Update and review of bone studies
Simon Collins for HIV i-Base
Previous reports of risk factors associated with associated changes in bone mineral density (BMD) in reports from the lipodystrophy and Glasgow meetings in October and November issues of HTB have highlighted the likely contribution of HIV and possibly HAART.
Further evidence of seriousness of these complications was indicated in an excellent overview of bone mineral changes and lactic acidemia in a lecture by Andrew Carr  and by the 16 or so studies presented as posters. These new studies looked to broadly determine the role of HIV, HAART or individual drugs, the causative mechanisms and whether a link is established with symptoms of lipodystrophy. Two late-breaker abstracts presented sobering data on the risk of BMD changes in children.
The four studies looking at prevalence all found evidence of reduced BMD, generally detected by DEXA scan and evaluation by z-score and t-score, in HIV-positive patients, often without finding a link to HAART or individual drug exposure. Unless stated otherwise, osteopenia follows the WHO definition of t-score -1.0 to -2.5 and osteoporosis as t-score < -2.5. One of the most interesting of these was from Knobel and colleagues from Barcelona. 
This group compared lumber spine and femoral neck BMD t-scores and z-scores in three groups of HIV-positive patients (treatment naive, PI-experienced and non-PI experienced) and HIV-negative controls. Osteopenia was found in 4/16 (25%) of naives, in 12/30 (40%) of PI-treated patients, in 3/12 (33 %) of non-PI-treated patients and in 8/50 (16%) of HIV-negative adults. Difference reaches statistical significance only between HIV-infected patients (34.5%) versus seronegative controls (p=0.00001 OR: 6.2 CI 95%: 3.1 – 12.6). Osteoporosis was present in 21% HIV patients compared to 5% of HIV-negative controls (p=0.0009, OR: 5.1 CI 95%: 1.7-18.5). The only difference relating to the potential role of individual treatment was that the 17 patients exposed to indinavir had lower z-score in femoral neck compared to HIV-infected patients not exposed to indinavir (-1.4 vs ).7, p=0.02).
Lawal and colleagues from St Roosevelts Hospital in New York compared results between from DEXA scans in pre-HAART and post-HAART studies and found that baseline total bone mineral content, calcium and density were similar in both groups.  Incidentally, neither of these studies (using oxandrolone or rHGH for wasting) showed any improvement on BMD over the course of the study. [4, 5]
Link to lipodystrophy and metabolic changes
Four posters investigated links with lipodystrophy or metabolic changes. Andrew Carr’s group in Sydney assessed possible relationships between osteopenia and demographics (age, smoking, exercise), symptoms (lactic acidemia, weight loss, neuropathy), body composition, metabolic (lipid and glycaemic parameters, lactate/anion gap) and HIV disease (ARV therapy and duration, AIDS diagnosis, CD4 count, viral load). 
Of 221 HIV-positive otherwise healthy male patients, enrolled in a lipodystrophy prevalence study, 32 were drug naive, 42 were receiving NRTIs and 147 were receiving PI and NRTI treatment. Osteoporosis and osteopenia were found in 7 (3%) and 44 (22%) respectively. Changes in BMD were also found to be statistically significantly related in a multivariate analysis to higher lactate levels (OR 2.39 [95% CI 1.39 to 4.11] per 1 mmol/l increase; p = 0.002) and lower weight pre-ARV therapy (OR 1.06 [95% CI 1.02 to 1.11] per 1 kg decrease; p = 0.006).
The link between osteoporosis and increased lactate levels was not confirmed by Claxton and colleagues, perhaps because of the smaller study size (n=30), although osteopenia (WHO definition) and increased lactate levels (>2.5mM) were present in 43% and 30% respectively in this group. 
Effect of indinavir and ritonavir on formation and reabsorbion
Although presentations at the conference sometimes provided a contradictory link to HAART and individual treatments, Wang and colleagues form Washington University Medical School provided evidence of different effects on bone regulation from each of these PIs.
Indinavir produced a dose dependent decrease in alkaline phosphatase when added to murine osteoblast cell lines, an effect that was repeated in an ex-vivo calvarian culture system. When injected intraperitoneally in mice for two weeks the researchers reported a tenfold decrease in osteoblast colony forming units. In vitro culturing showed an inhibitory effect of indinavir, but not ritonavir, on both adipocyte and osteoblast differentiation.
Opposite inhibitory effects were observed when the drugs were tested with osteoclasts. Ritonavir added to mature osteoclasts on bone slices, prevented resorbtion, even though OC number remained unchanged. Ritonavir was also found to block osteoclastogenesis when administered to mice. Neither effect was observed with indinavir. 
Avascular necrosis (AVN)
A comprehensive review of the medical records of 2493 patients from the Johns Hopkins HIV Clinic found 17 reports of AVN of the hip between 1995-2000 over 6900 person-years. Eleven cases were bilateral and 6 were unilateral. This produced an incidence rate of 2.47 per 1000 person years (population-based incidence is for AVN is 0.04). Keruly and colleagues found a significant annual trend (p=0.05) over this period. They found no association with age, concurrent lipodystrophy, PI or NNRTI use or specific RTI-use compared to the rest of the cohort. The strongest association in this study linked to low CD4 count and duration of infection. 
Bone changes in children
Several studies at the conference reported bone mineral changes as a common occurrence in children, both as separate reports and within the context of increased reporting of lipodystrophy symptoms.
Dr Stephen Arpadi reported significant reductions in total body bone mineral content (TBBMC) in a group of 51 perinatally infected children (age 4.2-14.7 yr) when compared to 282 HIV negative children of a similar age and racial background. These reductions progressed with age (HIV/age interaction, p=0.032) and the negative effect of HIV status on TBBMC (p<0.0001) persisted after adjustment for body size, race, gender and bone area. No association was found between TBBMC and PI-use, CD4 count or CD4 percentage. 
Data from the Italian group lead by Dr Alessandra Vigan˜ (who incidentally reported optimal viral suppression <50 copies/ml in 33/35 of their HAART-treated children) compared lumbar spine and total body BMD in 35 HAART treated, 5 treatment naive and 314 HIV-negative controls (age range = 4.5-18.5 yrs). Differences were found to be significant between HAART-treated and control children (p=0.004 and p=0.0001 respectively, compared to controls). Looking at markers of bone formation (bone alkaline phosphatase and serum N-terminal propeptide) and resorption (urinary N-terminal telopeptide) Vigan˜ identified an increased rate of bone turnover as the pathogenic mechanism for bone mineral loss in these children. 
Five cases of AVN were reported among 1011 perinatally infected children enrolled in PACTG Study 219, two at study entry and three during follow-up. This represents an incidence rate of 94 per 100,000 person years. 
Most studies at the meeting concluded that it was too early to recommend routine BMD monitoring as part of routine management as osteopenia is an asymptomatic condition, although it is difficult to understand how changes in BMD can be followed without baseline and subsequent monitoring. Suggestions for management included promoting adequate calcium intake and weight-bearing exercise together with an assessment of other risk factors (smoking, exercise, malnutrition and hypogonadism). Deferring treatment, which was also recommended, while avoiding complications over the short-term, is not going to impact on the reality of lifelong treatment and is an option that isn’t available to children and adults who are already dependent on treatment.
Complications from osteopenia are increasing, and as Andrew Carr pointed out ‘physician denial promotes patients non-adherence’. It is still unclear, however, as with lipodystrophy, what the relative contributions of HIV-infection itself and any treatments might be in the development of these problems.
In this light, clinicians may be encouraged to review policy on a regular basis toward a more proactive management. Regardless of the nature of osteopenia DEXA should be considered for any patient with a history of HIV-infection of several years.
Given the availability, relatively low cost and non-invasive nature of DEXA scans, and the broad bone and fat distribution changes being reported, the information they will provide in the future could become invaluable information for assessing risk and rate of progression and response to intervention strategies.
Management strategies including calcium and vitamin D supplementation as well as encouraging regular weight-bearing exercise are warranted until adequate treatment is defined.
- Carr A and Grinspoon S. Issues in metabolic complications: Controversy or Consensus. State of the Art Lecture (available on webcast). Session 64.
- Knobel H et al. Osteopenia in HIV-Infected Patients. Is It the Disease or Is It the Treatment? 8th CROI, Feb 3-7th 2001, Abstract 629.
- Lawal et al. Equivalent Osteopenia in HIV-Infected Subjects Studied Before and During the Era of HAART. 8th CROI, Feb 3-7th 2001, Abstract 6274
- Lawal et al. Effect of Growth Hormone on Osteopenia in HIV+Patients. 8th CROI, Feb 3-7th 2001, Abstract 635.
- Lawal et al. Effect of Oxandrolone upon Bone Mineral Content in Malnourished HIV+Patients.. 8th CROI, Feb 3-7th 2001, Abstract 636.
- Carr et al. Lactic Acidemia Is Associated with Spinal Osteopenia in HIV-Infected Men. 8th CROI, Feb 3-7th 2001. Abstract 631.
- Claxton S et al. Circulating Leptin and Lactate Levels Are Not Associated with Osteopenia in HIV-Infected Men. 8th CROI, Feb 3-7th 2001. Abstract 634.
- Wang et al. Indinavir Inhibits Bone Formation while Ritonavir Inhibits Osteoclast Differentiation and Function. 8th CROI, Feb 3-7th 2001. Abstract 541
- Keruly JC et al. Increasing Incidence of Avascular Necrosis of the Hip in HIV-Infected Patients. 8th CROI, Feb 3-7th 2001. Abstract 637.
- Arpadi S et al. Decreases in Total Body Bone Mineral Content Progress with Age in HIV-infected Children. 8th CROI, Feb 3-7th 2001. Abstract LB8.
- Vigano et al. HAART-Associated Bone Mineral Loss through Increased Rate of Bone Turnover in Vertically HIV-Infected Children. 8th CROI, Feb 3-7th 2001. Abstract LB9.
- Gaughan DM et al. Avascular Necrosis of the Hip (Leggs-Calve-Perthes Disease [LCPD]) in HIV-Infected Children in Long-Term Follow-Up: PACTG Study 219. 8th CROI, Feb 3-7th 2001. Abstract 638