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Bone and calcium disorders in patients with HIV

Bone and calcium disorders in patients with HIV
Literature review current through: Aug 2023.
This topic last updated: Jan 06, 2023.

INTRODUCTION — As the population with HIV infection continues to live longer due to effective antiretroviral therapy (ART), osteopenia and osteoporosis are becoming more common [1]. Certain lifestyle factors, hormonal changes, and comorbidities that increase the risk of bone loss are prevalent in patients with HIV. These include physical inactivity, suboptimal intake of calcium and vitamin D, cigarette smoking, alcohol and opiate use, low testosterone levels, and coinfection with hepatitis C virus (HCV). ART itself may be associated with decreased bone mineral density.

This topic will discuss pathogenesis, prevalence, risk factors, screening, and interventions for patients with bone loss. Topics of HIV and aging are addressed elsewhere. Issues of screening and management of osteoporosis in the general population are also discussed separately. (See "HIV infection in older adults" and "Overview of the management of osteoporosis in postmenopausal women" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men" and "Treatment of osteoporosis in men".)

DEFINITIONS — Osteoporosis is a skeletal disorder characterized by low bone mass, which predisposes to an increased risk of fracture. The World Health Organization defines osteoporosis in postmenopausal females and males older than age 50 as a bone mineral density (BMD) measurement by dual X-ray absorptiometry (DXA) at the spine, hip, or forearm that is at least 2.5 standard deviations below that of a "young normal" adult (T-score ≤-2.5) or a history of one or more fragility fractures. Osteopenia is characterized by low BMD (T-score between -1.0 and -2.5) and can be a precursor to osteoporosis. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women", section on 'Diagnosis'.)

For premenopausal females and males younger than 50 years old, using the Z-score to report BMD is preferred by the International Society of Clinical Densitometry position statement. Z-scores compare a patient's BMD with a population-based reference database of the same age and self-reported ethnicity (when available). A Z-score of -2.0 or lower is defined as "below the expected range for age" [2]. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Evaluation' and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men", section on 'Diagnosis of osteoporosis'.)

EPIDEMIOLOGY

Increased fracture rate — Several studies suggest that fracture rates are higher in individuals with HIV than among matched controls without HIV [3-12]. In a 2020 meta-analysis of studies evaluating the fracture burden among individuals with HIV, the estimated pooled prevalence was 6.6 percent, which represented an almost two-fold greater odds of fracture compared with the general population [11]. In the HIV Outpatient Study (HOPS), a prospective cohort study of 5826 patients with HIV in treatment at 10 HIV clinics throughout the United States, age-adjusted fracture rates were 1.98 to 3.69 times higher than rates in the general population [7]. Another cross-sectional study of 222 outpatients with HIV and an equal number of age-matched uninfected controls reported more fractures in the HIV group (45 versus 16 fractures) [10]. As in the general population, osteoporosis is a strong risk factor for fracture among individuals with HIV. Among 1006 participants in two HIV cohort studies, the presence of osteoporosis was associated with a fourfold increased risk of incident fracture (predominantly of the rib or sternum, hand, foot, and wrist) [13]. However, lower bone mineral density (BMD) does not fully explain the higher risk of bone fracture in people with HIV, highlighting the importance of other risk factors for fracture [14]. As the population with HIV ages, prevention of fractures is likely to become a significant therapeutic goal [15], especially since it is associated with a higher mortality rate [16]. (See "HIV infection in older adults", section on 'Bone health'.)

Prevalence of osteopenia and osteoporosis — Low BMD is one of the factors that predicts fracture risk. As an example, a meta-analysis of 35 observational studies showed that people with HIV had lower lumbar spine and hip BMD than patients without HIV, although the study did not control for potential confounders, such as traditional risk factors of low BMD [12].

Although prevalence estimates of low BMD in patients with HIV vary considerably, most studies indicate a high prevalence of osteopenia and osteoporosis:

A meta-analysis, which included 20 cross-sectional studies reporting BMD measurements among 884 patients with HIV, demonstrated that 67 percent had reduced BMD with 15 percent meeting criteria for osteoporosis [17].

In a study of 671 patients in Spain who were followed for a median of 2.5 years, osteopenia and osteoporosis were diagnosed in 48 and 23 percent of patients, respectively [18].

In a cross-sectional survey of 492 patients with HIV within the Aquitaine cohort, osteopenia was diagnosed in 55 percent of males and 51 percent of females; osteoporosis was diagnosed in 34 percent of males and 8 percent of females [19]. In this cohort, the higher prevalence of low BMD in males than in females may be explained by their slightly older age (median age 43 versus 41 years) and more frequent tobacco use (74 versus 59 percent).

Another cross-sectional study of 1143 patients with HIV in China confirmed high prevalence of osteopenia and osteoporosis, although it was not as pronounced as in the earlier studies [20]. In the ART-naïve group, 18.3 percent had osteopenia and 1 percent had osteoporosis, compared with 29.8 percent and 2.4 percent, respectively, in the ART group.

In addition to reduced BMD, people with HIV also have less favorable bone microarchitecture [21-23] and diminished strength [21] compared with controls, which may also contribute to the increased fracture risk.

RISK FACTORS FOR BONE LOSS AND FRACTURES — Low bone mineral density (BMD) among patients with HIV infection is usually multifactorial, since both traditional risk factors (eg, weight loss, malnutrition, hypogonadism, vitamin D deficiency, and HIV-associated risk factors [eg, antiretroviral therapy (ART) medications, associated body composition changes, duration of HIV infection, chronic illness]) may be present [24].

Traditional risk factors — Traditional risk factors for bone loss such as female sex, advanced age, low body mass index (BMI), malabsorption, physical inactivity, steroid use, duration of menopause, smoking, and injection drug use may act in concert with HIV-associated risk factors [20,25-29]. For females, the importance of the status of reproductive function was highlighted by a study of 84 normal-weight females with HIV that reported reduced bone density among females with oligomenorrhea or elevated follicle-stimulating hormone (FSH) levels compared with females with normal menses [30]. (See "Epidemiology and etiology of premenopausal osteoporosis", section on 'Secondary causes' and "Etiology of osteoporosis in men", section on 'Etiology'.)

Vitamin D deficiency — Several studies have demonstrated low vitamin D levels among patients with HIV [31,32]; however, it is unclear if the high rates of vitamin D deficiency and insufficiency are truly higher than those in the general population.

In a study of 270 patients with HIV on ART in the United States (85 percent males and 61 percent self-identified Black), the prevalence of a low 25-hydroxy-vitamin D level (<20 ng/L [<50 nmol/L]) was high but not statistically different from that among a matched control group without HIV (69 versus 59 percent) [32]. Furthermore, low 25-hydroxy-vitamin D levels were not associated with low BMD in this cohort. It should be noted, however, that this study reported on a predominantly Black population, among which low 25-hydroxy-vitamin D levels are more prevalent in general. The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN) found that, among 672 participants, 70 percent had a 25-hydroxy-vitamin D level <30 ng/L (<75 nmol/L) compared with 79 percent in the general United States population based on National Health and Nutrition Examination Survey (NHANES) data [33].

The optimal serum 25-hydroxy-vitamin D level for skeletal health is controversial. The authors of this topic recommend targeting a 25-hydroxy-vitamin D concentration greater than 30 ng/mL (75 nmol/L) in patients at risk for bone loss, which includes those infected with HIV. Experts agree that levels lower than 20 ng/mL are suboptimal for skeletal health. This is discussed in detail elsewhere. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D sufficiency'.)

HIV infection — In addition to the high prevalence of traditional risk factors for bone loss among the population with HIV, HIV infection itself may also contribute. This has been supported by epidemiologic data and studies of pathogenesis [17].

Several observational studies have suggested an association between HIV infection and low BMD [34-36]. As an example, in a study of 210 individuals with HIV and 264 without, HIV infection was independently associated with reduced femoral neck, total hip, and lumbar spine BMD after adjusting for demographic factors and BMI [35]. Additionally, the stage of HIV disease may also modify the risk. In the HIV Outpatient Study (HOPS) of almost 6000 patients with HIV, which demonstrated an elevated incidence of fracture among individuals with HIV compared with the general population, nadir CD4 cell count <200 cells/microL was associated with a higher risk of fracture [7].

Mechanistic studies of bone loss in HIV support these observations. HIV infection leads to chronic T-cell activation and increased production of proinflammatory cytokines that enhance osteoclast activity [37]. The cytokine Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL) induces bone loss, while osteoprotegerin (OPG) counteracts its activity. In individuals with HIV, RANKL expression is increased and OPG expression is decreased in immune cells, leading to accelerated bone loss [38]. Furthermore, HIV proteins decrease bone formation by promoting osteoblast apoptosis (programmed cell death) [39].

Hepatitis C infection — Infection with hepatitis C virus (HCV), regardless of the presence of HIV infection, has been associated with reduced BMD [40] as well as increased fracture risk [7,8,41,42]. In a large cross-sectional study of patients on public health insurance in the United States, the incidence of hip fracture, as assessed by diagnostic coding, was higher among those infected with HCV compared with either uninfected or HIV-monoinfected patients (2.7 versus 1.3 and 2.0 events per 1000 person-years, respectively) [8]. The highest rate of hip fracture was observed among patients coinfected with both HIV and HCV (3.1 events per 1000 person-years). Proposed mechanisms have included alterations in calciotropic and gonadotropic hormone levels and weight loss [41].

Non-ART medications — Opiates were associated with low BMD in a study of 14 male heroin addicts who showed an 11 percent reduction in lumbar BMD compared with previous users and healthy age- and sex-matched controls [43]. Associated hypogonadism in chronic opiate users may, at least partially, explain their reduced BMD.

Other medications used in patients with HIV that may accelerate bone loss include glucocorticoids and ketoconazole.

Antiretroviral therapy (ART) — Several studies have noted a decrease in BMD and increased fracture rate in patients with HIV and exposure to ART, particularly with certain agents (eg, tenofovir disoproxil fumarate [TDF]) [40]. This decrease appears to stabilize after the first one to two years of therapy [44].

Bone mineral density

Overall risk — Most studies have indicated an increased rate of bone loss with exposure to ART. Further studies are needed to clarify the clinical significance of these BMD declines, although the presence of frank osteoporosis is a strong risk factor for fracture.

In a meta-analysis of 10 studies comparing ART-naïve (n = 202) with ART-treated (n = 824) patients, there was a 2.5-fold increase in the odds of low BMD in ART-exposed patients; however, most of these studies did not adjust for HIV disease severity or duration of infection [17]. Studies published subsequent to this meta-analysis further suggest that initiation of ART induces a marked loss of BMD ranging from 2 to 6 percent within the first 48 weeks [45-49].

Other studies have suggested that traditional risk factors and duration of HIV infection may contribute more to decreased bone density than ART exposure [19,30,34,50-53]. Some of these studies, however, include patients treated before TDF was introduced in 2001. In a cross-sectional study of 142 study participants, osteopenia and osteoporosis were demonstrated more frequently in patients with HIV compared with uninfected controls. However, there were no differences in bone density among patients with HIV who were treatment-naïve or treatment-experienced, regardless of regimen [53]. Similarly, in a cohort of females greater than 40 years of age, the majority of whom had used illicit drugs, those with HIV infection had reduced BMD in the femoral neck and spine, independent of antiretroviral exposure, when compared with controls. Significant risk factors included self-identifying as non-Black, low weight, and use of methadone maintenance [34].

Risk with specific agents

Tenofovir disoproxil fumarate – The initiation of tenofovir disoproxil fumarate (TDF)-containing ART regimens has been shown to lead to initial, modest bone loss that subsequently stabilizes [26,47,54-58]. As an example, in a randomized trial of either TDF or stavudine in combination with lamivudine and efavirenz, patients in the tenofovir arm had a significantly greater percent change from baseline in lumbar spine BMD at 48 weeks compared with those in the stavudine arm. No further decrement was seen at 144 weeks of follow-up [54]. Similarly, in the STEAL trial of 357 virologically suppressed patients, those who switched to TDF-containing ART had greater bone loss at 48 and 96 weeks compared with those patients who were switched to abacavir-based ART [56]. TDF-containing regimens were also associated with more bone loss than maraviroc-containing regimens [59]. The negative effects of TDF on BMD have been observed when TDF is used for both HIV treatment and pre-exposure prophylaxis (PrEP), though the magnitude of this effect appears to be attenuated when it is used for PrEP [60].

Tenofovir alafenamide – Tenofovir alafenamide is a different formulation of tenofovir that is associated with less detrimental effects on bone density and similar viral suppression efficacy compared with TDF [61]. In several randomized trials of patients initiating therapy with either a TAF or TDF-containing regimen, those receiving TAF had smaller BMD decreases at the spine and hip at 48 weeks compared with TDF [62,63]. This BMD benefit was sustained at 96 weeks with no difference in viral suppression [64,65]. The rate of fractures and >5 percent decreases in BMD were also higher with TDF but were overall rare in both treatment arms. In subsequent trials, switching from a TDF regimen to a TAF regimen resulted in improved bone outcomes [66-70]. This unequal effect on BMD was also demonstrated in a study of PrEP, with the differences more pronounced in younger participants [71]. No effect on fracture was reported; thus, it is uncertain if these small differences in BMD translate into clinically meaningful change in overall fracture risk. (See 'Switching ART regimens' below.)

Protease inhibitors – Some data point to a negative effect of protease inhibitors on BMD [45,55,72,73]. As an example, a substudy of the AIDS Clinical Trial Group trial (A5202) found that patients randomly assigned to atazanavir had greater losses of BMD in the spine, but not the hip, than patients assigned to efavirenz [55]. Similarly, ritonavir-boosted atazanavir or darunavir were associated with greater declines in spine and hip bone density compared with raltegravir in another trial [73]. The observed difference may be related to the increase in tenofovir concentrations when TDF is given with boosted protease inhibitors.

Longitudinal studies, however, have not supported this finding. A study of 128 patients with HIV, 93 of whom were followed for 72 weeks, found a weak association with protease inhibitor use that was abrogated after controlling for traditional risk factors [51]. Another longitudinal study also noted similar observations and demonstrated that low BMI was a significant predictor of low BMD [52].

Osteoporotic fracture — In the EuroSIDA prospective cohort study of 11,820 patients with HIV, there were 619 fractures in 86,118 person-years of follow-up [74]. In a multivariate analysis, persons who had ever used TDF (relative risk [RR] 1.40, 95% CI 1.15-1.70) or who were currently on TDF (RR 1.25, 95% CI 1.05-1.49) had a higher incidence of fractures. There was no association between cumulative TDF exposure or exposure to other ART and fracture risk.

In a retrospective analysis of about 56,000 males with HIV in the United States Veterans Health Administration’s registry, 941 patients with probable osteoporotic fractures (wrist, hip, and vertebral fractures) were identified after a mean of 5.4 years of follow-up [75]. After controlling for other osteoporotic risk factors, cumulative ART use was not associated with an increased rate of fracture. TDF use specifically was associated with a small but significant increase in the fracture rate (hazard ratios [HR] 1.12, 95% CI 1.03-1.21 for every year of TDF use), but this was only seen in the subset of patients who entered the cohort in the era of combination ART. Furthermore, the traditional risk factors of age, race, low BMI, and smoking were substantially more strongly associated with fracture incidence.

In a case-control study, the 2477 patients with HIV and a history of nontraumatic fracture were more likely to have advanced HIV disease (41 versus 37 percent) and less likely to have taken ART (51 versus 60 percent) than the 9144 age- and sex-matched controls [76]. This study did not identify an increased risk of fracture with TDF. There was an association between fracture and darunavir exposure, but the small number of events in the subset limits the interpretation of this finding.

Further evaluation with prospective studies and longer follow-up are needed to assess more accurately the fracture risk with specific antiretroviral agents.

ALTERATIONS IN BONE AND CALCIUM METABOLISM — Changes in bone metabolism rarely result from direct viral infection of bone or parathyroid glands. More commonly, systemic inflammation and circulating cytokines, as well as HIV-associated opportunistic infections, neoplasms, and/or medications affect bone through indirect mechanisms [77].

Markers of bone metabolism — Biochemical markers of bone metabolism were measured in a cross-sectional analysis of 73 patients; those with advanced HIV disease demonstrated low levels of osteocalcin (a marker of bone formation) and high levels of C-telopeptide (a marker of bone resorption). In 16 of these patients who were followed after the initiation of antiretroviral therapy (ART), osteocalcin levels rose and were correlated with C-telopeptide, suggesting a beneficial effect of ART on bone remodeling [78].

Parathyroid hormone — Impaired parathyroid (PTH) secretion and action have been reported in patients with HIV infection, even in the absence of parathyroid infiltrative disease. Not only are baseline PTH levels lower in individuals with HIV than in controls [79], but a study of six patients with AIDS who underwent ethylenediaminetetraacetic acid (EDTA)-induced hypocalcemia showed diminished PTH response at all calcium concentrations [80].

Treatment with tenofovir disoproxil fumarate (TDF) has been associated with higher PTH levels than otherwise seen in those with HIV [81]. In one study, initiating antiviral therapy (ART) with a TDF-containing regimen led to an elevation in PTH soon after introducing the drug, with suboptimal 25-hydroxy-vitamin D levels (<30 mcg/liter) associated with higher PTH levels [82]. In a separate trial of young adults infected with HIV on ART, PTH levels were higher in the 120 patients on regimens containing TDF than in the 87 on regimens without TDF (mean 48 versus 31 pg/mL), independent of baseline serum 25-hydroxy vitamin D levels [83]. Although statistically significant, these differences in PTH level are of uncertain clinical significance. A single-center retrospective study of 132 patients showed that switching from TDF to TAF was associated with a decline in PTH levels, suggesting a potential mechanism for the improved bone outcomes observed with such a switch [84]. (See 'Switching ART regimens' below.)

Calcium — Hypercalcemia can result from malignant (eg, lymphoma) or granulomatous processes associated with extrarenal 1-alpha-hydroxylation of 25-hydroxy-vitamin D to the active 1,25-dihydroxy-vitamin D, resulting in enhanced intestinal calcium absorption. (See "Etiology of hypercalcemia".)

Several case reports have described hypercalcemia in association with the immune reconstitution inflammatory syndrome that can occur after the initiation of ART. Associated infections and diseases have included tuberculosis [85,86], Mycobacterium avium complex [87], cryptococcus [88], sarcoidosis [89], and high-grade lymphoma [90]. (See "Immune reconstitution inflammatory syndrome".)

Hypocalcemia, after adjusting for serum albumin, was found in 6.5 percent of patients with HIV compared with 1.1 percent of patients without HIV. In 10 of the 21 patients with AIDS, vitamin D deficiency was found to be the etiology [91].

Vitamin D — Several studies have shown an association between treatment with efavirenz and low vitamin D levels [33,92-94]. The mechanism for this may be reduced expression of cytochrome P450 2RI, which is involved in the 25-hydroxylation of vitamin D. Efavirenz may also promote the conversion of vitamin D into its inactive metabolites.

Phosphate — TDF administration has also been associated with Fanconi's syndrome, which is characterized by renal phosphate wasting, hypophosphatemia, metabolic acidosis, glycosuria, and aminoaciduria; skeletal complications of this syndrome include osteomalacia [95-97].

Medications — Abnormalities in calcium concentration may also be an adverse effect of several medications used in the treatment of the complications of HIV, such as foscarnet, pentamidine, and recombinant human growth hormone.

BONE MINERAL DENSITY SCREENING

Whom to screen — Bone mineral density (BMD) screening with dual X-ray absorptiometry (DXA) scan is recommended by several expert groups in the United States for all postmenopausal females and males with HIV >50 years of age [98,99].

The rationale for earlier screening among individuals with HIV compared to the general population is that, based on the results of several prospective and retrospective studies, HIV infection itself should be considered an additional risk factor for osteoporosis [98] (see "Screening for osteoporosis in postmenopausal women and men"). Other risk factors for bone loss include patients with low body mass index (BMI), smoking history, hypogonadism, chronic glucocorticoid use, or early menopause.

In resource-limited settings, using the Fracture Risk Assessment Tool (FRAX) without DXA for older patients is also reasonable to either target patients for DXA most likely to have low BMD or initiate treatment of osteoporosis if DXA is unavailable [100]. When calculating FRAX, country-specific algorithms and thresholds for intervention are recommended. FRAX was developed to predict 10-year probability of fracture based on clinical risk factors (eg, age, family history, smoking, glucocorticoid use) and BMD at the femoral neck. The FRAX model, however, has not been validated in the population with HIV. In a study of 153 adults with HIV infection, of whom 42 percent had low BMD, only three (2.2 percent) had a 10-year probability of major osteoporotic fracture >20 percent by the FRAX scoring system, but this may have been due to the relatively young age (median 48 years) and male predominance (98 percent) of the patient population [101]. In another study of mostly males who were older than 50 years of age, a FRAX score result >10 percent did not identify 99 percent of the patients in the cohort with osteoporosis [102]. Longitudinal studies documenting the relationship between FRAX score and fracture risk in the population with HIV are needed.

To decide whether to perform DXA in younger patients with HIV (males aged 40 to 49 years and premenopausal females aged >40 years), another international expert panel suggested using FRAX without DXA to identify patients with high 10-year risk of fracture [103]. This approach, however, is unlikely to identify candidates for DXA using current FRAX thresholds [40,104]. Twenty-three percent of patients under 50 years of age had low BMD in a longitudinal study of 217 patients with HIV, but none met criteria for DXA even when selecting "secondary osteoporosis" in the FRAX calculator [40]. We rarely perform DXA in these younger patients unless they have a history of or major risk factor for fragility fracture.

Interval for screening — The optimal interval for rescreening in the population with HIV is controversial. A study of the general population that included 4957 postmenopausal females (at least 67 years old) suggested that the timing to repeat screening DXA could be based on baseline BMD [105]. Osteoporosis developed in less than 10 percent of subjects during rescreening intervals of approximately 15 years for females with normal bone density (T-score of the femoral neck and total hip >-1) or mild osteopenia (T-score -1.1 to -1.49), five years for females with moderate osteopenia (T-score 1.50 to -01.99), and one year for females with advanced osteopenia (T-score -2.0 to -2.49). In a smaller study of mostly male (73 percent), younger (mean age 39.4 years) patients with HIV, those with mild osteopenia (T score -1.1 to -1.6) progressed to osteoporosis in >8.2 years, moderate osteopenia (T-score -1.6 to -2) in >8.5 years, and advanced osteopenia (T-score -2 to -2.4) in 3.2 years [106].

EVALUATING FOR SECONDARY CAUSES — If osteoporosis is present (based on T-score <-2.5 or presence of a pathological fracture), screening for secondary causes of osteoporosis should also be sought and treated appropriately, including evaluation for hypogonadism and/or wasting [107].

Laboratory evaluation for secondary causes of bone loss in individuals with HIV includes complete blood count, calcium, albumin, phosphorus, blood urea nitrogen (BUN) and creatinine, alanine aminotransferase (ALT), alkaline phosphatase, 25-hydroxy-vitamin D, intact parathyroid (PTH), thyroid-secreting hormone (TSH), 24-hour urine calcium and creatinine, morning total testosterone in males, and estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin in young, amenorrheic females [98]. Measuring 25-hydroxy-vitamin D levels, which indicate the body's vitamin D stores, may be especially useful given the high prevalence of vitamin D insufficiency or deficiency reported in populations with HIV [108,109]. Evaluation for other secondary causes (such as multiple myeloma, celiac disease, and Cushing syndrome) may be indicated based on the patient’s history and/or physical examination. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women", section on 'Evaluation' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Evaluation' and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men", section on 'Evaluation'.)

MANAGEMENT — Making recommendations for the management of low bone mineral density (BMD) in populations with HIV is especially challenging, given that most experience in the treatment of osteopenia and osteoporosis has been in postmenopausal females. Since age has an important effect on fracture risk [110], and individuals with HIV tend to be younger than other patients with osteoporosis, BMD alone may overestimate true fracture risk in these patients.

Treatment of osteopenia and osteoporosis in older patients with HIV does not differ from recommendations in older individuals without HIV [111]. Treatment approaches can include both lifestyle changes and pharmacologic therapy. In accordance with the National Osteoporosis Foundation guidelines, pharmacologic treatment of osteoporosis is recommended for:

Postmenopausal females and males >50 years with a T-score of the femoral neck or lumbar spine less than or equal to -2.5.

Patients with a history of fragility fracture of the spine or hip.

Patients with low bone mass (T-score between -1 and -2.5 at the femoral neck or lumbar spine) and high probability of a major fracture, based on the Fracture Risk Assessment Tool (FRAX). In the United States, the threshold for pharmacologic treatment is a 10-year probability of fracture that is >3 percent for the hip or >20 percent for any major osteoporotic fracture.

Lifestyle changes — Lifestyle changes such as smoking cessation, moderation of alcohol intake, weight-bearing exercise, and optimization of calcium and vitamin D intake can lead to modest improvements in BMD and should be encouraged. (See "Calcium and vitamin D supplementation in osteoporosis" and "Overview of the management of osteoporosis in postmenopausal women", section on 'Lifestyle measures' and "Treatment of osteoporosis in men", section on 'Lifestyle measures'.)

Calcium and vitamin D supplementation — Clinical trial data assessing the optimal doses in adults with HIV are limited.

In the United States, the Institute of Medicine (IOM) released a 2010 report establishing reference dietary intakes for calcium and vitamin D, depending on age and sex (table 1) [112]. If dietary calcium intake is inadequate, we suggest moderate calcium supplementation to reach the recommended dietary allowance (RDA). Calcium intake and absorption may be assessed through a 24-hour urine collection for calcium and creatinine. The RDA of vitamin D is 600 international units (15 mcg) for adults through age 70 years and 800 international units (20 mcg) after age 71 years [112]. The IOM committee concluded that 25-hydroxy-vitamin D levels above 20 ng/mL are adequate for bone health in most individuals.

In patients with HIV and osteoporosis, we generally target a 25-hydroxy-vitamin D level of at least 30 ng/mL since this population has increased risk for fracture and there is a low risk of harm from these moderate vitamin D doses. Most individuals do not achieve this level of vitamin D intake through diet alone and warrant supplementation. Dietary sources of calcium and vitamin D are discussed elsewhere. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Dietary sources'.)

These targets are consistent with the Endocrine Society Clinical Practice Guidelines on the management of vitamin D deficiency, which suggest targeting a 25-hydroxy-vitamin D level above 30 ng/mL and acknowledges that reaching this level may require at least 1500 to 2000 international units of supplemental vitamin D [113].

Pharmacologic therapy — The overall approach to pharmacologic management in patients with HIV is similar to that for the general population. (See "Evaluation and treatment of premenopausal osteoporosis", section on 'Management' and "Treatment of osteoporosis in men", section on 'Patient selection' and "Overview of the management of osteoporosis in postmenopausal women".)

Briefly, for postmenopausal females and males with HIV and established osteoporosis (T-score ≤-2.5) or for any patient with HIV and fragility fracture, we typically initiate pharmacologic therapy. Nevertheless, pharmacologic therapy for osteoporosis in patients with HIV should be considered carefully before initiation, given the lack of prospective data on fracture in this patient population. Long-term side effects are also not known, and some rare conditions, such as osteonecrosis of the jaw and atypical thigh fractures, have been associated with long-term use of bisphosphonates. This is a very important issue since patients with HIV may be initiating therapy at a younger age than in the general population.

For pharmacologic therapy in patients with HIV, we suggest bisphosphonates as first-line therapy for postmenopausal females and males. For females of reproductive potential, however, bisphosphonate use should generally be limited to special circumstances given toxic effects on pregnant rats that suggest the possibility of adverse fetal effects with exposure. Denosumab is a reasonable alternative therapy for patients who cannot tolerate bisphosphonates, have deteriorating BMD and/or clinical fractures on bisphosphonates, or in patients with impaired renal function, as there are limited data indicating safety and efficacy in those with HIV [114,115]. Other pharmacologic agents (eg, teriparatide, abaloparatide, selective estrogen receptor modulators, romosozumab) are reasonable alternatives but have not been specifically studied in patients with HIV.

Bisphosphonates — Bisphosphonates are pyrophosphate analogues that inhibit bone resorption by binding to hydroxyapatite crystals. They are generally considered first-line therapy for osteoporosis. As above, consideration of potential effects with long-term use is important when initiating therapy in patients with HIV. (See "Bisphosphonate therapy for the treatment of osteoporosis" and "Risks of bisphosphonate therapy in patients with osteoporosis".)

Studies suggesting benefit of bisphosphonates in patients with HIV are highlighted below.

Alendronate

In a 48-week prospective, randomized, open-label study of alendronate (70 mg once weekly) administered in combination with calcium and vitamin D in 31 patients with HIV, there was a significant increase in lumbar spine BMD compared with subjects taking calcium and vitamin D alone (5.2 versus 1.3 percent) [116].

Another small, open-label study of 25 individuals with HIV and osteoporosis evaluated the added efficacy of alendronate plus dietary counseling compared with counseling alone [117]. Patients randomly assigned to the alendronate arm demonstrated significant improvements in lumbar and hip BMD and reduced rates of osteoporosis (27 versus 96 percent) compared with counseling alone [118].

A prospective, randomized, placebo-controlled trial (AIDS Clinical Trial Group Study 5163) evaluated the effectiveness of calcium and vitamin D supplementation compared with calcium/vitamin D with alendronate in 58 male and 24 female patients with HIV and decreased BMD [119]. Patients randomly assigned to the alendronate arm had significant improvements in BMD at the lumbar spine, total hip, and trochanter compared with those assigned to supplementation alone. Alendronate was also well-tolerated.

Alendronate also reduces bone resorption markers in patients with HIV infection [117].

Zoledronic acid Zoledronic acid is a bisphosphonate that is administered by the intravenous route as an annual infusion; this offers the potential for greater adherence. Several trials in patients with HIV (predominantly males) with bone loss have demonstrated that zoledronic acid can increase BMD [120-123]. As an example, a two-year randomized, placebo-controlled study of 43 males with HIV and mild bone loss (T-score <-0.5) treated with annual infusions of 4 mg zoledronic acid showed significant increases in BMD in the lumbar spine (8.9 versus 2.6 percent) and in the total hip (3.8 versus 0.8 percent) [121]. Persistent improvement in BMD and bone turnover markers were observed in a subset of males in this study up to 11 years after the second dose [124]. In a randomized trial of patients on a TDF-containing regimen, two infusions of zoledronic acid increased BMD more than switching to a different ART regimen [125].

Denosumab — Denosumab is a human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), which inhibits osteoclast formation, reduces bone resorption, increases BMD, and decreases the risk of fracture (see "Denosumab for osteoporosis"). In an open-label, 12-month, prospective study of 23 males with HIV and low BMD who were administered either a single IV infusion of zoledronate or denosumab injections every six months, both agents were well tolerated and improved BMD compared with placebo [114]. BMD change in the lumbar spine did not differ between the two treatment groups, but zoledronate led to greater gains in femoral neck BMD.

Other — Other medications used in the treatment of osteoporosis include teriparatide (parathyroid hormone analog), abaloparatide (parathyroid hormone-related protein analog), romosozumab (monoclonal antibody that inhibits sclerostin), calcitonin, hormone replacement therapy with estrogen and/or progesterone, and selective estrogen receptor modulators (eg, raloxifene). Data on the use of these agents in populations with HIV are extremely limited.

A case report described the use of teriparatide in a male with HIV who showed significant improvement in BMD after initiation [126]. This patient was treated for two years and then received subsequent consolidation therapy with alendronate to sustain these gains in BMD. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)

Switching ART regimens — For patients on tenofovir disoproxil fumarate (TDF) who are diagnosed with low BMD, we suggest switching TDF to tenofovir alafenamide (TAF), based on studies discussed below that demonstrate an improvement in BMD with this strategy. However, given the lack of data on the impact on fracture rate, the decision to switch should also take into account cost, availability, and patient preference. Switching to a non-tenofovir-containing regimen is also reasonable, but there is less evidence to support this. For individuals on TDF who have renal phosphate wasting, we recommend switching the TDF to either TAF or a different agent [127]. This can be assessed by measurement of phosphate in a 24-hour urine collection or calculation of the fractional excretion of phosphate (wasting indicated by a value >20 to 30 percent). The general approach to switching antiretroviral therapy (ART) regimens is discussed in detail elsewhere. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

Although certain antiretroviral therapy (ART) regimens (such as TDF or protease inhibitor-containing regimens) may be associated with greater decreases in BMD, there is no evidence that switching ART will reduce fracture risk in those with established osteoporosis [98]. Some experts, however, have suggested avoiding both TDF and boosted-protease inhibitors in patients at high risk for fragility fracture [103].

Studies that evaluated switching TDF-containing to TAF-containing regimens have demonstrated modest benefits to BMD [66,67]. Whether these translate into long-term benefits in fracture incidence is unknown. In a trial of 1436 patients with HIV virally suppressed on a TDF-containing regimen, BMD values at 48 weeks were higher among those randomly assigned to switch to a TAF-containing regimen compared with those who remained on TDF (percent change difference of 1.8 and 2.0 percent for hip and spine, respectively) [67]. Improvements in BMD were noted in both patients with an estimated glomerular filtration rate (eGFR) of 50 mL/minute or greater [67] and those with renal impairment (eGFR 30 to 69 mL/minute) [67]. Virologic suppression with the TAF regimen was at least as high as with TDF.

Results of studies evaluating switching from TDF to non-tenofovir regimens vary by regimen but overall suggest a benefit to bone health. In a sub-study of a randomized trial of patients who had achieved stable viral suppression on a TDF-containing regimen, those who switched to dolutegravir plus rilpivirine had greater increases in hip and lumbar BMD at 48 weeks compared with those who remained on the TDF regimen [128]. In a small, randomized pilot study of patients on TDF who had osteopenia or osteoporosis, there was slight improvement in femoral neck BMD at 48 weeks among those who switched to abacavir but no significant difference compared with those who were maintained on TDF [129].

Studies evaluating switching from a protease inhibitor-based regimen have not demonstrated benefits to BMD. In one small study that evaluated 18 patients who switched from a protease inhibitor-based regimen to a non-nucleoside reverse transcriptase inhibitor-based regimen, no improvements in BMD were observed on dual X-ray absorptiometry (DXA) scanning after 48 weeks of follow-up [130].

PREVENTION OF BONE LOSS — As for the general population, measures to prevent osteoporosis in individuals with HIV include maintaining adequate calcium and vitamin D intake, engaging in physical activity (but not to excess), avoiding cigarette smoking, and limiting alcohol intake. (See "Prevention of osteoporosis".)

Vitamin D supplementation can help prevent bone loss, although the optimal dose in individuals with HIV has not been established. One trial evaluated the effects of high-dose vitamin D (4000 international units) and 1000 mg calcium carbonate supplementation among 167 predominantly male antiretroviral-naïve individuals with normal baseline bone density who were initiating efavirenz-tenofovir disoproxil fumarate (TDF)-emtricitabine [131]. Those randomly assigned to receive high-dose supplementation had slightly less bone loss at the hip and lumbar spine after 48 weeks compared with those assigned to placebo. However, the estimated baseline daily vitamin D intake was low in both groups (median 120 and 137 international units). A subsequent randomized trial of young individuals with HIV (ages 16 to 24, predominantly male and self-identifying as Black) who were taking a TDF-containing antiretroviral regimen suggested benefits with approximately 2000 international units per day [132]. In that trial, monthly vitamin D at a 50,000 international unit dose resulted in a higher 25-hydroxy-vitamin D level (37 versus 21 ng/mL) and greater gains in lumbar spine bone mineral density (BMD, 1.15 versus 0.09 percent increase) at 48 weeks compared with placebo; each was given in addition to a daily multivitamin that contained calcium and 400 international units of vitamin D. Among those who received monthly vitamin D, increases in BMD were similar regardless of baseline 25-hydroxy-vitamin D level.

Bisphosphonate administration appears to be protective of antiretroviral-associated bone loss, but this strategy is of uncertain clinical benefit and not recommended at this time. In a trial of 63 treatment-naïve individuals with HIV who were initiating treatment with TDF, emtricitabine, atazanavir, and ritonavir, markers of bone resorption were lower and bone mineral density (BMD) was slightly higher at 48 weeks after a single infusion of zoledronic acid versus placebo [133]. Given this study population's young age (average 39 years), normal baseline BMD, and short follow-up, it is unclear whether this modest BMD change will be sustained and/or will prevent fracture. Given the potential for adverse effects of long-term use of bisphosphonates, we favor deferring pharmacologic intervention until the risk of fracture warrants it. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Patient selection'.)

OSTEOMALACIA — Osteomalacia refers to defective bone mineralization, typically due to inadequate vitamin D, calcium, or phosphate (see "Epidemiology and etiology of osteomalacia" and "Clinical manifestations, diagnosis, and treatment of osteomalacia in adults"). In patients with HIV, osteomalacia has been associated with tenofovir disoproxil fumarate (TDF) use [134]. These patients typically present with diffuse bone pain, especially in the lower limbs due to multiple stress fractures, and difficulty ambulating. We recommend discontinuing TDF in these patients.

OSTEONECROSIS — Osteonecrosis, also called avascular necrosis, occurs when there is insufficient circulation to an area of bone and usually presents as either unilateral or bilateral bone or joint pain.

Osteonecrosis has been described in individuals with HIV in several case reports and case series [6]. A remarkably high prevalence of avascular necrosis of the hip (4.4 percent) was detected by magnetic resonance imaging (MRI) in a cross-sectional study in 339 asymptomatic patients with HIV as compared with no cases detected among the non-infected controls [135]. Although this study focused on the hip, avascular necrosis can affect other joints such as the shoulder [136]. Some patients, but not all, have other identifiable risk factors for osteonecrosis, including prior glucocorticoid exposure. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults".)

In the EuroSIDA prospective cohort study of 11,820 patients with HIV, there were 89 cases of osteonecrosis in 86,118 person-years of follow-up [74]. The risk of osteonecrosis was associated with self-identifying as White, lower nadir CD4 count, prior osteonecrosis, prior fracture, and an AIDS-defining diagnosis. In multivariate analysis, no association was identified with any type of antiretroviral therapy (ART).

The mainstay of therapy remains surgical intervention to alleviate symptoms.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary care of adults with HIV".)

SUMMARY AND RECOMMENDATIONS

Alterations in bone and calcium metabolism Changes in bone metabolism rarely result from direct HIV infection of bone or parathyroid glands. More commonly, systemic inflammation and circulating cytokines, as well as HIV-associated risk factors, opportunistic infections, neoplasms, and/or medications have indirect effects on bone metabolism. (See 'Alterations in bone and calcium metabolism' above.)

Prevalence of osteopenia and osteoporosis Although prevalence estimates of low bone mineral density (BMD) vary considerably, studies indicate that patients with HIV are at increased risk of osteoporosis and fracture compared with individuals without HIV. (See 'Prevalence of osteopenia and osteoporosis' above.)

Risk factors for bone loss and fractures

Non-HIV-related risk factors Low BMD among patients with HIV infection is usually multifactorial, since weight loss, malnutrition, malabsorption (leading to vitamin D deficiency), coinfection with hepatitis C virus (HCV), and hypogonadism may be present in addition to traditional risk factors, such as female sex, low body mass index (BMI), smoking, and opiate use. (See 'Risk factors for bone loss and fractures' above.)

HIV-related risk factors

-HIV infection itself may lead to bone loss by promoting osteoclast activity and osteoblast cell death. (See 'HIV infection' above.)

-Tenofovir disoproxil fumarate (TDF) is associated with loss of BMD and increased fracture risk. (See 'Risk with specific agents' above.)

Whom to screen We suggest screening for osteoporosis in females with HIV once they are postmenopausal and in males with HIV starting at 50 years of age (Grade 2B). (See 'Whom to screen' above.)

Management of osteoporosis The approach to therapy of osteoporosis in patients with HIV is similar to that of uninfected patients.

Evaluation for secondary causes When osteoporosis is confirmed, secondary causes of bone loss should be excluded.

Nonpharmacologic interventions Nonpharmacologic interventions include lifestyle changes and correction of vitamin D deficiency. (See 'Lifestyle changes' above and 'Calcium and vitamin D supplementation' above.)

Pharmacologic therapy For postmenopausal females and males with HIV and established osteoporosis (T-score ≤-2.5) or any patient with HIV and fragility fracture (except for premenopausal females seeking reproduction), we initiate pharmacologic therapy. For pharmacologic therapy in patients with HIV, we suggest bisphosphonates as first-line therapy (Grade 2C). Denosumab is a reasonable alternative for patients who do not respond or cannot tolerate bisphosphonates. Other pharmacologic agents (teriparatide, abaloparatide, selective estrogen receptor modulators, romosozumab) have not been specifically studied in patients with HIV. (See 'Pharmacologic therapy' above and "Overview of the management of osteoporosis in postmenopausal women", section on 'Summary and recommendations' and "Treatment of osteoporosis in men", section on 'Summary and recommendations' and "Evaluation and treatment of premenopausal osteoporosis", section on 'Management'.)

Change in antiretroviral therapy There is no evidence that switching antiretroviral regimens will reduce fracture risk in those with established osteoporosis. Nevertheless, for patients on TDF who have low BMD, we suggest switching TDF to tenofovir alafenamide (TAF) (Grade 2B). If cost or availability is an issue, it is reasonable for patients without phosphate wasting to continue TDF or switch to an alternate TDF-sparing regimen. For patients on TDF with renal phosphate wasting, we recommend switching the TDF to TAF or a different agent (Grade 1B). (See 'Switching ART regimens' above.)

Osteonecrosis Osteonecrosis has been described in individuals with HIV in several case reports and case series. The mainstay of therapy remains surgical intervention to alleviate symptoms. (See 'Osteonecrosis' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

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Topic 3738 Version 57.0

References

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