Young People Get Osteoporosis Too 

Osteoporosis and HIV Disease

Bone disorders have emerged as a worrisome complication in persons with HIV infection. Over the past few years there have been increasing reports of osteoporosis (wasting of bone tissue due to bone mineral depletion) and osteopenia (moderate bone mineral depletion) in HIV-positive adults and children. (Osteonecrosis, or death of bone tissue -- a complication apparently unrelated to bone mineral depletion also found in persons with HIV -- will be examined in an upcoming issue of BETA.) To date, the causes of bone mineral deficiencies in those with HIV have not been well characterized, and data related to bone health in this population are now increasingly being collected and analyzed. Though they are currently uncommon in HIV-positive individuals, skeletal fractures associated with osteoporosis can be painful, debilitating, and potentially life-threatening, offsetting any quality-of-life advantages gained by current use of antiretroviral medications where available.

Osteoporosis in HIV-Positive Persons

Recent reports of low BMD in individuals with HIV disease have confounded health experts. While it is true that in any group of people a certain number will have osteopenia and fewer still osteoporosis (see the normal distribution curve), men, women, and children with HIV infection appear to be far more prone to low BMD than their age-matched, HIV-negative counterparts. Remarkably, fractures related to low BMD in persons with HIV have been extremely rare to date -- but the risk is nevertheless very real and will likely increase over time.

The problem of thinning bones in HIV-positive persons has been described in the literature and at medical conferences only in the past few years. Mary Romeyn, M.D., of the University of California, San Francisco (UCSF) and Julia Ireland, D.O. (Doctor of Osteopathy), of the University of Southern California (USC) were among the first to report on this problem. At the 3rd International Conference on Nutrition and HIV Infection, held April 22-25, 1999, in Cannes, France, Drs. Romeyn and Ireland reported that among 20 HIV-positive men with CD4 cell count nadirs (lowest levels) at or below 100 cells/mm³, nine (45%) had evidence of osteopenia and eight (40%) were diagnosed with osteoporosis. Only three (15%) of the twenty subjects had normal BMD levels. Eight other men with CD4 cell nadirs above 100 cells/mm³ all showed signs of bone density deficiencies: one (13%) had osteoporosis and the remaining seven (87%) had osteopenia. At the 7th Conference on Retroviruses and Opportunistic Infections (CROI) held in San Francisco in early 2000, Pablo Tebas, M.D., and colleagues from Washington University in St. Louis, MO, reported that among 64 HIV-positive subjects taking protease inhibitors (PIs), 32 (50%) were found to have osteopenia and 14 (21%) had osteoporosis. At the same conference, Jennifer Hoy, M.D., of Alfred Hospital in Melbourne, Australia, reported that among a cohort of 74 HIV-positive persons with evidence of lipodystrophy (defined as total body fat less than 20% by DEXA scanning) and suppressed viremia (viral load below 400 copies/mL), 21 (28%) had evidence of osteopenia at baseline and an additional seven (9%) had osteoporosis.

At the 8th CROI this past winter, at least 15 abstracts, posters, and late-breaker presentations focused on bone mineral disorders. Overall, according to various reports presented at the 8th CROI, evidence of osteopenia (based on lumbar spine [comprising the lower back] studies) was found in 21-45% of persons with HIV infection.

Role of HAART

It is unknown what role, if any, highly active antiretroviral therapy (HAART) plays in the development of low BMD. Studies conducted so far offer conflicting evidence as to whether HAART use lowers BMD and which specific drug classes are more likely to be involved. At this early stage, theories regarding causes of bone mineral deficiencies in those with HIV disease are merely speculative.

The unexpectedly high rates of bone mineral loss reported by Drs. Tebas and Hoy (mentioned above) were found in cohorts of persons with extensive histories of PI therapy. Dr. Tebas' research team also noted that persons taking PI-containing regimens had rates of osteopenia (40-50%) about twice as high as those found in persons taking non-PI-containing regimens or no therapy (20-23%). Other researchers have noted similarly higher rates in persons taking PIs.

The precise mechanisms explaining how PIs might give rise to bone wasting are not known. Dr. Tebas has reported on in vitro (test-tube) studies showing that three PIs -- ritonavir, indinavir (Crixivan), and nelfinavir (Viracept) -- inhibit the conversion of 25(OH)-vitamin D3 (the natural form of the vitamin) to its most potent (bioactive) metabolite, known as 1,25(OH)2-vitamin D, by 80%, 66%, and 31%, respectively. Vitamin D must be in its most bioactive form to properly regulate calcium homeostasis (balance), and therefore BMD levels, in the body. These findings have yet to be reproduced in human studies.

Other researchers discount the possible role of PIs in bone wasting. Drs. Romeyn and Ireland have found in their cohort of 44 HIV-positive men that those with greater exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) were more likely to have osteoporosis. PI use did not seem to affect rates of bone loss in this cohort (26% of whom were diagnosed with osteoporosis). These data appeared in a poster presentation at the 4th International Conference on Nutrition and HIV Infection held April 19-21, 2001, in Cannes.

Some researchers believe that lactic acidemia and proposed mitochondrial toxicity associated with nucleoside analog (NRTI) use may be the main culprit. (Lactic acidemia refers to increased levels of lactic acid, which can reduce the normal pH of blood. Mitochondrial toxicity refers to dysfunction of mitochondria, which produce energy within cells.) At the 2nd International Workshop on Adverse Drug Reactions and Lipodystrophy held September 23-25, 2000, in Toronto, Andrew Carr, M.D., and colleagues from St. Vincent's Hospital in Sydney, Australia, reported results of a study assessing BMD in 221 HIV-positive men (mean age of 43 years) recruited to a lipodystrophy (fat redistribution) prevalence survey. The Australian researchers evaluated several parameters (markers) that they hypothesize may be linked with low BMD, including symptoms and signs associated with lactic acidemia (such as nausea, fatigue, and loss of at least 3 kg of body weight within the preceding three months). Forty-four subjects (20%) were found to have osteopenia and seven (3%) had osteoporosis. The only significant independent risk factors associated with low BMD were higher lactate levels (odds ratio [OR] of 2.39 per 1 mmol/liter) and lower weight (OR of 1.06 per 1 kg decrease) prior to starting antiretroviral therapy. (Lactate is the salt form of lactic acid found in the blood.) Both lactic acidemia and duration of NRTI therapy were associated with low spinal (but not low total) BMD. Associations, however, do not necessarily imply a cause-and-effect relationship.

Dr. Carr's team postulated that osteopenia in HIV-positive men may be more likely with lower body mass prior to antiretroviral therapy and "the cumulative duration and magnitude of NRTI-induced lactic acidemia." Dr. Carr suggested that NRTIs may have a direct, damaging effect on the mitochondria of osteoblasts, rendering them less able to form bone. (He did not prove this, however.) He has also suggested that chronic lactic acidemia may cause a bone salt vital to the compressional strength of the vertebrae (hydroxyapatite) to be leached from bone to buffer a higher acid load in the bloodstream.

To date, theories regarding lactic acidemia, NRTIs, and low BMD have not been adequately supported with data and remain controversial. Study design, as always, impacts the value of data and their potential to be widely applicable. Dr. Carr's study mentioned above was cross-sectional (evaluating subjects at one particular time), not prospective (evaluating subjects forward over time). Prospective, or longitudinal, studies yield more reliable data and are almost always preferable. Interestingly, another report given at the 8th CROI by S. Claxton and colleagues from Washington University School of Medicine in St. Louis found no association between osteopenia and lactate levels (or levels of leptin, a neurotransmitter that regulates appetite) in HIV-positive men. These nearly opposite findings may relate to differing methodologies used by the research teams.

Low Bone Mineral Density in Antiretroviral-Naive Persons

Several very recent studies have found high rates of bone mineral loss in HIV-positive persons who have never taken anti-HIV drugs. Such reports make it difficult to determine why bone mineral abnormalities were not commonly associated with HIV disease in the literature prior to widespread use of HAART (although anecdotal reports of low BMD in HIV-positive individuals date back to at least 1995, before the era of potent antiretroviral therapy). The majority of data presented at the 8th CROI this past February suggested that persons treated with HAART were not more likely to experience osteopenia than those who were antiretroviral-naive. For example, Adeyemi Lawal, M.D., and colleagues from St. Luke's-Roosevelt Hospital in New York City found equivalent rates of reduced BMD in a cohort of 36 HIV-positive men assessed in 1993 (pre-HAART) and a cohort of 22 HIV-positive, HAART-treated subjects (three women, 19 men) assessed in 1998. (However, there may have been confounding factors in those tested in 1993, e.g., use of corticosteroids as part of treatment for PCP and antifungal therapy.) Hernando Knobel, M.D., Ph.D., and colleagues from the Hospital del Mar in Barcelona found osteopenia in four of 16 antiretroviral-naive subjects (25%), and a statistical difference in osteopenia rates between only HIV-positive and HIV-negative subjects (not between HIV-positive subjects taking HAART and those who had never taken therapy).

Although very preliminary, reports of bone mineral loss in antiretroviral-naive persons are particularly troublesome, as they suggest that prolonged duration of HIV infection or some mechanism linked to HIV disease may be a key factor in the prevalence of the condition. The reports also appear to refute claims that various antiretroviral drugs are responsible for lowering BMD. Nevertheless, it may be that some anti-HIV medications are a cofactor in bone mineral loss if other cofactors are present.

Additional Factors

Numerous other factors, either alone or in combination, might explain unusually high osteopenia and osteoporosis rates in HIV-positive individuals. Interest in these potential contributing causes will likely increase, as data regarding loss of bone tissue in antiretroviral-naive persons continue to accumulate.

Some additional risk factors are characteristics found in older people that are present in some (nonelderly) people with HIV, especially those with later-stage disease and AIDS-related wasting syndrome. These include immobilization or extended bed rest, malnutrition, malabsorption (reduced capacity to absorb dietary nutrients), severe weight loss, and reduced production of sunlight-associated vitamin D.

Hypogonadism, a condition that commonly affects both older individuals and persons with HIV, is a particular concern. Hypogonadism refers to inadequate function of the gonads (sex organs including the ovaries or testes) characterized in part by deficient hormone secretion (estrogen or testosterone). Below-average serum testosterone levels (male hypogonadism) are found in approximately 25% of asymptomatic HIV-positive men who are not taking anti-HIV treatment and up to 50% of men with untreated AIDS. Low levels of sex hormones are known to cause low BMD in both men and women. Nevertheless, not all studies have shown significant bone loss in HIV-positive persons with low testosterone levels. (Women also produce small amounts of testosterone and may develop complications as a result of low levels.) Studies of BMD in HIV-positive women with low female sex hormone levels remain to be conducted.

Researchers have also been looking into the roles played by growth hormone and insulin-like growth factor 1 (IGF-1). Among its other effects on the body, growth hormone (secreted by the pituitary gland) profoundly influences the body's ability to regenerate lost bone tissue. Secretions of growth hormone trigger production of IGF-1 in the liver; IGF-1 in turn stimulates osteoblasts to increase bone mass. As people age, their growth hormone levels often progressively decrease, and adults with a deficiency of growth hormone and IGF-1 have been shown in some studies to have lower BMD. As the growth hormone-IGF-1 axis (or feedback loop) is known to be impaired in those with HIV infection, this metabolic disturbance may have a significant effect on BMD and bone loss in this population.

High cytokine levels also may be a risk factor for bone loss in people with HIV. Cytokines coordinate immune responses by communicating among immune system cells and between immune system cells and the rest of the body. Proinflammatory cytokines amplify immune responses, while anti-inflammatory cytokines diminish immune responses. Certain proinflammatory cytokines -- including interleukins 1, 6, 8, and 12, and tumor necrosis factor (TNF) -- intensify the resorptive activity of osteoclasts; aberrations in cytokine levels thus may lead to increased bone destruction and risk of osteoporosis. As cytokines arise from white blood cells, including CD4 cells, HIV-positive persons with higher activated CD4 cell levels tend to have higher levels of certain cytokines. Whether this phenomenon corresponds with higher rates of osteopenia and osteoporosis remains to be proven in clinical trials. Approaches to anti-HIV therapy may be affected if different classes of antiretroviral drugs influence cytokines in different ways.

Calcium homeostasis in the body is maintained partly by vitamin D activity and in part by a feedback loop that involves the interplay of two hormones: calcitonin and parathyroid hormone (PTH, or parathormone). Calcitonin, which is produced in the thyroid gland, lowers the level of calcium in blood plasma by inactivating osteoclasts and helps to maintain a strong, dense bone matrix. PTH, which is secreted by the parathyroid glands, enables bone resorption (and indirectly promotes increased intestinal absorption of calcium) by activating osteoclasts. PTH levels tend to increase with age and, reportedly, in those with HIV disease. While the mechanisms disrupting the PTH-calcitonin axis are not known, future research may shed light on ways to inhibit this phenomenon.

Unusually high levels of thyroid hormone (thyroxine) can also cause bone loss. Excess thyroxine may be due to hyperthyroidism or poorly monitored thyroxine replacement therapy in persons with hypothyroidism (diminished thyroid function).

Lipodystrophy and Wasting

Some researchers have conjectured that bone mineral deficiencies may be associated with body fat abnormalities (also called lipodystrophy) seen in HIV-positive persons, as low BMD was first widely detected in people enrolled in lipodystrophy studies. However, studies to date have not shown a correlation between bone wasting and raised levels of blood lipids (fats) and/or disturbances in the locations and quantity of adipose (fat-storing) tissue.

Dr. J.S. Huang and colleagues from Massachusetts General Hospital and Children's Hospital, Boston, reported at the 8th CROI that increased visceral (intra-abdominal) fat among 41 HIV-positive subjects was significantly associated with decreased BMD. In this cross-sectional, observational study, Dr. Huang's team found that the association between low BMD and an accumulation of visceral fat remained significant after controlling for age, PI use, lowest body weight, BMI, and extremity fat (in the arms and legs) in a multivariate analysis. (Once again, however, an association does not necessarily imply a cause-and-effect relationship.) At the same conference, Dr. Tebas and colleagues from Washington University reported that increased intra-abdominal fat did not affect BMD T-scores of the lumbar spine in their cohort of 34 subjects (one woman, three African-Americans). Osteopenia was observed in 15 HIV-positive subjects (45%) regardless of the quantity of adipose tissue in their abdominal region. No significant correlation was found between lumbar spine BMD T-scores and visceral adipose mass or the visceral fat/total abdominal area ratio using DEXA and magnetic resonance imaging (MRI) scans.

Unlike those with lipodystrophy, persons with AIDS-related wasting syndrome clearly exhibit known risk factors for bone deficiencies; it is therefore not surprising that studies have shown low BMD levels in this population. Steven Grinspoon, M.D., and colleagues from Massachusetts General Hospital and Harvard Medical School recently described low lumbar spine and total hip BMD values among 54 men with AIDS wasting compared with 35 healthy, HIV-negative controls. Total hip T-scores were below -1 (indicating osteopenia of the hip) in 17 (33%) of the men with AIDS wasting. All of the subjects with AIDS wasting had free (unbound) testosterone levels in the normal range; hypogonadism was therefore not a factor in the development of osteopenia in these men. Dr. Grinspoon's team published their study data in the May 2001 issue of the Journal of Clinical Endocrinology and Metabolism.

As with HIV-positive adults, bone mineral deficiencies in HIV-positive children and adolescents have been reported only recently. Evidence of osteopenia and osteoporosis in these young people is particularly disturbing not only because they are at risk for achieving suboptimal peak bone mass (a risk factor for osteoporosis) but also because their BMD levels appear to decrease with age. Stephen Arpadi, M.D., M.S., of St. Luke's-Roosevelt Hospital in New York City described a cross-sectional study of 51 HIV-positive children and 282 healthy control children (average age was 8.4 years; 52% males and 48% females) in a late-breaker session at the 8th CROI. Dr. Arpadi's team found that abnormal reductions in total body bone mineral content (TBBMC) were significantly associated with HIV status in their cohort and that TBBMC reductions progressed with age. TBBMC levels were not significantly associated with CD4 cell counts, CD4 cell percentages, or use of PI drugs.

Treatment

While researchers and physicians attempt to identify the cause or causes of brittle bones in HIV-positive persons, those who have this health problem are in need of interventions. Fortunately, several standard treatments have been used to prevent further bone deterioration and a handful of possible therapies may even reverse the loss of bone. Physiologic differences between women and men, as well as between younger and older women, must be taken into account when considering treatment strategies related to bone health.

Adequate intake of calcium and vitamin D should be part of any treatment regimen involving loss of bone. Calcium is the most essential micronutrient for achieving and sustaining bone mass and for treating osteoporosis. However, while calcium supplementation helps to maintain adequate BMD in postmenopausal women, it has not been shown to prevent loss of bone by itself. The National Academy of Sciences recommends a daily calcium intake of 1,000mg in adult women aged 19-50 and 1,200-1,500mg per day in postmenopausal women (above age 50). Currently no standard recommendations have been established for men or persons with HIV. Good sources of dietary calcium include dairy products, fruits, and vegetables. Calcium supplements also may be used, although they may cause adverse effects such as constipation. Vitamin D, which is fat-soluble (able to dissolve in fat), helps to maintain normal blood levels of calcium and phosphorous, and allows for optimal absorption of calcium. The National Institutes of Health (NIH) recommends an intake of 200 IU (international units) per day in adults aged 19-50, 400 IU per day in adults aged 51-69, and 600 IU in adults aged 70 and older (recommendations are identical for women and men). At least part of the recommended daily intake may be met with 15 minutes or more of (unclothed) skin exposure to natural sunlight three times per week. Good dietary sources include fish-liver oils, egg yolks, and milk and other foods such as breads and breakfast cereals that are fortified with vitamin D. Persons taking PI drugs for HIV should consult with a health-care provider before considering raising vitamin D intake, as PIs tend to result in high rather than low levels of vitamin D and other fat-soluble vitamins.

Weight-bearing, or high-impact, exercise is also highly recommended (by the American Academy of Orthopaedic Surgeons, among many others) in persons with low BMD. Weight-bearing exercise -- in which force is exerted against the weight of gravity -- stimulates bone formation and strengthens muscles that are attached to bone. It also improves overall balance and agility, which reduces risk of falls and bone injuries. Examples of this type of exercise include weight training, use of Nautilus or Thera-Band equipment, brisk walking, hiking, jogging, and exercising on a stair-climbing or cross-country ski machine. (Weight training and use of Nautilus-type machinery are also known as progressive resistance exercise.) Swimming and bicycling are not weight-bearing activities and do not put adequate stress on bone. To gain maximum benefit, weight-bearing exercise should be performed for one hour at least three times per week on a regular basis.

A variety of drug and hormonal interventions has shown efficacy in treating either the disrupted mechanisms of bone metabolism and/or low BMD and brittle bones in people who are HIV negative. Biphosphonates are antiresorptive molecules that help to restore bone mass in persons with established osteoporosis and reduce the incidence of fracture. Two biphosphonates have been approved by the FDA to treat osteoporosis in women: alendronate (Fosamax) and risedronate (Actonel). These two drugs, in addition to etidronate (Didrocal, which is not FDA-approved for treating osteoporosis), all increased BMD of the spine and hip in a dose-dependent manner and reduced the risk of vertebral fractures by 30-50% in placebo-controlled, randomized clinical trials. Data for use of biphosphonates in men are still being gathered for review. Calcitonin supplementation has been shown in some settings to reduce the risk of fracture. A small prospective study done by Drs. Romeyn and Ireland found that calcitonin stabilized or improved BMD in some osteoporotic HIV-positive men who were also receiving optimal care for their HIV infection, endocrine deficiencies (all were hypogonadal), and nutritional needs (all had a history of AIDS wasting). However, the five-year Prevent Recurrence of Osteoporotic Fractures (PROOF) study of calcitonin involving 1,255 women was inconclusive due to the lack of a dose-dependent response (a significant reduction in vertebral fracture risk was found in the 200 IU daily calcitonin dose but not in the 100 IU and 400 IU doses), the lack of supporting BMD data, and a 60% dropout rate. Salmon calcitonin (Miacalcin) inhaled as a nasal spray is preferable to oral forms in development, which may cause nausea and diarrhea.

Remarkably, PTH may also be used to treat osteoporosis. As mentioned above, PTH enables bone destruction and opposes the bone strengthening activity of calcitonin. However, research presented in the May 10, 2001 issue of the New England Journal of Medicine suggests that PTH (1-34), also called Forteo -- an experimental form of parathyroid hormone comprising the first 34 (of 84) hormonal amino acids -- has the opposite effect by stimulating osteoblasts and promoting bone growth. In their study of 1,326 postmenopausal women in 17 countries, Robert M. Neer, M.D., of Harvard Medical School and colleagues found that treatment with PTH (1-34) in 20 µg and 40 µg doses increased spinal BMD by an average of 11% (compared with placebo), and decreased the risk of vertebral and nonvertebral fractures by an average of 67% and 37%, respectively (compared with placebo). PTH (1-34) was well-tolerated; the most common adverse events were nausea and headache, which were more prevalent in the 40 µg arm. PTH (1-34) must be taken daily by self-injection, a potential drawback for some people. In addition, the study was halted when osteosarcomas (malignant bone tumors) were found in rats during a separate, long-term toxicologic study of the drug. While none of the women developed bone tumors in the clinical trial conducted by Dr. Neer and colleagues, future use of the drug may be limited in persons with compromised immune systems.

As mentioned previously, adequate sex hormone levels are important for bone health in both men and women. Supplementation with testosterone is recommended in HIV-positive men who have low levels of the hormone (compared with healthy controls). According to Dr. Grinspoon, testosterone treatment also benefits eugonadal men (i.e., with normal testosterone levels) experiencing AIDS wasting. (Testosterone supplementation in women may cause unwanted masculinizing effects and is under study at this time.) Similarly, anabolic steroids (synthetic testosterone derivatives) such as oxandrolone (Oxandrin) may prove beneficial as bone treatments. Human growth hormone (HGH, somatotropin, Serostim) is also being investigated by some physicians to counteract bone loss in people with HIV, perhaps by restoring imbalances in the growth hormone-IGF-1 axis. Like testosterone and anabolic steroids, HGH is used mainly to treat AIDS-related wasting syndrome and, in some cases, visceral fat accumulation. Statin drugs (e.g., pravastatin [Pravachol]), which are used to treat high blood lipid (fat) levels, have not been associated with a reduction in the risk of bone fractures. For women, hormone (typically estrogen) replacement therapy or selective estrogen receptor modulators (SERMs, e.g., raloxifene [Evista]) are accepted osteoporosis treatment strategies.

Therapies that address potential causes of low BMD such as altered cytokine levels might play a role in the future management of the condition. Proinflammatory cytokine modulators may include omega-3 fatty acids (found in fish oils) and flavonoids (plant extracts) such as quercetin, curcumin, boswellia, and Pycnogenol. Ipriflavone, however, is not recommended as a treatment for bone wasting. This synthetic flavonoid has not been found in clinical trials to prevent bone loss or improve biochemical bone markers and it appears to induce lymphocytopenia (a reduction in blood lymphocytes).

In addition to therapeutic and dietary interventions, reducing alcohol intake and eliminating tobacco smoking should be encouraged in all persons with low BMD. Almost all studies to date have shown that even moderate levels of alcohol consumption (1-2 drinks per day) contribute to osteopenia, although one curious study published in the November 2000 issue of the American Journal of Clinical Nutrition found that moderate alcohol consumption increased BMD in an analysis of 489 postmenopausal women. As with alcohol intake, tobacco smoking has been linked to osteopenia. Nicotine may also inhibit fracture repair.

Prevention

Until more is known about the etiology (cause) of osteopenia and osteoporosis in HIV-positive persons, certain lifestyle behaviors may contribute to optimal skeletal health. These include sufficient calcium and vitamin D intake throughout life; an adequate, balanced diet; regular weight-bearing exercise; avoidance of tobacco and alcohol; and limited glucocorticoid use.

Recommendations

Even though nearly all HIV-positive persons with osteopenia and osteoporosis to date have been asymptomatic, reports of fractures are expected to increase in the coming years. Routine BMD screening for all persons with HIV infection is strongly recommended by Dr. Romeyn and other (though not all) researchers. Screening should include a baseline DEXA measurement as well as annual BMD monitoring. Osteoporosis screening is especially needed for people with HIV who are more prone to severely low bone mineral levels and related adverse effects, including those with a documented episode of AIDS wasting, a low CD4 cell nadir, or a history of prior fractures. In addition, improved treatments for osteoporosis should continue to be explored and tested. Future strategies to combat bone deterioration will clearly benefit the general population.