With HIV infections, various complications arise which affect different systems of the body. These include cardiac, metabolic, endocrine, renal and inflammatory/immune systems to name but a few. Apart from these complications, changes in lipid and glucose metabolism, adipose tissue disorders and abnormal bone metabolism are also prevalent. One of the major focuses of research has been the association between HIV, HAART, metabolic disorders and vascular disease. However, the specific effects of HIV on the metabolic, endocrine and renal systems, as well as the bone, and the interactions between these systems have not been that extensively studied. Furthermore, although the use of HAART has improved the prognosis of HIV-infected patients dramatically, long-term HAART is associated with several cardio-metabolic, endocrine, renal and bone perturbations, which will be discussed in the next section.
Insulin resistance, impaired glucose tolerance, impaired fasting glucose and diabetes mellitus (DM) are a spectrum of glucose metabolism disorders reported in persons with HIV infection both with and without HAART. In a HIV-positive population, approximately 25–35% of patients have impaired glucose tolerance, whereas 2–7% have DM [
86,
87]. Genetic susceptibility and lifestyle seem to be some of the factors that most often cause variation in the prevalence of HIV from one population to another [
87].
There is a strong association between insulin resistance and lipid accumulation in muscle and liver tissue in HIV-positive patients with lipodystrophy—increased VAT is associated with excess free fatty acids, increased intramyocellular fat content and reduced adiponectin [
88]. Glucose uptake into abdominal subcutaneous adipose tissue (SAT) is increased in HIV-infected patients, whereas glucose uptake in VAT and muscle cells does not differ [
88].
With specific reference to BMD, inconsistencies exist regarding the relationship between VAT and BMD. Whilst some studies suggest an inverse relationship [
89,
90], a study by Yamaguchi et al. suggests a potential protective effect of VAT especially in patients with DM [
91]. A study by Bredella et al. confirmed the findings of an inverse relationship between VAT and BMD in pre-menopausal obese women [
92]. They further go on to suggest that this effect may at least by partially mediated by IGF-1, since IGF-1 and muscle mass are positive predictors of BMD. The growth hormone (GH)/IGF-1 axis is a major determinant of BMD [
93,
94] and seems to be dysregulated in females specifically in proportion to the degree of VAT [
95]. Other potential explanations could include the release of proinflammatory cytokines secreted by adipocytes, such as IL-6, TNF-α, and adipokines, such as E-selectin and adiponectin, stimulating osteoclast activity [
90,
96,
97].
A previous study also found that lean body mass is an important predictor of BMD in premenopausal women, whereas fat mass correlated positively with BMD of the hip [
98]. The adipokine, leptin, is responsible for regulating several hypothalamic pituitary adrenal (HPA) axes which are involved in mediating the connection between leptin and bone by means of direct and indirect mechanisms. Since the leptin receptor can be found in adult primary osteoblasts, it is suggested that leptin has a direct effect on bone growth through its inhibitory action against bone resorption (osteoblastic activity) [
99]. It regulates osteocalcin which in turn regulates bone metabolism [
100]. Furthermore, bone marrow adipocytes also secrete leptin which may mediate leptins’ local effect on bone. On the other hand, indirect mechanisms are more complex and involve cortisol, thyroid and parathyroid hormones, as well as growth hormones and IGF-1 [
101].
HIV and the endocrine system
A wide spectrum of endocrine complications is associated with HIV infection and acquired immunodeficiency syndrome (AIDS). However, these disorders may also be as a consequence of systemic illness, opportunistic infections, body composition and/or HIV-related therapies [
102]. The pituitary, thyroid, adrenal gland, gonadal, pancreas and bone are all involved.
Although HIV brings about secondary issues such as endocrine dysregulation, hormonal imbalances are not a common occurrence. HIV does however involve almost all of the hormonal systems and axes. One of the most common endocrine axes to be affected by HIV is the HPA axis [
103]. During a condition such as HIV, viral proteins and cytokines activate or inhibit the hormonal system, further contributing to HPA dysregulation, a condition which is exacerbated with HAART [
103]. The adrenal gland malfunctions as a result of adrenal insufficiency. Furthermore, due to a glucocorticoid resistant state, impaired adrenal and pituitary reserves cannot react to increased cortisol levels. Various different thyroid hormone disorders also occur which is associated with altered metabolism, poor oral intake and increased prevalence of weight loss and wasting syndrome [
103].
Oestrogens and androgens have also been implicated to contribute to changes in BMD, not only during adulthood, but also during the growth of the skeleton. Oestrogen specifically has been shown to inhibit osteoclast function, and stimulate osteoblasts to produce growth factors and cytokines that mediate oestrogen’ action, some of which regulate the osteoblasts indirectly [
104]. More importantly, oestrogen may play a role in determining the life span of bone cells by controlling the rate of apoptosis, thus decreasing the lifespan of osteoblasts and increasing the longevity of osteoclasts [
104]. Two specific and complementing mechanisms have been implicated to explain the effect of oestrogen on bone. Firstly, oestrogen deficiency (most commonly as a result of menopause) causes bone loss through its activation of new bone remodelling sites and through exaggeration of the imbalance between bone formation and resorption [
104]. Oestrogen deficiency stimulates osteoblast production of IL-1 and -6 and TNF-α and inhibits apoptosis, thus extending the life span of osteoclasts. Oestrogen deficiency decreases IL-1ra leading to enhanced osteoclast sensitivity to IL-1. These actions mainly occur via oestrogen receptor (ER)α, which then elicits a prominent effect on the regulation of bone turnover and the maintenance of bone mass [
105]. Although osteoblast numbers are also elevated, the increase in bone formation is not sufficient to replace the bone matrix removed by osteoclasts, resulting in net bone loss.
One has to take into consideration that HIV-infected subjects already have low BMD, and even more so when treated with HAART. Given the vast proportion of women living with HIV, who are and will be transitioning through menopause, one also needs to consider the additional burden that low oestrogen levels will place on a BMD level that is already compromised by HIV and HAART. Statistics in the USA are largely alarming, as it is anticipated that by 2020, more than 50% of HIV infection will be in patients over the age of 50 years [
106]. In women living with HIV, an intricate relationship between HIV and menopause appears to exist in that HIV may influence the natural history, experience, and complications of menopause, while menopause itself could potentially influence the course of HIV infection [
107]. This relationship between HIV and menopause further complicates the management of HIV infection in women as they age and challenges clinicians, since lymphocyte subsets, including CD4 counts have been found to decrease with increasing age in non-HIV-infected adults [
108]. Considering that older individuals are usually diagnosed later with a more advanced stage of HIV, CD4 counts will be even lower. Therefore, the combination of all of these factors predisposes women to an earlier and even more severe bone loss compared to those individuals without HIV.
In males, testosterone affects BMD through its direct effect on the androgen receptors in trabecular and cortical bone [
109,
110]. Testosterone’s effect is more complex than that of oestrogen as it is converted to estradiol in adipose tissue or bone, with subsequent stimulation of the oestrogen receptors [
110‐
112]. When androgen levels are low, it is associated with bone loss and increased bone remodelling in men [
113,
114]; however, a reduction in oestrogen seems to play a key role in the age-related decrease of BMD [
115,
116]. With advancing age, testosterone is also considered the major source of circulating estradiol in women (menopause), and testosterone can regulate local production of cytokines and growth factors in bone, including IL-6, IL-1β, TGFβ and IGFs [
109]. The anabolic effects of testosterone on muscle mass and strength can also indirectly affect bone mass.
Data on the effect of low testosterone levels on BMD are not in agreement. One specific study suggests that serum total estradiol, but not testosterone is associated with reduced BMD in HIV-infected men [
117]. This study showed that among men with low testosterone, it is only those men that develop an oestrogen deficiency that will have lower BMD, a result which was also evident in other studies [
118,
119], although some studies found the opposite to be true [
120,
121].
It is therefore evident that older age, and therefore the decrease in sex hormones, impacts BMD even more negatively when associated with HIV and HAART treatment.
HIV and the renal system
Patients with HIV usually show signs of proteinuria which progress rapidly to end-stage renal disease, commonly referred to as HIV-associated nephropathy (HIVAN) [
122]. The nucleoside reverse transcriptase inhibitor (NRTI), tenofovir (TDF), has been linked to proximal renal dysfunction (PRTD), which can result in excessive renal phosphate, uric acid and bicarbonate loss. Furthermore, it can also result in proteinuria and glucosuria especially in patients with pre-existing nephropathy [
123]. A study by Fux et al. showed that PRTD may promote BMD loss through renal phosphate wasting [
124]. Studies originally reported on nephrotoxic effects as a result of TDF, but the incidence of adverse renal effects were low in initial randomized trials [
125,
126]. A small but significant loss in renal function was observed in patients on TDF-containing regimens compared to abacavir (ABC)-containing regimens [
127]; however, studies are not conclusive regarding renal endpoints and more patients developed clinical renal impairment [
128,
129]. Additionally, although both the STEAL and ASSERT study indicated no difference in estimated glomerular filtration rate (eGFR) between patients [
130,
131], increases in markers of proximal tubule dysfunction were evident as a result of TDF treatment in the ASSERT study [
130]. This is comparable to results obtained by Rasmussen et al. In this particular study, although no difference in renal function was evident when plasma cystatin C (cysC) and estimated creatine clearance (CrCl) were measured (indicative of stable GFR), a minor increase in urinary neutrophil gelatinase-associated lipocalin (NGAL)/creatinine ratio (as a marker of renal dysfunction) was observed in the TDF-containing regimen compared to the ABC-containing regimen [
132]. CrCl is however dependent on factors other than plasma creatinine and GFR, such as changes in muscle mass and tubular secretion of creatinine.
A different formulation of TDF was approved by the FDA in order to try and overcome the side effects associated with TDF. Patients that switched to tenofovir alafenamide (TAF) seemed to be more likely to keep their viral load low, whilst kidney function and bone density was improved [
133,
134]. Even after 2–3 years, TAF was better at suppressing viral load and safer for the bones and kidneys [
135,
136]. A similar study by Brown et al., also showed that participants who switched from TDF to TAF showed improved bone health, including a reduction in osteoporosis [
137].
HIV and bone mineral density
A reduction in BMD is a common complication of HIV and its treatment, with low BMD, osteopenia and osteoporosis more commonly associated with both male and female HIV-infected subjects [
138,
139], compared to non-infected subjects [
140,
141].
The rates of osteopenia and osteoporosis were found to be as high as 67 and 15% respectively, whilst the magnitude of BMD reduction was 6.4-fold higher, and that of osteoporosis 3.7-fold higher in HIV-positive patients, as reported in a meta-analysis [
142]. Cazavane et al. indicated that more than half the HIV-infected patients had osteopenia, and approximately a third had osteoporosis [
138], results which were verified by a study from McComsey et al. [
143]. Triant et al. also reported a higher prevalence of fracture risk in HIV-positive patients compared to HIV-negative patients [
144]. A more recent study reported the rates for osteopenia and osteoporosis to be 47.5 and 23% respectively, whilst BMD decreased in about 28% of subjects in a follow-up study of 2.5 years [
145]. Sharma et al. found similar results, where rates of 42 and 12% were reported for osteopenia and osteoporosis respectively—the degree of osteopenia was three times higher in the HIV-infected subjects with 12% of patients progressing to osteoporosis [
146]. These studies highlighted the existence of high prevalence of osteopenia and osteoporosis in the HIV-positive population.
HIV-positive patients have reduced bone size, mass and strength due to altered metabolism and the infection of bone cells [
147]. It has been suggested by Duvivier et al. and Borderi et al. that HIV infection of osteoblasts may be related to a negative balance of bone remodelling [
148,
149]. Since osteopenia and osteoporosis is highly prevalent in HAART-naïve patients, it suggests that if viremia is not controlled properly, it might impact BMD via its effects on persistent systemic inflammation and bone remodelling. Not only do the HIV proteins increase osteoclast activity, but they promote osteoblast apoptosis, thereby decreasing bone formation [
150].
Under normal conditions, both vitamin D and phosphate metabolism are important for skeletal integrity; however, in HIV, vitamin D and phosphate contributes to low BMD due to impaired mineralization [
148]. Approximately 60–75% of patients in a HIV-infected population have low vitamin D levels [
151]. Furthermore, hypogonadism may also play a role [
152], and lipoatrophy seems to mediate bone loss through adipocyte hormone signalling [
89].
Since persistent systemic inflammation can impact bone density, the involvement of various cytokines involved in this process are of great importance. T-cells (specifically targeted by HIV infection), B-cells and monocytes are responsible for the production and regulation of key osteoclastogenic cytokines such as RANKL and OPG [
153]. It is speculated that HIV infection results in the alteration of B cell function and subsequently a switch from bone sparing OPG production to the production of bone destroying RANKL, thus leading to increased osteclastogenesis [
154]. This data is consistent with the fact that B-cells are mainly regulated by interactions with T-cells, as well as the fact that severe perturbations of the B-cell linage are mediated by HIV infection (through direct effects of viral infection and/or indirectly though disruption of co-stimulatory signals from T-cells and other disrupted immune components) [
155,
156]. Along with upregulation of RANKL by HIV gp120 protein, there is further activation of RANKL by TNF-α that is represented in higher numbers in advanced HIV disease [
157].
A dramatic increase in the number of osteoclast precursors (defined as monocytes expressing the RANKL receptor, RANK) were also evident, whilst OPG expression was significantly diminished [
156]. Data from animal studies showed that HIV infection results in alterations in the immuno-skeletal interface favourable to accelerated bone resorption and loss of bone mass. Low serum OPG concentrations have been reported in HIV/AIDS patients [
158], verifying some of the data seen from animal studies. Furthermore, peripheral blood T-cells have been implicated as a potential source of OPG [
158]. Other studies have shown that HIV-infected women have higher levels of both RANKL and OPG than their HIV-negative counterparts, suggesting increased overall bone turnover in HIV-infected patients [
159], while HAART initiation has been associated with increases in both, again suggesting increased bone turnover [
160,
161].
One of the most recent studies performed were able to show that the combination of all B cells were responsible for the increase in RANKL, whilst the decrease in OPG was due to changes in the distribution of B cell subsets [
162]. Therefore it is crucial to distinguish between the different B cells and to include naïve and resting memory B cells (decreased number with high expression of OPG), and tissue-like B cells (increased number with low expression of OPG). When the relationship between these markers and BMD in HIV-positive participants was investigated, RANKL/OPG correlated significantly with BMD and T- and/or Z-scores in the femur neck and hip region, which was not evident in the HIV-negative participants. The data therefore supports the concept of B cell alterations in RANKL and OPG production which may contribute to the decline in BMD in the context of HIV. Interestingly, although a decrease in OPG expression in the B cells was observed overall, serum OPG levels were elevated whilst RANKL was decreased, which was also shown in other studies [
163,
164]. However, whereas some of the studies showed a decrease in RANKL, the study by Gibellini et al. indicated an increase in RANKL suggesting that relying only on circulating markers is not a true reflection of what happens in bone.
Interferon (IFN-γ) has also been shown to interfere with the RANKL receptor through its action on the adapter protein, (tumour necrosis factor receptor-associated factor-6; TRAF-6) that links RANK to its downstream transcription factors, ultimately inhibiting osteoclast formation [
165,
166]. These alterations in the immune-skeletal interface may therefore account for much of the loss of BMD observed in HIV patients.
Even though there are growing concerns regarding osteoporosis, the impact of HIV and its treatment on bones in resource-limited countries is poorly documented.