has the potential to lead to accelerated bone loss.
In adjuvant trials, all three third-generation AI have been associated both numerically and statistically with more fractures than tamoxifen or placebo (Table 2).
Table 2. Incidence of fractures associated with aromatase inhibitors in early breast cancer
In the anastrazole, tamoxifen, alone or in combination (ATAC) trial in post-menopausal women with early stage breast cancer, anastrazole significantly increased fracture risk compared with tamoxifen (11% compared to 7.7% after a median of 68 months follow-up; odds ratio 1.49; 95% CI 1.25–1.77).31 Importantly, the fracture rate was not increased in the hip. The overall increased risk of fracture correlated with a decrease in BMD. In a subset of 308 ATAC patients who were specifically assessed for bone safety, there was a 4% decrease in lumbar spine BMD and a 3.2% decrease in hip BMD after 2 years of treatment with anastrazole. Patients on tamoxifen had increases of 1.9% in lumbar spine BMD and 1.2% in hip BMD.35
Letrozole has been studied in early breast cancer both in the upfront setting against tamoxifen (BIG 1–98 trial) and in the extended adjuvant setting against placebo (MA-17 trial). The Breast International Group (BIG) 1–98 trial, which enrolled 8010 women, recently reported its results after a median follow-up of 25.8 months.32 Fractures were seen in 5.7% of women in the letrozole group compared to 4.0% of women in the tamoxifen group (P < 0.001). The MA-17 trial investigated the antitumor effect of letrozole after 4.5–6 years of tamoxifen. In the first 4299 women enrolled on study (out of a total of 5187), at a median follow-up of 2.4 years, the clinical fracture rate for letrozole was 3.6% versus 2.9% for placebo but this difference did not reach statistical significance (P = 0.24).33 More women in the letrozole group than in the placebo group reported a diagnosis of new onset osteoporosis (5.8% versus 4.5%, P = 0.07).
The Intergroup Exemestane Study (IES)34 enrolled 4742 post-menopausal women with early breast cancer to investigate whether exemestane given to women who were free of recurrence after receiving tamoxifen for 2 to 3 years could prolong disease-free survival, as compared with continued tamoxifen therapy. At a median follow-up of 30.6 months, the incidence of osteoporosis was 7.4% with exemestane compared to 5.7% with tamoxifen (P = 0.05). The fracture rate for exemestane was 3.1% versus tamoxifen 2.3% which was not statistically significant (P = 0.08).
Thus, it appears that both steroidal and non-steroidal AI lead to bone loss and increase the risk of bone fractures. However, when AI are given following tamoxifen (as in MA-17 and IES), the fracture risk appears not to be as large compared to when AI are given up-front.
Ovarian suppression may be recommended to women as adjuvant endocrine therapy without chemotherapy and to women who remain pre-menopausal following chemotherapy. A combined analysis of 12 studies of women with early breast cancer indicated a highly significant improvement in both recurrence rates and survival for ovarian suppression in women under 50 years old, both with and without chemotherapy.36 Methods for ovarian suppression include bilateral oophorectomy, gonadotrophin suppression with gonadotrophin releasing hormone (GnRH) agonists, or ovarian radiation. This leads to a marked decrease in circulating estrogen. A reduction in BMD is an expected side-effect and has been reported within 6 months of commencing GnRH agonist therapy.37
Hypogonadism in patients with prostate cancer
Long-term androgen suppression is an effective systemic treatment for men with advanced prostate cancer, and can be achieved by either bilateral orchidectomy or GnRH agonists. This results in decreases of approximately 90% in serum testosterone as well as decreases in concentrations of estradiol; it does not affect adrenal androgen biosynthesis.
Both orchidectomy and GnRH agonists lead to a decrease in BMD38–41 (Table 3). In the setting of metastatic prostate cancer, these men may be elderly and already osteopenic or osteoporotic, and thus have a substantial fracture risk, prior to commencing androgen deprivation therapy.
Table 3. Change in BMD associated with androgen suppression in men with prostate cancer
Another issue is the increased fracture risk with the use of castration in men in non-metastatic prostate cancer, either as initial or adjuvant therapy, where life expectancy may be many years. A cohort study that involved 11 661 men with non-metastatic prostate cancer42 found that with one or more years of GnRH agonist therapy, the hazard ratio for fracture risk was 1.16 (95% CI 1.08–1.26; P < 0.0001).
ETHNIC DIFFERENCES AND CTIBL
It is well recognized that rates of osteoporosis and fracture differ among different racial groups. Blacks have a lower risk of fractures than whites.43 Asians have lower BMD than Caucasians, yet fracture rates are generally lower in Asians.44
Despite these known differences, there is a paucity of literature concerning CTIBL and ethnic differences. While most of the data published relates to a white population, a multivariate analysis conducted by Smith et al. found that black men had a significantly lower fracture risk than white men when treated with GnRH analogs for non-metastatic prostate cancer in America.42 The extent of CTIBL in black women treated for breast cancer, and in Asian and other populations, remains uncertain and is worthy of future study.
CONSEQUENCES OF CTIBL
CTIBL can result in osteoporosis, which increases risk of bone fracture and consequent morbidity and mortality. Common fractures sites are the femoral neck (hip), thoracic and lumbar spine, and radius, with the important potential morbidities being acute and chronic pain; loss of mobility; and loss of function, sometimes requiring placement in assisted accommodation. Hip fracture in patients without cancer is associated with a 10–20% mortality over the first 6 months following the fracture.45
MANAGEMENT OF CTIBL
Management of CTIBL should involve strategies aimed at both preventing and treating the problem. To prevent CTIBL, methods to stop the imbalance between bone resorption and formation are required. Effective treatment of CTIBL must stop, and then reverse, this imbalance.
Basic management of bone strength includes ensuring adequate vitamin D levels and calcium intake. Within populations in Australia, where sunlight exposure is the main source of vitamin D, vitamin D deficiency is a significant problem. In studies of people living in hostels or nursing homes in Victoria, New South Wales and Western Australia, up to 80% of women and 70% of men were deficient in vitamin D.46,47 Other studies have revealed a proportion of younger adults who have mild vitamin D deficiency, particularly during winter.48 The recommended daily dietary dose of vitamin D depends age and vitamin D levels. It ranges from 200 international units (IU) per day to prevent vitamin D deficiency, to 3000–5000 IU per day to treat moderate to severe deficiency.49 The recommended daily calcium intake also varies according to age, ranging from 500 to 1300 mg per day.50 Supplementation with calcium and vitamin D can increase BMD by up to 2% in primary osteoporosis in both men and women.51 Other measures for good bone health include weight bearing exercise and avoidance of smoking.
Bisphosphonates are currently the most effective agents that inhibit bone resorption.52 Bisphosphonates are compounds with a chemical structure similar to that of inorganic phosphate (PPi), an endogenous regulator of bone mineralization.53 Like PPi, bisphosphonates form a three-dimensional structure capable of binding divalent metal ions such as calcium, and their affinity for calcium can be increased further if one of the side chains of the bisphosphonate molecule is a hydroxyl (-OH) or primary amino (-NH2) group.54 Thus potency varies according to side-chain structure.55,56
The ability of bisphosphonates to adsorb to bone mineral via exposed calcium selectively delivers them to sites of active bone remodelling, where they are potent inhibitors of bone resorption mediated by osteoclasts.57
Bisphosphonates are indicated in the treatment of diseases that involve excessive osteoclast activity, such as established osteoporosis in healthy men and women, and Paget’s disease. Similarly, bisphosphonates are the cornerstone of treatment for skeletal metastases in the hormone-dependent malignancies, breast and prostate cancer, and in multiple myeloma. There is also evidence that bisphosphonates are effective in both the prevention and management of CTIBL.58
There is a number of oral and intravenous bisphosphonates available. Those most commonly used in oncologic practice are clodronate, pamidronate and zoledronate. Others used more commonly for primary osteoporosis include etidronate, alendronate and risedronate.
Bisphosphonates and premature menopause secondary to chemotherapy in early stage breast cancer
Studies with clodronate, risedronate and pamidronate have shown that bisphosphonates are at least partially able to prevent bone loss in women with chemotherapy-induced premature menopause. Saarto et al.25 studied the effect of clodronate on the prevention of bone loss in 148 pre-menopausal women with breast cancer undergoing adjuvant CMF chemotherapy. Patients who developed amenorrhoea after chemotherapy had a rapid bone loss, which was significantly reduced (although not eliminated) by clodronate. In controls, bone loss was 9.5% in the lumbar spine and 4.6% in the femoral neck; in the clodronate group, bone loss was 5.9% and 0.4%, respectively, at 2 years. Two years after termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.26
Delmas et al.27 studied the effect of risedronate in 53 women with premature menopause following chemotherapy for breast cancer. In contrast to the placebo group, there was an increase in BMD in the risedronate group during the 2-year treatment period. After treatment withdrawal, a difference could still be demonstrated in BMD between the two groups at 3 years.
A small study, involving 40 pre-menopausal women with newly diagnosed breast cancer undergoing adjuvant chemotherapy, randomised patients to either pamidronate 60 mg i.v. every 3 months for 4 doses or to placebo.59 Over half the patients became amenorrhoeic during the study. In the overall study group, BMD stabilized at the lumbar spine in the pamidronate group and decreased in the placebo group, with a significant treatment effect at 6- and 12-months; the trend was similar at the hip but not statistically significant. In the amenorrhoeic group, BMD stabilized in both the spine and the hip in the pamidronate group, whilst decreasing in the placebo group. In the nonamenorrhoeic group, there were no differences between the pamidronate and placebo groups. This suggests that pamidronate can prevent CTIBL in women undergoing adjuvant chemotherapy for breast cancer, particularly if the chemotherapy results in ovarian failure.
Bisphosphonates and endocrine therapies in early breast cancer
The ABSCG-12 trial60 was a large, multicentre, randomised phase III trial comparing anastrazole with tamoxifen in the adjuvant treatment of hormone-responsive breast cancer in pre-menopausal patients in combination with the GnRH agonist goserelin. No patient received chemotherapy. Following surgery (± radiation therapy) patients with stage I and II breast cancer received goserelin and were then randomised into the four treatment arms:
2Tamoxifen and zoledronic acid.
4Anastrazole and zoledronic acid.
The zoledronic acid was given as a 4 mg, 15 min intravenous infusion every 6 months. Study endpoints included changes in BMD. Patients who received combination endocrine therapy without zoledronic acid had significant bone loss after 2 years (overall −12% BMD, relative T-score −1.2); the bone loss was more severe in patients who received anastrazole/goserelin (mean −16% BMD with relative T-score −1.6) as compared to tamoxifen/goserelin (mean −8% BMD with relative T-score −1.0). Patients who received zoledronic acid had stable BMD with no measurable change in BMD (P < 0.0001).
The Z-FAST and ZO-FAST trials were designed to compare immediate versus delayed zoledronic acid used in conjunction with letrozole in post-menopausal women undergoing adjuvant therapy for early breast cancer. In the US-based Z-FAST trial, 612 women with stage I-IIIa hormone receptor-positive breast cancer commencing letrozole 2.5 mg per day for 5 years were randomised to up-front zoledronic acid (4 mg intravenous infusion every 6 months) versus delayed zoledronic acid. In the delayed group, zoledronic acid was commenced if the postbaseline T-score reached <−2 or if a bone fracture occurred. Initial results (343 of 602 patients evaluable) showed that the up-front zoledronic acid group had a mean increase in BMD of 2.02% while the delayed group had a mean decrease of 2.61% at 12 months, resulting in a significant difference of 4.63% between groups (P < 0.001). Zoledronic acid was reported to be safe and well tolerated.61
The ZO-FAST study (conducted in Europe and Australasia) recruited 1050 patients. Initial results confirmed that up-front zoledronic acid is effective at increasing BMD in post-menopausal women with early breast cancer being treated with adjuvant letrozole.62
Bisphosphonates and androgen deprivation in prostate cancer
Studies with cyclic etidronate,63 pamidronate64 and zoledronate65 have been done to evaluate bisphosphonates in preventing bone loss due to androgen deprivation therapy used for prostate cancer (Table 4). A beneficial effect of cyclic etidronate on bone loss was found in 12 men with prostate cancer who were treated with combined androgen blockade (GnRH agonists and the androgen antagonist flutamide).63 In the first 6 months of treatment with combined androgen blockade there was an increase in bone turnover and a 6.5% decrease in the mean femoral neck BMD; treatment with etidronate in the following 6 months led to an increased BMD.
Table 4. Changes in BMD associated combined androgen suppression and bisphosphonate use
A study evaluating the GnRH agonist leuprolide with and without pamidronate64 demonstrated no significant change in BMD in those given pamidronate, compared to the decrease in BMD seen in those without pamidronate. Even more promising, a study that evaluated zoledronate was able to show an increase in BMD when used in conjunction with a GnRH agonist with or without an antiandrogen.65
These trials demonstrate that bisphosphonates are effective at preventing, and possibly treating CTIBL in the hormone-dependent cancers. Although it would appear that zoledronate is the most effective of the bisphosphonates, no head-to-head comparisons have been done between agents. Thus, there are still unanswered questions; in particular, which bisphosphonate should be used and at what dosage, when should treatment commence, and how frequently should treatment be administered? Trials are underway that should answer some of these questions.
Selective estrogen receptor modulators (SERMs)
Unlike tamoxifen, which is not considered a stand-alone treatment for osteoporosis, raloxifene is used for treatment of osteoporosis in post-menopausal women. The Multiple Outcomes of Raloxifene Evaluation (MORE) study, which looked at raloxifene in the prevention of osteoporosis, found raloxifene was protective against breast cancer development.66 Nevertheless, there is a lack of direct evidence supporting the use of raloxifene for management of CTIBL in women with early breast cancer.67
One of the original arms of the ATAC trial was combination therapy with tamoxifen and anastrazole; this arm was closed following initial analyzes because of lower efficacy compared with anastrazole alone with respect to endpoints. It is interesting to note that after a median follow-up of 33 months, the fracture rate for combination therapy was in between that observed for both anastrazole and tamoxifen.68 From this we can conclude that tamoxifen administered with anastrazole may have a partially protective effect with regard to bone health but at the expense of reducing anastrazole’s efficacy in breast cancer endpoints.
Therapeutic strategies targeting RANK-ligand/RANK/OPG system and RANK signaling
The RANK-ligand/RANK/OPG system is critically involved in bone biology and extensive research is currently underway looking at various ways of targeting this system for management of bone disorders, including osteoporosis and CTIBL. The molecule AMG 162 (also known as denosumab) is an anti-RANK-ligand antibody. It has entered phase III trials in patients with bone metastases and in non-cancer patients with osteoporosis.
In 2003, the American Society of Clinical Oncology (ASCO) recommended a bone management strategy for patients diagnosed with non-metastatic breast cancer.67 The initial step is the assessment of a patient’s osteoporosis risk. If low, screening BMD is not recommended but patients need to have their risk status reassessed annually. If high risk (defined as age > 65; age 60–64 years with positive family history, body weight < 70 kg, prior non-traumatic fracture; post-menopausal women of any age receiving aromatase inhibitors; pre-menopausal women with therapy-associated premature menopause) then DEXA testing for BMD is recommended. Management recommendations are based on T score (Table 5) with repeat BMD testing annually. A similar management approach can be applied to all patients at risk of CTIBL.
Table 5. ASCO recommended management strategy for patients diagnosed with non-metastatic breast cancer67
−2.5 or lower
Begin calcium and vitamin D
Begin therapy, e.g. alendronate, risedronate, zoledronic acid
−1.0 and −2.5
Begin calcium and vitamin D
Greater than −1.0
Begin calcium and vitamin D
At present in Australia, the oral bisphosphonates alendronate and risedronate are only available through the Pharmaceutical Benefits Scheme (PBS) for established osteoporosis associated with fragility fracture. Intravenous bisphosphonates are not funded for this indication. There are no bisphosphonates available through the PBS for osteoporosis without fracture, or for the prevention or treatment of CTIBL.
CTIBL is a real and increasing problem that has potential to cause substantial morbidity and mortality. Fortunately it is manageable, and ongoing studies are likely to show that it is preventable with currently available bisphosphonate therapy. The challenge to medical practitioners caring for patients at risk of CTIBL is to identify the potential problem early, then to investigate and treat appropriately.
Dr Frances Barnett has no conflicts of interest. Dr Richard de Boer is a member of the ZO-FAST study steering committee, and receives an honorarium from Novartis for participation in this committee.