Aromatase inhibitors associated with knee ...

CLIMACTERIC 2012;15:1–7

Aromatase inhibitors associated with knee subchondral bone expansion without cartilage loss S. R. Davis, R. J. Bell, Y. Wang, F. Hanna, M. Davies-Tuck, R. Bell*, J. Chirgwin† and F. Cicuttini School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria; *Andrew Love Cancer Centre, Geelong Hospital, Geelong, Victoria; †Department of Medical Oncology, Box Hill and Maroondah Hospitals, Maroondah Breast Clinic, Ringwood East, Victoria, Australia

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Key words: AROMATASE INHIBITORS, SUBCHONDRAL BONE, OSTEOARTHRITIS, CARTILAGE, ESTROGEN DEFICIENCY

ABSTRACT Background The profound estrogen depletion caused by aromatase inhibitors (AIs) is associated with musculoskeletal symptoms, but the underlying pathophysiology remains unclear. Objective To assess the effects of AI therapy on structural changes in knee cartilage and subchondral bone over 2 years in postmenopausal women. Setting and participants Thirty women with breast cancer, mean age 58.5 (standard deviation ⫹ ⫺ 5.6) years and 62 healthy controls, mean age 56.5 (standard deviation ⫹ 4.6) years. ⫺ Main outcome measures Annualized changes in tibial cartilage volume and subchondral bone area, and worsening of tibiofemoral cartilage defects from paired knee magnetic resonance imaging 2 years apart were compared between the two groups. Results The AI-treated women had significantly greater expansion of the tibial plateau than the control group. The mean annualized differences, after adjusting for age, body mass index and baseline bone area, were 22.1 mm2 (95% confidence interval (CI) 7.6–36.6, p ⫽ 0.003) for the medial tibial plateau and 19.1 mm2 (95% CI 9.6–28.5, p ⬍ 0.001) for the lateral tibial plateau. The annual change in tibial cartilage volume and the worsening of cartilage defects did not differ between women taking AI therapy and controls. Conclusions AI therapy is associated with knee subchondral bone expansion knee with no effect on knee cartilage in postmenopausal women without pre-existing joint symptoms. This suggests the effect of severe estrogen depletion on knee is on bone, with the tibial bone expansion most likely a response to mechanical load in the setting of bone loss. Whether this then results in an increased risk of knee osteoarthritis will need to be determined.

INTRODUCTION The aromatase inhibitors (AIs) systemically block non-ovarian estrogen production in postmenopausal women, resulting in profound estrogen depletion. Hence, AIs are widely prescribed as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive (HR⫹) breast cancer. The side-effects of AIs reflect the profound estrogen deficiency achieved and include hot flushes and night sweats, urogenital atrophy, increased cholesterol, bone loss and a significantly increased risk of fracture. AI use is also associated with a high

incidence of arthralgia which can substantially impair quality of life and frequently is the prime reason for treatment discontinuation1. Tenosynovial changes suggesting tenosynovitis of the wrist and hand have been found in women with AI-induced arthralgia, which may partly explain the joint pain and stiffness experienced in ultrasound and magnetic resonance imaging (MRI) studies2. However, the effect of AIs on other joint structures, such as articular cartilage and subchondral bone, are unclear. MRI facilitates direct visualization of all joint structures and has been shown to be a useful tool to assess

Correspondence: Dr S. R. Davis, Women’s Health Research Program, Department of Epidemiology and Preventive Medicine, Monash University, 99 Commercial Road, Melbourne, VIC 3004, Australia ORIGINAL ARTICLE © 2012 International Menopause Society DOI: 10.3109/13697137.2012.746656

Received 09-10-2012 Accepted 01-11-2012


Aromatase inhibitors and knee subchondral bone expansion

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early structural changes prior to the onset of clinical joint diseases. Cartilage volume, cartilage defects and subchondral bone area can be measured accurately and reproducibly from MRI and they are associated with pain3 and predictive of disease progression of knee osteoarthritis (OA)4. Estrogen acts directly on both cartilage and bone5. We have demonstrated that postmenopausal estrogen use, for at least 5 years, is associated with retention of articular cartilage in the knee6. Although estrogen replacement therapy maintains bone mass and decreases bone resorption, the data for effects of estrogen use on subchondral bone in animal studies have been conflicting7,8. The aim of this study was to examine whether the use of an AI for 2 years was associated with adverse effects on knee cartilage and subchondral bone using MRI. Postmenopausal women without breast cancer recruited from the community provided comparative data. The latter was considered the optimal comparator group as the alternate endocrine therapy to AI therapy, tamoxifen, may have favorable bone effects9. Hence, tamoxifen users would not be appropriate as controls. Women with breast cancer who are not candidates for tamoxifen or an AI have hormone receptor-negative disease, represent the minority of postmenopausal women with breast cancer and have a poor prognosis in the first 2 years.

therapy and had a body mass index (BMI) between 20 and 37 kg/m2. Of the 70 women who met these criteria, eight had missing MRI data. The women were not individually matched with the women in the AI group. Women with breast cancer were excluded if they had used AI therapy for ⬎ 12 weeks before their baseline knee MRI or had been treated with tamoxifen for ⬎ 8 weeks in the 2 years prior to enrolment. Controls and women with breast cancer were excluded from the study if they had experienced significant knee pain (pain requiring any intervention by a health professional, medication or necessitating non-weightbearing therapy) or a knee injury in the previous 5 years that necessitated treatment or required rest for more than 1 day, ever been diagnosed with rheumatoid arthritis, been treated for any other form of arthritis, had a contraindication to undergoing MRI, or were unlikely to be available to complete the full 2-year study. Knee radiographs were not obtained. The study was performed according to the Declaration of Helsinki and approved by the Human Research Ethics Committee of Monash University. All participants gave written informed consent.

METHODS

Magnetic resonance imaging

Study design

All women had a baseline MRI scan on their dominant knee (defined as the lower limb from which the subject stepped off from when initiating gait) and a follow-up MRI scan on the same knee approximately 2 years later. Knees were imaged in the sagittal plane on a 1.5-T whole body magnetic resonance unit (Signa Advantage GE Medical Systems Milwaukee, WIS, USA) with use of a commercial transmit-receive extremity coil as previously described12. All MRI measurements were performed by trained observers blinded to clinical data, AI or control group, and sequence of MRIs.

This was a prospective cohort study conducted at the Alfred Hospital Campus of Monash University in Melbourne and the Andrew Love Cancer Centre, Geelong Hospital, Geelong, Australia.

Study population Women aged 40–65 years with HR⫹ breast cancer who had undergone breast surgery, with or without radiotherapy or chemotherapy, and were to be treated with an AI (anastrozole 1 mg/day or letrozole 2.5 mg/day) were invited to participate in the study by their treating physician (AI group). After expressing interest in the study, potential participants were contacted by telephone and screened for the exclusion criteria. If eligible and wishing to participate, a study visit and a knee joint MRI were booked. Prior to a date 2 years after study entry, each participant was re-contacted to arrange the final study visit which involved a repeat MRI of the same knee. The 62 controls were selected from 176 women who had previously participated in a longitudinal study of factors affecting knee cartilage10. These women were initially recruited from a database established from the electoral roll in Victoria, Australia, between April 2002 and August 200311. From this group, we selected women who were postmenopausal, non-hysterectomized, not taking any hormone replacement

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Measurement of cartilage volume, bone area and cartilage defects

Quantification of knee cartilage volume Articular tibial cartilage volume was determined by means of 3D-image processing on an independent workstation using the software program OSIRIS (University Hospital of Geneva, Geneva, Switzerland). The image data were transferred to the workstation and an isotropic voxel size was obtained by a trilinear interpolation routine. The volume of individual cartilage plates was isolated from the total volume by manually drawing disarticulation contours around the cartilage boundaries on a section-by-section basis. These data were resampled by means of bilinear and cubic interpolation (area of 312 ⫻ 312 μm and 1.5 mm thickness, continuous sections) for the final 3D-rendering. The volume of the particular cartilage plate was determined by summing all the pertinent voxels within the resultant binary volume. The coefficients of variation (CVs) of this method were 3.4% for medial tibial and 2.0% for lateral tibial cartilage

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Aromatase inhibitors and knee subchondral bone expansion volume12,13. Change in cartilage volume (follow-up cartilage volume subtracted from initial cartilage volume) over the period of time was divided by time between MRI scans to obtain an annual rate of change.

Bone area measurement


The tibial plateau bone area was defined as the cross-sectional surface area of the tibial plateau, as previously described14. Medial and lateral cross-sectional areas of tibial plateau were determined by creating an isotropic volume from the input images which were reformatted in the axial plane. Areas were directly measured from these images. CVs for the medial and lateral tibial plateau areas were 2.3% and 2.4%13. Change in bone area (initial bone area subtracted from follow-up bone area) over the period of time was divided by time between MRI scans to obtain an annual rate of change.

Assessment of cartilage defects Cartilage defects were graded on the MR images in the medial and lateral tibial and femoral cartilages using a validated classification system15,16. The cartilage defect score for a cartilage plate was defined by the most severe cartilage defect present, graded as follows: grade 0, normal cartilage; grade 1, focal blistering and intra-cartilaginous low-signal intensity area with an intact surface and bottom; grade 2, irregularities on the surface or bottom and loss of thickness of less than 50%; grade 3, deep ulceration with loss of thickness of more than 50%; grade 4, full-thickness cartilage wear with exposure of subchondral bone. A cartilage defect had to be present in at least two consecutive slices. Intra-observer reliability (expressed as intra-class correlation coefficient) was 0.90 for the medial tibiofemoral compartment and 0.89 for the lateral tibiofemoral compartment17. Worsening cartilage defect was defined as any increase in cartilage defect grade in the tibial or femoral cartilage plate over 2 years in the medial and lateral tibiofemoral compartment.

Statistical analysis Our original sample size calculation was based on an estimated annual decrease in total cartilage volume of 2% (standard deviation, SD 2%) for the healthy women. If the treated group had a 50% larger decrease in the rate of cartilage loss, i.e. 3% (SD 2%), then we would have had a study power of 80% with 48 women in the treated group and 95 healthy women (with the ratio of healthy to treated women being deliberately set at 2 : 1 to optimize study power as we knew it would be challenging to recruit and retain treated women in this study). With the numbers eventually analyzed, we had an 80% power of detecting a 60% larger decrease in cartilage volume in the treated group. Standard diagnostic checks of model adequacy and unusual observations were performed. The annual changes in tibial cartilage volume and tibial plateau bone area were assessed

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Davis et al. for normal distribution before being analyzed using multiple linear regression. Logistic regression was used to examine the associations between AI use and worsening of cartilage defects. Age, BMI, baseline tibial cartilage volume and bone area were adjusted when analyzing the change in cartilage volume or cartilage defects; age, BMI, and baseline bone area were adjusted when analyzing the change in bone area. A p-value less than 0.05 (two-tailed) was regarded as statistically significant. All analyses were performed using the SPSS statistical package (version 19, SPSS, Chicago, IL, USA).

RESULTS Of 45 women recruited with HR⫹ breast cancer prescribed an AI, 30 women provided paired MRI data, including one woman who withdrew at 0.8 years due to metastatic disease. Three women did not have even a baseline MRI (two gave no reason and one withdrew with joint pain), two had no follow-up MRI, one stopped her AI, three cited personal reasons, one withdrew due to cancer complications, three changed to tamoxifen, one was lost to follow-up and one gave no reason for withdrawal. The women who did not continue in the study did not differ from the study completers in terms of age or BMI. Of the remaining 30, 16 women had undergone chemotherapy and 24 had undergone radiotherapy. All were taking anastrozole at baseline and one woman finished the study on letrozole. The average duration of AI treatment prior to baseline MRI was 50.8 days for the AI-treated women and two women had used tamoxifen for less than 5 weeks. The AI group underwent baseline MR imaging between September 2005 and February 2008 and the controls had their baseline MRI between October 2003 and August 2004. For the women included in the analyses presented, there were no missing data. The two groups were well matched for baseline characteristics, as shown in Table 1. There were no differences at baseline between groups for cartilage volume, bone area or cartilage defects. At follow-up, the lateral tibial bone area was significantly greater amongst women taking an AI than for controls (p ⫽ 0.002). There were no differences between the two groups for annual changes in medial and lateral tibial cartilage volumes over 2 years in univariate analysis or after adjusting for age, BMI, baseline tibial cartilage volume and bone area (Table 2). We observed a significant difference between the two groups in the annualized change in tibial plateau area in both univariate analysis and after adjusting for confounders. The AI group exhibited significant increases in both medial and lateral tibial plateau bone areas compared with the control group. The mean differences between the two groups in annual bone expansion, after adjusting for age, BMI and baseline tibial bone area, were 22.1 mm2 (95% confidence interval (CI) 7.6–36.6, p ⫽ 0.003) for the medial tibial plateau and 19.1 (95% CI 9.6–28.5, p ⬍ 0.001) for the lateral tibial plateau. Women treated with AI therapy did not differ from the control group for the worsening of cartilage defects over the study period.

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Table 1 Participant characteristics at baseline and 2 years. Data are given as mean (standard deviation) unless otherwise stated

Age at baseline (years) Body mass index (kg/m2) Time between MRIs (years) median range Medial tibial cartilage volume (mm3) baseline at 2 years Lateral tibial cartilage volume (mm3) baseline at 2 years Medial tibial bone area (mm2) baseline at 2 years Lateral tibial bone area (mm2) baseline at 2 years Tibiofemoral cartilage defects, n (%)† medial lateral

Aromatase inhibitor group (n ⫽ 30)

Healthy controls (n ⫽ 62)

Mean difference (95% confidence interval)

58.5 (5.6) 27.4 (5.0)

56.5 (4.6) 28.0 (4.7)

⫺2.0 (⫺4.2–0.2) 0.6 (⫺1.5–2.7)

2.05* 0.8–2.63

2.18 1.95–2.55

0.08 (⫺0.01–0.17)

1486 (257) 1438 (259)

1505 (308) 1454 (286)

19 (⫺110–149) ⫺15 (⫺137–107)

0.77 0.81

1669 (312) 1438 (259)

1702 (338) 1454 (286)

34 (⫺112–179) ⫺15 (⫺137–107)

0.65 0.81

2020 (180) 2042 (151)

1992 (204) 1971 (207)

⫺27 (⫺114–59) ⫺70 (⫺155–14)

0.53 0.10

1241 (155) 1275 (149)

1187 (126) 1184 (121)

⫺54 (⫺114–5.8) ⫺91 (⫺148– ⫺33)

0.08 0.002

10 (33) 6 (20)

13 (21) 20 (32)

p Value 0.07 0.57 0.01 (Mann–Whitney)

0.20 0.22

*,The woman who withdrew early is responsible for the difference in follow-up time between the two groups; †, difference in proportions between groups tested using χ2 test For continuous variables, differences were compared using independent samples t-test

DISCUSSION This is the first prospective study to evaluate the effect of AI therapy on the structural changes at the knee joint. Over 2 years, we found a significant increase in tibial plateau bone area in women treated with an AI compared with healthy age-matched controls. There was no identifiable impact of AI therapy on changes in cartilage volume or cartilage defects over 2 years. It is well recognized that estrogen deficiency with the use of an AI results in increased rate of bone modelling18 and significant bone depletion19. AI use has been associated with significant loss of bone mineral density and increased risk of fractures19. No previous study has examined the effect of AI treatment on the structures at the knee joint which include articular cartilage and subchondral bone. In this study, we found significant subchondral bone expansion in women taking an AI, but not in the control group, and no effect on knee cartilage. The knee is a weight-bearing joint with loads of up to four times body weight transmitted through the joint. The proximal end of the tibia is a bearing surface for the weight of the body which is transmitted through the femur. The bone responds to loading in two main ways as per Wolff ’s law20. One is through subcortical thickening, and the other by an increase in bone size which dissipates load21. As AI therapy results in reduced

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bone mineral density through increased bone resorption compared to formation22, the option left is for the tibial plateau to expand to maintain adequate bone mechanical competence in order to bear compressive loads and cope with bending loading efficiently23. Although we did not assess local knee bone density, the results of this study suggest that the knee has compensated for bone depletion from AI by subchondral bone expansion which was not seen in the control group. Although OA is characterized by progressive degenerative damage to articular cartilage, it is ultimately a disease of the whole joint24. Characteristic changes in the subchondral bone are increased trabecular bone mass and sclerosis, typified by increased subchondral plate thickness and osteophyte formation, but with reduced mineralization25–27, possibly as a result of increased bone remodelling28. Subchondral bone expansion is seen with increased radiological severity of OA29 and predicts the development30 and worsening31 of knee cartilage defects, thus playing an important role in the pathogenesis of OA. Tibial bone expansion is an early response to loading at the knee and predates cartilage changes. In a population of healthy asymptomatic women with no radiological knee OA, increased loading at the knee, a consequence of their natural gait pattern, was associated with significant tibial bone expansion with no effect on knee cartilage volume32. Also peak knee adductor

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Table 2 Effect of aromatase inhibitor use on knee structural changes over 2 years in comparison with the control group Univariate regression coefficient (95% CI) Annual change in cartilage volume (mm3)* Medial tibial 0.7 (⫺13.7–15.1) Lateral tibial 11.8 (⫺2.8–26.3) Total tibial 12.5 (⫺11.5–36.4) Annual bone expansion (mm2)† Medial tibial 21.8 (7.2–36.3) Lateral tibial 17.0 (7.7–26.4) Total tibial 38.8 (22.0–55.6)


Worsening of cartilage defects (yes/no)* Medial tibiofemoral Lateral tibiofemoral Total tibiofemoral

Univariate odds ratio (95% CI) 2.28 (0.61–8.58) 1.69 (0.53–5.40) 1.99 (0.72–5.49)

p

Multivariate regression coefficient (95% CI)

p

0.92 0.11 0.30

⫺1.8 (⫺15.8–12.2) 10.1 (⫺4.1–24.2) 7.3 (⫺16.2–30.8)

0.80 0.16 0.54

0.004 0.001 ⬍ 0.001

22.1 (7.6–36.6) 19.1 (9.6–28.5) 40.2 (23.2–57.2)

0.003 ⬍ 0.001 ⬍ 0.001

p

Multivariate odds ratio (95% CI) 2.49 (0.62–10.00) 1.52 (0.45–5.13) 1.77 (0.61–5.14)

p

0.22 0.38 0.19

0.20 0.50 0.29

*, Adjusted for age, body mass index, baseline tibial cartilage volume and bone area; †, adjusted for age, body mass index and baseline tibial bone area CI, confidence interval

moment (KAM) and KAM impulse are associated with increased subchondral bone area in patients with knee OA33, suggesting that increased mechanical loading plays a role in the pathological process in knee OA which is linked to bone changes. Recently, there has been an increased appreciation of the importance of the role of bone in OA. This has led to recent clinical trials that have targeted bone in intervention studies of knee OA. One study showed that a single intravenous dose of zoledronic acid was associated with improved structural outcomes at the knee over 6 months34, and another study showed a reduction in joint space narrowing with oral strontium ranelate in spinal OA35. Neither examined local bone density or tibial bone size. The strengths of our study include having a healthy comparative control group recruited from the community and having a 2-year study period. Limitations include the modest study size and, by necessity, the observational design. It is possible that our study did not have sufficient power to show the effect of AIs on cartilage loss over 2 years and thus longer follow-up may be needed. However, this is in contrast to the effect we observed with bone, suggesting that the effect on cartilage is significantly less. An additional study limitation is that the AI users who completed the study were not highly symptomatic in terms of arthralgia, as evidenced by their persistence with therapy. However, the adverse effects of AIs on joints may not always be clinically manifest. In addition, we did not measure bone mineral density and knee alignment in this study. In the current study, cartilage defects were assessed on T1-weighted MR images. This method, although less sensitive that proton density or T2-weighted MR images for

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detecting cartilage defects, has been shown to be valid, reproducible and able to detect cartilage defect changes over 2 years in healthy people36 and detects clinically important outcomes including pain, cartilage volume loss and risk of knee replacement4. However, it may have resulted in an underestimation of cartilage defects. In summary, this study suggests that the effect of severe estrogen depletion on the knee joint causes an expansion of subchondral bone at the tibia, most likely as a compensative response to daily mechanical load in the setting of reduced bone mineral density resulting from AI therapy. Whether this then results in an adverse effect on cartilage and an increased risk of knee OA will need further investigation. Since OA is a significant cause of reduced quality of life and morbidity and the long-term outcomes of breast cancer are now very good, the AI-induced musculoskeletal syndrome warrants further investigations, and prevention and treatment of the musculoskeletal conditions will be needed in order to improve the quality of life of the AI-treated women.

ACKNOWLEDGEMENTS The authors wish to thank the following individuals who assisted with the study conduct: Angeline Ferdinand, Corallee Morrow and Elaine Yeow; and the clinicians who supported the study: Adam Broad, Alexandra Dodic, Peter Gregory, Mitchell Chipman, Andrew Haydon, David Speakman, Gary Richardson, Jane Fox, Jenny Senior, Jim Griffiths, Karen Taylor, Karen White, Lara Lipton, Michelle White, Ray Snider,

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Aromatase inhibitors and knee subchondral bone expansion Rick Masters, Serene Foo, Robert Stanley, Rodney Bond, Romayne Holmes, Sanjeev Seewak and Choi Lee. Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper.

Davis et al. Source of funding This work was supported by grants from the National Health and Medical Research Council of Australia (grants number 219279) and AstraZeneca Australia. Dr Davis is a recipient of an NHMRC Australia Fellowship (No.490938) and Dr Robin Bell is a Victorian Cancer Agency Public Health Fellow.


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