Incidence and Risk Factors of Osteonecrosis of Femoral Head in Multiple Myeloma Patients Undergoing Dexamethasone-Based Regimens

Wu, Xinjie; Geng, Chuanying; Sun, Wei; Tan, Mingsheng

doi:https://doi.org/10.1155/2020/7126982

BioMed Research International

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2020 | Article ID 7126982 | https://doi.org/10.1155/2020/7126982

Incidence and Risk Factors of Osteonecrosis of Femoral Head in Multiple Myeloma Patients Undergoing Dexamethasone-Based Regimens

Xinjie Wu,^1,2Chuanying Geng,³Wei Sun,^1,2and Mingsheng Tan²

Academic Editor: Francesco Di Raimondo

Received05 Nov 2019

Revised14 Apr 2020

Accepted29 Apr 2020

Published16 May 2020

Abstract

Objectives. To investigate the incidence and risk factors for osteonecrosis of femoral head (ONFH) in multiple myeloma (MM) patients undergoing dexamethasone-based regimens (DBRs). Methods. A retrospective study was conducted in MM patients administered DBRs between December 2012 and April 2015. Demographic, clinical, and laboratory data were extracted to compare between two groups. Incidence of ONFH were calculated and risk factors identified by both univariate and multivariate analysis. Results. The study group comprised 105 patients undergoing DBRs. Seven patients with ONFH after DBRs were classified as the ONFH group, and the other 98 patients without ONFH were included in the non-ONFH group. Incidence of ONFH was 6.7%. Median age of developing ONFH was 51 years (45–64), and the male to female ratio was 6 : 1. A total of 12 femoral heads were involved, including unilateral in 2 patients and bilateral in 5 patients. After the multivariate analysis, four risk factors were confirmed including male, younger age, cumulative dose of dexamethasone, and hyperlipidemia. Conclusion. The overall incidence of ONFH in MM patients treated with DBRs is 6.7%, and 4 risk factors are confirmed including male, younger age, cumulative dose of dexamethasone, and hyperlipidemia in our study.

1. Introduction

Multiple myeloma is a cancer originated from bone marrow plasma cells and influences more than 120,000 individuals each year worldwide [1, 2]. Dexamethasone-based regimens (DBRs) are the backbone of treatment in both first-line relapsed and refractory MM patients. Although DBRs have improved the prognosis of such disease significantly, it may also bring about some complications. Among them, osteonecrosis of femoral head (ONFH) is a rare adverse event in patients undergoing systemic corticosteroid treatment but one with considerable possibility of disability [3]. While corticosteroid-induced ONFH has been reported extensively in systemic lupus erythematosus, renal transplantation, and leukemia patients [4–6], there are few studies to identify the incidence and risk factors for ONFH in MM patients.

2. Materials and Methods

2.1. Patients

With institutional review board approval, we performed a retrospective study to investigate the incidence and risk factors for ONFH following DBRs for MM patients between December 2012 and April 2015. The inclusion criteria were in accordance with the diagnostic criteria of the International Myeloma Working Group [7]: at least 18 years of age and newly diagnosed MM with start of DBRs; no history of glucocorticoid use >2 g of prednisolone or its equivalent within a 3-month period; no ONFH sign in MRI before chemotherapy [8]; complete radiological data; and a follow-up period of more than 2 years. The exclusion criteria were the following: another tumor diagnosis; pediatric cases; history of radiation therapy for femoral head; patients with high risk of alcohol-associated osteonecrosis according to ARCO criteria [9]; poor compliance; unavailability of regular follow-up information; and insufficiency of the follow-up materials. Due to the fact that patients’ information was anonymized and deidentified before analysis in this study, informed consent was not required.

2.2. Evaluation Indicators

Demographic and clinical data included gender, age of disease onset, weight, time to develop ONFH, symptom of ONFH, myeloma type, Durie-Salmon staging, International Staging System (ISS staging), hyperlipidemia, statin using, smoking, thalidomide using, bortezomib using, total days of dexamethasone treatment, cumulative dose of dexamethasone, and cumulative dose of dexamethasone per weight. Laboratory data included level of hemoglobin, albumin, β2-microglobulin, creatinine, calcium, lactate dehydrogenase, uric acid, and cytogenetics. All data were evaluated at diagnosis.

2.3. Statistical Analysis

Data analysis was carried out in the Stata software (version 15.0). The Shapiro-Wilk test was used to assess the normal distribution of data. Accordingly, data are presented as (SD) or as median (range). Comparisons between groups were made using Student’s -test or Wilcoxon’s rank-sum test, as appropriate. Categorical data were compared using the chi-squared test or Fisher’s exact test. Variables with a value less than 0.2 were evaluated in a multivariate logistic regression model. values less than 0.05 were considered significant.

3. Results

Based on inclusion and exclusion criteria, a total of 105 patients were included in the present study. The baseline characteristics for non-ONFH and ONFH patients are shown in Tables 1 and 2. Seven patients (6.7%) developed ONFH after DBR treatment. In cases with ONFH, the median time to develop ONFH was 11.1 months (range, 1.6 to 76.4 months) and the male to female ratio was 6 : 1. A total of 12 femoral heads were involved, including unilateral in 2 patients and bilateral in 5 patients. The most common symptom of ONFH included pain on asymptomatic (, 57.1%), weight bearing (, 42.9%), pain at rest (, 14.3%), and limping (, 14.3%).

Six risk factors for ONFH were identified by univariate analysis, including age, gender, total days of dexamethasone treatment, cumulative dose of dexamethasone, dexamethasone dose per weight, and hyperlipidemia. Adjusted odds ratio (OR) for ONFH events from the multivariate logistic regression modeling is presented in Figure 1. Finally, 4 risk factors were confirmed including male, younger age, cumulative dose of dexamethasone, and hyperlipidemia. Notably, total days of dexamethasone treatment and dexamethasone dose per weight were not included in the final multivariate logistic regression model due to its strong collinearity with cumulative dose of dexamethasone.

4. Discussion

In present retrospective study, we found that ONFH occurred in 6.7% of patients with MM. Due to the retrospective nature of our study, the incidence is a little lower than the previous study (8.9%) [10]. Unlike the lower rates of osteonecrosis in renal allograft recipients (3.4%) [6], our results are comparable to the prevalence of osteonecrosis in other diseases treated with corticosteroids, such as SLE [4, 11]. Higher dose of corticosteroid in MM patients and immunosuppressive agents using such as cyclosporin or tacrolimus in renal transplantation may contribute to the result.

Five of 7 patients in our study got bilateral osteonecrosis in the femoral heads. 57.1% of the ONFH cases were found to have asymptomatic osteonecrosis, while 42.9% patients developed symptomatic osteonecrosis. Previous studies showed that 10-33% patients had symptoms of affected joints and monthly bisphosphonate prophylaxis may contribute to the low rate of symptoms [10, 12]. Notably, bisphosphonate, as a protective factor for hip, may increase risks for developing osteonecrosis of the jaw according to recent studies [13–15]. In addition, other drugs such as thalidomide and bortezomib were not found to be significantly related to the occurrence of osteonecrosis. Previous studies also showed that thalidomide was not a risk factor for ONFH despite its antiangiogenic properties [10, 16]. Bortezomib, as a proteasome inhibitor, was even reported that its anti-inflammatory effects may lead to the improvement of the jaw osteonecrosis in a MM patient [17].

The median time to develop ONFH was 11.1 months. ONFH usually occurs within 2 years after the initiation of corticosteroid-based therapy. It may develop just for a short period of steroid apply. In our study, the shortest period to develop ONFH is 1.6 months (Figure 2). Unfortunately, ONFH can also develop after many years of corticosteroid therapy, and the longest period to occur is 76.4 months (Figure 3). Hence, asymptomatic changes of ONFH may initiate at any stage during the course of corticosteroid therapy, and early and periodic MRI examination could benefit patients.

(a)

(b)

(c)

(a)

(b)

(c)

For demographic characteristics, younger age and male are found to be related to ONFH, which is in accordance with previous studies [10, 18]. In human cells, there are around 6500 cytoplasmic binding sites per cell for dexamethasone and saturated around 50 nM [19]. However, receptors may decrease with age and result in insensitivity to corticosteroid. In general population, the male to female ration in osteonecrosis patients is 7 : 3 and even 8 : 1 [10, 20]. We also confirm being male as a risk factor for ONFH. Current studies demonstrate controversy regarding the relationship between cigarette smoking and ONFH. In our study, we did not find a significant difference in the risk of ONFH between two groups. A previous meta-analysis also showed that no significant difference in risk identified in light smokers (<20 pack-years) when compared with nonsmokers. This may contribute to the result of our study [21].

The mechanism of corticosteroid-induced ONFH remains obscure. According to literatures, dexamethasone is 6-fold toxic to bones compared with prednisolone, particularly when applied continuously [5, 22]. Although higher dose of dexamethasone may raise anti-MM response, it may also induce ONFH. We found that OR for ONFH is 1.16 when cumulative dose of dexamethasone increases 40 mg. Thus, judicious and minimizing use of dexamethasone and detection at early stage may help decrease the incidence of ONFH. Notably, for some cases, even small doses of corticosteroid could cause osteonecrosis and genetic predisposition may contribute the result. Genetic polymorphisms in many genes including SERPINE1, VEGF, VDR, CYP3A4, ACP1, and NOS3 are reported to be associated with ONFH [23]. These genes also play an important role in MM susceptibility and drug effects. Basmaci et al. [24] reported that the TNFα gene polymorphism (-308) GG genotype and NOS3 (+894) TT genotype were more common in the MM group compared to healthy controls. NOS3 (VNTR) AA and NOS3 (+894) GG genotypes were decreased in the MM group in contrast. Chen et al. [25] found that the A allele of rs699947 within VEGF and T allele of rs2228570 within VDR gene were all associated with increased MM risk. Hence, polymorphisms in such genes may increase the rate of osteonecrosis in MM patients.

It remains controversial whether hyperlipidemia influences the development of steroid-induced osteonecrosis [26–29]. Based on our data, there is a significant association between hyperlipidemia and osteonecrosis. Kuroda et al. reported that high triglyceride level is an important risk factor for silent ONFH in patients with SLE [27]. In addition, Mogensen et al. found that both hypertriglyceridemia and hypercholesterolemia are related to the development of osteonecrosis in children and young adults with acute lymphoblastic leukemia [28]. However, Calvo-Alen et al. reported a protective effect for hyperlipidemia in development of symptomatic osteonecrosis in lupus patients [30]. In a recent study, Zhao et al. found that preexisting hypercholesterolemia does not increase the risk of developing osteonecrosis in rabbits and lanolin-rich diets may be a protective factor [29].

Previous studies have reported that statins may improve hyperlipidemia and enhances femoral head neovascularization through suppresses PPARγ expression and activates Wnt3a/LRP5/b-catenin/RUNX2 signaling pathway in steroid-induced animal models [31–33]. In addition, PPARγ receptor protein is also expressed in myeloma cells. Previous studies showed that its natural and synthetic ligands induce apoptosis of tumor cells [34, 35]. Hence, PPARγ ligands may represent a novel therapy for MM. However, clinical studies reported different and controversial results for the effect of statin in osteonecrosis patients [36, 37]. In our study, we did not detect a significant association between statin and ONFH.

There are several limitations in present study. Firstly, due to the retrospective nature, it may influence the true incidence of ONFH in MM patients and identification of risk factors. Secondly, treatment protocols may evolve and dose of dexamethasone may vary over the course. In spite of these limitations, our results successfully provide relevant information on a rare complication.

5. Conclusion

In summary, the overall incidence of ONFH in MM patients treated with DBRs is 6.7%, and 4 risk factors are confirmed including male, younger age, cumulative dose of dexamethasone, and hyperlipidemia in our study.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors report no conflicts of interest in this work.

Authors’ Contributions

Xinjie Wu and Chuanying Geng contributed equally to this work.

Acknowledgments

This study was funded by the National Natural Science Foundation of China (81672236, 81871830), the Natural Science Foundation of Beijing Municipality (7182146), and the Fundamental Research Funds for the Central Universities and Research Projects on Biomedical Transformation of China⁃Japan Friendship Hospital (PYBZ1828).

References

T. King and B. Faiman, “Steroid-associated side effects: a symptom management update on multiple myeloma treatment,” Clinical Journal of Oncology Nursing, vol. 21, no. 2, pp. 240–249, 2017.
View at: Publisher Site | Google Scholar
O. Landgren, J. N. Hofmann, C. M. McShane et al., “Association of immune marker changes with progression of monoclonal gammopathy of undetermined significance to multiple myeloma,” JAMA Oncology, vol. 5, no. 9, p. 1293, 2019.
View at: Publisher Site | Google Scholar
K. Nawata, J. Nakamura, K. Ikeda et al., “Transitional changes in the incidence of osteonecrosis in systemic lupus erythematosus patients: focus on immunosuppressant agents and glucocorticoids,” Rheumatology, vol. 57, no. 5, pp. 844–849, 2018.
View at: Publisher Site | Google Scholar
S. M. Tse and C. C. Mok, “Time trend and risk factors of avascular bone necrosis in patients with systemic lupus erythematosus,” Lupus, vol. 26, no. 7, pp. 715–722, 2017.
View at: Publisher Site | Google Scholar
B. Padhye, L. Dalla-Pozza, D. Little, and C. Munns, “Incidence and outcome of osteonecrosis in children and adolescents after intensive therapy for acute lymphoblastic leukemia (ALL),” Cancer Medicine, vol. 5, no. 5, pp. 960–967, 2016.
View at: Publisher Site | Google Scholar
M. Takao, T. Sakai, T. Nishii, H. Yoshikawa, S. Takahara, and N. Sugano, “Incidence and predictors of osteonecrosis among cyclosporin- or tacrolimus-treated renal allograft recipients,” Rheumatology International, vol. 31, no. 2, pp. 165–170, 2011.
View at: Publisher Site | Google Scholar
The International Myeloma Working Group, “Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group,” British Journal of Haematology, vol. 121, no. 5, pp. 749–757, 2003.
View at: Publisher Site | Google Scholar
B. H. Yoon, L. C. Jones, C.-H. Chen et al., “Etiologic classification criteria of ARCO on femoral head osteonecrosis part 1: glucocorticoid-associated osteonecrosis,” The Journal of Arthroplasty, vol. 34, no. 1, pp. 163–168.e1, 2019.
View at: Publisher Site | Google Scholar
B.-H. Yoon, L. C. Jones, C. H. Chen et al., “Etiologic classification criteria of ARCO on femoral head osteonecrosis part 2: alcohol-associated osteonecrosis,” The Journal of Arthroplasty, vol. 34, no. 1, pp. 169–174.e1, 2019.
View at: Publisher Site | Google Scholar
G. Talamo, E. Angtuaco, R. C. Walker et al., “Avascular necrosis of femoral and/or humeral heads in multiple myeloma: results of a prospective study of patients treated with dexamethasone-based regimens and high-dose chemotherapy,” Journal of Clinical Oncology, vol. 23, no. 22, pp. 5217–5223, 2005.
View at: Publisher Site | Google Scholar
D. D. Gladman, N. Dhillon, J. Su, and M. B. Urowitz, “Osteonecrosis in SLE: prevalence, patterns, outcomes and predictors,” Lupus, vol. 27, no. 1, pp. 76–81, 2017.
View at: Publisher Site | Google Scholar
W. M. Smith, T. A. Larson, A. D. Meleth, N. Krishnadev, R. B. Nussenblatt, and H. N. Sen, “Corticosteroid-associated osteonecrosis: a rare, but serious, complication in uveitis,” Ocular Immunology and Inflammation, vol. 21, no. 2, pp. 102–107, 2013.
View at: Publisher Site | Google Scholar
J. S. Goodwin, J. Zhou, Y.-F. Kuo, and J. Baillargeon, “Risk of jaw osteonecrosis after intravenous bisphosphonates in cancer patients and patients without cancer,” Mayo Clinic Proceedings, vol. 92, no. 1, pp. 106–113, 2017.
View at: Publisher Site | Google Scholar
R. C. Hatton, P. Patel, and W. Liu, “Bisphosphonate exposure and osteonecrosis of the jaw,” Journal of Bone and Mineral Research, vol. 30, no. 4, pp. 748–748, 2015.
View at: Publisher Site | Google Scholar
T. Wazzan, D. Kashtwari, W. F. Almaden et al., “Radiographic bone loss and the risk of medication-related osteonecrosis of the jaw (MRONJ) in multiple myeloma patients-a retrospective case control study,” Special Care in Dentistry, vol. 38, no. 6, pp. 356–361, 2018.
View at: Publisher Site | Google Scholar
N. Burwick and S. Sharma, “Glucocorticoids in multiple myeloma: past, present, and future,” Annals of Hematology, vol. 98, no. 1, pp. 19–28, 2019.
View at: Publisher Site | Google Scholar
A. Timurağaoğlu, C. Özkaynak, S. Tüzüner, F. Bostan, and L. Ündar, “Improvement of zoledronic-acid-induced jaw osteonecrosis with bortezomib,” Acta Haematologica, vol. 118, no. 4, pp. 203-204, 2008.
View at: Publisher Site | Google Scholar
Y. Torii, Y. Hasegawa, T. Kubo et al., “Osteonecrosis of the femoral head after allogeneic bone marrow transplantation,” Clinical Orthopaedics and Related Research, vol. 382, pp. 124–132, 2001.
View at: Publisher Site | Google Scholar
A. L. Thomas, C. Coarfa, J. Qian et al., “Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma,” Nuclear Receptor Signaling, vol. 13, no. 1, p. nrs.13006, 2018.
View at: Publisher Site | Google Scholar
L. Cui, Q. Zhuang, J. Lin et al., “Multicentric epidemiologic study on six thousand three hundred and ninety five cases of femoral head osteonecrosis in China,” International Orthopaedics, vol. 40, no. 2, pp. 267–276, 2016.
View at: Publisher Site | Google Scholar
Z. Wen, Z. Lin, W. Yan, and J. Zhang, “Influence of cigarette smoking on osteonecrosis of the femoral head (ONFH): a systematic review and meta-analysis,” HIP International, vol. 27, no. 5, pp. 425–435, 2017.
View at: Publisher Site | Google Scholar
S. V. Rajkumar, S. Jacobus, N. S. Callander et al., “Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial,” The Lancet Oncology, vol. 11, no. 1, pp. 29–37, 2010.
View at: Publisher Site | Google Scholar
X. Zhao, F. Yang, L. Sun, and A. Zhang, “Association betweenNOS3polymorphisms and osteonecrosis of the femoral head,” Artificial Cells, Nanomedicine, and Biotechnology, vol. 47, no. 1, pp. 1423–1427, 2019.
View at: Publisher Site | Google Scholar
C. Basmaci, M. Pehlivan, A. Tomatir et al., “Effects of TNFα, NOS3, MDR1 gene polymorphisms on clinical parameters, prognosis and survival of multiple myeloma cases,” Asian Pacific Journal of Cancer Prevention, vol. 17, no. 3, pp. 1009–1014, 2016.
View at: Publisher Site | Google Scholar
P. Chen, Z.-L. Du, Y. Zhang et al., “Association of VEGF and VDR gene- gene and gene- smoking interaction on risk of multiple myeloma in Chinese Han population,” Oncotarget, vol. 8, no. 22, pp. 36509–36516, 2017.
View at: Publisher Site | Google Scholar
S. T. Faezi, A. S. Hoseinian, P. Paragomi et al., “Non-corticosteroid risk factors of symptomatic avascular necrosis of bone in systemic lupus erythematosus: a retrospective case-control study,” Modern Rheumatology, vol. 25, no. 4, pp. 590–594, 2015.
View at: Publisher Site | Google Scholar
T. Kuroda, N. Tanabe, A. Wakamatsu et al., “High triglyceride is a risk factor for silent osteonecrosis of the femoral head in systemic lupus erythematosus,” Clinical Rheumatology, vol. 34, no. 12, pp. 2071–2077, 2015.
View at: Publisher Site | Google Scholar
S. S. Mogensen, K. Schmiegelow, K. Grell et al., “Hyperlipidemia is a risk factor for osteonecrosis in children and young adults with acute lymphoblastic leukemia,” Haematologica, vol. 102, no. 5, pp. e175–e178, 2017.
View at: Publisher Site | Google Scholar
G. Zhao, T. Yamamoto, G. Motomura et al., “Cholesterol- and lanolin-rich diets may protect against steroid-induced osteonecrosis in rabbits,” Acta Orthopaedica, vol. 84, no. 6, pp. 593–597, 2013.
View at: Publisher Site | Google Scholar
J. Calvo-Alén, G. McGwin, S. Toloza et al., “Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIV. Cytotoxic treatment is an additional risk factor for the development of symptomatic osteonecrosis in lupus patients: results of a nested matched case-control study,” Annals of the Rheumatic Diseases, vol. 65, no. 6, pp. 785–790, 2006.
View at: Publisher Site | Google Scholar
Y. Nozaki, K. Kumagai, N. Miyata, and M. Niwa, “Pravastatin reduces steroid-induced osteonecrosis of the femoral head in SHRSP rats,” Acta Orthopaedica, vol. 83, no. 1, pp. 87–92, 2012.
View at: Publisher Site | Google Scholar
Z. Yang, H. Liu, D. Li et al., “The efficacy of statins in preventing glucocorticoid-related osteonecrosis in animal models: a meta-analysis,” Bone & Joint Research, vol. 5, no. 9, pp. 393–402, 2016.
View at: Publisher Site | Google Scholar
Y. Jiang, Y. Zhang, H. Zhang et al., “Pravastatin prevents steroid-induced osteonecrosis in rats by suppressing PPARγ expression and activating Wnt signaling pathway,” Experimental Biology and Medicine, vol. 239, no. 3, pp. 347–355, 2014.
View at: Publisher Site | Google Scholar
D. M. Ray, S. H. Bernstein, and R. P. Phipps, “Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands,” Clinical Immunology, vol. 113, no. 2, pp. 203–213, 2004.
View at: Publisher Site | Google Scholar
T. Kumagai, T. Ikezoe, D. Gui et al., “RWJ-241947 (MCC-555), a unique peroxisome proliferator-activated receptor-gamma ligand with antitumor activity against human prostate cancer in vitro and in beige/nude/X-linked immunodeficient mice and enhancement of apoptosis in myeloma cells induced by arsenic trioxide,” Clinical Cancer Research, vol. 10, no. 4, pp. 1508–1520, 2004.
View at: Publisher Site | Google Scholar
M. Ajmal, A. J. Matas, M. Kuskowski, and E. Y. Cheng, “Does statin usage reduce the risk of corticosteroid-related osteonecrosis in renal transplant population?” Orthopedic Clinics of North America, vol. 40, no. 2, pp. 235–239, 2009.
View at: Publisher Site | Google Scholar
J. W. Pritchett, “Statin therapy decreases the risk of osteonecrosis in patients receiving steroids,” Clinical Orthopaedics and Related Research, vol. 386, pp. 173–178, 2001.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2020 Xinjie Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1056

Downloads

1114

Citations