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Bone Metabolism in HIV: CROI 2008 Update
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15th CROI, Feb 3-6, 2008, Boston
Todd T. Brown, MD, PhD
Assistant Professor of Medcine
Division of Endocrinology and Metabolism
Johns Hopkins University
Baltimore, MD
At the end of this report, after the References is a comment by Jules Levin and a Glossary of terms in bone disease.
Most evidence suggests that the prevalence of osteoporosis is higher among HIV-infected persons compared to matched HIV-negative controls . The reasons for this increased risk is likely multifactorial with potential contributions stemming from patient-related factors (low BMI [skinny, fat loss], increased prevalence of smoking and alcohol use, hypogonadism, etc), HIV-infection related factors, perhaps factors related to antiretroviral therapy.
Several abstracts were presented in Boston to help shed light on bone disease in HIV-infected patients. In a study from the WIHS, Yin et al (Poster #965) reported that lumbar and hip BMD were lower in HIV+ premenopausal women (n=114) compared to HIV-negative women (n=74). However, changes in BMD over a two year interval were similar regardless of HIV status. Protease inhibitor treated women had the highest levels of bone resorption markers and the lowest levels of bone formation markers, but did not exhibit increased risk of bone loss. These results confirm other findings in post-menopausal women in which BMD is lower in HIV infected women, but longitudinal measurements of BMD remain relatively constant1.
Two studies examined BMD changes with ART initiation. One study (Poster #966) examined the change in total BMD in HIV-infected persons randomized to either AZT/3TCc/EFV or AZT/3Tc/LPV/r. After 24 weeks, those randomized to AZT/3Tc/LPV/r received a simplified regimen on LPV/r monotherapy. There was an average BMD loss over 96 weeks of ~2.4%, regardless of treatment. Notably, there was no attenuation of bone loss when AZT/3Tc was removed from the regimen. Bone loss > 5% over the 96 week interval was associated with lower baseline CD4 cell count and non-black race. Taken together, these results confirm modest bone loss seen with ART initiation regardless of ART treatment used. It is unclear whether this bone loss is clinically significant.
Another clinical trial (Poster #967) randomized 71 ART-naive persons to an NNRTI/PI regimen, PI/2NRTI regimen, or NNRTI/2 NRTI and assessed changes in BMD using site-specific DXA over 48 weeks. During the follow-up interval, there was a -4.1± 3.9 % decrease in lumbar spine and -2.7± 4.7% decrease in the hip. Unlike the previous study, those receiving PIs (LPV/r or IDV/r) had the largest decrease in BMD, suggesting a differential effect of PI therapy.
The effects of PIs on bone mineral density have been controversial. From the initial report of reduced bone mineral density in HIV-infected patients in the HAART era, PIs have been implicated in the pathogenesis of low bone density2. The findings of many of the cross-sectional studies suggesting a PI effect may have been confounded by factors such as HIV-disease severity or treatment duration3. Indeed, longitudinal studies of HIV-treatment experienced person receiving PIs have generally shown stability of BMD over time 1;4;5. Individual PIs may have differential effects on BMD, however. Another recent study of ART-naive persons initiating antiretrovirals showed a larger decrease in BMD in those receiving PIs (Bonnet, 9th ADRL Workshop, Sydney, 2007). Even if some PIs are indeed associated with reductions in BMD, the effects are likely to be modest.
In previous studies6;7, tenofovir has been implicated in the pathogenesis of reduced bone density. Several posters addressed this issue from different angles. In the Swiss HIV Cohort (poster #968), serum alkaline phosphatase (sAP), a non-specific marker of bone turnover, was assessed in participants initiating, re-initiating and discontinuing ART with and without tenofovir. ART initiation with TDF was associated with increases in sAP and TDF-ART discontinuation was associated with decreases in sAP. Similar changes in sAP with non-TDF regimens were not observed. It was suggested that changes in renal phosphate and calcium balance with TDF lead to increased bone turnover and high sAP, although this hypothesis was not specifically tested in this study. The clinical implications of these associations, including the effects on BMD require further clarification.
At least in the short term, however, it appears that switching to TDF from AZT does not have adverse effects on BMD. In the SWEET study (poster #938), 250 ART-experienced participants on AZT/3TC/EFV were randomized to continue on this regimen or to switch to TDF/FTC/EFV. Over 48 weeks, limb fat was significantly lower in those who continued on AZT/3Tc compared to the switch group (mean difference 448 g, 95% CI 57-839 g). However, there was no change from baseline in lumbar or hip BMD in either group.
A cross sectional study (poster #969) carried out in an ambulatory population in British Columbia suggested showed that reduced mineral density was seen in 67% of HIV-infected patients and was associated with lower BMI, older age, low CD4 cell count, low physical activity, and alcohol use. These latter two findings remind us of the importance of lifestyle factors in the pathogenesis of low BMD. In this study, a cross-sectional relationship was found between TDF use (< 6 months), but not other ART medications, and low BMD. Given the previous studies, the nature of the relationship between TDF-use and bone density is far from clear. Longitudinal studies, particularly with randomized treatment assignment, are needed to better understand the changes in calcium and phosphate homeostasis with TDF-use and any resulting impact on BMD.
Taken together, the findings of the bone studies from CROI 2008 modestly advanced our understanding of the pathogenesis of losses in bone mineral density in HIV-infected persons. Many questions still remain, particularly regarding the impact of specific antiretroviral therapies, the risk of fracture in HIV-infected persons and associated risk factors, and the need for BMD screening.
Reference List
1. Dolan SE, Kanter JR, Grinspoon S. Longitudinal analysis of bone density in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 2006;91:2938-45.
2. Tebas P, Powderly WG, Claxton S, Marin D, Tantisiriwat W, Teitelbaum SL, Yarasheski KE. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000;14:F63-F67.
3. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006;20:2165-74.
4. Nolan D, Upton R, McKinnon E, John M, James I, Adler B, Roff G, Vasikaran S, Mallal S. Stable or increasing bone mineral density in HIV-infected patients treated with nelfinavir or indinavir. AIDS 2001;15:1275-80.
5. Mondy K, Yarasheski K, Powderly WG, Whyte M, Claxton S, DeMarco D, Hoffmann M, Tebas P. Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin Infect Dis 2003;36:482-90.
6. Castillo AB, Tarantal AF, Watnik MR, Martin RB. Tenofovir treatment at 30 mg/kg/day can inhibit cortical bone mineralization in growing rhesus monkeys (Macaca mulatta). J Orthop Res 2002;20:1185-89.
7. Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292:191-201.
From Jules Levin
Note: the issue of bone disease in HIV appears neglected. As people age with HIV bone disease becomes an increasing health concern, but is getting little attention by HIV research. A number of recent cohort studies report 70-80% rates of reduced bone mineral density, 60% osteopenia, and 5-15% osteoporosis. But of note to me is the average age of the HIV+ individuals is young, in their 40s. So, what will happen as individuals age into their 50s and 60s. Will fracture rates skyrocket? There is no education or discussion among HIV thought leaders. There is no discussion or guidelines or recommendations regarding doing bone DEXAs. That is the test to evaluate bone mineral density. There is little discussion about care, prevention, and treatment. Of major concern to me, is bone disease pathogenesis different in HIV. There is no prospective studies to better characterize the risk factors in HIV: do they include additional factors beyong the traditional risk factors. And are the tradional risk factors more prevalent in HIV> The answer to these questions appear to me to be yes: HIV appears to cause bone metabolism dysfunction; initiating ART appears to perhaps cause dysregulation. Do NRTIs cause mitochondrial toxicity in bone cells that lead to bone dysregulation? Perhaps, donft this has not been studied. I think our research establishment owes us more attention to this health concern.
Glossary
Bone resorption: Bone resorption is the gradual loss of bone. Bone is under a constant process of resorption and formation. As we age, formation lessens and after a peak bone mass is achieved, bone mass remains stable (resorption and formation are equal).
Osteoclasts are the principal cells responsible for bone resorption and an antiresorptive is something that works against bone loss due to osteoclastic activity.
When damaged areas of bone need to be replaced, these bone-destroying osteoclasts dig tunnels, or trenches, by dissolving packets of old bone. As the old bone is broken down, calcium is released into the bloodstream. The osteoclasts detach, as another group of cells takes over to build the new bone.
Remodeling
Remodeling or bone turnover is the process of resorption followed by replacement of bone with little change in shape and occurs throughout a person's life. Osteoblasts and osteoclasts, coupled together via paracrine cell signalling, are referred to as bone remodeling units.
Purpose
The purpose of remodeling is to regulate calcium homeostasis, repair micro-damaged bones (from everyday stress) but also to shape and sculpture the skeleton during growth.
Calcium balance
The process of bone resorption by the osteoclasts releases stored calcium into the systemic circulation and is an important process in regulating calcium balance. As bone formation actively fixes circulating calcium in its mineral form, removing it from the bloodstream, resorption actively unfixes it thereby increasing circulating calcium levels. These processes occur in tandem at site-specific locations.
Repair
Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of maximum stress (Wolff's law). It has been hypothesized that this is a result of bone's piezoelectric properties, which cause bone to generate small electrical potentials under stress.[1]
Bone Formation
The process of bone formation (osteogenesis) involves three main steps:
--production of the extracellular organic matrix (osteoid);
--mineralization of the matrix to form bone;
--and bone remodeling by resorption and reformation.
The cellular activities of osteoblasts, osteocytes, and osteoclasts are essential to the process. Osteoblasts synthesize the collagenous precursors of bone matrix and also regulate its mineralization.
As the process of bone formation progresses, the osteoblasts come to lie in tiny spaces (lacunae) within the surrounding mineralized matrix and are then called osteocytes.
The cell processes of osteocytes occupy minute canals (canaliculi) which permit the circulation of tissue fluids.
To meet the requirements of skeletal growth and mechanical function, bone undergoes dynamic remodeling by a coupled process of bone resorption by osteoclasts and reformation by osteoblasts.
Osteoblasts and Bone Matrix
Osteoblasts are derived from mesenchymal stem cells of the bone marrow stroma.
They possess a single nucleus, have a shape that varies from flat to plump, reflecting their level of cellular activity, and in later stages of maturity line up along bone-forming surfaces.
Osteoblasts synthesize and lay down precursors of collagen 1, which comprises 90-95% of the organic matrix of bone.
Osteoblasts also produce osteocalcin -the most abundant non-collagenous protein of bone matrix- and the proteoglycans of ground substance and are rich in alkaline phosphatase, an organic phosphate-splitting enzyme.
Osteoblasts have receptors for parathyroid hormone and apparently for estrogen.Hormones, growth factors, physical activity, and other stimuli act mainly through oteoblasts to bring about their effects on bone.
The collagen 1 formed by osteoblasts is typically deposited in parallel or concentric layers to produce mature (lamellar) bone.
But when bone is rapidly formed, as in the fetus or certain pathological conditions (fracture callus, fibrous dysplasia, hyperparathyroidism), the collagen is not deposited in a parallel array but in a basket-like weave and is called woven, immature, or primitive bone.
In fully decalcified bone sections, the extracellular matrix stains pink with H+E, similar to collagen elsewhere but with a more homogeneous than fibrillar structure which latter is easily observed by polarizing microscopy.
Bone Mineralization
The main mineral component of bone is an imperfectly crystalline hydroxyapatite [Ca10(PO4)6(OH)2] which comprises about 1/4 the volume and 1/2 the mass of normal adult bone.
The mineral crystals, as shown by electron microscopy, are deposited along, and in close relation to, the bone collagen fibrils.
Calcium and phosphorus (Pi, inorganic phosphate) are, of course, derived from the blood plasma and ultimately from nutritional sources.
Vitamin D metabolites and parathormone (PTH) are important mediators of calcium regulation, and lack of the former or excess of the latter leads to bone mineral depletion.
Undecalcified bone sections, such as those stained with the von Kossa stain, are best used for the histological study of bone mineral distribution.
The extracellular matrix of bone is mineralized soon after its deposition, but a very thin layer of unmineralized matrix is seen on the bone surface, and this is called the osteoid layer or osteoid seam.
In some pathological conditions, the thickness and extent of the osteoid layer may be increased (hyperosteoidosis) or decreased.
Hyperosteoidosis may be caused by conditions of delayed bone mineralization (as in osteomalacia/rickets resulting from vitamin D deficiency) or of increased bone formation (as in fracture callus, Paget's disease of bone, etc.). [see each of them as detailed.
Osteoclasts and Bone Resorption
Osteoclasts are derived from hematopoietic stem cells that also give rise to monocytes and macrophages.
Typically multinucleated, osteoclasts adhere to the surface of bone undergoing resorption and lie in depressions termed Howship's lacunae or resorption bays.
The boundary between the old and new bone is distinguished in an H+E section by a blue (basophilic) line called a cement line or reversal line.
Several metabolic bone diseases (such as hyperparathyroidism, Paget's disease, and others) are characterized by increased modeling and increased osteoclastic activity.
Osteoclasts are apparently activated by "signals" from osteoblasts. For example, osteoblasts have receptors for PTH whereas osteoclasts do not, and PTH-induced osteoclastic bone resorption is said not to occur in the absence of osteoblasts.
Bone Development
At an early stage of human embryonic development, a cartilage model of much of the skeleton ( of extremities, trunk, and base of the skull) is formed from the mesenchyme.
In the further fetal development of long bones, a rim of primitive bone is first laid down in layers over the middle of the shaft by osteoblasts arising from the overlying periosteum, and subperiosteal bone formed in this way soon extends up and down the shaft (diaphysis).
The process by which bone tissue replaces membranous fibrous tissue is called intramembranous ossification.
This is the process by which the diaphysis increases in width throughout postnatal growth.
Some bones, such as the flat bones of the calvarium, are formed entirely, or in great part, by intramembranous ossification.
The cartilage cells of the core of the fetal shaft degenerate upon contact with penetrating buds of periosteal osteoblasts, the cartilage matrix becomes mineralized and resorbed, and the resulting surfaces and spaces are lined by osteoblasts which lay down woven bone and form primitive bone trabeculae.
The process by which bone tissue replaces cartilage is called endochondral ossification and begins in the femur at about the ninth week of fetal life
Some of the trabeculae fuse with the subperiosteal new bone while others are resorbed to form a medullary cavity which will be occupied by hematopoietic tissue.
Thus, the primitive bone shaft is formed and lies between the cartilaginous ends which become the epiphyses.
In the later months of fetal life, the woven bone of the diaphysis will be replaced by lamellar bone of mature type.
Over time, the bone cortex is thickened and remodeled to serve mechanical functions and is permeated by haversian systems (bone-forming units) of longitudinal, vascularized canals bounded by concentric lamellae of bone, culminating in the typical appearance of compact cortical bone as seen in the adult
The longitudinal growth of the long bones occurs in the epiphysial (epiphyseal) growth plate as cartilage cells, arising from reserve cells, undergo mitosis and proliferate in orderly longitudinal columns
The proliferated cartilage cells vacuolate as they move toward the cartilage-bone junction (metaphysis), the cartilage matrix becomes mineralized, and buds of osteoblasts emerging from the metaphysis replace the mineralized cartilage with bone.
This process of cartilage cell proliferation and endochondral ossification is repeated over and over, and the bones become longer and larger.
Meanwhile, at age-related intervals, secondary centers of endochondral ossification ("radiologic epiphysis") begin to form on the articular side of the growth plate.
When skeletal maturity is reached, the cartilage cells of the growth plate cease to proliferate, the growth plate becomes thinner, is replaced by bone and disappears, and the epiphysis is "closed" or fused with the shaft.
Cellular structure
There are several types of cells constituting the bone;
* Osteoblasts are mononucleate bone-forming cells which descend from osteoprogenitor cells. They are located on the surface of osteoid seams and make a protein mixture known as osteoid, which mineralizes to become bone. Osteoid is primarily composed of Type I collagen. Osteoblasts also manufacture hormones, such as prostaglandins, to act on the bone itself. They robustly produce alkaline phosphatase, an enzyme that has a role in the mineralisation of bone, as well as many matrix proteins. Osteoblasts are the immature bone cells.
* Bone lining cells are essentially inactive osteoblasts. They cover all of the available bone surface and function as a barrier for certain ions.
* Osteocytes originate from osteoblasts which have migrated into and become trapped and surrounded by bone matrix which they themselves produce. The spaces which they occupy are known as lacunae. Osteocytes have many processes which reach out to meet osteoblasts probably for the purposes of communication. Their functions include to varying degrees: formation of bone, matrix maintenance and calcium homeostasis. They possibly act as mechano-sensory receptors-regulating the bone's response to stress. They are mature bone cells.
* Osteoclasts are the cells responsible for bone resorption (remodeling of bone to reduce its volume). Osteoclasts are large, multinucleated cells located on bone surfaces in what are called Howship's lacunae or resorption pits. These lacunae, or resorption pits, are left behind after the breakdown of bone and often present as scalloped surfaces. Because the osteoclasts are derived from a monocyte stem-cell lineage, they are equipped with engulfment strategies similar to circulating macrophages. Osteoclasts mature and/or migrate to discrete bone surfaces. Upon arrival, active enzymes, such as tartrate resistant acid phosphatase, are secreted against the mineral substrate.
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