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Increased Risk for Stress Fractures and Delayed Healing with NSAID Receipt, U.S. Armed Forces, 2014–2018

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Medical Surveillance Monthly Report

ABSTRACT

Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with an increased risk of stress fractures due to their inhibitory effect on bone formation. The current study evaluated the relative risk of stress fractures in active duty service members with and without previous receipt of NSAIDs. A total of 7,036 cases of stress fracture and 28,141 matched controls were identified between June 2014 and December 2018 and included in the analysis. A subset of cases were evaluated for delayed healing diagnoses within 90 days following incident case diagnosis using International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Prior receipt of NSAIDs was associated with an increased incidence of stress fractures (adjusted incidence rate ratio=1.70; 95% confidence interval [CI]:1.58–1.82; p<.0001). Among stress fracture cases, prior receipt of NSAIDs was associated with increased diagnosis of delayed healing (adjusted odds ratio=1.41; 95% CI: 1.12–1.77; p=.004). These findings may have significant implications for military readiness because NSAIDs are used extensively and stress fractures are already a major contributor to the burden of healthcare encounters and lost duty time.

WHAT ARE THE NEW FINDINGS?   

This is the first MSMR report on the association between prior NSAID receipt and incident stress fracture diagnosis in service members. Prior NSAID receipt was associated with a 70% increased incidence of stress fracture. Among cases, the odds of a delayed healing diagnosis among NSAID recipients were 1.4 times that of nonrecipients.

WHAT IS THE IMPACT ON READINESS AND FORCE HEALTH PROTECTION?

This study suggests that receiving NSAIDs may increase the risk for stress fracture among active component service members. These stress fracture injuries may contribute to lost duty days and reduce deployment readiness because of physical limitation.

BACKGROUND

Service members in the U.S. Armed Forces participate in intense physical activity when training and performing their job responsibilities. The physical activity can potentially result in overuse injuries because the repetitive force exerted by the musculoskeletal system may cause cumulative microtraumatic damage leading to strains, sprains, and stress fractures.1–3 Injuries, including stress fractures, are a major public health concern among the military because of their high prevalence, the associated lost working time, and the cost of treatment. A previous MSMR article estimated that there were 31,349 incident stress fractures diagnosed (a rate of 3.2 per 1,000 person-years) among active component service members from 2004 through 2010.3 A recent study among the Royal Marines during commando training found that, on average, the rehabilitation time for stress fractures ranged from 12 to 21 weeks depending on the site of fracture.4 The burden associated with stress fractures is high when taking into consideration the incidence rate, slow recovery time, and medical cost of treatment.

Hughes and colleagues examined the association between stress fractures and nonsteroidal antiinflammatory drugs (NSAIDs) in a U.S. Army population and found that both NSAIDs and acetaminophen potentially increase the risk for stress fractures.2 If NSAID use is associated with an increase in stress fracture risk, this finding could have a sizable impact on military readiness given the widespread use of these drugs. In 2014, approximately 82% (n=418,579) of active duty U.S. Army service members filled at least 1 NSAID prescription.5 Many service members could be unknowingly increasing their risk for stress fractures by taking medications to decrease the pain and swelling associated with other physical complaints.

The use of NSAIDs to treat swelling and pain from fractures has been widely debated. Studies have claimed that NSAIDs could increase the risk of a fracture or delay the healing of a fracture because of the drug’s inhibitory effect on bone metabolism.2,6–10 In theory, this claim is plausible when considering the impact of the mechanism of action for NSAIDs on the physiological process of bone metabolism. Bone metabolism involves osteoclasts and osteoblasts, which are responsible for the removal of bone and the growth of bone, respectively.9–12 Bone metabolism can be grouped into 2 processes: bone modeling and bone remodeling.10,11 During bone modeling, there is bone formation on the surface of bones in response to mechanical loading.10,11 The loading initiates osteoclast-mediated biochemical signaling and Wnt/ß-catenin pathway activation, which are crucial for osteoblast differentiation, proliferation, and bone formation.10 During bone remodeling, there is bone resorption and then bone formation to replace old or damaged bone.10,11 During remodeling, osteoclasts remove the area of damaged bone and osteoblasts then replace it with new bone. However, the new bone is temporarily more porous, and in turn, more fragile and injury prone.10

Bone metabolism can be both stimulated and inhibited by a group of physiologically active lipid compounds called prostaglandins, which are responsible for the differentiation of osteoclasts and osteoblasts as well as resorbing activity of mature osteoclasts.9,10,12,13 There are 2 initiators to the production of prostaglandins: cyclooxygenase-1 (COX-1) enzyme and cyclooxygenase-2 (COX-2) enzyme. COX-1 produces prostaglandins in response to physiological conditions such as tissue homeostasis and cell-to-cell signaling, while COX-2 produces them in response to inflammation.9,10,12,14 NSAIDs inhibit the activity of COX by competing with arachidonic acid for binding to the enzyme.9,12 Therefore, NSAIDs reduce the production of prostaglandins, limiting the differentiation of osteoclasts and osteoblasts and the resorbing activity of osteoclasts, which then inhibits bone resorption and formation. In theory, this inhibition could interfere with bone modeling and remodeling and increase the risk of fracture or delayed healing. Studies have shown that the timing of NSAID use is key to the inhibition of bone modeling.10,15–17 Bone formation is suppressed if NSAIDs are taken before bone loading, but not if NSAIDs are taken afterwards.10,15–17

NSAIDs can be categorized by their inhibiting effect on the COX enzymes. Each class of NSAID is selective to binding to COX enzymes with varying degrees. The nonselective COX inhibitors impede the activity of both COX-1 and COX-2 enzymes with no discrimination.14 Preferentially selective COX-2 inhibitors impede COX-2 activity at lower drug concentrations, but there is some COX-1 inhibition at label dose. Selective COX-2 inhibitors (coxibs) impede COX-2 activity but not COX-1 at label dose.14 Studies have indicated a negative effect of NSAIDs on the bone healing process because NSAIDs limit osteogenesis and angiogenesis through blocking COX-2.14,18–20 However, NSAIDs have other mechanisms that can impair healing from a bone injury. Besides limiting osteogenesis and angiogenesis, NSAIDs can initiate apoptosis, alter collagen content and fiber size, and modify genes produced from a signaling pathway that plays a role in differentiation and proliferation of osteoblast precursor cells.14,21

Some animal studies have provided evidence that bone repair is either delayed or impaired by NSAID treatment and that the degree of delay in bone healing depends on the type of fracture and type of NSAID prescribed.7,11,22 Human studies examining the effect of NSAIDs on fracture healing have observed inconsistent results. A retrospective study of patients with tibia fractures found that patients taking any NSAIDs were more likely to have delayed healing compared to those patients not taking any NSAIDs.7,23 In addition, a retrospective analysis examining healing from a fracture of the femur diaphysis found that there was an association between nonunion and use of NSAIDs after injury.7,24 This study also identified patients who, although their fractures had united, showed a delay in healing after taking NSAIDs.7,24 In contrast, a double-blind randomized study examined healing from Colles fractures after treating postmenopausal women with either piroxicam or placebo and found no statistically significant delay in healing with the NSAID treatment.7,25

Although it has been suggested that NSAIDs may increase risk for fractures and delay bone repair, the findings from studies on such topics have been mixed. The objective of this study was to estimate the risk of stress fracture following receipt of NSAIDs among active component military service members between June 2014 and December 2018. In addition, the current study evaluated the association between NSAID receipt and International Classification of Diseases, 10th Revision (ICD-10) coded diagnosis of delayed healing among incident stress fracture cases.

METHODS

The eligible study population consisted of active component service members in the Army, Air Force, Navy, or Marine Corps who served for any length of time between 1 June 2014 and 31 December 2018. This study period was selected based on the availability of pharmacy data in the Defense Medical Surveillance System (DMSS). All study data were derived from the DMSS, a relational database maintained by the Armed Forces Health Surveillance Branch. Multiple data sources feed information into the DMSS, forming tables related to demographic characteristics, prescriptions dispensed, and administrative health records. Pharmacy data in the DMSS are derived from the Pharmacy Data Transaction Service (PDTS), which has information on outpatient prescriptions dispensed by mail order, at military treatment facilities (MTFs), by Veterans Affairs for dual eligible beneficiaries, and at civilian facilities if billed through TRICARE. The medical encounters in the DMSS contain records of both hospitalizations and ambulatory visits in fixed MTFs and civilian treatment facilities billed through TRICARE.

To qualify as an incident case of stress fracture, an individual had to have either 1) an outpatient medical encounter with a qualifying ICD-9 or ICD-10 diagnosis code for stress fracture (Table 1) in any diagnostic position followed by another outpatient medical encounter for a diagnosed stress fracture within 14 to 90 days later or 2) a hospitalization with a diagnosis code for stress fracture in any diagnostic position. The incidence date, also referred to as reference date for controls, was the date of the first qualifying encounter. If there was a hospitalization and an outpatient encounter on the same day, then inpatient records were prioritized over outpatient encounters. If the first encounter occurred before the surveillance period, the service member was considered a prevalent case and was excluded from the analysis. An individual could be counted as an incident case only once per lifetime. Those who had any outpatient diagnoses of stress fracture during their military service before the first qualifying encounter were excluded.

The first part of the study employed a case-control design with risk-set matching to assess the association between prescribed NSAID and incident stress fracture diagnosis among active component service members from June 2014 through December 2018. Up to 4 controls were matched to each case based on sex, race/ethnicity, service branch, age (within 1 year), and time in service category. Random selection was performed if more than 4 controls were matched to a case. Race/ethnicity was coded as non-Hispanic white, non-Hispanic black, Hispanic, Asian/Pacific Islander, American Indian/Alaska Native, and other/unknown. Time in service was categorized as less than 4 months, 4 months to less than 1 year, 1 year to less than 2 years, 2 years to less than 5 years, and 5 years or more. Controls were allowed to be matched to multiple cases if they fit the matching criteria and were able to become a case later in the study. Controls with any diagnosis of a stress fracture in an inpatient or outpatient encounter on or before the reference date were excluded from being a control for that match.

To measure exposure, prescription records were included in the analysis if the records contained an American Hospital Formulary Service (AHFS) therapeutic class code for NSAID (280804) and the drug (brand or generic) name (Table 2). An individual was considered exposed to an NSAID if the prescription date was 30 to 180 days before the reference date. NSAID use within 30 days before the reference date was not considered a qualifying exposure in order to avoid the potential effects of reverse causation from the use of prescribed NSAIDs to treat the pain of a pre-clinical stress fracture.2 Service members could be exposed to multiple NSAIDs during the 30-to 180-day exposure period, and indicator variables were created to identify the different NSAID classes.

Vitamin D deficiency was included in the analysis as a potential confounding factor since several studies have suggested that this deficiency is related to both NSAID use and stress fractures.26–29 For this study, a case of vitamin D deficiency was defined as having a hospitalization or ambulatory encounter with an ICD-9 or ICD-10 diagnosis code for vitamin D deficiency in any diagnostic position within 1 year before to 6 months following the reference date (Table 2).

The study secondarily assessed the association between NSAID receipt and diagnosis of delayed healing among the subset of incident stress fracture cases identified during the period between October 2015 and December 2018. A case was considered delayed healing if there was an ICD-10 diagnosis code beginning with “M843” (stress fracture) and ending in “G” (subsequent encounter for fracture with delayed healing) recorded during an inpatient or outpatient encounter within 90 days of the incident stress fracture diagnosis.

For the first part of the study, adjusted incidence rate ratios and associated 95% confidence intervals (CIs) were calculated using a multivariable logistic regression model to estimate the effect of NSAID receipt on incident stress fracture diagnosis. The model adjusted for sex, race/ethnicity, service, age, time in service, recruit status, occupation, and diagnosis of vitamin D deficiency. The same adjusted incidence rate ratio was calculated for just the Army population. For the second part of the study, adjusted odds ratios and associated 95% CIs were calculated using multivariable logistic regression to estimate the effect of NSAID receipt on delayed healing diagnosis among stress fracture cases. Covariates adjusted for in the model were age, sex, race/ethnicity, vitamin D deficiency, time in service, service branch, military occupation, and recruit status.

RESULTS

A total of 7,039 incident stress fracture cases were identified among active component service members from June 2014 through December 2018; however, 3 cases were excluded from the analysis because matched controls could not be identified. The cases excluded were an Asian female Marine and two additional females who were older than 45 years old. A total of 28,141 controls were selected, resulting in a total sample size of 35,177 (Table 3). Among the cases, stress fractures occurred predominantly within the leg (54.0%). As a result of the matching process, the distribution of sex, race/ethnicity, age, service, and time in service was similar between cases and controls. Compared to controls, cases consisted of higher percentages of recruits (21.1% vs. 31.5%, respectively), enlisted personnel (89.1% vs. 94.4%, respectively), individuals with diagnosed vitamin D deficiency (0.6% vs. 6.5%, respectively), and NSAID receipt (17.5% vs. 22.9%, respectively). Propionic acid derivatives were the most common NSAIDs dispensed within the 30 to 180 days before the stress fracture diagnosis (for cases) or reference date (for controls) in the study population (16.7%), followed by preferential COX-2 inhibitors (1.6%) (Table 3). Of the propionic acid derivatives, the most commonly dispensed drugs were ibuprofen (56.4%) and naproxen (27%) (data not shown). In the final adjusted model, service members who received NSAIDs had an incidence of stress fracture diagnoses that was 1.70 times (95% CI: 1.58–1.82; p<.0001) that of those who had not received NSAIDs (data not shown). When this model was restricted to the Army population, soldiers who received NSAIDs had 1.64 times (95% CI: 1.49–1.80; p<0.0001) the incidence of stress fracture diagnosis compared to nonrecipients (data not shown).

Of the 7,036 incident stress fracture cases identified in the first part of the study, 5,295 were diagnosed on or after 1 October 2015, after the transition to the ICD-10 coding system, and were included in the second part of the analysis (Table 4). A total of 496 (9.4%) of these cases had a diagnosis for delayed healing within 90 days after the incident stress fracture diagnosis. Distribution of demographic and selected military characteristics among cases with and without delayed healing diagnoses were broadly similar, with the exception that a smaller percentage of delayed healing cases were among recruits (21.0% vs. 32.5%, respectively) and there was a greater percentage of diagnosed vitamin D deficiency among those with delayed healing diagnoses compared to those without (13.1% vs. 6.4%, respectively). In addition, a greater percentage of delayed healing fracture cases occurred among service members in the Air Force (16.7% vs 12.2%, respectively), among service members in communications/intelligence occupations (20.8% vs. 15.9%, respectively), and among service members with 1–3 years of time in service (25.4% vs 16.1%, respectively) compared to controls. In the final adjusted model, those stress fracture cases who received any NSAIDs had odds of a delayed healing diagnosis that were 1.41 times (95% CI: 1.12–1.77; p=.004) those of cases who did not receive any NSAIDs (data not shown).

EDITORIAL COMMENT

This study found that active component service members who had previously received any NSAIDs experienced a 70% increased incidence in stress fracture diagnoses compared to those who had not received any NSAIDs. Studies of the risk of stress fracture after NSAID use have produced contradictory results. However, several studies suggest that NSAIDs increase risk of stress fractures, especially during times of intense physical training. One study conducted among U.S. Army personnel found that risk of stress fractures was significantly higher in NSAID users, and that this risk increased among the recruits in basic combat training,2 suggesting that NSAIDs do increase the risk for fractures, especially during times of intense physical training.

In a previous retrospective cohort study of regular and incidental NSAID users and control patients, the relative rate for nonvertebral fractures was higher among regular NSAID users in comparison to the control patients.6,7 However, there was no difference in rates of nonvertebral fractures between the regular and incidental users, which suggests that use of NSAIDs, not the duration of use, increases the risk for fractures.6,7

As a secondary objective, the current study examined whether dispensed NSAIDs were associated with diagnoses of delayed healing and found that stress fracture cases with previous NSAID receipt experienced 1.41 times the odds of a delayed healing diagnosis compared to nonrecipients. Previous animal and human studies have provided inconclusive evidence on the effect of NSAIDs on fracture healing.7,9,10,13–25 Results of several studies suggest the effect of NSAIDs on healing may be different depending on the type of fractures and the timing of NSAID use.7,10,11,15–17,22 Previous in vitro studies have found that NSAIDs inhibit the proliferation potential of osteogenic cells, deterring the differentiation of osteoblasts, which then prevents the formation of new bone.9,30–35 This finding lends support to the hypothesis that NSAID use may delay bone healing since the inhibition of these osteogenic cells would result in reduced bone resorption and formation.

The current study was designed to replicate a case-control study by Hughes and colleagues that examined NSAID use and risk of stress fracture among Army members.However, there were some key differences in the designs of this study and the current study. The current study used the same NSAID exposure definition; however, more classes of NSAIDs were included in the current analysis because literature has suggested that these drugs have an effect on osteoblast and osteoclast proliferation.9,10,15,16,32–34 The current study used a case definition similar to that used by Hughes and colleagues with the exception that pathological fractures were excluded to avoid any misclassification of fractures from illness.10 The current study also randomly sampled controls by a 4:1 ratio, with risk-set matching on several demographic variables, while the Hughes and colleagues’ study only matched on time in service. The stricter matching rules and shorter study period employed in the current study identified a smaller number of cases than in the reference study. Both studies had a potential for reverse causation because service members could have had prior NSAID use to treat the pain of a pre-clinical stress fracture. In an effort to minimize potential reverse causation, the current study did not consider NSAID use within 30 days before the reference date as exposure to NSAIDs. The reference study used the same rule after conducting a lagged analysis comparing 15-, 30-, and 45-day gaps between NSAID use and stress fracture-related encounter.Based on their analysis, the reference study used a 30-day gap in the exposure definition.2 The reference study found that NSAID receipt was associated with a 2.9 times increase in stress fracture risk for the Army population, while the current study found a 1.64 times increase in incidence of stress fracture when restricted to Army service members only (data not shown).2 Although both studies demonstrated a statistically significant positive association between prior NSAID receipt and incident stress fracture, the reference study found a more pronounced association.

There are several limitations to the current study. Service members were included as exposed if they had received prescribed NSAIDs; however, medication adherence could not be measured. In addition, severity of stress fracture cannot be determined from administrative healthcare records. Furthermore, individuals may be misclassified as nonexposed if they took over-the-counter NSAIDs. In particular, it is likely the study did not capture instances of ibuprofen or aspirin self-medication for service members who used only over-the-counter drugs, which would not be reflected in Military Health System prescription records. Service members were considered exposed if they received NSAIDs 30 to 180 days before the reference date; however, for recruits, prescription data before basic training were not available, so this data gap may also have resulted in exposure misclassification.

Prospective studies are recommended to confirm the associations between prior receipt of NSAIDs and increased incidence of stress fractures and delayed bone healing and to reduce the possibilities of misclassification bias and reverse causation. If confirmed, these findings may have significant implications for military readiness because NSAIDs are used extensively and stress fractures are already a major contributor to the burden of healthcare encounters and lost duty time.36,37 Treatment recommendations for stress fractures may need to be adapted to focus more heavily on preventive measures and ensuring adequate healing time with reduced emphasis on NSAID use for relieving pain and swelling symptoms.

REFERENCES

1. Jones BH, Hauschild VD, Canham-Chervak M. Musculoskeletal training injury prevention in the U.S. Army: evolution of the science and the public health approach. J Sci Med Sport. 2018;21(11):1139–1146.

2. Hughes JM, McKinnon CJ, Taylor KM, et al. Nonsteroidal anti-inflammatory drug prescriptions are associated with increased stress fracture diagnosis in the US Army population. J Bone Miner Res. 2019;34(3):429–436.

3. Armed Forces Health Surveillance Branch. Stress fractures, active component, U.S. Armed Forces, 2004–2010. MSMR. 2011;18(5):8–11.

4. Wood AM, Hales R, Keenan A, et al. Incidence and time to return to training for stress fractures during military basic training. J Sports Med. 2014;2014:282980.

5. Walker L, Zambraski E, Williams RF. Widespread use of prescriptions nonsteroidal antiinflammatory drugs among U.S. Army active duty soldiers. Mil Med. 2017;182(3):e1709–e1712. 

6. van Staa TP, Leufkens HG, Cooper C. Use of nonsteroidal anti-inflammatory drugs and risk of fractures. Bone. 2000;27(4):563–568.

7. Wheeler P, Batt ME. Do non-steroidal antiinflammatory drugs adversely affect stress fracture healing? A short review. Br J Sports Med. 2005;39(2):65–69.

8. Stovitz SD, Arendt EA. NSAIDs should not be used in treatment of stress fractures. Am Fam Physician. 2004;70(8):1452–1454.

9. Pountos I, Georgouli T, Calori GM, Giannoudis PV. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. ScientificWorldJournal. 2012;2012:606404.

10. Hughes JM, Popp KL, Yanovich R, Bouxsein ML, Matheny RW Jr. The role of adaptive bone formation in the etiology of stress fracture. Exp Biol Med (Maywood). 2017;242(9):897–906.

11. Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone: bad cop, good cop? Trends Endocrinol Metab. 2010;21(5):294–301.

12. Kaji H, Sugimoto T, Kanatani M, Fukase M, Kumegawa M, Chihara K. Prostaglandin E2 stimulates osteoclast-like cell formation and boneresorbing activity via osteoblasts: role of cAMPdependent protein kinase. J Bone Miner Res. 1996;11(1):62–71.

13. Lisowska B, Kosson D, Domaracka K. Positives and negatives of nonsteroidal anti-inflammatory drugs in bone healing; the effects of these drugs on bone repair. Drug Des Devel Ther. 2018;12;1809–1814.

14. Gerstenfeld LC, Thiede M, Seibert K, et al. Differential inhibition of fracture healing by nonselective and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs. J Orthop Res. 2003;21(4):670–675.

15. Chow JW, Chambers TJ. Indomethacin has distinct early and late actions on bone formation induced by mechanical stimulation. Am J Physiol. 1994;267(2 pt 1):e287–e292.

16. Jankowski CM, Shea K, Barry DW, et al. Timing of ibuprofen use and musculoskeletal adaptations to exercise training in older adults. Bone Rep. 2015;1:1–8.

17. Kohrt WM, Barry DW, Van Pelt RE, Jankowski CM, Wolfe P, Schwartz RS. Timing of ibuprofen use and bone mineral density adaptations to exercise training. J Bone Miner Res. 2010;25(6):1415–1422.

18. Daluiski A, Ramsey KE, Shi Y, et al. Cyclooxygenase-2 inhibitors in human skeletal fracture healing. Orthopedics. 2006;29(3);259–261.

19. Herbenick MA, Sprott D, Stills H, Lawless M. Effects of a cyclooxygenase 2 inhibitor on fracture healing in a rat model. Am J Orthop (Belle Mead NJ). 2008;37(7):e133–e137.

20. Murnaghan M, Li G, Marsh DR. Nonsteroidal anti-inflammatory drug-induced fracture nonunion: an inhibition of angiogenesis? J Bone Joint Surg Am. 2006;88(suppl 3):140–147.

21. Nagano A, Arioka M, Takahasi-Yanaga F, Matsuzaki E, Sasaguri T. Celecoxib inhibits osteoblast maturation by suppressing the expression of Wnt target genes. J Pharmacol Sci. 2017;133(1):18–24.

22. Altman RD, Latta LL, Keer R, Renfree K, Hornicek FJ, Banovac K. Effect of nonsteroidal antiinflammatory drugs on fracture healing: a laboratory study in rats. J Orthop Trauma. 1995;9(5):392–400.

23. Butcher CK, Marsh DR. Nonsteroidal anti-inflammatory drugs delay tibial fracture union. Injury. 1996;27(5):375.

24. Giannoudis PV, MacDonald DA, Matthews SJ, Smith RM, Furlong AJ, De Boer P. Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br. 2000;82(5):655–658.

25. Adolphson P, Abbaszadegan H, Jonsson U, Dalén N, Sjöberg HE, Kalén S. No effects of piroxicam on osteopenia and recovery after Colles’ fracture. A randomized, double-blind, placebo-controlled, prospective trial. Arch Orthop Trauma Surg. 1993;112(3):127–130.

26. Furuya T, Hosoi T, Tanaka E, et al. Prevalence of and factors associated with vitamin D deficiency in 4,793 Japanese patients with rheumatoid arthritis. Clin Rheumatol. 2013;32(7):1081–1087.

27. Nadolski, CE. Vitamin D and chronic pain: promising correlates. US Pharm. 2012;37(7):42–44.

28. Sonneville KR. Gordon CM, Kocker MS, Pierce LM, Ramappa A, Field AE. Vitamin D, calcium, and dairy intakes and stress fractures among female adolescents. Arch Pediatr Adolesc Med. 2012;166(7):595–600.

29. Miller JR, Dunn KW, Ciliberti LJ Jr, Patel RD, Swanson BA. Association of vitamin D with stress fractures: a retrospective cohort study. J Foot Ankle Surg. 2016;55(1):117–120.

30. Wang Y, Chen X, Zhu W, Zhang H, Hu S, Cong X. Growth inhibition of mesenchymal stem cells by aspirin: involvement of the wnt/ß-catenin signal pathway. Clin Exp Pharmacol Physiol. 2006;33(8):696–701.

31. Chang JK, Wang GJ, Tsai ST, Ho ML. Nonsteroidal anti-inflammatory drug effects on osteoblastic cell cycle, cytotoxicity, and cell death. Connect Tissue Res. 2005;46(4–5):200–210.

32. Chang JK, Li CJ, Lia HJ, Wang CK, Wang GJ, Ho ML. Anti-inflammatory drugs suppress proliferation and induce apoptosis through altering expressions of cell cycle regulators and pro-apoptotic factors in cultured human osteoblasts. Toxicology. 2009;258(2–3):148–156.

33. Ho ML, Chang JK, Chuang LY, Hsu HK, Wang GJ. Effects of nonsteroidal anti-inflammatory drugs and prostaglandins on osteoblastic functions. Biochem Pharmacol. 1999;56(6):983–990.

34. Evans CE, Butcher C. The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes. J Bone Joint Surg Br. 2004;86(3):444–449.

35. Díaz-Rodríguez L, García-Martínez O, Morales MA, Rodríguez-Pérez L, Rubio-Ruiz B, Ruiz C Effects of indomethacin, nimesulide, and diclofenac on human MG-63 osteosarcoma cell line. Biol Res Nurs. 2012;14(1):98–107.

36. Stahlman S, Taubman, SB. Incidence of acute injuries, active component, U.S. Armed Forces, 2008–2017. MSMR. 2018;25(7):2–9.

37. Armed Forces Health Surveillance Branch. Absolute and relative morbidity burdens attributable to various illnesses and injuries, active component, U.S. Armed Forces, 2018. MSMR. 2019;26(5):2–10.

 Stress fracture and vitamin D deficiency case defining ICD-9 and ICD-10 codes

NSAID classes and drug names included in the analysis

Characteristics of stress fracture cases and matched controls at the time of matching, active component, U.S. Armed Forces, 30 June 2014–31 December 2018

Characteristics of stress fracture cases with and without delayed healing, active component, U.S. Armed Forces, 1 October 2015–31 December 2018

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2/14/2018
Since 1999, the Medical Surveillance Monthly Report (MSMR) has published periodic updates on the incidence of malaria among U.S. service members. Malaria infection remains an important health threat to U.S. service members, who are located in endemic areas because of long-term duty assignments, participation in shorter-term contingency operations, or personal travel. This update for 2017 describes the epidemiologic patterns of malaria incidence in active and reserve component service members of the U.S. Armed Forces. Findings •	A total of 32 service members were diagnosed with or reported to have malaria, which is the lowest number of cases in any given year during the 10-year surveillance period. •	Health records documented the performance of laboratory tests for malaria for 22 of the cases. The tests for 17 of the 22 were positive for malaria ( stick figure graphic visually depicts this information). •	In 2017, 75.0% (24 of 32) of malaria cases among U.S. service members were diagnosed during May – October (calendar graphic showing the months visually). •	Of the 32 malaria cases in 2017, more than 1/3 of the infections were considered to have been acquired in Africa. Two bar charts display the following information: •	Bar chart 1: Numbers of malaria cases by Plasmodium species and calendar year of diagnosis/report, active and reserve components, U.S. Armed Forces, 2008 – 2017  •	Bar chart 2: Annual numbers of cases of malaria associated with specific locations of acquisition, active and reserve components, U.S. Armed Forces, 2008 – 2017  The majority of U.S. military members diagnosed with malaria in 2017 were: •	Male (96.9%) •	Active component (81.3%) •	In the Army (75.0%) •	In their 20’s (56.3%) Access the full report in the February 2018 MSMR (Vol. 25 No. 2). Go to www.Health.mil/MSMR  Picture of a mosquito displays on the graphic.

This update for 2017 describes the epidemiologic patterns of malaria incidence in active and reserve component service members of the U.S. Armed Forces.

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Outbreak of Influenza and Rhinovirus co-circulation among unvaccinated recruits, U.S. Coast Guard Training Center Cape May, NJ, 24 July – 21 August 2016

Infographic
2/5/2018
On 29 July 2016, the U.S. Coast Guard Training Center Cape May (TCCM), NJ, identified an increase in febrile respiratory illness (FRI) among recruits who were unvaccinated against seasonal influenza as a result of the annual vaccine’s expiration. This report characterizes the outbreak and containment measures implemented at TCCM during the outbreak period. In 2016, respiratory infections affected more than 250,000 U.S. service members and comprised approximately 22% of medical encounters among military recruit populations – who are highly susceptible to respiratory infections. Seasonal influenza and rhinovirus are two of the leading respiratory pathogens. During the Surveillance Period: 115 recruits reported respiratory infection symptoms. Pie chart 1 shows the following data: •	41 (35.7%) suspected cases •	74 (64.3%) confirmed cases Among confirmed cases, lab specimens tested positive for: •	Influenza A 34 (45.9%) •	Rhinovirus 28 (37.8%) •	Influenza A and rhinovirus co-infection 11 (14.9%) •	Rhinovirus and adenovirus co-infection 1 (1.4%) Data above depicted in pie chart 2. •	24 July – 6 August, Influenza predominated •	7 August – 20 August, Rhinovirus predominated Although the outbreak significantly affected operations at TCCM, a timely and comprehensive response resulted in containment of the outbreak within 5 weeks. Key Factor for Outbreak Control •	Rapid detection through FRI sentinel surveillance •	Quick decision-making •	Streamlined response by using a single chain of command •	Rapid implementation of both nonpharmaceutical and pharmaceutical interventions Access the full report in the January 2018 MSMR (Vol. 25, No. 1). Go to: www.Health.mil/MSMR

This report characterizes the outbreak and containment measures implemented at the U.S. Coast Guard Training Center Cape May (TCCM), New Jersey, during a July 24 – August 21, 2016 outbreak period.

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Department of Defense Global, Laboratory-based Influenza Surveillance Program’s Influenza vaccine effectiveness estimates and surveillance trends, 2016 – 2017 Influenza Season

Infographic
2/5/2018
Each year, the Department of Defense (DoD) Global, Laboratory-based Influenza Surveillance Program performs surveillance for influenza among service members of the DoD and their dependent family members. In addition to routine surveillance, vaccine effectiveness (VE) studies are performed and results are shared with the Food and Drug Administration, Centers for Disease Control and Prevention, and the World Health Organization for vaccine evaluation. This report documents the annual surveillance trends for the 2016 – 2017 influenza season and the end-of-season VE results. The analysis was performed by the U.S. Air Force School of Aerospace Medicine Epidemiology Laboratory, and the DoD Influenza Surveillance Program staff at Wright-Patterson Air Force Base, OH. FINDINGS: A total of 5,555 specimens were tested from 84 locations: •	2,486 (44.7%) negative •	1,382 (24.9%) influenza A •	1,093 (19.7%) other respiratory pathogens •	443 (8.0%) influenza B •	151 (2.7%) co-infections The predominant influenza strain was A (H3N2), representing 73.8% of all circulating influenza. Pie chart displays this information. Graph showing the numbers and percentages of respiratory specimens positive for influenza viruses, and numbers of influenza viruses identified, by type, by surveillance week, Department of Defense healthcare beneficiaries, 2016 – 2017 influenza season displays. The vaccine effectiveness (VE) for this season was slightly lower than for the 2015 – 2016 season, which had a 63% (95% confidence interval: 53% - 71%) adjusted VE. The adjusted VE for the 2016 – 2017 season was 48% protective against all types of influenza.  Access the full report in the January 2018 MSMR (Vol. 25, No. 1). Go to: www.Health.mil/MSMR

This infographic documents the annual surveillance trends for the 2016 – 2017 influenza season and the end-of-season vaccine effectiveness.

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2018 #ColdReadiness Twitter chat recap: Preventing cold weather injuries for service members and their families

Fact Sheet
2/5/2018

To help protect U.S. armed forces, the Armed Forces Health Surveillance Branch (AFHSB) hosted a live #ColdReadiness Twitter chat on Wednesday, January 24th, 12-1:30 pm EST to discuss what service members and their families need to know about winter safety and preventing cold weather injuries as the temperatures drop. This fact sheet documents highlights from the Twitter chat.

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Insomnia and motor vehicle accident-related injuries, Active Component, U.S. Armed Forces, 2007 – 2016

Infographic
1/25/2018
Insomnia is the most common sleep disorder in adults and its incidence in the U.S. Armed Forces is increasing. A potential consequence of inadequate sleep is increased risk of motor vehicle accidents (MVAs). MVAs are the leading cause of peacetime deaths and a major cause of non-fatal injuries in the U.S. military members. To examine the relationship between insomnia and motor vehicle accident-related injuries (MVAs) in the U.S. military, this retrospective cohort study compared 2007 – 2016 incidence rates of MVA-related injuries between service members with diagnosed insomnia and service members without a diagnosis of insomnia. After adjustment for multiple covariates, during 2007 – 2016, active component service members with insomnia had more than double the rate of MVA-related injuries, compared to service members without insomnia. Findings:  •	Line graph shows the annual rates of motor vehicle accident-related injuries, active component service members with and without diagnoses of insomnia, U.S. Armed Forces, 2007 – 2016  •	Annual rates of MVA-related injuries were highest in the insomnia cohort in 2007 and 2008, and lowest in 2016 •	There were 5,587 cases of MVA-related injuries in the two cohorts during the surveillance period. •	Pie chart displays the following data: 1,738 (31.1%) in the unexposed cohort and 3,849 (68.9%) in the insomnia cohort The highest overall crude rates of MVA-related injuries were seen in service members who were: •	Less than 25 years old •	Junior enlisted rank/grade •	Armor/transport occupation •	 •	With a history of mental health diagnosis •	With a history of alcohol-related disorders Access the full report in the December 2017 (Vol. 24, No. 12). Go to www.Health.mil/MSMR Image displays a motor vehicle accident.

To examine the relationship between insomnia and motor vehicle accident-related injuries (MVAs) in the U.S. military, this retrospective cohort study compared 2007 – 2016 incidence rates of MVA-related injuries between service members with diagnosed insomnia and service members without a diagnosis of insomnia.

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Seizures among Active Component service members, U.S. Armed Forces, 2007 – 2016

Infographic
1/25/2018
This retrospective study estimated the rates of seizures diagnosed among deployed and non-deployed service members to identify factors associated with seizures and determine if seizure rates differed in deployment settings. It also attempted to evaluate the associations between seizures, traumatic brain injury (TBI), and post-traumatic stress disorder (PTSD) by assessing correlations between the incidence rates of seizures and prior diagnoses of TBI and PTSD. Seizures have been defined as paroxysmal neurologic episodes caused by abnormal neuronal activity in the brain. Approximately one in 10 individuals will experience a seizure in their lifetime. Line graph 1: Annual crude incidence rates of seizures among non-deployed service members, active component, U.S. Armed Forces data •	A total of 16,257 seizure events of all types were identified among non-deployed service members during the 10-year surveillance period. •	The overall incidence rate was 12.9 seizures per 10,000 person-years (p-yrs.) •	There was a decrease in the rate of seizures diagnosed in the active component of the military during the 10-year period. Rates reached their lowest point in 2015 – 9.0 seizures per 10,000 p-yrs. •	Annual rates were markedly higher among service members with recent PTSD and TBI diagnoses, and among those with prior seizure diagnoses. Line graph 2: Annual crude incidence rates of seizures by traumatic brain injury (TBI) and recent post-traumatic stress disorder (PTSD) diagnosis among non-deployed active component service members, U.S. Armed Forces •	For service members who had received both TBI and PTSD diagnoses, seizure rates among the deployed and the non-deployed were two and three times the rates among those with only one of those diagnoses, respectively. •	Rates of seizures tended to be higher among service members who were: in the Army or Marine Corps, Female, African American, Younger than age 30, Veterans of no more than one previous deployment, and in the occupations of combat arms, armor, or healthcare Line graph 3: Annual crude incidence rates of seizures diagnosed among service members deployed to Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn, U.S. Armed Forces, 2008 – 2016  •	A total of 814 cases of seizures were identified during deployment to operations in Iraq and Afghanistan during the 9-year surveillance period (2008 – 2016). •	For deployed service members, the overall incidence rate was 9.1 seizures per 10,000 p-yrs. •	Having either a TBI or recent PTSD diagnosis alone was associated with a 3-to 4-fold increase in the rate of seizures. •	Only 19 cases of seizures were diagnosed among deployed individuals with a recent PTSD diagnosis during the 9-year surveillance period. •	Overall incidence rates among deployed service members were highest for those in the Army, females, those younger than age 25, junior enlisted, and in healthcare occupations. Access the full report in the December 2017 MSMR (Vol. 24, No. 12). Go to www.Health.mil/MSMR

This infographic documents a retrospective study which estimated the rates of seizures diagnosed among deployed and non-deployed service members to identify factors associated with seizures and determine if seizure rates differed in deployment settings. The study also evaluated the associations between seizures, traumatic brain injury (TBI), and post-traumatic stress disorder (PTSD) by assessing correlations between the incidence rates of seizures and prior diagnoses of TBI and PTSD.

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Exertional heat injuries pose annual threat to U.S. service members

Article
7/20/2017
Two U.S. service members perform duties in warm weather where they may be exposed to extreme heat conditions and a higher risk of heat illness.

Exertional heat injuries pose annual threat to U.S. service members, according to a study published in Defense Health Agency’s Armed Forces Health Surveillance Branch (AFHSB) peer-reviewed journal, the Medical Surveillance Monthly Report.

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Demographic and Military Traits of Service Members Diagnosed as Traumatic Brain Injury Cases

Fact Sheet
3/30/2017

This fact sheet provides details on the demographic and military traits of service members diagnosed as traumatic brain injury (TBI) cases during a 16-year surveillance period from 2001 through 2016, a total of 276,858 active component service members received first-time diagnoses of TBI - a structural alteration of the brain or physiological disruption of brain function caused by an external force.

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Heat Illnesses by Location, Active Component, U.S. Armed Forces, 2012-2016 Fact Sheet

Fact Sheet
3/30/2017

This fact sheet provides details on heat illnesses by location during a five-year surveillance period from 2012 through 2016. 11,967 heat-related illnesses were diagnosed at more than 250 military installations and geographic locations worldwide. Three Army Installations accounted for close to one-third of all heat illnesses during the period.

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Rhabdomyolysis by Location, Active Component, U.S. Armed Forces, 2012-2016 Fact Sheet

Fact Sheet
3/30/2017

This fact sheet provides details on Rhabdomyolysis by location for active component, U.S. Armed Forces during a five-year surveillance period from 2012 through 2016. The medical treatment facilities at nine installations diagnosed at least 50 cases each and, together approximately half (49.9%) of all diagnosed cases.

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2016 marks first year of zero combat amputations since the start of the Afghan, Iraq wars

Article
3/28/2017
An analysis by the Medical Surveillance Monthly Report recently reported 2016 marks the first year without combat amputations since the wars in Afghanistan and Iraq began. U.S. Armed Forces are at risk for traumatic amputations of limbs during combat deployments and other work hazards. (DoD photo)

An analysis by the Medical Surveillance Monthly Report (MSMR) recently reported 2016 marks the first year of zero combat amputations since the wars in Afghanistan and Iraq began.

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