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HIV Infection-A Risk Factor for Osteoporosis
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JAIDS Journal of Acquired Immune Deficiency Syndromes July 2003; 33(3):281-291
Joegi Thomas; Sheelagh M. Doherty. Centre for Metabolic Bone Disease, Hull & East Yorkshire Hospitals NHS Trust & Hull University, Kingston Upon Hull, United Kingdom
".....The underlying mechanism triggering bone mineral loss in patients with HIV infection is unknown...... The results of the various studies suggest that bone demineralization is a feature of HIV infection before, as well as during, HAART.... a causal relationship has not yet been proved.....The abnormalities in bone and mineral metabolism associated with HIV infection may be caused by direct invasion of the cells of the bone and bone marrow microenvironment, chronic T-cell activation and abnormal cytokine production affecting osteoblast and osteoclast functions, disturbances of calcium homeostasis, parathyroid hormone (PTH) functions, vitamin D metabolism, opportunistic or neoplastic diseases, and adverse effects of drugs..... There are no data yet available showing that reduced BMD translates into an increased risk of fracture in HIV-positive individuals. This may be because most patients are young and do not have any risk factors for falls..... Patients with advanced disease, prolonged duration of HIV infection, and PI therapy should be considered for DXA imaging. In addition, patients with known predisposing risk factors for osteoporosis (ie, patients with corticosteroid treatment, family history of osteoporosis, history of excessive alcohol consumption, history of low-trauma fractures, and hypogonadism and women with premature menopause and maternal history of hip fractures) should be referred for DXA assessment...... All patients found to have a low BMD should be given lifestyle advice on a high-calcium diet (1500 mg/d), weight-bearing exercise, avoidance of smoking, and only moderate consumption of alcohol. Scanning should be repeated in 2 years.... As the number and life expectancy of HIV-positive patients currently treated with potent antiretroviral therapy increase, the development of osteoporosis should be taken into consideration in the long-term management of HIV disease."
Summary:
Osteopenia and osteoporosis have recently been described as complications of antiretroviral therapy in HIV-infected patients. The advent of highly active antiretroviral therapy in conjunction with improved standard antiviral and
antibiotic regimens has dramatically changed the clinical course of HIV infection, resulting in prolonged survival. The pathogenesis and role of each individual medication are poorly understood. Avascular necrosis has also been
described in AIDS patients receiving or not receiving antiretroviral therapy. This article is a clinically focused review of the literature on osteopenia, osteoporosis, and mineral metabolism related to HIV infection. In patients with HIV infection, the risks of osteopenia and osteoporosis are not very clear. The suggested risk factors for the development of osteopenia are use of protease inhibitors, longer duration of HIV infection, high viral load, high lactate levels, low bicarbonate levels, raised alkaline phosphatase level, and lower body weight before antiretroviral therapy. There have also been a few case reports of pathologic fractures in AIDS patients with antiretroviral therapy-induced osteopenia and osteoporosis. The underlying mechanism triggering bone loss in HIV-infected patients is unknown. The proinflammatory cytokines tumor necrosis factor and interleukin-6 have been found to be constitutionally produced in increased amounts in HIV-positive individuals, and they may have a role in osteoclast activation and resorption. Serum markers of bone formation are decreased and resorption is increased in patients with advanced clinical disease. Hypocalcemia, hypercalcemia, and abnormalities of the parathyroid hormone axis have been described in HIV infection. Histomorphometric analyses have shown altered bone remodeling in HIV-infected patients when compared with controls. Patients with known risk factors for osteoporosis-advancing age, low body weight, and prolonged duration of HIV infection-and those receiving protease inhibitor treatment should be considered for dual x-ray absorptiometry imaging. If bone mineral density is osteopenic or osteoporotic, then the patient should also be screened for other known medical causes of osteoporosis and consider treatment with a bisphosphonate or, if hypogonadal, testosterone replacement under close monitoring.
Osteoporosis is a common disorder of bone that results in significant morbidity, mortality, and health care expenditures. It is characterized by severe loss of bone mass and disruption of skeletal microarchitecture that, in turn, lead to increased risk of spontaneous and traumatic fractures of the bones. Osteopenia refers to a thinning of bone that can precede osteoporosis.
Gradual demineralization of bone is a normal feature of aging. Men and women naturally begin to lose bone at around the age of 35, at a rate of 0.5% to 1% per year. Women lose bone at an accelerated rate after menopause. The most widely used method to measure bone density uses dual energy x-ray absorptiometry (DXA). For bone mineral density (BMD) measurements to be clinically useful, they need to be expressed in comparison with established normative data. All BMD measurement device manufacturers provide normative databases for this purpose. These databases are derived from measurements of large groups of both men and women of different ages and races. Comparisons are expressed both as the percentage of age-matched and young normal values and as SD scores (ie, the SD from the expected normal values). The age-matched SD score is commonly referred to as the z score, whereas the young normal SD score has been labeled the t score. The age-matched or z score is calculated as the difference between the patient's BMD and the normal BMD for those of the same age, sex, and race (age-matched normal) divided by the SD of the normal population. This is calculated by DXA system using the following equation: z score = BMD - age-matched normal/SD. The young normal or t score is defined in a similar fashion except the BMD difference is expressed in terms of the young normal BMD: t score = BMD - young normal/SD.
According to the WHO classification, osteoporosis is defined as a t score less than -2.5, and osteopenia is defined as a t score between -1 and -2.5. Established osteoporosis denotes a t score less than -2.5 in the presence of >1 fragility fractures.
Bone turnover is characterized by two opposite activities: the formation of new bone by osteoblasts and the degradation (resorption) of old bone by osteoclasts. The rate of formation or degradation of bone matrix can be assessed either by measuring an enzymatic activity of the bone-forming or -resorbing cells, such as alkaline phosphatase, or by measuring bone matrix components released into the circulation during formation or resorption.
These have been separated into markers of formation and resorption. In osteoporosis, bone turnover markers have been suggested to predict the rate of bone loss, to predict the occurrence of osteoporotic fractures, and to monitor the efficacy of treatment.
Many risk factors have been identified for osteoporosis, and the main clinical indications for bone densitometry are presence of strong risk factors like premature menopause (<45 years), prolonged secondary amenorrhea (abnormal suppression or absence of menstruation), primary hypogonadism, corticosteroid therapy (>7.5 mg/d for [ge]1 year), anorexia nervosa, excessive alcohol consumption, malabsorption, primary hyperparathyroidism, organ transplantation, chronic renal failure, myelomatosis, hyperthyroidism, prolonged immobilization, radiologic evidence of osteopenia or vertebral deformity, previous fragility fracture, and maternal history of hip fracture. (Note: if I recall properly elevated lipids are also a risk factor or associated with bone loss).
HIV infects many cell types in the body leading to diverse immunologic and metabolic effects. Much attention has been paid to emerging complications of HIV infection in patients receiving potent antiretroviral therapy. The main
focus has been on metabolic problems associated with cardiovascular disease such as insulin resistance, hyperlipidemia, and fat redistribution. However, with the increasing life expectancy conferred by the new therapies, there is also an emerging increase in the risk of bone pathologies. The main issues are apparent increased rate of osteonecrosis and increased risk of developing osteopenia and osteoporosis. Decreased physical activity, prolonged bed rest associated with chronic illness, severe weight loss, malnutrition, disruption of the parathyroid hormone axis, and hypogonadism, which are all recognized risk factors for osteoporosis in men, are all common features in advanced HIV infection.
METHODS
MEDLINE (January 1980 to October 2002), the Cochrane Library, and the Database of Systematic Reviews (4th Quarter 2002) were searched using the following key words: HIV, osteopenia, osteoporosis, bone, and osteonecrosis. A manual search for additional studies was performed using the bibliographies of the reports and reviews located. In addition, abstracts presented at the Conference on Retroviruses and Opportunistic Infections were also included. No systematic review was found on the specific topic of HIV and osteoporosis.
CLINICAL FINDINGS
Evidence Before Introduction of Highly Active Antiretroviral Therapy
Bone Density
Osteopenia and osteoporosis have recently been recognized as new complications affecting HIV-positive patients. Before the availability of protease inhibitors (PIs), low BMD was rarely observed in HIV-infected individuals. Data on BMD in HIV-positive patients before the advent of highly active antiretroviral therapy (HAART) are limited.
In a study by Paton et al. who followed 45 HIV-infected men (mean age, 36 years) for 15 months in comparison with age- and sex-matched controls, only a minor reduction in BMD of 3% at the lumbar spine was seen, and they found no significant loss in total body and hip BMD. Two similar studies that involved 22 and 16 HIV-infected patients (mean ages of 28 years4 and 29 years5) reported no significant difference in BMD when compared with age- and sex-matched controls.
Histomorphometry
Infection of osteoblasts by HIV has been documented in vitro, and the virus has also been detected in bone taken at autopsy from patients who died of AIDS. There are few data on histomorphometric analyses of bone remodeling in patients with HIV infection. Serrano et al. assessed bone histomorphometry for 22 HIV-positive patients with normal BMD and observed that trabecular separation, osteoid volume, osteoid thickness, osteoclast number, bone
formation rate, wall thickness, and activation frequency were significantly lower in patients than in controls. In contrast, the formation period and remodeling period were significantly higher in patients than in controls. Most of
the histomorphometric parameters were found to be more altered in patients who presented with greater disease severity according to the Centers for Disease Control and Prevention's classification.
Bone Turnover
Bone mass may be considered the net result of two opposing metabolic processes: bone formation and bone resorption. Bone markers are the ideal tools to detect the dynamics of metabolic imbalance but are currently used only in specialized centers for research, although they have been commercially available in kits for nearly 10 years. They are likely to be used in the future for monitoring response to therapy. One main disadvantage is that laboratory assays of these bone turnover markers are very expensive. These biochemical markers of bone turnover can help identify patients with rapid turnover, monitor response to therapy, and encourage compliance with therapy. The bone formation markers commonly assayed in the laboratory are serum osteocalcin and bone-specific alkaline phosphatase. A significant increase in formation markers means an increase in osteoblastic activity and increased bone formation. The resorption markers now commonly assayed in the laboratory are the C-terminal telopeptide of type 1 collagen and the N-terminal telopeptide of type 1 collagen. A significant increase in resorption markers means an increase in osteoclastic activity and loss of bone mass.
There are few data on bone markers before the advent of HAART. A small study involving 16 HIV-positive patients reported low serum osteocalcin levels and urinary calcium/creatine ratio compared with 27 healthy controls. This
study also found that these changes seemed to appear soon after infection, as osteocalcin levels were markedly decreased in patients with a history of HIV infection of <24 months; in addition, the study failed to show any direct
correlation between serum osteocalcin level and CD4 cell count. Serrano et al. also found lower serum levels of osteocalcin in 22 HIV-positive patients compared with controls.
Fractures
There are no data showing that reduced BMD leads to an increased risk of fracture in HIV-positive individuals, which may become evident with increasing survival and longevity. This may be because most patients are young and
do not have any risk factors for falls. There have been two case reports of fragility fractures in AIDS patients with antiretroviral therapy-induced osteoporosis and osteopenia.
Clinical Evidence After the Introduction of HAART
Bone Density
The available data on BMD studies after the introduction of HAART are much more contradictory than those from before this era. The variety and complexity of changes in bone metabolism in patients with HIV infection and the different pathomechanisms leading to changes in bone mass, as well as the different stages of disease at the time of clinical investigation, may contribute to the contradictory data on BMD measurements in HIV-infected patients after HAART.
There are few published data on BMD in the post-HAART era, and most of the available data are from studies of men. These studies concluded that subjects treated with PIs were more at risk for osteoporosis, but HIV infection as such is also a risk factor for reduced BMD. There are reports from several unpublished
longitudinal and cross-sectional studies presented at conferences that also confirmed the risk of low BMD with HIV infection and HAART use. There are also reports of impaired fasting glucose levels in PI-treated groups contributing to low BMD and absence of bone loss with HAART in an Asian population. We await confirmation of these findings in published studies.
Published Studies
Tebas et al., who conducted a cross-sectional analysis of whole-body, lumbar spine, and proximal femur BMD in 112 male subjects (including HIV-infected patients receiving HAART with a PI, HIV-infected patients not treated with a PI, and healthy seronegative adults), found that men treated with PIs had a higher incidence of osteopenia and osteoporosis. Using lumbar spine BMD t scores, 50% of the subjects treated with PIs were classified as osteopenic or osteoporotic according to the WHO criteria. Only 6% of the controls and 11% of the HIV-infected patients not treated with PIs were classified as osteoporotic using the same criteria.
In another study by Carr et al. that involved 221 men treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs), PIs, and a combination of both, with and without lipodystrophy, found that 23% of the study group had reduced total body BMD, with 20% being osteopenic and 3% being osteoporotic. They found that patients with osteopenia or osteoporosis had longer duration of both HIV infection and stavudine therapy, higher HIV load and lactate level, low bicarbonate level, raised alkaline phosphatase level, and disordered lactic acid metabolism. The reduced BMD group also had more lipoatrophy, lower body weight before antiretroviral therapy, and lower current weight, lean body mass, and total fat mass. Their study concluded that the only parameters independently associated with osteopenia or osteoporosis were higher lactate level and lower weight before commencing antiretroviral therapy.
Fairfield et al., in a study of osteopenia in 54 eugonadal men with AIDS, found that lumbar spine as well as hip BMD was lower in eugonadal men with the AIDS wasting syndrome, and this reduced BMD was independent of PI use. Moorea et al.15 looked at BMD in 105 HIV-positive patients; they found the prevalence of reduced BMD to be 71%, and it was higher among patients treated with PIs.
Nolan et al. studied the factors contributing to changes in BMD over time in HIV-infected patients receiving HAART. They analyzed lumbar spine BMD in 183 white male participants and found no evidence of accelerated bone loss in patients treated with nelfinavir- or indinavir-containing HAART regimens; these investigators suggested that indinavir therapy might be associated with an increase in BMD over time. This is the only study to report an increase in BMD with HAART. On the contrary, Gold et al. failed to show any effect on BMD with indinavir use.
In one case-control study comparing 47 HIV-infected patients and sex-matched controls, BMD was lower in patients than in controls. There was a statistically significant difference in the spine and hip BMD between male cases and controls, whereas it was statistically significant only at the spine in women. This study concluded that HIV-infected men are more likely to have osteoporosis and osteopenia, but it failed to show any evidence supporting a relationship between bone loss and PI use.
Conference Proceedings
The incidence of osteoporosis and osteopenia is higher among HIV-infected patients treated with PIs than those treated with NRTIs or controls. An impaired fasting glucose level also correlated with reduced BMD in HIV-infected patients treated with PIs. Osteoporosis and osteopenia were more common in HIV-infected patients than in controls, and cortical bone is more affected than trabecular bone. Both HAART-treated and HAART-naive patients had low BMD compared with controls, but osteoporosis and osteopenia were more severe in
the HAART-treated group. Osteopenia is a feature of HIV infection before and after HAART. The incidence of osteopenia and that of osteoporosis were not different among HAART-treated, HAART-naive, and healthy adults in an Asian study.
The results of the post-HAART studies suggest that bone demineralization is a feature of HIV infection before as well as during HAART. This is in contradiction to findings of BMD studies before the era of HAART and may be because of the short duration of these studies and small sample sizes. Most of these studies involved white populations, and there are few studies on other populations.
Potential Relationship Between Lipodystrophy and Bone Loss
Body composition indexes have been found to be strong predictors of bone density in previous studies of women. Historically, HIV infection has been thought to affect body composition primarily through loss of lean body mass.
As the use of HAART became widespread, many patients reported a new phenomenon of fat redistribution, with central adiposity often accompanied by a peripheral loss of subcutaneous fat. McDermott et al. compared total and regional body composition, as measured by DXA, in 203 HIV-positive men and 62 HIV-positive women according to HAART and concluded that HAART is associated with redistribution of fat mass from the legs to the trunk, despite no significant differences in total fat mass or weight. In men, HAART was also associated with a reduction in bone mineral content, suggesting that HAART increases the risk of central obesity and osteoporosis. Huang et al. investigated bone density at multiple sites in a group of women with AIDS wasting and found
significant sarcopenia and bone loss in this group of patients compared with healthy age-matched and body mass index-matched controls. Amiel et al. also demonstrated that the association between reduced lumbar spine bone density and reduced muscle mass remained significant, controlling for other known predictors of bone density. Lipodystrophy was present in 89% of patients treated with PIs, 74% of patients treated without PIs, and 4% of untreated patients.
Fractures
There are no data showing that reduced BMD leads to an increased risk of fracture in HIV-positive individuals. There are case reports of pathologic fractures in AIDS patients with antiretroviral therapy-induced osteopenia and
osteoporosis. Guaraldi et al. reported two cases of antiretroviral therapy-induced osteopenia and osteoporosis,which later caused pathologic fracture after trivial trauma. One patient was a 49-year-old man receiving HAART who
fractured a rib, and subsequent DXA documented osteopenia. The other patient was a 51-year-old man also receiving HAART who sustained a fracture of the first lumbar vertebra following trivial trauma, and DXA showed evidence of
osteoporosis.
Stephens et al. described two cases of symptomatic osteoporosis in young HIV-positive black women receiving HAART (aged 29 and 33) who both presented with sudden onset severe lumbar back pain. BMD in both these patients showed gross osteoporosis of the spine.
Mechanism of Bone Mineral Loss
The underlying mechanism triggering bone mineral loss in patients with HIV infection is unknown. The abnormalities in bone and mineral metabolism associated with HIV infection may be caused by direct invasion of the
cells of the bone and bone marrow microenvironment, chronic T-cell activation and abnormal cytokine production affecting osteoblast and osteoclast functions, disturbances of calcium homeostasis, parathyroid hormone (PTH)
functions, vitamin D metabolism, opportunistic or neoplastic diseases, and adverse effects of drugs. Systemic activation of T cells in vivo leads to an osteoprotegerin ligand-mediated increase in osteoclastogenesis and bone
loss. There are many factors in HIV disease that might be expected to result in decreased BMD. The proinflammatory cytokines tumor necrosis factor and interleukin-6 have been found to be constitutionally produced in increased amounts in HIV-positive individuals, and these cytokines may have a role in osteoclast activation and bone resorption. Lactic acidosis has been postulated as a cause of osteopenia. Lendru et al. reported that cytokine dysregulation may persist during HAART, with excess expression of tumor necrosis factor-[alpha] in circulating mononuclear cells. The effect of chronic illness on the hypothalamic-pituitary-adrenal axis may also contribute to bone demineralization, as decreased insulin like growth factor-1 and increased corticosteroid levels have been found in HIV infectin. Growth hormone levels are elevated and serum insulin like growth factor-1 responses to growth hormone are decreased in men with AIDS-related wasting, suggesting a pattern of acquired growth hormone resistance similar to that seen in non-HIV-infected patients with protein calorie malnutrition.
One postulated mechanism for bone demineralization is through PI inhibition of the hepatic p450 enzyme that also mediates vitamin D to its most potent circulating metabolite, part of an essential process for vitamin D control of
calcium homeostasis. In vitro studies were run in the human monocyte-macrophage cell line THP-1, which expresses a 1[alpha]-hydroxylase identical to the renal enzyme responsible for the final formation of bioactive 1,25-dihydroxy-cacholecalciferol (OH)2-vitamin D. The level of inhibition of the most active metabolite in this cell line by the three PIs studied was 80% by ritonavir, 66% by indinavir, and 32% by nelfinavir. This may only be one of several mechanisms that affect multiple steps of a very delicate metabolic balance.
Osteoporosis has been linked to mitochondrial deletions in young HIV-uninfected males with no other clinical features of mitochondrial disease, although some had asymptomatic lactic acidemia. Claxton et al. failed to
show any association with circulating leptin, lactate, and osteopenia in HIV-infected men.
Lactic acidemia is a well-described mitochondrial toxicity of NRTI therapy for HIV infection. Infection of osteogenic cells by HIV has been documented in vitro, and the virus has also been detected in bone taken at autopsy from patients who died of AIDS. In addition to the potential effects on skeletal homeostasis that might result directly from HIV infection of osteogenic cells, there are several indirect ways in which the infection might cause
osteoporosis. Decreased physical activity, prolonged bed rest associated with chronic illness, severe weight loss, disruption of the PTH axis, malnutrition, and hypogonadism are all recognized risk factors for osteoporosis in men
and are all common features in advanced HIV infection.
The mechanism of bone loss in HIV infection is complex. Cytokines, acquired growth hormone resistance, decreased insulin like growth factor-1, vitamin D dysregulation, increased corticosteroid levels, and abnormalities of
lactic acid metabolism have all been attributed to the mechanism of bone loss in HIV infection. However, at the end, whether they are merely associative markers or causation is really unknown. There are few interventional studies
testing for their causality. Treatment with growth hormone and anabolic steroids failed to show any significant difference in bone mineral content in these patients. More interventional studies are needed in the future to
elucidate the mechanism of bone loss in these subjects.
Biochemical Markers of Bone Metabolism in HIV-Positive Patients
Aukrust et al. looked at serum and urine markers in 73 HIV-positive patients receiving antiretroviral therapy and found that patients with advanced clinical and immunologic disease and high viral loads were characterized by increased C-telopeptide and depressed osteocalcin levels. These abnormalities, indicating disturbed bone remodeling in HIV infection, were significantly correlated with increased activity of TNF system. HAART reduced serum tumor necrosis factor-[alpha] levels and increased serum osteocalcin levels in excess of normal controls, whereas serum C-telopeptide levels remained in the high normal range. An elevated serum osteocalcin level indicates that bone cell turnover was accelerated after HAART was initiated, but it is not direct proof that bone density was altered. Collectively, these findings suggest that HAART may increase bone cell turnover.
Osteocalcin levels were lower in the advanced stage of the disease and were positively correlated with CD4 lymphocyte counts. Teichmann et al. performed a cross-sectional study of 100 patients with proven HIV infection, which looked into the changes in calciotropic hormones and biochemical markers of bone metabolism. They measured bone markers in serum and urine and found significantly lower concentrations of osteocalcin, indicating a reduced bone formation rate whose severity showed a significant correlation with the progressive loss of CD4 helper cells. Increased urinary excretion of cross-links was also significantly correlated with the loss of CD4 helper cells. They concluded that the changes in bone metabolism are mainly due to mechanisms of the impaired immune defense of HIV-infected patients.
Fairfield et al. reported lower levels of serum osteocalcin levels and increased urinary levels of N-telopeptide and deoxypyridinoline in 54 men with AIDS wasting illness compared with controls. Serum osteocalcin levels did not
change in response to testosterone in this study. Androgen receptors are present on osteoblasts, but the effect of androgens on bone markers is complex.
O'Brien et al. examined calcium status and bone growth in children; they measured calciotropic hormones, urinary calcium excretion, bone mineral content, and body composition in 19 young girls who were infected perinatally with HIV. They found that serum concentrations of 1,25-(OH)2-vitamin D3, PTH, and urinary calcium excretion normalized for creatinine excretion were elevated above normal ranges in 25%, 12%, and 17% of these girls, respectively. They also found significant positive correlation between urinary N-Tx and 1,25-(OH)2-vitamin D3 and between serum N-Tx and total alkaline phosphatase, suggesting that calcium insufficiency may be increasing bone resorption in this group. Huang et al.31 in a study of women with AIDS wasting who were both eumenorrheic and amenorrheic and between 18 and 45 years of age demonstrated increased N-Tx levels but no difference in osteocalcin levels.
One longitudinal study18 that followed HIV-positive patients for 48 weeks (85% males and 65% taking PIs) reported no association with any antiretroviral class, and patients as a group had evidence of high bone turnover. There was
no significant change in markers of bone formation and resorption during the 48-week period of follow-up.
The results of the various studies on bone markers in HIV infection, both before and after the introduction of HAART, suggest that bone turnover is increased in these patients, irrespective of whether they are receiving any specific treatment or not. Increase in osteocalcin levels after HAART is also further evidence that bone turnover is increased in these patients.34, 44
Osteonecrosis
Osteonecrosis, also termed avascular necrosis (AVN), denotes ischemic death of the cellular constituents of bone. Risk factors for nontraumatic osteonecrosis include sickle-cell disease, Gaucher disease, collagen vascular disease,
pancreatitis, alcoholism, irradiation, hyperlipidemia, and corticosteroid use.66 Over the past decade, multiple case reports have suggested an association between HIV infection and osteonecrosis. Recent reports suggest that the
incidence of osteonecrosis among HIV-infected patients may be increasing68; however, it is unclear whether this increase is due to greater recognition of the entity, prolonged patient survival owing to potent antiretroviral therapy,
or direct or indirect adverse effects of newer antiretroviral agents. Glesby et al. found an association between corticosteroid use and osteonecrosis that was independent of HIV disease stage and PI therapy. Belmonte et al. suggested a possible association between the presence of antiphospholipid antibodies and AVN in patients with HIV infection. These antibodies have been described in a high proportion of patients with HIV infection. Musculoskeletal pain is common in persons with HIV infection, and clinicians should be aware of the possible
association between AVN and HIV infection and maintain a high index of suspicion for AVN in HIV-infected patients with unexplained bone pain.
Advances in magnetic resonance imaging have made earlier diagnoses of AVN possible, allowing determination of the exact stage and extent of the pathologic process without use of invasive methods. The commonest site for
osteonecrosis is the femoral head. No treatment method has proved to be effective in arresting the disease process before subchondral collapse or in slowing the progression of femoral head destruction and osteoarthritis after
subchondral collapse. Conservative treatment-such as crutch ambulation or bed rest-generally is ineffective. The surgical treatment modalities available for AVN are core decompression, bone grafting, vascularized fibular grafting,
and intertrochanteric osteotomies of the proximal femur.
PTH, Vitamin D, and Calcium Balance in HIV Infection
The leading cause of hypocalcemia in HIV infection is decreased production and action of 1,25-(OH)2-vitamin D3. In HIV-infected patients, serum levels of 1,25-(OH)2-vitamin D3 are markedly low with normal levels of 25-(OH)-vitamin D3 and vitamin D binding protein, suggesting impaired 1[alpha]-hydroxylation as its primary cause. Advanced disease stage and increased serum levels of tumor necrosis factor-[alpha] were also associated with 1,25-(OH)2-vitamin D3 deficiency. Frank hypocalcemia is uncommon in HIV infection, but mild
hypocalcemia was observed in a group of patients with HIV infection.75 The causes of HIV-related hypocalcemia include vitamin D deficiency, inadequate PTH response despite hypocalcemia, overt hypoparathyroidism, hypomagnesemia, and secondary hyperparathyroidism. Severe hypocalcemia reported in HIV infection is usually drug related. The most common agent associated with severe hypocalcemia in HIV infection is foscarnet, which is used to treat cytomegalovirus infection. It is usually caused by a combination of nephrotoxicity causing renal wasting of calcium and magnesium, and foscarnet, being a phosphate analogue, results in the formation of a complex with calcium and thus reduces serum ionized calcium levels.80 Hypocalcemia has also been described in 10% of patients receiving trimethoprim-sulfamethoxazole and in 15% of patients receiving pentamidine for Pneumocystis jiroveci pneumonia. Other drugs associated with hypocalcemia in HIV-infected subjects are ketoconazole and aminoglycosides.
Peter et al. demonstrated hypercalcemia in 2.9% of patients. Hypercalcemia in HIV-infected patients can be drug induced or can be caused by infections with granulomatous or neoplastic origin. Infections associated with hypercalcemia in HIV-positive patients include those due to cytomegalovirus, P jiroveci, Mycobacterium avium-intercellulare, Cryptococcus neoformans, and Coccidioides immitis. Hypercalcemia in protozoal, fungal, and mycobacterial infections may result from extrarenal 1[alpha]-hydroxylation of 25-(OH)-vitamin D3 by macrophages, monocytes, epithelioid cells, and multinucleated giant cells.
Hypercalcemia in cytomegalovirus infection is presumed to be the result of direct osteoclastic activation by activated T cells or proinflammatory cytokines. The use of recombinant human growth hormone for HIV-associated
wasting was associated with a slight increase in serum concentrations of total calcium. The possible mechanism for the rise in serum calcium levels includes increased intestinal absorption of calcium through induction of calcium-binding protein91 and increased PTH secretion.
PTH axis may be functionally impaired in HIV infection. The causes include infections, neoplasms, impaired secretion of PTH at baseline and after provocation, and PTH resistance. Parathyroid cells express receptors with structural similarity to the CD4 molecule that act as a cellular receptor for HIV, facilitating access of the virus to immune cells. This might explain the reason for symptomatic hypoparathyroidism as a clinical manifestation of HIV infection when the virus load is high and the immune system is intact. Levels of serum PTH are significantly lower in patients with HIV infection than in normal controls.
Clinical Management
There are no data yet available showing that reduced BMD translates into an increased risk of fracture in HIV-positive individuals. This may be because most patients are young and do not have any risk factors for falls. The results of
the above-mentioned studies show that screening for reduced BMD in the HIV-positive population cannot be justified unless additional risk factors are present, as most patients are asymptomatic. The clinical significance of reduced BMD in this group of patients is uncertain. Early knowledge of this diagnosis may be harmful to patients who already have to cope with a chronic, incurable condition. One large multicenter study reported no beneficial impact on BMD from withdrawal of PI therapy.
Guaraldi et al. reported a case of antiretroviral therapy-induced osteoporosis presenting with spinal fractures and a baseline lumbar spine BMD of 0.691 g/cm2 (t score, -3.85). Six months of treatment with alendronate, along with
calcium and vitamin D, produced a 20% increase in lumbar spine BMD; this treatment had to be discontinued as the patient developed lactic acidosis.
Lawal et al. looked at bone mineral content in 12 HIV-infected men treated with recombinant human growth hormone for lipodystrophy and failed to show any significant difference in total bone mineral content in HIV-infected
subjects after 24 weeks of treatment with growth hormone. Treatment with the anabolic steroid oxandrolone failed to show any significant increase in total bone mineral content after 24 weeks in malnourished HIV-positive patients.
Lumbar spine BMD increased with short-term high-dose testosterone therapy for eugonadal osteopenic men with AIDS wasting syndrome.14 Most prior studies examined the effect of testosterone replacement on BMD in
hypogonadal men. Whereas increases in BMD are probably beneficial, serum high-density lipoprotein cholesterol levels decreased in response to high-dose testosterone administration in men.100 Therefore, any recommendation to
administer testosterone to improve BMD in eugonadal men with AIDS wasting must be made with caution, as the long-term effects of testosterone therapy on other metabolic and cardiovascular parameters remain unknown.
The effect of alendronate on BMD in HIV-infected patients with osteoporosis has not been evaluated. On the other hand, no approved treatment exists for osteoporosis that develops secondary to antiretroviral therapy. Clinical trials
are needed to study the effect of bone active treatment on HIV-infected patients with metabolic bone disease and also the safety of these drugs in combination with HAART.
Patients with advanced disease, prolonged duration of HIV infection, and PI therapy should be considered for DXA imaging. In addition, patients with known predisposing risk factors for osteoporosis (ie, patients with corticosteroid treatment, family history of osteoporosis, history of excessive alcohol consumption, history of low-trauma fractures, and hypogonadism and women with premature menopause and maternal history of hip fractures) should be referred for DXA assessment. If BMD is osteopenic or osteoporotic, the patient should also be screened for other known medical causes of osteoporosis with biochemical profile analysis including testing for urea and electrolytes, liver function, calcium levels, PTH, vitamin D levels, and antigliadin and endomyoseal antibodies. In addition, serum testosterone, sex hormone-binding globulin, and free androgen index should be measured in men, and follicle-stimulating hormone, luteinizing hormone, and estradiol should be measured in
women.
All patients found to have a low BMD should be given lifestyle advice on a high-calcium diet (1500 mg/d), weight-bearing exercise, avoidance of smoking, and only moderate consumption of alcohol. Scanning should be repeated in 2 years. If BMD is osteoporotic, consider treatment with a bisphosphonate or, if hypogonadal, testosterone replacement. If dietary intake of calcium is inadequate, supplementation with calcium and vitamin D should be considered in these patients.
CONCLUSION
Osteopenia and osteoporosis are newly recognized complications affecting HIV-positive patients, and the etiology and pathogenesis of osteoporosis in HIV infection are uncertain. The results of the various studies suggest that bone
demineralization is a feature of HIV infection before, as well as during, HAART. Antiretroviral therapy has been linked in cohort studies to the development of osteopenia and osteoporosis; however, a causal relationship has not yet been proved. In the absence of HIV infection, bone demineralization is multifactorial in development, and HIV-related and -unrelated factors may play a role in osteopenia in these subjects. Further studies are needed to look into the natural history of bone loss in HIV disease as well as to understand the mechanisms of uncoupled bone turnover and the effects of PI therapy on HIV-infected patients. As the number and life expectancy of HIV-positive
patients currently treated with potent antiretroviral therapy increase, the development of osteoporosis should be taken into consideration in the long-term management of HIV disease.
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