The risk of bone loss is greater in persons infected with HIV (HIV+) compared with those without HIV infection (HIV−)1 and translates into a higher risk of fracture among people living with HIV (PLWH).2–4 The etiology of metabolic bone disease in PLWH is multifactorial, with contributions from a high prevalence of traditional osteoporotic risk factors in this population, certain antiretroviral therapies, and the effects of chronic systemic inflammation.
Proteinuria has been associated with bone loss and increased risk of fracture in the general population5–7 and among patients with diabetes,8 even after controlling for additional risk factors including kidney function. The mechanisms underlying this relationship are largely unknown and probably multifactorial. Albuminuria has been associated with endothelial dysfunction, reduced bone blood flow resulting in decreased bone remodeling and bone loss, and decreased bone quality by inflammation and oxidative stress.9,10 Additional factors frequently associated with albuminuria, such as hypertension (HTN) and use of antihypertensive medications,11–14 have also been linked to higher risk of fracture.15,16 Although albuminuria (glomerular proteinuria) is a marker of glomerular disease, proteinuria includes both glomerular and tubular proteins and can be a marker of both tubulointerstitial and glomerular disease, both prevalent in treated HIV+ individuals. Unlike most of the previous studies that used albumin-to-creatinine ratios, we defined proteinuria based on urine protein-to-creatinine ratios (UPCRs). Nevertheless, proteinuria has been previously shown as a reliable test for the presence of microalbuminuria.17 HIV infection is a known independent risk factor for excessive urinary protein loss in several studies.10,18–20 Whether proteinuria is associated with an increased risk of fracture in HIV+ individuals has not been studied, and data from the general population may not permit extrapolation to PLWH, given the unique contributors to proteinuria in this population. We used prospectively collected data from the Multicenter AIDS Cohort Study (MACS) to assess the relationship between proteinuria and incident fracture in men with or at risk of HIV infection.
The MACS is an ongoing, prospective multicenter cohort study of the natural and treated history of HIV infection in men. As of March 2015, 3898 HIV+ and 3439 HIV− men who have sex with men had been enrolled [1984–1985 (N = 4954); 1987–1991 (N = 668); 2001–2003 (N = 1350); 2010+ (N = 365)] at 4 sites in the United States. (Baltimore, MD/Washington, DC; Chicago, IL; Los Angeles, CA; and Pittsburgh, PA). The MACS design and methods have been described previously.21–23 In brief, at each semiannual study visit, participants complete a standardized questionnaire soliciting information about their medical history, HIV treatment, behaviors, depression, and daily activities; undergo physical examinations; and have blood and urine specimens collected for laboratory testing and storage.24 Study questionnaires are available at http://aidscohortstudy.org/. Informed consent was obtained from all participants. Study protocols were approved by the institutional review boards at each study site.
Between October 2006 and March 2015, urine protein and creatinine levels were measured at semiannual study visits using a spot urine test (Quest Diagnostics). A UPCR was reported if both measurements were taken and values were above the assay-specific lower limit of detection (4 mg/dL for urine protein; 20 mg/dL for urine creatinine). Individuals aged 40 years or older with ≥2 UPCR measurements and no self-reported fracture before the first available UPCR (defined as index visit) were included in this study. We excluded HIV+ participants who were naïve to antiretroviral therapy before March 2015.
Proteinuria was defined as having a UPCR ≥200 mg/g and confirmed at the following visit. Participants were considered exposed from the first visit of the visit-pairs at which proteinuria was determined without regard for subsequent reversal of proteinuria status before the endpoint (last seen in the MACS before March 2015 or occurrence of fracture).
From October 2001 onward, self-reported bone-related diagnoses (including any new broken or fractured bones) in the preceding 6 months were collected at each study visit. In addition, retrospective data collection on self-reported history of fracture occurred at 2 study visits in 2010. The date of incident fracture was estimated as the midpoint between the dates of the last report of no fracture and the first report of fracture (if ascertained prospectively) or estimated using the self-reported age of incident fracture (if ascertained retrospectively). The occurrence and types of fracture were determined using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Similar to our previous analysis,25 in this study, we examined 2 composite fracture outcomes: (1) all fractures, except for the face, skull, or digits (ICD-9: 805–815, 817–825, 827–829) and (2) fragility fractures which include fractures that occurred at the vertebral column, wrist, femur, and humerus (ICD-9: 805, 812, 813, 814, 820, 821).
Date of birth and race were collected at enrollment into the MACS. Time-varying covariates included self-reported cigarette smoking and alcohol use, body mass index (BMI), hepatitis C virus (HCV) infection, diabetes mellitus, and HTN; all were assessed at 6-month intervals. Heavy drinking was defined as having ≥3 drinks per day more than once a month and lagged by 1 study visit to account for the effect of drinking cessation among sicker individuals. BMI was calculated as body weight (kg)/height (m2) and categorized into normal (<25 kg/m2) and overweight/obese (≥25 kg/m2). The Chronic Kidney Disease Epidemiology Collaboration equation was used to estimate glomerular filtration rate (eGFR) from serum creatinine.26 HCV infection was determined by the presence of HCV RNA. Diabetes was defined as a fasting glucose level ≥126 mg/dL or a self-reported or clinical history of diabetes with the receipt of diabetic medications. HTN was defined as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, or self-reported or clinical history of diagnosis with the receipt of antihypertensive medications. For HIV-infected participants, CD4+ T-lymphocyte cell count/mm3 (CD4) and plasma HIV-1 RNA concentrations were measured using standard assays.
Descriptive statistics were summarized by HIV serostatus at the index visit (ie, first UPCR measurement after age 40). The Wilcoxon rank-sum test and Fisher exact test were performed to compare the distributions of continuous and categorical variables, respectively. Survival analysis was performed to determine the association between proteinuria and risk of fractures. We used age as the time scale and anchored the origin of analysis at age 40. Individuals with the first UPCR measured after age 40 were treated as late entries and contributed to analysis time only after the first UPCR measurement. Individuals who remained fracture-free throughout the analytical period were censored at the time they were last seen in the MACS before March 31, 2015. Multivariable Cox proportional hazard models were used to assess the relationship between proteinuria and fracture outcomes. Potential risk factors considered in these models included HIV serostatus, age, race, BMI, hypertension, diabetes, HCV infection, eGFR, current smoking, and alcohol use. We also considered HIV-specific risk factors including recent CD4, HIV-1 RNA level, clinical AIDS diagnosis, and cumulative tenofovir disoproxil fumarate (TDF) use (per 1 year). The proportional hazard assumption was checked by graphical exploration of Schoenfeld residuals and assessed by incorporation of a time interaction term in models. A P-value <0.05 guided interpretation of statistical significance. Missing covariates data (22%) were multiply imputed using the Markov Chain Monte Carlo method. Ten imputations were performed for the entire study population and after stratification by HIV serostatus. All statistical analyses were performed using SAS version 9.4 (SAS Institute). Unadjusted Nelson–Aalen cumulative incidence curves were created using Stata/SE 13.1 (College Station, TX).
Participant Characteristics at Index Visit
The study population included 947 HIV+ men and 969 HIV− men (Table 1). At the index visit, the HIV+ men were younger (median age 49 vs 53 years old, P < 0.001) and had lower BMI (median 25 vs 26 kg/m2, P < 0.001) and higher eGFR (median 92 in HIV+ vs 87 mL/min/1.73 m2 in controls, P < 0.001). The 2 groups were similar with respect to presence of comorbidities such as diabetes and HTN, as well as moderate/heavy and binge alcohol consumption. A greater proportion of HIV+ men were nonwhite (45% vs 27%, P < 0.001), HCV-infected (10% vs 5%, P < 0.001), and current smokers (34% vs 22%, P < 0.001). Median UPCR was higher in the HIV+ men (100 vs 70 mg/g creatinine, P < 0.001). Throughout the follow-up period, proteinuria was more common in HIV+ than in HIV− men (29% vs 6% in controls, P < 0.001).
Among the HIV+ men, at the index visit, the median CD4+ T-cell count was 535 cells/µL, 68% had HIV-1 RNA < 50 copies/mL, 14% had AIDS before the index visit, and median cumulative TDF use was 1 year.
Crude Incidence Rates of all Fractures and Fragility Fractures
The median (interquartile range) follow-up time was 7.4 (3.9–8.0) years. The crude incidence rates (IRs) per 1000 person-years (IR/1000 PYR) of all fractures and fragility fractures by HIV serostatus and proteinuria are summarized in Table 2. Among the HIV− men, the IRs of all fractures were 14.4/1000 PYR among men without proteinuria and 14.4/1000 PYR among men with proteinuria. HIV+ men without proteinuria had an IR of all fractures of 14.8/1000 PYR, which increased to 23.4/1000 PYR in those with proteinuria. The IRs of fragility fractures were 4/1000 PYR and 9.6/1000 PYR among the HIV− men without and with proteinuria, respectively, and 4.2/1000 PYR and 10.2/1000 PYR among the HIV+ men without and with proteinuria, respectively. For the outcomes of all fractures and fragility fractures, the log rank test indicates significantly different event curves based on proteinuria status (P = 0.026 for all fractures and P = 0.003 for fragility fractures) (Fig. 1).
Associations Between Proteinuria and Risk of all Fractures
Table 3 displays the unadjusted (HR) and adjusted hazard ratios (aHR) of proteinuria and other covariates for all fractures. In the univariable model, proteinuria was associated with 1.53 [95% confidence interval (CI): (1.05 to 2.24)] times increase in the risk of all factures. However, after adjusting for potential confounders including HTN, BMI, and eGFR, this association was no longer statistically significant [aHR = 1.31 (0.84–2.05)]. BMI ≥ 25 kg/m2 [aHR = 0.67 (0.48–0.95)] was protective against all fractures, whereas HTN was associated with a higher risk of all fractures [aHR = 1.54 (1.10–2.15)] (Table 3).
Associations Between Proteinuria and Risk of Fragility Fracture
Table 4 shows the associations between proteinuria and the risk of fragility fracture. In the univariable model, proteinuria was associated with a higher risk of fragility fractures [HR = 2.43 (1.34–4.39)], whereas HIV infection trended toward significance [HR = 1.60 (0.92–2.78)]. BMI ≥ 25 kg/m2 was protective against fragility fractures [HR = 0.55 (0.31–0.96)] (Table 4). After multivariable adjustments, proteinuria remained significantly associated with a higher risk of fragility fractures [aHR = 2.29 (1.12–4.66)]. None of the other variables included in the adjusted model was significantly associated with the risk of fragility fractures (Table 4).
Proteinuria and Fracture in HIV-Infected Men
In analysis restricted to HIV-infected men, only HTN was associated with a higher risk of all fractures [aHR = 1.68 (1.04–2.70)], whereas the association between proteinuria and fragility fractures trended toward significance [aHR = 2.12 (0.95–4.73)] (see Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B306). A formal test of the interaction between HIV serostatus and proteinuria for the risk of fractures was performed. P-values were not statistically significant for either type of fractures (0.56 for all fractures; 0.83 for fragility fractures).
Similar to recently published data,20 in this cohort of men who have sex with men followed prospectively in the MACS, we found that proteinuria was more common among HIV+ men. Proteinuria was also associated with a significantly higher risk of fragility fracture, regardless of HIV serostatus and independent of confounders like GFR, HTN, diabetes, or HCV infection. Qualitatively similar results were seen among HIV+ men, independent of TDF use and HIV disease severity. To the best of our knowledge, this is the first study to find that proteinuria is a potent risk factor for fractures among HIV+ persons. Our findings highlight the importance of screening for bone loss in HIV+ adults with proteinuria.
Albuminuria has been associated with increased risk of fracture in several studies of diabetic and nondiabetic patients. In the Atherosclerosis Risk in Communities study, albuminuria was independently associated with fracture hospitalization.27 Doubling of albuminuria was associated with an increased risk of hip fracture in a cohort of 3110 adults from the Cardiovascular Health Study who were followed up for up to 9.5 years, even after adjustment for osteoporosis-related factors, frailty, and falls.5 In another study from the same group examining people at risk of cardiovascular disease, baseline albuminuria was associated with a higher risk of pelvic and hip fractures [HR = 2.01 (1.21–3.35)]. In the adjusted model, the association was apparent for macroalbuminuria [HR = 1.71 (1.007–2.91)] but not for microalbuminuria [HR = 1.28 (0.92–1.78)].6 Other studies have evaluated the association of both proteinuria and albuminuria with fracture risk. Several potential mechanisms for proteinuria's association with fracture risk have been proposed. Albuminuria is a marker of endothelial dysfunction and has been associated with diminished blood flow supply to the bone, which directly impairs bone remodeling, resulting in bone loss.9,28 In a subcohort of 1208 participants from the Cardiovascular Health Study with available bone mineral density (BMD) measurements, increased urine albumin levels were associated with decreased hip BMD in men.27 Another hypothesis is that albuminuria is associated with impaired bone quality by inflammation and oxidative stress.29 In support of this theory are data from diabetic patients, who have a higher prevalence of proteinuria and in whom, despite higher BMD, increased rates of fractures are observed.30 More recently, albuminuria has been associated with elevation in parathyroid hormone (PTH) levels, independent of kidney function.31 High PTH levels are associated with a higher risk of fracture in patients with primary hyperparathyroidism32 and patients undergoing hemodialysis.33 The rise in PTH is generally preceded by increases in fibroblast growth factor 23 (FGF23), a hormone associated with important roles in phosphorus homeostasis. Among PLWH who participated in the Mr. Bean study, higher baseline FGF23 levels were associated with a higher risk of progressive albuminuria.34 Moreover, inflammation increases FGF23 levels.35
In our unadjusted model, proteinuria was associated with a higher risk of all fractures and fragility fractures. Adjustment for additional risk factors including HIV serostatus, HTN, and kidney function attenuated the association, which remained significant only for fragility fractures. This suggests that the effect of proteinuria on fracture risk could be mediated through factors associated with skeletal fragility not measured in our population. Of note, BMD measurements were not collected for the entire MACS cohort, so whether low BMD partially explains the observed association between proteinuria and fragility fractures cannot be answered in our study. Moreover, the aHR for all fractures and fragility fractures among HIV+ participants was attenuated when proteinuria was added to the model (aHR decreased from 1.2 to 1.14 for all fractures and from 1.43 to 1.16 for fragility fractures) suggesting that the high risk of fragility fracture observed among HIV+ individuals could be partly explained by the high prevalence of proteinuria in this population.
We found no association between eGFR and risk of all fractures or fragility fractures. Previous studies have variably demonstrated an association between eGFR and risk of fracture. Some have reported a graded increase in fracture incidence with lower eGFR,36 whereas others found a higher risk of fracture only with moderate to severe chronic kidney disease,26,37 and yet others reported no significant association.38 The lack of an association between eGFR and fractures in our study population may be explained by the small number of participants with moderate and severe kidney function impairment.
In the multivariable analysis, BMI ≥25 kg/m2 and nonwhite race were protective against all fractures. An unexpected finding was the protective effect of moderate/heavy alcohol consumption on all fractures. We conducted additional data analysis by lagging the drinking variable by 1 study visit to account for the unexpected protective effect on fracture. We found that sicker individuals (with comorbidities like low eGFR, diabetes, and hypertension) were more likely to quit drinking. The apparent protective effect of heavy drinking observed in our analysis may actually be reflective of a lower risk of fracture among individuals who were healthy enough to be drinking excessively.
Consistent with data from previous studies,39 the prevalence of proteinuria observed in our cohort was higher in men with HIV compared with men without HIV (29% vs 6%). HIV− related kidney disease is multifactorial, resulting from direct HIV infection and damage of the renal epithelial cells,39,40 antiretroviral therapy-related renal tubular toxicity,41–43 comorbidities such as HCV,44 diabetes mellitus, or HTN, and low CD4.45 In the multivariable analysis restricted to HIV+ men, proteinuria was associated with a higher risk of fragility fracture independent of other HIV-specific and nonspecific risk factors such as HTN and eGFR. A higher risk of all fractures was significantly associated with HTN and low CD4. We found no associations between the incidence of all or fragility fractures and other factors such as HCV infection, TDF use, HIV-1 RNA level, or history of an AIDS diagnosis. Variable associations between fracture risk and low CD4 cell count25,43 and HCV infection have been reported in previous studies.25,46 TDF use has been associated with a higher risk of proteinuria20,41,45 and fractures in several studies,47 whereas others failed to demonstrate such associations.25,43 Because the median TDF exposure at the index visit was only of 1 year, we further examined the distribution of cumulative TDF use at visits after the index visit. At the last study follow-up visit, the median (interquartile range) TDF use was of 4.88 (1.58–8.02).
Our study has several strengths, including a large sample size, incidence of all fractures and fragility fractures as main outcomes, and data on several fracture risk factors. The MACS population includes HIV− men who have similar risk behaviors as HIV+ men and who were similarly followed semiannually, completed the same fracture questionnaires, and whose data regarding HIV-specific risk factors were collected at semiannual visits. We accounted for multiple urine protein and creatinine levels measured at semiannual study visits, and we used 2 sequential elevated UPCR measurements to define proteinuria.
We also recognize several limitations to our study. First, fractures were self-reported without confirmation by medical chart review or radiographic evaluation, although some studies suggest that fractures tend to be reliably self-reported by patients.48 We have no data on use of calcium and vitamin D supplementation, and we did not adjust for use of other drugs potentially affecting bone health, such as proton pump inhibitor use. In addition, specific information regarding testosterone and glucocorticoid use was unavailable for the time period represented in this analysis but has been introduced in the MACS questionnaire only more recently. Finally, the MACS includes only men; therefore, our findings cannot be generalized to women. Sex differences in BMD and fracture risk have been reported in some studies, whereas others reported similar results regardless of sex. In the Cardiovascular Health Study, albuminuria was associated with a higher risk of hip fracture in women [HR = 1.12 (1.001–1.25)] but not in men [HR = 1.02 (0.89–1.17)],5 and increased urine albumin-to-creatinine ratios were associated with nonvertebral fractures in women only.11 In a study of people at risk of cardiovascular disease, albuminuria was associated with a higher risk of pelvic and hip fractures irrespective of sex.6
In conclusion, proteinuria was more common among HIV+ men in the MACS and was associated with a higher risk of fragility fracture independent of other risk factors, including HTN and kidney function. To the best of our knowledge, this is the first study demonstrating the association between proteinuria and higher fracture risk in an HIV-infected population. These data highlight the importance of osteoporosis screening and treatment in PLWH with proteinuria. Further investigation is required to understand underlying mechanisms common to both processes, such as chronic inflammation or microvascular disease.
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