Osteoporosis in HIV: Epidemiology

Osteoporosis is a significant public health problem independent of HIV infection. Although the prevalence is higher in postmenopausal women, the rates of bone loss are similar in women and men after about age 60.(1)In Canada, where the population is aging,(2)it is estimated that one in four women and one in eight men have osteopenia that poses and increased risk of bone fracture.(3-4)Data from the United States suggest that 50% of individuals have developed osteoporosis by the time they reach the age of 80 years.(5)In patients with HIV, the incidence of osteoporosis appears to begin at a much earlier age and the prevalence climbs more steeply.(6)(see Figure 1) Although it was initially hypothesized that osteoporosis might primarily be a complication of antiretroviral therapy,(7)HIV infection is now recognized as an independent risk factor for bone disease.(8)While specific antiretroviral therapies do appear to accelerate the process, osteopenia begins to develop early in the infection and in the absence of therapy.(6, 9)Within two years of HIV infection, bone density declines by as much as 6%,(10)which is similar to that observed among women within the first two years of menopause.(11) The definition of osteopenia in individuals greater than 50 years of age is more than 1.0 but less than 2.5 standard deviations below the average bone mineral density (BMD) of adults between the ages of 25 and 35, according to the World Health Organization (WHO).(12)This is typically referred to as a T score. The definition of osteoporosis is 2.5 standard deviations below average. Both osteopenia and osteoporosis can also be defined by Z scores, which evaluate standard deviations related to sex- and ethnicity-matched populations of the same age. More commonly used in younger individuals, including those infected with HIV, an abnormal Z score is considered to be 2.0 standard deviations below the benchmark.(13)There is a steep increase in fracture rate with each standard deviation below the mean.(14) The risk for fracture among individuals with HIV varies based on numerous risk factors, but population-based studies suggest that the overall increase in risk is large. In one study that compared fracture rates among 8525 HIV-infected and 2,208,792 non-infected individuals, the fracture prevalence calculated per 100 years was 2.87 for those with HIV vs. 1.77 among the comparator group.(15)This 62.1% increase in rate was highly statistically significant (P<0.0001). Although the increased risk of specific fractures was not evenly distributed by site (for example, vertebral facture rates were nearly twice as great in women with HIV, but hip fractures were not significantly different), the overall increase in fracture prevalence among HIV-infected males was even greater (68.3%; P<0.0001) than in females (44.7%; P=0.002) (Fig. 1). Specific antiretroviral agents have been shown to exacerbate of the bone mineral density loss associated with HIV. In a substudy of the ANRS 121 study, which randomized HIV-infected individuals to a regimen that included a ritonavir-boosted protease inhibitor (PI/r), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or both, the mean reduction in bone density in the lumbar spine was significantly more on the PI/r arm (-5.8%; P=0.007) and the PI/r and NNRTI combination arm (-4.4%; P=0.001) than on the NNRTI only arm (-1.5%).(16) The strongest association between antiretroviral therapy and risk of accelerated bone mineral density loss has been with tenofovir (TDF). In a multicenter 385-patient, 96-week study comparing TDF in combination with emtricitabine (FTC) to abacavir (ABC) in combination with lamivudine (3TC), the mean change from baseline was 1.9% in the group receiving ABC/3TC and -3.6% in those receiving TDF/FTC.(17) (Fig. 2). This 89.4% increase was highly statistically significant (P<0.001). Moreover, when bone loss greater than 6% was compared at specific sites, many showed loss that was three or four times greater in patients receiving the TDF-containing regimen rather than the combination with ABC. This included the hip (13% vs. 3%) and the spine (15% vs. 5%). Previous controlled studies have also associated TDF exposure with increased risk of bone density loss.(18-19) The aging of the HIV population predicts rising rates of fractures, but the consequences of bone mineral density loss are progressive, suggesting that early prevention may modify clinical risks. While the rising rates of fracture in individuals with long-term HIV infection demonstrate that bone mineral density loss is an important challenge, the complications of osteoporosis have the potential to reduce survival in aging HIV-infected individuals.

Pathogenesis

Bone metabolism is a dynamic process of bone remodeling in which stable bone density is dependent on a balance between the bone resorption provided by osteoclasts and bone formation by osteoblasts.(20)Although low accumulation of peak bone mass, which is reached in late adolescence or early adulthood,(21)can be a susceptibility factor for osteopenia later in life, the pace of bone mineral density loss over the course of adulthood is influenced by a broad array of factors, including nutrition, exercise, hormone levels, and factors that influence bone metabolism signaling.(22) While HIV-infected patients are susceptible to the same risks for osteoporosis as those without HIV, including poor nutrition and genetic susceptibility, HIV and its therapies have unique effects on bone metabolism. Perhaps most importantly, HIV proteins have been shown to promote osteoblast apoptosis, inhibiting bone formation,(23)while both HIV proteins and inflammatory cytokines associated with HIV, infection, such as tumor necrosis factor alpha (TNF-α), have been associated with increased osteoclast activity and bone resorption.(23) (Fig. 3). These activities are consistent with the evidence that significant bone loss begins soon after infection irrespective of the type of therapy or whether therapy is initiated.(10) In experimental studies, antiretroviral therapies have demonstrated a variety of potential adverse effects on bone metabolism. For example, efavirenz, an NNRTI, has been associated with an impairment of hepatic enzymes important to vitamin D metabolism, while some PIs, such as nelfinavir and ritonavir, increase gene expression of selected pro-inflammatory cytokines, such as interleukin-8 (IL-8), that adversely affect osteoblasts. However, the association of these agents and exacerbation of bone loss beyond that produced by HIV has been inconsistent.(24-25) The association of TDF and bone loss, demonstrated in a prospective, randomized controlled trial,(17)has been far more consistent. Several mechanisms may be involved, including alterations in gene expression that control osteoblast and osteoclast activity.(26)TDF, a phosphonate with the potential to be taken up by osteoclasts, may also induce stress that alters reciprocal signaling important to osteoblast activity.(27)In addition, TDF is associated with impairment of renal function,(28)which is a risk factor for osteoporosis.(29)The interaction of TDF with conventional risk factors for osteoporosis deserves further study. In addition, osteoporosis in patients with HIV may be understood as a consequence of an accelerated aging phenomenon related to immunosenescence.(30)The premise of immunosenescence is that progressive functional impairment in the immunoregulatory system associated with age is the basis for a broad array of diseases that become more common in aging adults, including cancer, atherosclerosis, and osteoporosis.(31)Due to the stress placed on the immune system by HIV infection, this age-related process appears to begin earlier and progress more rapidly.(32)

Diagnosis and Monitoring

Due to the broadly shared risk of osteoporosis in aging individuals, screening for bone mineral density is recommended in all Canadians 65 years of age or older.(33)The age for screening is lower to 50 years for both men and menopausal women with risk factors. These risk factors include a fragility fracture after the age of 40, a family history of osteoporosis, current smoking, high alcohol intake, a low body weight, or disorders associated with osteoporosis, such as rheumatoid arthritis, type 1 diabetes, or chronic inflammation. Screening is recommended in younger adults who have had a fragility fracture, prolonged use of glucocorticoids, or diseases associated with osteoporosis, such as hyperparathyroidism. Screening is performed with bone mineral density evaluations typically conducted with dual x-ray absorptiometry (DEXA). The Osteoporosis Canada guidelines do not specifically identify HIV as a risk factor, but other organizations, such as the Infectious Diseases Society of American (IDSA) have, advocating DEXA scans in all HIV patients with risk factors beginning at 50 years.(34)However, in a more recently published multinational collaborative review, scanning at the age of 50 years was recommended in all patients with HIV regardless of risk factors.(8)This group, comprised largely of clinicians and researchers active in the field of HIV, recommended repeating the test every two to five years. Although screening earlier than age 50 is not routinely recommended, any history of fragility fractures, whether or not patients have HIV, is an indication for a DEXA scan.

Management

In patients with clinically significant bone density loss as defined by T or Z scores, a complete evaluation to determine risk factors is essential to develop an appropriate management plan. (Fig. 4). While alcoholism, glucocorticoid exposure, and hypogonadism are common risk factors for osteoporosis in general,(35)risk factors for osteoporosis that have been specifically identified to be common in patients with HIV include low body weight, insulin resistance, and hyperlactatemia (36-37). A thorough examination to identify secondary causes of osteoporosis should include routine blood chemistry tests, renal function tests, serum hydroxyvitamin D level determinations, and appropriate hormone level tests by gender. While secondary causes of osteoporosis should be addressed directly, acute or chronic nutritional and pharmacologic therapies are appropriate to improve bone metabolism. It is reasonable to employ the same treatments in patients with HIV as in those who do not have HIV, although the data demonstrating benefit in the setting of HIV is generally more limited. In addition to ensuring adequate levels of calcium and vitamin D intake, sun exposure, and exercise, this can includes bisphosphonates, which have been shown to reduce the risk of fracture in individuals without HIV.(38)In patients with HIV, bone density has improved in patients in a placebo-controlled trial of the bisphosphonate zoledronate, although follow-up was not sufficient to demonstrate an effect on fracture risk.(39) Selecting an antiretroviral therapy with minimal influence on bone metabolism may also be appropriate. Although sustained suppression of HIV is the single most important priority for preventing life-threatening complications of HIV, there is now strong evidence that TDF increases the risk of bone mineral density loss. Although the evidence that TDF increases the risk of fracture is weaker, it may be appropriate to institute closer monitoring of HIV-infected patients with risk factors for osteoporosis who are taking a regimen that contains TDF or to consider alternatives in those who already have osteoporosis. Prevention of osteoporosis in patients with HIV has not been well explored. However, due to the high risk of this complication, it is reasonable to consider prophylactic strategies, such as adequate exercise and intake of nutrients important to bone metabolism, even in young adults. Such lifestyle modifications should be implemented immediately in those individuals with osteopenia even if pharmacologic therapies are not yet indicated. In patients with osteoporosis, DEXA scans should be considered one to two years after initiating a treatment program so that pharmacologic therapies, which are not without adverse effects or costs,(40)can be stopped if adequate bone density has been restored.

Conclusion

Osteoporosis is a major health threat in aging individuals with HIV infection. Bone mineral density loss and clinical complications of osteoporosis can be observed a decade or more earlier in individuals with HIV than in the general population. The HIV infection appears to impose direct adverse effects on bone metabolism, but the increased rate of osteoporosis is multifactorial and may be part of a syndrome of frailty in individuals with HIV driven by accelerated immunosenescence. Osteoporosis in patients with HIV does appear to be modifiable by addressing risk factors, employing pharmacologic therapies that increase bone density, and reducing exposure to antiretroviral agents that exacerbate bone loss. Greater attention to this problem may be essential to efforts to extend survival in HIV-infected patients who are otherwise well controlled on their antiretroviral therapies.

Conclusion

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