From:	"NATAP HIV mailing list" <hiv@...>
Subject:	NATAP: Bone Metabolism in HIV
Date:	August 31, 2008 8:34:16 AM EDT
To:	hiv@...,

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Bone and Mineral Metabolism in Human Immunodeficiency Virus Infection

Journal of Bone and Mineral Research, January 2001:16:2-9

CHRISTIAN A. KÜHNE,    ARMIN E. HEUFELDER,    LORENZ C. HOFBAUER  

Division of Gastroenterology, Endocrinology and Metabolism, Zentrum für Innere Medizin, Philipps-University, Marburg, Germany.

"Chronic viral infection, altered immune function, abnormal cytokine production, opportunistic infections, HIV-related neoplasms, and drugs are the major causes of bone and mineral disturbances in HIV-infected individuals.....A high index of clinical suspicion, early recognition, rapid establishment of the diagnosis, appropriate treatment, and correction of the underlying pathology are crucial in the management of patients suffering from HIV-associated abnormalities of bone and mineral metabolism."

"it is obvious that the magnitude of this problem is underestimated and that osteoporotic fractures will become more significant once this population of HIV-infected individuals ages......Although measurement of BMD is not recommended as a routine test in HIV-infected patients, we recommend taking a detailed history to assess the personal risk for osteoporotic fractures and to perform a thorough clinical examination of the skeleton in every patient with HIV infection. Once additional risk factors of osteoporosis have been identified, assessment of biochemical markers of bone metabolism and measurement of BMD are recommended, especially in patients with overt hypogonadism and in those who are scheduled to receive a highly active antiretroviral therapeutic regimen that includes a protease inhibitor...... The use of rhGH for HIV-associated wasting was associated with a slight increase of serum concentrations of total calcium.(45) Possible mechanisms of rhGH-related hypercalcemia include increased intestinal calcium absorption through induction of calcium binding protein(46) and increased PTH secretion.(47) Sakoulas et al. reported a case of severe hypercalcemia following rhGH treatment in a patient with AIDS-related wasting and weight loss who required pamidronate therapy......Hypercalcemia in HIV-infected individuals usually is of infectious, granulomatous, or neoplastic origin or a side effect of drugs (Table 2).(4,27) Infections associated with hypercalcemia in HIV-infected patients include opportunistic pathogens such as CMV,(35,36) Pneumocystis carinii,(37) Mycobacterium avium intracellulare,(38,39) Cryptococcus neoformans,(40,41) and Coccoides immitis.(41) Hypercalcemia in CMV disease is thought to result from direct osteoclastic activation by activated T cells or proinflammatory cytokines.....Of note, serum PTH levels were significantly lower in patients with AIDS (n = 23, 1.5 pmol/liter, range 0.2-4.3) as compared with patients with asymptomatic HIV infection (n = 20; 2.6 pmol/liter; range, 0.8-7.5), indicating that parathyroid impairment is a function of progression of HIV infection.(33) In the largest study on hypocalcemia in HIV infection to date, inappropriately low PTH secretion (despite hypocalcemia) accounted for as many as one-third of cases with hypocalcemia......Youle et al.(51) reported the occurrence of hypocalcemia after concurrent therapy with foscarnet and pentamidine for CMV infection in 4 patients, one of whom died with a serum calcium concentration of 1.4 mM (5.6 mg/dl). During foscarnet treatment for CMV retinitis in 13 patients with AIDS, 85-100% developed hypocalcemia(52,53) and 69% developed hypomagnesemia.(52) Foscarnet-induced hypocalcemia is caused by a combination of nephrotoxicity, resulting in renal wasting of calcium and magnesium,(52) and of complex formation of calcium with foscarnet (a phosphate analog), thus rapidly decreasing serum ionized calcium levels.(53) Hypocalcemia has also been reported in 10% of patients with AIDS receiving trimethoprim-sulfamethoxazole and in 15% receiving pentamidine for P. carinii pneumonia, respectively.(54,55).....Advanced disease stage and increased serum levels of TNF-α were associated with 1,25(OH)2D3 deficiency, and increased TNF-α serum levels were most prevalent in patients with undetectable levels of 1,25(OH)2D3.(55)....

.....From a clinical perspective, calcium and magnesium serum levels should be measured in all patients receiving these drugs. In addition, close monitoring of ionized calcium levels is mandatory during and shortly after foscarnet treatment.....

.....Sex hormone deficiency is a risk factor of osteoporosis in women and men.(13,92-94) Bone loss associated with sex hormone deficiency is mediated through direct osteoblastic and osteoclastic effects, modulation of the cytokine milieu, and extraskeletal effects on calcium homeostasis. Replacement with sex steroid hormones, at least in part, can prevent these abnormalities.(13,92-94) Sex hormone deficiency is among the most frequent endocrine abnormalities in HIV-infected men, and its clinical symptoms (impotence and decreased libido) have been reported in 33% and 67%, respectively, of 70 patients with AIDS evaluated in an outpatient clinic."

    

INTRODUCTION

INFECTION WITH the human immunodeficiency virus (HIV; abbreviations are listed in Table 1) or acquired immunodeficiency syndrome (AIDS) may have adverse effects on any organ system. Because there is no cure for HIV infection and because of ongoing new infection, the number of patients with HIV infection is still growing, especially in developing countries.(1) Moreover, the advent of highly active antiretroviral therapy in conjunction with improved standard antiviral and antibiotic regimens has dramatically changed the clinical course of HIV infection, resulting in prolonged survival in those with access to it.(1) As the population of HIV-infected individuals grows and ages, diseases of bone and mineral metabolism may become increasingly apparent, which may cause considerable mortality, morbidity, and impaired quality of life.

In principle, the abnormalities of bone and mineral metabolism associated with HIV infection may be caused by direct interaction of HIV with cells of the bone and bone marrow microenvironment, chronic T cell activation, and abnormal cytokine production affecting osteoblast and osteoclast functions, disturbances of calcium homeostasis, parathyroid hormone (PTH) function, vitamin D metabolism, opportunistic or neoplatic diseases, and adverse effects of drugs.(2-4) To provide optimal health care for HIV-infected patients, early diagnosis and adequate treatment of HIV-associated disorders of bone and mineral metabolism are required. In this article, we review the spectrum of bone and mineral diseases in HIV infection and AIDS, discuss the mechanisms underlying their pathogenesis, and provide practical guidelines for prevention and treatment.

EFFECTS OF HIV INFECTION ON THE BONE AND BONE MARROW MICROENVIRONMENT

Effects on osteoblastic lineage cells

Because of the high prevalence of hematological abnormalities in HIV-infected individuals such as anemia, thrombocytopenia, and leukopenia, it has been hypothesized that HIV may target pluripotent bone marrow-residing stromal cells and impair their proliferative capacity. Several studies have indicated clearly that latent persistent HIV infection of bone marrow stromal cells and subsequent alterations of the cytokine milieu may cause profound impairment of the bone marrow microenvironment, which may result in pancytopenia.(5-8) Direct adverse effects of HIV on preosteoblastic marrow stromal cells and on their differentiation toward the mature osteoblastic phenotype have not been observed. The ability of HIV to infect mature osteoblastic cells is still controversial. Although one study indicated that osteosarcoma cell lines (TE-85 and SaOS-2) when exposed to HIV revealed an infection rate of 1-5% of cells,(9) another study failed to confirm this.(10)

Infection of osteoblastic lineage cells may provide HIV with a nonlymphoid target and reservoir for latent infection and may directly explain abnormalities of bone formation in HIV-infected individuals. Moreover, it emphasizes the potential of HIV transmission through bone allografts.(11)

 Effects on osteoclastic lineage cells

Direct effects of HIV on the differentiation or activation of osteoclasts have not been reported. However, persistent HIV infection or episodes of opportunistic infections have been shown to result in chronic T cell activation and a proinflammatory cytokine milieu.(12,13) Recent data suggest that activated T cells are capable of inducing functionally active osteoclasts by expressing both a cell-bound and a soluble form of receptor activator of nuclear factor (NF)-κB ligand (RANKL).(14,15) In the presence of permissive concentrations of macrophage colony-stimulating factor (M-CSF), RANKL is both necessary and sufficient to promote osteoclast formation and activation and to inhibit osteoclast apoptosis, thus expanding the pool of active osteoclasts.(16) Of note, RANKL gene expression is enhanced by cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α), which are elevated in HIV infection.(14,16) Moreover, IL-1 and TNF-α are capable of directly inducing differentiation and activation of osteoclasts in the absence of RANKL.(17,18)

 Effects on biochemical markers of bone metabolism

Several studies have assessed biochemical markers of bone formation and resorption in patients with HIV(19-22) and their changes after therapeutic intervention.(21,22) Serrano et al.(19) reported lower serum concentrations of osteocalcin (a marker of bone formation) in 22 patients with HIV as compared with normal controls. Osteocalcin concentrations were lower in advanced stages of disease and were positively correlated with CD4+ lymphocyte counts.(19) Another small study reported a decrease of serum osteocalcin concentrations in 16 patients with HIV as compared with normal controls, especially after ongoing HIV infection of more than 2 years.(20) Serum levels of propeptide of type I collagen (PICP), another marker of bone formation, were found to be slightly lower in 13 patients with AIDS as compared with normal controls or patients with HIV infection.(21) Of note, treatment with recombinant human growth hormone (rhGH) significantly increased PICP levels in normal subjects and in patients with AIDS.(21)

In the largest analysis conducted to date, Aukrust et al.(22) evaluated bone markers and inflammatory cytokines in 73 HIV-infected patients. As HIV infection advanced, serum levels of osteocalcin decreased and those of C-telopeptide, a marker of bone resorption, increased. Serum levels of soluble TNF receptor (TNFR; a marker of inflammation) were correlated negatively with serum concentrations of osteocalcin and were correlated positively with serum levels of C-telopeptide.(22) After 24 months of therapy with highly active antiretroviral therapy, viral load decreased, the number of CD4+ lymphocytes increased, and serum levels of osteocalcin increased. Although there was no correlation between the serum concentrations of osteocalcin and C-telopeptide at baseline, both parameters were significantly correlated after treatment, indicating synchronization of bone remodeling once the virus load and inflammatory response are suppressed.(22)

 Effects on bone histomorphometrical parameters

Data on histomorphometric analyses of bone remodeling in patients with HIV infection are sparse. Serrano et al.(19) assessed bone histomorphometry in 22 HIV-infected patients with normal bone mineral density (BMD). Surface-based bone formation rate, activation frequency, and osteoclast index were significantly lower in HIV-infected patients. Moreover, bone formation rate and activation frequency were lower in patients with advanced disease as compared with early disease and were correlated positively with the number of CD4+ T lymphocytes.(19)

 Effects on BMD

Data on BMD in patients with HIV are limited. Using dual-energy X-ray absorptiometry, Paton et al.(23) reported a decreased BMD (−3%) at the lumbar spine in 45 HIV-infected men with a mean age of 36 years and different stages of the disease as compared with sex- and age-matched controls but no differences of total body or hip BMD. Serial measurements after a mean interval of 15 months revealed a slight decrease of 1.6% of total body BMD but no changes of spine or hip BMD. None of the patients had a T score < 2.5 at any time of the follow-up. Two smaller studies of 22 patients with a mean age of 28 years(19) and of 16 patients with an age range from 21 to 37 years(20) reported no differences between HIV-infected and normal individuals. However, because these studies assessed a small sample size and a population (young adults) at or around peak bone mass when the prevalence of osteoporosis is low, it is obvious that the magnitude of this problem is underestimated and that osteoporotic fractures will become more significant once this population of HIV-infected individuals ages. Two cases of severe osteoporosis in young African women with HIV infection may indicate a substantial change in the future epidemiology of osteoporosis in sub-Saharan Africa where HIV infection rates are as high as 30-40%.(24)

More recently, the use of a protease inhibitor has been identified as a risk factor of low bone mass.(25) In a study on 112 HIV-infected men, users of protease inhibitors had a 2.2-fold increased relative risk of osteopenia or osteoporosis as assessed by a whole-body BMD measurement.(25) Interestingly, these subjects also developed central obesity, which is considered to protect against bone loss, suggesting that the protease inhibitor had independent adverse effects on bone and fat tissue. Further studies using state-of-the-art bone densitometry techniques at various skeletal sites in larger numbers of HIV-infected patients are required to assess systematically BMD in HIV infection and to detect subtle abnormalities of BMD in this population.

Although measurement of BMD is not recommended as a routine test in HIV-infected patients, we recommend taking a detailed history to assess the personal risk for osteoporotic fractures and to perform a thorough clinical examination of the skeleton in every patient with HIV infection. Once additional risk factors of osteoporosis have been identified, assessment of biochemical markers of bone metabolism and measurement of BMD are recommended, especially in patients with overt hypogonadism and in those who are scheduled to receive a highly active antiretroviral therapeutic regimen that includes a protease inhibitor.

THE PTH SYSTEM IN HIV INFECTION

In HIV infection, the PTH system may be impaired through various mechanisms, including infectious or neoplastic etiologies,(26) impaired secretion of PTH at baseline and after provocation,(27-29) and PTH resistance.(30) Infiltration and destruction of the parathyroid glands has been reported in disseminated opportunistic infections with neck involvement, particularly with extrapulmonary Pneumocystis carinii or cytomegalovirus (CMV) disease.(26) Of note, parathyroid cells express receptors with structural similarity to the CD4 molecule, which acts as a cellular receptor for HIV and facilitates access of the virus to immune cells.(31) This mechanism may account for symptomatic hypoparathyroidism as the initial presentation of HIV infection when the virus load is high and the immune system is still intact.(32)

PTH serum levels were significantly lower in patients with HIV infection (n = 38; 13.9 ± 2.3 ng/liter) as compared with normal controls (n = 38; 38.1 ± 3.1 ng/liter).(28) Similar results were observed in 6 patients with AIDS (CD4+ count < 50/μl) who had PTH serum concentrations of 14 ± 2 ng/liter as compared with a normal population (n = 10; 23 ± 3 ng/liter) and patients with malignancies (n = 6; 35 ± 7 ng/liter).(29) After EDTA-induced hypocalcemia, patients with AIDS had a blunted PTH surge as compared with controls.(29) Of note, serum PTH levels were significantly lower in patients with AIDS (n = 23, 1.5 pmol/liter, range 0.2-4.3) as compared with patients with asymptomatic HIV infection (n = 20; 2.6 pmol/liter; range, 0.8-7.5), indicating that parathyroid impairment is a function of progression of HIV infection.(33) In the largest study on hypocalcemia in HIV infection to date, inappropriately low PTH secretion (despite hypocalcemia) accounted for as many as one-third of cases with hypocalcemia.(34)

In HIV-infected patients at any stage of the disease who present with tetany, muscle cramps, or electrocardiographic abnormalities, symptomatic hypoparathyroidism should be suspected, and serum concentrations of calcium, phosphate, and intact PTH should be assessed. If confirmed, rapid treatment consisting of a combination of calcium and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] should be initiated.(32)

CALCIUM HOMEOSTASIS IN HIV INFECTION

Hypercalcemia

Hypercalcemia has been confirmed in 2.9% of 66 patients with AIDS.(27) Hypercalcemia in HIV-infected individuals usually is of infectious, granulomatous, or neoplastic origin or a side effect of drugs (Table 2).(4,27) Infections associated with hypercalcemia in HIV-infected patients include opportunistic pathogens such as CMV,(35,36) Pneumocystis carinii,(37) Mycobacterium avium intracellulare,(38,39) Cryptococcus neoformans,(40,41) and Coccoides immitis.(41) Hypercalcemia in CMV disease is thought to result from direct osteoclastic activation by activated T cells or proinflammatory cytokines.(35,36) Carbone et al. reported a patient with AIDS-related hypercalcemia of unknown origin but with increased levels of TNF-α, IL-6, and IL-8, and serum calcium levels normalized after treatment with pamidronate.(42) Hypercalcemia in protozoal, fungal, and mycobacterial infection may result from extrarenal 1α-hydroxylation of 25-hydroxyvitamin D3 [25(OH)D3] by macrophages, monocytes, epithelioid cells, and multinucleated giant cells.(37-41) A similar mechanism has also been suggested in patients who present with AIDS-associated lymphoma and hypercalcemia.(43,44)

The use of rhGH for HIV-associated wasting was associated with a slight increase of serum concentrations of total calcium.(45) Possible mechanisms of rhGH-related hypercalcemia include increased intestinal calcium absorption through induction of calcium binding protein(46) and increased PTH secretion.(47) Sakoulas et al. reported a case of severe hypercalcemia following rhGH treatment in a patient with AIDS-related wasting and weight loss who required pamidronate therapy.(48) In this patient, PTH, PTH-related protein (PTHrP), and vitamin D levels were suppressed, indicating that alternative pathways caused hypercalcemia.(48) Hypercalcemia also has been reported in a patient treated with foscarnet for disseminated CMV infection.(49)

Severe hypercalcemia in HIV infection is managed by generous fluid replacement, use of calcium-lowering diuretics, and, in severe cases, treatment with a bisphosphonate. In any case, treatment of the underlying neoplastic or infectious disease and tapering the dose or discontinuation of drugs known to cause hypercalcemia is crucial.

 Hypocalcemia

Overt, symptomatic hypocalcemia is uncommon in HIV-infected patients (Table 2), although subtle hypocalcemia has been detected in 6.5% of a total of 828 outpatients with HIV infection (compared with 1.1% of the normal population)(34) and 17.9% of patients with AIDS (n = 66).(27) Among patients with HIV-related hypocalcemia, a subgroup analysis identified vitamin D deficiency in 48%, inappropriate PTH secretion despite hypocalcemia in 33%, overt hypoparathyroidism in 10%, and hypomagnesemia and secondary hyperparathyroidism in 4.8%, respectively.(34)

Severe hypocalcemia has been reported in HIV-infected patients after treatment with various drugs.(50) The most common agent associated with severe hypocalcemia in HIV infection is foscarnet, which is used to treat CMV infection.(51-53) Youle et al.(51) reported the occurrence of hypocalcemia after concurrent therapy with foscarnet and pentamidine for CMV infection in 4 patients, one of whom died with a serum calcium concentration of 1.4 mM (5.6 mg/dl). During foscarnet treatment for CMV retinitis in 13 patients with AIDS, 85-100% developed hypocalcemia(52,53) and 69% developed hypomagnesemia.(52) Foscarnet-induced hypocalcemia is caused by a combination of nephrotoxicity, resulting in renal wasting of calcium and magnesium,(52) and of complex formation of calcium with foscarnet (a phosphate analog), thus rapidly decreasing serum ionized calcium levels.(53) Hypocalcemia has also been reported in 10% of patients with AIDS receiving trimethoprim-sulfamethoxazole and in 15% receiving pentamidine for P. carinii pneumonia, respectively.(54,55)

From a clinical perspective, calcium and magnesium serum levels should be measured in all patients receiving these drugs. In addition, close monitoring of ionized calcium levels is mandatory during and shortly after foscarnet treatment.

VITAMIN D SYSTEM AND HIV INFECTION

Abnormalities of the vitamin D system

In HIV infection, decreased production and action of 1,25(OH)2D3 is the leading cause of hypocalcemia, accounting for 48% of cases.(34) Serum concentrations of 1,25(OH)2D3 were found to be markedly decreased despite normal levels of 25(OH)D3, to correlate positively with the severity of immunodeficiency and survival, and to drop to markedly low levels in patients with active infection with M. avium complex infection.(56,57) Detailed assessment of vitamin D metabolism in HIV-infected patients showed marked 1,25(OH)2D3 deficiency whereas serum concentrations of 25(OH)D3 and vitamin D binding protein were normal, suggesting impaired 1α-hydroxylation as its primary cause.(58) Of note, malabsorption, diarrhea, or weight loss were not correlated with 1,25(OH)2D3 levels, whereas phosphate levels were inversely correlated.(58) Advanced disease stage and increased serum levels of TNF-α were associated with 1,25(OH)2D3 deficiency, and increased TNF-α serum levels were most prevalent in patients with undetectable levels of 1,25(OH)2D3.(55) As suggested by Haug et al.,(58) lack of an increased 1α-hydroxylase activity in response to low 1,25(OH)2D3 levels may be caused by increased phosphate levels,(50) increased TNF-α levels,(59) partial PTH resistance,(2) and increased prolactin levels,(60) all of which may be present during HIV infection and may act in concert to reduce 1α-hydroxylase activity. As evident from in vitro studies, TNF-α may contribute to partial vitamin D deficiency by decreasing vitamin D receptors in osteoblastic lineage cells.(61) By contrast, enhanced 1,25(OH)2D3 synthesis is rare in HIV infection and usually is caused by excessive extrarenal 1α-hydroxylation.(37-39,43,44)

 Modulation of the immune system

The immunomodulatory effects of vitamin D and its metabolites have long been appreciated.(62) 1,25(OH)2D3 modulates HIV expression and replication in monocytic cell lines, and has been found to either stimulate or inhibit it.(63-69) Because 1,25(OH)2D3 stimulates monocyte-to-macrophage maturation, its effect could be, at least in part, related to its regulation of cell differentiation. Alternatively, cytokines such as TNF-α released in response to 1,25(OH)2D3 could alter the susceptibility of immune cells toward the cytopathic effects of HIV.(70) Because of these ambiguous data and the potential stimulation of HIV replication by vitamin D and its metabolites in vitro—one study reported a 10,000-fold increase(65)—vitamin D supplementation or treatment is not recommended unless frank 1,25(OH)2D3 deficiency and concurrent hypocalcemia is present.

DIRECT INVOLVEMENT OF BONE

Skeletal complications resulting from direct involvement of bone by HIV-related infections or tumors are rare and generally reflect disseminated disease.(71) HIV-related osseous tumors usually represent non-Hodgkin’s lymphoma or Kaposi’s sarcoma (KS), and accounted for 16% and 4%, respectively, of HIV-infected patients who present with musculoskeletal abnormalities.(71) KS is the most frequent AIDS-related neoplasm with a prevalence of up to 20% in homosexual men.(72) At the time of skeletal manifestation, cutaneous, orofacial, pulmonary, and abdominal involvement of KS usually is present. KS may present as single or multiple osteolytic lesion(s). Less frequently, nonosteolytic disease may occur and can affect any bone site.(73-77) Osseous non-Hodgkin’s lymphoma in HIV-infected individuals may be either primary(78-80) or secondary(81) and is usually a high-grade B cell lymphoma, although T cell lymphoma affecting bone have also been reported.(78) HIV-related osseous lymphoma usually presents as osteolytic lesions, and their propensity to cause hypercalcemia is related to their ability to express 1α-hydroxylase.(43,44) Of note, unusual tumors such as metastatic giant cell bone tumor (usually a benign and nonmetastatic disease)(82) and nonsecretory multiple myeloma(83) may account for osteolytic bone disease in HIV infection.

Among HIV-related skeletal infections, a distinct spectrum of infectious agents has to be considered.(71) In an analysis of 45 HIV patients with musculoskeletal abnormalities, bacillary angiomatosis (caused by infection with Rochalimaea henselae or Rochalimaea quintana) accounted for 16% of musculoskeletal abnormalities.(71) Because of its cutaneous signs and symptoms and osteolytic lesions, bacillary angiomatosis has been termed a “pseudoneoplastic” infection and must be distinguished from KS.(84-87) Other infectious agents with skeletal tropism in HIV-infected patients include Mycobacterium haemophilum,(88) Aspergillus species,(89) Treponema pallidum,(90) and Acanthamoeba species.(91)

A high index of clinical suspicion, knowledge of the distinct etiology, rapid and straight-forward diagnosis, including early bone biopsy, and appropriate treatment are crucial in the management of bone involvement by HIV-related infections and neoplasms.

HYPOGONADISM IN HIV INFECTION

Sex hormone deficiency is a risk factor of osteoporosis in women and men.(13,92-94) Bone loss associated with sex hormone deficiency is mediated through direct osteoblastic and osteoclastic effects, modulation of the cytokine milieu, and extraskeletal effects on calcium homeostasis. Replacement with sex steroid hormones, at least in part, can prevent these abnormalities.(13,92-94) Sex hormone deficiency is among the most frequent endocrine abnormalities in HIV-infected men, and its clinical symptoms (impotence and decreased libido) have been reported in 33% and 67%, respectively, of 70 patients with AIDS evaluated in an outpatient clinic.(95) Sex hormone deficiency in HIV-infected men is multifactorial and may be caused by hypothalamic and pituitary failure, direct gonadal destruction by HIV-related opportunistic infections or neoplasms, Leydig cell dysfunction induced by abnormal cytokine production, adverse effects of drugs (ketoconazole, ganciclovir, and chemotherapeutic agents), or the chronic and consumptive nature of HIV infection (fever, chronic stress, weight loss, and malnutrition).(96-98) Both gonadal and adrenal steroids have been shown to decline with progression of HIV infection and are correlated positively with lymphocyte counts.(95,99-102)

Neither the contribution of hypogonadism on bone metabolism nor the effect of hormone replacement therapy on bone metabolism and immune function have been assessed systematically in HIV-infected patients. Safe sex education is crucial before initiating hormone replacement therapy to prevent HIV transmission, once libido and sexual potency have been reestablished.

CONCLUSIONS

Patients with HIV infection or AIDS may display various abnormalities of bone and mineral metabolism. Chronic viral infection, altered immune function, abnormal cytokine production, opportunistic infections, HIV-related neoplasms, and drugs are the major causes of bone and mineral disturbances in HIV-infected individuals (Table 3). Bone formation is decreased, bone resorption is normal or increased, and BMD generally is normal but may be decreased in users of protease inhibitors. Hypercalcemia and hypocalcemia are multifactorial in origin and usually caused by infections, neoplasms, or drugs. Hormonal changes in HIV infection include suppressed PTH secretion, impaired synthesis and action of 1,25(OH)2D3, and development of hypogonadism, all of which become most pronounced in advanced stages of HIV infection. A high index of clinical suspicion, early recognition, rapid establishment of the diagnosis, appropriate treatment, and correction of the underlying pathology are crucial in the management of patients suffering from HIV-associated abnormalities of bone and mineral metabolism.

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From:	julev <julev@...>
Subject:	NATAP: Reduced BMD in HIV+ Not Due to ART
Date:	August 30, 2008 10:54:02 AM EDT
To:	julev <julev@...>,
Cc:

BMD Is Reduced in HIV-Infected Men Irrespective of Treatment

"....We show in this study that there was a high prevalence of osteoporosis in the HIV+ patients. Low BMD has been reported in HIV+ patients by several groups, but our data showing a high prevalence of osteoporosis (16%) and osteopenia (66%) in all HIV+ male patients are among the highest reported thus far.....

.....Our finding show that low bone density is present in HIV-infected males before treatment and that it is neither exacerbated nor cured by the treatment.....Multivariate analysis showed that the Z-score of HIV-infected patients was significantly correlated to BMI....and to the lowest BMI recorded since the onset of the disease....but not to how long they had been HIV+, the treatment they received, duration of the treatment, CD4 and viral load, whether they smoked, or amount of calcium in their diet. Weight accounted for 21% of the bone density.....Compared with control, bone alkaline phosphatase, a marker of bone formation, was significantly lower in the untreated patients......Because adipocytes and osteoblasts differentiate from a common precursor, it has been suggested that there could be some link between reduced bone density and abnormal fat repartition.....Beside low BMI, other osteoporosis risk factors such as smoking, low physical activity, low calcium intake, and periods of immobilization could account for decreased bone density...

....In conclusion, our data show that low bone density presents early in HIV+ men and is associated with both high cytokine levels before treatment and a risk factor for common osteoporosis (low weight). However, these factors do not explain the high prevalence of osteoporosis in HIV+ men. Further studies are needed to explain why this decrease in bone density does not improve over time with treatment. Larger populations of untreated HIV+ patients followed longitudinally are required to discover whether the length of time before beginning treatment is a risk factor for osteoporosis."

Journal of Bone and Mineral Research, March 2004:19:402-409 (doi: 10.1359/JBMR.0301246)

C Amiel, 1   A Ostertag, 2   L Slama, 1   C Baudoin, 2   T N'Guyen, 1   E Lajeunie, 2   L Neit-Ngeilh, 1   W Rozenbaum, 1   MC De Vernejoul2  

1Department of Infectious Disease, Hôpital Tenon, Paris, France;

2INSERM U349, Department of Rheumatology and Biochemistry, Hôpital Lariboisière, Paris, France.

ABSTRACT

Osteoporosis has be reported to be a complication of active antiretroviral therapy of HIV infection. We studied 148 HIV-infected men stratified according to their treatment. Our data show that these patients have an average 9% decreased BMD, irrespective of their treatment. Low body mass index and high resorption markers were associated with low bone density.

Introduction: Osteoporosis has been reported in HIV-infected (HIV+) patients, and it has been suggested that it may be linked to protease-inhibitor treatments (PI).

Materials and Methods: To assess this risk and to investigate its putative link with treatments, we compared the bone density of HIV+ men, who were either receiving treatment (including PI [PI+], n = 49; without PI [PI-], n = 51) or untreated (UT, n = 48). We included 81 age-matched control HIV-negative (HIV) males (age, 40 ± 8 years).

Results: BMD adjusted for age (Z-score) was lower in the HIV+ patients at the lumbar spine (HIV+: −1.08 ± 1.21, HIV-: −0.06 ± 1.26, p < 0.001) and the femoral neck (HIV+: −0.39 ± 1.05, HIV: 0.25 ± 0.87, p < 0.001). The prevalence of osteoporosis was 16% in HIV+ and 4% in HIV subjects (p < 0.01). In the HIV+ subjects, the Z-score was correlated only to body mass index (r = 0.27 at lumbar spine and 0.35 at femoral neck). Untreated HIV+ patients had a negative Z-score (−0.82 ± 1.15 for the lumbar spine), which was not different from the one of treated HIV+ patients. In the PI+ and PI- groups, the Z-score did not depend on the presence of lipodystrophy or the proportion of fat in the abdomen and legs measured by DXA. Markers of bone remodeling were measured in the 132 HIV+ and 35 HIV- subjects. Compared with controls, HIV+ patients had lower bone alkaline phosphatase and higher urinary cross-laps/Cr, which was negatively correlated with the Z-score at both the femoral neck (r = −0.22) and lumbar spine (r = −0.21). TNFα was increased in untreated compared with treated HIV+ subjects and was not correlated to the Z-score.

Conclusion: Our cross-sectional study does not show any deleterious effect of the treatment but does indicate a decrease in bone density in HIV+ patients irrespective of the treatment. This low bone density is in part related to the low body weight and is associated with increased bone resorption.

INTRODUCTION

THE INTRODUCTION OF highly active antiretroviral therapy (HAART) has dramatically modified the course of HIV infection.(1) However, long-term HAART has been associated with several metabolic complications, including hyperlipidemia,(2) abnormal fat distribution,(3) and osteoporosis in men.(4)

Osteoporosis is a common disorder in postmenopausal women, and its occurrence in middle-aged men infected with HIV is an unexpected complication of the disease or its treatment. Osteoporosis in males has been neglected during decades but has received increasing attention as the incidence of osteoporotic fractures in elderly males increases.(5) Osteoporosis in men is often secondary to detrimental environmental factors or to endocrine disease, namely alcohol abuse, glucocorticoid excess, and hypogonadism.(5,6) None of these causes can clearly account for osteoporosis in HIV-infected patients. The main complication of osteoporosis is fragility fractures, but the prevalence of osteoporosis and fractures in HIV-infected patients has not been investigated. Central to the debate is the possible link between HAART and osteoporosis: several authors have observed an association between HAART and osteoporosis(4,7); however, methodological bias, particularly the lack of control groups, could have obscured the data. Furthermore, the possible association between osteoporosis and another complication of the treatment, lipodystrophy, has also been a matter of debate.(8)

We therefore decided to investigate a cohort of HIV-infected males to determine the prevalence of osteoporosis and fractures and to identify the possible mechanisms of bone loss by evaluating markers of bone remodeling. We included in the study a group of untreated HIV-infected patients and compared the cohort to controls. Our finding show that low bone density is present in HIV-infected males before treatment and that it is neither exacerbated nor cured by the treatment.

MATERIALS AND METHODS

Patients

This was a non-interventional cross-sectional study with no individual benefit. The inclusion criteria were a documented positive HIV test, age above 20 years and under 60 years, male gender, never treated (UT) with antiretroviral drugs (ARVs) or receiving treatment for more than 18 months with the same classes of ARV including two nucleoside reverse transcriptase inhibitors (NRTIs) + one protease inhibitor (PI; PI+ group), two NRTI + 1 non-nucleoside transcriptase inhibitors (NNRTIs), or three NRTIs (PI group subdivided into PI- 2n1nn and PI- 3n), and having signed an informed consent form. The exclusion criteria were acute infection or uncontrolled chronic infection, treatment with corticosteroids, hormones, immunomodulators, cytotoxic agents, or diuretics, calcium supplementation, and any bone or rheumatic disorder. All patients were white.

A total of 148 HIV-infected patients (HIV+) were included: 48 untreated patients (UT group), 49 patients treated with PI (PI+ group), and 51 patients treated without PI (PI group: 25 in the PI2n1nn group and 26 in the PI- 3n group).

Patients completed a questionnaire about previous personal fractures and physical and nutritional habits. All fractures were reported, irrespective of site, with the date and the circumstances. Lipodystrophy was defined as the presence of peripheral loss of fatty tissue and abnormal fat distribution including one or more of the following clinical signs: breast hypertrophy, increased waist measurement, visceral abdominal fat hypertrophy, and enlargement of the dorsocervical pad “buffalo hump.”

Bone density

BMD was measured at the femoral neck and at the lumbar spine (L2-L4) using a Lunar DPX-L (Lunar Corp., Madison, WI, USA). All measurements were performed with the same densitometer and by the same technician. Age-adjusted values were based on a French reference population between 20 and 89 years of age from several centers (provided by Lunar France). The data were adjusted for age and gender and expressed as a Z-score and a T-score. For the Z-score, the results were based on the observed BMD value minus the mean of normal BMD values for men of the same age, divided by the SD of this reference population. For the T-score, the results were based on the observed BMD value minus the mean of normal BMD values for men between 20 and 30 years of age, divided by the SD of this reference population. Osteopenia was defined as a T-score of between −1 and −2.5, and osteoporosis was defined as a T-score of less than −2.5 relative to this normal French population.

Whole body scans were performed to obtain the fat and lean mass. The software provided by the manufacturer included cut-off lines positioned at anatomical regions of interest. In addition to the whole body, we selected the regions of the trunk and the legs and calculated the ratio of the fat in these two regions, divided by the whole body fat.

Biochemical measurements

Testosterone was measured using a radioimmunoassay (BYK-Sangtec, Dietzenbach, Germany) (normal range, 350-1160 ng/dl). Free testosterone was calculated according to Vermeulen et al.(9) Sex hormone binding protein (SHBG), dehydroepiandrosterone (DHEA), and parathyroid hormone (PTH) were measured by automated chemiluminescent immunoassay (Diagnostic Products Corp., Los Angeles, CA, USA). Normal values were 13-71 nM, 800-5600 ng/ml, and 7-53 pg/ml, respectively. Total insulin-like growth factor (IGF)1 was measured by IRMA (Immunotech, Marseilles, France) (normal range for males of this age, 90-492 ng/ml). Leptin was measured using a radioimmunoassay (LINCO, St Charles, MO, USA) (normal range for males, 2-5.6 ng/ml). 25(OH)vitamin D was measured after extraction using a commercial RIA kit (DiaSorin, Stillwater, MN, USA) (normal range, 8-35 ng/ml). Plasma TNFα was measured using immunoradiometric assay (Biosource Europe, Brussells, Belgium). The minimum detectable concentration was 5 pg/ml. TNFα was not measured in the controls.

Bone resorption was assessed by measuring urinary type I C-telopeptide breakdown products (CTX) using an ELISA kit (Cross-laps; Osteometer, Herlev, Denmark). Calculation of the corrected Cross-laps value gave a normal range of Cross-laps/creatinine values of 100-300 μg/mmol. Bone formation was assessed by measuring both osteocalcin and bone alkaline phosphatase. Serum bone-specific alkaline phosphatase (BAP) was measured using an immunoradiometric assay (Tandem-R, Ostase) provided by Hybritech Europe S.A. (Liege, Belgium) (normal range, 7.5-16 ng/ml). Serum osteocalcin (OC) was measured using a radioimmunoassay (OSTK-PR; CIS Biointernational, Gif-sur-Yvette, France) (normal range for men, 0.9-18 ng/ml).

Statistical methods

The study involved two steps. First, to study the prevalence of osteoporosis, we compared the whole group of HIV+ patients to 81 (HIV-) male controls from 20 to 60 years of age who were employees (students, physicians, etc.) at our hospital. These subjects were volunteers and had filled out the same questionnaire as the HIV+ patients and had undergone a bone densitometry. We excluded subjects using a treatment that could induce bone disease and those who had a chronic pathology. We used the χ2 test to compare the qualitative data and Student’s t-test for the quantitative data. The effect of the disease on BMD (Z-score) was also tested after adjusting for body mass index (BMI), current smoking (yes or no), and calcium intake using multivariate analysis.

Second, to assess the effect of treatment on BMD, we analyzed the four HIV+ groups PI+, PI- (PI- 2n1nn and PI- 3n) and the UT group using a one-way ANOVA. The sample size of PI+, PI-, and UT HIV+ patients were roughly equilibrated. When hypothesis of equal effect was rejected, we compared the differences, defined a priori, between treated and untreated patients, between the overall PI- group and the PI+ group and between the PI- 2n1nn and PI- 3n groups, using multiple orthogonal comparison based on Helmert contrasts. In addition, we compared each HIV+ subgroup to the HIV controls using the posthoc test of Dunnett.

The effect of the treatment on BMD was also tested after adjusting for actual BMI, the previous lowest BMI, calcium intake, smoking, age at HIV onset, how long the subject had been HIV positive, duration of the treatment, CD4 and viral load, and the interactions between these factors. We used multiple linear regression. The best fitting and most parsimonious subsets of factors were selected using the lack-of-fit method based on the likelihood ratio test.

To study the effect of the disease and treatments on biochemical parameters related to bone metabolism, we used 35 of the 81 controls and the four HIV+ groups described above. We first analyzed the difference between the five groups using a one-way ANOVA; second, when the test was significant, we used a multiple comparison between groups (Tukey test). We evaluated the relationship between the Z-score and the biochemical parameters using Pearson’s correlations.

Results were expressed as mean ± SD. All tests were two-sided, and the significance level was fixed at 0.05. The statistical computations were performed with S plus 2000.(10)

RESULTS

Prevalence of osteoporosis and association with fractures

Table 1 shows that BMD, Z-score, and T-score were all significantly decreased in the patients, both at the lumbar spine and femoral neck, and the difference in BMD was 9% at both sites. The weight and BMI of the patients was lower than the controls, although BMI was only moderately decreased in the patients (23 ± 3 versus 24 ± 3; p < 0.02). Fifty-two percent of the patients and 33% of controls were current smokers. The model including disease, BMI, calcium intake, and smoking explained 21% of the variance of the Z-score (p < 0.001).After adjusting for BMI, smoking, and calcium intake, there was still a significant difference (p < 0.001) for the Z-score at the spine and femoral neck between the HIV+ patients and controls.

Sixty-six percent of the patients and 32% of the controls presented with osteopenia (−2.5 < T-score < −1) at at least one site (p < 0.001). When a T-score of ≤ −2.5 at any site was taken to be the threshold, the prevalence of osteoporosis reached 16% in this population of men (mean age, 40 years) and was significantly higher than in the 81 controls (4%; p < 0.001; Fig. 1).

Thirty-seven percent of controls reported a previous fracture. Among the HIV+ patients, 41% reported a previous fracture, including 22% who had had their first fracture after the disease had been diagnosed. All the fractures were reported as being traumatic. Six patients had a crushed vertebra, confirmed by an X-ray. It was performed because of pain after an injury that had occurred for 3/6 of the patients before the disease had been diagnosed. None of them had osteoporosis. Osteoporosis was not associated with the occurrence of fractures: 45% of the patients with fractures had osteoporosis and 39% had no osteoporosis.

 BMD in HIV+ patients according to treatment

About one-half the patients were smokers (52%), and 41% had a calcium intake of less than 900 mg/day. Patients whose treatment included PI had a slightly lower calcium intake, were more frequently smokers, had a higher viral load, and had been receiving treatment for longer than those whose treatment did not include PI. Untreated patients were younger, had been HIV+ for a shorter time, and had a higher current viral load and a lower CD4 count nadir than the treated patients (Table 2).

The Z-score at the lumbar spine and femoral neck did not depend on whether the patient was receiving treatment or whether this included PI (Table 3) or the patient belonged to one of the two subgroups treated without PI (data not shown).

The overall Z-score at the lumbar spine was significantly reduced to less than zero (p < 0.001). Each subgroup of HIV+ patients had a Z-score lower (p < 0.05) than the controls. Untreated patients had a mean Z-score of −0.82 at the lumbar spine and of −0.19 at the femoral neck (Table 3). Four of 48 untreated patients had osteoporosis, which was not different from the treated patients, 18 of 100 of whom had osteoporosis (not significant).

Multivariate analysis showed that the Z-score of HIV-infected patients was significantly correlated to BMI (r = 0.27 at the lumbar spine and 0.32 at the femoral neck) and to the lowest BMI recorded since the onset of the disease (r = 0.35 at the lumbar spine and 0.39 at the femoral neck), but not to how long they had been HIV+, the treatment they received, duration of the treatment, CD4 and viral load, whether they smoked, or amount of calcium in their diet. Weight accounted for 21% of the bone density.

 BMD and lipodystrophy

Lipodystrophy was present in most of the treated patients but in only one untreated patient. We also assessed lipodystrophy by measuring the amount of fat and the proportion of fat in the abdomen and the legs. Treated patients, independently of whether they were receiving PI or not, had less fat than the untreated patients. They also had a percentage of fat higher in the trunk and lower in the legs than the untreated patients (Table 4). Among the treated patients whose treatment did not include PI, patients receiving two NRTIs + one NNRTI (n = 26) had a lower fat mass (7.8 ± 3.5 kg) than patients receiving three NRTIs (n = 25, 10.1 ± 4.4 kg, p < 0.05), and they also more frequently had lipoatrophy (77% versus 48%, p < 0.04). There was no other treatment-related difference for any of the parameters describing lipodystrophy (Table 4).

In the group of HIV+ patients as a whole, lipodystrophy was not associated with osteoporosis or with Z-score. In the subgroup of treated patients, there was no influence of lipodystrophy, lipoatrophy, or hypertrophy on the Z-score. BMC was correlated to both lean mass and fat mass in the untreated patients; however, whereas the correlation between BMC and lean mass persisted, the correlation between the BMC and fat mass was not more significant in the treated patients (Table 5).

 Endocrinology and bone markers

First, we compared the controls to each group of HIV+ patients (Table 6). Plasma testosterone and SHBG were higher in untreated patients than in the controls, and free testosterone was not increased in any of the patient subgroups. Vitamin D and PTH levels, as well as levels of IGF1, were in the normal ranges and did not differ in patients and controls. The one-way variance analysis among the four groups was not significant for osteocalcin. Compared with control, bone alkaline phosphatase, a marker of bone formation, was significantly lower in the untreated patients. Urinary cross-laps, a marker of bone resorption, was increased in HIV+ patients treated without PI compared with control. When comparing all the HIV+ patients to the 35 controls, urinary cross-laps was increased (0.22 ± 013 versus 0.15 ± 0.07 μg/mmol, p < 0.01) and alkaline phosphatase was decreased (9.5 ± 4.2 versus 11.9 ± 4.3 ng/ml, p < 0.01) in the patients, whereas osteocalcin was not different between the groups. There was a significant negative correlation between osteocalcin and the Z-score at the lumbar spine (r = −0.18, p < 0.04) and also between urinary cross-laps and the Z-score at both the lumbar spine (r = −0.21, p < 0.012) and the femoral neck (r = −0.22, p < 0.005). There was no correlation between alkaline phosphatase and Z-score.

Untreated HIV+ patients had higher serum TNFα values than treated patients. TNFα was not correlated to the markers of bone formation or resorption or to Z-score.

The level of leptin was not different between the HIV+ patients and the 35 controls. Among patients treated without PI, those receiving two NRTIs + one NNRTI (n = 26) had a significantly lower serum leptin level than those receiving three NRTIs (2 ± 0.9 versus 3.2 ± 1.9 ng/ml, p < 0.05).

DISCUSSION

We show in this study that there was a high prevalence of osteoporosis in the HIV+ patients. Low BMD has been reported in HIV+ patients by several groups, but our data showing a high prevalence of osteoporosis (16%) and osteopenia (66%) in all HIV+ male patients are among the highest reported thus far.(4,11) Although single case reports of fractures have already been published about HIV+ patients,(12) this is the first time that the occurrence of fragility fractures in these patients had been assessed in a cohort. In our population of young men, the fractures could not be related to osteoporosis. However, our data do not exclude the possibility that fragility fractures could occur at an older age in this population.

In the multivariate analysis, we could not see any association between bone density and nature or duration of treatment. This cross-sectional study with stratification according to treatment used a large group of untreated HIV+ patients who could be used as controls for investigating the possible implication of various treatments in the occurrence of osteopenia. This stratification was made to assess the responsibility of various treatment-related factors that have been suggested as possible etiologies for the low bone mass observed in other studies. Our study shows that BMD is reduced in HIV+ patients regardless of the treatment and quite early in the course of the disease. Several hypotheses could explain reduced bone density in HIV+ patients.

Because adipocytes and osteoblasts differentiate from a common precursor, it has been suggested that there could be some link between reduced bone density and abnormal fat repartition. Indeed, in a small group of 41 HIV+ patients, Huang et al.(8) observed that bone density was lower in patients with lipodystrophy than those without lipodystrophy and controls and that abdominal fat was a negative predictor of bone density measured by QCT. McDermott et al.(13) also observed that men receiving HAART had a higher proportion of fat in the trunk and lower bone density, both of which were related to treatment duration, but they did not detect any relationship between these two factors. However, in other studies, neither BMD nor osteoporosis was associated with fat accumulation.(4,11) We measured fat accumulation in the trunk accurately and did not find any negative relationship between bone density and the accumulation of fat in the abdomen, even when patients with lipodystrophy were selected. As in this study, the amount of fat is usually positively correlated with the BMC, but in patients treated with HAART, we showed that this had no positive or negative effect on the BMC.

Protease inhibitors have been reported to be either positively or negatively associated with bone density. In a small cross-sectional study, Tebas et al.(4) reported that the use of PI was associated with lower bone density than that found in a mixed group of patients treated without PI or not treated at all, and this was also confirmed by another study.(7) However, this was not observed in any of the subsequent cross-sectional studies.(8,13) Even in two short-term longitudinal studies, there was an increase or no decrease in BMD with time in patients receiving PI.(14,15) In our study, which included 100 treated patients, one-half of whom received PI, we could not see any treatment-related difference in bone density. Compared with controls, there was an increased level of cross-laps, a marker of bone resorption, in patients treated without PI. The same trend for this was observed in patients receiving PI and in untreated patients who also had a slight insignificant increase in Cross-laps level as already observed by other.(16) It is not certain that the increased bone resorption is attributable to the treatment, although, in vitro, some PIs can induce increased bone resorption.(17) We did not observe any decrease in either osteocalcin or bone alkaline phosphatase in these patients receiving HAART, and moreover, one study show that PI treatment is associated with an increase in osteocalcin.(16) Our data do not preclude any positive or negative action of HAART on bone, because the results of BMD were not different from the group of untreated patients, who had decreased bone density.

We could not see any biochemical endocrine change induced by treatment in the whole group or in any of the subgroups that could offer a simple explanation for the lower bone density: free testosterone was normal, and there was no patient with hypogonadism that has been shown to occur in advanced HIV disease.(18) Similarly, DHEA was, as previously reported,(19) slightly decreased in patients treated without PI but it is not likely that it can account for the decreased bone density. There was no vitamin D deficiency or increase in PTH level. Modification of the IGF system has been reported in patients infected with HIV.(20) We measured only IGF1 that has been shown to be decreased in males with idiopathic osteoporosis,(21) and we observed no changes in our HIV+ patients.

Most of the studies of BMD in HIV+ patients have included only a small proportion of untreated patients or none at all. It is in fact difficult to persuade these patients to take part in a clinical study. They also differ from treated patients in terms of age, how long they have been HIV+, and their viral load and tCD4 count. Unexpectedly, we found that they had low bone density that was similar to that of the treated patients. In accordance with previous studies,(16) this low bone density was associated with low bone formation; bone alkaline phosphatase levels are reduced in this population. That could be because of the secretion of cytokines as a result of the high level of viral replication. Pro-inflammatory cytokines have been shown to be elevated in untreated HIV+ patients.(22,23) Indeed, we also observed that TNFα serum levels were increased in untreated HIV+ patients comparatively to both treated subgroups. There is an association between cytokines and bone remodeling in several metabolic bone diseases, including postmenopausal osteoporosis.(24,25) Interleukin (IL)1 and TNF not only increased bone resorption but also decreased bone formation.(26) The role of TNF on bone remodeling in HIV infection has been suggested in a previous biochemical study based on a correlation between decreased plasma levels of osteocalcin and TNF.(15) However, in our study, we could not find any correlation between TNFα and the Z-score.

When comparing all the HIV+ patients to their controls, we observed an increase in urinary cross-laps and a decrease in alkaline phosphatase. Although these changes were of variable importance and maybe of different etiologies in the different HIV+ subgroups, these data point to an identical mechanism of the bone loss in all the HIV+ patients. Moreover, there was a negative correlation between these markers and the Z-score. The imbalance between decreased bone formation and increased bone resorption would induce bone loss.

Finally, the low bone density could be present before HIV infection or be related to any common osteoporosis risk factor. Our HIV+ patients have a slightly lower BMI than a population of uninfected patients. Indeed, we observed a relationship with the BMI and the lower BMI of these patients as previously observed in another study.(11) However, our patients did not have a wasting syndrome that is associated with markedly decreased BMD.(27) When comparing the HIV+ patients and controls, the Z-score was still lower in the HIV+ patients after adjusting for BMI. Body weight accounted for only 21% of the bone density in the patients and cannot be the only factor responsible for their low bone density.

Beside low BMI, other osteoporosis risk factors such as smoking, low physical activity, low calcium intake, and periods of immobilization could account for decreased bone density. When we adjusted Z-score for current smoking, the difference between HIV+ patients and controls persisted. Average calcium intake was around 800 mg/day (Table 2), and the patients had a normal-to-high current physical activity. However, all these parameters could have been altered in the past for significant periods of time in these patients.

In conclusion, our data show that low bone density presents early in HIV+ men and is associated with both high cytokine levels before treatment and a risk factor for common osteoporosis (low weight). However, these factors do not explain the high prevalence of osteoporosis in HIV+ men. Further studies are needed to explain why this decrease in bone density does not improve over time with treatment. Larger populations of untreated HIV+ patients followed longitudinally are required to discover whether the length of time before beginning treatment is a risk factor for osteoporosis.

---

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This is my first posting on this list. I'm 47 yrs old from Denmark, Europe. Have
been HIV+
since -83. Started HAART treatment in -96. My butt got smaller and flatter by
the time.

  2 months ago I flew over to see Dr Casavantes in his clinic in Tijuana  for a
buttock augmentation and vein camouflage using PMMA. Since I have to travel that
far we decided to
have all done in 1 session. Had over 400cc in my butt  "brazilian lift" +
subcutaneous. 160cc
in legs for vein camouflage.

I found both Dr Casavantes and his partner RN Wade Zobel very professional and
the result
is amazing. I spend 6-7 hours in their clinic and I felt well taken care of and
the procedure
went very smoth with no pain what so ever. Felt a bit sore for a few days after
surgery  but
flew back to Europe 5 days after with no problems at all.

I just love my new  bubble butt and planning to be back next summer to have my
face done.

Erik

From:	"NATAP Mailing List"�
Subject:	NATAP: HIV Bone Loss Treatment Studies
Date:	August 30, 2008 8:10:02 AM EDT
To:	hiv@...,�

NATAP http://natap.org/
_______________________________________________

These are 2 main studies in HIV of treatment for bone loss. There has not been very much research in HIV regarding bone loss directed at understanding pathogenesis or at understanding unique risk factors to HIV. For example, mitcochondrial toxicity may have an effect on bone loss since there are mitochondria in bone cells but little or no research has been conducted on this in HIV. There were several studies from years ago finding HIV causes bone metabolism dysfunction but this has not been followed up on with more exploratory research. HIV+ individuals have much higher rates of bone loss than HIV-negatives and much higher rates of risk factors including smoking, alcohol use, and use of SSRIs and PPIs may also cuase bone loss. In HIV men have higher rates of bone loss than women. Another key risk factor for bone loss is low BMI or weight, so lipoatrophy may be a key factor bone loss. Chronic inflammation appears to be associated with bone loss, some HIV studies find ART may stop bone loss, but there are so many risk factors for bone loss in HIV that have not been identified or well characterized that confound larger studies' results. HCV also appears to be a risk factor for bone loss. Cohort studies have repeatedly reported very high rates of bone loss among HIV+ individuals, 60-65% at the average age of 45 yrs old. This is astounding because serious bone loss doesn't occur among normal populations until they are elderly.�

GUIDELINES/RECOMMENDATIONS: there needs to be an organized discussion regarding Guidelines and Recommendations for screening & testing for bone loss in HIV. In my opinion, the risk factors are so high it is clear everyone should receive a baseline screening for bone loss with a bone dexa-scan. Followup scans should be regular; at the same time patients should receive education regarding risk factors for bone loss including diet, exercise, smoking, and alcohol.

Alendronate, Vitamin D, and Calcium for the Treatment of Osteopenia/Osteoporosis Associated With HIV Infection�- (03/21/05)

Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV�- (11/26/07)

NATAP.org has an entire section devoted to Bone Disease, it is called the Bone Disease section and these key articles were selected because they are particularly informative:

1. Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture�- (07/04/08)
   �
   
2. Use of Antidepressants and Rates of Hip Bone Loss in Older Women�- (07/04/08)
3. Guidelines Recommend Screening for Men at Increased Risk for Ostoeporosis.�- (05/10/08)
   
4. Diabetes drugs (glitazones) double fracture risk: Swiss study�- (05/01/08)
   
5. Gut (liver), inflammation and osteoporosis: basic and clinical concepts�- (04/16/08)
   
6. Effects of Alendronate on BMD and Fracture Risk: The FOSIT Study�- (03/17/08)
   
7. Osteopenia: intervention & therapy�- (03/17/08)
   
8. Smoking Increases Bone Loss and Decreases Intestinal Calcium Absorption�- (03/14/08)
   
9. Clinical Use of Serum and Urine Bone Markers in the Management of Osteoporosis�- (03/14/08)
   
10. Bone disorders in chronic liver disease�- (03/10/08)
    
11. Low Serum Testosterone Caused Fractures, study found�- (01/29/08)
    
12. CROI:�Risk Factors for Reduced Bone Mineral Density In HIV-Infected Individuals In The Modern HAART Era- (02/22/08)
    
13. Bone Health: calcium, vitamin D�- (01/29/08)
    
14. Serum 25-Hydroxyvitamin D and Bone Mineral Density in a Racially and Ethnically Diverse Group of Men�- (01/29/08)
    

---

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From:	julev <JuLev@...>
Subject:	[ATAC-DrugDev] NATAP: Bone Fractures HIGHER in HIV+, the study
Date:	August 30, 2008 6:47:04 AM EDT
To:	"ATAC new" <ATAC-Discuss@yahoogroups.com>,�ATAC-DrugDev <ATAC-DrugDev@yahoogroups.com>

Fracture Prevalence Among HIV-Infected versus Non HIV-Infected Patients in a Large U.S. Healthcare System�- (07/02/08)

J Clin Endocrin Metab. First published ahead of print July 1, 2008

Virginia A. Triant, MD, MPH, Todd T. Brown, MD, PhD, Hang Lee, PhD, and Steven K. Grinspoon, MD

"To our knowledge, these data are the first to compare fracture prevalence between HIV-infected and non HIV-infected patients with a large patient sample using ICD-based outcome ascertainment. The�results provide strong evidence that HIV-infected patients have a higher prevalence of fractures than non HIV-infected patients, across both genders and critical fracture sites. Moreover, our data suggest that the relative difference in fracture prevalence between HIV-infected and non HIV-infected patients�increases with age for both genders.�As the HIV-infected population ages, reduced bone mineral density and increased fracture risk may become an even greater problem. Whether increased fractures are the sequelae of antiretroviral therapy, increased rates of traditional risk factors such as low weight among HIV-infected patients, or HIV infection - and its accompanying metabolic and inflammatory disturbances - itself remains to be determined.....Mitochondrial dysfunction has been associated with the use of nucleoside reverse transcriptase inhibitors,(23) and it is interesting to speculate that this may contribute to a "premature aging" in HIV-infected patients which may contribute to reduced BMD and increased fracture rates.�This study suggests the importance of assessing bone density and minimizing factors contributing to increased fracture risk in the HIV-infected population."

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I just got discharged from a week in the hospital after a little fluid
on the kneecap turned into a staph infection.  Even though it was
normal staph and not MRSA, I had to have the knee cleaned surgically
and must undergo a month of IV antibiotic post operatively.  I give
myself the IV injections through a PICC line, and thought the main
cost would be from having to have a nurse come to the house once a
week to change the line dressing. Turns out though that the antibiotic
(cefazolin) is being charged to me at $182 per day - or $60.66 per 1
gram prepared syringe.  That comes to nearly $5500 per month, or more
than $65,000 per year!  With my BC/BS I'm looking at paying 10 percent
of the cost of home IV drugs, so this will be a big expense.  I looked
online and found the wholesale cost of cefazolin is $5.50 for 10
grams.  I realize my syringes are prepared individually (I'm not sure
why this drug isn't available in 1 gram IV doses already prepared),
but it seems unbelievable that a drug costing 50 cents per gram could
cost $60 when put into sterile water.
Has anybody else had any experience with this, or have any pharmacy
background to explain this apparently outrageous cost?

The risk is very low, despite the fear of some other respondents to
your question. The Swiss government study was pretty clear, and the
announcements about it were in the interest of protecting health and
acknowledging scientific statistics.

Things that can increase the risk:

1. If your partner is large or rough, so that you bleed during
intercourse. This can make your blood available to possibly infect him.

2. If your partner is uncut. There is some evidence that the cells in
the foreskin are more susceptible to HIV than the rest of the cells on
his penis. He should wash and pee immediately after sex to minimize
risk.

3. If you aren't completely regular in taking your meds. This can
cause a spike in your HIV load, which may make you infectious.

4. If you have herpes or other STD which may have sores which leak the
virus.

Peridot

I am using Androgel, HCG and Arimidex.  Still experimenting with doses
and timing.

HCG can be prescribed and picked up at CVS or other pharmacy.


--- In PozHealth@yahoogroups.com, "Craig Hoffman" <craigwh51@...> wrote:
>
> Is that true?  I use Androgel, but I used to alternate with HCG.  Is
> anyone else doing that?
>

Hi All,
I am looking for recommendations for a good Sculptra doctor in the
Denver area, and I would greatly appreciate any and all experiences
people have had with docs in Denver.

I had Sculptra injections a couple years ago, which were very
successful.  But, now it's time for touch ups, and the doc that did
my injections two years ago is deceased.  So, I am hoping to find a
doc that does lots of faces of people with HIV in Denver.

I am familiar with the Sculptra website and the provider locator
available on that site.  The locator lists about ten docs in Denver,
but no information about their experience with people with HIV is
provided.

If you have had Sculptra in Denver, would you please share your
experience with me?

Thank you very much!

Christopher

From:	nataphcvhiv@...
Subject:	NATAP: Aging/HIV-Early Cognitive Decline
Date:	August 28, 2008 3:47:46 PM EDT
To:	hiv@...,�nataphcvhiv@...,�natapindustry@...,�natapdoctors@...

NATAP http://natap.org/
_______________________________________________

from Jules:�Aging with HIV�is the major theme that emerged this year in the western world. The CDC reported at CROI 08 that in the last few years there has been an increase of 30% in the number of HIV+ individuals over 50 yrs old. This trend will continue. Since�HIV+ individuals are at greater risk for diseases associated with aging they are perhaps at greater risk for steeper declines in mental functioning.�The authors of this study refer to cardiovascular disease and frailty and lack of exercise that may accelerate declines in mental skills associated with aging. I add to this list bone disease, diabetes, and neurological complications that may be associated with HIV. The study below reports cognitive decline can begin as much as 15 years before death for persons in the study. The study of cognitive decline in the context of neurological complications and other aging-associated diseases for HIV+ individuals would be an important subject to begin thinking about and incorporating into studies.

The concerns regarding Aging with HIV need to be addressed by our research community.

Cognitive Decline May Begin 15 Years Before Death

Posted by Jane Akre

http://www.injuryboard.com

Thursday, August 28, 2008�

A decline in verbal skills may indicate that an age-related cognitive decline is underway.

A new study reports that key mental skills drop by as much as 15 years before death, even without dementia. The skills in decline include verbal ability, spatial reasoning and perceptual speed.

This is not part of the aging process.

So why are we losing abilities? � Researchers from Goteborg University in Sweden, credit undetected dementia, insufficient physical and mental exercise, and perhaps early heart disease that interrupt blood flow to the brain.

Valgeir Thorvaldsson, from the department of psychology at Goteborg University, in Sweden said,� "[And] our findings clearly showed there to be a pattern of terminal decline, even among relatively healthy individuals, that the brain changes that influence our cognitive abilities in old age occur over a relatively long period of time, even among individuals who remain non-demented until they die."

The researchers said they were surprised at how far in advance of death the decline begins.

Verbal ability started a sharply accelerated decline more than six years prior to death, while it�s 7.8 years for spatial ability.

However, perceptual speed, the ability to quickly compare figures, begins to decline as much as 15 years before death.

In the study, 288 people without dementia were followed from age 70 to their death, which occurred at an average age of 84. Their mental skills were measured up to a dozen times over 30 years.

On a more positive note, the study finds that the elderly remain stable in their verbal abilities until they are burdened by diseases.�

"A change in verbal ability might therefore be considered a critical marker for degeneration in health in older people," Thorvaldsson said.

The peak of mental functioning is reached for most people between the ages of 35 to 40 after which a steady decline begins, then speeds up before death.� The Swedish team was trying to determine when the acceleration starts.

The research may help those who work with the elderly derive markers when trying to determine a degeneration of mental health.

Age-related cognitive decline has long been evaluated along with dementia.

The value of the study may be the distinction it makes between the normal aging process and the dying process.

The work is presented to today�s issue of Neurology.�

The changes may not be inevitable.

Evidence suggests among those who participate in regular strenuous aerobic activity, that there is four times less shrinkage in the brain when compared to those who do not exercise.

The average U.S. life expectancy is now 78 years up 30 years since 1900 and 10 years since 1950. And while aging fears are often used in the hiring of corporate America some believe those fears are misplaced.

A 45-year-old and a 75-year-old "absolutely" have the same mental capacity, and energy is a function of health rather than aging, said Neil Resnick, chief of geriatric medicine at the University of Pittsburgh tells the Wall Street Journal.

But much of our genealogy influences how fact we decline. John Rowe, a physician and former Aetna Inc. chair tells the Wall Street Journal that our genes influence how much and how fast we decline. He says genes account for about 30 percent of longevity and perhaps half of age-related changes in the brain.

The implications for U.S. society are huge. The over-65 population will double to 80 million in 30 years when one in five will be older than 65, up from one in eight now.�

Onset of terminal decline in cognitive abilities in individuals without dementia

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Neurology 2008 Aug 27 2008

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V. Thorvaldsson MSc*, S. M. Hofer PhD, S. Berg PhD, I. Skoog MD, PhD, S. Sacuiu MD, and B. Johansson PhD

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From the Department of Psychology (V.T., B.J.), and Institute of Neuroscience and Physiology, Sahlgrenska Academy (I.S., S.S.), G�teborg University, Sweden; Department of Human Development and Family Sciences (S.M.H.), Oregon State University, Corvallis; and Institute of Gerontology (S.B.), School of Health Sciences, J�nk�ping University, Sweden.

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�Our purpose was to examine terminal decline in three cognitive abilities in an age- homogeneous, population-based sample without dementia, followed from age 70 to the end of life. The main finding was that accelerated cognitive change, indicating a terminal decline phase, occurred on average 6.5 years prior to death for verbal ability, about 8 years for spatial ability, and almost 15 years before death for perceptual speed. In all cognitive abilities, we found a substantial acceleration in decline in the terminal decline phase relative to earlier age-related within-person change�.

�

�..�There are a number of interacting factors that may explain these findings of terminal decline. Cardiovascular conditions (e.g., heart diseases) and undetected preclinical dementia (e.g., Alzheimer disease) are two such candidates. Increased medical burden and frailty in old age often further leads to inactivity (i.e., lack of physical exercise and cognitive stimulation) that can accelerate cognitive decline.�

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ABSTRACT

Objective: To identify time of onset and rate of mortality-related change (terminal decline) in cognitive abilities in later life.

Method: The sample consisted of 288 individuals without dementia (born 1901�1902) drawn from the population of G�teborg, Sweden. Participants were followed from age 70 until death, with up to 12 measurement occasions on three cognitive abilities. Change-point analysis was performed using an automated piecewise linear mixed modeling approach to identify the inflection point indicating accelerated within-person change related to mortality. A profile likelihood method was used to identify the change point that best fit the data for each of three cognitive abilities.

Results: Onset of terminal decline was identified 6.6 years prior to death for verbal ability, 7.8 years for spatial ability, and 14.8 years for perceptual speed.

Conclusions: There is substantial acceleration in cognitive decline many years prior to death among individuals without dementia. Time of onset and rate of terminal decline vary considerably across cognitive abilities.

Terminal decline in cognition refers to acceleration in within-person change prior to death and is distinct from, but possibly moderated by, aging-related changes.1,2 Several studies have demonstrated terminal decline by comparing survivals and nonsurvivals but relatively few longitudinal studies have identified terminal decline at the level of the individual with complete information about age at death in a population-based representative sample.3,4 Little is therefore known about time of onset of terminal decline, rate of change, and whether terminal decline varies across cognitive abilities.

We are aware of two studies that have identified terminal decline as acceleration in within-person change before death and relative to prior within-person age-related change. One study5 reported a terminal decline period ranging from 2.75 years to 6 years before death on various cognitive abilities based on data from a sample of Roman Catholic nuns, priests, and brothers. Another study4 reported a longer terminal decline period ranging over 8.4 years in a measure of episodic memory based on data from a sample of community-based North Americans. Explanations for the discrepancy between these findings in terms of the length, and magnitude, of the terminal decline phase is somewhat unclear but is likely related to different sample compositions, testing instruments, and design (i.e., differences in length of the follow-ups).

Dementia, including its preclinical phase, has been shown in longitudinal studies to be a major contributor for age-related heterogeneity in cognitive change. Most studies of terminal decline, however, exclude individuals with dementia only at the initial assessment,6,7 leaving estimates of cognitive change affected by a�subsequent incidence of dementia. To our knowledge, little is known about terminal decline in populations that remain without dementia until death. The aim of this study is to examine time of onset (i.e., change point) and rate of change in terminal decline across three distinct cognitive abilities (i.e., verbal ability,

spatial ability, and perceptual speed). The change point for terminal decline is identified within the context of two time-dependent change processes�age and proximity to death�in a population-based age-homogeneous sample of individuals without dementia followed from age 70 to death.

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DISCUSSION

Our purpose was to examine terminal decline in three cognitive abilities in an age- homogeneous, population-based sample without dementia, followed from age 70 to the end of life. The main finding was that accelerated cognitive change, indicating a terminal decline phase, occurred on average 6.5 years prior to death for verbal ability, about 8 years for spatial ability, and almost 15 years before death for perceptual speed. In all cognitive abilities, we found a substantial acceleration in decline in the terminal decline phase relative to earlier age-related within-person change.

The terminal decline phases in our study were considerably longer than the estimates from the two other studies reporting onset of terminal decline.

One study5 found evidence for terminal decline 3.33 years before death in semantic memory, 6 years in visuospatial ability, and only 2.75 years in perceptual speed. The other study4 found a terminal decline phase on episodic memory ranging over 8.4 years before death. Our findings for both verbal ability and spatial ability are similar to this estimate, but our estimate for perceptual speed is much longer. Measures of processing speed are typically one of the�most sensitive markers of age-related change and between-person age differences. Our finding that speed was the earliest marker of mortality-related decline is in line with these findings. Otherwise, we can only speculate about the various reasons that might contribute to the discrepancy between the present�and previous findings but most likely the explanation is related to differences in health-related characteristics of the samples and length of follow-ups.

The steep average estimate of verbal ability change in the terminal decline period, along with the nonsignificant age slope, and consequently relatively�large terminal decline effects, indicates that individuals remain stable in this ability unless affected by mortality-related pathology. Change in verbal ability

might therefore be considered a relatively robust indicator of mortality-related processes in old age and might consequently be considered as a critical marker�for compromised health in older individuals. The terminal decline effect in spatial ability and perceptual speed was also relatively large. For example, in spatial ability this estimate was 90% of the average age-based change and in perceptual speed 100% of the average age-based change. Note, however, the substantial individual differences in the effects of terminal decline in verbal and spatial ability as indicated by the significant estimates of death slope random effects.

One contribution of this study is that it allows evaluation of terminal decline in a population-based sample examined over 30 years on three cognitive abilities. Information about age at death is available for all deceased individuals (i.e., 99% of the sample). However, as in all studies, there are several shortcomings to be addressed. One relates to a possible lack of generalizability of findings in an age-homogenous sample.15 That is, other birth cohorts may differ in onset and rate of terminal decline. Age-homogeneity can, however, also be considered as a major strength as it reduces potential bias due to cohort differences in estimates of between-person differences in both aging and mortality-related change. Another potential shortcoming relates to the relatively large measurement occasion intervals in the study, ranging from 1 to 5 years. This might reduce sensitivity in identification of the change points. Retest effects might present another shortcoming.16 Analyses of this issue suggest small retest effects on verbal ability and spatial ability but not on perceptual speed.17 Initial and subsequent attrition (not due to mortality) from the H70 study is relatively small.8,10

The left censoring of data is an additional issue that should be addressed. In verbal ability and spatial ability this is less of a problem because the majority�(i.e., 59% and 61%) of the sample is contributing to both sides of the terminal change point. In perceptual speed, however, this might present problems because only 41% of the sample is contributing to both sides of the change point, a fact that encourages a careful interpretation. There are few studies18 that�would allow a within-person identification of terminal decline change points over a period ranging over 14 years. Although there might be bias in the estimate�of the change point in perceptual speed we are inclined to interpret our findings in terms of a substantially longer terminal decline period for speed compared with that for verbal and spatial ability.

There are a number of interacting factors that may explain these findings of terminal decline. Cardiovascular conditions (e.g., heart diseases) and undetected preclinical dementia (e.g., Alzheimer disease) are two such candidates. Increased medical burden and frailty in old age often further leads to inactivity (i.e., lack of physical exercise and cognitive stimulation) that can accelerate cognitive decline.�Subsequent studies need to illuminate these issues and identify the neurobiological markers for terminal decline. The analytical framework that we used in the present analyses provides a general framework to test hypotheses underlying terminal decline as it separates�between-person differences in age-related change and terminal decline at the level of the individual. Time-constant or time-varying covariates can also be included on either slope and thereby obtain separate estimates of the determinants for age-related and terminal decline trajectories.

There is increasing awareness of the need to account for population mortality selection in analysis of aging-related change in later life. Changes in cognition

are related to changes in health status and mortality with a pronounced decline typically observed in individuals who are more likely to die, producing a selection effect in the population. This can contribute to a bias in an age-based description of the population trend and obscure identification of between-person differences in within-person change if analyses are not conducted as conditional on subsequent mortality. The present findings strongly support this notion by demonstrating that�cognitive change in a sample that remains without dementia until death is related to survival.

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METHODS Sample.

The study is part of the Gerontological and Geriatric Population Studies in Go�teborg, Sweden (H70).8,9 The sample consisted of 482 participants, systematically selected at age 70 in 1971 from the total population in Go�teborg born June 1, 1901� June 1, 1902. A total of 70 individuals declined participation (leaving 86% response rate), 10 individuals had diagnosed dementia at baseline, and 114 were diagnosed with dementia over the course of the study. The remaining sample of patients without dementia consisted of 288 participants (women=162, men =126) measured at ages 70, 75, 79, 81, 85, 88, 90, 92, 95, 97, 99, and 100 with occasional dropout. At each occasion between ages 70 to 85 diagnosis of dementia was based on information about severe disorientation for time and place or a longstanding severe memory impairment as measured by rating scales and information from case records or relatives. After age 85, the diagnoses were based using the DSM-III-R with information obtained from psychiatric examinations and interview with relatives (further information about the diagnosis procedures is reported elsewhere10,11). Confirmed date of death was available for 284 individuals and 4 individuals were still living at the last update on June 1, 2003, at the approximate age of 101. In order to prevent missing data on the age at death variable we imputed the date of last update as the date of death for these four individuals (i.e., 101 years). The average age at death was 83.9 years (SD�=8.3).

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Cognitive measurements.�We used three cognitive tests from the Dureman and Salde12 psychometric test battery which was widely used in Sweden at the time of the original start of the H70 study. The Synonyms test was used throughout all measurements occasions, while the Block Design test was omitted from the testing at age 81 and the Figure Identification test was omitted from testing at age 81 and age 100. Otherwise, the same testing procedure was conducted throughout all measurement occasions. Further information about the testing procedures and the statistical properties of the tests can be found elsewhere.13

Raw score trajectories for each individual and cognitive test used in the analyses, plotted as a conditional function of mortality, can be found as supplemental data (figures e-1� e-3 on the�Neurology��Web site at www.neurology.org). All test scores were standardized to a pseudo T-score metric with mean of 50 and�SD of 10 in order to facilitate comparability across cognitive domains. We used mean and SD at age 70 (i.e., first occasion of measurement) for each test as a base for the standardization procedure.

The Synonyms test is a measure of verbal ability, or more generally, a test of an individual�s ability to understand ideas expressed in words. Participants match a target word with one synonym among five choices. The test has a time limit of 7

minutes and a maximum score of 30 points. The words were presented in a magnified form if participants had visual impairments. Block Design test is a measure of spatial ability where participants are presented with two-color blocks and asked to construct replicas of a prototype model design which have been

presented to the participant. The test has a time limit of 20 minutes and a maximum score of 42 points. Figure Identification is a test of perceptual speed where participants match, as quickly as possible, a target figure with one identical figure that is placed in line among five figures. The test has a time limit of 4 minutes and a maximum score of 60 points.

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Analyses.�We used a series of mixed linear models with a change point in order to determine an average time point when rate of decline in the three examined cognitive abilities starts to accelerate prior to death. We varied the location of the change point by 0.01 year increment up to a maximum of 20 years before death and used a profile-likelihood to select the best fitting model.14 Prior to the estimated change point, we structured individual differences in change as a conditional function of chronological age (centered at baseline) but after that time point we structured changes as a conditional function of time to death. Fixed effects in these models refer to the estimated average performances and changes. The random effects refer to the variability components. We estimated parameters in the models with full maximum likelihood. Detailed description of this modeling procedure can be found elsewhere.4

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RESULTS

In figures 1�3, the estimated likelihood functions for each cognitive test are plotted against time before death with 0.1 year increment. The best fitting model determines the maximum likelihood estimates of the terminal decline change point as relative to age-related change. The reference lines in the figures indicate a 95% CI where estimates above the line fall within the interval while estimates below the line fall outside the interval. The estimated change points before death for verbal ability (Synonyms) was 6.58 (4.33, 11.67) years, for spatial ability

(Block Design) 7.83 (6.25, 10.58), and for perceptual speed (Figure Identification) 14.83 (10.75, 16.58). These figures indicate the estimated average onset of terminal decline on the cognitive abilities in the population.

Estimates for the best fitting models are shown in the table. The fixed effects intercepts refer to an average standardized performance at age 70. The fixed�effects age slopes show the estimated annual average change in the three cognitive abilities before the terminal decline change point. This estimate is nonsignificant for verbal ability indicating no average change until 6.58 years prior to death. For spatial ability the age slope indicates a significant average�annual decline by 0.031 standard deviations until 7.83 years prior to death. For the perceptual speed the age slope indicates a significant average annua�decline by 0.022 standard deviations until 14.83 years prior to death.

The fixed effects death slopes indicate the average acceleration in change on the cognitive abilities after the estimated terminal decline change point. Estimates�for mortality slopes were significant across cognitive abilities. On verbal ability the death slope indicates an average annual decline of 0.056 standard deviations within 6.58 years before death. For spatial ability the death slope estimate was higher with an average annual decline of 0.090 standard deviations within 7.83 years before death. On perceptual speed the death slope estimate indicated an average annual decline of 0.066 standard deviations within 14.83 years before death. The fixed effects based on these models are plotted in figure 4 and demonstrate the onset of the terminal decline period and the average rate of change within each period on the cognitive outcomes. Note that for each of the cognitive abilities the estimated average change within the terminal decline period is indicated by the sum of the age and death slopes. In subsequent analyses, we included a fixed quadratic term for the death slopes. This estimate was occasionally significant but produced only minor differences in the estimate of the change point. In order to facilitate the comparability across the domains on both the fixed and random effects we retained the linear model assumption.

The differences between the age and death slopes provide an estimate of the additional effect of terminal decline. Due to the relatively low estimate in the�age slope, this estimate was particularly large in verbal ability or -0.48 (p�<0.001) where the post change point slope was 13 times larger than the age slope. In spatial ability the terminal decline effects estimate was -0.28 (p�<0.001) and the post change slope was almost twice as large as the age slope. In perceptual speed the terminal decline effects estimate was -0.22 (p�<0.001) and the post change slope was twice as large as the age slope. These findings demonstrate that the effect of terminal decline is large relative to age-related change on all cognitive abilities. Furthermore, there is a substantial proportional difference in change across abilities that is partly due to variability in age-related change and�partly due to terminal decline.

The lower part of the table shows the random effects (i.e., the variability and co-variability components) for the intercept, age slope, and death slope. All variability components (shown in the diagonals) are significant (p�<0.01 determined by the likelihood ratio test) except for the death slope in perceptual speed that had a�p�value of 0.07. The co-variability among age slope and death slope was nonsignificant for all three cognitive abilities indicating that the rate of change before the terminal decline change point was unrelated to the rate of change after the change point. Co-variability between intercept and death slope were significant for verbal ability (r= -0.42,�p�<0.05) and spatial ability (r= -0.78,�p�<0.001) indicating that individuals who declined faster in the terminal phase generally had a higher estimate at baseline. Co-variability between intercept and the age slope was significant for perceptual speed (r�= -0.40,�p�<0.001) indicating that individuals who decline faster before the terminal phase generally show higher baseline estimate. These estimates must, however, be interpreted with caution and may be influenced by left-censoring (unknown information about cognitive performance prior to baseline) of individuals already in a decline phase at baseline and more reliable measurements in the higher range of cognitive functioning. Other co-variability estimates were nonsignificant.

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