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OSTEOPENIA IN HIV: tests and markers to evaluate bone loss
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This article is a review by the ACTG of bone loss in HIV-infected patients and potential treatments for this. The ACTG is planning a study of Fosomax and calcium/vitamin D supplements so Fosomax and study results using Fosomax are discussed below.
Recent observational studies in HIV-infected subjects have reported prevalence rates of osteopenia and osteoporosis of up to 50% and 5%, respectively. Tebas et al. (1) have reported that up to 50% of HIV-1 infected men receiving highly active antiretroviral therapy (HAART) have osteopenia or osteoporosis and 21% of these patients have severe osteoporosis as determined by dual energy x-ray absorptiometry (DEXA). These patients were all young (median age 41 years) and well-nourished (body mass index 24 kg/m2) males, a group at relatively low risk for development of osteoporosis. Data from other investigators echoed this observation (2).
The mechanism of HIV-associated bone loss, and the relative contribution of HAART to this problem remains unknown; recent observations have suggested a possible role of nucleoside reverse transcriptase inhibitors (NRTIs). Nolan et al. found a significant correlation between changes in bone mineral density (BMD) and changes in percent subcutaneous fat believed to be NRTI-related (3). Carr et al. (4) reported that the only factors independently associated with osteoporosis in a cohort of 221 men were low weight prior to starting ART and high lactate levels; each 1 mmol/L increase in plasma lactic acid resulted in a 2.4-fold higher risk of osteopenia. NRTIs are capable of inducing decreased BMD in two ways: 1) severe osteoporosis may be linked to mitochondrial deletions and free radical-induced apoptosis of bone cells as suggested in studies of otherwise healthy males (5, 6), 2) NRTI therapy can lead to hyperlactatemia, and a state of chronic acid loading, which is known to mobilize bone alkali, and subsequently lead to progressive bone demineralization.
While ART may be a putative etiology (cause) in BMD loss, demonstration of decreased BMD in HIV-positive ART-naive patients indicates that HIV therapies alone may not be the only cause of these bone abnormalities. Higher rates of osteopenia in HIV-positive adults than in HIV-negative adults, regardless of ART, have been described in cross-sectional studies, which almost uniformly suggest that up to a quarter of ART-naive HIV-infected patients have osteopenia or osteoporosis (7, 8). Prospective longitudinal studies of BMD before and after ART are needed to dissect the effects of HIV infection and drugs.
In addition to possible effects of NRTI and of HIV itself, several osteoporosis risk factors are relevant for HIV-positive subjects. These include prolonged bed rest associated with chronic illness, smoking, severe weight loss, hyperthyroidism, hypogonadism, malabsorption, and medications including corticosteroids, phenobarbital, pentamidine, and ketoconazole.
There are limited data on rate of progression of osteopenia in the HIV-positive population, but at the same time, preliminary data do suggest that progression is likely to occur. Negredo et al. recently reported a prospective trial on 244 HIV-positive subjects who underwent serial DEXA scanning; results showed that BMD at the hip and lumbar spine declined in 148 patients (60%) over the course of 24 weeks (9).
Fractures are the clinical consequence of osteoporosis. Fractures result in morbidity, mortality, and an increased expenditure of health-care resources. After a hip fracture only 50% of patients regain the independence they enjoyed 12 months before the hip fracture occurred; 40% of patients are still unable to walk independently and 60% of patients have difficulty with activities of daily living 6 months after a hip fracture (10). The direct and indirect costs of caring for these patients are high, resulting in a total cost of $21,000 per patient for the first year after the fracture (11). Since the life span of HIV-positive patients on therapy is increasing, the risk of fracture and subsequent expenditure promises to outweigh the cost of osteoporosis treatment.
The most widely used method to measure bone mineralization uses bone densitometry. BMD can be measured using a variety of techniques and commonly is assessed at the hip, spine, radius, and calcaneus. The most common technique for BMD assessment is DEXA, and results are reported as areal density in units of g/cm2. Results also can be expressed in terms of z-score and t-score. The z-score (which uses age-matched controls) compares the patient with population norms adjusted for age, race, and sex; the t-score (using young normal controls) compares the patient with race- and sex-adjusted population norms at peak bone mass (approximately age 30 years). Fracture risk correlates well with standardized bone densitometry (12).
The World Health Organization (WHO) established the following definitions of osteoporosis and osteopenia:
Normal BMD is within 1 SD of a "young normal" adult (t-score > -1)
Osteopenia BMD is between 1 and 2.5 SD below that of a "young normal" adult (t-score between -1 and -2.5)
Osteoporosis BMD is 2.5 SD or more below that of a "young normal" adult (t-score £ -2.5).
Severe Osteoporosis BMD is 2.5 SD or more below that of a "young normal" adult
(t-score £ -2.5) and the patient has experienced one or more fractures
The WHO criteria for the diagnosis of osteoporosis were developed for postmenopausal Caucasian women, and further studies are being performed to determine whether the same diagnostic criteria should apply to men. Recently, it has been shown that men tend to fracture at higher BMD than do women (13, 14). In addition, because the average bone mass among a healthy population of young women is lower than that observed in a similar population of men, few men are classified as osteoporotic or osteopenic when female normative data are used. Therefore, significant controversy surrounds the validity of WHO criterion for predicting risk of fracture in men; the WHO definition of osteoporosis = t-score of <-2.5 should only be used for females. Few non-traumatic fractures have been reported in HIV-positive patients (15, 16), but it is notable that such a fracture occurred in a male with a t-score -1.5 (15). Since the majority of HIV-infected patients are male, waiting until a t-score reaches -2.5 to initiate therapy does not seem justifiable.
There are no data in the HIV-negative population to suggest that osteopenia reverses without any intervention, if the offending agent/condition is not eliminated. This holds true for glucocorticoid-induced osteopenia when intervention is indicated for t score <-1, and for post-menopausal osteopenia when intervention is indicated for a t-score < -2 or <-1.5, depending on the absence or presence of other osteoporosis risk factors (17-19). Each standard deviation reduction in bone density is associated with a 2.5-fold increase in the risk of vertebral fracture (20).
It is unclear why HIV-positive patients are predisposed to a higher rate of decreased BMD. But whether it is HIV itself, immune restoration, or any of the components of ART, these predisposing conditions/agents are either irreversible or necessary for HIV control. Thus, an osteopenic HIV-positive patient on a stable ART regimen will likely need intervention to decrease his/her fracture risk.
Bone Markers:
Biochemical markers of bone turnover measure the rate of bone formation and resorption. They are useful for the management of osteoporosis because they provide information that is different from and complementary to BMD measurement. Baseline biochemical measures might reflect the current rate of bone loss and can predict future fracture risk (21), although this is still controversial. The measurement of bone turnover markers enhances the predictive value of bone mass measurement. High bone turnover independently predicts fracture risk in postmenopausal women (22). Bone turnover markers also provide the clinician with critical information on the effectiveness of interventions, skeletal effects of treatment, and potential long-term outcome of BMD measures. After an intervention, follow-up of bone turnover markers is recommended at 3 to 6 months, by which time most of them have reached nadir levels (21).
Aukrust et al. (23) analyzed serum markers of bone formation (osteocalcin) and bone resorption (C-telopeptide) in 73 HIV-positive patients. Patients with advanced clinical and immunological disease and high viral load were characterized by increased C-telopeptide and particularly by markedly depressed osteocalcin levels. These patients had enhanced activation of the TNF system. In their study, serum concentrations of p55 and p75-TNF receptors were negatively correlated with osteocalcin, and p75-TNF receptor was positively correlated with C-telopeptide. Patients with advanced disease also had decreased serum concentrations of 1,25-(OH)2D, but this parameter was not correlated with osteocalcin or C-telopeptide. Aukrust et al. also analyzed 17 patients who started potent ART (zidovudine, lamivudine and indinavir) during 24 months after the initiation of HAART. There was a marked rise in serum osteocalcin levels together with a profound fall in viral load and TNF components and a marked rise in CD4+ T cell counts. Also, there was a shift from no correlation to a significant correlation between osteocalcin and C-telopeptide levels during such therapy. Their data suggests an increase in markers of bone turnover with the initiation of ART. Unfortunately, the results of the study are limited because no BMD data were obtained.
Tebas et al. (24) performed an assessment of bone metabolism in a cohort of 73 HIV-infected patients receiving protease inhibitor (PI)-containing potent ART. To perform the assessments, the patients received a Hologic QDR-2000 enhanced-array regional DEXA scan of the lumbar spine (L1-L4), and the proximal femur (Hologic, Waltham, MA, regional array software [v4.74A:1]) and multiple bone metabolic parameters were evaluated, including measurements of the concentration of several hormones, bone remodeling markers, calcium and vitamin D metabolites. Ninety-five percent of the patients had an undetectable viral load at the time these tests were done, and the median CD4 cell count was > 540 cells/mm3, so this represented a group of patients who had responded remarkably well to potent ART. Fifty percent of the patients were receiving an indinavir-containing combination, 25% a nelfinavir-containing combination, and the rest, combinations of ritonavir with other PIs. Forty-three percent of the patients were osteopenic/osteoporotic according to the WHO definition, confirming a previous observation in the earlier cohort. There was no association of osteopenia with specific PIs, nor differences in bone metabolic parameters among them.
As a group, a significant proportion of patients taking potent ART that included a PI had increased markers of bone resorption: increased urine pyridinoline and urine deoxypyridinoline. Also, patients taking PI-containing potent ART had increased markers of bone formation: increased alkaline phosphatase (mainly of bone origin) and osteocalcin. This is in sharp contrast with the previous observations of low osteocalcin levels in patients with advanced disease. The levels of bone alkaline phosphatase and pyridinolines in urine correlated with bone mineral density in the lumbar spine and the hip. Testosterone levels and thyroid-stimulating hormone (TSH) levels were normal in this population and they did not correlate with bone mineral density either in the lumbar spine or in the hip. More than 50% of the patients had urinary calcium levels >200 mg every 24 hours, and 25% had >300 mg every 24 hours.
Bone alkaline phosphatase correlated with t-scores in the lumbar spine and the hip
(r = -.324 p=0.008). Patients with higher bone alkaline phosphatase tended to have lower BMD in the lumbar spine and hip than patients with lower values.
Markers of bone resorption urine pyridinoline and urine deoxypyridinoline, also correlated inversely with BMD in the spine and the hip (r= -0.367 p=0.003; r=-0.390, p=0.001, respectively). Markers of bone formation (such as bone alkaline phosphatase) correlated strongly with markers of bone resorption in the urine (r=0.581, p<0.0001).
These findings suggest that subjects receiving PI-containing potent ART have a state of low BMD secondary to increased bone remodeling, or alternatively an alteration of bone mineralization that leads to increased urinary calcium loss.
Serum bone-specific alkaline phosphatase: Bone-specific alkaline phosphatase is synthesized by osteoblasts and released into the circulation during the process of bone formation. Its levels reflect osteoblastic activity due to either increased bone formation or osteoblastic stimulation associated with excessive bone destruction.
Serum osteocalcin: Serum osteocalcin is a small protein predominantly synthesized by the osteoblasts and incorporated into the extracellular matrix of the bone. A fraction of newly synthesized osteocalcin is released into the circulation, where it can be measured by radioimmunoassay. It is a specific marker of bone formation.
Type I collagen telopeptide breakdown products (includes C- or N- terminal telopeptides): Type I collagen molecules in the bone matrix are linked by pyridinoline crosslinks (pyridinoline and deoxypyridinoline) in the region of N- and C- telopeptides. These crosslinks serve to create interchain bonds that stabilize the molecule within the extracallular matrix. During osteoclastic bone resorption, both molecules are released into the circulation as peptide-bound crosslinks attached to fragments of N- terminal (NTX) or C- terminal (CTX) telopeptides. NTX can be measured from both urine and serum, but urine testing requires 24-hour collection and is associated with significant circadian variability. Therefore, serum NTX is more practical for use in multicentered clinical trials.
There is significant circadian variability in the measurements of markers of bone turnover. Most bone markers are increased at night, reach a peak around 2:00-8:00 a.m., with subsequent decline and nadir between 1:00-11:00 p.m. In order to decrease intrasubject variability, these markers should be obtained approximately at the same time of the day (in the morning) (25).
Potential Therapies for Decreased BMD
Therapeutic options are somewhat limited, even for HIV-uninfected patients with decreased BMD.
Calcium and vitamin D: Calcium and vitamin D suppress parathyroid hormone secretion, thus reducing bone loss. The absorption of calcium can be improved by adding 400 to 1000 IU of vitamin D to the daily diet (26). Clinical trials have demonstrated a significant reduction in fractures with calcium and vitamin D3 (27, 28). Billsten et al. (29) showed a significant reduction in the risk of fractures in a trial of vitamin D given to 2,404 older women. This effect was maintained even after exclusion of women who received calcium supplementation. Supplemental calcium and vitamin D are now considered standard of care; most therapeutic trials of various drug therapies for osteoporosis have been achieved in the presence of calcium and vitamin D supplementation among control and intervention groups (30).
The optimal dietary requirements of vitamin D and calcium for healthy adults are estimated to be 400 IU and 1000 mg, respectively (31). For all women and men over 65, and for patients with osteoporosis, recommended daily intake of calcium is 1,500 mg/day. Calcium intake, up to a total intake of 2,000 mg/day, appears to be safe. The maximal effective dose of vitamin D is uncertain, but thought to be 400 to 1,000 IU/day (32). It appears perhaps advisable to consider limiting calcium intake to 1000 mg of elemental calcium per day and 400 IU of vitamin D per day.
Estrogen therapy: In postmenopausal women, osteoporosis can be effectively treated with estrogen-replacement therapy, but because of their hormonal effects, estrogens will not be a treatment option for most HIV-positive patients with osteoporosis. The same is true for Selective Estrogen Receptor Modulators (SERMs), such as Raloxifene which has been shown to have an estrogen agonistic effects on bone, and a beneficial effect on BMD (33).
Intranasal calcitonin has been used for osteoporosis, but with low tolerability and efficacy.
Parathyroid hormone (PTH) is a new approach to osteoporosis therapy, because unlike current available therapies (estrogens, bisphosphonates, SERMs, and calcitonin) that all function by decreasing bone resorption, PTH stimulates new bone formation and resorption. The end result seems to be a significant increase in BMD (34). PTH therapy is nonetheless new, and its long-term effect remains to be determined.
Bisphosphonates are the most thoroughly investigated drugs in the field of osteoporosis. The precise mechanism of action of bisphosphonates is not completely understood. They are known to strongly inhibit osteoclast-mediated bone resorption (35), and to stimulate the osteoblast to produce inhibitors of osteoclast formation and therefore of bone resorption (36). But whether these agents increase bone formation by increasing osteoblast progenitors or by increasing the osteoblast life span is uncertain. (37). Several controlled trials have shown significant efficacy of bisphosphonates, including alendronate, in post-menopausal as well as in glucocorticoid-induced osteoporosis. Efficacy was demonstrated as an increase in BMD as well as a significant decrease in fractures (30, 38-42). Patients should be receiving calcium supplements and vitamin D in combination with bisphosphonates. In trials of biphosphonates, the reduction in fracture risk is usually seen within the first 12-18 months of treatment. There is a growing amount of information suggesting that short-term changes in urinary and plasma markers of bone turnover are associated with and predictive of long-term changes in bone mass density, as measured by DEXA scans (40, 43).
As previously mentioned, the exact mechanism of bisphosphonates is unknown. They are structural analogs of alkyl phosphates (APs), which are potent stimulators of T cell proliferation and activity in mammals. Underscoring this chemical similarity, T cell proliferation was demonstrated following pamidronate administration to normal health individuals (45). T cell numbers rose to the highest levels in patients having an "acute phase reaction" to pamidronate. In vitro studies also demonstrate that aminobisphosphonates (ABPs) induce T cell proliferation and activation (46, 47). Bisphosphonates lacking nitrogen (clodrinate, etidronate) were inactive in these studies. T cell activation by ABPs was interleukin-2 dependent, and led to the production of the Th1 cytokines IFN-and TNF- (46, 47). ABP-stimulated T cells demonstrated cytotoxicity against a variety of cells including plasma cells associated with multiple myeloma (46), primary monocytes, and virally-transformed lymphoid cells (B-LCLs) (47).
The predominant T cell population in human blood expresses the V2 and V2 T cell antigen receptor subunits (V22 T cells). These cells proliferate in response to both ABPs and APs. Das recently demonstrated that, like APs, the V2 and V2 segments are required for ABP reactivity (47).
Although they constitute a minority of total CD3+ T cells, T cells are believed to play an important role in initiating the immune response directed against pathogens and tumor cells, and in shaping the direction and severity of the acquired immune response. Stimulatory ligands for T cells are evolutionarily-conserved and associated with host cells as well as pathogens. Unlike T cells, these T cells recognize antigens through conserved T-cell receptor (TCR) gene segments resulting in polyclonal stimulation. Thus, precursor frequencies are much higher in this T cell lineage. T cell proliferation and activation is associated with many viral, bacterial, and protozoal infections. During the course of HIV infection however, V2V2 T cells are rapidly depleted from the blood, and the remaining cells lose the ability to respond to AP antigens in vitro (48). We believe that overstimulation of these cells during the infection period leads to activation-induced cellular death (AICD) (49). The loss of V2V2 T cells may contribute to AIDS progression and the formation of opportunistic infections (OIs) and AIDS-related tumors. V2V2 cell numbers and activity are eventually recovered following the administration of HAART (50). We believe that the restoration of this T cell population will have beneficial effects on the incidence of OIs and AIDS-related tumors and can be achieved through the administration of stimulatory antigens under conditions where viral activity is kept under control.
There is some evidence that ABP treatment can affect peripheral blood T cells. The in vitro effects of ABPs have been examined using PBMC from patients with multiple myeloma who were treated for hypercalcemia. Alendronate (Fosomax), ibandronate, and pamidronate were tested and shown to elicit proliferative responses from patient PBMC. The proliferating cells had cell surface V2 chains and produced IFN-gamma after stimulation (47). In other malignancies, single doses of pamidronate using 60 to 90 mg by intravenous infusion, eliminated hypercalcemia with minor side effects (51) and were occasionally associated with substantially increased T cell levels in blood (52). Overall, ABPs are powerful stimulators of T cells and are safe for clinical studies.
Two recent studies emphasize the importance of T cells for controlling infectious disease. Bukowski's group at Harvard used SCID mice to study the pathogenesis of bacterial infections, including Eschericia, Staphylococcus, and Morganella. Infected mice were infused with human V2V2+ cells that had been treated with pamidronate. Mouse survival was markedly enhanced in treated groups, and this was related to V2V2+ T cell proliferation in the animal (53). Importantly, these experiments could only be done with transplanted cells, because the T cell response to phosphoantigens is not observed in rodents. Another example of T cells in disease was provided by experiments using BCG to vaccinate rhesus macaques against M. tuberculosis. BCG immunization elicited V2V2+ T cell expansion in vivo and the animals were protected against challenge; macaques lacking the T cell expansion succumbed to lethal M. tuberculosis (54). We hope that A5163 will help to define the role for T cells in HIV disease, and confirm these cells as important targets for immunotherapy.
Alendronate (brand name: Fosomax) is one of the newer nitrogen-containing bisphosphonates, with improved efficacy over older bisphosphonates. After oral ingestion of alendronate, up to 80% is rapidly taken up by bone, and the rest rapidly excreted unchanged in the urine. These properties, added to the fact that alendronate is not metabolized by the liver, make it unlikely to result in any significant drug-drug interactions. This has been supported by numerous studies performed to date involving non-HIV-infected subjects. Alendronate demonstrated an excellent safety profile when used in clinical trials. In particular, the magnitude and frequency of significant upper GI complications are similar to those with placebo (39, 41-42). However, in post marketing surveillance, alendronate has been associated with some GI toxicity, mainly esophagitis, gastritis, and ulceration (44). Side effects were noted in cases where subjects had not followed the directions for administration or had continued therapy even after developing upper gastrointestinal symptoms. When administered appropriately, alendronate is very well tolerated. Calcium may interfere with the absorption of alendronate, therefore calcium/vitamin D supplements will be administered at least two hours after alendronate. The AIDS Clinical Trials Group (ACTG) is cplanning a study of Fosomax and calcium/vitamin D supplements in HIV+ individuals with bone loss.
Two recent reports of improvement of BMD after initiation of ART raised questions regarding the effect of antiretrovirals on BMD in the setting of HIV infection (3, 55). These studies reported improvement of BMD after initiation of indinavir- and amprenavir-containing regimens, respectively. These observations may not represent a true improvement of BMD as the studies did not account for changes in weight, or in other known risk factors of osteopenia.
It must be recognized that changes in diet, exercise habits, and ART among patients can alter what happens to bones.
Alendronate is the only bisphosphonate demonstrated to be effective in men and approved for treatment of osteoporosis in men (30). In addition, it is the only bisphosphonate with an approved once-weekly dosing regimen. The once-weekly (70 mg) dose of alendronate was recently shown to be equivalent to 10 mg once daily in terms of increases in bone density and decreases in bone markers (56). In addition, once-weekly dosage would eliminate many of the scheduling difficulties faced by HIV-infected patients. In two randomized placebo-controlled studies of once-weekly 70 mg alendronate versus placebo, tolerability and safety between the two arms were similar (57-58).
Calcium and/or vitamin D supplementation have been shown to increase bone mineral density and decrease fracture risk, even though at a modest level (27-30, 59-60). The standard of care for osteoporosis in the HIV-negative population includes at a minimum calcium supplementation, along with vitamin D to enhance calcium absorption. In addition, all studies of bisphosphonates in HIV-uninfected populations included at least 600 mg of calcium daily and most included 400 IU of vitamin D daily supplements; thus current recommendations are to give supplemental calcium and vitamin D when using bisphosphonates.
Several trials of alendronate in both glucocorticoid-induced and post-menopausal osteoporosis showed a 4%-5% increase in lumbar BMD after 48 weeks of therapy (30, 39 39, 41, 52, 61-62). These changes were associated with a reduction in fractures of 40%-50%.
Even though osteopenia is found in about 40-50% of HIV-infected subjects, testing for decreased BMD is not routinely performed in HIV-infected subjects. This may relate, in part to, the lack of available data on the appropriate management of osteopenia in this population.
Limited bone DEXA is usually more reliable than total body DEXA in evaluating BMD and the risk of fracture, but a recent study in HIV-infected subjects showed that BMD measurements with both methods correlated well (1).
In both post-menopausal and glucocorticoid-induced osteoporosis, positive effect of alendronate on BMD was evident by 48 weeks, and effect on bone markers was seen within 3 months.
In order to maximize the benefit from Fosomax, after the Fosomax dose one should refrain from eating for 30 minutes and wait 2 hours before taking any calcium supplement.
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