Bone Disease

“There is strong clinical evidence that implicates tenofovir in the loss of bone mineral density…Our findings demonstrate for the first time that tenofovir treatment of primary osteoblasts [bone producing cells] results in gene expression changes that implicate loss of osteoblast function in tenofovir-associated bone mineral density loss.”

“The 214 participants were followed for a mean [of] 2.4 years. With continuous ART [anti-retroviral therapy], BMD [bone mineral density] declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART…In the parent study, 10 of 2753 participants in the VS [continuous ARV] group and two of 2720 in the DC [intermittent ART] group reported serious fractures”

“High prevalence of osteopenia and osteoporosis has been recently observed in HIV-infected patients. The pathogenesis of these bone metabolism disorders in HIV infection has not been fully elucidated, even though multiple factors seem to be involved. Osteopenia was initially attributed to highly active antiretroviral therapy (HAART), especially regimens containing protease inhibitors; however, further studies did not confirm this relationship. Then, HIV infection per se was postulated as a possible cause [despite this problem arising after protease inhibitors were approved]…We report of [sic] two AIDS patients who suffered from vertebral fractures [broken back] just a few months after HAART introduction.”

“Among men, the following factors significantly associated with the diagnosis of bone mass loss in the univariable model were included in the multivariable analysis: age, follow-up time since HIV diagnosis, transmission group, AIDS clinical stage, HIV plasma viral load <500 copies/ ml, log-based plasma viral load, tobacco consumption, physical activity, cumulative exposure to antiretroviral drug class, BMI [body mass index] <20.6 kg/m^2 and lipodystrophy. Independent factors associated with the diagnosis of osteoporosis were older age, homosexual HIV transmission, low BMI and HIV plasma viral load <500 copies/ml. Only older age and lower BMI were marginally associated with osteopenia. In women, all bone disorders were pooled without distinction between osteopenia and osteoporosis because of the lower number of observations in each subgroup. Factors analysed in the multivariable model were menopausal status, age, follow-up time since HIV diagnosis, transmission group, AIDS clinical stage, HIV plasma viral load <500 copies/ml, log-based plasma viral load zenith, CD4 lymphocyte count nadir, alcohol consumption, calcium intake >1 g/day, physical activity, cumulative exposure to antiretroviral drug class and lipodystrophy. Older age and low CD4 cell count nadir were identified as factors associated with reduced BMD [bone mineral density]. To explore further whether the association between low HIV plasma RNA and osteoporosis in men was related to antiretroviral exposure, the effect of cumulative exposure to HAART was analysed without adjustment for HIV plasma RNA. Three different multivariable models were developed but in none was the treatment variable effect significant: cumulative exposure to any antiretroviral drug (OR, 1.01), cumulative exposure to HAART (OR, 1.02), and naive versus drug experienced status (OR, 0.28) [note that although this was not statistically significant, probably because of small numbers included who had never taken any drugs, this does indicate a possible massive (more than 3 times greater) risk with taking any AIDS drugs]”

“Although early data suggested that protease inhibitors might have a deleterious effect on bone metabolism, recent results do not support these findings [cleverly, this study studied whether protease inhibitors were more likely than other AIDS drugs to cause bone disease, there were few if any patients in the study not taking drugs in other classes]. Likewise, preliminary warnings have appeared with respect to tenofovir, suggesting an increased loss of BMD [bone mineral density] with the use of this nucleotide, in comparison with other nucleosides. However, other clinical studies with a long follow-up did not reveal changes in BMD or an increased incidence of bone fractures in patients receiving a tenofovir-containing regimen. [Again, this does not show that Tenofovir doesn't cause bone disease, just that it's not significantly different than other drugs to do so]”

“Among HIV-infected patients receiving antiretroviral therapy (ART), reduced BMD [bone mineral density] has been reported with increasing frequency…We conducted a systematic review and six meta-analyses of cross-sectional studies published in English to determine the pooled odds ratios (OR) of reduced BMD and osteoporosis in the following groups: HIV-positive versus HIV-negative; ART[antiretroviral therapy]-treated versus ART-naive [untreated]; and PI[protease inhibitor]-treated versus PI-untreated individuals…ART-treated subjects had a higher prevalence of reduced BMD compared with ART-naive subjects. In addition, for the seven studies that included appropriate data, the odds of osteoporosis was increased 2.4 times in ART-treated subjects compared with ART-naive subjects. None of the studies adjusted for potentially important confounding factors, such as age or the duration of HIV infection [which is to some extent a measure of the total amount of ART consumed]”

“Osteonecrosis [bone decay] was diagnosed in 104 subjects [out of 56,393], corresponding to an incidence rate of 4.5/10 000 person-years and affected the hip in 83, the knee in 14 and other joints in 16 patients. Of these patients, 63 received analgesics and 52 were treated surgically…The incidence of osteonecrosis was also higher among subjects exposed to cART [combination antiretroviral therapy]. The adjusted RR [risk ratio] ranged from 2.6 among patients treated with cART for < 12 months (compared with patients unexposed to cART), to 5.1 among patients treated for 60 months.”

“Bone disorders in HIV-1 patients treated with highly active antiretroviral therapy (HAART) are an emerging issue…After approximately 27 months of treatment with indinavir (800 mg three times a day), zidovudine [AZT] and lamivudine [3TC], a 56-year-old HIV-1-infected bisexual man noticed thickenings on almost all fingers of his hands. He also noted several small protrusions at the costosternal [breastbone] junctions…After the introduction of indinavir [a protease inhibitor] in June 1998, the patient experienced myalgia [muscle pain], arthralgia [joint pain], dry skin, body hair loss, and ingrown toenails developed. The patient has also been taking trimethoprim–sulfamethoxazole…On examination in November 2000, a hand X-ray revealed periostal [near the bone] reactions in the diaphyseal [shaft] regions of all proximal phalanges, the middle phalanges [finger bones] of both index fingers, and navicular bones. Osteosclerosis [bone thinning] was present throughout the spine, this was now also apparent in the lumbar region. Radiographic evidence of osteosclerosis [bone thinning] was also observed in the skull, and a marked periostal reaction was present in the middle part of both radial bones…In December 2000, indinavir was replaced with nelfinavir, nucleoside analogues were not changed, but the patient refused to stop taking multivitamins [which he had been taking for 20 years]. Four months after indinavir therapy was discontinued, an X-ray showed a strikingly reduced periostal reaction on the patient's fingers…We have presented the first patient with osteosclerosis and new bone formation during indinavir therapy…The concomitant long-term use of indinavir with vitamin A, even at the recommended daily dietary allowance, should be discouraged [note that the doctors have no evidence that stopping Vitamin A would have reduced this problem]”

“Bone mineral density (BMD) of total body and lumbar spine (L2-L4) was assessed by dual-energy X-ray absorptiometry in 40 children vertically infected with HIV: 35 taking HAART and 5 naive to any antiretroviral treatment (untreated). 6 HAART-treated children showed clinical evidence of lipodystrophy [abnormal fat redistribution]...HAART-treated children showed lower spine BMD values than untreated (P = 0.045) and healthy (P = 0.004) children and lower total body BMD values than untreated (P = 0.012) and healthy (P < 0.0001) children. Spine and total body BMD were similar between untreated and healthy children.”

“Bone density...was reduced significantly in the HIV+ lipodystrophy versus HIV- control groups...and HIV+ non-lipodystrophy groups...PI [Protease Inhibitor] and NRTI [Nucleoside Analog] use were more prevalent among those diagnosed with lipodystrophy [Table 1 shows that, comparing HIV+ with lipodystrophy against HIV+ without, current NRTI use/duration of use was 100%/67 months vs. 60%/26 months and PI use/duration of use was 90%/35 months vs. 45%/11 months]”

“Prior to the introduction of long-term highly active antiretroviral therapy, healthy HIV-infected adults generally had normal bone mineral density that was stable over time...The present study has confirmed previous studies that found osteopenia [loss of bone mass] to be common in HIV-infected adult males receiving antiretroviral therapy even after adjustment for age. This osteopenia may result from mitochondrial toxicity of nucleoside analogues [which also may be the cause of excessive, sometimes fatal, levels of lactic acid]”

“We describe 5 patients whose symptoms of osteonecrosis [bone disintegration] developed with viral suppression and improvement in CD4 lymphocyte counts as a result of antiretroviral therapy. In addition, we review previously reported cases…We conclude that osteonecrosis is an emerging manifestation of HIV infection and that it may be either a consequence of immunologic and virologic improvement resulting from antiretroviral therapy or a complication caused by the drugs themselves.”

“We report on six patients (out of a cohort of 508 HIV-infected patients, including 280 on triple antiretroviral treatment) who were diagnosed with bilateral avascular necrosis of the femoral head, all between 1998 and January 2000...Four of the six patients had to undergo hip replacement surgery (bilateral in three cases). Of note was the fact that no case of osteonecrosis had been diagnosed in our cohort between 1992 and 1998. As shown in Table 1, all six patients had long exposure to antiretroviral treatments, including protease inhibitors; five out of six had signs of fat redistribution. When on therapy including a protease inhibitor, all patients had an elevated level of plasma triglycerides or cholesterol, and three had developed diabetes linked to insulin resistance...osteonecrosis may be more frequent in HIV-infected individuals, and two cases have already been reported in patients on highly active antiretroviral therapy In our cohort, osteonecrosis involved 2% of all treated patients and approximately 10% of patients had clinical features of lipodystrophy.”

“Osteopenia and osteoporosis [bone weakening disorders] are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution…HIV-infected individuals receiving PI-based HAART are more likely to have significant bone demineralization…which may increase the risk of fracture”