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Longitudinal Evolution of Bone Mineral Density and Bone Markers in Human Immunodeficiency Virus—Infected Individuals

  1. Kristin Mondy1,
  2. Kevin Yarasheski2,
  3. William G Powderly1,
  4. Michael Whyte3,
  5. Sherry Claxton1,
  6. Debra DeMarco1,
  7. Mary Hoffmann1, and
  8. Pablo Tebas1
  1. 1Divisions of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri
  2. 2Divisions of Endocrinology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri
  3. 3Divisions of Bone and Mineral Metabolism, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri
  1. Dr. Pablo Tebas, Dept. of Medicine, Washington University, 4511 Forest Park Ave., Ste. 304, Saint Louis, MO 63108 (tebas{at}im.wustl.edu).
 
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Abstract

The underlying mechanisms of several bone disorders in human immunodeficiency virus (HIV)–infected persons and any relation to antiretroviral therapy have yet to be defined. A longitudinal study was conducted to estimate the prevalence of osteopenia or osteoporosis in HIV-infected persons; to assess bone mineralization, metabolism, and histomorphometry over time; and to evaluate predisposing factors. A total of 128 patients enrolled the study, and 93 were observed for 72 weeks. “Classic” risk factors (low body mass index, history of weight loss, steroid use, and smoking) for low bone mineral density (BMD) and duration of HIV infection were strongly associated with osteopenia. There was a weak association between low BMD and receipt of treatment with protease inhibitors; this association disappeared after controlling for the above factors. Markers of bone turnover tended to be elevated in the whole cohort but were not associated with low BMD. BMD increased slightly during follow-up. Traditional risk factors and advanced HIV infection play a more significant pathogenic role in the development of osteopenia and osteoporosis associated with HIV infection than do treatment-associated factors.

The use of HAART has resulted in a significant reduction in HIV-related morbidity and mortality. HIV infection and HAART have been associated with the development of numerous acute and long-term toxicities [1–10], with pathogeneses that are still under scrutiny [3–10].

Recently, several bone disorders, including premature osteopenia, osteoporosis, and osteonecrosis, have been detected in HIV-infected persons [11–15]. The underlying mechanisms that account for these findings and any relation to use of antiretroviral medications have yet to be defined. Multiple factors associated with alterations in bone metabolism have been postulated, including the use of protease inhibitors (PIs), nucleoside-related mitochondrial toxicity and/or lactic acidosis, development of lipodystrophy, immune reconstitution, nutritional and hormonal factors, prior AIDS-related wasting, and HIV infection itself [12–14, 16–20].

Given the likely multifactorial nature of the various bone disorders previously described in HIV-infected persons, we sought to provide a more comprehensive characterization of the bone mineralization, metabolism, and morphology in the HIV-infected population and of how these changes in bone evolve over time. The objectives of our study were to estimate the prevalence of osteopenia and osteoporosis in HIV-infected persons receiving HAART; to assess bone mineralization, metabolism, and histomorphometry over an extended period of time; and to assess factors associated with osteopenia or osteoporosis in affected persons.

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Patients and Methods

Design. Originally, the research design was conceived as a cross-sectional study to evaluate bone metabolism and bone mineral density (BMD) in HIV-infected patients recruited from the AIDS Clinical Trials Unit and the Infectious Diseases Outpatient Clinic at Washington University School of Medicine (St. Louis). We subsequently expanded the study into a longitudinal analysis of the evolution of BMD and parameters of bone metabolism during a 72-week time period (figure 1). All patients from the original cross-sectional cohort were invited to participate. The study was approved by the Human Studies Committee of the Washington University Medical Center.

Figure 1
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Figure 1

Profile of longitudinal study to estimate the prevalence of osteopenia or osteoporosis in HIV-infected persons; to assess bone mineralization, metabolism, and histomorphometry over time; and to evaluate predisposing factors. The original study was a cross-sectional study of 128 patients. Ninety-three of these patients agreed to be observed longitudinally for 72 weeks, 3 of whom were subsequently excluded.

Baseline and follow-up studies. At baseline, sociodemographic and clinical data were obtained, as was as a detailed 3-day dietary intake history (including vitamin D, calcium, caffeine, alcohol, and average energy intake) and medication history (including type and duration of all antiretroviral therapy and past use of any medications that may potentially alter bone metabolism). Anthropomorphic data included body mass index (BMI) and dual-energy radiographic absorptiometry, which were measured at 6-month intervals. Serum and 24-h urine bone markers (levels of parathyroid hormone, calcium, phosphate, bone-specific alkaline phosphatase, osteocalcin, 25(OH) vitamin D3, 1,25(OH)2 vitamin D3, urine calcium, pyridinolines, and deoxypyridinolines) were measured for all patients at 6-month intervals. Transiliac bone biopsy with dual oxytetracycline bone labeling was performed for 7 patients who consented to the biopsy procedure.

BMD measurements. A Hologic QDR-2000 enhanced-array, whole-body, dual-energy radiographic absorptiometry scanner and software, version 5.71A, were used to measure whole-body lean, adipose, and bone mass [21]. Regional array software, version 4.74A:1 (Hologic), was used to determine BMD of the whole body, lumbar spine (L1–L4), and proximal femur.

Laboratory measurements. Serum bone alkaline phosphatase levels were measured with use of the Chemical Inhibition and Differential Inactivation assay (Mayo Medical Laboratories) with normal reference intervals of 24–146 U/L. Serum intact osteocalcin levels were measured with the chemiluminoimmunoassay (Mayo Medical Laboratories) with normal reference intervals of 2–15 mg/L. After 21 June 2000, an RIA was used by Mayo Medical Laboratories (normal reference interval, 8–52 ng/mL). Urine pyridinoline and deoxypyridinoline levels were measured with the Pyridinoline-Deoxypyridinoline U high-pressure liquid chromatography assay (Mayo Medical Laboratories) with normal reference intervals of 18–40 nmol/mmol of creatinine for men and 20–62 nmol/mmol of creatine for women for pyridinolines and 5–14 nmol/mmol of creatine for men and 5–22 nmol/mmol of creatine for women for deoxypyridinolines. Because of the diurnal variation of crosslink excretion, only the morning's first urine samples were used. Intact parathyroid hormone levels were measured with use of the Immulite Intact Parathyroid Hormone kit (Diagnostic Products Corporation; normal reference range, 12–72 pg/mL in serum). 25(OH) vitamin D3 and 1,25(OH)2 vitamin D3 levels were measured with an RIA (DiaSorin). Normal values fluctuate from 22 to 67 pg/mL, depending on the subjects' exposure to sun. All other laboratory tests were done by a central laboratory (Barnes-Jewish Hospital, St. Louis).

Bone biopsies. Subjects who consented to undergo transiliac bone biopsy received two 3-day courses of tetracycline (250 mg q.i.d.) separated by a 10-day interval. On the third day after the last dose, a bone biopsy was done under local anesthesia at Barnes-Jewish Hospital. The biopsy core specimen was placed in 70% ethanol for ≥48 h. The specimen was dehydrated, defatted, embedded, and sectioned on the basis of a published method and evaluated with fluorescent microscopy in the Johns Hopkins Bone Histomorphometry Laboratory (Baltimore). Measures of trabecular bone (TB/bone volume [BV]), bone surface (BS), eroded surface (ES/BS), osteoid surface (OS/BS), mineralization surface (MS/BS), wall thickness, osteoid thickness, and mineral apposition rate were made.

Definitions. Osteopenia and osteoporosis were defined on the basis of World Health Organization criteria [22]. Patients with a BMD t score between -1 and -2.5 were categorized as having osteopenia, and patients with a BMD t score less than or equal to -2.5 were categorized as having osteoporosis. Physical activity level was defined as “moderate”if the patient performed ≥30 min of an activity equivalent to brisk walking or jogging ≥3 times per week, as “high,” if brisk activity was performed for >30 min ≥5 times per week, and “low,” if minimal to no physical activity was performed. Low calcium intake was defined as an average ingestion of <1000 mg/day on the basis of a 3-day dietary intake history. Current or past excessive alcohol intake was defined as having a current or past average alcohol intake of >2 drinks per day. Patients with a past documented weight loss of >10% of their ideal body weight (since acquiring HIV infection) were considered to have a history of wasting. Patients with a nadir BMI of <20 kg/m2 during their follow-up since infection were categorized as having a history of severe wasting. Exposure to drugs was calculated by the number of days or weeks receiving an antiretroviral agent. In the case of dual-PI or dual-nucleoside combinations, each drug was considered independently. Duration of HIV infection was defined as the time difference between enrollment in the trial and the first documented HIV-positive test result.

Statistical analysis. Comparisons between categorical groups were done with use of χ2 and Fisher's exact tests. Student's t test was used for continuous variables. All P values were 2-tailed. Partial correlations testing was done to estimate the strength of association between various clinical and laboratory characteristics. Potential predictors of osteopenia or changes in BMD were further evaluated for statistical significance by multiple regression analysis. Evolution of BMD over time was evaluated by one-way, repeated-measures, within-subject analysis of variance, with the factor being the number of weeks of follow-up. As the result was significant, pairwise comparisons between each time point and baseline were done. The levels of significance for multiple comparisons were corrected by the Bonferroni procedure. Data were analyzed with use of the SPSS software package (SPSS/Systat).

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Results

Baseline Cross-Sectional Study

Clinical characteristics. A total of 128 patients were recruited for the original cross-sectional study (table 1). Three patients were subsequently excluded from all statistical analyses: 1 patient was a clear outlier with a BMI of >50, dual-energy radiographic absorptiometry was not performed for 1 patient, and 1 patient was an outlier with a t score of -5.89 (this patient subsequently had severe osteomalacia secondary to phosphate wasting diagnosed while receiving treatment with foscarnet). Ninety-three of the remaining 125 patients agreed to be observed longitudinally.

Figure 2
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Figure 2

Evolution of bone mineral density (BMD) for the entire cohort during a 72-week follow-up period. Patients who started receiving treatment with alendronate (n = 3) were excluded. All pairwise comparisons were significant (P <.01).

Figure 3
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Figure 3

Evolution of bone mineral density (BMD) from baseline values among patients receiving protease inhibitor (PI)–based regimens for the majority of the follow-up period and among patients who were receiving nonnucleoside reverse-transcriptase inhibitors (NNRTIs). There were no significant differences between groups. Patients taking blinded medications (n = 5), who remained naive to therapy (n = 5), or who began taking alendronate (n = 3) were excluded.

Figure 4
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Figure 4

Bone markers at baseline (week 0) and evolution during a 72-week follow-up period. Dotted lines indicate low and high normal ranges for each bone marker. Alk. Phos., alkaline phosphatase. *Osteocalcin values obtained with a different method (after 21 June 2000) are excluded (see Methods).

Table 1
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Table 1

Summary of baseline data for 125 HIV-infected subjects, according to presence or absence of osteopenia or osteoporosis.

The majority of the patients were male (86%), white (84%), and currently taking a PI-based HAART regimen (68%). Seventy percent had an undetectable virus load, and the mean duration of HIV infection was 76.9 months. The mean age of the cohort was 42 years, with mean current and nadir CD4 T cell counts of 516 cells/mm3 and 236 cells/mm3. The mean durations of nucleoside reverse-transcriptase inhibitor, PI, and nonnucleoside reverse-transcriptase inhibitor therapies were 349, 135, and 33 weeks, respectively.

Although the mean current weight (75.3 kg) and BMI (25.1) were typical, a large percentage of subjects had a history of significant weight loss (27%) and severe wasting (14%). Many patients also had other known risks for low BMD, including current or past tobacco use (35%), low activity level (55%), and calcium intake less than the US recommended daily allowance (70%).

Laboratory characteristics. Among the cohort of patients, the mean serum levels of total testosterone, parathyroid hormone, thyroid-stimulating hormone, phosphorus, vitamin D, cholesterol, and triglycerides were within normal ranges for both osteopenic and nonosteopenic patients (table 2). Bone-specific markers, including serum osteocalcin, bone alkaline phosphatase, and urine pyridinoline levels, were frequently elevated in both groups. Mean 24-h urine calcium excretion and ionized calcium levels were also higher than expected. There were no statistically significant differences in any laboratory parameter between osteopenic and nonosteopenic groups.

Table 2
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Table 2

Baseline laboratory characteristics for 125 HIV-infected subjects, according to lumbar t score.

Prevalence and features of bone abnormalities at the time of enrollment. At baseline, a total of 57 patients (46%) had osteopenia or osteoporosis, as determined on the basis of World Health Organization criteria. Median lumbar and hip BMD t scores were -0.92 (interquartile range, -0.3 to -1.7) and -0.95 (interquartile range, -0.2 to -1.6), respectively. Seven patients consented to undergo transiliac bone biopsy. Bone histomorphologic results were categorized into 4 distinct groups. Group 1 (1 patient) had osteomalacia, characterized by greatly increased osteoid volume, thickness, and surface area (OV/BV, osteoid thickness, and OS/BS), increased mineralization lag time, and diffuse, irregular tetracycline labeling. Serum bone alkaline phosphatase and osteocalcin levels were also greatly increased in this patient, and he was subsequently excluded from additional analyses because of the diagnosis of osteomalacia. Group 2 (1 patient) had high bone turnover osteoporosis, characterized by moderately increased OV/BV, OS/BS, and osteoblast content; elevated indices of bone turnover, including an increased mineralizing surface (MS/BS); increased bone formation rate (BFR/BV and BFR/TB); and extensive double tetracycline labeling at all osteoid/mineralized bone interfaces. The serum bone alkaline phosphatase level was also moderately increased. Patients in group 3 (n = 2) had inactive osteoporosis, characterized by a paucity of osteoblasts and osteoclasts, decreased OV/BV, osteoid thickness, OS/BS, BFR/BV, BFR/TB, MS/BS, and minimal tetracycline labeling. Patients in group 4 (n = 3) had osteoporosis, with normal rates of remodeling and tetracycline labeling as well as normal indices of bone turnover [23].

Risk factors associated with osteopenia and osteoporosis. On univariate analysis, there was no association between osteopenia and any specific antiretroviral class. Patients with osteopenia were much more likely than patients without osteopenia to currently smoke or to have a past history of smoking (43.9% vs. 27.9; P =.06), to have a history of steroid use for >1 month (10.5% vs. 2.9%; P =.08), and to have history of significant weight loss (36.8% vs. 19.1 %; P =.04). There was a particularly strong association between osteopenia and a low current weight, BMI, trunk fat mass, whole body fat mass, and peripheral fat mass (P <.01 for all). There was no correlation between osteopenia and trunk/extremities fat ratio. Other potential risks were analyzed, but only duration of HIV infection was additionally found to be strongly associated with osteopenia (P =.05). Finally, no specific serum or urine bone marker was found to correlate with either osteopenia or spine and hip BMD t scores.

A significant correlation was noted between hip or spine BMD t scores and having ever been treated with a PI (P =.04 and P =.08, respectively). However, an even stronger correlation existed between BMD t scores and current weight/BMI, peripheral and trunk fat, nadir weight, and history of significant weight loss or severe wasting (P <.01 for all).

Additional multivariate analyses were done to evaluate whether HAART or factors associated with HIV infection (i.e., duration of infection, nadir CD4 cell count, and HIV load) predicted BMD t scores over or in addition to known risk factors for osteopenia (i.e., steroid use, wasting, alcohol use, poor nutrition, inactivity, female sex, and aging). Although the relationship between known risk factors for osteopenia and hip and spine BMD t scores was significant (r2 =.19 and r2 =.17, respectively; P <.001 and P <.01, respectively), the additional HAART- and HIV-associated factors did not predict hip and spine BMD t scores significantly over or in addition to these known risk factors.

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Longitudinal Follow-Up

Evolution of BMD and bone metabolism over time. Thirty-two of the original 125 patients declined participation in the longitudinal follow-up. There were no significant differences in baseline clinical and laboratory characteristics between the 93 subjects who participated in the longitudinal study and the 32 subjects who declined. Three of these 93 patients were subsequently excluded from the longitudinal evaluation (but not the baseline evaluation) because they began receiving alendronate therapy.

There was a small but statistically significant mean (±SEM) percentage increase in lumbar and hip BMD for the cohort (n = 90) during the 72-week follow-up (lumbar, 2.6% ± 0.6% at week 72 [all pairwise comparisons between baseline and week 24, 48, and 72 were significant; P <.01]; hip, 2.4% ± 0.4% at week 72 [all pairwise comparisons were significant; P <.01]; figure 2). The mean percentage increases in lumbar and hip BMD during the 72-week period remained significant regardless of the duration of HIV infection or the overall duration of HAART. However, a significant positive correlation was observed between CD4 T cell increase while receiving HAART and percentage increase in lumbar (but not hip) BMD during the 72-week follow-up period (P =.02). Patients who had an undetectable HIV load at enrollment also had greater percentage gains in lumbar BMD than did patients who had a detectable virus load (3.28% vs. 0.75% gain; P =.07). There was not a significant correlation between gains in BMD and fat or weight gain during the 72-week period.

Participants were further classified into 2 groups on the basis of the treatment they received for the majority of the time of follow-up (PI-based HAART regimen for 61 and non—PI-based HAART regimen for 19; 5 patients who received blinded medications, 5 who were not receiving therapy, and 3 who started receiving alendronate were excluded). Both groups had statistically significant mean percentage increases in lumbar and hip BMD during the 72-week follow-up period (PI and non-PI groups, respectively, 2.5% and 3.8% for spine and 2.6% and 2.5% for hip), but the differences were not significant (figure 3).

Bone metabolic markers remained elevated but generally stable for all patients during the 72-week follow-up period, regardless of type of antiretroviral therapy, immune status, or bone mineral density, thus indicating a chronic high bone turnover state (figure 4).

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Discussion

In the present study, we found a very high prevalence of low BMD in our HIV-infected cohort, confirming the findings of previous reports [11–14]. Currently, there is considerable uncertainty as to the contributions of HIV infection and its treatment toward the development of bone demineralization in this population. Two alternative hypotheses (not necessarily mutually exclusive) can be generated to explain the bone mineral loss observed in several cohorts of HIV-infected persons: first, bone demineralization could be related to HIV infection itself, with a nonsignificant or minimal contribution from antiretroviral treatment; second, bone demineralization in HIV-infected patients could be initiated and/or accelerated after they start receiving potent antiretroviral therapy.

Although earlier studies, including ours [12], have implicated specific antiretroviral medications or HIV infection itself as causative factors in the development of osteopenia, no study has carefully controlled for the multiple established risk factors for osteopenia that are frequently present in patients with chronic HIV infection or included longitudinal follow-up. In the present study, we found that persons with low BMD were much more likely to have ≥1 of these known risk factors for osteopenia. We also found that no particular aspect of HIV infection or specific antiretroviral class predicted bone demineralization (at baseline or longitudinally) above that predicted on the basis of these known factors. Nonetheless, given that the vast majority of the subjects were already receiving HAART (>95%) and had prior PI and nucleoside reverse-transcriptase inhibitor experience at the time of enrollment, it would be important to confirm these observations in additional prospective, longitudinal studies that would ideally contain clinical and laboratory information on subjects early in the course of HIV disease and before the initiation of HAART.

Of interest, during the 72-week follow-up period, there was an increase in the mean percentage change in BMD, regardless of type or total duration of HAART or duration of HIV infection. However, the amount of BMD gained appeared to depend on immune status and virological control of HIV infection, as indicated by the correlation between CD4 T cell count increase during therapy and HIV suppression. The majority of subjects also had high indices of bone metabolism and turnover that remained generally elevated throughout the 72-week follow-up period, regardless of baseline or evolution of BMD, type of HAART received, or immune status. These results further emphasize that traditional risk factors as well as factors associated with HIV infection are likely more important contributors to the pathogenesis of osteopenia or osteoporosis than are HAART-related factors.

The observed lack of correlation between BMD and indices of bone turnover may be partially explained by the bone biopsy results. These findings suggest that multiple mechanisms may underlie the pathogenesis of osteopenia in HIV-infected persons.

Evaluation of causality is complex in epidemiology, and the evaluation in our study is not an exception. In 1965, Bradford-Hill [24] proposed a series of criteria, which epidemiologists have since used to evaluate causation. In the present study, the strength of the association of osteopenia or osteoporosis was greater for traditional risk factors and advanced HIV infection than for treatment-associated factors.

There are limitations to this study. First, at baseline, a majority of patients had already been taking HAART for an extended period of time. It is possible that we missed any acute effect on BMD caused by the initiation of antiretroviral therapy and that our baseline measurements were made during a subsequent stabilization of BMD. Also, like the majority of HIV-infected persons who receive long-term antiretroviral therapy, many patients in our cohort changed various antiretroviral medications during longitudinal follow-up because of virological failure and/or intolerable side effects, thus severely limiting our ability to evaluate the impact of specific classes of antiretroviral medications. Finally, some of the demographic data on duration of HIV infection and known risk factors for osteoporosis were obtained from patients as historical data, thus resulting in possible recall bias.

Although there is growing experimental evidence that antiretroviral therapy affects bone metabolism [25, 26], the magnitude and the exact nature of its contributory effects on osteopenia and osteoporosis will likely be gained only by conducting prospective, longitudinal studies of patients who are early in the course of HIV infection, who are naive to antiretroviral therapy, and who later go on to initiate various antiretroviral therapy regimens.

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Acknowledgments

We thank the patients who were involved in the trial and all of the nurses in the Washington University AIDS Clinical Trials Unit (St. Louis) for their excellent assistance.

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Footnotes

  • National Institutes of Health (NIH; grants AI-25903, AI-01612, DK-5656341 [Washington University Clinical Nutrition Research Unit], and RR-00036 [Washington University General Clinical Research Center]) and Campbell Foundation. P.T. is a recipient of the Glaxo SmithKline Development Partners Junior Faculty award. K.M. is supported by a training grant (AI-07172) from the NIH.

  • Received June 4, 2002.
  • Accepted October 2, 2002.
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  1. Clin Infect Dis. (2003) 36 (4): 482-490. doi: 10.1086/367569
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