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

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

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

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

Bone Structure, Metabolism, and Assessment

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.

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;7:1015-1026.

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;11:985-1009.

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. http://www.nof.org/aboutosteoporosis/detectingosteoporosis/bmdtest. Accessed June 30, 2012. 3National Institutes of Health. JAMA. 2001;285:785–795. 4American College of Rheumatology. 2011 National Medicare Fee Schedule. http://www.rheumatology.org/practice/office/medicare/medicare_table_01.asp. Accessed July 12, 2012.

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.

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. 1994. 2The International Society for Clinical Densitometry. 2007 Official Positions & Pediatric Official Positions.

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;11:985-1009. 4World Health Organization. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. 1994. 5The International Society for Clinical Densitometry. 2007 Official Positions & Pediatric Official Positions.

Prevalence of Bone Disease

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. http://www.nof.org/node/40. Accessed June 29, 2012. 2World Health Organization. Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis. 1994. 3Center JR, et al. Lancet. 1999;353:878-82. 4Keene GS, et al. BMJ. 1993;307:1248–50. 5Leibson CL, et al. J Am Geriatr Soc. 2002;50:1644-50.

Prevalence of Low BMD/Osteoporosis in Patients With HIV vs Controls SUN study: 5-year prospective cohort of adults with HIV1 Data collected 2004-2006 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.

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;20:2165-2174.

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;93:3499-3504. 2Womack J, et al. PLoS One. 2011;6:e17217. 3Young B, et al. Clin Infect Dis. 2011;52:1061-1068. 4Hansen A-BE, et al. AIDS. 2012;26:285-293. NHAMCS-OPDs = National Hospital Ambulatory Medical Care Survey of Out-Patient Departments

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. http://www.nof.org/node/40. Accessed June 29, 2012. 2Overton ET, et al. 14th CROI 2007: Poster 836. 3Brown T, et al. AIDS. 2006;20:2165-2174. 4Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504. 5Young B, et al. Clin Infect Dis. 2011;52:1061-1068. 6Womack J, et al. PLoS One. 2011;6:e17217. 7Hansen A-BE, et al. AIDS. 2012;26:285-293.

Risk Factors for Osteoporosis and Fracture

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

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. http://www.niams.nih.gov/Health_Info/Bone/osteoporosis/ 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.

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.

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.

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;203:1791-1801. 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.

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. 2009:23:817-824. 2Brown T, et al. AIDS. 2006;20:2165-2174. 3Stellbrink H-J. Clin Infect Dis. 2010:51:963-972. 4McComsey GA, et al. J Infect Dis. 2011;203:1791-1801. 5Bolland MJ, et al. J Clin Endocrinol Metab. 2012;76:643-648. 6Gallant JE, et al. JAMA. 2004:292:191-201. 7van Vonderen MGA. AIDS. 2009;23:1367-1376. 8Brown TT. J Acquir Immune Defic Syndr. 2009;51:554-561.

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;52:1061-1068. 2Yong MK, et al. J Acquir Immune Defic Syndr. 2011;57:205-210.

Fracture: Variable Association With ART 1Hansen A-BE, et al. AIDS. 2012;26:285-293. 2Bendimo R, et al. AIDS. 2012;26:825-831. 3Yin MT, et al. 18th CROI 2011: Poster 830. 4Mundy LM, et al. AIDS. 2012:26:1073-1082. 5Collin F, et al. AIDS. 2009;23:1021-1026.

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 836. 3Bruera D, et al. AIDS. 2003;17:1917–1923. 4Mondy K, et al. Clin Infect Dis. 2003;36:482–490. 5McComsey GA, et al. J Infect Dis. 2011;203:1791-1801. 6Duvivier C, et al. AIDS. 2009:23:817-824. 7Brown T, et al. AIDS. 2006;20:2165-2174. 8Stellbrink H-J. Clin Infect Dis. 2010:51:963-972. 9Bolland MJ, et al. J Clin Endocrinol Metab. 2012;76:643-648. 10Gallant JE, et al. JAMA. 2004:292:191-201. 11van Vonderen MGA. AIDS. 2009;23:1367-1376. 12Brown TT. J Acquir Immune Defic Syndr. 2009;51:554-561. 3Yong MK, et al. J Acquir Immune Defic Syndr. 2011;57:205-210. 14Young B, et al. Clin Infect Dis. 2011;52:1061-1068.

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

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 www.shef.ac.uk/FRAX/index.jsp 1World Health Organization. FRAX® WHO Fracture Risk Assessment Tool. http://www.shef.ac.uk/FRAX/index.jsp. Accessed July 2, 2012. 2National Institutes of Health. Osteoporosis Handout on Health. http://www.niams.nih.gov/Health_Info/Bone/osteoporosis/ osteoporosis_hoh.asp#5. Accessed June 30, 2012.

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 (http://www.health.vic.gov.au/agedcare/maintaining/ 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). http://www.dhs.vic.gov.au/health/agedcare/maintaining/falls/providers/rac/plans_frat.htm. Accessed July 2, 2012.

Recommendations for Evaluation of Bone Disease in HIV HIV-Infected Population Assessment Monitoring Men 40-49 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;60:1242-1251.

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

FRAX https://www.shef.ac.uk/FRAX/tool.jsp

FRAX and Fractures in the HIV population

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;51:937-946. 4PubMedHealth. Osteomalacia. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001414/. Accessed July 5, 2016.

Vitamin D levels and Health Vitamin D Fact Sheet for Health Professionals https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

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;52:396-405. 2Guaraldi G, et al. Antivir Ther. 2006;11:Lx (abstract no. 12). 3Vescini F, et al. J Acquir Immune Defic Syndr. 2011;58:163-172.

Calcium and Vitamin D Recommendations for Daily Intake Recommended dietary allowances for the general population Calcium1 Age (years) Men Women 19 – 50 1000 mg 1000 mg 51 – 70 1000 mg 1200 mg >70 1200 mg 1200 mg Recommended dietary allowances for patients with HIV3 Calcium: 1000-1500 mg Vitamin D: 800-1000 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 – 70 600 IU >70 800 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;96:1911-1930. 3McComsey GA, et al. Clin Infect Dis. 2010;51:937-946.

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

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.

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

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 2016. 2. Brown TT, et al. J Infect Dis. 2015;212:1241-1249. 3. Tebas P, et al. AIDS. 2015;29:2459-2464.

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;51:937-946. 2Aberg JA, et al. Clin Infect Dis. 2009;49:651-681.

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. http://www.shef.ac.uk/FRAX/index.jsp. Accessed July 2, 2016. 2National Institutes of Health. Osteoporosis Handout on Health. http://www.niams.nih.gov/Health_Info/Bone/osteoporosis/osteoporosis_hoh.asp #5. Accessed June 30, 2012. 3National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis, 2010. 4McComsey GA, et al. Clin Infect Dis. 2010;51:937-946. 5Aberg JA, et al. Clin Infect Dis. 2009;49:651-681. 6European AIDS Clinical Society, Guidelines, Version 6 – October 2011. www.europeanaidsclinicalsociety.org. Accessed July 3, 2012. 7Walker Harris V, Brown TT. J Infect Dis. 2012;205:S391-S398. 8Guaraldi G, et al. Antivir Ther. 2006;11.

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