HIV/AIDS and bone: an unrecognised threat?

Abstract

Since the first isolated cases of acquired immunodeficiency syndrome (AIDS) was described in homosexual men in the United States in 1981, the Human Immunodeficiency Virus (HIV) infection has spread globally affecting 33 million people. With the advent of highly active antiretroviral therapy (HAART) there has been a paradigm shift in the clinical profile of patients with HIV. Prior to effective HAART, patients usually had a progressive fatal course characterised by recurrent opportunistic infections. Since the introduction of HAART, which has dramatically improved these patients survival, conditions associated with accelerated aging, have come to the fore, especially cardiovascular disease, malignancy, diabetes mellitus and metabolic bone disease. The aim of this review is to increase the knowledge of HIV associated metabolic bone disease, alert health care providers of the possible bone complications associated with HIV and HAART and stimulate further research in the field.

Introduction

The human immunodeficiency virus (HIV) infection has spread globally, affecting 33 million people since the first isolated cases of acquired immunodeficiency syndrome (AIDS) were described in homosexual men in the USA in 1981.¹ It is estimated to have lead to 35 million deaths. The brunt of the pandemic is concentrated in sub-Saharan Africa, with 22.5 million people being infected and a seroprevalence of 5%.¹

With the advent of highly active antiretroviral therapy (HAART), there has been a shift in the clinical profile of patients with HIV. Prior to effective HAART, patients usually had a progressive course, characterised by recurrent opportunistic infections, eventually culminating in death. Since the introduction of HAART, which has dramatically improved patient survival, non-infective complications have come to the fore, especially cardiovascular disease, malignancy, diabetes mellitus and metabolic bone disease.^2–5 The latter has been neglected in terms of research and management in South Africa. This is evident from the lack of sufficient South African data on HIV/AIDS and metabolic bone disease. Additionally, the South African guidelines for the management of HIV do not incorporate the possibility of bone disease.⁶ As a result, metabolic bone disease and fractures are greatly overlooked and untreated in HIV patients.

Metabolic bone disease associated with HIV/AIDS results from a complex interplay of a host of different factors, including HIV infection itself, HAART and vitamin D deficiency.^7–9 The bone disease that is observed can usually be divided into three main categories; osteoporosis, osteomalacia, or a combination of the two. Osteoporosis is characterised by decreased bone mineral density (BMD), changes in bone microarchitecture, decreased bone strength and an increased risk of fragility fractures.¹⁰ Fractures of the hip, spine and distal radius are the most common in osteoporosis.¹⁰ Osteomalacia is a disorder characterised by defective mineralisation, the accumulation of unmineralised bone matrix and an increase in osteoid thickness. Vitamin D deficiency, primary or secondary, is the most common cause of osteomalacia. Primary vitamin D deficiency occurs mainly because of decreased sun exposure, and to a lesser extent, decreased dietary vitamin D. Secondary causes of vitamin D deficiency include partial gastrectomy, chronic renal failure and anticonvulsants, for example, phenobarbitone.

HIV/AIDS and metabolic bone disease

Definite increases in the prevalence of osteopaenia and osteoporosis have been described in patients suffering from HIV/AIDS, especially in the Northern Hemisphere.⁵ There is a paucity of sub-Saharan data, and specifically South African data.

A recent meta-analysis by Brown et al using BMD as a marker of metabolic bone disease in HIV sufferers, demonstrated a 6.7-fold increase in the odds ratio of developing osteopaenia.⁵ The odds ratio for osteoporosis was 3.7. A substudy of the AIDS Clinical Trials Group, a North American group investigating the effect of antiretroviral therapy on BMD, demonstrated a similar prevalence of osteopenia and osteoporosis. The baseline prevalence of osteopaenia and osteoporosis before the initiation of HAART was 28% and 7%, respectively.⁹ More than 60% of patients included in the trials were males, which differs from the HIV gender distribution in South Africa and the rest of the world.^1,11 A South African study by Hamill et al in which BMD in black premenopausal South African females was evaluated, could not illustrate a difference between the HIV-negative and HIV-positive patients, irrespective of the cluster of differentiation (CD4) count.¹² This illustrates the indefiniteness of current South African data.

HAART has a considerable impact on bone health, independent of the regimen used.^9,13 The bone loss seen in patients with HIV on HAART seems to stabilise between 24 and 48 weeks.⁹ This effect is similar to that observed with glucocorticoid therapy.¹⁴ A sub-Saharan study performed in Dakar, Senegal, utilised quantitative heel ultrasound (QUS) for the evaluation of BMD.¹⁵ Patients on HAART had a significantly lower BMD (p 0.003) when compared to HIV-negative HAART-naïve controls. Although reduced body mass index (BMI) explained one third of the reduced QUS BMD observed, HAART was responsible for the majority of BMD loss.

The Southern African HIV Clinicians Society guidelines for antiretroviral therapy, published in 2012, only mention the bone toxic effects of tenofovir, although it has been shown that other drugs are also bone toxic.^6,9,13 The three most common drugs used in South Africa are a combination of tenofovir, efavirenz (EFV) and lamivudine (3TC). It was shown in a South American study that this combination caused a statistically significant reduction in BMD within the first 48 weeks of initiation.¹⁶ The BMD stabilised for the remainder of the study.¹⁶

Tenofovir is a nucleoside reverse transcriptase inhibitor (NRTI) and its effects on bone health have been the best studied of all the antiretroviral drugs. The drug has been associated with the development of osteomalacia due to multiple effects on the calcium, vitamin D and parathyroid hormone (PTH) system, as well as proximal renal tubular toxicity.^17,18 In a UK study by Klassen et al in which the effect of tenofovir on vitamin D metabolism was examined, it was shown that tenofovir was associated with an increase in PTH levels in non-white men.¹⁹ The increase in PTH levels was confirmed in a Spanish cohort.²⁰ The UK study also illustrated that tenofovir use was associated with increased urinary phosphate excretion and reduced serum phosphate levels. Acquired Fanconi syndrome has also been linked to tenofovir use.¹⁷ It was shown in mouse models that tenofovir induced genetic changes that led to reduced osteoblast and osteoclast function, with a negative impact on bone remodelling, and subsequently BMD.^21,22 It must be noted that the clinical significance of this was recently questioned by a meta-analysis performed by Cooper et al. The study investigated the renal safety of tenofovir, and found that although there was a significant drop in renal function and serum phosphate levels, the clinical effect was moderate at most.²³

EFV, a nonnuceloside reverse transcriptase inhibitor, upregulates the expression of CYP24.²⁴ CYP24, a member of the cytochrome P450 super family of enzymes, initiates the degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)₂ D], causing the increased conversion of 1,25(OH)₂ D to its inactive form.

3TC is an example of an NRTI.²⁵ Zidovudine (AZT) and didanosine (ddI) are examples of other drugs in this category. It was shown in a mouse model that AZT enhanced osteoclastogenesis in a receptor activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) ligand (RANKL)-dependent manner.²⁶ Similar results were seen with 3TC and ddI.²⁵

The effects of other drugs are outside the scope of this article and can be reviewed elsewhere.²⁷

An important question that arises is whether or not a decrease in BMD in HIV-positive patients on HAART translates into an increase in fracture risk. A population-based cohort study showed that patients with HIV infection have an increased incidence ratio of 1.6 (95% confidence interval: 1.4–1.8) of low-energy fractures, compared to HIV-naïve patients.²⁸ The incidence of fractures was significantly increased after exposure to HAART.²⁸ Similarly, Guaraldi et al compared the prevalence of fractures (traumatic or non-traumatic) in HIV-naïve and HIV-positive patients on HAART, and found that there was a 10-fold increase in fracture risk over all age groups in the HIV-population on HAART.²⁹ Once again, it must be noted that more than 60% of the patients in the trials were males, and the studies were conducted in the Northern Hemisphere. Despite the male ratio that was observed in the above studies, it has been shown that HAART reduces BMD, as well as increasing fracture risk.

Multiple risk factors have been identified as contributing to a decreased BMD and associated fragility fractures in patients with HIV. HIV-related bone disease can be attributed to classical and non-classical risk factors. Classical risk factors for metabolic bone disease, which also occur with HIV infection, include poor nutrition, a low BMI, current tobacco use, alcohol use, increased age and low vitamin D levels.^15,30 Non-classical risk factors include concurrent hepatitis C infection and a CD4 count less than 200 cells/mm³ or the diagnosis of AIDS.^15,30

HIV infection has direct effects on bone remodelling, and influencing osteoclast and osteoblast function. HIV envelope protein, gp120, increases the receptor activation of the NF-κB ligand and HIV viral protein of regulation increases RANKL expression.^7,31 This leads to an increase in osteoclast number and function, which results in increased bone resorption.³² HIV infection is associated with elevated tumour necrosis factor alpha (TNF-α) levels.³² TNF-α is a well known stimulator of NF-κB, leading to increased osteoclast formation, bone resorption and metabolic bone disease. This was recently reviewed by Barkhordarian et al.³³ Osteoblasts are negatively affected by HIV.⁷ HIV infection increases apoptotic stimuli in the mesenchymal stem cells, which are precursors to osteoblasts, leading to decreased pre-osteoblast formation, and subsequently, osteoblast formation.³⁴ HIV envelope protein gp120 interacts with the cell membrane of the osteoblast, leading to an increased rate of apoptosis.⁷ HIV does not seem to directly infect the osteoblast.

Management

HIV-infected patients should undergo a detailed history and physical examination in order to identify clinical risk factors, a propensity for falls and previous fragility fractures. Traditional risk factors for the development of osteoporosis should be excluded. These must include a family history of hip fractures, alcohol abuse, smoking, vitamin D deficiency, a low BMI (< 20 kg/m²), hyperthyroidism and glucocorticoid use.³⁵

The current National Osteoporosis Foundation of South Africa (NOFSA) guidelines state that bone mass measurement is indicated in female patients aged 65 years and older, and in male patients aged 70 years and older.³⁵ Bone mass measurement is also indicated in patients older than 40 years in whom secondary causes for osteoporosis are present, or in patients who sustain a fragility fracture after the age of 40 years. HIV infection and HAART are not currently listed by NOFSA as risk factors for osteoporosis, and further South African data are necessary to determine whether or not these two risk factors should be included in future guidelines. It must also be kept in mind that the majority of South Africans who are infected with HIV are between the ages of 20 and 50 years.¹¹

Baseline special investigations should include a full blood count, erythrocyte sedimentation rate, creatinine, calcium, magnesium, phosphate, thyroid-stimulating hormone and 25-hydroxyvitamin D levels.³⁵ Additional special investigations should be considered in selected patients.

General measures must include stopping smoking, reducing alcohol intake, participating in weight-bearing exercises, fall prevention and adequate calcium and vitamin D supplementation. The NOFSA guidelines state that a daily elemental calcium intake of up to 1 200 mg in most adults is safe and effective in preventing bone loss.³⁵ Calcium supplementation should be individualised according to dietary intake as excessive calcium intake may have detrimental effects on cardiovascular health.³⁶ Vitamin D levels must be maintained above 30 ng/ml for optimal bone health.³⁵

The prevalence of vitamin D deficiency in the HIV-positive population is more than 50% when using a cut-off point of < 20 ng/ml.^8,37 Risk factors for vitamin D deficiency include race (black or Hispanic), poor nutrition, advanced disease and the use of HAART.^8,37 A vitamin D intake of between 800 IU and 1 000 IU per day is suggested in patients with adequate vitamin D levels. Vitamin D levels of less than 30 ng/ml might warrant treatment with a weekly dose of 50 000 IU vitamin D₂ or D₃ for 6–8 weeks in order to obtain a level of more than 30 ng/ml.³⁵ Higher dosages might be needed in patients using HAART because of the negative effects of HAART on vitamin D metabolism.²⁴

Ethnic differences in bone metabolism have been described, which may explain the possible differences in fracture risk between black and white South Africans.³⁸ Increased fracture risk associated with HIV infection has been demonstrated internationally, but once again, South Africa-specific data are needed.²⁸ The specific therapeutic agent (bone-active drug) that is effective and safe in this group of patients still needs to be determined. Anti-osteoporotic drugs are usually investigated in female patients aged 50 years and older. There are data on only a few drugs in the younger population. Bisphosphonates are well known and widely used drugs in the treatment of osteoporosis. The effects of once-weekly oral alendronate, in combination with calcium and vitamin D supplementation, were compared to calcium and vitamin D supplementation alone, in HIV sufferers on HAART, in a trial by Mondy et al. ³⁹ There was a statistically significant change in lumbar spine BMD in the alendronate group, compared to that in the non-alendronate group. It must also be noted that there were no serious adverse events. Bolland et al demonstrated that intravenous zoledronic acid was also associated with an increase in BMD, not only at the lumbar spine, but also at the hip and total body.⁴⁰ However, it must be noted that most of the patients in these trials were males aged approximately 50 years, whereas as previously mentioned, the majority of HIV sufferers in South Africa are females in their reproductive years.

The future

With the advent of effective HAART, HIV infection has undergone a metamorphosis from being a fatal disease characterised by progressive deterioration and associated with opportunistic infections, to a chronic controllable condition. It is now frequently complicated by diseases of lifestyle, including osteoporosis, which increase the burden of disease associated with HIV.

HIV infection is associated with a decrease in BMD and an increased fracture risk in non-South African populations, and it seems that this effect is compounded by HAART, irrespective of the drug class used.^9,13,29,30 Current South African data are inconclusive, and further research is warranted in order to determine whether or not the South African HIV population carries the same risk for metabolic bone disease as that of its Northern Hemisphere counterparts.

If the South African HIV population is found to have an increased risk of fragility fractures, disregard could lead to an escalation in the morbidity, mortality and economic burden associated with HIV infection in a country already straining with limited resources. BMD testing is currently expensive, and not freely available to the majority of South African citizens who are dependent on public health services. If data from local studies indicate that HIV is a threat to bone health, BMD testing should be incorporated in the management of HIV patients.