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Bone Loss in HIV Persists Through Chronic Infection for Years
  and is Associated with CD4 Reconstitution Following Initial HAART and Persists Due to Chronic Immune Abnormalities, Inflammation, Activation
.......5-fold increased risk for frailty combines with & contributes to increased falls and fractures in older aging HIV+.....at CROI 2015 in WIHS fracture were 30% higher in HIV+ women vs HIV-negative women [Cocaine and injection drug use were also significant predictors of incident fracture" " of note age matters, every 10-year increase in age increased risk for fracture in HIV+ women by 25%]....bone loss is one of many comorbidities HIV+ patients can experience including kidney decline, cognitive impairment, gait problems, frailty and heart disease which may be the most dangerous

Bone Loss in HIV persists, does not stop 6 months initiation of first HAART: Immediate ART in START Linked to Bigger Bone Loss Over 3 Years.....The START team concluded that people randomized to immediate ART had greater BMD loss at both the hip and spine. Spine BMD dropped steeply in the first year of ART then stabilized, while hip BMD loss continued through 3 years of follow-up.
in this SUN Study analysis at CROI 2015 in Seattle decline in bone loss persisted for 4 years despite viral suppression and again as mentioned below the length of the followup was only for 4 years so the study did not follow patients for longer to see if bone loss continued to decline. Low BMD [bone loss] was associated with inflammation markers (sCD14, IL-6) and immune activation and inversely with certain types of immunity immunity. Bone loss was associated with older age, lower BMI, lower nadir CD4, TDF exposure & duration of HIV, and HCV coinfection also is associated with increased bone loss. STUDY AUTHORS CONCLUDED: Conclusions: In this healthy HIV adult cohort with predominantly controlled viremia, total hip BMD decline was associated with IL-6, replicative senescent T-cells, CCR5+ and tissue factor expressing monocytes. Memory CD4+ and CD8+ CD28+ T cells were associated with increases in BMD. Immunologic alterations that persist after virologic suppression may contribute to ongoing loss of BMD.
In this START sub study on bone loss after immediate ART where followup was for 3 years bone loss persisted through the entire 3 years and after 3 years the slope of decline persisted downward certainly for hip bone loss (BMD), [not only that osteoporosis rates were double in the immediate ART group although the p-value was only 0.27 so it was not significant but this could be because the number of patients with osteoporosis was very small] countering the argument that many researchers had been making for years that bone loss STARTs after initiate HAART but levels off after 2 years, NO - I never believed that, I have been certain that bone loss continues, does not level off, at least for a significant proportion of patients, remember TDF is used by everyone & TDF is associated with bone loss, and EFV as well is associated with bone loss, I also think that ART in general may be associated with persisting bone loss although studies have found raltegravir was not associated with bone loss in short term studies, NRTIs in general can cause mitochondrial toxicity, so does HIV & all ARTs may be implicated in some way...these authors from Emory in the main article below found immune reconstitution & the inflammation associated with that after initial ART causes bone loss, SO what happens if a patient experiences changes in immune reconstitution drink chronic ongoing ART - for example, if a patient changes ART - HELLO - immune reconstitution may be occurring.....in addition after years of chronic HIV patients experience immune affects, for example, senescence sets in shortly after initial HIV infection BUT in older aging HIV+ patients the slope of immune system decline I think more precipitously drops in HIV+ vs HIV-negatives, for example after 65 years of age, causing a more precipitous decline in immunity, bone loss, and risk for onset for other comorbidities including cognitive impairment AND FRAILTY, all these combine for an increased serious risk for older aging HIV+ to experience a fall & fracture - and studies are reporting this !!!!
.....Effects of immediate versus deferred initiation of antiretroviral therapy on bone mineral density: a substudyof the INSIGHT Strategic Timing of Antiretroviral Therapy (START) study - (10/23/15)


Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection - (01/19/16)
It has long been recognized that HIV infection and antiretroviral therapy (ART) lead to significant deterioration of the adult skeleton [1-7] and may prevent attainment of optimal peak bone mineral density (BMD) in young men infected with HIV early in life [8]. Recent studies report osteopenia in up to two thirds, and outright osteoporosis in up to 15% of HIV-infected patients [9-11]. With the aging of the HIV/AIDS population, higher prevalence of low BMD has been reported in postmenopausal women infected with HIV that could place them at high risk for future fractures [12]. Furthermore, .....http://www.natap.org/2016/HIV/011916_03.htm recent large observational studies reveal that compared with the general population there is a 2-4 fold higher prevalence of overall bone fracture in HIV-infected patients [13-16] and almost nine-fold increase in risk of hip fracture.....Mortality rates for hip fracture victims range between 24 and 32% in just the first year.....our data demonstrate that bone loss begins almost immediately following ART initiation in humans and is associated with repopulation of T cells. ART-associated bone loss may thus be related, in large part, to immune regeneration/reactivation rather than, or in addition to, direct effects of ART on bone cells
In conclusion, our data demonstrate that bone loss begins almost immediately following ART initiation in humans and is associated with repopulation of T cells. ART-associated bone loss may thus be related, in large part, to immune regeneration/reactivation rather than, or in addition to, direct effects of ART on bone cells. As the present study cannot exclude a direct effect of ART, additional mechanistic studies are warranted to demonstrate a cause effect relationship between bone loss, CD4+ repopulation and immune recovery. Furthermore, short-term antiresorptive therapy to prevent bone loss associated with T-cell repopulation during the early reconstitution period should be explored further in HIV-infected patients STARTing ART. [from Jules: at thisCROI next week the authors will present new data on treating early with therapy:
A Single Dose Zoledronic Acid Prevents Antiretroviral-Induced Bone Loss- Ighovwerha Ofotokun1; Kehmia Titanji1; Aswani Vunnava1; Antonina Foster1; Anandi N. Sheth1; Cecile D. Lahiri1; Jeffrey L. Lennox1; Andrea Knezevic2; Kirk A. Easley2; M. N. Weitzmann1 - 1Emory Univ Sch of Med, Atlanta, GA, USA; 2Emory Univ Rollins Sch of PH, Atlanta, GA, USA
"......activation of the expanding CD4+ T-cell pool, together with the reactivation of antigen presenting cells during ART-induced disease reversal leads to excessive production of key osteoclastogenic cytokines including TNF╬▒ and RANKL, tilting the RANKL/OPG balance in favor of enhanced bone breakdown.
Interestingly, increased plasma osteocalcin signaled a significant increase in bone formation likely as a compensatory response to elevated bone resorption. This coupling response may significantly ameliorate the extent of bone loss in some patients, although our studies revealed that high rates of bone resorption were not matched by equivalent robust increases in bone formation in many patients and such patients may be at particularly high risk for bone loss and development of osteoporosis. In other cases robust changes in bone formation accompanied relatively small or modest increases in bone resorption and these study participants may be better protected from bone loss. It should however be pointed out that the stoichiometry of changes in metabolic turnover markers is currently not clear and it is unknown what magnitude of change in osteocalcin is needed to offset a particular change in CTx, or even if the association is linear.
It has been reported that patients with low baseline CD4+ cell count have greater bone loss following ART initiation [48]. Our studies verify this response and show a significant negative correlation between basal CD4+ T-cell count and CTx concentrations after ART. Mechanistically, although unclear why this is the case, we hypothesize that these observations may suggest that the extent of homeostatic repopulation may have an impact on bone turnover. Interestingly, in our mouse model we did indeed find that relatively fewer transplanted CD4+ T cells elicited greater bone loss than very large numbers [42].
The limitations of our study include the small sample size and the brevity of the 24-week clinical follow-up period that limited our ability to capture the effect of ART-induced disease reversal and immune reconstitution on the skeleton over a longer period of time. Nonetheless, the magnitude and the robustness of bone resorption following ART initiation allowed significant changes to be observed with the cohort size examined.
It is well established that BMD decline follows ART initiation and our studies reveal that ART-initiates bone turnover providing a mechanistic basis for these later changes.

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