User login
Take-Home Points
Analysis of patients in the Medicare database showed that each successive ESI decreased the risk of an osteoporotic spine fracture by 2%, and that each successive LJSI decreases it by 4%.
Although statistically significant, this may not be clinically relevant.
Successive ESI did not influence the risk of developing an osteoporotic hip or wrist fracture, but that each additional LJSI reduced the risk.
Prolonged steroid exposure was found to increase the risk of spine fracture for ESI and LJSI patients.
Acute exposure to exogenous steroids via the epidural space, transforaminal space, or large joints does not seem to increase the risk of an osteoporotic fracture of the spine, hip, or wrist.
Epidural steroid injections (ESIs) are widely used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. The treatment rationale is that locally injected anti-inflammatory drugs, such as steroids, reduce inflammation by inhibiting formation and release of inflammatory cytokines, leading to pain reduction.1,2 According to 4 systematic reviews, the best available evidence of the efficacy of ESIs is less than robust.3-6 These reviews were limited by the heterogeneity of patient selection, delivery mode, type and dose of steroid used, number and frequency of ESIs, and outcome measures.
The association of chronic oral steroid use and the development of osteoporosis was previously established.7,8 One concern is that acute exposure to steroids in the form of lumbar ESIs may also lead to osteoporosis and then a pathologic fracture of the vertebra. Several studies have found no association between bone mineral density and cumulative steroid dose,9,10 mean number of ESIs, or duration of ESIs,10 though other studies have found lower bone mineral density in postmenopausal women treated with ESIs.11-13
In a study of 3000 ESI patients propensity-matched to a non-ESI cohort, Mandel and colleagues14 found that each successive ESI increased the risk of osteoporotic spine fracture by 21%. This clinically relevant 21% increased risk might lead physicians to stop prescribing or using this intervention. However, the association between osteoporotic fractures and other types of steroid injections remains poorly understood and underinvestigated.
To further evaluate the relationship between steroid injections and osteoporotic fracture risk, we analyzed Medicare administrative claims data on both large-joint steroid injections (LJSIs) into knee and hip and transforaminal steroid injections (TSIs), as well as osteoporotic hip and wrist fractures. Our hypothesis was that a systemic effect of steroid injections would increase fracture risk in all skeletal locations regardless of injection site, whereas a local effect would produce a disproportionate increased risk of spine fracture with spine injection.
Materials and Methods
Medicare is a publicly funded US health insurance program for people 65 years old or older, people under age 65 years with certain disabilities, and people (any age) with end-stage renal disease or amyotrophic lateral sclerosis. The 5% Medicare Part B (physician, carrier) dataset contains individual claims records for a random sample of Medicare beneficiaries (~2.4 million enrollees). Patients who received steroid injections were identified from 5% Medicare claims made between January 1, 2004 and December 31, 2011. LJSIs were identified by Current Procedural Terminology (CPT) code 20610 and any of 16 other CPT codes: J0702, J1020, J1030, J1040, J1094, J1100, J1700, J1710, J1720, J2650, J2920, J2930, J3300, J3301, J3302, and J3303. ESIs were identified by CPT code 62310, 62311, 62318, or 62319, and TSIs by CPT code 64479, 64480, 64483, or 64484. Patients were followed in their initial injection cohort. For example, a patient who received an ESI initially and later received an LJSI remained in the ESI cohort.
Several groups of patients were excluded from the study: those who received Medicare coverage because of their age (under 65 years) and disabilities; those who received Medicare health benefits through health maintenance organizations (healthcare expenses were not submitted to the Centers for Medicare & Medicaid Services for payment, and therefore claims were not in the database or were incomplete); those with a prior claim history of <12 months (incomplete comorbidity history); and those who received a diagnosis of osteoporotic fracture (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 733.1x) before the initial steroid injection.
We determined the incidence of osteoporotic wrist, hip, and spine fractures within 1, 2, and 8 years after LJSI, ESI, and TSI. Wrist, hip, and spine fractures were identified by ICD-9-CM diagnosis codes 733.12, 733.13, and 733.14, respectively. We also determined the number of steroid injections given before wrist, hip, or spine fracture or, if no fracture occurred, before death or the end of the data period.
Statistical Analysis
Multivariate Cox regression analysis was performed to evaluate the risk factors for wrist, spine, and hip fractures. The covariates in this model included age, sex, race, census region, Medicare buy-in status, Charlson Comorbidity Index (CCI),15 year, and number of steroid injections before fracture, death, or end of data period. Medicare buy-in status, which indicates whether the beneficiary received financial assistance in paying insurance premiums, was used as a proxy for socioeconomic status. CCI is used as a composite score of a patient’s general health status in terms of comorbidities.15,16 Four previously established categories17 were used to group CCIs in this study: 0 (none), 1 to 2 (low), 3 to 4 (moderate), and 5 or more (high). In addition, several diagnoses made within the 12 months before initial steroid injection were considered: osteoporosis (ICD-9-CM codes 733.0x, V82.81), Cushing syndrome (ICD-9-CM code 255.0), long-term (current) use of bisphosphonates (ICD-9-CM code V58.68), asymptomatic postmenopausal status (ICD-9-CM code V49.81), postmenopausal hormone replacement therapy (ICD-9-CM code V07.4), and long-term (current) use of steroids (ICD-9-CM code V58.65). The comparison of relative risk between any groups was reported as the adjusted hazard ratio (AHR), which is the ratio of the hazard rates of that particular outcome, taking into account inherent patient characteristics such as age, sex, and race as covariates. AHR of 1 corresponds to equivalent risk, AHR of >1 to elevated risk, and AHR of <1 to reduced risk.
Results
Using the 5% Medicare data for 2004 to 2011, we identified 275,999 Medicare beneficiaries who underwent LJSI, 93,943 who underwent ESI, and 32,311 who underwent TSI. During this period, TSI use increased, ESI use decreased, and LJSI use was relatively stable (Figure). 
The risk for osteoporotic spine fracture 1, 2, and 8 years after ESI, TSI, or LJSI was affected by age, race, sex, and CCI (P < .001 for all; Tables 2-4). 
The risk for osteoporotic hip fracture after 1 and 2 years was affected by age and number of LJSIs and TSIs but not by number of ESIs. Sex and CCI were also risk factors for hip fracture at 1 and 2 years for ESI and LJSI patients, as was race for LJSI patients. Risk for osteoporotic wrist fracture at 1 and 2 years was affected by sex and race for ESI and LJSI patients; age, race, CCI, and long-term steroid use were risk factors for TSI patients at all time points. Higher number of LJSIs, but not ESIs or TSIs, was associated with lower wrist fracture risk.
Discussion
ESIs continue to be used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. Although the present study found ESI use increased in the Medicare population between 1994 and 2001,18 the trend is reversing, decreasing by 25%, with rates of 264 per 10,000 Medicare enrollees in 2004 and 194 per 10,000 enrollees in 2011. ESI use may have changed after systematic reviews revealed there was no clear evidence of the efficacy of ESIs in managing low back pain and radicular leg pain3,5,6 or spinal stenosis.4
Nevertheless, ESIs are widely used because of the perceived benefit balanced against the perceived rarity of adverse events.6 Even if patients recognize a low likelihood of significant benefit, they may accept ESI as preferable to surgery. In addition, most private payers require extensive nonoperative treatment before they will approve surgery as a treatment option.
In a study by Mandel and colleagues,14 ESI increased the risk of vertebral compression fractures by 21%, which in turn increased the risk of death.19 If accurate, these findings obviously would challenge the perception that ESI is a low-risk intervention. In contrast to the Mandel study,14 the present analysis of the Medicare population revealed no clinically relevant change in risk of osteoporotic spine fracture with each successive ESI after the initial injection. After the initial injection, each successive ESI decreased the relative risk of osteoporotic spine fracture by 2%, and each successive LJSI decreased it by 4%. Although statistically significant, the small change in relative risk may not be clinically relevant. However, taken cumulatively over a number of successive injections, these effects may be clinically relevant.
The data also showed that, after the initial injection, each successive ESI had no effect on risk of osteoporotic hip or wrist fracture, and each successive LJSI reduced the risk. Similar to earlier findings,20,21 long-term steroid use increased the risk of spine fracture in ESI and LJSI patients. Prolonged exposure to steroids may be necessary to reduce bone formation and increase bone breakdown.12
Although the study by Mandel and colleagues14 and our study both used administrative databases and survival analysis methods, conclusions differed. First, Mandel and colleagues14 used a study inclusion criterion of spine-related steroid injections, whereas we used a criterion of any steroid injection. Second, they used 50 years as the lower age for study inclusion, and we used 65 years. Third, to control for patients who had osteoporosis before study entry, they excluded those who had a fracture in an adjacent vertebra after kyphoplasty and vertebroplasty. It is unclear if patients who had osteoporotic fractures at other sites were excluded as well. Thus, the 2 cohorts may not be directly comparable.
Whereas Mandel and colleagues14 based their definition of osteoporotic spine fracture on a keyword search of a radiology database, we used a specific reportable ICD-9-CM diagnosis code. As a result, they may have overreported osteoporotic spine fractures, and we may have underreported. Finally, our sample was much larger than theirs. Given the relative rarity of osteoporotic fractures, a study with a larger sample may have more power to detect differences. In addition, unlike Mandel and colleagues,14 we focused on an injection cohort. We did not include or make comparisons with a no-injection cohort because our study hypothesis involved the potential systemic effects of steroid injections based on injection site. Although chronic steroid use was found to have a significant effect in our study, it is unclear to what extent the diagnosis code was used, during the comorbidity assessment or only in the event of steroid-related complications.
Our study also found that, after the initial injection, each successive LJSI decreased the risk of osteoporotic wrist fracture by 10%, and each successive TSI decreased the risk of osteoporotic hip fracture by 5%. It is plausible these injections allowed improved mobility, mitigating the effects of osteoporosis induced by inactivity and lack of resistance training. It is also possible that improved mobility limited falls.
In summary, this analysis of the Medicare claims database revealed that ESI, TSI, and LJSI decreased osteoporotic spine fracture risk. However, the effect was small and may not be clinically meaningful. After the initial injection, successive ESIs had no effect on the risk of osteoporotic hip or wrist fracture, and successive LJSIs reduced the risk of osteoporotic wrist fracture, perhaps because of improved mobility. Prolonged oral steroid use increased spine fracture risk in ESI and LJSI patients. More studies are needed to evaluate the risk-benefit profile of steroid injections.
1. Pethö G, Reeh PW. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev. 2012;92(4):1699-1775.
2. Saal J. The role of inflammation in lumbar pain. Spine. 1995;20(16):1821-1827.
3. Choi HJ, Hahn S, Kim CH, et al. Epidural steroid injection therapy for low back pain: a meta-analysis. Int J Technol Assess Health Care. 2013;29(3):244-253.
4. Chou R, Loeser JD, Owens DK, et al; American Pain Society Low Back Pain Guideline Panel. Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society. Spine. 2009;34(10):1066-1077.
5. Savigny P, Watson P, Underwood M; Guideline Development Group. Early management of persistent non-specific low back pain: summary of NICE guidance. BMJ. 2009;338:b1805.
6. Staal JB, de Bie RA, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low back pain: an updated Cochrane review. Spine. 2009;34(1):49-59.
7. Angeli A, Guglielmi G, Dovio A, et al. High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone. 2006;39(2):253-259.
8. Donnan PT, Libby G, Boyter AC, Thompson P. The population risk of fractures attributable to oral corticosteroids. Pharmacoepidemiol Drug Saf. 2005;14(3):177-186.
9. Dubois EF, Wagemans MF, Verdouw BC, et al. Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain. Clin Rheumatol. 2003;22(1):12-17.
10. Yi Y, Hwang B, Son H, Cheong I. Low bone mineral density, but not epidural steroid injection, is associated with fracture in postmenopausal women with low back pain. Pain Physician. 2012;15(6):441-449.
11. Al-Shoha A, Rao DS, Schilling J, Peterson E, Mandel S. Effect of epidural steroid injection on bone mineral density and markers of bone turnover in postmenopausal women. Spine. 2012;37(25):E1567-E1571.
12. Kang SS, Hwang BM, Son H, Cheong IY, Lee SJ, Chung TY. Changes in bone mineral density in postmenopausal women treated with epidural steroid injections for lower back pain. Pain Physician. 2012;15(3):229-236.
13. Kim S, Hwang B. Relationship between bone mineral density and the frequent administration of epidural steroid injections in postmenopausal women with low back pain. Pain Res Manag. 2014;19(1):30-34.
14. Mandel S, Schilling J, Peterson E, Rao DS, Sanders W. A retrospective analysis of vertebral body fractures following epidural steroid injections. J Bone Joint Surg Am. 2013;95(11):961-964.
15. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
16. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613-619.
17. Murray SB, Bates DW, Ngo L, Ufberg JW, Shapiro NI. Charlson index is associated with one-year mortality in emergency department patients with suspected infection. Acad Emerg Med. 2006;13(5):530-536.
18. Friedly J, Chan L, Deyo R. Increases in lumbosacral injections in the Medicare population: 1994 to 2001. Spine. 2007;32(16):1754-1760.
19. Puisto V, Rissanen H, Heliövaara M, et al. Vertebral fracture and cause-specific mortality: a prospective population study of 3,210 men and 3,730 women with 30 years of follow-up. Eur Spine J. 2011;20(12):2181-2186.
20. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effects of low-dose corticosteroids on the bone mineral density of patients with rheumatoid arthritis: a meta-analysis. J Investig Med. 2008;56(8):1011-1018.
21. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 1994;20(3):629-650.
Take-Home Points
Analysis of patients in the Medicare database showed that each successive ESI decreased the risk of an osteoporotic spine fracture by 2%, and that each successive LJSI decreases it by 4%.
Although statistically significant, this may not be clinically relevant.
Successive ESI did not influence the risk of developing an osteoporotic hip or wrist fracture, but that each additional LJSI reduced the risk.
Prolonged steroid exposure was found to increase the risk of spine fracture for ESI and LJSI patients.
Acute exposure to exogenous steroids via the epidural space, transforaminal space, or large joints does not seem to increase the risk of an osteoporotic fracture of the spine, hip, or wrist.
Epidural steroid injections (ESIs) are widely used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. The treatment rationale is that locally injected anti-inflammatory drugs, such as steroids, reduce inflammation by inhibiting formation and release of inflammatory cytokines, leading to pain reduction.1,2 According to 4 systematic reviews, the best available evidence of the efficacy of ESIs is less than robust.3-6 These reviews were limited by the heterogeneity of patient selection, delivery mode, type and dose of steroid used, number and frequency of ESIs, and outcome measures.
The association of chronic oral steroid use and the development of osteoporosis was previously established.7,8 One concern is that acute exposure to steroids in the form of lumbar ESIs may also lead to osteoporosis and then a pathologic fracture of the vertebra. Several studies have found no association between bone mineral density and cumulative steroid dose,9,10 mean number of ESIs, or duration of ESIs,10 though other studies have found lower bone mineral density in postmenopausal women treated with ESIs.11-13
In a study of 3000 ESI patients propensity-matched to a non-ESI cohort, Mandel and colleagues14 found that each successive ESI increased the risk of osteoporotic spine fracture by 21%. This clinically relevant 21% increased risk might lead physicians to stop prescribing or using this intervention. However, the association between osteoporotic fractures and other types of steroid injections remains poorly understood and underinvestigated.
To further evaluate the relationship between steroid injections and osteoporotic fracture risk, we analyzed Medicare administrative claims data on both large-joint steroid injections (LJSIs) into knee and hip and transforaminal steroid injections (TSIs), as well as osteoporotic hip and wrist fractures. Our hypothesis was that a systemic effect of steroid injections would increase fracture risk in all skeletal locations regardless of injection site, whereas a local effect would produce a disproportionate increased risk of spine fracture with spine injection.
Materials and Methods
Medicare is a publicly funded US health insurance program for people 65 years old or older, people under age 65 years with certain disabilities, and people (any age) with end-stage renal disease or amyotrophic lateral sclerosis. The 5% Medicare Part B (physician, carrier) dataset contains individual claims records for a random sample of Medicare beneficiaries (~2.4 million enrollees). Patients who received steroid injections were identified from 5% Medicare claims made between January 1, 2004 and December 31, 2011. LJSIs were identified by Current Procedural Terminology (CPT) code 20610 and any of 16 other CPT codes: J0702, J1020, J1030, J1040, J1094, J1100, J1700, J1710, J1720, J2650, J2920, J2930, J3300, J3301, J3302, and J3303. ESIs were identified by CPT code 62310, 62311, 62318, or 62319, and TSIs by CPT code 64479, 64480, 64483, or 64484. Patients were followed in their initial injection cohort. For example, a patient who received an ESI initially and later received an LJSI remained in the ESI cohort.
Several groups of patients were excluded from the study: those who received Medicare coverage because of their age (under 65 years) and disabilities; those who received Medicare health benefits through health maintenance organizations (healthcare expenses were not submitted to the Centers for Medicare & Medicaid Services for payment, and therefore claims were not in the database or were incomplete); those with a prior claim history of <12 months (incomplete comorbidity history); and those who received a diagnosis of osteoporotic fracture (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 733.1x) before the initial steroid injection.
We determined the incidence of osteoporotic wrist, hip, and spine fractures within 1, 2, and 8 years after LJSI, ESI, and TSI. Wrist, hip, and spine fractures were identified by ICD-9-CM diagnosis codes 733.12, 733.13, and 733.14, respectively. We also determined the number of steroid injections given before wrist, hip, or spine fracture or, if no fracture occurred, before death or the end of the data period.
Statistical Analysis
Multivariate Cox regression analysis was performed to evaluate the risk factors for wrist, spine, and hip fractures. The covariates in this model included age, sex, race, census region, Medicare buy-in status, Charlson Comorbidity Index (CCI),15 year, and number of steroid injections before fracture, death, or end of data period. Medicare buy-in status, which indicates whether the beneficiary received financial assistance in paying insurance premiums, was used as a proxy for socioeconomic status. CCI is used as a composite score of a patient’s general health status in terms of comorbidities.15,16 Four previously established categories17 were used to group CCIs in this study: 0 (none), 1 to 2 (low), 3 to 4 (moderate), and 5 or more (high). In addition, several diagnoses made within the 12 months before initial steroid injection were considered: osteoporosis (ICD-9-CM codes 733.0x, V82.81), Cushing syndrome (ICD-9-CM code 255.0), long-term (current) use of bisphosphonates (ICD-9-CM code V58.68), asymptomatic postmenopausal status (ICD-9-CM code V49.81), postmenopausal hormone replacement therapy (ICD-9-CM code V07.4), and long-term (current) use of steroids (ICD-9-CM code V58.65). The comparison of relative risk between any groups was reported as the adjusted hazard ratio (AHR), which is the ratio of the hazard rates of that particular outcome, taking into account inherent patient characteristics such as age, sex, and race as covariates. AHR of 1 corresponds to equivalent risk, AHR of >1 to elevated risk, and AHR of <1 to reduced risk.
Results
Using the 5% Medicare data for 2004 to 2011, we identified 275,999 Medicare beneficiaries who underwent LJSI, 93,943 who underwent ESI, and 32,311 who underwent TSI. During this period, TSI use increased, ESI use decreased, and LJSI use was relatively stable (Figure).
The risk for osteoporotic spine fracture 1, 2, and 8 years after ESI, TSI, or LJSI was affected by age, race, sex, and CCI (P < .001 for all; Tables 2-4).
The risk for osteoporotic hip fracture after 1 and 2 years was affected by age and number of LJSIs and TSIs but not by number of ESIs. Sex and CCI were also risk factors for hip fracture at 1 and 2 years for ESI and LJSI patients, as was race for LJSI patients. Risk for osteoporotic wrist fracture at 1 and 2 years was affected by sex and race for ESI and LJSI patients; age, race, CCI, and long-term steroid use were risk factors for TSI patients at all time points. Higher number of LJSIs, but not ESIs or TSIs, was associated with lower wrist fracture risk.
Discussion
ESIs continue to be used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. Although the present study found ESI use increased in the Medicare population between 1994 and 2001,18 the trend is reversing, decreasing by 25%, with rates of 264 per 10,000 Medicare enrollees in 2004 and 194 per 10,000 enrollees in 2011. ESI use may have changed after systematic reviews revealed there was no clear evidence of the efficacy of ESIs in managing low back pain and radicular leg pain3,5,6 or spinal stenosis.4
Nevertheless, ESIs are widely used because of the perceived benefit balanced against the perceived rarity of adverse events.6 Even if patients recognize a low likelihood of significant benefit, they may accept ESI as preferable to surgery. In addition, most private payers require extensive nonoperative treatment before they will approve surgery as a treatment option.
In a study by Mandel and colleagues,14 ESI increased the risk of vertebral compression fractures by 21%, which in turn increased the risk of death.19 If accurate, these findings obviously would challenge the perception that ESI is a low-risk intervention. In contrast to the Mandel study,14 the present analysis of the Medicare population revealed no clinically relevant change in risk of osteoporotic spine fracture with each successive ESI after the initial injection. After the initial injection, each successive ESI decreased the relative risk of osteoporotic spine fracture by 2%, and each successive LJSI decreased it by 4%. Although statistically significant, the small change in relative risk may not be clinically relevant. However, taken cumulatively over a number of successive injections, these effects may be clinically relevant.
The data also showed that, after the initial injection, each successive ESI had no effect on risk of osteoporotic hip or wrist fracture, and each successive LJSI reduced the risk. Similar to earlier findings,20,21 long-term steroid use increased the risk of spine fracture in ESI and LJSI patients. Prolonged exposure to steroids may be necessary to reduce bone formation and increase bone breakdown.12
Although the study by Mandel and colleagues14 and our study both used administrative databases and survival analysis methods, conclusions differed. First, Mandel and colleagues14 used a study inclusion criterion of spine-related steroid injections, whereas we used a criterion of any steroid injection. Second, they used 50 years as the lower age for study inclusion, and we used 65 years. Third, to control for patients who had osteoporosis before study entry, they excluded those who had a fracture in an adjacent vertebra after kyphoplasty and vertebroplasty. It is unclear if patients who had osteoporotic fractures at other sites were excluded as well. Thus, the 2 cohorts may not be directly comparable.
Whereas Mandel and colleagues14 based their definition of osteoporotic spine fracture on a keyword search of a radiology database, we used a specific reportable ICD-9-CM diagnosis code. As a result, they may have overreported osteoporotic spine fractures, and we may have underreported. Finally, our sample was much larger than theirs. Given the relative rarity of osteoporotic fractures, a study with a larger sample may have more power to detect differences. In addition, unlike Mandel and colleagues,14 we focused on an injection cohort. We did not include or make comparisons with a no-injection cohort because our study hypothesis involved the potential systemic effects of steroid injections based on injection site. Although chronic steroid use was found to have a significant effect in our study, it is unclear to what extent the diagnosis code was used, during the comorbidity assessment or only in the event of steroid-related complications.
Our study also found that, after the initial injection, each successive LJSI decreased the risk of osteoporotic wrist fracture by 10%, and each successive TSI decreased the risk of osteoporotic hip fracture by 5%. It is plausible these injections allowed improved mobility, mitigating the effects of osteoporosis induced by inactivity and lack of resistance training. It is also possible that improved mobility limited falls.
In summary, this analysis of the Medicare claims database revealed that ESI, TSI, and LJSI decreased osteoporotic spine fracture risk. However, the effect was small and may not be clinically meaningful. After the initial injection, successive ESIs had no effect on the risk of osteoporotic hip or wrist fracture, and successive LJSIs reduced the risk of osteoporotic wrist fracture, perhaps because of improved mobility. Prolonged oral steroid use increased spine fracture risk in ESI and LJSI patients. More studies are needed to evaluate the risk-benefit profile of steroid injections.
Take-Home Points
Analysis of patients in the Medicare database showed that each successive ESI decreased the risk of an osteoporotic spine fracture by 2%, and that each successive LJSI decreases it by 4%.
Although statistically significant, this may not be clinically relevant.
Successive ESI did not influence the risk of developing an osteoporotic hip or wrist fracture, but that each additional LJSI reduced the risk.
Prolonged steroid exposure was found to increase the risk of spine fracture for ESI and LJSI patients.
Acute exposure to exogenous steroids via the epidural space, transforaminal space, or large joints does not seem to increase the risk of an osteoporotic fracture of the spine, hip, or wrist.
Epidural steroid injections (ESIs) are widely used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. The treatment rationale is that locally injected anti-inflammatory drugs, such as steroids, reduce inflammation by inhibiting formation and release of inflammatory cytokines, leading to pain reduction.1,2 According to 4 systematic reviews, the best available evidence of the efficacy of ESIs is less than robust.3-6 These reviews were limited by the heterogeneity of patient selection, delivery mode, type and dose of steroid used, number and frequency of ESIs, and outcome measures.
The association of chronic oral steroid use and the development of osteoporosis was previously established.7,8 One concern is that acute exposure to steroids in the form of lumbar ESIs may also lead to osteoporosis and then a pathologic fracture of the vertebra. Several studies have found no association between bone mineral density and cumulative steroid dose,9,10 mean number of ESIs, or duration of ESIs,10 though other studies have found lower bone mineral density in postmenopausal women treated with ESIs.11-13
In a study of 3000 ESI patients propensity-matched to a non-ESI cohort, Mandel and colleagues14 found that each successive ESI increased the risk of osteoporotic spine fracture by 21%. This clinically relevant 21% increased risk might lead physicians to stop prescribing or using this intervention. However, the association between osteoporotic fractures and other types of steroid injections remains poorly understood and underinvestigated.
To further evaluate the relationship between steroid injections and osteoporotic fracture risk, we analyzed Medicare administrative claims data on both large-joint steroid injections (LJSIs) into knee and hip and transforaminal steroid injections (TSIs), as well as osteoporotic hip and wrist fractures. Our hypothesis was that a systemic effect of steroid injections would increase fracture risk in all skeletal locations regardless of injection site, whereas a local effect would produce a disproportionate increased risk of spine fracture with spine injection.
Materials and Methods
Medicare is a publicly funded US health insurance program for people 65 years old or older, people under age 65 years with certain disabilities, and people (any age) with end-stage renal disease or amyotrophic lateral sclerosis. The 5% Medicare Part B (physician, carrier) dataset contains individual claims records for a random sample of Medicare beneficiaries (~2.4 million enrollees). Patients who received steroid injections were identified from 5% Medicare claims made between January 1, 2004 and December 31, 2011. LJSIs were identified by Current Procedural Terminology (CPT) code 20610 and any of 16 other CPT codes: J0702, J1020, J1030, J1040, J1094, J1100, J1700, J1710, J1720, J2650, J2920, J2930, J3300, J3301, J3302, and J3303. ESIs were identified by CPT code 62310, 62311, 62318, or 62319, and TSIs by CPT code 64479, 64480, 64483, or 64484. Patients were followed in their initial injection cohort. For example, a patient who received an ESI initially and later received an LJSI remained in the ESI cohort.
Several groups of patients were excluded from the study: those who received Medicare coverage because of their age (under 65 years) and disabilities; those who received Medicare health benefits through health maintenance organizations (healthcare expenses were not submitted to the Centers for Medicare & Medicaid Services for payment, and therefore claims were not in the database or were incomplete); those with a prior claim history of <12 months (incomplete comorbidity history); and those who received a diagnosis of osteoporotic fracture (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 733.1x) before the initial steroid injection.
We determined the incidence of osteoporotic wrist, hip, and spine fractures within 1, 2, and 8 years after LJSI, ESI, and TSI. Wrist, hip, and spine fractures were identified by ICD-9-CM diagnosis codes 733.12, 733.13, and 733.14, respectively. We also determined the number of steroid injections given before wrist, hip, or spine fracture or, if no fracture occurred, before death or the end of the data period.
Statistical Analysis
Multivariate Cox regression analysis was performed to evaluate the risk factors for wrist, spine, and hip fractures. The covariates in this model included age, sex, race, census region, Medicare buy-in status, Charlson Comorbidity Index (CCI),15 year, and number of steroid injections before fracture, death, or end of data period. Medicare buy-in status, which indicates whether the beneficiary received financial assistance in paying insurance premiums, was used as a proxy for socioeconomic status. CCI is used as a composite score of a patient’s general health status in terms of comorbidities.15,16 Four previously established categories17 were used to group CCIs in this study: 0 (none), 1 to 2 (low), 3 to 4 (moderate), and 5 or more (high). In addition, several diagnoses made within the 12 months before initial steroid injection were considered: osteoporosis (ICD-9-CM codes 733.0x, V82.81), Cushing syndrome (ICD-9-CM code 255.0), long-term (current) use of bisphosphonates (ICD-9-CM code V58.68), asymptomatic postmenopausal status (ICD-9-CM code V49.81), postmenopausal hormone replacement therapy (ICD-9-CM code V07.4), and long-term (current) use of steroids (ICD-9-CM code V58.65). The comparison of relative risk between any groups was reported as the adjusted hazard ratio (AHR), which is the ratio of the hazard rates of that particular outcome, taking into account inherent patient characteristics such as age, sex, and race as covariates. AHR of 1 corresponds to equivalent risk, AHR of >1 to elevated risk, and AHR of <1 to reduced risk.
Results
Using the 5% Medicare data for 2004 to 2011, we identified 275,999 Medicare beneficiaries who underwent LJSI, 93,943 who underwent ESI, and 32,311 who underwent TSI. During this period, TSI use increased, ESI use decreased, and LJSI use was relatively stable (Figure).
The risk for osteoporotic spine fracture 1, 2, and 8 years after ESI, TSI, or LJSI was affected by age, race, sex, and CCI (P < .001 for all; Tables 2-4).
The risk for osteoporotic hip fracture after 1 and 2 years was affected by age and number of LJSIs and TSIs but not by number of ESIs. Sex and CCI were also risk factors for hip fracture at 1 and 2 years for ESI and LJSI patients, as was race for LJSI patients. Risk for osteoporotic wrist fracture at 1 and 2 years was affected by sex and race for ESI and LJSI patients; age, race, CCI, and long-term steroid use were risk factors for TSI patients at all time points. Higher number of LJSIs, but not ESIs or TSIs, was associated with lower wrist fracture risk.
Discussion
ESIs continue to be used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. Although the present study found ESI use increased in the Medicare population between 1994 and 2001,18 the trend is reversing, decreasing by 25%, with rates of 264 per 10,000 Medicare enrollees in 2004 and 194 per 10,000 enrollees in 2011. ESI use may have changed after systematic reviews revealed there was no clear evidence of the efficacy of ESIs in managing low back pain and radicular leg pain3,5,6 or spinal stenosis.4
Nevertheless, ESIs are widely used because of the perceived benefit balanced against the perceived rarity of adverse events.6 Even if patients recognize a low likelihood of significant benefit, they may accept ESI as preferable to surgery. In addition, most private payers require extensive nonoperative treatment before they will approve surgery as a treatment option.
In a study by Mandel and colleagues,14 ESI increased the risk of vertebral compression fractures by 21%, which in turn increased the risk of death.19 If accurate, these findings obviously would challenge the perception that ESI is a low-risk intervention. In contrast to the Mandel study,14 the present analysis of the Medicare population revealed no clinically relevant change in risk of osteoporotic spine fracture with each successive ESI after the initial injection. After the initial injection, each successive ESI decreased the relative risk of osteoporotic spine fracture by 2%, and each successive LJSI decreased it by 4%. Although statistically significant, the small change in relative risk may not be clinically relevant. However, taken cumulatively over a number of successive injections, these effects may be clinically relevant.
The data also showed that, after the initial injection, each successive ESI had no effect on risk of osteoporotic hip or wrist fracture, and each successive LJSI reduced the risk. Similar to earlier findings,20,21 long-term steroid use increased the risk of spine fracture in ESI and LJSI patients. Prolonged exposure to steroids may be necessary to reduce bone formation and increase bone breakdown.12
Although the study by Mandel and colleagues14 and our study both used administrative databases and survival analysis methods, conclusions differed. First, Mandel and colleagues14 used a study inclusion criterion of spine-related steroid injections, whereas we used a criterion of any steroid injection. Second, they used 50 years as the lower age for study inclusion, and we used 65 years. Third, to control for patients who had osteoporosis before study entry, they excluded those who had a fracture in an adjacent vertebra after kyphoplasty and vertebroplasty. It is unclear if patients who had osteoporotic fractures at other sites were excluded as well. Thus, the 2 cohorts may not be directly comparable.
Whereas Mandel and colleagues14 based their definition of osteoporotic spine fracture on a keyword search of a radiology database, we used a specific reportable ICD-9-CM diagnosis code. As a result, they may have overreported osteoporotic spine fractures, and we may have underreported. Finally, our sample was much larger than theirs. Given the relative rarity of osteoporotic fractures, a study with a larger sample may have more power to detect differences. In addition, unlike Mandel and colleagues,14 we focused on an injection cohort. We did not include or make comparisons with a no-injection cohort because our study hypothesis involved the potential systemic effects of steroid injections based on injection site. Although chronic steroid use was found to have a significant effect in our study, it is unclear to what extent the diagnosis code was used, during the comorbidity assessment or only in the event of steroid-related complications.
Our study also found that, after the initial injection, each successive LJSI decreased the risk of osteoporotic wrist fracture by 10%, and each successive TSI decreased the risk of osteoporotic hip fracture by 5%. It is plausible these injections allowed improved mobility, mitigating the effects of osteoporosis induced by inactivity and lack of resistance training. It is also possible that improved mobility limited falls.
In summary, this analysis of the Medicare claims database revealed that ESI, TSI, and LJSI decreased osteoporotic spine fracture risk. However, the effect was small and may not be clinically meaningful. After the initial injection, successive ESIs had no effect on the risk of osteoporotic hip or wrist fracture, and successive LJSIs reduced the risk of osteoporotic wrist fracture, perhaps because of improved mobility. Prolonged oral steroid use increased spine fracture risk in ESI and LJSI patients. More studies are needed to evaluate the risk-benefit profile of steroid injections.
1. Pethö G, Reeh PW. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev. 2012;92(4):1699-1775.
2. Saal J. The role of inflammation in lumbar pain. Spine. 1995;20(16):1821-1827.
3. Choi HJ, Hahn S, Kim CH, et al. Epidural steroid injection therapy for low back pain: a meta-analysis. Int J Technol Assess Health Care. 2013;29(3):244-253.
4. Chou R, Loeser JD, Owens DK, et al; American Pain Society Low Back Pain Guideline Panel. Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society. Spine. 2009;34(10):1066-1077.
5. Savigny P, Watson P, Underwood M; Guideline Development Group. Early management of persistent non-specific low back pain: summary of NICE guidance. BMJ. 2009;338:b1805.
6. Staal JB, de Bie RA, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low back pain: an updated Cochrane review. Spine. 2009;34(1):49-59.
7. Angeli A, Guglielmi G, Dovio A, et al. High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone. 2006;39(2):253-259.
8. Donnan PT, Libby G, Boyter AC, Thompson P. The population risk of fractures attributable to oral corticosteroids. Pharmacoepidemiol Drug Saf. 2005;14(3):177-186.
9. Dubois EF, Wagemans MF, Verdouw BC, et al. Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain. Clin Rheumatol. 2003;22(1):12-17.
10. Yi Y, Hwang B, Son H, Cheong I. Low bone mineral density, but not epidural steroid injection, is associated with fracture in postmenopausal women with low back pain. Pain Physician. 2012;15(6):441-449.
11. Al-Shoha A, Rao DS, Schilling J, Peterson E, Mandel S. Effect of epidural steroid injection on bone mineral density and markers of bone turnover in postmenopausal women. Spine. 2012;37(25):E1567-E1571.
12. Kang SS, Hwang BM, Son H, Cheong IY, Lee SJ, Chung TY. Changes in bone mineral density in postmenopausal women treated with epidural steroid injections for lower back pain. Pain Physician. 2012;15(3):229-236.
13. Kim S, Hwang B. Relationship between bone mineral density and the frequent administration of epidural steroid injections in postmenopausal women with low back pain. Pain Res Manag. 2014;19(1):30-34.
14. Mandel S, Schilling J, Peterson E, Rao DS, Sanders W. A retrospective analysis of vertebral body fractures following epidural steroid injections. J Bone Joint Surg Am. 2013;95(11):961-964.
15. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
16. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613-619.
17. Murray SB, Bates DW, Ngo L, Ufberg JW, Shapiro NI. Charlson index is associated with one-year mortality in emergency department patients with suspected infection. Acad Emerg Med. 2006;13(5):530-536.
18. Friedly J, Chan L, Deyo R. Increases in lumbosacral injections in the Medicare population: 1994 to 2001. Spine. 2007;32(16):1754-1760.
19. Puisto V, Rissanen H, Heliövaara M, et al. Vertebral fracture and cause-specific mortality: a prospective population study of 3,210 men and 3,730 women with 30 years of follow-up. Eur Spine J. 2011;20(12):2181-2186.
20. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effects of low-dose corticosteroids on the bone mineral density of patients with rheumatoid arthritis: a meta-analysis. J Investig Med. 2008;56(8):1011-1018.
21. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 1994;20(3):629-650.
1. Pethö G, Reeh PW. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev. 2012;92(4):1699-1775.
2. Saal J. The role of inflammation in lumbar pain. Spine. 1995;20(16):1821-1827.
3. Choi HJ, Hahn S, Kim CH, et al. Epidural steroid injection therapy for low back pain: a meta-analysis. Int J Technol Assess Health Care. 2013;29(3):244-253.
4. Chou R, Loeser JD, Owens DK, et al; American Pain Society Low Back Pain Guideline Panel. Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society. Spine. 2009;34(10):1066-1077.
5. Savigny P, Watson P, Underwood M; Guideline Development Group. Early management of persistent non-specific low back pain: summary of NICE guidance. BMJ. 2009;338:b1805.
6. Staal JB, de Bie RA, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low back pain: an updated Cochrane review. Spine. 2009;34(1):49-59.
7. Angeli A, Guglielmi G, Dovio A, et al. High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study. Bone. 2006;39(2):253-259.
8. Donnan PT, Libby G, Boyter AC, Thompson P. The population risk of fractures attributable to oral corticosteroids. Pharmacoepidemiol Drug Saf. 2005;14(3):177-186.
9. Dubois EF, Wagemans MF, Verdouw BC, et al. Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain. Clin Rheumatol. 2003;22(1):12-17.
10. Yi Y, Hwang B, Son H, Cheong I. Low bone mineral density, but not epidural steroid injection, is associated with fracture in postmenopausal women with low back pain. Pain Physician. 2012;15(6):441-449.
11. Al-Shoha A, Rao DS, Schilling J, Peterson E, Mandel S. Effect of epidural steroid injection on bone mineral density and markers of bone turnover in postmenopausal women. Spine. 2012;37(25):E1567-E1571.
12. Kang SS, Hwang BM, Son H, Cheong IY, Lee SJ, Chung TY. Changes in bone mineral density in postmenopausal women treated with epidural steroid injections for lower back pain. Pain Physician. 2012;15(3):229-236.
13. Kim S, Hwang B. Relationship between bone mineral density and the frequent administration of epidural steroid injections in postmenopausal women with low back pain. Pain Res Manag. 2014;19(1):30-34.
14. Mandel S, Schilling J, Peterson E, Rao DS, Sanders W. A retrospective analysis of vertebral body fractures following epidural steroid injections. J Bone Joint Surg Am. 2013;95(11):961-964.
15. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383.
16. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45(6):613-619.
17. Murray SB, Bates DW, Ngo L, Ufberg JW, Shapiro NI. Charlson index is associated with one-year mortality in emergency department patients with suspected infection. Acad Emerg Med. 2006;13(5):530-536.
18. Friedly J, Chan L, Deyo R. Increases in lumbosacral injections in the Medicare population: 1994 to 2001. Spine. 2007;32(16):1754-1760.
19. Puisto V, Rissanen H, Heliövaara M, et al. Vertebral fracture and cause-specific mortality: a prospective population study of 3,210 men and 3,730 women with 30 years of follow-up. Eur Spine J. 2011;20(12):2181-2186.
20. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effects of low-dose corticosteroids on the bone mineral density of patients with rheumatoid arthritis: a meta-analysis. J Investig Med. 2008;56(8):1011-1018.
21. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 1994;20(3):629-650.
