• Reports of osteopenia and osteoporosis have started to surface in patients with HIV infection.1, 2 HIV disease, perhaps in association with protease inhibitor therapy, is now considered an important risk factor for osteopenia.

• Osteopenia is defined as a reduction in bone mineral density, while osteoporosis refers to a reduced bone mass per unit volume. Osteoporosis is used to define any degree of skeletal fragility sufficient to increase the risk of fracture. It occurs when the rate of bone reabsorption is greater than the rate of bone formation.

• Several factors may place a patient at increased risk for developing osteoporosis. These include the failure to achieve an optimal bone mass by age 30, acromegaly, hyperparathyroidism, the presence of a malignancy, cigarette smoking, and the use of glucocorticoids.

• Complications from osteoporosis include vertebral and other bony fractures.

References:

1. Hoy J, Hudson J, Law M et al. Osteopenia in a randomized, multicenter study of protease inhibitor substitution in patients with the lipodystrophy syndrome and well-controlled HIV viremia. 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000, San Francisco, CA. Abstract 208.

2. Tebas P, Powderly WG, Claxton S et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. 7th Conference on Retroviruses and Opportunistic Infections; January 30-February 2, 2000, San Francisco, CA. Abstract 207.

• There are three classifications of osteoporosis not associated with other diseases.

• Idiopathic osteoporosis can be further classified into juvenile and adult types.

• Type I osteoporosis is seen in postmenopausal women between 51 and 75 years of age. In these cases, there is accelerated trabecular bone loss as well as fractures of vertebral bodies and the distal forearm.

• Type II osteoporosis is seen in both men and women over the age of 70. Fractures of the femoral neck, the proximal humerus, proximal tibia, and pelvis are frequently seen.

• Patients with HIV infection may have other disorders that are associated with the development of osteoporosis.

• On the endocrine side, patients may be experiencing hypogonadism, hyperadrenalism, hyperparathyroidism, and thyrotoxicosis.

• They may also be suffering from nutritional difficulties such as malabsorption, scurvy, and calcium deficiency.

• Other conditions associated with osteoporosis are extended immobilization of the body, alcoholism, and chronic obstructive pulmonary disease.

• The diagnosis of osteoporosis may be made by a number of ways, although some are more accurate than others. Diagnostic methods include plain x-rays, bone densitometry, DEXA scanning, quantitative computerized tomography, and neutron activation analysis. Of these, DEXA is probably the most reliable.

• The treatment of osteoporosis depends on the individual needs of the patient. Oral calcium can be given in the form of elemental calcium, 1 to 1.5 g/day, along with vitamin D.

• Postmenopausal women may benefit from estrogen-replacement therapy, while hypogonadal men may benefit from androgen therapy.

• Additional therapies include the use of biphosphonates, thiazide diuretics, and sodium fluoride.

• Two recent studies have looked at the association between osteopenia and osteoporosis and antiretroviral therapy.

• Tebas et al1 examined 122 patients comprised of three groups: 64 HIV-infected patients on HAART that included a protease inhibitor, 36 patients who were not receiving a PI, and 36 healthy seronegative adults. Dual energy x-ray absorptiometry was used to analyze whole body, lumbar spine, and proximal femur bone mineral density.

• Half of the men receiving PIs were found to have osteopenia and/or osteoporosis. Of these, 21% had severe osteoporosis. Only 23% of the healthy seronegative adults were found to have either condition.

• Hoy et al2 have looked at the incidence of osteopenia in 80 HIV-infected patients with lipodystrophy and undetectable viral load. Again, DEXA was used as the diagnostic method.

• Evidence of osteopenia at baseline appeared in 28.4% of patients. An additional 9.5% had osteoporosis. Both of these studies indicate a high prevalence of osteopenia and osteoporosis in patients with HIV infection.

References:

1. Tebas P, Powderly WG, Claxton S et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA; Jan 30-Feb 2, 2000. Abstract 207.

2. Hoy J, Hudson J, Law M, et al. Osteopenia in a randomized, multicenter study of protease inhibitor substitution in patients with the lipodystrophy syndrome and well-controlled HIV viremia. 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA; Jan 30-Feb 2, 2000. Abstract 208.

• Patients with HIV infection are known to have enhanced levels of proinflammatory cytokines as well as 1,25-dihydroxyvitamin D deficiency. Since both of these have an important role in bone homeostasis, such patients may have disturbed bone metabolism.

• Aukrust et al1 analyzed osteocalcin, a serum marker for bone formation, and C-telopeptide, a serum marker for bone resorption, in 73 HIV-infected patients.

• Those with advanced clinical and immunological disease and high viral loads had increased levels of C-telopeptide, markedly depressed osteocalcin levels, and an enhanced activation of their tumor necrosis factor systems. No correlation between osteocalcin and C-telopeptide levels was present.

Reference:

1. Aukrust P, Haug CJ, Ueland T et al. Decreased bone formation and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab. 1999;84:145-50.

• After 24 months of treatment with highly active antiretroviral therapy, patients experienced a marked rise in serum osteocalcin levels.1

• There were also profound drops in viral loads and TNF components along with marked increases in CD4 T cell counts.

• After HAART, there was also a significant correlation between osteocalcin and C-telopeptide levels.

• Given the presence of disturbed bone formation and resorption in patients with HIV infection, HAART has the beneficial effect of synchronizing bone remodeling in these patients.

Reference:

1. Aukrust P, Haug CJ, Ueland T et al. Decreased bone formation and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab. 1999;84:145-50.

• Another disturbing bone disorder surfacing in patients with HIV infection is avascular necrosis, more properly termed osteonecrosis.

• It is caused by the death of cellular elements of bone. This process is often secondary to impairment in the blood supply.

• Risk factors for avascular necrosis include glucocorticoid treatment, connective tissue disease, and the use of alcohol.

• Common sites for this disorder in patients with HIV infection are the femoral and humeral heads, femoral condyles, and the proximal tibia. Hip disease is bilateral in 50% of cases.

Reference:

1. Paiement GD, Biuiji A, Ries M. Association between chronic use of protease inhibitors and avascular necrosis of the femoral head. Annual Meeting of the American Orthopedic Association, Hot Springs, VA; June 17-20, 2000.

• Avascular necrosis often presents in patients as the abrupt onset of articular pain.

• Plain x-rays demonstrate the classic finding of the crescent sign in the hip. Magnetic resonance imaging is more sensitive as a diagnostic method.

• Treatment options for this disorder include surgery with possible joint replacement.

• Paiement et al1 have recently reported on 18 HIV-infected patients who had been diagnosed with avascular necrosis of the femoral head since 1991.

• Of these, 11 had been taking protease inhibitors. Only one of these individuals had one of the usual risk factors associated with the disease.

• In the other 7 patients who were not receiving protease inhibitor therapy, 6 were found to have risk factors for the disease.

• The differences were statistically significant, suggesting that protease inhibitors increase the risk for developing avascular necrosis.

• Although the mechanism is unclear, patients taking protease inhibitors do have high levels of triglycerides. Bits of fat could block the flow of blood feeding the bone tissue. There might also be some direct toxicity to bone cells from protease inhibitors.

Reference:

1. Paiement GD, Biuiji A, Ries M. Association between chronic use of protease inhibitors and avascular necrosis of the femoral head. Annual Meeting of the American Orthopedic Association, Hot Springs, VA; June 17-20, 2000.

• In summary, bone disorders such as osteopenia, osteoporosis, and avascular necrosis are being reported with increasing frequency in patients with HIV infection.

• Although the mechanism is poorly understood, there appears to be an association between the development of these disorders and HAART regimens containing protease inhibitors.

• A number of risk factors, such as the use of glucocorticoids, may contribute to the development of these disorders in patients with HIV infection.

• Clinicians need to be aware of these disorders so that early treatment can be started. For example, if caught early, avascular necrosis can be effectively treated before it leads to arthritis and the need for hip replacement.

• Additional studies are needed to determine the etiology of loss of bone mineral density, the identification of risk factors, and the appropriate prevention strategies.