What factors contribute to poor bone health in the HIV population?
Several factors that contribute to low bone density are present at a higher rate in the HIV population (Table 4). These include poor nutritional status in terms of suboptimal calcium and vitamin D intake, hypogonadism, low body weight, and alcohol, tobacco and substance abuse.
Vitamin D deficiency is very common in HIV-infected patients, with a prevalence of up to 60% to 75% [77]. Hypogonadism is also relatively common among HIV population [78], contributing to lower bone density. Co-infection with HCV is also associated with increased risk of fractures. In a large cohort of Medicaid beneficiaries, a significant increase in the risk of hip fracture was demonstrated in HCV/HIV co-infected subjects compared either with HCV mono-infected, HIV mono-infected or non-infected individuals [79]. In another large database study, a significantly higher risk of osteoporotic fracture (closed wrist, vertebral or hip fracture) was reported in HCV/HIV co-infected versus HIV mono-infected individuals [80] with fracture rates of 2.57 and 2.07/1000 patient-years (P < 0.001). Dual treatment for HIV/hepatitis B co-infection has also been shown to be associated with a higher risk of hip fracture compared to treatment of HIV mono-infected individuals [81].
HIV infection itself can increase bone loss and reduce bone formation through direct effects related to the HIV antigen load or indirect effects related to activation of the pro-inflammatory cytokines resulting in bone resorption and loss [82]. Co-infection with HCV and/or hepatitis B also contributes to lower bone density in this population. Certain ARVs may also contribute to low bone density in the HIV population. Lipoatrophy related to HIV may also mediate bone loss through complex relationship between central signaling of adipocyte hormones [82,83].
Direct Viral Effects
Several HIV viral proteins have been shown to promote osteoclast activity (vpr and gp120), suppress osteoblast activity (p55-gag) and increase osteoblast apoptosis [84], resulting in increased bone resorption and reduced bone formation, leading to low bone mass. High HIV RNA viral load and T-cell activation are also associated with elevated levels of receptor activator of nuclear factor kappa-B ligand (RANKL), which results in osteoclast formation and increased bone resorption [85]. Other endogenous physiological inhibitors of osteoclastogenesis such as osteoprotegrin and interferon-γ levels are also remarkably downregulated in advanced HIV infection, resulting in increased bone resorption [86]. At a cellular level, HIV proteins including Tat and Nef reduce the number of available mesenchymal stem cell (MSC) precursors that proliferate into osteoblasts by inducing MSC senescence, due to increased oxidative stress and mitochondrial dysfunction resulting in reduced proliferation of osteoblasts and lower rates of bone formation [87]. Collectively, these mechanisms result in significant uncoupling of bone formation and resorption, resulting in less bone formation and greater rate of bone loss and lower bone density.
Pro-inflammatory Pathways
Cytokines and other soluble immune factors play a major role in the physiology of osteoblast maturation and osteoclastic bone resorption [88,89]. Immune dysfunction and persistent inflammation in HIV result in increased levels of several inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and RANKL, resulting in stimulation of osteoclastogenesis and bone resorption [90]. Due to a disruption between T and B cells in HIV and decreased osteoprotegrin (OPG) production and increased RANKL level, RANKL/OPG ratio is elevated, favoring osteoclastogenesis [91].
Is antiretroviral therapy associated with bone loss?
The initiation of ART has been reported to cause 2% to 6% bone loss irrespective of the regimen used, similar to that sustained in the first 2 years after menopause [92]. Certain NRTIs and PIs are associated with higher rates of bone loss than others. TDF has been associated most commonly with decreased bone mineral density, which usually stabilizes with continued use [93]. In a randomized trial comparing 4 treatment arms of ABC/3TC or TDF/FTC with EFV or ATV/ritonavir, TDF was associated with a greater reduction in BMD compared to abacavir-based regimens [94]. The likely cause of this may be TDF-mediated renal toxicity, including proximal tubular dysfunction and hypophosphatemia, resulting in increased PTH and bone resorption, and nephrogenic diabetes insipidus [95]. TAF is another prodrug of tenofovir diphosphate associated with less renal and bone toxicity compared with TDF. TAF has been associated with significantly less decrease in bone mineral density and renal dysfunction in randomized studies compared to regimen using TDF [17]. Vitamin D deficiency and hypophosphatemia associated with TDF therapy may present with osteomalacia, which predisposes to bone pain and fractures. Treatment with TDF may rarely be associated with the development of Fanconi syndrome and osteomalacia [96]. BMD is often severely reduced and bone pain and pathological fractures are characteristic features. Certain PI regimens containing ritonavir-boosted atazanavir have also been associated with greater bone loss in the spine than the hip, compared to efavirenz-containing regimens [97].
The universal bone loss associated with ART is thought to be a result of the "immune reconstitution inflammatory syndrome" (IRIS). This occurs as a result of rapid improvement in immune function after the commencement of ARV as a result of systemic or local inflammation, resulting in increased levels of cytokines that may contribute to bone loss. This has been shown in animal studies where T cell transplantation into immunocompromised mice to mimic ARV-induced T-cell expansion resulted in increased RANKL and TNF-α production by B cells and/or T cells, accompanied by enhanced bone resorption and BMD loss. When TNF-α or RANKL-null T-cells or TNF-α antagonists were used instead, the loss of cortical bone was prevented [98]. In a prospective study evaluating changes in bone turnover markers and inflammatory cytokines with ARV therapy in HIV infected subjects, a significant increase in bone resorption markers, RANKL and TNF-α were seen after initiation of ARV. The magnitude of CD4-cell recovery correlated with the increase in markers of bone resorption [99], suggesting that recovery of the immune system contributes to the increase in cytokine-mediated bone resorption.
How is bone health and fracture risk assessed in the HIV-positive population?
The predictive value of low BMD for fracture risk assessment in the HIV-positive population has not been established. In the absence of definitive data, the fracture risk assessment and standard methods of measuring bone density using DXA are utilized. In a large study of 1000 men and women, osteoporosis defined as a BMD T-score –2.5 as measured by DXA, was associated with a significantly increased risk of incident fractures but was not a good predictor of morphometric vertebral fractures [100]. In the absence of prospective longitudinal studies evaluating the bone density parameters at which fracture risk is significantly increased in the HIV population, it is reasonable to follow the guidelines used in the non-HIV population.
The approach to treatment of osteopenia and osteoporosis is similar to that in non HIV-infected population and is directed at lifestyle changes and treatment of secondary causes of osteoporosis [101], followed by initiation of antiresorptive therapy.
Management of Bone Disease
There are several guidelines available for the management of bone disease in the HIV population. The most recent guidelines from the IDSA [12] recommend assessing the risk of fragility fracture using the Fracture Risk Assessment Tool (FRAX), without DXA, in all HIV-infected men aged 40–49 years and HIV-infected premenopausal women aged ≥ 40 years. DXA should be performed in men aged ≥ 50 years, postmenopausal women, patients with a history of fragility fracture, patients receiving chronic glucocorticoid treatment, and patients at high risk of falls. In resource-limited settings, FRAX without bone mineral density can be substituted for DXA. ART guidelines should be followed. TDF and boosted PIs should be avoided if possible in at-risk patients. Dietary and lifestyle management strategies for high-risk patients should be employed and anti-osteoporosis treatment initiated if indicated [102].
The FRAX tool is available at www.shef.ac.uk/FRAX/ and is used to calculate 10-year fracture risk using patient clinical data, including presence of risk factors for osteoporosis. The tool is population-specific by race and region. It has not been validated for the HIV-positive population and may underestimate fracture risk [103]. HIV status is considered a secondary cause of osteoporosis in FRAX calculation.
The National Osteoporosis Foundation recommends screening with DXA for all women > 65 years of age, all men > 70 years of age, and adults > 50 years of age with additional risk factors for osteoporosis. Evaluation for secondary causes for low BMD should always be considered in the HIV-positive population including evaluation of calcium and vitamin D intake. Laboratory testing may include complete blood count, calcium, phosphate, albumin, creatinine, PTH, 25 hydroxy vitamin D (25,OHD) and 24 hour urine for evaluation of calcium, creatinine and phosphate (especially if on TDF) excretion. Testosterone level can be checked in men and estradiol, prolactin, FSH and LH in women for evaluation of hypogonadism. Bone turnover markers (bone specific alkaline phosphatase and serum C-terminal telopeptide) can also be assessed at baseline.
Studies using high-resolution peripheral quantitative computed tomography (HSPQCT) have shown significant reductions in tibial trabecular bone density and trabecular number in pre-menopausal and postmenopausal HIV-infected women [104], with reduced bone stiffness measured using finite element analysis [105]. Co-infection with HCV is also associated with significantly lower trabecular volumetric BMD and smaller cortical dimensions in the tibia, compared to healthy subjects [106]. HSPQCT is not widely available for clinical use at this time. Lateral imaging of the spine or vertebral morphometric analysis may be done in cases of height loss to assess for occult vertebral compression fractures.
There is a high prevalence of vitamin D deficiency in the HIV-infected population [107]. Treatment goal is to have a vitamin D level of at least 30 ng/mL, based on Endocrine Society practice guidelines [108], and may require supplementation with 1000–2000 units of vitamin D daily. Calcium intake should be optimized, averaging 1000 mg per day including diet and supplements, to be taken in divided amounts through the day for optimal absorption. Secondary causes of low bone density as mentioned in Table 4 should also be addressed. Patients should be counseled on tobacco and alcohol abuse. Corticosteroids should be dosed at the lowest dose needed. Medications such as proton pump inhibitors can impair the absorption of calcium carbonate, in which case calcium citrate supplements should be used if there is suboptimal calcium intake in the diet.