Risk of Fractures in Older Adults Living with HIV

Jesus Daniel Aguilar Martinez; Barron Garcia Sevigne Tania; Arontes Montes de Oca David Alejandro; Vázquez Soto Andrea Sacramento; Caldera Finol Alberto Jose

doi:10.37871/jbres1577

ISSN: 2766-2276

Biology Group . 2022 October 17;3(10):1189-1193. doi: 10.37871/jbres1577.

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Review Article

Risk of Fractures in Older Adults Living with HIV

Jesus Daniel Aguilar Martinez^1*, Barron Garcia Sevigne Tania¹, Arontes Montes de Oca David Alejandro¹, Vázquez Soto Andrea Sacramento¹ and Caldera Finol Alberto Jose²

¹National Autonomous University, Mexico
²Anáhuac University, Mexico

*Corresponding author: Jesus Daniel Aguilar Martinez, National Autonomous University, Mexico E-mail:

Received: 12 October 2022 | Accepted: 15 October 2022 | Published: 17 October 2022

How to cite this article: Aguilar Martinez JD, Sevigne Tania BG, de Oca David Alejandro AM, Andrea Sacramento VS, Alberto Jose CF. Risk of Fractures in Older Adults Living with HIV. 2022 Oct 17; 3(10): 1189-1193. doi: 10.37871/jbres1577, Article ID: jbres1577

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Abstract

Recently, the impact of Human Immunodeficiency Virus (HIV) in older patients has began to be observed, creating a field that has not being explored at its fullest by infectologists and geriatricians. The complications associated with the pathogenesis of the disease and the antiretroviral therapy have a great impact on bone disease, specifically the risk of suffering bone fractures.

The aim of this article is to make a compilation of the most recent evidence that supports the relation of the repercussions that the pathogenesis of HIV, the Highly Active Antiretroviral Therapy (HAART) medication and the social aspects has with the increased risk of bone fracture on HIV+ elder individuals.

Introduction

The Highly Active Antiretroviral Therapy (HAART) has exponentially increased life expectancy in people with HIV. This caused a change in the epidemiology of HIV [1]. Currently, 50% of people that live with this disease in the United States of America are older than 50 years [1,2]. The success of the HAART is partially affected due to the higher than expected prevalence of associated complications with age: cognitive impairment, loss of bone density, falls. These conditions increase the risk of bone fractures and can lead to a poor quality of life for this group of patients [2].

Fractures in elderly people represent a major challenge for health systems because of the significantly increased complications related to the injury, morbidity, and total or partial disabilities and the. In 2014, our country's health system reported an average of $97 million USD cost for hip fractures [3], an important type of disabling injury that is rising among old patients due to osteoporosis and fragility syndrome.

Around 20% of patients in their eight decades of life with this type of fractures, die due to complications. Half survive with sequels. Costs rise significantly and progressively with age as a consequence of comorbidities and incapacities. It is estimated that in Mexico, 1 out of 12 women older than 50 years and 1 out of 20 men older than 50 years will suffer a fracture [3]. Other factors that increase the risk of suffering an important fall are fragility syndrome, comorbidities just as HIV and its treatment.

Antiretroviral drugs	Pathophysiological implications
Efavirenz (non-nucleoside analogue reverse transcriptase inhibitors)	With the use of this drug, a change in the microarchitecture of the bone has been seen, as well as a deterioration of the biomechanical properties of the bone (increased activity of osteoclasts and decreased bone regeneration) that increase the risk of fractures [4].
Emtricitabina/ Tenofovir (Nucleoside analogue reverse transcriptase inhibitors)	High and therapeutic doses can produce hyperphosphaturia, which can generate secondary hyperparathyroidism, causing a decrease in bone mineral density. A relationship has been seen with the appearance of fanconi syndrome, which can cause osteomalacia due to damage to the proximal tubule. Mainly affecting children, and in patients with prolonged therapy. These effects are much lower with the tenofovir alafenamide fumarate Pro-drug [5].
Zidovudina (nucleoside analogue reverse transcriptase inhibitors)	This drug increases the production of osteoclasts which causes accelerated bone resorption. It induces mitochondrial DNA damage by inhibiting γ-polymerase and mitochondrial DNA synthesis, creating lactic acidosis which has been shown to be related to decreased bone mineral density [6].
Ritonavir/Lopinavir ( Protease Inhibitors)	It has been seen that protease inhibitor drugs decrease the proliferative capacity of osteoblasts, showing an increase in oxidative stress and markers of senescence. Causing an imbalance between the bone-forming capacity of osteoblasts and that of osteoclasts. With a clear tendency to osteoporosis and increased risk of fractures in older adults [7].
Dolutegravir/lamivudina (Integrase Inhibitor/nucleoside analogue reverse transcriptase inhibitors)	The evidence supports that the combined use of these two drugs has the least effect on bone mineral density, and in some cases improves it (increase in lumbar T-score). More prospective studies are needed to obtain more evidence in this regard [8].
Maravirovic (Fusion inhibitor anti- CCR5)	Epidemiological studies suggest that the loss of CCR5 correctors is related to a lower incidence of bone destruction. As well as, with less loss of bone mineral density in the hip and lumbar spine. Various studies have shown a positive effect in relation to the balance between osteoblasts vs. Osteoclasts [9].

AGE

The possibility of a fracture increases with age, just as in men with HIV+ as the ones that don’t. In the study “An increased rate of fracture occurs a decade earlier in HIV+ compared with HIV− men'', Andaa Gonciulea observes that their weren’t differences in the incidence of fractures in men who here between 40 and 50 years old [10], but a higher one was observed in men between 50 and 60 years old. This concludes that HIV reshaped the effect on age in all types of fractures, including traumatic fracture and associated with fragility.

These results promote current available guidelines that recommend Dual-Energy X-Ray Absorptiometry (DEXA) screening as the gold standard for HIV+ men from 50 years and older [10].

Fragility and falls

Falls are very important in older patients with HIV+ due to a major prevalence of loss of bone mineral density (BMD) and fractures, compared with non infected poblation [11].

Falls in adults HIV+ can take place at medium age with an incidence nearly to the ones in elder people (> 65 years), increasing with every additional comorbidity as hypertension [10]. It was found that non incidental fractures and fractures associated with fragility are two times most likely to occur in patients living with HIV [12]. Another important finding is that the risk of fracture also increases almost three times in patients with both HIV+ and hepatitis C virus infection [13].

Population studies with similar groups, found that the risk can be directly related to use of drugs with a higher probabilities of traumas, falls and nutritional deficiencies [10].

From the same stem cells, bone and muscle develop [14] so the metabolic pathways are similar, involving growth hormone and insulin like growth factor, so they are being affected in a related way [15]. The decrease of bone mineral density and low body weight are strongly related [16]. Therefore, a loss of lean body mass leads to a loss of Bone Mineral Density (BMD) that is observed at the beginning of the HAART treatment and decreases in subsequent months [17].

On the other hand, studies have proven that some patients with low mineral bone density and low lean body mass already had a deficient physical function or fragility. The deficient physical function represents an important element for the danger of falls and adding each positive fragility phenotype criteria (Fried), the probabilities of suffering a fall increased three times [18].

For a better understanding of the relation between sarcopenia, fragility, falls and risk of fracture in older adults HIV+, a series of interventions can be given to prevent and treat these entities from a more integral view in these group of patients.

Neurocognitive disorder

Hypothesis suggests that aging increases the probability of cognitive impairment in patients HIV+. Evidence show that the fact of being HIV+ does not leads to risk of falls. However, comorbidities along that damage cognitive function just as depression, neuroleptic drugs, neuropathies, and cognitive complaints, do increase the risk.

Modifiable risk factors that jeopardize cognitive function and can lead to falls are substance abuse (marijuana, alcohol, cocaine) and multiple active drugs for nervous central system. These drugs and substances produce excessive sedation, dizziness, gait impairment, unsteadiness, impaired judgment or cognition [18]. The combined use of these substances can escalate the drug concentrations on blood, take to metabolic disturbances and increase adverse effects of other medications, and aggravate comorbidities. The use of opioids without prescription are associated with falls and fractures. The consumption of marijuana is considered the keystone to evaluate falls in the older adults population.

A study evaluated the risk of falls in HIV+ women aging. It was found that the use of multiple drugs and central nervous system active drugs (antipsychotics, anticonvulsants, antihypertensives and opioids), simultaneously increased the risk of falls [18]. These evaluated drugs had anticholinergic activity that were related with a poor cognitive function, besides of gait impairment and unsteadiness in older adults. This is especially important considering the dangers of polypharmacy in the elderly and the medication used in HIV.

Bone mineral density

Regardless of age, bone mineral density decreases by 2 to 6% within 1 or 2 years after the starting of HAART, leading to an increased risk of fracture [19].

This loss of bone mineral density is because of the own virus’s proinflammatory cytokines just as the damage to the immunologic system. It is seen that the CD4 <50 cell/mm^3 count [20] and AIDS-defining illnesses have increased the fracture rate due to a loss of bone mineral density [10].

Some of the drugs that are used such as Efavirenz are related to a decrease of the 25-hydroxyvitamin D; Tenofovir is associated to secondary hyperparathyroidism, leading to an elevated bone turnover [21]; keeping in mind that these are first line drugs, this creates a complicated outlook on the early management of infected patients. The side effects of some of the antiretroviral therapy, as protease inhibitors, and the main pathogenesis of the illness, cause kidney failure that is associated with proteinuria, leading to a low bone mineral density and elevated risk of fracture [22].

Low bone mineral density provoked by pathogenesis of HIV and HAART treatment, it is exacerbated by the risk factors that are usually related with the infection: low physical activity, smoking, use of alcohol and drugs [23].

Some studies found that despite an adequate Vitamin D supplementation, men with advanced age with the virus that have received HAART, have alterations in the trabecular cortical bone microstructure associated to a greater bone resorption [23], increasing the risk of suffering a hip, vertebrae or forearm fracture.

Prevention and Different Treatments

Preventive measures against osteoporosis should be implemented in all people living with HIV. Recent studies show that it is recommended a daily intake of calcium (1000mg/day) that is usually cover with a balanced diet (with protein). I case of low calcium intake, calcium and vitamin D supplements should be consider as they are known for lower bone mineral density loss [24]. Regulary physical activity should be promoted and stopping toxic habits just as smoking, use of drugs and alcohol.

Pharmacological treatment

Prescription is indicated in these scenarios: patients with prior low - trauma vertebral or hip fracture, patients whose 10 year fracture probability is above de age appropriate intervention and in case of low BMD [25].

Biphosphonate treatment is the main option because are the best tolerated, safe and efficacious in patients HIV+. Response to treatment should be assessed after 2 years by DEXA scan. The need for additional treatment should be reexamined after 3 - 5 years as in the general population.

In the case of patients with osteoporosis or high fracture risk, it should be consider an TAF (tenofovir/alafenamide) or Abacavir - containing regimen, avoiding TDF (tenofovir disoproxil fumarate) - containing regimens [25].

It should be noted that there are specific HIV treatment drugs that are associated with a lower degree of bone loss.

In a 2017 study, it has been reported that the use of Maraviroc has shown a decrease in bone loss in the hip and lumbar spine of HIV-infected patients. This is mediated by the loss of functional CCR5 receptors, which have been shown to be associated with an increased number of osteoclasts and impaired bone formation [26].

Physical activity

As showed in various studies, exercise has shown to increase bone density, but not all exercises are recommended to preserve and/or increase bone density.

Aerobic exercise has not shown to be beneficial enough to be prescribed to HIV-infected patients. On the other hand, high intensity progressive resistance training are effective to increase bone density [27-33].

Discusion

The elderly patient with HIV infection is necessary to see him as a complex patient who requires comprehensive care, not only for HIV infection but also for multiple comorbilities, and risk factors that may suffer (geriatric syndromes and substance abuse).

It is important to implement measures to prevent sexually transmitted infections, as well as screening for HIV infection, establish an early treatment and monitor a correct adherence to the treatment.

It is important to individualize each patient since there are different combination regiments that can have numerous adverse effects that can have an impact on bone mineral density. Taking the point of view of many articles, evidence has been found that there are drugs that do not affect bone mineral density, instead they can even improve it. However, there aren’t enough clinical trials comparing these treatment options.

No studies were found where female patients with HIV infection in the postmenopausal stage were investigated, since being a patient who, because of the gender, presents a decrease of strogen, has a greater probability of suffering from osteoporosis. Therefore an increased risk of fractures. It is very important to emphasize the difference in the natural history of the disease since it is totally different in men than in women.

There is contradictory evidence about CD4 T lymphocytes and viral load levels, and their role in the decrease of bone mineral density, more studies are needed to be able to intervene in a better way in the evolution of patients, based on these quantitative variables. Without forgetting that the priority is to avoid the immunosuppression.

More research is needed on the subject in Latin American countries. Because the human being is a biopsychosocial entity. Therefore, non-biological aspects alone influence, also social, nutritional, genetic, economic, educational, access to health; and above all, the way of seeing and living the disease.

CONCLUSION

The population of people infected by the human immunodeficiency virus is having a longer life expectancy, thanks to HAART therapies. As a result of this situation we are facing a new scenario in geriatrics and infectology. The pathogenesis of the virus, the comorbidities in this group of patients and HAART therapy with its complications are increasing the probability of suffering a fracture. This can cause a disability in patients and enormous cost in public health system, making the management of this group more complex. Definitely we need more research in this topic, especially studying the factors that increase the risk of fracture in HIV+ older adults, and screening tests for the prevention of them. It is needed an integral attention and work with geriatricians and infectologists to improve the quality of life of these patients.