An unexpected higher incidence of osteopenia and osteoporosis has been reported in both antiretroviral naive  and treated  HIV-1-infected patients in comparison with the matched HIV-negative population. The incidence and aetiopathogenic mechanism of this disorder remain elusive, but it has been related to severe clinical complications such as spontaneous vertebral or hip fracture . Osteopenia and osteoporosis increase the risk of suffering pathological bone fractures twofold and fourfold, respectively. The treatment options for osteoporosis in HIV-1-infected patients are also still unclear. Alendronate (alendronic acid) is a nitrogen-containing biphosphonate that binds to bone surfaces and inhibits bone resorption by osteoclasts. Oral alendronate produces sustained increases in bone mineral density (BMD), reducing the risk of vertebral and hip fractures in postmenopausal women , in men with primary osteoporosis , and in corticosteroid-induced osteoporosis.
In order to test the efficacy and safety of alendronate in the management of osteoporosis in antiretroviral-experienced patients we conducted a pilot, randomized, open label study in HIV-1-infected patients on stable protease-inhibitor or non-nucleoside reverse transcriptase inhibitor-including highly active antiretroviral therapy (HAART). All participants fulfilled the World Health Organization criteria of osteoporosis based on BMD determination by bone dual energy X-ray absorptiometry (DEXA) scan within the previous 12 weeks. Osteoporosis was defined as a BMD t-score of 2.5 or less in the lumbar spine, hip or trochanter. Any other cause of secondary osteoporosis excluded patients from the study. Participants gave informed consent.
Participants were randomly assigned to receive alendronate, 70 mg once a week plus dietary counselling at each study visit to ensure a dietary calcium intake of 1200 g/day (alendronate group) or to dietary counselling alone (control group). Alendronate was administered with tap water, at least 30 min before breakfast, avoiding supine decubitus 30 min after drug intake. All patients continued their HAART treatment.
Patients were followed every 24 weeks for a total of 96 weeks. At every study visit the following variables were recorded: body mass index, dietary calcium intake, smoking habit, alcohol intake and exercise. A bone DEXA scan was performed at each study visit to determine the t-score of the lumbar spine (L2–L4) and femur (femoral neck, trochanter, hip and total femur). In addition, at the screening visit, thyroid-stimulating hormone and thyroxin, testosterone, prolactine, luteinizing hormone and follicular stimulating hormone, total cortisol, parathyroid hormone and total and free calcium determinations were performed to exclude other causes of secondary osteoporosis. The HIV-1 plasma viral load and lymphocyte CD4 cell counts were routinely determined in all patients every 12 weeks. Chi-Square (with Yates correction as needed), Wilcoxon and Mann–Whitney tests were performed to compare variables between treatment groups. Statistical analyses were performed using SPSS version 11.5 (SPSS Inc., Chicago, IL, USA), with two-tailed significance levels of 5%.
Twenty-six patients were recruited; 12 were allocated to receive alendronate and 14 were controls. One patient allocated to the alendronate group refused to initiate treatment after recruitment and was withdrawn from the study. The groups were well balanced at baseline except for older age (P = 0.012) and lower dietary calcium intake (P = 0.024) in the alendronate group (Table 1). An appropriate calcium intake was achieved in 100% of study participants throughout the follow-up.
The percentage of patients fulfilling criteria for osteoporosis among those receiving alendronate decreased from 100% (11/11) at baseline to 73% (8/11) at week 48 (P = 0.042), and 27% (3/11) at week 96 (P = 0.001). In contrast, the percentage of controls with osteoporosis was 100% (14/14) at baseline, 100% (14/14) at week 48, and 96% (13/14) at week 96 (P = 0.299). The differences between groups were significant at weeks 48 (P = 0.042) and 96 (P = 0.002). The relative risk of suffering osteoporosis in patients treated with alendronate versus controls was 0.73 [95% confidence interval (CI) 0.51–1.04, P = 0.214] at week 48, and 0.29 (95% CI 0.11–0.78, P = 0.003) at week 96. The prevented fraction of osteoporosis at week 96 was 70.6% (95% CI: 22.1–88.9) in patients given alendronate. The three patients retaining osteoporosis criteria in the alendronate group at week 96 also showed a marked but not statistically significant improvement in BMD, mainly in the spine.
At week 48, significant t-score increments from baseline were first found in the spine (P = 0.045) and femoral neck (P = 0.024), but not in the trochanter, only in patients receiving alendronate. However, there were no significant differences in absolute t-score values between groups (P = 0.645) (Fig. 1). At this timepoint, the spine t-score had increased 22% from baseline in patients receiving alendronate but only 10% in controls (P = 0.21).
At week 96, t-score differences in the spine increased further in the alendronate group from baseline values (L2–L4 t-score P = 0.018 for the alendronate group versus P = 0.905 for controls; P = 0.246 between groups), but now significant improvements from baseline were also detected in the hip, trochanter and total femur t-score measures (Fig. 1). Percentage t-score improvements from baseline to week 96 were 24% in the spine and 20% in the trochanter in patients treated with alendronate, whereas no significant changes were found in controls (0% in L2–L4 and −10% in the trochanter; P = 0.015 between groups for the spine, P = 0.027 between groups for the trochanter).
No differences were seen within and between groups in any other variable assessed. All patients tolerated alendronate adequately and none suffered adverse events or discontinued the study because of toxicity.
No significant HIV/AIDS-related clinical events or changes in CD4 cell counts occurred during the 96-week follow-up. All patients maintained the same initial HAART regimen throughout the study, with the exception of one patient receiving alendronate who voluntarily discontinued antiretroviral therapy for 9 months through the study, and one patient from the control group who switched antiretroviral therapy as a result of virological failure at week 72.
Given the increase in life expectancy seen after the introduction of HAART, we expect an increase in HIV-1-infected patients also targeted by the usual risk factors for osteoporosis (e.g. postmenopausal HIV-infected women) in the forthcoming years. Therefore, it is essential to tackle specific treatment strategies against BMD loss in HIV-infected patients, balancing the highest efficacy with the minimal interaction with antiretroviral therapy. We chose once-weekly administered alendronate because it has an extensively demonstrated efficacy in several other conditions leading to secondary osteoporosis, is well tolerated, implies a minimal treatment burden increase, and has no significant interaction with antiretroviral drugs because it is directly excreted in the urine without previous metabolization. We opted for not adding oral calcium and vitamin D to alendronate treatment because, although this may have exerted supplementary benefits on BMD, it would also have increased the overall pill burden and may have endangered adherence. However this strategy may also be useful in selected patients.
This study shows marked improvements in BMD in HIV-infected patients treated with once-weekly alendronate that are not achieved with dietary counselling alone. Such improvements are first achieved in the lumbar spine during the first year of treatment, and after 2 years of treatment are also achieved in the femur. Similarly, a recent longitudinal study with a 48-week follow-up only found significant BMD improvements in the lumbar spine but not in the femur in patients receiving alendronate. Of note is the fact that in our study the prevented fraction of osteoporosis was 70% after 2 years of treatment. Therefore, despite the small size of this study, our data clearly suggest that HIV-infected patients with osteoporosis may benefit from once-weekly treatment with alendronate. Given these results, it is our belief that HIV-infected patients, especially those having other risk factors for osteoporosis (e.g. prolonged corticoid therapy, menopause, hyperthyroidism, etc.), individuals with acute bone pain after trivial trauma, and those with advanced HIV disease should be screened for BMD status by bone DEXA at their first HIV diagnosis and followed thereafter at regular one or 2-year intervals in order to consider the introduction of once-weekly alendronate in those showing evidence of osteoporosis. Further studies including more patients should be carried out promptly to confirm and extend our findings.
E. Negredo conceived and designed the study and drafted the manuscript. E. Martínez-Lopez and S. Gel undertook the dietary counselling. R. Paredes participated in manuscript preparation and statistical advice. N. Pérez-Álvarez carried out the statistical analyses, J. Rosales and L. del Río performed bone DEXA scan follow-up. S. Holgado, X. Tena and C. Rey-Joly contributed to the study design. B. Clotet participated in study analyses and manuscript preparation.
Conflict of interest statement
The pharmaceutical industry did not have any direct or indirect participation in this study. E. Negredo (corresponding author) had full access to all the data in the study and had final responsibility for the decision to submit for publication. E. Negredo has received honoraria for speaking for and participation in advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, MSD. B. Clotet has received honoraria for speaking for and participation in advisory boards from Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline and Roche. E. Martínez-López, R. Paredes, J. Rosales, N. Pérez-Álvarez, S. Holgado, S. Gel, L. del Río, X. Tena and C. Rey-Joly have no potencial conflicts of interest.
1. Tebas P, Powderly WG, Claxton S, Marin D, Tantisiriwat W, Teitelbaum SL, Yarasheski KE. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS 2000; 14:F63–F67.
2. Negredo E, Gel E, Arisa ER, Rosales J, Paredes R, Del Rio L, et al
. Bone mineral density (BMD) in HIV-1-infected patients.
In: Program and Abstracts of the 8th Conference on Retroviruses and Opportunistic Infections
. Chicago, Washington, DC: Foundation for Retroviruses and Human Health, 2001, p. 232 [Abstract 626].
3. Guaraldi G, Ventura P, Albuzza M, Orlando G, Bedini A, Amorico G, Esposito R. Pathological fractures in AIDS patients with osteopenia and osteoporosis induced by antiretroviral therapy. AIDS 2001; 15:137–141.
4. Jeal W, Barradell LB, McTavish D. Alendronate: a review of its pharmacological properties and therapeutic efficacy in postmenopausal osteoporosis. Drugs 1997; 53:415–434.
5. Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, et al
. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000; 343:604–610.