A Tool for Preventing and Managing Bone Disease in HIV-Infected Adults

A Tool for Preventing and Managing Bone Disease in HIV-infected Adults

Development Team: Reviewers: Michelle Foisy, PharmD 1 Todd Brown, MD, PhD, Christine Hughes, PharmD 1,2 Tara Pfau, RD Nese Yuksel, PharmD 2 Ryan Cooper, MD Alice Tseng, PharmD 1 Northern Alberta Program, Edmonton, Alberta 2 Faculty of Pharmacy & Pharmaceutical Sciences, Debbie Kelly, PharmD University of Alberta, Edmonton, Alberta Linda Robinson, BScPharm

April 2012 VERSION 1 For additional copies, contact Michelle Foisy at [email protected] or Christine Hughes at [email protected] Copyright© 2012, Development This project was sponsored by an unrestricted educational grant from ViiV Healthcare. Team authors. All rights reserved. A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS 1 Risk Factors for Fractures/Bone Loss

Patient Characteristics • Age ≥ 50 y.o. • Major weight loss of 10% after age of 25 years old • History of fragility fracture • Sedentary lifestyle • Vertebral Fracture • Caucasian, East Asians • Parental Hip Fracture history • Premature menopause (< 45 y.o.) • Low body weight (< 60 kg) • Post-menopausal women

Diseases/Disorders • Chronic kidney disease • HIV factors – lower extremity neuropathy • Chronic viral hepatitis ( risk falls), lipoatrophy, low nadir CD4, longer • Endocrine – hypogonadism, hyperthyroidism, duration of HIV infection primary hyperparathyroidism, adrenal • Malabsorption – celiac disease, infl ammatory insuffi ciency, Type I diabetes bowel disease • Rheumatoid arthritis Nutrition • Inadequate calcium intake • Malnutrition • Vitamin D defi ciency

Substances • Alcohol abuse (> 3 units/day): 1 unit = 8-10 g of • Cigarette smoking alcohol (285 mL of regular beer, 30 mL of spirits, • Opiate use 120 mL of wine, or 60 mL of an aperitif)

Medications • Anti-androgen therapy • Chemotherapy • Anticoagulants – chronic heparin, warfarin • Glucocorticoids (> 3 months in past year at a • Anticonvulsants – e.g. phenytoin, phenobarbital, prednisone-equivalent dose > 7.5 mg/day) carbamazepine; valproate • Medroxyprogesterone, depo (Depo-Provera®) • Antiretrovirals – certain protease inhibitors (e.g. • Pre-formed retinol (vitamin A) supplements ritonavir-boosted atazanavir and lopinavir) and > 10,000 IU/day tenofovir can impact BMD; efavirenz is associated • Proton pump inhibitors with vitamin D deﬁ ciency • Selective serotonin reuptake inhibitors • Aromatase inhibitors A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS

LEGEND: 2 Patient Assessment BMD – bone mineral density DXA – dual-energy x-ray absorptiometry

Initial Screening Assessment (prior to BMD Scan) • Screen post-menopausal women and men > 50 y.o. • Assess history and risks for falls in the past year for risk factors • Tenofovir: in those with a history of fragility • In patients > 65 y.o., consider measuring height fracture or diagnosed osteoporosis, consider other annually antiretroviral options instead of tenofovir – > 2 cm loss in height could indicate a vertebral fracture – signiﬁ cant height loss should be investigated radiogaphically

Indications for initial BMD (DXA) testing in HIV patients • History of fragility fracture (any age) • Men and women > 65 y.o. • Post-menopausal women and men > 50 y.o. with • Consider repeating BMD screening every 2-5 years > 1 additional risk factor for fracture in patients with major risk factors where therapy is not warranted yet Fracture Risk Assessment (post BMD scan) • Both a T-score and Z-score are reported in BMD reports. 2) FRAX® Algorithm • Generally, a T-score < - 2.5 indicates osteoporosis, – Considers additional risk factors, but generally however decisions regarding therapy are based on 10- correlates well with results from the CAROC year fracture risk. system • There are two scoring systems used to predict the 10- – Validated in Canada in patients > 40 y.o. and year risk of fracture in therapy-naïve patients. These can use as an additional tool. are validated in the non-HIV population. – Calculates the 10-year probability (%) of major 1) CAROC System fracture and hip fracture – BMD reports in Canada use the CAROC system; – Can be used without BMD as an initial screen validated in patients > 50 y.o. to assess for fracture risk – Risk is reported as low (< 10%), moderate (10- 20%) and high (> 20%)

Rule-out secondary causes of osteopenia/osteoporosis • Review history and physical exam rule-out secondary • Tenofovir Fractional excretion of phosphate for causes those on tenofovir consider discontinuing tenofovir • Suggested Laboratory Tests: if a fragility fracture occurs OR Z-score < - 2.0 plus – Complete blood count, blood chemistries, serum urinary PO4 present with hypophosphatemia (this BLUE ITEMS: creatinine, calcium corrected for albumin, phosphate, indicates phosphate wasting and potential bone When ruling- alkaline phosphatase demineralization) out secondary – To calculate fractional excretion of phosphate, causes, it is – Vitamin D deﬁ ciency 25(OH) Vitamin D recommended – Hyperparathyroidism Parathyroid hormone, Calcium obtain a fasting urine and serum phosphate at the same time as a urine and serum creatinine to order these – Subclinical Hyperthyroidism Thyroid stimulating tests initially. hormone – Phosphate concentrations can vary throughout the day depending on diet, therefore a fasting – Hypogonadism Males: Free Testosterone state is optimal when doing the test – Phosphate wasting Fractional Excretion of – FE PO4 (%) = (UPO4/SPO4) ÷ (UCr x 1000/ Phosphate SCr) x100 – Idiopathic Hypercalciuria 24 hr Urinary Calcium – FE PO4 < 20% is generally acceptable; > 20% – Celiac Sprue Tissue Transglutaminase indicates tubular dysfunction/phosphate wasting – Multiple Myeloma Serum Protein Electrophoresis – Mastocytosis Serum Tryptase A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS 3 Treatment

Who to Treat? HIGH RISK • Duration of Therapy: Long term use of • CAROC System: High risk (> 20%) bisphosphonates has been associated with atypical • FRAX® Algorithm: Major fracture risk > 20% or hip fractures and osteonecrosis of the jaw. The optimal fracture risk > 3% duration of bisphosphonate use has not been established.Some clinicians are considering a drug MODERATE RISK holiday after 4 to 5 years of bisphosphonate use in • CAROC System: Moderate risk (10-20%) patients who are at low risk of fracture. • Initiating therapy is a clinical decision that depends MONITORING on the presence of additional signifi cant risk factors and careful evaluation for such risk factors is - The goal of therapy is to prevent further bone loss recommended. and/or increase the BMD • Plain X-rays of thoracic and lumbar spine can be - CAROC and FRAX® tools are not validated to useful to evaluate for subclinical vertebral fracture. If monitor changes in fracture risk in patients on present, treatment is strongly encouraged. therapy - Monitor BMD 1-2 years after starting therapy to LOW RISK evaluate drug effi cacy • General preventative measures only; reassess in 5 - The interval for monitoring can be increased to years. every 3-5 years once results are stable TREATMENT - A decrease in BMD at one year may be considered • Treat any identifi ed secondary causes of osteopenia signifi cant and warrants further investigation (e.g. • Vitamin D replacement therapy: Correct underlying adherence to therapy, how medication is taken/ vitamin D defi ciency to normalize 25(OH)D absorbed, consider other secondary causes of concentrations osteoporosis) • First-line therapies for the prevention of fractures EXAMPLES OF WHEN TO REFER TO AN in the general population: OSTEOPOROSIS SPECIALIST Postmenopausal women: - Evidence of phosphate wasting and low BMD – Prevent vertebral, non-vertebral and hip fractures - Patients who fail fi rst-line therapy – alendronate, risedronate, zoledronic acid, - Younger patients with a history of fragility fracture denosumab, hormone therapy (if vasomotor symptoms also present) – Prevent vertebral and non-vertebral fractures – teriparatide – Prevent vertebral only – raloxifene Men: – Alendronate, risedronate, zoledronic acid A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS

3. TREATMENT CONTINUED Avoid if patient is at risk of osteosarcoma. Avoid Antiresorptive therapy required post- teriparatide to maintain BMD gains. current reference for additional information hours before or after eating medication with full glass of water medication with full glass of water DR form with food to be taken NSAIDS) • Self administered safety in HIV patients is unknown • Increased risk of infections, • May decrease pain from vertebral fractures though no reports in humans. • Osteosarcoma reported in rats, • Indicated for a maximum of 18 months duration. • Breast cancer risk after 5 years duration • Cardiovascular risk depending on age and CVD factors Consult a • Potential for interactions with certain antiretrovirals. • Can be taken with or without food • Take 30 minutes before the fi rst food, beverage or rst food, 30 minutes before the fi Take • Do not lie down for 30 minutes after taking • Safety with CrCl<35 ml/min unknown • beverage or rst food, 30 minutes before the fi Take • Do not lie down for 30 minutes after taking • • Safety with CrCl<30 ml/min unknown • 15-30 minute infusion • Safety with CrCl<30 ml/min unknown • tenofovir, Caution with use of other nephrotoxins (e.g. • sc – subcutaneous • BMD bone mineral density CVD cardiovascular LEGEND: quired for fracture reduction esophagitis, ulcers (esophageal, gastric), gastric), ulcers (esophageal, esophagitis, osteonecrosis of the jaw, esophagitis, atypical osteonecrosis of the jaw, osteonecrosis of the jaw infections, hypercalcemia Hypocalcemia, cellulitis, back/limb pain, back/limb pain, cellulitis, Hypocalcemia, hypercholesterolemia arthralgias, Headache, nausea, water retention, breast water retention, nausea, Headache, venous vaginal bleeding, tenderness, thromboembolism GI upset, dyspepsia, diarrhea, muscle/joint pain diarrhea, dyspepsia, GI upset, Etidronate tablets should be taken on empty stomach 2 • muscle/joint pain u-like symptoms, fl – fever, GI upset, dyspepsia, diarrhea, muscle/joint pain diarrhea, dyspepsia, GI upset, RARE: RARE: RARE: RARE: RARE: thromboembolism osteonecrosis of the jaw, atypical fractures osteonecrosis of the jaw, muscle/joint pain diarrhea, dyspepsia, GI upset, atypical fractures acute renal failure fractures, 60 mg sc injection every six months 0.3 – 0.625 mg daily* 0.5 – 1 mg daily 25 – 50 µg daily 1-2 pumps daily then calcium carbonate (500 mg elemental) x 76 days 5 mg IV infusion once yearly Acute phase reaction after injection (2-3 days) 200 IU intranasal daily20 µg sc daily epistaxis sinusitis, rhinitis, Nasal dryness, • May decrease pain from vertebral fractures leg cramps orthostatic hypotension, Dizziness, 70 mg once weekly 10 mg daily one tab once weekly 60 mg daily venous leg cramps, ashes, Hot fl 35 mg once weekly 5 mg daily 150 mg monthly 35 mg weekly with food DR:

3 3 If intolerant to ﬁ rst-line therapy for prevention of vertebral fracture. * 0.625 conjugated estrogen dose or equivalent is re rst-line therapy for prevention of vertebral fracture. If intolerant to ﬁ Prolia® 60 mg sc injection Premarin® generics CES®, Estrace® Estradot® Estraderm®/generic Climara® EstroGel® Fosamax®, generics Fosamax®, 70 mg tabs 10, 5, 70 mg/75 ml oral solution Fosavance® 70 mg/2800 IU vit D 70 mg/5600 IU vit D genericsDidrocal®, Aclasta® 400 mg/day x 14 days, Cyclic: 5 mg/100 ml IV solution generics Miacalcin®, 200 IU (per dose) nasal spray Forteo® 20 µg (per dose sc pen Evista®, generics Evista®, 60 mg tabs Actonel®, generics Actonel®, 35 mg tabs 5, 150 mg tabs Actonel DR 35 mg

-estradiol -estradiol Studied in the HIV population; Calcitonin peptide calcitonin Monoclonal antibodies against RANKL denosumab transdermal estrogens: 17 DrugBisphosphonates alendronate names Trade dose Treatment Side effects Comments zoledronic acid Anabolic agent teriparatide Selective Estrogen Receptor Modulators (SERMS) raloxifene Hormone Therapy oral estrogens: conjugated estrogens 17 risedronate etidronate

Osteoporosis Medications A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS 4 Prevention

General Preventative Measures • Evaluate/treat modiﬁ able risk factors • Weight bearing exercise – 30 minutes 3 days/week • Smoking cessation and resistance training • Alcohol – limit use • Fall assessment and prevention; balance and gait • Limit sodium intake to < 2300 mg daily exercises • Limit caffeine intake to < 400 mg daily • Calcium and vitamin D supplementation

Calcium Calcium Supplementation in Adults- Recommended Daily Allowance (RDA) Oral Calcium Salts

Age (years) Daily Calcium Elemental Requirement Calcium Salt Calcium (%) 19-50 1000 mg Calcium acetate 25.3 50 + 1200 mg Calcium carbonate 40 Pregnancy or lactating women 18 + 1000 mg Calcium citrate 21 Note: When possible, it is recommended to get the majority of calcium via dietary sources. Calcium glucoheptonate 8 Calcium gluconate 9 Calcium lactate 13 Examples of Oral Calcium Products

Calcium Salt Product Examples Elemental Calcium Calcium carbonate OS-CAL 500® 500 mg OS-CAL Chewable® Calcium carbonate Caltrate® 600 mg Calcium lactate, Calcium Sandoz Forte® 500 mg gluconate and carbonate Calcium Sandoz Gramcal® 1000 mg Calcium citrate Citracal Regular® 500 mg + 400 IU Vitamin D3 Calcium lactogluconate Wampole Liquid Calcium® 300 mg/15 mL solution Note: Calcium is best absorbed when given in doses ≤ 500 mg/dose (elemental). When possible, dietary sources of calcium are recommended rather than taking supplements.

Examples of Dietary Sources of Calcium Calcium Food Product Qty Calcium Food Product Qty (mg) (mg) Dairy Products Other foods Buttermilk 250 mL 300 Almonds, dry roast 125 mL 186 Cheese 245 mg 200-250 Beans, white 250 mL 191 Cottage Cheese, 1-2% 250 mL 150 Broccoli 125 mL 33 Ice cream - soft serve 1 cone 232 Figs 10 150 32 g Milk – whole, 2%, 1%, skim 250 mL 300 Oatmeal – instant, fortifi ed 150 Yogurt – plain, 1-2% 175 mL 332 (1 pouch) Yogurt – Frozen 250 mL 218 Orange 1 med. 50 Salmon, with bones 105 g 240 Yogurt – Fruit-fl avoured 175 mL 200 (canned) Other beverages Sardines, with bones 55 g 200 Orange juice – fortifi ed 250 mL 300 (canned) Rice or Soy beverage-fortifi ed 250 mL 300 Soybeans, cooked 250 mL 170 Tofu, with calcium sulphate 84 g 130 A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS

4. PREVENTION CONTINUED

Vitamin D Vitamin D Supplementation in Adults – Recommended Daily Allowance (RDA) Age (years) Daily Vitamin D Requirement Note: Daily doses up to 2000 IU can be 19-50 400-1000 IU safely taken without medical supervision 50 + 800-2000 IU Adults with osteoporosis ≥ 800 IU

Vitamin D Forms and Examples of Oral Products Chemical Name Product Examples Indication/Comments Calciferol General Term Vitamin D group Ergocalciferol Drisdol® (8288 IU/mL solution) Pediatrics – liquid formulation Vitamin D2 (plant, native form) Erdol® (8288 IU/mL solution) Less potent than vitamin D3 40 IU= 1 mcg D-Forte® (50,000 IU/capsule)* Osto-D2® (50,000 IU/capsule)* Cholecalciferol Calciferol® (400 IU/tablet) Preferred supplement Vitamin D3 (animal) Euro-D® (400, 10,000 IU/capsule)* More potent than vitamin D2 40 IU= 1 mcg Generics (400, 1000/IU tablet) Wampole Liquid Vitamin D (1000 IU/15 mL) Calcitriol Calcijex® (calcitriol 1.0 or 2.0 mcg/mL Chronic renal failure 1,25-diOH vitamin D (kidney) injectable) Most active form of vitamin D Rocaltrol® (calcitriol 0.25 or 0.50 mcg/capsule; Renal hydrolysis not required to activate 1.0 mcg/mL solution) calcitriol One-Alpha® (alfacalcidol 0.25 or 1.0 mcg/ Prescription products for renal disease only capsule; 2 mcg/mL oral solution and injectable) * D-Forte® 50,000 IU (Euro Pharm International) is a prescription drug and is distributed in Quebec only. Euro-D® 10,000 IU (EuroPharm International) is a prescription drug and is distributed in Canada. Osto-D2® 50,000 IU (Triton Pharma Inc.) is a prescription drug and distributed in Canada. Ostoforte® (Merck Frosst) is now discontinued. ** Conversion (conventional to SI units): 25(OH)D ng/mL x 2.5 nmol/L Note: Calcidiol is 25(OH) vitamin D and circulates in blood in this form. This is the lab test used when ordering vitamin D concentrations.

Examples of Dietary Sources of Vitamin D Food Product Qty Vit. D (IU) Eggs – yolk 1 25 Cod liver oil 5 mL 450 Fish 90-100 g Ranges depending on ﬁ sh spp. Mackerel 310 Salmon 250-1000 Sardines 250 Tuna 236 Margarine 5 mL 60

Milk - fortifi ed with Vit D3 250 mL 100 Orange juice – fortifi ed 250 mL 100 Soy beverage – fortifi ed 250 mL 120 A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS

4. PREVENTION CONTINUED

Vitamin D Deﬁ ciency Who to screen for vitamin D deﬁ ciency?

• Patients with recurrent fractures, hip fracture Note: Routine screening is unnecessary in most healthy adults at low • Patients with osteoporosis risk for vitamin D deﬁ ciency (e.g. < 50 y.o., with no osteoporosis or • Patients with a history of falls conditions affecting vitamin D absorption or action)

What to order? • Serum 25-hydroxyvitamin D [25(OH)D] (i.e. calcidiol) Classifi cation of Vitamin D Status Serum 25(OH)D Concentration (nmol/L) Category < 25 Vitamin D defi ciency Conversion (conventional to SI units): 25-75 Vitamin D insuffi ciency (suboptimal) 25(OH)D ng/mL x 2.5 nmol/L > 75 Desirable vitamin D status > 250 Potential toxicity

Examples of Oral Vitamin D Replacement Therapy in Adults with Vitamin D Deﬁ ciency Replacement Therapy*

25(OH)D insufﬁ ciency Vitamin D3: 2000 IU daily for 12 weeks 25(OH)D deﬁ ciency Vitamin D2: 50,000 IU once weekly for 8-12 weeks

*Dosing Tips:

• Generally, 25(OH)D concentrations by 1.0 nmol/L per 40 IU (1 ug) of vitamin D3 given daily • Calculate daily replacement dose and decide on the best administration schedule

Sample calculation: • If the baseline 25(OH)D level is 10 nmol/L and target is 75 nmol/L, then calculate as follows: – 75-10= 65 nmol/L; 65/1= 65; 65 x 40 IU= 2600 IU of Vitamin D3 daily round up to 3000 IU daily x 8 weeks

• This calculation assumes that 25(OH)D concentrations by 1.0 nmol/L per 40 IU of Vitamin D3

Monitoring • Repeat 25(OH)D levels after about 3-4 months of adequate supplementation • Goal of Therapy: 25(OH)D level > 75 nmol/L (optimal) • Do not repeat serum concentrations if an optimal concentration is achieved • Maintenance Therapy: Continue with RDA dosing once optimal concentrations are achieved A TOOL FOR PREVENTING AND MANAGING BONE DISEASE IN HIV-INFECTED ADULTS

Defi nitions Fragility Fracture: Fracture that occurs spontaneously or Z-Score: Refers to the number of standard deviations a person’s following a minor trauma (e.g. falling from standing height) BMD varies from the mean BMD (matched for age, gender and www.osteoporosis.ca/multimedia/pdf/Executive_Summary_ ethnicity). October_2010.pdf CAROC System: Risk Assessment Tool developed by a “Joint Osteopenia: Decreased bone mineral density initiative of the Canadian Association of Radiologists and Osteoporosis: “Osteoporosis is defi ned as a skeletal disorder Osteoporosis Canada.” www.osteoporosis.ca/multimedia/pdf/ characterized by compromised bone strength predisposing to an CAROC.pdf increased risk of fracture”. http://consensus.nih.gov/2000/2000O FRAX®Algorithm: World Health Organization (WHO) Fracture Risk steoporosis111html.htm Assessment Tool. The FRAX®algorithm was developed by the Osteomalacia: Impaired bone mineralization, often caused by WHO and gives a 10-year probability of the risk of fracture (hip, severe vitamin D defi ciency; accompanied by muscle weakness, clinical spine, forearm, hip and/or shoulder). The tool has been bone pain, stiffness, bone fracture; treated with Vitamin D, Ca++, validated for use in Canada and a number of other countries. +/- phosphate, not bisphosphonates; most important differential www.shef.ac.uk/FRAX/ diagnosis for low BMD T-Score: Refers to the number of standard deviations a person’s BMD varies from the mean BMD of a healthy gender-matched individual with peak bone mass (25-30 y.o.). This value has been validated in post-menopausal women and men > 50 y.o. as a predictor of fracture risk.

References 1. Papaioannou A et al. 2010 clinical practice guidelines for 8. Health Canada. Vitamin D and Calcium: Updated Dietary the diagnosis and management of osteroporosis in Canada: References Intakes, November 30, 2010. www.hc-sc.gc.ca/ summary. Can Med Assoc J 2010;182(17):1864-73. fn-an/nutrition/vitamin/vita-d-eng.php. Accessed 25 January 2. Hanley DA et al. Vitamin D in adult health and disease: a 2012. review and guidelines statement form Osteoporosis Canada 9. Alberta Health Services. HealthLink Alberta. Vitamin D – The (summary). Can Med Assoc J 2010;182(12):1315-1319. Sunshine Vitamin, July 27, 2006. www.healthlinkalberta. 3. McComsey GA et al. Bone disease in HIV infection: a practical ca/Topic.asp?GUID={2D84CB6E-4590-45C2-9D9C- review and recommendations for HIV care providers. Clin Infect FD5F363598A5} Dis 2010;51(8):937-946. Accessed 25 January 2012. 4. Aberg JA et al. Primary care guidelines for the management 10. NIH Consensus Development Program. National Institutes of persons infected with human immunodefi ciency virus: of Health Consensus Development Conference Statement. 2009 update by the HIV medicine Association of the Infectious Osteoporosis Prevention, Diagnosis and Therapy, March 27-29, Diseases Society of America. Clin Infect Dis 2009;49(5):651- 2000. http://consensus.nih.gov/2000/2000Osteoporosis111ht 681. ml.htm. Accessed 25 January 2012. 5. FRAX WHO Fracture Risk Assessment Tool. University of 11. Compendium of Pharmaceuticals & Specialties, on-line version Sheffi eld, UK. www.sheffi eld.ac.uk/FRAX/tool.jsp. Accessed 25 (e-CPS). CPhA monograph, Calcium Salts:Oral, October 2010. January 2012. 12. Osteoporosis in Primary Care. Can Pharm J 2011;144 6. CAROC – Canadian Association of Radiologists and (suppl 1):S2-24. www.cpjournal.ca/toc/cpha/144/sp1. Osteoporosis of Canada. www.osteoporosis.ca/multimedia/pdf/ Accessed 1 April 2012. CAROC.pdf. Accessed 25 January 2012. 7. Osteoporosis Canada, 2011. www.osteoporosis.ca/. Accessed 25 January 2012.