HIV-positive people are at increased risk for thinning bones or reduced bone density. Thinner bones are weaker and have difficulty supporting a person's weight, therefore, they are prone to break or fracture.
The reasons for the elevated risk for bone issues in people with HIV may be related to at least the following factors:
- excess inflammation, a consequence of long-term viral infection
- poor nutrition
- being underweight
- tobacco use
- excess use of alcohol
- lower-than-ideal levels of vitamin D
Readers should note that other researchers have found thinner-than-normal bones in some young men at high risk for HIV before they acquired this infection.
Role of ART
Potent combination anti-HIV therapy (commonly called ART or HAART) has made a dramatic difference to the survival prospects of HIV-positive people. Research suggests the possibility that some young people who are diagnosed with HIV today and who initiate ART shortly thereafter will live into their 70s and 80s.
Despite this beneficial role of ART, some researchers, doctors and patients have raised questions about the impact that ART might have on bone health. Well-designed studies have found that once ART is initiated, bone density can diminish by an average of 2% to 6% for a year or two and then stabilize. Why this should occur during the first few years of using ART is not clear. One drug in particular, the nuke tenofovir (Viread and found in Truvada, Atripla, Complera and Stribild), has been associated with bone loss in some patients in some studies but not others. The reasons for this are not clear.
Faced with the bone-related issues mentioned here, a team of doctors and researchers from Australia, Europe, East Asia, Latin America and the U.S. collaborated to develop bone-focused guidelines to assist doctors and nurses caring for HIV-positive people. The team reviewed data from relevant studies that dealt with key common biomedical issues relating to bone health and arrived at agreement and recommendations. Before getting into the recommendations, we first discuss a term used.
A Note on Terms
Doctors sometimes use the term "fragility fractures." This term refers to bones that have broken because of simple, everyday activities, such as falling from standing height. Fragility fractures can be a concern for people with less-than-ideal bone density.
Major risk factors for fragility fractures include the following:
- a history of fragility fractures
- taking corticosteroids at doses of 5 mg/day or greater for more than three months
- a high risk for falling (perhaps because of difficulty with balance or vision)
The team made the following recommendations:
- all HIV-positive adults should be assessed for fragility fractures and low bone mineral density (BMD)
- patients who have fragility risk factors should undergo a bone density scan. Such scans are called DEXA (dual-energy X-ray absorptiometry) and use low-dose X-rays.
The team stated that certain patients might not need DEXA scans, as follows:
- patients without major risk factors for fragility fractures
- men aged 40 to 49 years
- women who have not entered menopause and who are at least 40 years old
In such cases, the team recommended that doctors use the Fracture Risk Assessment Tool (FRAX). This is an online calculator that can provide predictions about the risk of a person developing a major fracture over the next 10 years of his/her life. Specifically, FRAX estimates the risk of a fracture occurring in the backbone (spine), forearm, shoulders and hips.
FRAX calculators have been developed by the World Health Organization (WHO) and optimized for many countries, including Canada.
The team recommends that FRAX be repeated "every two to three years or when a new clinical risk factor develops."
FRAX takes into account at least the following risk factors:
- height and weight
- parental history of fracture
A FRAX calculator is available online.
The team stated that it is "reasonable" to assess bone density with DEXA scans in the following groups of HIV-positive people whose likelihood of developing a major fracture in the next decade of their life (as predicted by FRAX) is at least 10%:
- men aged 40 to 49 years
- women aged 40 to 49 years who have not begun the transition to menopause
The team also recommended the use of DEXA scans in the following populations:
- all post-menopausal women
- all men 50 years of age and older
- adults "with a major fragility risk factor regardless of age"
The team stated that "routine DEXA screening of all HIV-[positive] patients on ART is not recommended."
The doctors stated that initially painless fractures in the backbone are "common" among HIV-positive people, with such problems occurring in up to 25% of this population. Furthermore, the team noted that the presence of these fractures is "a strong risk [factor] for future fractures."
The team recommends that the height of patients should be measured every one to two years in adults who are aged 50 years and older. The loss of 2 cm or more in height in such a period is suggestive of osteoporosis and possibly a fracture in the spine.
To screen for these subclinical (initially painless) fractures, the team recommends that X-rays of the spine or a DEXA-based fracture assessment be done, particularly in women aged 70 years and older and men aged 80 years and older. Readers should note that a recent report (appearing later in this issue of TreatmentUpdate) suggests that these subclinical fractures have been found to occur in HIV-positive people who are much younger than these thresholds suggested by the researchers.
The team stated that blood tests should not be used to "determine fracture risk or low bone density." Although such tests exist, their findings are not always definitive and their use is largely restricted to research settings.
The team stated, "As the benefits of ART far outweigh the potential negative long-term effects on [bone density and bone] metabolism and fracture risk, local or national guidelines for initiation and choice of ART regimen should be followed."
In patients with low bone density or who have osteoporosis, the team recommends that certain anti-HIV medicines be avoided, including the following:
- tenofovir (Viread and found in Truvada, Atripla, Complera and Stribild)
- boosted protease inhibitors
Today most protease inhibitors are used with a small dose of the protease inhibitor ritonavir (Norvir). The purpose of a low dose of ritonavir is to raise and maintain, or boost, levels of the other protease inhibitor being used so that once-daily dosing is possible. Over the past five years, commonly prescribed combinations of boosted protease inhibitors have included the following:
- darunavir (prezista) + ritonavir
- atazanavir (Reyataz) + ritonavir
- lopinavir + ritonavir (co-formulated in one pill called Kaletra)
In 2015, the U.S. Department of Health and Human Services (DHHS) recommended that for the initial treatment of HIV infection doctors prescribe combinations of ART containing an integrase inhibitor or the combination of darunavir + ritonavir.
The reasoning behind the recommendation by the team to avoid tenofovir-containing medicines or boosted protease inhibitors other than darunavir + ritonavir is as follows:
"... these regimens have been associated with greater decreases in bone density compared with other [nucleoside analogues] and raltegravir [Isentress]."
The team stated that the combination of dolutegravir (Tivicay) and Kivexa (abacavir + 3TC) is a regimen that they recommend. Dolutgravir is an integrase inhibitor. However, they caution that only limited information on the impact of dolutegravir-containing regimens on bone health is available.
Osteomalacia (soft bones) generally occurs when bones do not get enough of the minerals calcium and/or phosphorus. This can cause bone pain, weak muscles, low bone density and fragility fractures.
There are some reports of osteomalacia occurring in HIV-positive people who were using tenofovir or efavirenz (in Sustiva, Stocrin and Atripla).
The team advised doctors that osteomalacia should be suspected in patients with low bone density and the following:
- higher-than-normal levels of phosphorus (or phosphate) in the urine
- low levels of phosphate in the blood
- elevated levels of parathyroid hormones in the blood
- severe vitamin D deficiency -- less than 25 nmol/L (or less than 10 ng/mL) in the blood
In cases of osteomalacia, the team recommended that the use of efavirenz and/or tenofovir should be avoided.
Fragility Fractures and Healthier Habits
The team recommends that all HIV-positive people who are at high risk for fragility fractures be counselled about healthier living strategies. Counselling should include at least the following topics:
- smoking cessation (where appropriate)
- avoid excessive intake of alcohol
- engage in regular weight-bearing and muscle-strengthening exercises
- take steps to prevent falls
The team encourages doctors to remind their patients to eat foods containing a sufficient amount of calcium every day (referral to a dietician may be necessary).
The team recommends that, ideally, the first approach to attaining daily calcium requirements is to increase the intake of calcium from food. However, the team noted that "calcium supplements may be appropriate if dietary calcium intake is insufficient."
Recommended calcium intakes by the team are as follows:
- men (50 to 70 years) -- 1,000 mg of calcium daily
- men (71 and older) -- 1,200 mg of calcium daily
- women (51 and older) -- 1,200 mg of calcium daily
Multiple studies have found that HIV-positive people tend to have lower-than-ideal levels of vitamin D in their blood. The team encourages doctors to have laboratories assess the amount of vitamin D in the blood of their patients who have low bone density or who have a history of fractures. In addition, the team noted that doctors should consider testing vitamin D levels in people with the following factors associated with low vitamin D:
- dark skin
- avoiding sun exposure
- malabsorption of nutrients
- a diet poor in vitamin D
- chronic kidney disease
- past or current use of efavirenz
Recommendations about vitamin D dosage
The team recommends that supplementary vitamin D be given to HIV-positive people whose levels in the blood are graded as follows:
- insufficient -- less than 50 nmol/L (20 ng/mL)
- deficient -- less than 25 nmol/L (10 ng/mL)
The goal of vitamin D supplementation, the team stated, is to raise levels in the blood to "approximately 75 nmol/L (30 ng/mL)." Once this is achieved, the next goal should be maintenance of this level and that dosing should be driven by blood test results.
The Importance of Vitamin D
Vitamin D helps people absorb calcium from their diet and has an important impact on bone and muscle health. Furthermore, many medicines used to treat osteoporosis work best when vitamin D levels in the blood are at least 75 nmol/L. The team stated that it is important for patients to achieve the target level of vitamin D (in their blood) before therapy for low bone density is prescribed.
Vitamin D Dosing
When a patient's blood concentration of vitamin D is greater than 75 nmol/L, the team says that 1,000 IU/day of vitamin D3 should be sufficient to maintain this concentration.
For patients whose blood levels are between 50 and 70 nmol/L, the team says that 2,000 IU/day of vitamin D3 should help to raise these levels to the target of approximately 75 nmol/L. However, the team notes that doctors may need to "consider a more aggressive replacement strategy" if patients have any of the following conditions or features:
- taking medicines that affect the production of vitamin D
Higher doses of vitamin D need to be considered because patients with any of these conditions may take longer to reach the target concentration of 75 nmol/L of vitamin D in their blood.
For patients whose blood levels are between 37.5 and 50 nmol/L, the team recommends higher doses, such as the following:
- 50,000 IU/week of vitamin D2 or D3 for between eight and 12 consecutive weeks (or "the equivalent of 6,000 IU/day of vitamin D3").
Again, the team cautions that doctors may need to "consider a more aggressive replacement strategy" if patients have any of the previously listed conditions or features.
Prior to initiating therapy for low bone density, the team encourages doctors to screen their patients for potential causes of low bone density, including the following:
- low levels of vitamin D in the blood
- elevated levels of parathyroid hormone in the blood
- higher-than-normal levels of thyroid hormone in the blood
- lower-than-normal levels of testosterone in both men and women
- Cushing syndrome (a disorder where the body produces too much of the hormone cortisol)
- kidney disorders
- some cancers
- some gastrointestinal disorders
For more information about vitamin D, its forms, sources and recommendations by specialists, see Treatment Update 185.
A future issue of _TreatmentUpdat_e will have more information on vitamin D.
Additionally, the team asks doctors to avoid prescribing certain medicines that are associated with thinning bones, such as the following, "if appropriate alternatives are available":
- anti-seizure drugs
- proton pump inhibitors (used to reduce stomach acidity)
- certain antidiabetic drugs called glitazones
Specific Therapy for Low Bone Density
The team recommends one of the following medicines for treating low bone density:
- alendronate (Fosamax, Fosavance) -- 70 mg once weekly by mouth, accompanied by calcium carbonate 1,000 mg/day and vitamin D3 400 IU/day
- zoledronic acid (Aclasta, Zometa) -- 5 mg administered intravenously once yearly
The team states that treatment with these drugs needs to be individualized; that is, treatment should be reviewed after the first three to five years of administration. The reasons for this period of reassessment are to assess changes in bone density and fracture risk and to screen for the possibility of rare side effects such as osteonecrosis of the jaw and fracture of the thigh bone. For more information about these potential side effects, see Understanding the risk/benefit of bone drugs.
There are other medicines that could be used for the therapy of osteopenia or osteoporosis; however, the team did not provide detailed recommendations about them.
The team mentions several ways to assess whether therapy has been successful (these assessments have been validated with thousands of HIV-negative people):
- lack of new fractures or signs/symptoms of new fractures
- maintaining height (less than a 1-cm decrease)
- either no decrease or an increase in bone density in the hip and spine when assessed by DEXA scans
- reduction in the level of proteins in the blood or urine that are associated with thinning bones (these may only be available from research laboratories)
If the recommended therapies do not work, the team suggests that doctors refer patients to a specialist.
- Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clinical Infectious Diseases. 2015 Apr 15;60(8):1242-51.
- Hileman CO, Labbato DE, Storer NJ, et al. Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study. AIDS. 2014 Jul 31;28(12):1759-67.
- Kooij KW, Wit FW, Bisschop PH, et al. Low bone mineral density in patients with well-suppressed HIV infection: association with body weight, smoking, and prior advanced HIV disease. Journal of Infectious Diseases. 2015 Feb 15;211(4):539-48.