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Aromatase inhibitor-induced arthralgia: Is vitamin D deficiency responsible?
Maturitas 69 (2011) 3–4
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Editorial
Aromatase inhibitor-induced arthralgia: Is vitamin D deficiency responsible?
Keywords: Vitamin D Aromatase inhibitor (AI) Hormone receptor Breast cancer Postmenopausal wome
Aromatase inhibitor (AI) treatment is an established component of adjuvant therapy for hormone receptor-positive early breast cancer among postmenopausal women. However, side effects are common, and can lead to discontinuation. AI-induced arthralgia is one of the most common side effects described, present in about 30% of the treated women, and causing up to about 20% of therapy discontinuations. Several predictors have been described for the appearance of AI-induced arthralgia [1]: obesity (OR 1.32 [1.14–1.53]), history of hormone replacement therapy (OR 1.72 [95%CI 1.53–1.93]), prior chemotherapy (OR 1.34 [95%CI 1.17–1.53]). Recently it has been highlighted that vitamin D deficiency is highly prevalent in women with breast cancer, even in Southern European regions [2] and is associated as a risk factor for breast cancer: in a population-based case-control study including 1026 incident cases and 1075 controls, women with plasma 25-hydroxyvitamin D (25OHD) serum levels ≥40 ng/ml appeared at lower risk for breast cancer (OR 0.59 [95%CI 0.44–0.77]). In addition, vitamin D has several potential roles in musculoskeletal health in women receiving AI therapy: in addition to the recognized association between low vitamin D status and future fracture risk, there are a number of potential non-skeletal effects on a number of tissues including synovium and muscle with putative consequences in term of arthritis, arthralgia and fatigue. Supporting this hypothesis, a correlation between musculoskeletal pain intensity and lower vitamin D plasma concentration has been shown among breast cancer survivors on aromatase inhibitor therapy [3]. In addition, two observational studies have described a potential role of Vitamin D supplementation to minimize the intensity of AI-induced arthralgia, and to prevent its occurrence. Khan et al. [4] showed that high-dose Vitamin D (50,000 IU oral Vitamin D3 weekly) is effective in optimizing Vitamin D levels in women on AI therapy, and results in clinically significant improvement in disability from joint symptoms: after 4 months of letrozole and 3 months of Vitamin D supplements, arthralgia scores were better in individuals whose 25OHD concentrations were above the median of 66 ng/ml. Similarly, we conducted a prospective cohort study which included a consecutive sample of 290 women treated with AIs and Vitamin D supplements followed up for three months [5]. In this 0378-5122/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2011.01.001
population, we found that patients who reached 25OHD concentrations ≥40 ng/ml had attenuated joint pain intensity (as assessed using a visual analogyc scale) when compared to those with 25OHD < 40 ng/ml: p = 0.02). In the same study, among the 80 participants who reported no arthralgia at baseline, 25 (53.2%) with a 3-month 25OHD concentration of less than 40 ng/ml developed incident pain, compared with only 7/33 (21.2%) of those with concentrations ≥40 ng/ml (OR 0.12 [0.03–0.40], p = 0.008). We concluded that a target concentration of 40 ng/ml 25OHD may prevent development of AI-induced arthralgia in women with no joint pain before starting AIs, and minimise its intensity in those with prevalent arthralgia. The observed therapeutic threshold for vitamin D status was defined using serum 25OH vitamin D, the current gold standard. However, the therapeutic strategy to achieve this concentration is not currently known and data from these studies can give us some clues: in the study by Khan et al. [4], all the participants achieved a concentration of 25OHD > 40 ng/ml after 6 weeks on oral 50,000 IU Vitamin D3 per week, with no cases of hypercalcemia or renal stones; in our study [5], women received daily 800 IU and additional oral 16,000 IU Vitamin D3 every 2 weeks (equivalent to 13,600 IU per week) for three months, and only 52.1% of them reached serum levels of ≥40 ng/ml. Hence, higher loading doses are required to attain this level in women with deficiency, probably closer to the weekly 50,000 IU proposed by Khan et al. Whatever strategy is used, it is likely should 25OH vitamin D concentration continue to be used as the endpoint for defining vitamin D status, the dose will have to be titrated given the marked inter-individual response to supplementation likely to be due to both genetic and other factors that potentially influence vitamin D bioavailability such as obesity, administration with food and concurrent calcium intake. As it is known, observational studies such as these are fraught with potential biases and limitations, and a randomized clinical trial provides the best evidence for causality. Fortunately, a randomized clinical trial is currently ongoing, which will probably elucidate the safety and efficacy of 30,000 IU vitamin D3 weekly supplementation to prevent AI-induced joint pain and fatigue (clinicaltrials.gov NCT00867217). Its results are eagerly awaited. In the meantime it would seem prudent to test for vitamin D deficiency and treat those with levels of less than 25 nmol/L with whatever oral vitamin D3 supplements are available locally. Contributors Both authors contributed equally to the writing of the manuscript.
4
Editorial / Maturitas 69 (2011) 3–4
Conflicts of interest None declared. Funding No funding. Provenance and peer review Commissioned, not externally peer reviewed. References [1] Sestak I, Cuzick J, Sapunar F, Eastell R, Forbes JF, Bianco AR, et al. Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol 2008;9(9):866–72. [2] Nogues X, Servitja S, Pena MJ, Prieto-Alhambra D, Nadal R, Mellibovsky L, et al. Vitamin D deficiency and bone mineral density in postmenopausal women receiving aromatase inhibitors for early breast cancer. Maturitas 2010. [3] Waltman NL, Ott CD, Twiss JJ, Gross GJ, Lindsey AM. Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy. Cancer Nurs 2009. [4] Khan QJ, Reddy PS, Kimler BF, Sharma P, Baxa SE, O’Dea AP, et al. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 2010;119(1):111–8. [5] Prieto-Alhambra D, Javaid MK, Servitja S, Arden NK, Martinez-Garcia M, DiezPerez A, et al. Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study. Breast Cancer Res Treat, 2010; Jul 28.
a
D. Prieto-Alhambra a,b Universitat Autonoma de Barcelona, Departament de Medicina; IDIAP Jordi Gol; Institut Catala de la Salut, Spain
b
Oxford NIHR Musculoskeletal BRU, The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK M.K. Javaid ∗ Oxford NIHR Musculoskeletal BRU, The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK ∗ Corresponding
author at: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7LD, UK. Tel.: +44 01865 737851; fax: +44 01865 737811. E-mail address: [email protected] (M.K. Javaid) 4 January 2011
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Editorial
Aromatase inhibitor-induced arthralgia: Is vitamin D deficiency responsible?
Keywords: Vitamin D Aromatase inhibitor (AI) Hormone receptor Breast cancer Postmenopausal wome
Aromatase inhibitor (AI) treatment is an established component of adjuvant therapy for hormone receptor-positive early breast cancer among postmenopausal women. However, side effects are common, and can lead to discontinuation. AI-induced arthralgia is one of the most common side effects described, present in about 30% of the treated women, and causing up to about 20% of therapy discontinuations. Several predictors have been described for the appearance of AI-induced arthralgia [1]: obesity (OR 1.32 [1.14–1.53]), history of hormone replacement therapy (OR 1.72 [95%CI 1.53–1.93]), prior chemotherapy (OR 1.34 [95%CI 1.17–1.53]). Recently it has been highlighted that vitamin D deficiency is highly prevalent in women with breast cancer, even in Southern European regions [2] and is associated as a risk factor for breast cancer: in a population-based case-control study including 1026 incident cases and 1075 controls, women with plasma 25-hydroxyvitamin D (25OHD) serum levels ≥40 ng/ml appeared at lower risk for breast cancer (OR 0.59 [95%CI 0.44–0.77]). In addition, vitamin D has several potential roles in musculoskeletal health in women receiving AI therapy: in addition to the recognized association between low vitamin D status and future fracture risk, there are a number of potential non-skeletal effects on a number of tissues including synovium and muscle with putative consequences in term of arthritis, arthralgia and fatigue. Supporting this hypothesis, a correlation between musculoskeletal pain intensity and lower vitamin D plasma concentration has been shown among breast cancer survivors on aromatase inhibitor therapy [3]. In addition, two observational studies have described a potential role of Vitamin D supplementation to minimize the intensity of AI-induced arthralgia, and to prevent its occurrence. Khan et al. [4] showed that high-dose Vitamin D (50,000 IU oral Vitamin D3 weekly) is effective in optimizing Vitamin D levels in women on AI therapy, and results in clinically significant improvement in disability from joint symptoms: after 4 months of letrozole and 3 months of Vitamin D supplements, arthralgia scores were better in individuals whose 25OHD concentrations were above the median of 66 ng/ml. Similarly, we conducted a prospective cohort study which included a consecutive sample of 290 women treated with AIs and Vitamin D supplements followed up for three months [5]. In this 0378-5122/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2011.01.001
population, we found that patients who reached 25OHD concentrations ≥40 ng/ml had attenuated joint pain intensity (as assessed using a visual analogyc scale) when compared to those with 25OHD < 40 ng/ml: p = 0.02). In the same study, among the 80 participants who reported no arthralgia at baseline, 25 (53.2%) with a 3-month 25OHD concentration of less than 40 ng/ml developed incident pain, compared with only 7/33 (21.2%) of those with concentrations ≥40 ng/ml (OR 0.12 [0.03–0.40], p = 0.008). We concluded that a target concentration of 40 ng/ml 25OHD may prevent development of AI-induced arthralgia in women with no joint pain before starting AIs, and minimise its intensity in those with prevalent arthralgia. The observed therapeutic threshold for vitamin D status was defined using serum 25OH vitamin D, the current gold standard. However, the therapeutic strategy to achieve this concentration is not currently known and data from these studies can give us some clues: in the study by Khan et al. [4], all the participants achieved a concentration of 25OHD > 40 ng/ml after 6 weeks on oral 50,000 IU Vitamin D3 per week, with no cases of hypercalcemia or renal stones; in our study [5], women received daily 800 IU and additional oral 16,000 IU Vitamin D3 every 2 weeks (equivalent to 13,600 IU per week) for three months, and only 52.1% of them reached serum levels of ≥40 ng/ml. Hence, higher loading doses are required to attain this level in women with deficiency, probably closer to the weekly 50,000 IU proposed by Khan et al. Whatever strategy is used, it is likely should 25OH vitamin D concentration continue to be used as the endpoint for defining vitamin D status, the dose will have to be titrated given the marked inter-individual response to supplementation likely to be due to both genetic and other factors that potentially influence vitamin D bioavailability such as obesity, administration with food and concurrent calcium intake. As it is known, observational studies such as these are fraught with potential biases and limitations, and a randomized clinical trial provides the best evidence for causality. Fortunately, a randomized clinical trial is currently ongoing, which will probably elucidate the safety and efficacy of 30,000 IU vitamin D3 weekly supplementation to prevent AI-induced joint pain and fatigue (clinicaltrials.gov NCT00867217). Its results are eagerly awaited. In the meantime it would seem prudent to test for vitamin D deficiency and treat those with levels of less than 25 nmol/L with whatever oral vitamin D3 supplements are available locally. Contributors Both authors contributed equally to the writing of the manuscript.
4
Editorial / Maturitas 69 (2011) 3–4
Conflicts of interest None declared. Funding No funding. Provenance and peer review Commissioned, not externally peer reviewed. References [1] Sestak I, Cuzick J, Sapunar F, Eastell R, Forbes JF, Bianco AR, et al. Risk factors for joint symptoms in patients enrolled in the ATAC trial: a retrospective, exploratory analysis. Lancet Oncol 2008;9(9):866–72. [2] Nogues X, Servitja S, Pena MJ, Prieto-Alhambra D, Nadal R, Mellibovsky L, et al. Vitamin D deficiency and bone mineral density in postmenopausal women receiving aromatase inhibitors for early breast cancer. Maturitas 2010. [3] Waltman NL, Ott CD, Twiss JJ, Gross GJ, Lindsey AM. Vitamin D insufficiency and musculoskeletal symptoms in breast cancer survivors on aromatase inhibitor therapy. Cancer Nurs 2009. [4] Khan QJ, Reddy PS, Kimler BF, Sharma P, Baxa SE, O’Dea AP, et al. Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 2010;119(1):111–8. [5] Prieto-Alhambra D, Javaid MK, Servitja S, Arden NK, Martinez-Garcia M, DiezPerez A, et al. Vitamin D threshold to prevent aromatase inhibitor-induced arthralgia: a prospective cohort study. Breast Cancer Res Treat, 2010; Jul 28.
a
D. Prieto-Alhambra a,b Universitat Autonoma de Barcelona, Departament de Medicina; IDIAP Jordi Gol; Institut Catala de la Salut, Spain
b
Oxford NIHR Musculoskeletal BRU, The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK M.K. Javaid ∗ Oxford NIHR Musculoskeletal BRU, The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK ∗ Corresponding
author at: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7LD, UK. Tel.: +44 01865 737851; fax: +44 01865 737811. E-mail address: [email protected] (M.K. Javaid) 4 January 2011