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Therapeutic management of bone demineralization in the HIV-infected population
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Editorial review
AIDS: Volume 21(6) 30 March 2007 p 657-663
Negredo, Eugenia; Martinez, Eva; Cinquegrana, Denise; Estany, Carla; Clotet, Bonaventura
From the 'Lluita contra la SIDA' Foundation, Germans Trias i Pujol University Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.
Author Conclusion
The lack of response to some of the questions regarding the most appropriate treatment for HIV-infected patients with bone demineralization, and the management of such treatment, makes further investigation in this field essential. Moreover, some basic recommendations for therapeutic interventions in such cases should be predefined to diminish the consequences of bone demineralization in the near future. The detection of patients with predisposing factors for the risk of developing osteoporosis, the performance of bone densitometry in these cases, and the recommendation of changes in lifestyle, including nutritional counselling, should be incorporated into routine care regimens for the HIV-infected population.
Data from the first studies carried out on patients with HIV infection confirm the benefit of alendronate for the treatment of osteoporosis, due to its efficacy, high tolerability, minimal additional pill burden, and its lack of interaction with antiretrovirals. These results, together with those of a multi-centre study (the Adult AIDS Clinical Trials Group 5163), which will be published shortly and which includes a large number of patients on treatment with alendronate, will help to better and more specifically define the best strategy for managing HIV-infected patients with BMD loss. ACTG reported positive study results at CROI Feb 2007.
Introduction
Bone demineralization is a common metabolic problem in patients infected with HIV [1-7] and the incidence of this problem is actually greater in the HIV-infected population than in the general population [8,9]. The widespread utilization of highly active antiretroviral therapy has notably increased the survival of the HIV-infected population, prolonging the time that patients live with the HIV infection. The increasing age of these individuals, the virus itself, and the presence of other concomitant factors that accelerate the loss of bone mineral density (BMD), are all factors that could explain the high prevalence of osteopenia and osteoporosis in this group, and particularly in the female population as many HIV-infected women reach menopause and experience its typical manifestations, such as osteoporosis.
For these reasons, there is a need for special attention to be dedicated to this pathology, in order to reduce the clinical consequences of bone demineralization that may well be observed in HIV-infected patients over the next few years [10,11]. In the general population, the risk of fractures in individuals with osteopenia is two-fold and in patients with osteoporosis, this risk is multiplied by four (by 20 in those with a previous history of fractures). Therefore, why should we expect different outcomes in the HIV-infected population?
Currently there are no well-defined guidelines for the treatment of this condition in the HIV-infected population. The available data in this field do not suggest that there are any differences in general risk factors, diagnosis, the benefit of alendronate and the consequences of bone demineralization between the HIV-infected and the seronegative populations. However, a higher incidence of bone demineralization has been observed in HIV-infected patients, most likely due to the HIV virus itself, as well as factors related to the chronic nature of HIV infection [1-9]. As a result, this review attempts to outline a set of preliminary recommendations for the management of bone demineralization in this context (Fig. 1), which should be revised according to the availability of data from new trials.
General evaluation
In the light of data published regarding the multiple factors that have a negative impact on bone metabolism in this population [2,5,8,9,12-14], it is fundamentally necessary to identify those subjects with predisposing factors to bone fractures due to fragility.
A risk evaluation of each patient to assess bone demineralization should be included as a part of regular clinical visits (Table 1). Long-term HIV infection and the presence of lipodystrophy or lactic acidemia are considered to be factors that predispose these patients to develop osteoporosis [12-14]. In addition, it is necessary to interview the patient in-depth about other pathologies and concomitant treatments in order to detect other factors that can accelerate the loss of BMD, such as menopause, malnutrition, malabsorption, prolonged treatment with steroids, immobility, etc., which are frequently present in these subjects.
In cases such as those mentioned above, as well as after the diagnosis of HIV infection or in patients with a clinical history of pathologic fracture, the performance of a bone densitometry would be recommended (Fig. 1).
In those cases in which the densitometry demonstrates a significant loss of BMD, secondary causes of osteoporosis should be ruled out, and any necessary treatment should be administered.
Following the World Health Organization (WHO) criteria, the definition of osteopenia or osteoporosis should be based on BMD, evaluated by densitometry. Osteopenia and osteoporosis are defined, respectively, as BMD t-score between -1 and -2.5 or < -2.5 in the lumbar spine, hip and/or trochanter [15].
Antiretroviral treatment
Although early data suggested that protease inhibitors might have a deleterious effect on bone metabolism [1], recent results do not support these findings [16].
Likewise, preliminary warnings have appeared with respect to tenofovir, suggesting an increased loss of BMD with the use of this nucleotide, in comparison with other nucleosides [17-19]. However, other clinical studies with a long follow-up did not reveal changes in BMD or an increased incidence of bone fractures in patients receiving a tenofovir-containing regimen [20].
The real clinical relevance of these data is unknown and conclusive results that suggest the need to substitute tenofovir in the case of bone demineralization are lacking. Consequently, while long-term clinical results indicate a lack of negative effect of tenofovir on bone mass [20], there is no clear reason to withdraw it. However, a close monitoring of BMD in patients showing bone loss who are on long-term treatment with tenofovir should be recommended.
Lifestyle and dietary measures
In the case of bone loss, lifestyle changes, including the incorporation of exercise (for a minimum of 30-45 min, three times per week), smoking cessation, and the reduction of alcohol intake, should be recommended when appropriate, as in the general population, given that the positive benefit on bone mass associated with these changes is well-known [21-23].
At the nutritional level, a diet rich in calcium is recommended, according to the established recommended dietary allowances (RDA), which includes 1400-1500 mg of calcium and 400-1000 IU of vitamin D per day [24]. The best manner to achieve optimal calcium intake is through the consumption of dietary calcium (Table 2). Exogenous sources of calcium should only be considered and used secondary to dietary sources.
In order to improve its absorption, calcium should be consumed in conjunction with other foods, which slow its passage through the intestinal tract. In addition, intestinal absorption of calcium should be in the ionic form [25]. For this reason, it is recommended that calcium should not be consumed in conjunction with nutrients that prevent its ionization, in order to encourage correct absorption. Likewise, the following substances should be avoided: dietary fibre, fats, folic acid (present in grains, vegetables, and cereals), oxalic acid (found in spinach, beets, rhubarb, escarole, cauliflower, leeks, peanuts, cocoa, chocolate, tea, etc.). It should also be noted that the loss of calcium is greater when food is boiled or steamed than when it is fried [24].
Moreover, the diet is the body's principal source of vitamin D, in addition to calcium. In order to ensure an adequate dietary supply of vitamin D, the consumption of tomatoes, carrots and fortified milk, as well as regular sun exposure is recommended.
Pharmacologic therapy
One should be cautious when making decisions related to the prescription of pharmacological treatment for osteoporosis in the HIV-infected population until more data are available. Special care should be taken considering the present lack of information on the efficacy of such treatment in this field as well as a lack of information regarding pharmacokinetic drug interactions with antiretrovirals. For the moment the few studies in this field are limited to alendronate. Nonetheless, these data are quite clear and represent encouraging results [26-28].
Biphosphonates act by binding to the surface of the bone and inhibiting the reabsorption of osteocytes. Oral alendronate has been shown to substantially increase bone mass in different contexts of the general population [29-31], reducing the risk of vertebral and femoral fractures. One point in favour of the utilization of alendronate in the seropositive population is its easy administration (70 mg, once per week). Moreover, for patients taking antiretroviral therapy the lack of interaction of alendronate with antiretrovirals, due to its direct excretion through the urine, is even more interesting.
A first study, conducted by the present authors, was designed in order to evaluate the efficacy and tolerability of alendronate for the management of osteoporosis in patients with HIV infection and on stable antiretroviral therapy [26]. The candidates were patients with osteoporosis criteria according to the WHO definition (t-score < -2.5 in the lumbar column, hip, and/or trochanter), which were diagnosed by densitometry. Patients were randomized to receive alendronate (70 mg, once per week) plus a dietary intervention which ensured the ingestion of a minimum of 1200 mg of calcium daily (alendronate group, n = 11), or to receive only a dietary intervention (control group, n = 14).
A rapid and significant increase was observed in L2-4 t-scores at week 48 in patients receiving alendronate (P = 0.024), although this improvement was not observed for the femur at this time (Fig. 2). At 96 weeks, the results showed a significant increase in BMD in the patients receiving alendronate with respect to the control arm in L2-4 (24% in comparison with 0%, respectively) and in the trochanter (20% in comparison with -10%, respectively), with a decline in the percentage of patients who fulfilled the osteoporosis criteria from 100 to just 27% (P = 0.001). The percentage of control patients who continued to fulfil the osteoporosis criteria at week 96 was 96%.
Likewise, Mondy et al. evaluated the same objectives through a prospective, randomized clinical study of 48 weeks' duration [27]. Thirty-one HIV-infected patients with criteria for osteopenia or osteoporosis (t-score < -1) were randomized to receive treatment with alendronate (70 mg, once per week), calcium (1000 mg of calcium carbonate daily), and vitamin D (400 IU daily), or to receive treatment only with calcium and vitamin D. After 1 year of follow-up, Mondy et al. also observed an increase in the spinal BMD of patients treated with alendronate, independently of the grade of bone loss (osteopenia or osteoporosis) that patients presented at baseline (Fig. 3). Nevertheless, this increase was less than the increase observed in the previous study and did not reach statistically significant differences (5.2% in the alendronate group in comparison with 1.3% in the group that received only calcium and vitamin D). Furthermore, no improvement in BMD in other regions of the body was observed.
Finally, Guaraldi et al. conducted a 52-week study, with 41 patients that were randomized to initiate therapy with alendronate, calcium, (1000 mg per day) and vitamin D (500 IU per day), or to receive therapy with calcium and vitamin D only [28]. The investigators concluded that alendronate, in combination with calcium and vitamin D, increased spinal BMD (4% in comparison with 3.7% in the control group) and stopped the progression of bone loss in the hip (a decrease of 0.5% in the alendronate group in comparison with a decrease of 3.5% in the control group).
These three studies confirm the benefit and safety of alendronate in HIV patients, as in the general population. Three tangible differences exist among the previous studies: the selection criteria for participation in the study (osteopenia and/or osteoporosis), the follow-up (48-96 weeks) and the co-administration of calcium and vitamin D. However, these data allow several conclusions to be drawn.
First, it should be noted that the most severe form of BMD loss did not translate into a smaller effect when therapy was introduced [27]. Additionally, the longest follow-up period of the first investigation described (96 weeks) demonstrates a significant improvement in bone density, not only in the lumbar zone as in other studies, but also at the femoral level [26]. The lack of improvement in BMD at the femoral level in studies with a shorter follow-up period [27,28] suggests a slower recuperation in cases of hip osteoporosis and the consequent necessity of a longer treatment period. Finally, our study evaluated treatment exclusively with alendronate, without calcium and without vitamin D, in order to avoid increasing the number of pills in patients' daily medication regimens [26]. Nevertheless, treatment with alendronate, together with dietary calcium, was sufficient to demonstrate a rapid and significant BMD recovery. Continuous nutritional counselling, thereby ensuring an adequate daily calcium and vitamin D intake, would not only contribute to the recovery of bone mass in those cases in which the pathology is evident, but also would slow the process of bone loss, especially considering the generally insufficient intake of dairy products in the adult population. However, more trials are necessary in order to determine whether calcium and vitamin D have a supplementary benefit when used with biphosphonates to treat osteoporosis, as in the HIV-negative population.
On the other hand, data on experience with the use of other drugs that are indicated for the treatment of osteoporosis in the general population do not exist for the seropositive population. More specifically, treatment with raloxiphene, a selective modulator of the estrogen receptor used in postmenopausal women, should be evaluated in HIV-infected women, taking into consideration its interactions with cytochrome P450. Finally, treatment with testosterone in eugonadal men with BMD loss associated with weight loss [32] should be also investigated. However, for the moment its use should be indicated exclusively for cases of hypogonadism.
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