Bone disease and HIV
Simon Collins, HIV i-Base
Many studies have highlighted the significantly increased rates of osteopenia and osteoporosis in HIV-positive individuals compared to the general population, but, although this is one of the foremost concerns in an aging patient group, very few clinics actively incorporate either screening or monitoring of bone disease into routine HIV care.
The following summary covers an overview of osteoporosis and HIV presented at the conference by Dr Paddy Mallon from University College Dublin. 
The WHO defines osteopenia and osteoporosis as individual bone mineral density (BMD) scores that are between -1.0 and -2.5 (for osteopenia) and > -2.5 (for osteoporosis) standard deviations from the norm. T-scores relate to levels for a 30 year-old Caucasian woman and Z-scores relate to norms adjusted for age and gender.
In the setting of HIV, where the main outcome is to reduce the risk of fracture, T-score is the best validated surrogate marker, because the main management goal is to reduce fractures and each reduction of 1.0 in the T-score indicates an approximately doubled risk of fracture.
Cross-sectional studies have shown remarkably high incidence rates of reduced bone mineral density of between 40-80% in HIV-positive people, and a prevalence of 10-15% for osteoporosis. HIV-positive people are 6.4 times more likely to have osteopenia and 3.7 times more likely to have osteoporosis. 
As with the general population, risk factors include patient factors (female gender, Caucasian race, family history and falls risk) and lifestyle factors (smoking, exercise and alcohol use). However, HIV-related factors (which have included duration of infection, use of PI and NRTIs, hypogonadism, steroid use, and vitamin deficiency and low BMI) are less consistently clear, perhaps because HIV-specific studies have involved lower numbers of patients to have the statistical power to find significant associations.
In the HIV-negative people, BMD increases until around age 30 where it remains stable for perhaps 5-10 years before starting to decline (at a rate of 0.5-1% per year), especially, in women during menopause (during which it declines at -2% bone volume a year).  Women generally have lower BMD than men.
The importance of the bone health in the context of HIV is that many people will be diagnosed and treated for HIV before they are 30, prior to reaching their natural peak bone health.
This is a particular concern for children, and recent data from the paediatric ACTG studies have shown statistically lower BMD in HIV-positive compared to HIV-negative children, and also that this increases with Tanner development stage, particularly in males. 
Several prospective studies suggest that BMD in HIV-positive patients on stable therapy declines at similar rates to HIV-negative individuals, perhaps with an additional decrease associated with starting treatment. In the Gilead 903 study patients using tenofovir/FTC had a greater loss in hip BMD compared to the d4T/3TC arm but this difference became non significant at year three with both groups losing 2.4-2.8% from baseline levels. 
Importantly, similar reductions have been reported for combinations using AZT/3TC (with efavirenz or lopinavir/r), and these reductions continued in patients after discontinuing nucleoside analogues.  Some studies have continued to report a potentially greater effect with protease inhibitors. 
Results from a sub-study of the SMART trial (see report from the Lipodystrophy Workshop later in this issue of HTB) reported a similar rate of reduction in hip and spine BMD in patients who used continuous treatment to the studies above, but less of a reduction in patients who used CD4 guided treatment interruptions. 
Finally, a large US database, that included over 8,000 HIV positive patients and over 2 million HIV-negative patients, provided convincing results that lower HIV-related BMD does result in a clinically significant increase in the risk of fractures (even though the study didn’t measure BMD directly). In this study, HIV was significantly associated with increased rates of vertebral, wrist and hip fractures (overall 2.87 vs 1.77 per 100 patient years, p=0.0001) with a slightly higher impact for men compared to women. 
Pathogenic mechanisms in HIV are relatively complicated. The principal hormonal control of bone disease revolves around parathyroid hormone (PTH). In the kidney this affects tubular calcium re-absorption by upregulating 1-alpha hydroxylase, which is involved with the production of active vitamin D (1.25vitD), which in turn acts upon calcium absorption in the gut to maintain serum calcium levels. In bone, PTH acts at the osteoblast level to induce production of RANKL factor. This increases osteoclast activity to shift the balance of bone turnover in favour of bone resorption, increasing calcium levels which itself feeds back to reduce levels of PTH.
Several studies have also highlighted vitamin-D deficiency in HIV positive patients, related both to low dietary intake (40-60% patients estimated at less than 10 ug daily) and access to sunlight. A US study in disadvantaged youths, in both southern and northern states, found that almost 90% had low vitamin D levels (less than 37.5 nmol/L) and that these were predicted by latitude, dietary intake and alcohol use. 
A possible complication from HAART, presented at ICAAC this year, included preliminary findings from a small New York study of 34 men on tenofovir-containing HAART and 17 men on non-tenofovir HAART and highlighted the potential complexity of the PTH mechanism. While over 80% of the whole study group were vitamin D deficient (unrelated to use of tenofovir), significantly higher PTH levels were found in the tenofovir group (median 80 vs 55 pg/mL, p=0.03; and 39% vs 7% with levels >65pg/mL, p=0.02) and within the subgroup of patients with lowest vitatmin D levels. 
Most interestingly, recent research has also suggested an interaction between bone metabolism and metabolic changes, through the production in adipose tissue of an adipokine called leptin that acts on the hypothalamus to induce the sympathetic nervous system to increase osteoclast activity. A less well-described feedback mechanism may be mediated back to adipose tissue by the bone-derived factor osteocalcin. The increase in adipose tissue generally seen in the first 6 months of HAART may therefore be directly related to the higher rates of bone loss reported in the same period.
Other pathogenic mechanisms have looked at the effect of individual ARVs on osteoblasts and osteoclasts function and vitamin D metabolism in vitro, although interpreting the clinical implications of these findings is less clear.
In terms of management, there are currently no consistent evidence-based guidelines relating to osteoporosis in HIV-positive patients and a few studies from treating men in general. Both treatment and management however should focus on reducing the risk of fractures.
Modifiable risk factors include stopping smoking, reducing alcohol intake, increasing exercise, and monitoring use of steroids. Treatment with bisphosphonates, calcitonin, parathyroid hormone and oestrogen are supported by studies in the general population.  Alendronate increased lumbar BMD in HIV-positive patients by an additional 4% from baseline at week 48, compared to the approximate +1.5% from vitamin D and calcium supplementation alone.  Vitamin D and calcium replacement, while widely used to correct low serum levels, and known to increase BMD, are less supported by data relating to their impact on reducing fractures. 
The link between bone and metabolic changes may be particularly important. This presentation rightly concluded with a call for more research and for the productions guidelines for management and treatment in HIV.
A useful overview article on this issue was posted online on Medscape in December. 
Several London clinics have already reported low vitamin D levels in HIV-patients. In Glasgow, a poster from the Chelsea and Westminster reported that 20% of 74 patients (17 women, 57 men) admitted to their hospital in a two month period were vitamin D deficient (<15nmol/L) and 45% had insufficient levels (15-50nmol/L). 
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