Metabolic bone disease in HIV infection
Borderi, Marcoa; Gibellini, Davideb; Vescini, Fabioc; De Crignis, Elisab; Cimatti, Laurab; Biagetti, Carloa; Tampellini, Liviaa; Re, Maria Cb,d
aSection of Infectious Diseases, Department of Internal Medicine, Geriatric Medicine and Nephrology, University of Bologna, Bologna, Italy
bDepartment of Haematology and Oncologic Sciences, Section of Microbiology, Italy
cCenter for Metabolic Bone Diseases, Gorizia Hospital, Gorizia, Italy
dInteruniversity Consortium, National Institute Biostructure and Biosystem (INBB), Rome, Italy.
Received 15 April, 2009
Accepted 15 April, 2009
Correspondence to Davide Gibellini, Department of Haematology and Oncologic Sciences, Section of Microbiology, University of Bologna, Italy. Tel: +39 051 636 3165; fax: +39 051 307 397; e-mail: firstname.lastname@example.org
HIV mainly replicates in CD4+ T lymphocytes and monocyte/macrophages causing severe immunological impairment. In addition to the immune system, HIV infection affects tissues and organs such as kidney, liver, the central nervous system, heart and bone showing a complex pathogenesis .
The advent and widespread use of highly active antiretroviral therapy (HAART) in the last two decades has led to a marked improvement in the treatment of HIV disease even though viral infection cannot be eradicated because HAART does not completely eliminate the viral reservoirs . HAART has dramatically changed the course of HIV infection from a fatal infection to a chronic and relatively manageable disease. The increased life expectancy of HIV patients and the effects of HAART have changed the management of HIV infection. Nowadays medical treatment is no longer focused solely on HIV infection, opportunistic diseases and monitoring immune derangement, but also includes the control of metabolic, cardiovascular, liver, bone and kidney complications. In particular, bone alterations have been observed in the course of HIV disease representing a pivotal clinical problem in the management of HIV patients especially for a possible development of bone fractures . The major bone lesions detectable in HIV patients are related to bone demineralization (osteopenia/osteoporosis and osteomalacia) and osteonecrosis ( for a review).
This report will discuss the pathogenesis, diagnosis and treatment of major bone complications represented by bone demineralization diseases during HIV infection and HAART treatment.
Osteopenia/osteoporosis in HIV-infected patients
Bone alterations have been observed in the course of HIV disease since for nearly two decades (Table 1). In particular, reduced bone mineral density (BMD) is the most common bone lesion found in HIV-infected individuals [5,6]. BMD is a parameter that predicts fracture risk, which in turn correlates with a shorter life expectancy . BMD is measured by the dual X-ray absorptiometry scan (DXA). According to the WHO Classification, BMD is commonly reported in terms of DXA T-score, which represents the number of standard deviations below the mean of a young, sex-matched control population. T-score values are considered normal above the limit of −1. Values between −1 and −2.5 indicate osteopenia (low bone mass) whereas a T-score value below −2.5 signifies osteoporosis [8,9]. Osteoporosis is a systemic condition characterized by both quantitative and qualitative alterations that reduce bone strength .
Several groups have used DXA to study BMD status during HIV infection. A meta-analysis of selected reports on bone loss in the whole HIV patient population (HAART treated plus naive) from 1994 to 2005 showed that these individuals had 6.4 fold increased odds of osteopenia and 3.7-fold increased odds of osteoporosis in comparison with uninfected individuals . The relation between antiretroviral treatment and osteopenia/osteoporosis has been noted in several studies [12–18] although other reports failed to find any influence of HAART on bone loss, disclosing no major differences between naive and HAART treated patients [19–23]. A recent study on 492 patients belonging to the Aquitaine Cohort reported osteopenia in 50% and osteoporosis in 30% of HIV-positive cases but multivariate analysis did not show a significant correlation to bone loss and cumulative HAART or specific drug class .
In spite of these opposing findings, a meta-analysis of selected cross-sectional studies demonstrated that the odds of osteoporosis were increased 2.4 times in HAART-treated patients compared with naïve individuals . In addition, the meta-analysis by Brown and Qaqish on 12 studies disclosed that patients treated with protease inhibitors have a higher prevalence of reduced BMD and the odds of osteoporosis in protease inhibitor-treated patients are 1.6 greater than in protease inhibitor-untreated individuals . The controversy over the role of antiretroviral compounds in BMD decrease could be explained by shortcomings in some studies. HAART typically combines nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), thus, the antiretroviral cocktail composition may differ within the same cohort with conceivably different effects on bone. In addition, some DXA studies analysed only the spine (mainly confined to trabecular bone), or hip (mostly cortical bone) or both bone sites. The choice of bone for DXA assay is not negligible; the human skeleton is composed of two different types of bone tissue: trabecular bone (comprising around 20% of the bone and mainly involved in the maintenance of mineral homeostasis) and cortical bone (80% and responsible for most support functions). Plainly, high bone turnover states, such as HIV-induced osteoporosis, involve trabecular bone (spine) earlier and to a greater extent compromising cortical bone (hip) only much later . Moreover, the effectiveness and duration of HAART treatment may also affect bone biology and hence the interaction between HAART and bone is noteworthy [26,27].
Mechanisms of HIV-associated osteopenia/osteoporosis
The pathogenesis of reduced BMD in HIV-infected patients is probably multifactorial. Osteopenia and osteoporosis are bone lesions mainly correlated to risk factors such as sex, age, low body weight, malnutrition, immobility, lifestyle factors (smoking, alcohol abuse), glucocorticoid, hypogonadism and lipodystrophy . The sum of traditional patient-related risk factors with HIV infection and HAART side effects can determine the onset of these bone lesions in HIV-infected patients.
Bone cellular components
Bone is a mineralized tissue composed of bone matrix and bone cells. Its homeostasis is mainly due to the tightly integrated contrasting activity of two major bone cell types: bone forming osteoblasts and bone resorbing osteoclasts. These cells are functionally connected and regulated by mediators such as hormones, vitamins and cytokines that strongly affect the skeletal biology throughout life .
Osteoblasts arise from mesenchymal stem cells and determine the formation and structural organization of bone extracellular matrix and its mineralization . Mature osteoblasts synthesize several molecules involved either in bone formation or in regulating osteoclast activity such as type I collagen, osteocalcin, osteopontin, proteoglycans, receptor activator for nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) . Notably, osteoblasts may also evolve to osteocytes when embedded in bone matrix, playing an important role in the control of architectural bone structure [32,33]. Osteoclasts are members of the monocyte/macrophage lineage originating from multiple cellular fusions of their precursors  that proliferate and differentiate towards mature osteoclasts by means of macrophage colony-stimulating factor (M-CSF) and RANKL . M-CSF mainly induces precursor cell proliferation whereas RANKL plays a pivotal role in their differentiation, full functional activation and multiple cellular fusions of osteoclasts. Mature osteoclasts are able to resorb bone both by acid environment induction and secretion of lytic enzymes [36–38] such as cathepsin K and tartrate-resistant acid phosphatase (TRAP).
The functional balance and cross-talk between osteoblasts and osteoclasts are crucial in determining bone mass (Fig. 1), which depends on the well tuned bone remodelling characterized by osteoclast bone resorption and osteoblast bone rebuilding phases . An imbalance of the osteoblast/osteoclast interaction due to pathological conditions such as infection, hormonal, immunological and metabolic disorders, impairs both bone mass and structure impairment resulting in increased bone fragility and fracture risk.
The role of HIV infection
As avian, feline and murine retroviruses are known to infect osteoblasts and osteocytes [39–41], early studies focused on the hypothesis that human osteoblasts may be a permissive target for HIV infection decreasing BMD through a direct viral mechanism. Some reports showed that HIV-1 transmission can occur during bone transplantation  and HIV-positive PCR assay has been observed in bone graft . H9 cell line or peripheral blood mononuclear cells (PBMC) cocultivated with bone fragments from HIV-1-positive individuals displayed both a positive HIV RT activity and p24 detection in cell supernatants . However, it was not clear whether blood or bone marrow HIV-positive cells contamination could be excluded in these studies. Mellert et al.  found that osteoblast-like cell lines were infected when challenged by HIV. Together, these data suggested that bone might be considered an HIV reservoir where the limited blood flow and the particular anatomical structure may also induce a poor antiretroviral concentration to tackle the HIV infection . Moreover, the infection of osteoblasts may be closely related to the incomplete refilling of bone lacunae during bone remodelling with subsequent bone loss. In spite of these observations, further studies performed on human primary osteoblasts did not confirm the results obtained in osteoblast-like cell lines. The primary osteoblasts taken from HIV-positive individuals did not show viral DNA and RNA in PCR assays . In addition, another study disclosed the failure of HIV productive infection when cultures of primary osteoblasts were challenged with classical HIV laboratory strains . The lack of susceptibility may be partially explained by shortage of CD4 receptor and coreceptor proteins on osteoblast cell membrane [47,48]. In addition, as observed on CD34+ hematopoietic progenitor cell membrane , conceivably the CD4/CXCR4 complexes might be not so sterically closed to constitute the trimeric complex with gp120 essential for HIV entry.
In addition to the direct effect of HIV replication, the apoptosis process plays a pivotal role in HIV pathogenesis. The progressive loss of CD4+ T lymphocytes is also related to apoptosis activated by the interaction between HIV gp120 and the CD4 receptor [50,51]. In addition, HIV-related apoptosis is a major mechanism involved in anaemia, thrombocytopenia and induction of neuronal cell death [52–54]. A recent paper showed an increased rate of apoptosis in primary osteoblasts treated by gp120 or challenged with heat-inactivated HIV laboratory strains . Apoptosis activation occurs by a paracrin/autocrin mechanism due to TNF-α increase . This finding may suggest that part of the bone loss detected in HIV-infected patients may be related both to apoptosis and the decreased biological activity of osteoblasts. The inhibitory effect of HIV gp120 on osteoblast function was confirmed by Cotter et al.  who found that gp120 (Fig. 2 and Table 2) reduces calcium deposition, alkaline phosphatase activity and bone specific Runt-related transcription factor 2 (RUNX-2) transcription factor expression after 24 h of treatment in primary osteoblast cultures. In agreement with these data, histomorphometric and serological analysis showed impairment in primary osteoblast functional activity and a consistent decrease of serum osteocalcin in HIV-infected patients [5,56,57].
Osteoblasts are derived from bone marrow mesenchymal stem cells. Hence, some studies sought to establish whether mesenchymal stem cells and their differentiation towards osteoblasts are impaired by HIV infection (Fig. 2). Wang et al.  showed that bone marrow mesenchymal stem cells could be infected to a low extent by X4 tropic HIV strains leading to persistent harbouring of the virus inside these cells with subsequent inhibition of proliferation and survival. Several differentiation pathways from mesenchymal cells are also impaired by Tat through the upregulation of TNF-α and IL-1β expression.
More recently, the interaction between specific HIV proteins and mesenchymal cells differentiating towards osteoblasts was analysed. In particular, p55gag and gp120 viral proteins elicited a derangement of specific transcription factors involved in the differentiation and activity of osteoblasts. HIV gp120 (Fig. 2) is also able to trigger the activation of peroxisome proliferator-activated receptor gamma (PPARγ) determining an MSC differentiation switch from osteoblasts to adipocytes [55,59].
Several reports have also analysed the influence of HIV on osteoclasts (Table 2). RANKL and M-CSF are key factors modulating the proliferation and differentiation of osteoclast lineage cells. A significant increase in plasma RANKL levels with an impairment of RANKL/OPG ratio was described in HIV-positive patients . The RANKL increase correlated with high plasma viral RNA load indicating a direct relation between HIV infection status and RANKL synthesis [60–62]. Moreover, gp120 upregulated RANKL secretion (Fig. 3) in primary T cells  whereas Vpr synergized the glucocorticoid-mediated activation of RANKL in several cell systems such as primary T cells and Jurkat lymphoblastoid cell line . In turn, RANKL upregulates HIV replication in acutely and chronically infected monocyte and T-lymphocyte lineages suggesting a feedback loop between HIV replication and RANKL production .
M-CSF is a haematopoietic growth factor controlling the survival, proliferation and differentiation of the monocyte-macrophage lineage and it is closely involved in the early phases of osteoclast differentiation. The pivotal involvement of M-CSF and its receptor in osteoclast differentiation was also confirmed by osteopetrosis and bone alterations in mice mutated in the CSF-1 or c-fms gene [66,67]. HIV infection of macrophages induces a significant increase in M-CSF production and secretion , which in turn promotes further HIV infection of macrophages through the increase in CD4/CCR5 receptors and virus gene expression [69–72]. M-CSF elicits osteoclast differentiation also enhancing the RANKL effect (Fig. 3). In addition, Yamada et al.  showed that bone marrow macrophages (BMMs) cultured without M-CSF produce a large amount of OPG compared with cells cultured with M-CSF. This finding suggests that M-CSF downregulates OPG production in BMMs. As OPG, a TNF receptor family secreting glycoprotein, inhibits osteoclast differentiation by acting as a decoy RANKL receptor, the increasing level of M-CSF during HIV infection impairs the balance between RANKL/RANK and OPG, increasing osteoclasts (Table 2).
The role of HAART
In 1995, the introduction of HAART in the treatment of HIV infection led to a dramatic and sustained decrease in HIV-related morbidity and mortality . HAART typically combines nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs). Despite controversial results regarding antiretroviral molecules and bone loss, several groups investigated the possible bone damage mechanisms of specific antiretroviral classes.
The role of N(n)RTIs
The nucleoside analogues (NRTIs) are antiretroviral molecules whose chemical structure is a modified nucleoside. These compounds suppress the replication of retroviruses by interfering with the reverse transcriptase enzyme activity causing premature termination of the proviral HIV DNA chain. Abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine and zidovudine are currently used in HAART.
Despite the major positive impact of these molecules in HIV therapy, clinical observations disclosed severe side effects such as mitochondrial toxicity, hyperlactataemia and lactic acidosis. To varying degrees, NRTIs inhibit the DNA polymerase-γ , the enzyme involved in the replication of mitochondrial DNA, leading to mitochondrial damage and dysfunction . In-vitro studies disclosed some differences in the induction of specific NRTI-related mitochondrial DNA depletion. The so-called ‘d-drugs’ ddC (zalcitabine), ddI (didanosine), and d4T (stavudine) are relatively stronger inhibitors of polymerase-γ than other nucleoside analogues, called ‘non-D drugs’ [77,78]. In the presence of mitochondrial dysfunction or depletion, the metabolism of pyruvate is shifted toward the production of lactate with a decrease in energy production. Hyperlactataemia does not inevitably lead to lactic acidosis even though this condition is more prevalent in women, obese individuals, individuals with hepatitis C virus (HCV) coinfection and patients receiving stavudine plus didanosine [79,80]. Several studies based on NRTIs-treated patients demonstrated that hyperlactataemia is a relatively common event occurring in 15–20% of individuals a year, whereas lactic acidosis is encountered in less than 0.4% of patients [79,80].
Carr et al.  analysed 221 patients by univariate logistic regression and found an association between NRTIs, elevated lactate levels and reduced BMD (Table 3). These data suggest that lactic acidaemia induced by NRTIs may cause osteopenia by a mechanism related to calcium hydroxyapatite loss as the bone tries to buffer chronic acidosis. This damage mainly affects the trabecular bone, which represents the majority of vertebral bone and is a more labile store of calcium than cortical bone. In addition the systemic effects of NRTIs, a paper by Pan et al. (Table 3) showed a specific interaction between zidovudine (ZDV) and bone. ZDV enhances the RANKL-mediated osteoclastogenesis inducing osteopenia in a murine model .
Although it is commonly classified with NRTIs, tenofovir disoproxil fumarate (TDF) is a nucleotide analogue with anti-HIV activity. In-vitro studies demonstrated that the potential of TDF to cause mitochondrial toxicity is very low compared with other NRTIs [82,83]. Preclinical animal studies have shown that renal excretion is the primary route of TDF elimination by a combination of tubular secretion and glomerular filtration and some evidence of mild nephrotoxicity was noted in different animal species . This renal toxicity is dose-dependent , related to tubular dysfunction due to proximal tubular epithelial cell damage, and correlates with an impaired glomerular filtration rate. The tubular dysfunction may elicit the appearance of hypophosphataemia, whereas the reduced glomerular filtration is associated with a parallel decrease in the function of the alpha-1-hydroxylase, an enzyme involved in vitamin D metabolism . Some papers and case reports have described a nephrotoxicity with hypophosphataemia (Table 3) in HIV-infected patients receiving TDF [87–90] and, in rare cases, the presence of Fanconi syndrome [91,92]. Fanconi syndrome was mainly observed in patients treated with salvage therapy containing ritonavir [93–95] or lopinavir/ritonavir . The impaired phosphorus balance and vitamin D metabolism related to renal toxicity may determine an osteomalacic pattern in HIV patients: some studies found an association between use of TDF and bone damage [97,98] and a higher incidence of foot fracture was also found in TDF-treated patients compared with TDF-untreated individuals [99,100].
The association between TDF and nephrotoxicity was not confirmed by other studies. A cohort study published in 2006  showed a low-grade hypophosphataemia in TDF-treated patients with normal baseline renal function, but it was not statistically significant with respect to TDF-untreated patients. The GS 902  and GS 907 studies , performed on a large number of patients with no history of renal disease, found the same incidences of elevated serum creatinine and hypophosphataemia in the TDF arm and placebo arm after 24 weeks of treatment. The larger GS 903 study, a randomized, double-blind, parallel, placebo-controlled trial over 144 weeks, compared a treatment regimen of TDF, lamivudine and efavirenz with a treatment regimen of stavudine, lamivudine and EFV in antiretroviral-naive patients [104,105], confirming the GS 902 and GS 907 results.
These controversial results may be related to cohort selection, as the patients in the GS studies did not show low GFR at baseline. It is conceivable that the continuous therapeutic regimen, specific HAART pharmacological association and basal functional renal conditions of patients affected the interaction between TDF and bone.
The role of protease inhibitors
Protease inhibitors impair HIV replication by preventing the viral protease enzymatic action, a pivotal step in the final stages of the viral replication cycle. The viral progeny obtained in the presence of protease inhibitor cannot infect the target cells. Amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and tipranavir are the protease inhibitors used for antiretroviral therapy.
The protease inhibitors/bone interaction has been studied in in-vitro bone cell cultures (Table 3). The effects of protease inhibitors on osteoclasts were studied measuring osteoclast activity in rat neonatal calvaria . Nelfinavir, indinavir, saquinavir and ritonavir treatments showed proosteoclast activity whereas lopinavir and amprenavir did not. Further studies demonstrated that saquinavir and ritonavir improved osteoclast activity through the abrogation of a physiological block to RANKL signalling represented by interferon gamma (IFN-γ)-mediated proteosomal degradation of TNF receptor associated factor 6 (TRAF-6) . RANKL recruits signal adapter TRAF-6 to the cytoplasmic tail of RANK resulting in the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPKinase) pathways  involved in the survival and differentiation of osteoclasts. A subsequent paper  showed that ritonavir had opposite effects blocking osteoclastogenesis by impairing RANKL-induced signals. This finding suggested a complex scenario in the interactions between protease inhibitors and the osteoclast lineage. Protease inhibitors were also assayed on the human mesenchymal stem cells differentiating to osteoblast lineage. These experiments indicated that nelfinavir and lopinavir inhibited bone formation and calcium deposition thereby decreasing osteoblast activity . A recent paper by Malizia et al.  assayed four protease inhibitors (nelfinavir, saquinavir, indinavir, ritonavir) on primary osteoblasts and found a significantly decreased osteoblast activity (decrease of alkaline phosphatase, calcium deposition and RUNX-2 mRNA expression) when indinavir and ritonavir were used. Altogether these in-vitro studies suggest that some protease inhibitors may determine bone loss by increasing osteoclast resorption and inhibiting the osteoblast rebuilding function.
It is noteworthy that some in-vitro studies investigated the possible association between use of protease inhibitors and decreased vitamin D serum levels. Vitamin D is essential for the maintenance of a normal bone structure increasing the phosphate bone bioavailability . The biological effects on bone remodelling are exerted by 1,25-dihydroxyvitamin D3 (calcitriol), a potent calcitropic hormone . Vitamin D activation to calcitriol involves 25-hydroxylation in the liver followed by 1α -hydroxylation of 25-hydroxyvitamin D3 in the renal proximal tubular cells, whereas vitamin D catabolism is mainly determined by 24-hydroxylase. The vitamin D deficit can progressively determine osteomalacia through the reduction of phosphates available to bone .
The 1α-hydroxylase and 25-hydroxylase enzymes, involved in vitamin D activation, are cytochrome P450 monoxygenases  and protease inhibitors are potent in-vivo inhibitors of human hepatic cytochrome P450s namely CYP3A4 [113–115]. Ritonavir, but also indinavir and nelfinavir, negatively affect the 1α-hydroxylase enzyme and, to a lesser extent, 25-hydroxylase enzyme activity reducing 1,25-dihydroxyvitamin D3 production (Table 3) whereas no inhibition of 24-hydroxylase is observed [115,116].
Some clinical studies investigated vitamin D deficiency in HIV-infected individuals. Hypovitaminosis D was observed before the advent of HAART and a severe depletion of vitamin D was associated with advanced infection and immune system hyperactivation . Recent studies performed on a cohort of naive and HAART-treated patients demonstrated a high prevalence of hypovitaminosis D suggesting a risk of osteomalacia [118,119]. These results, coupled with the TDF effects on vitamin D regulation indicate that HAART-mediated osteomalacia may be an additional mechanism of bone depletion. Osteomalacia could be underestimated as a pathogenetic event of bone impairment in HIV infection. This problem is not fully appreciated in the literature, because the few studies that have tried to explore bone impairment have usually used the DXA scan. This procedure is a good approach to determine bone mineral content but cannot discriminate between osteoporosis (low BMD and bone architecture deterioration) and osteomalacia (low BMD with normal bone architecture).
Management of osteopenia/osteoporosis in HIV-infected patients
In daily clinical practice, doctors must address many problems affecting their HIV-infected patients, such as the prevention of cardiovascular disease, diabetes, dyslipidaemia and lipodystrophy. Although specific complete guidelines are not yet available, several diagnostic approaches have been recommended to monitor bone conditions during HIV disease and the HAART regimen (Table 4).
Hip and lumbar-spine DXA analysis is a valuable approach to determine BMD variations and will discriminate between cortical and trabecular bone, two different compartments that may respond differently to antiretroviral drugs. Hence, DXA should be performed in all patients, at least at baseline visit, as many prospective studies have demonstrated that it will predict fracture risk . A widely cited meta-analysis indicated that the risk of hip fracture increased 2.6-fold for each standard deviation decrease in BMD at the femoral neck . Unfortunately, DXA machines are not widely available and many doctors cannot prescribe the analysis easily, but a major effort should be made to obtain at least one BMD measurement in all HIV-infected patients.
The recent guidelines devised by the International Society for Clinical Densitometry (ISCD) recommend using the T-score with the diagnostic cut-off value specified by WHO only for women in menopause. Although definitive data are lacking, it is generally accepted that the same method can be applied to men over the age of fifty if they have at least one major risk factor for osteoporosis. For individuals aged less than 50 years, diagnosis is recommended using the Z-score that compares the patient's BMD with that of a healthy age-matched and sex-matched population. However, the Z-score has no clear cut-off value for osteopenia and osteoporosis and the following scores are recommended: patients with values lower than −1 are classified as having low bone mass, whereas a severe bone mass reduction is identified by Z-score values lower than −2 . The Z-score may allow further in-depth analysis of BMD and a useful application of this parameter in the evaluation of bone loss in HIV-infected individuals. Osteomalacia can only be diagnosed by bone histomorphometry that will disclose large amounts of unmineralized bone matrix. As bone biopsies are invasive, the diagnosis of osteomalacia is indirect and is generally established by coupling DXA analysis with some blood analytes (i.e. vitamin D, calcium, phosphate, PTH). Hence, DXA alone may underestimate the osteomalacia rate in this population as an unknown number of patients may have been misdiagnosed with osteoporosis. Nonetheless, a correct diagnosis must be established in order to institute appropriate therapy. Osteoporosis is commonly treated with antiresorptive or anabolic agents  whereas osteomalacia requires high doses of vitamin D .
Dorsal and lumbar spine radiograph are useful to assess vertebral fractures. Radiological investigation must be entertained in patients with back pain (particularly occurring in the upright position), patients with marked height reduction and in patients with severe kyphosis; at follow-up spine radiograph must rely upon the physician's decision particularly in patients with a diagnosis of vertebral fractures. Bone biology parameters can be monitored by laboratory tests: calcaemia, phosphataemia and albuminaemia (for ionized calcium calculation), urinary calcium and phosphate excretion. In addition, bone formation markers (i.e. osteocalcin or bone-associated alkaline phosphatase) and bone resorption markers (pyridinoline cross links or CTx, or NTx) can yield useful information together with vitamin D and PTH assays. Important information may be obtained by GFR determination (age and TDF, together with a low GFR, inducing a decrease in the function of alpha-1-hydroxylase in the kidney and in vitamin D availability) and the evaluation of kidney tubular function (some proximal tubular alterations may occur with normal GFR, and may signify an initial impairment of tubular function potentially unsafe for bone). Plasma lactic acidaemia monitoring at baseline and periodically during follow-up may provide valuable information on the side effects of NRTIs on bone. Mora et al.  suggested that plasma RANKL and OPG determination may be employed in some cases of therapy evaluation, as impairment of the RANKL/OPG system is well described in patients receiving protease inhibitor-based HAART. Even though short-term data indicate that replacing stavudine and protease inhibitor with tenofovir and efavirenz restores the RANKL/OPG equilibrium and may thus lead to a reduction in the bone resorption rate. The determination of these cytokines is not yet part of the routine evaluation of HIV-infected patients.
The management of osteopenia/osteoporosis in the course of HIV infection may be based on a change in risk factors, calcium and vitamin D diet supplementation and biphosphonate drugs (Table 5).
Patients can be advised to stop smoking and take physical exercise to control body weight. In addition, patients should have correct diet indications to ensure an adequate uptake of calcium and vitamin D. However, cholecalciferol should be administered to all HIV-infected patients presenting vitamin D deficiency. The daily upper tolerable limit for vitamin D is fixed at 2000 international unit (IU), but this is far below the toxic threshold, that has never been reached even with the administration of 10000 IU per day . A supplementation of 800 IU cholecalciferol daily can be suggested to all outpatients. The only contraindication to cholecalciferol administration is hypercalcaemia and therefore when serum ionized calcium is normal, vitamin D can be used.
A low calcium diet has been demonstrated to reduce BMD and maybe to increase the hip fracture risk [123,124]. The daily calcium recommended allowance for adults is between 800 and 1000 mg per day , but it is very difficult to reach this threshold in cholesterol lowering diets. Therefore, it is very important for correct diet counselling to be given to all HIV-infected patients.
When vitamin D deficiency and low calcium intake have been corrected, drugs can be used. Many treatments are available to combat osteoporosis. The antifracture efficacy, at least for vertebral fractures, is well demonstrated for bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate), hormone replacement therapy, raloxifene, strontium ranelate, teriparatide and recombinant human parathyroid hormone (PTH) .
Four studies have been published on the pharmacological treatment of HIV-induced osteoporosis with alendronate. Due to the low number of individuals analysed, the results obtained have a limited statistical significance, even though they showed that alendronate increased BMD with respect to placebo [126–129]. More recently, similar results were obtained in two trials comparing once yearly zoledronate therapy with placebo [130,131]. No data are available on fracture incidence reduction yet. Further studies are necessary to investigate the effects of bisphosphonates both on BMD and fracture risk reduction in HIV-related bone disease. Nevertheless, especially in fractured patients, the risk of new fractures is very high and therefore this therapeutic approach is mandatory.
The advantages and disadvantages of bisphosphonate treatment must be clearly evaluated for each patient. Notwithstanding the scant data available, alendronate or zoledronate must be considered to enhance bone mineral density and possibly decrease fracture incidence. The adverse effects associated with bisphosphonates include gastrointestinal intolerance (with oral administration), short-lived acute phase reaction (with intravenous administration) and jaw osteonecrosis , but the relatively low risk of this last adverse effect does not contraindicate the use of bisphosphonates at present.
A possible future direction in the treatment of osteoporosis may be the use of the anti-RANKL monoclonal antibody (denosumab). As described earlier, RANKL induces osteoclast activation and its upregulation was noted both in HIV-positive [60–62] and HIV-negative patients with osteopenia/osteoporosis . A clinical study on 412 HIV-negative postmenopausal women given denosumab for 1 year demonstrated an increase in BMD and a decrease of bone turnover . This finding suggested its possible use in osteoporosis treatment even in HIV-positive individuals. Other compounds such as OPG (RANK/RANKL interaction inhibitor), raloxifene (selective estrogen receptor modulator), teriparatide (PTH analogue), PTH and strontium ranelate (dual action bone agent) are under study but, like denosumab (RANK/RANKL interaction inhibitor), further evaluation is needed before these drugs can be administered in HIV-infected patients (Table 6).
Bone derangement is a major clinical complication in the course of HIV infection . The advent of HAART has led to a longer life expectancy and therefore HIV/HAART-related bone disease is destined to increase, enhancing the physiological age-related bone loss. Some epidemiological surveys in HIV-uninfected individuals indicate that the percentage of osteoporosis after 45 years of age ranges between 10 and 20%, and the lifetime fracture risk for a 50-year-old White woman is greater than 50% [136,137]. These data suggest that the number of HIV patients with bone disease and silent fractures can be expected to increase dramatically in the next few years because these patients also have two other potentially worsening factors: HIV itself and antiretroviral therapy. Hence, antiretroviral therapy must be accompanied by the clinical management of HIV/HAART-related bone disease to reduce the risk of osteoporosis and fractures in these patients.
This work was funded by Fondazione Cassa di Risparmio Bologna, Italy (n° 2006.0035, June 2006), ‘AIDS projects’ (30G.27) of the Italian Ministry of Health, the SIVIM study group for test standardization, Funds for selected research topics of the University of Bologna and MURST 60%.
Transparency Declaration: all the authors declare that they have no relationship (commercial or otherwise) that may constitute a dual or conflicting interest.
1. Levy JA. HIV pathogenesis: 25 years of progress and persistent challenges. AIDS 2009; 23:147–160.
2. Haggerty C, Pitt E, Siliciano R. The latent reservoir for HIV in resting cells and other viral reservoirs during chronic infection: insight from treatment and treatment-interruption trials. Curr Opin HIV AIDS 2006; 1:62–68.
3. Arnsten JH, Freeman R, Howard AA, Floris-Moore M, Lo Y, Klein RS. Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection. AIDS 2007; 21:617–623.
4. Allison GT, Bostrom MP, Glesby MJ. Osteonecrosis in HIV disease: epidemiology, etiologies, and clinical management. AIDS 2003; 17:1–9.
5. Serrano S, Marinoso ML, Soriano JC, Rubies-Prat J, Aubia J, Coll J, et al
. Bone remodelling in human immunodeficiency virus-1-infected patients. A histomorphometric study. Bone 1995; 16:185–191.
6. Mondy K, Tebas P. Emerging bone problems in patients infected with human immunodeficiency virus. Clin Infect Dis 2003; 36:S101–S105.
7. Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 2001; 12:989–995.
8. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis
. WHO technical report series 843. Geneva: WHO, 1994.
9. Kanis JA, McCloskey EV, Johansson H, Oden A, Melton LJ, Khaltaev N. A reference standard for the description of osteoporosis. Bone 2008; 42:467–475.
10. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy
11. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165–2174.
12. Tebas P, Powderly WG, Claxton S, Marin D, Tantisiriwat W, Teitelbaum SL, et al
. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14:F63–F67.
13. Carr A, Miller J, Eisman JA, Cooper DA. Osteopenia in HIV-infected men: association with asymptomatic lactic acidemia and lower weight preanti-retroviral therapy. AIDS 2001; 15:703–709.
14. Moore AL, Vashisht A, Sabin CA, Mocroft A, Madge S, Phillips AN, et al
. Reduced bone mineral density in HIV-positive individuals. AIDS 2001; 15:1731–1733.
15. Fernandez-Rivera J, Garcia R, Lozano F, Macias J, Garcia-Garcia JA, Mira JA, et al
. Relationship between low bone mineral density and highly active antiretroviral therapy including protease inhibitors in HIV-infected patients. HIV Clin Trials 2003; 4:337–346.
16. Vescini F, Borderi M, Buffa A, Sinicropi G, Tampellini L, Chiodo F, et al
. Bone mass in HIV-infected patients: focus on the role of therapy and sex. J Acquir Immune Defic Syndr 2003; 33:405–407.
17. Madeddu G, Spanu A, Solinas P, Calia GM, Lovigu C, Chessa F, et al
. Bone mass loss and vitamin D metabolism impairment in HIV patients receiving highly active antiretroviral therapy. Q J Nucl Med Mol Imaging 2004; 48:39–48.
18. Bongiovanni M, Fausto A, Cicconi P, Menicagli L, Melzi S, Ligabo VE, et al
. Osteoporosis in HIV-Infected subjects: a combined effect of highly active antiretroviral therapy and HIV itself? J Acquir Immune Defic Syndr 2005; 40:503–504.
19. Lawal A, Engelson ES, Wang J, Heymsfield SB, Kotler DP. Equivalent osteopenia in HIV-infected individuals studied before and during the era of highly active antiretroviral therapy. AIDS 2001; 15:278–280.
20. Dubé MP, Qian D, Edmondson-Melançon H, Sattler FR, Goodwin D, Martinez C, et al
. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin Infect Dis 2002; 35:475–481.
21. Bruera D, Luna N, David DO, Bergoglio LM, Zamudio J. Decreased bone mineral density in HIV-infected patients is independent of antiretroviral therapy. AIDS 2003; 17:1917–1923.
22. Amiel C, Ostertag A, Slama L, Baudoin C, N'Guyen T, Lajeunie E, et al
. BMD is reduced in HIV-infected men irrespective of treatment. J Bone Miner Res 2004; 19:402–409.
23. Landonio S, Quirino T, Bonfanti P, Gabris A, Boccassini L, Gulisano C, et al
. Osteopenia and osteoporosis in HIV+ patients, untreated or receiving HAART. Biomedicine and Pharmacotherapy 2004; 58:505–508.
24. Cazanave C, Dupon M, Lavignolle-Aurillac V, Barthe N, Lawson-Ayayi S, Mehsen N, et al
. Reduced bone mineral density in HIV-infected patients: prevalence and associated factors. AIDS 2008; 22:395–402.
25. Eriksen E, Axelrod D, Melsen F. Bone histomorphometry. New York: Raven Press; 1994.
26. Nolan D, Upton R, McKinnon E, John M, James I, Adler B, et al
. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS 2001; 15:1275–1280.
27. Mallon PW, Miller J, Cooper DA, Carr A. Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS 2003; 17:971–979.
28. Sambrook P, Cooper C. Osteoporosis. Lancet 2006; 367:2010–2018.
29. Kartsogiannis V, Ng KW. Cell lines and primary cell cultures in the study of bone cell biology. Mol Cell Endocrinol 2004; 228:79–102.
30. Marie PJ. Transcription factors controlling osteoblastogenesis. Arch Biochem Biophys 2008; 473:98–105.
31. Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Bioph 2008; 473:201–209.
32. Yellowley CE, Li Z, Zhou Z, Jacobs CR, Donahue HJ. Functional gap junctions between osteocytic and osteoblastic cells. J Bone Miner Res 2000; 15:209–217.
33. Taylor AF, Saunders MM, Shingle DL, Cimbala JM, Zhou Z, Donahue HJ. Mechanically stimulated osteocytes regulate osteoblastic activity via gap junctions. Am J Physiol Cell Physiol 2007; 292:545–552.
34. Burger EH, Van der Meer JW, Van de Gevel JS, Gribnau JC, Thesingh GW, Van Furth R. In vitro
formation of osteoclasts from long-term cultures of bone marrow mononuclear phagocytes. J Exp Med 1982; 156:1604–1614.
35. Väänänem HK, Laitala-Leinonen T. Osteoclast lineage and function. Arch Biochem Biophys 2008; 473:132–138.
36. Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, et al
. Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem 1996; 271:12517–12524.
37. Vääräniemi J, Halleen JM, Kaarlonen K, Ylipahkala H, Alatalo SL, Andersson G, et al
. Intracellular machinery for matrix degradation in bone-resorbing osteoclasts. J Bone Miner Res 2004; 19:1432–1440.
38. Halleen JM, Tiitinen SL, Ylipahkala H, Fagerlund KM, Väänänen HK. Tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of bone resorption. Clin Lab 2006; 52:499–509.
39. Murray AB, Schmidt J, Rieke L. Retrovirus-induced osteopetrosis in mice. Ultrastructural evidence of early virus production in osteoblasts and osteocytes. Am J Pathol 1986; 124:319–323.
40. Foster RG, Lian JB, Stein G, Robinson HL. Replication of an osteopetrosis-inducing avian leukosis virus in fibroblasts, osteoblasts, and osteopetrotic bone. Virology 1994; 205:179–187.
41. Labat ML. Retroviruses and bone diseases. Clin Orthopaed 1996; 326:287–308.
42. Centers for Disease Control. Transmission of HIV through bone transplantation
43. Roder W, Muller H, Muller WEG, Merz H. HIV infection in human bone. J Bone Joint Surg Br 1992; 74:179–180.
44. Buck BE, Resnick L, Shah SM, Malinin TI. Human immunodeficiency virus cultured from bone. Implications for transplantation. Clin Orthop Relat Res 1990; 251:249–253.
45. Mellert W, Kleinschmidt A, Schmidt J, Festl H, Emler S, Roth WK, et al
. Infection of human fibroblasts and osteoblast-like cells with HIV-1. AIDS 1990; 4:527–535.
46. Fessel WJ, Hurley LB. Is HIV sequestered in bone? Possible implications of virological and immunological findings in some HIV-infected patients with bone disease. AIDS 2003; 17:255–257.
47. Nacher M, Serrano S, Gonzalez A, Hernàndez A, Luisa Mariñoso M, Vilella R, et al
. Osteoblasts in HIV-infected patients: HIV-1 infection and cell function. AIDS 2001; 15:2239–2243.
48. Gibellini D, De Crignis E, Ponti C, Cimatti L, Borderi M, Tschon M, et al
. HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNFalpha activation. J Med Virol 2008; 80:1507–1514.
49. Aiuti A, Turchetto L, Cota M, Cipponi A, Brambilla A, Arcelloni C, et al
. Human CD34+ cells express CXCR4 and its ligand stromal cell derived factor-1. Implications for infection by T-cell tropic human immunodeficiency virus. Blood 1999; 94:62–73.
50. Perfettini JL, Castedo M, Roumier T, Andreau K, Nardacci R, Piacentini M, Kroemer G. Mechanisms of apoptosis induction by the HIV-1 envelope. Cell Death Differ 2005; 12:S916–923.
51. Herbeuval JP, Shearer GM. Are blockers of gp120/CD4 interaction effective inhibitors of HIV-1 immunopathogenesis? AIDS Rev 2006; 8:3–8.
52. Badley AD, Dockrell D, Simpson M, Schut R, Lynch DH, Leibson P, et al
. Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor. J Exp Med 1997; 185:55–64.
53. Alirezaei M, Watry DD, Flynn CF, Kiosses WB, Masliah E, Williams BR, et al
. Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. J Neurosci 2007; 27:11047–11055.
54. Gibellini D, Vitone F, Buzzi M, Schiavone P, De Crignis E, Cicola R, et al
. HIV-1 negatively affects the survival/maturation of cord blood CD34(+) hematopoietic progenitor cells differentiated towards megakaryocytic lineage by HIV-1 gp120/CD4 membrane interaction. J Cell Physiol 2007; 210:315–324.
55. Cotter EJ, Malizia AP, Chew N, Powderly WG, Doran PP. HIV proteins regulate bone marker secretion and transcription factor activity in cultured human osteoblasts with consequent potential implications for osteoblast function and development. AIDS Res Hum Retroviruses 2007; 23:1521–1530.
56. Aukrust P, Haug CJ, Ueland T, Lien E, Müller F, Espevik T, et al
. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab 1999; 84:145–150.
57. Teichmann J, Stephan E, Discher T, Lange U, Federlin K, Stracke H, et al
. Changes in calciotropic hormones and biochemical markers of bone metabolism in patients with human immunodeficiency virus infection. Metabolism 2000; 49:1134–1139.
58. Wang L, Mondal D, La Russa VF, Agrawal KC. Suppression of clonogenic potential of human bone marrow mesenchymal stem cells by HIV Type 1: putative role of HIV type 1 Tat protein and inflammatory cytokines. AIDS Res Hum Retroviruses 2002; 18:917–931.
59. Cotter EJ, Mallon PW, Doran PP. Is PPARγ a prsospective player in HIV-1 associated bone disease? PPAR Res 2009; 2009:1–9.
60. Gibellini D, Borderi M, De Crignis E, Cicola R, Vescini F, Caudarella R, et al
. RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men. J Med Virol 2007; 79:1446–1454.
61. Konishi M, Takahashi K, Yoshimoto E, Uno K, Kasahara K, Mikasa K. Association between osteopenia/osteoporosis and the serum RANKL in HIV-infected patients. AIDS 2005; 19:1240–1241.
62. Mora S, Zamproni I, Cafarelli L, Giacomet V, Erba P, Zuccotti G, et al
. Alterations in circulating osteoimmune factors may be responsible for high bone resorption rate in HIV-infected children and adolescents. AIDS 2007; 21:1129–1135.
63. Fakruddin JM, Laurence J. HIV envelope gp120-mediated regulation of osteoclastogensis via receptor activator of nuclear factor κb ligand (RANKL) decretion and its modulation by certain HIV protease inhibitors through interferon-γ/RANKL cross-talk. J Biol Chem 2003; 278:48251–48258.
64. Fakruddin JM, Laurence J. HIV-1 Vpr enhances production of receptor of activated NF-κB ligand (RANKL) via potentiation of glucocorticoid receptor activity. Arch Virol 2005; 150:67–78.
65. Fakruddin JM, Laurence J. Interactions among HIV-1, interferon γ and receptor of activated NF-kB ligand (RANKL): implications for HIV pathogenesis. Clin Exp Immunol 2004; 137:538–545.
66. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, et al
. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 1990; 345:442–444.
67. Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, et al
. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 2002; 99:1116–1202.
68. Gruber MF, Weih KA, Boone EJ, Smith PD, Clouse KA. Endogenous macrophage CSF production is associated with viral replication in HIV-1-infected human monocytederived macrophages. J Immunol 1995; 154:5528–5535.
69. Kalter DC, Nakamura M, Turpin JA, Baca LM, Hoover DL, Dieffenbach C, et al
. Enhanced HIV replication in macrophage colony stimulating factor treated monocytes. J Immunol 1991; 146:298–306.
70. Bergamini A, Perno CF, Dini L, Capozzi M, Pesce CD, Ventura L, et al
. Macrophage colony-stimulating factor enhances the susceptibility of macrophages to infection by HIV and reduces the activity of compounds that inhibit virus binding. Blood 1994; 84:3405–3412.
71. Wang J, Roderiquez G, Oravecz T, Norcross MA. Cytokine regulation of human immunodeficiency virus type 1 entry and replication in human monocytes/macrophages through modulation of CCR5 expression. J Virol 1998; 72:7642–7647.
72. Haine V, Fischer-Smith T, Rappaport J. M-CSF in the pathogenesis of HIV infection: potential target for therapeutical intervention. J Neuroimmune Pharmacol 2006; 1:32–40.
73. Yamada N, Tsujimura T, Ueda H, Hayashi S, Ohyama H, Okamura H, et al
. Down-regulation of osteoprotegerin production in bone marrow macrophages by macrophage colony-stimulating factor. Cytokine 2005; 31:288–297.
74. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al
. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43:27–34.
75. Martin JL, Brown CE, Matthews-Davis N, Reardon JE. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob Agents Chemother 1994; 38:2743–2749.
76. Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1:417–422.
77. Brinkman K, ter Hofstede HJ, Burger DM, Smeitink JA, Koopmans PP. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12:1735–1744.
78. Walker UA, Setzer B, Venhoff N. Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. AIDS 2002; 16:2165–2173.
79. Boubaker K, Flepp M, Sudre P, Furrer H, Haensel A, Hirschel B, et al
. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin Infect Dis 2001; 33:1931–1937.
80. Moyle GJ, Datta D, Mandalia S, Morlese J, Asboe D, Gazzard BG. Hyperlactatæmia and lactic acidosis during antiretroviral therapy: relevance, reproducibility and possible risk factors. AIDS 2002; 16:1341–1349.
81. Pan G, Wu X, McKenna MA, Feng X, Nagy TR, McDonald JM. AZT enhances osteoclastogenesis and bone loss. AIDS Res Hum Retroviruses 2004; 20:608–620.
82. Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemoter 2002; 46:716–723.
83. Venhoff N, Setzer B, Melkaoui K, Walker UA. Mitochondrial toxicity of tenofovir, emtricitabine and abacavir alone and in combination with additional nucleoside reverse transcriptase inhibitors. Antivir Ther 2007; 12:1075–1085.
84. Tarantal AF, Marthas ML, Shaw JP, Cundy K, Bischofberger N. Administration of 9-(2-(R)-(phosphonomethoxy)propyl) adenine (PMPA) to gravid and infant Rhesus macaques (Macaca mulatta
): safety and efficacy studies. J Acquir Immun Defic Syndr Hum Retrovirol 1999; 20:323–333.
85. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, et al
. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2005; 40:1559–1585.
86. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest 2006; 116:2062–2072.
87. Izzedine H, Hulot JS, Vittecoq D, Gallant JE, Staszewski S, Launay-Vacher V, et al
. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral naïve HIV-1-infected patients. Data from a double-blind randomized active-controlled multicentre study. Nephrol Dial Transplant 2005; 20:743–746.
88. Peyrière H, Reynes J, Rouanet I, Daniel N, Merle de Boever C, Mauboussin JM, et al
. Renal tubular dysfunction associated with tenofovir therapy report of 7 cases. J Acquir Immune Defic Syndr 2004; 35:269–273.
89. Barrios A, Garcia Benayas T, Gonzàlez-Lahoz J, Soriano V. Tenofovir-related nephrotoxicity in HIV-infected patients. AIDS 2004; 18:960–963.
90. Labarga P, Barreiro P, Martin-Carbonero L, Rodriguez-Novoa S, Solera C, Medrano J, et al
. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS 2009; 23:689–696.
91. Parsonage MJ, Wilkins EG, Snowden N, Issa BG, Savage MW. The development of hypophosphataemic osteomalacia with myopathy in two patients with HIV infection receiving tenofovir therapy. HIV Med 2005; 6:341–346.
92. Brim NM, Cu-Uvin S, Hu SL, O'Bell JW. Bone disease and pathologic fractures in a patient with tenofovir-induced Fanconi syndrome. AIDS Read 2007; 17:322–328.
93. Callens S, De Roo A, Colebunders R. Fanconi-like syndrome and rhabdomyolysis in a person with HIV infection on highly active antiretroviral treatment including tenofovir. J Infect 2003; 47:262–263.
94. Creput C, Gonzalez-Canali G, Hill G, Piketty C, Kazatchkine M, Nochy D. Renal lesions in HIV-1–positive patient treated with tenofovir. AIDS 2003; 17:935–937.
95. Rollot F, Nazal EM, Chauvelot-Moachon L, Kelaidi C, Daniel N, Saba M, et al
. Tenofovir-related Fanconi syndrome with nephrogenic diabetes insipidus in a patient with acquired immunodeficiency syndrome: the role of lopinavir-ritonavir-didanosine. Clin Infect Dis 2003; 37:e174–e176.
96. Karras A, Lafaurie M, Furco A, Bourgarit A, Droz D, Seren D, et al
. Tenofovir-related nephrotoxicity in human immunodeficiency virus–infected patients: three cases of renal failure, Fanconi Syndrome, and Nephrogenic Diabetes Insipidus. Clin Infect Dis 2003; 36:1070–1073.
97. Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio An, DeCarlo E, et al
. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics 2005; 116:e846–e854.
98. Jones S, Restrepo D, Kasowitz A, Korenstein D, Wallenstein S, Schneider A, et al
. Risk factors for decreased bone density and effects of HIV on bone in the elderly. Osteoporos Int 2008; 19:913–918.
99. Calmy A, Norris R, Fux C, Vallier N, Samaras K, Hesse K. Osteopenia and proximal renal tubular disease are independently associated with tenofovir therapy. Abstract at XVII IAS International Conference. Mexico City 2008.
100. Guillemi S, Ng F, Zhang W, Lima V, Rocha C, Harris M, et al.
Risk factors for reduced bone mineral density in HIV-infected individuals in the modern HAART era, Abtract poster # 969 at 15th CROI 2008.
101. Buchacz K, Brooks JT, Tong T, Moorman AC, Baker RK, Holmberg SD, et al
. The HIV Outpatient Study (HOPS) Investigators Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy. HIV Medicine 2006; 7:451–456.
102. Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, et al
. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002; 16:1257–1263.
103. Squires K, Pozniak AL, Pierone JG, Steinhart CR, Berger D, Bellos NC, et al
. Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection A Randomized Trial. Ann Intern Med 2003; 139:313–320.
104. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, et al
, 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292:191–201.
105. Izzedine H, Isnard-Bagnis C, Hulot JS, Vittecoq D, Cheng A, Jais CK, et al
. Renal safety of tenofovir in HIV treatment experienced patients. AIDS 2004; 18:1074–1076.
106. Jain RG, Lenhard JM. Select HIV protease inhibitors alter bone and fat metabolism ex vivo
. J Biol Chem 2002; 277:19247–19250.
107. Wong BR, Besser D, Kim N, Arron JR, Vologodskaia M, Hanafusa H, et al
. RANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 1999; 4:1041–1049.
108. Wang MW, Wei S, Faccio R, Takeshita S, Tebas P, Powderly WG, et al
. The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. J Clin Invest 2004; 114:206–213.
109. Malizia A, Cotter E, Chew N, Powderly WG, Doran PP. HIV protease inhibitors selectively induce gene expression alterations associated with reduced calcium deposition in primary human osteoblasts. AIDS Res Hum Retroviruses 2007; 23:243–250.
110. Holick MF. Vitamin D and bone health. J Nutr 1996; 126:1159S–1164S.
111. Whitfield GK, Hsieh JC, Jurutka PW, Selznick SH, Haussler CA, MacDonald PN, et al
. Genomic actions of 1,25-dihydroxyvitamin D3. J Nutr 1995; 125:1690S–1694S.
112. Holick MF. Optimal vitamin D status for the prevention and treatment of osteoporosis. Drugs Aging 2007; 24:1017–1029.
113. Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997; 44:190–194.
114. Von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Duan SX, Fogelman SM, et al
. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol 1998; 38:106–111.
115. Dusso A, Vidal M, Powderly WG, Yarasheski KE, Tebas P. Protease inhibitors inhibit in vitro conversion of 25(OH)-vitamin D to 1,25 (OH)2
-vitamin D. Antiviral Therapy 2000; 6:10–18.
116. Cozzolino M, Vidal M, Arcidiacono MV, Tebas P, Yarasheski KE, Dusso A. HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D. AIDS 2003; 17:513–520.
117. Haug CJ, Aukrust P, Haug E, Mørkrid L, Müller F, Frøland SS. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab 1998; 83:3832–3838.
118. Ramayo E, González-Moreno MP, Macías J, Cruz-Ruíz M, Mira JA, Villar-Rueda AM, et al
. Relationship between osteopenia, free testosterone, and vitamin D metabolite levels in HIV-infected patients with and without highly active antiretroviral therapy. AIDS Res Hum Retroviruses 2005; 21:915–921.
119. Tomazic J, Ul K, Volcansek G, Gorensek S, Pfeifer M, Karner P, Prezelj J, et al
. Prevalence and risk factors for osteopenia/osteoporosis in an HIV-infected male population. Wien Klin Wochenschr 2007; 119:639–646.
120. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 1996; 312:1254–1259.
121. Hans DB, Shepherd JA, Schwartz EN, Reid DM, Blake GM, Fordham JN, et al
. Peripheral dual-energy X-ray absorptiometry in the management of osteoporosis: the 2007 ISCD Official Positions. J Clin Densitom 2008; 11:188–206.
122. Vieth R. Vitamin D Toxicity, Policy, and Science. J Bone Min Res 2007; 22:V64–V68.
123. Welten DC, Kemper HC, Post GB, van Staveren WA. A meta-analysis of the effect of calcium intake on bone mass in young and middle aged females and males. J Nutr 1995; 125:2802–2813.
124. Cumming RG, Nevitt MC. Calcium for prevention of osteoporotic fractures in postmenopausal women. J Bone Miner Res 1997; 12:1321–1329.
125. Prentice A. Diet, nutrition and the prevention of osteoporosis. Public Health Nutr 2004; 7:227–243.
126. Guaraldi G, Orlando G, Madeddu G, Vescini F, Ventura P, Campostrini S, et al
. Alendronate reduces bone resorption in HIV-associated osteopenia/osteoporosis. HIV Clin Trials 2004; 5:269–277.
127. Mondy K, Powderly WG, Claxton SA, Yarasheski KH, Royal M, Stoneman JS, et al
. Alendronate, vitamin D, and calcium for the treatment of osteopenia/osteoporosis associated with HIV infection. J Acquir Immune Defic Syndr 2005; 38:426–431.
128. Negredo E, Martínez-López E, Paredes R, Rosales J, Pérez-Alvarez N, Holgado S, et al
. Reversal of HIV-1-associated osteoporosis with once-weekly alendronate. AIDS 2005; 19:343–345.
129. McComsey GA, Kendall MA, Tebas P, Swindells S, Hogg E, Alston-Smith B, et al
. Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV. AIDS 2007; 21:2473–2482.
130. Bolland MJ, Grey AB, Horne AM, Briggs SE, Thomas MG, Ellis-Pegler RB, et al
. Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial. J Clin Endocrinol Metab 2007; 92:1283–1288.
131. Huang J, Meixner L, Fernandez S, McCutchan JA. A double-blinded, randomized controlled trial of zoledronate therapy for HIV-associated osteopenia and osteoporosis. AIDS 2009; 23:51–57.
132. Ott S. Long-term safety of biphosphonates. J Clin Endocrinol Metab 2005; 90:1897–1899.
133. Roux S. RANKL inhibitors: a bright future? Joint Bone Spine 2006; 73:129–131.
134. McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al
, AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354:821–831.
135. De Crignis E, Cimatti L, Borderi M, Gibellini D, Re MC. Bone alterations during HIV infection. New Microbiol 2008; 31:155–164.
136. Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 1989; 149:2445–2448.
137. Meunier PJ, Delmas PD, Eastell R, McClung MR, Papapoulos S, Rizzoli R, et al
. Diagnosis and management of osteoporosis in postmenopausal women: clinical guidelines. International Committee for Osteoporosis Clinical Guidelines. Clin Ther 1999; 21:1025–1044.
This article has been cited 9 time(s).
Malawi Medical Journal
Case Report: A man on antiretroviral therapy with painful thighs
Malawi Medical Journal, 25(1):
Bmc MedicineSmoking and HIV: time for a change?Bmc Medicine
International Journal of Std & AIDSEndocrine and metabolic abnormalities among HIV-infected patients: A current reviewInternational Journal of Std & AIDS
Analysis of the effects of specific protease inhibitors on OPG/RANKL regulation in an osteoblast-like cell line
New Microbiologica, 33(2):
Experimental Cell ResearchBone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injuryExperimental Cell Research
Journal of Orthopaedic ResearchHIV-1 Protein Induced Modulation of Primary Human Osteoblast Differentiation and Function Via a Wnt/beta-Catenin-Dependent MechanismJournal of Orthopaedic Research
Journal of Translational MedicineAssociation between peripheral T-Lymphocyte activation and impaired bone mineral density in HIV-infected patientsJournal of Translational Medicine
Bmc Infectious DiseasesEarly loss of bone mineral density is correlated with a gain of fat mass in patients starting a protease inhibitor containing regimen: the prospective Lipotrip studyBmc Infectious Diseases
Journal of Antimicrobial ChemotherapySafety and feasibility of treatment simplification to atazanavir/ritonavirlamivudine in HIV-infected patients on stable treatment with two nucleos(t)ide reverse transcriptase inhibitorsatazanavir/ritonavir with virological suppression (Atazanavir and Lamivudine for treatment Simplification, AtLaS pilot study)Journal of Antimicrobial Chemotherapy
bone; HAART; HIV; osteoblasts; osteoclasts
© 2009 Lippincott Williams & Wilkins, Inc.
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Highlight selected keywords in the article text.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read