1. International Association of Providers of AIDS Care (IAPAC)
Get a Spine:
Osteoporosis and HIV
Benjamin Young, MD PhD
International Association of Providers of AIDS Care (IAPAC)
HIV/AIDS on the Front Line. 3 May 2017

2. Disclosures Consultant/Advisory Board Research Support Speaker Bureau
Gilead Sciences, Merck & Co, ViiV Healthcare
Research Support
Speaker Bureau
Merck & Co

3. Outline Bone Structure, Metabolism, and Assessment
Prevalence of Bone Disease
Risk Factors for Low BMD, Osteoporosis, and Fracture
Diagnosis and Management of Osteoporosis

4. Background
People >50 years old account for 17% of new and 42% of known HIV diagnoses
Many of these patients are also facing diseases associated with aging
Osteoporosis is a common age-related condition
CDC. HIV Surveillance Report 2014

5. Bone Structure, Metabolism, and Assessment

6. Bone Structure
Bone is an active organ that undergoes constant remodeling via bone formation (mediated by osteoblasts) and bone resorption (mediated by osteoclasts)1
In people with osteoporosis, there are changes in both bone mass and bone architecture2
Normal Bone
Osteoporotic Bone
1Orwall E & Bliziotes M. Osteoporosis: Pathophysiology and Clinical Management. New Jersey: Humana Press, 2003.
2National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010.

7. Normal and Osteoporotic Bone Metabolism
The Bone Multicellular Unit
A. Resorption
B. Remodeling
Lining cells
Osteoclasts
Normal resorption depth
Osteoblasts
Osteoporosis resorption depth
Bone
Newly formed bone matrix (osteoid)
C. Mineralization and Mineral Maturation
D. Quiescence
Normal filling depth
Osteoporosis filling depth
Newly formed bone matrix (osteoid)
Calcified bone matrix
Completed remodelling unit (new bone)
Srivastava AK, et al. Curr Med Res Opin. 2005;7:

8. Etiology of Osteoporosis
Bone mineral density (BMD) changes with age1
Peak BMD usually occurs by age 18 to 25 years
Osteoporosis can occur as a result of:
Faster than normal loss of bone mass, either due to decreased bone formation or increased bone resorption1
Failure to reach peak bone mass, potentially due malnutrition, childhood illness, inadequate exercise, or genetic factors1,2
1National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010.
2Heaney RP, et al. Osteoporos Int. 2000;11:

9. Measuring Bone Health
Bone health is most often assessed by measuring BMD of the hip and spine with a dual energy X-ray absorptiometry (DXA) scanner1
Scans are non-invasive, painless, and result in little radiation exposure1,2
BMD is reported as a score3
T-score: number of standard deviations between the measured BMD and the mean BMD of young healthy white women
Z-score: number of standard deviations between the measured BMD and the mean BMD of individuals of the same age and gender
Using Medicare’s 2011 fee schedule, the cost of a DXA scan is about $1304
1National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010.
2National Osteoporosis Foundation. Having a Bone Density Test. Accessed June 30, National Institutes of Health. JAMA. 2001;285:785–795.
4American College of Rheumatology National Medicare Fee Schedule. Accessed July 12, 2012.

10. Relationship Between BMD and Fracture Risk
The risk of fracture increases as BMD decreases
For every unit decrease in T-score (one standard deviation [SD] away from the mean), the risk of fracture doubles
A T-score of 0 is the mean BMD for healthy young women and is assigned a relative risk of 1.0 as the reference value.
Meunier PJ, et al. Clin Ther. 1999;21:1025–1044.

11. Defining Osteopenia and Osteoporosis
The World Health Organization (WHO) defines osteopenia (low BMD) and osteoporosis based on T-score1
These categories are intended for postmenopausal women and men ≥50 years of age2
For premenopausal women, men under 50 years of age, and children, The International Society for Clinical Densitometry recommends Z-scores instead of T-scores2
A Z-score of ≤ -2.0 is defined as “below the expected range for age”
1World Health Organization. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis
2The International Society for Clinical Densitometry Official Positions & Pediatric Official Positions.

12. Summary: Bone Structure, Metabolism, and Assessment
Bone is an active organ that undergoes constant remodeling through a person’s life1
Osteoporosis can occur as a result of2,3:
Faster than normal loss of bone mass
Failure to reach peak bone mass
Bone health is most often assessed by measuring BMD with a DXA scanner2
A diagnosis of osteoporosis depends on BMD score4,5
T-score ≤ -2.5 (use for postmenopausal women and men ≥50 years)
Z-score ≤ -2.0 (use for premenopausal women, men under 50 years of age, and children)
1Orwall E & Bliziotes M. Osteoporosis: Pathophysiology and Clinical Management. New Jersey: Humana Press, 2003.
2National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010.
3Heaney RP, et al. Osteoporos Int. 2000;11:
4World Health Organization. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis
5The International Society for Clinical Densitometry Official Positions & Pediatric Official Positions.

13. Prevalence of Bone Disease

14. Prevalence of Osteoporosis and Fragility Fractures in General US Population
In the general population, 55% of people ≥50 years of age have low BMD or osteoporosis1
In white women ≥50 years of age, a population often associated with decreased BMD, the prevalence of osteoporosis is 30%2
Men account for 20% of people with osteoporosis1
In the remaining lifetime of people ≥50 years of age, osteoporosis-related fractures will occur in1:
Approximately 50% of women
Approximately 20% of men
Consequences of fractures can include decreased quality of life, decreased mobility, and death1
In the 12 months following a hip fracture, the estimated rate of mortality is 14% to 37%1,3-5
1National Osteoporosis Foundation. Fast Facts. Accessed June 29, 2012.
2World Health Organization. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis
3Center JR, et al. Lancet. 1999;353: Keene GS, et al. BMJ. 1993;307:1248–50.
5Leibson CL, et al. J Am Geriatr Soc. 2002;50:

15. Prevalence of Low BMD/Osteoporosis in Patients With HIV vs Controls
SUN study: 5-year prospective cohort of adults with HIV1
Data collected
NHANES: healthy controls matched for age, race, gender, and BMI1
Rates of low BMD and osteoporosis were higher in patients with HIV compared with matched controls (based on femoral neck T-scores)1
NHANES = National Health and Nutrition Examination Study III
1Overton ET, et al. 14th CROI 2007: Poster 836.

16. Prevalence of Osteoporosis in Patients With HIV vs Controls
In a meta-analysis of 11 studies, the overall prevalence of osteoporosis (T-score ≤ -2.5) in patients infected with HIV (n=884) was 15%, 3.7 times greater than in HIV-uninfected controls (n=654)
Brown T, et al. AIDS. 2006;20:

17. Fracture Rates in Patients With HIV vs Controls
Triant, et al.1: patients with HIV had higher rates of fracture than uninfected patients, regardless of sex and age
Womack, et al. (VA)2: incidence rate of fragility fractures was significantly higher among people with HIV compared with matched controls
Young, et al. (HOPS)3: sex- and age- standardized fracture rates were higher among people with HIV compared with general US population
Hansen, et al.4: patients with HIV had a higher rate of low-energy fractures than matched controls
1Triant V, et al. J Clin Endocrinol Metab. 2008;93:
2Womack J, et al. PLoS One. 2011;6:e17217.
3Young B, et al. Clin Infect Dis. 2011;52:
4Hansen A-BE, et al. AIDS. 2012;26:
NHAMCS-OPDs = National Hospital Ambulatory Medical Care Survey of Out-Patient Departments

18. Summary: Prevalence of Bone Disease
Osteoporosis is a significant health issue in the general population1
Rates of low BMD are higher among people with HIV compared with controls who are not infected with HIV2,3
There is also an increased risk of fracture among people with HIV compared with controls who are not infected with HIV4-7
In studies of the general population, fractures have been associated with decreased quality of life, decreased mobility, and death1
1National Osteoporosis Foundation. Fast Facts. Accessed June 29, 2012.
2Overton ET, et al. 14th CROI 2007: Poster 836.
3Brown T, et al. AIDS. 2006;20:
4Triant V, et al. J Clin Endocrinol Metab. 2008;93:
5Young B, et al. Clin Infect Dis. 2011;52:
6Womack J, et al. PLoS One. 2011;6:e17217.
7Hansen A-BE, et al. AIDS. 2012;26:

19. Risk Factors for Osteoporosis and Fracture

20. BMD and Fractures in the HIV population
Battalora, et al., Antiviral Ther. 2016

21. Risk Factors for Osteoporosis in the General Population
Non-modifiable1
Increasing age
Female sex
Small frame
Race
Family history
Modifiable1
Hormone deficiencies due to amenorrhea/premature menopause1
Insufficient nutrition1
Smoking1
Alcohol use (≥3 drinks/day)1
Inadequate physical activity1
Some multi-morbidities (eg, genetic disease, hypogonadal states, endocrine disorders, gastrointestinal disorders, hematologic disorders, rheumatic and autoimmune disorders)2
Some medications (eg, anticoagulants, anticonvulsants, barbiturates, glucocorticoids, some cancer drugs, lithium, antidepressants)2,3
1National Institutes of Health. Osteoporosis Handout on Health. osteoporosis_hoh.asp#5. Accessed June 30, 2012.
2National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010.
3Rizzoli R, et al. Bone. 2012: Epub ahead of print.

22. Risk Factors for Decreased BMD in Patients Infected With HIV
All risk factors for general population
HIV infection
Glesby MJ. Clin Infect Dis. 2003;37:S91–S95.

23. Osteoporosis: Risk Increases With Duration of HIV Infection
NHANES = National Health and Nutrition Examination Study III
1Overton ET, et al. 14th CROI 2007; Poster 836.
2Personal communication. Turner Overton, MD. July 12, 2012.
3Mondy K, et al. Clin Infect Dis. 2003;36:482–490.
4Bruera D, et al. AIDS. 2003;17:1917–1923.

24. Low BMD/Osteoporosis: Variable Association With CD4 Cell Count
NHANES = National Health and Nutrition Examination Study III
1McComsey GA, et al. J Infect Dis. 2011;203:
2Overton ET, et al. 14th CROI 2007; Poster 836.
3Personal communication. Turner Overton, MD. July 12, 2012.
4Bruera D, et al. AIDS. 2003;17:1917–1923.

25. Decreased BMD: Risk Increases With ART
Numerous studies have documented decreases in BMD in patients on ART1-8
Decreases are usually most pronounced during the first 24 to 48 weeks of therapy4-7
Over longer periods of time on ART, average loss of BMD slows or stabilizes
Differences in BMD changes have been observed among ART regimens1-4,6-7
1Duvivier C, et al. AIDS. 2009:23: Brown T, et al. AIDS. 2006;20: Stellbrink H-J. Clin Infect Dis. 2010:51: McComsey GA, et al. J Infect Dis. 2011;203: Bolland MJ, et al. J Clin Endocrinol Metab. 2012;76: Gallant JE, et al. JAMA. 2004:292: van Vonderen MGA. AIDS. 2009;23: Brown TT. J Acquir Immune Defic Syndr. 2009;51:

26. Fracture: Risk is Higher at Lower CD4 Cell Counts
NHAMCS-OPDs = National Hospital Ambulatory Medical Care Survey of Out-Patient Departments
1Young B, et al. Clin Infect Dis. 2011;52:
2Yong MK, et al. J Acquir Immune Defic Syndr. 2011;57:

27. Fracture: Variable Association With ART
1Hansen A-BE, et al. AIDS. 2012;26: Bendimo R, et al. AIDS. 2012;26: Yin MT, et al. 18th CROI 2011: Poster 830.
4Mundy LM, et al. AIDS. 2012:26:
5Collin F, et al. AIDS. 2009;23:

28. Summary: Risk Factors for Osteoporosis and Fracture
Patients with HIV have more risk factors for osteoporosis than the general population1
Risk of osteoporosis increases with:
Duration of HIV infection2-4
ART5-12
Risk of fracture increases with:
Lower CD4 cell count13,14
1Glesby MJ. Clin Infect Dis. 2003;37:S91–S95. 2Overton ET, et al. 14th CROI 2007; Poster Bruera D, et al. AIDS. 2003;17:1917–1923.
4Mondy K, et al. Clin Infect Dis. 2003;36:482– McComsey GA, et al. J Infect Dis. 2011;203:
6Duvivier C, et al. AIDS. 2009:23: Brown T, et al. AIDS. 2006;20: Stellbrink H-J. Clin Infect Dis. 2010:51:
9Bolland MJ, et al. J Clin Endocrinol Metab. 2012;76: Gallant JE, et al. JAMA. 2004:292:
11van Vonderen MGA. AIDS. 2009;23: Brown TT. J Acquir Immune Defic Syndr. 2009;51:
3Yong MK, et al. J Acquir Immune Defic Syndr. 2011;57: Young B, et al. Clin Infect Dis. 2011;52:

29. Diagnosis and Management of Osteoporosis
Risk Assessment
Next Steps for At-Risk Patients
Secondary Causes of Osteoporosis
Treatment Considerations

30. Risk Assessment
Making an initial assessment of a patient’s risk for osteoporosis does not require a DXA scan1
Consider common risk factors, such as1,2:
Age
Low BMI
Personal and family fracture history
Smoking
Alcohol use (≥3 drinks/day)
Physical activity level
FRAX® is a free online tool that calculates the 10-year probability of a major osteoporotic fracture or hip fracture1
Developed by the World Health Organization
DXA measurement (femoral neck) is optional
1World Health Organization. FRAX® WHO Fracture Risk Assessment Tool. Accessed July 2, 2012.
2National Institutes of Health. Osteoporosis Handout on Health. osteoporosis_hoh.asp#5. Accessed June 30, 2012.

31. Next Steps for At-Risk Patients
For patients at risk for osteoporosis, consider lifestyle counseling, eg1:
Stop smoking
Decrease alcohol intake
Increase physical activity level
Review all of the patient’s medications for drugs that may disrupt normal bone turnover1
Complete Falls Risk Assessment Tool (FRAT)
Factors assessed include history of falls, medications, psychological conditions, cognitive status, vision, mobility, and environment
Validated in the general population
Available online ( falls_dev/downloads/b2b_1a_frat.pdf)
1National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010.
2Peninsula Health. Falls Risk Assessment Tool (FRAT). Accessed July 2, 2012.

32. Recommendations for Evaluation of Bone Disease in HIV
HIV-Infected Population
Assessment
Monitoring
Men yrs of age
Premenopausal women ≥ 40 yrs of age
Assess risk of fragility fracture using FRAX
For pts with FRAX score ≤ 10%, monitor FRAX in 2-3 yrs
For pts with FRAX score > 10%, perform DXA
Men ≥ 50 yrs of age
Postmenopausal women
Pts with fragility fracture history, receiving chronic glucocorticoids, or at high risk of falls
Assess BMD using DXA
For pts with advanced osteopenia, monitor DXA in 1-2 yrs
For pts with mild or moderate osteopenia, monitor DXA in 5 yrs
For pts started on bisphosphonates (significantly reduced BMD or fracture history), repeat DXA in 2 yrs
Brown TT, et al. Clin Infect Dis. 2015;60:

33. Recommendations for Evaluation of Bone Disease in HIV
EACS Guidelines Version 8.0 Oct 2015

34. FRAX

35. FRAX and Fractures in the HIV population

36. If Osteoporosis Is Diagnosed, Consider Secondary Causes
There are numerous secondary causes of osteoporosis, including:
Hyperparathyroidism1,2
Hyperthyroidism1,2
Hypogonadism1,2
Renal disorders (phosphate wasting, hypercalciuria)1
Celiac sprue1
Hematologic disorders (multiple myeloma, mastocytosis)1
Low body weight (body mass index <20 kg/m2)2
Vitamin D deficiency1,2
Very low levels of vitamin D or severe phosphate wasting may cause osteomalacia (impaired bone mineralization that can result in weakness, pain, stiffness, and fractures3,4)
1Walker Harris V, Brown TT. J Infect Dis. 2012;205:S391-S398.
2Guaraldi G, et al. Antivir Ther. 2006;11:Lx (abstract no. 12).
3McComsey GA, et al. Clin Infect Dis. 2010;51:
4PubMedHealth. Osteomalacia. Accessed July 5, 2016.

37. Vitamin D levels and Health
Vitamin D Fact Sheet for Health Professionals

38. Vitamin D Levels are Often Low in People Infected With HIV
Vitamin D insufficiency: between 30 ng/mL and 75 ng/mL4
Vitamin D deficiency: ≤30 ng/mL4
NHANES = National Health and Nutrition Examination Study III
1Dao CN, et al. Clin Infect Dis. 2011;52:
2Guaraldi G, et al. Antivir Ther. 2006;11:Lx (abstract no. 12).
3Vescini F, et al. J Acquir Immune Defic Syndr. 2011;58:

39. Calcium and Vitamin D Recommendations for Daily Intake
Recommended dietary allowances for the general population
Calcium1
Age (years) Men Women
19 – mg 1000 mg
51 – mg 1200 mg
> mg 1200 mg
Recommended dietary allowances for patients with HIV3
Calcium: mg
Vitamin D: IU
Recommended daily allowances should not be exceeded2
High levels of calcium have been associated with kidney stones
High levels of vitamin D have been associated with kidney and tissue damage
Vitamin D1,2
Age (years) Amount
18 – IU
> IU
1Institute of Medicine of the National Academies. Dietary Reference Intakes for Calcium and Vitamin D. November 2010.
2The Endocrine Society. J Clin Endo Metab. 2011;96:
3McComsey GA, et al. Clin Infect Dis. 2010;51:

40. Estimating dietary calcium
Clinician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation. 2014

41. Treatment Considerations in the General Population
The National Osteoporosis Foundation (NOF) recommends the consideration of pharmacologic therapy for osteoporosis in postmenopausal women and men aged ≥50 years with any of the following:
A hip or vertebral (clinical or morphometric) fracture
T-score ≤ -2.5 at the femoral neck or spine after appropriate evaluation to exclude secondary causes
Low bone mass* and at least one of the following (based on the US-adapted FRAX tool):
10-year probability of a hip fracture ≥3%
10-year probability of a major osteoporosis-related fracture ≥20%
*T-score between -1.0 and -2.5 at the femoral neck or spine
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010.

42. FDA-approved Treatments for Osteoporosis
Medication Type
Drug
Brand Name
Antiresorptive bisphosphonates
Alendronate
FosamaxTM
Risedronate
ActonelTM
Ibandronate
BonivaTM
Zoledronic acid
ReclastTM
Other antiresorptives
Estrongen therapy
Raloxifene
EvistaTM
Denosumab
ProlialTM
Anabolic medication
Teriparatide
ForteoTM

43. ART Considerations for Pts With Bone Complications
DHHS considerations[1]
Consider avoiding TDF: associated with greater decrease in BMD along with renal tubulopathy, urine phosphate wasting, and osteomalacia
Consider ABC/3TC or FTC/TAF
Significantly greater BMD loss with PI-based regimens vs RAL-based regimens (when used with FTC/TDF)[2]
DTG/ABC/3TC associated with less bone turnover than EFV/TDF/FTC[3]
3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BMD, bone mineral density; COBI, cobicistat; DHHS, US Department of Health and Human Services; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir disoproxil fumarate.
1. DHHS Guidelines. July Brown TT, et al. J Infect Dis. 2015;212: Tebas P, et al. AIDS. 2015;29:

44. Long-Term Follow-Up of Bone Health in Patients Infected With HIV
Continue lifestyle counseling1,2
Consider calcium and vitamin D supplementation1,2
In patients with T-scores > -2.5 (low BMD or normal)1
Repeat DXA every 2 to 5 years
In patients being treated for osteoporosis
Repeat DXA 1 to 2 years after treatment initiation1,2
If BMD is stable or improved, less frequent monitoring can be considered1
Consider referral to endocrinologist/rheumatologist if1:
Osteoporosis is unexpectedly severe
Patient has significant secondary causes of low BMD
If treatment fails to increase BMD
If treatment is intolerable
1McComsey GA, et al. Clin Infect Dis. 2010;51:
2Aberg JA, et al. Clin Infect Dis. 2009;49:

45. Summary: Diagnosis and Management of Osteoporosis
A patient’s risk for low BMD may often be assessed by considering common risk factors1,2
A DXA scan is not required for an initial evaluation1
Regardless of risk, all patients should receive counseling about lifestyle factors and calcium/vitamin D supplementation3,4
For patients with risk factors, consider the guidelines for DXA scans 3-6
If osteoporosis is diagnosed, consider secondary causes7,8 and guidelines for treatment initiation3-5
Long-term follow-up of BMD is recommended in all patients infected with HIV4-5
1World Health Organization. FRAX® WHO Fracture Risk Assessment Tool. Accessed July 2, 2016.
2National Institutes of Health. Osteoporosis Handout on Health. #5. Accessed June 30, National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, McComsey GA, et al. Clin Infect Dis. 2010;51: Aberg JA, et al. Clin Infect Dis. 2009;49: European AIDS Clinical Society, Guidelines, Version 6 – October Accessed July 3, Walker Harris V, Brown TT. J Infect Dis. 2012;205:S391-S Guaraldi G, et al. Antivir Ther. 2006;11.

46. Questions?