Preventing Osteoporosis and Reducing Fracture Risk Usman Malabu; FACP, FRCPI, FRACP Staff Endocrine Specialist & Assoc. Prof. of Medicine The Townsville Hospital & James Cook University Townsville, North Queensland -Australia

Case Presentation 68 year old female –Mrs. KY CXR for cough: ‘osteopenic’ bones

Outline Management Plan What further history Clinical examination Investigations Treatment & Prevention

History: Mrs. KY Hx of Prior Fractures Falls Hx Neurological D-Z Hx Hx of Muscular Weakness Nutritional Hx Medication Hx Functional Hx 4

Nutritional History: Mrs. KY Deficiency States Calcium Vitamin D Vitamin C Excess Intake Caffeine Alcohol Smoking

Physical Examination: Mrs. KY Orthostatics Gait & Mobility Height Kyphosis Clinical Features of Hypercortisolism Hyperthyroid

Evaluation for Suspected Osteoporosis in Selected Patients Test Possible etiology Alkaline phosphates Osteomalacia Calcium Vitamin D deficiency Malabsorption Hyperparathyroidism Liver or kidney function Liver or kidney disease TSH Hyperthyroidism Total testosterone (men) Hypogonadism 25-hydroxyvitamin D Complete blood count Multiple myeloma

Evaluation for Osteoporosis in Selected Patients Test Possible etiology FSH, LH, Estradiol (women) Hypogonadism PTH Hyperparathyroidism ESR, uBJP Multiple myeloma CTX –bone turn over marker Assess activity of osteoporosis

Hip BMD Spine

WHO Definitions Normal T score > -1 SD Osteopenia Osteoporosis T score  -2.5 SD Established Osteoporosis T score  -2.5 SD + low energy fracture

Bone Health Normal Osteoporotic Bone quality is not the only factor … 07/16/13 19:23 Bone Health Normal Osteoporotic Bone quality is not the only factor … 11

Diagnosis of Osteoporosis History: etiology and RFs Exam: kyphosis, prox weakness X-rays: fractures BMD: bone mass Laboratory tests: etiology, BTOM

After mid-30’s: slow loss Post-menopause: rapid loss Men lose bone mass too. Source: The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means to You at http://www.surgeongeneral.gov/library/bonehealth

The Domino Fracture Effect This ‘domino fracture effect’ can lead to impaired mobility and have devastating consequences on a patient’s quality of life through a decline of independence and dignity 14 14

Fracture Risk Reduction Look for risk factors other than low bone mineral density Minimize over-zealous Rx of those at indeterminate risk

Fracture Risk Assessment Developed by WHO: FRAX Enhances ability to predict fracture risk: BMI of femoral neck Clinical risk factors ABSOLUTE RISK 10-year period >3% for hip fracture >15% for major fractures FRAX™. Available at: http://www.shef.ac.uk/FRAX/index.htm. 16 16

FRAX™. Available at: http://www.shef.ac.uk/FRAX/index.htm. Prof. John A Kanis University of Sheffield FRAX™. Available at: http://www.shef.ac.uk/FRAX/index.htm.

Risk factors The “red flags” for osteoporosis risk. 20

Older than 65 # after age 50 Underweight Previous falls FMH of Osteo/# IDENTIFY RISK FACTORS OF OSTEOPOROSIS 1 Older than 65 # after age 50 Underweight Previous falls FMH of Osteo/#

> 2 drinks of alcohol/week IDENTIFY RISK FACTORS OF OSTEOPOROSIS 2 Smoking > 2 drinks of alcohol/week

RISK FACTORS: CURRENT OR PMH Cancer Chronic lung disease Chronic liver or kidney disease Inflammatory bowel disease Rheumatoid arthritis Hyperparathyroidism Vitamin D deficiency Cushing's syndrome Hyperthyroidism 3

RISK FACTORS OF OSTEOPOROSIS: MEDICATIONS 4 One of these medicines: Oral glucocorticoids (steroids) TZDs –pioglitazone PPIs Cancer treatments (radiation, chemo) Thyroxine Antiepileptic medications –phenytoin, CMZ Gonadal hormone suppression -medroxyprog Immunosuppressive agents

The good news: Osteoporosis is preventable for most people! Diet and lifestyle

Management of Osteoporosis Treatment / Secondary Prevention Lifestyle Diet Exercise Smoking Alcohol Intake Sunlight Exposure Pharmacological Drugs altering BMD Analgesia Non-pharmacological Physiotherapy Pain Relief Falls Assessment Prevention / Primary Prevention Lifestyle Diet Exercise Smoking Alcohol Intake Sunlight Exposure Pharmacological Drugs altering BMD Non-pharmacological Physiotherapy Hip Protectors Although the management of Osteoporosis can be broken down into treatment and prevention,in clinical practice the distinction is less appropriate as there is a great deal of overlap and both involve changes in lifestyle centred around exercise, stopping smoking and diet, drug therapy to reduce fracture risk non-pharmacological therapies to reduce the effects of fractures and prevent further fractures. stopping smoking Prevention of Falls 27

Lifestyle Advice Diet Exercise Smoking Sunlight Exposure Alcohol Balanced diet containing adequate calcium 1000 mg/day Exercise Regular weight bearing exercise 3 times a week for 20 minutes minimum Smoking Stop smoking All patients should receive lifestyle advice re Diet rich in calcium Alcohol intake Exposure to sunlight Stopping smoking Exercise Sunlight Exposure 15-20 minutes on face, hands and forearms twice weekly form April to October Alcohol Within safe limits 2u/day women 3u/day men 28

Calcium Rich Diet Vitamin D Prevent Falls Weight-Bearing Exercise

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Walking Dancing Gardening Tennis Jump Rope Volleyball Skating Activity – Exercise Guide

Don’t Smoke Minimize Caffeine & Alcohol Testing & Medication if Needed

Calcium Requirements: age related Goal 500 mg 1,300 mg http://www.osteoporosis.org.au/news/latest-news/new-guidelines-released-in-mja-open/

Dietary sources of calcium 07/16/13 19:23 Dietary sources of calcium Dairy foods Most readily absorbed Ca Main source of calcium in Australian diets RDI = 3 serves per day Ca-enriched soy drinks Fish with bones RDI for older people = 1300 mg = 4.5 glasses of milk http://www.racgp.org.au/download/documents/Guidelines/Musculoskeletal/racgp_osteo_guideline.pdf 34

Vitamin D for Ca absorption 400 IU daily Vitamin D is in milk (100 IU in 1 cup)

Current treatments in OP Antiresorptive Estrogens and SERMs Calcitonin Bisphosphonates Denosumab Anabolic (stimulate bone formation) Parathyroid hormone Dual action agents Strontium ranelate

Estrogen WHI raised concerns about CV risks ERT increases BMD > SERM Prestwood, KM et al. J Clin Enodocrinol Metab. 2000; 85(6): 2197-2202 WHI raised concerns about CV risks E2 still approved for hot flashes Low-dose ERT at menopause will delay bone thinning not as first-line therapy MORE trial 7705 women mean age 66. 39

HRT: A CONSENSUS Prime role of HRT is relief of menopausal Sx Risks/benefits: breast Ca 2-6/1000 women treated with HRT for 5 years Use lowest effective E2 dose, assess CV risk Review need annually (esp aged>60)

HRT: A CONSENSUS Can give up to age 50 if prem menopause Do not use in IHD/CVA, or Alzheimer's Transdermal E2 has lower DVT risk

RALOXIFENE -SERMS Reduces vertebral (not hip) fracture risk Reduces development of new breast Ca No increased risk of CVD (reduces CV events!) Increased risk of DVT/PE & may worsen flushes Well tolerated, easy dosing: 60 mg OD

Calcitonin Calcitonin is effective for OP fracture pain Effect takes about 2 weeks. Silverman, SL. Osteoporos Int. Nov 2002;13(11):858-867. No significant effect in the hip

Bisphosphonates Binds to bone Inhibits osteoclast activity Supports osteoblast bone formation First line treatment for osteoporosis

Bisphosphonates Alendronate (Fosamax) generic Risedronate (Actonel) better GI profile Ibandronate (Boniva) no hip protection Zoledronic Acid (Aclasta) once a year

Unusual Complications of BisPO4s Osteonecrosis of jaw- Rare 1/100,000 patient years 94% in cancer patients receiving zoledronic acid or pamidronate Woo S-B, et al. 2006 Ann Int Med 144(10):753-61

Atypical # 5/10,000; risk: > 5 yrs Rx NEJM 364;18 nejm.1730 org may 5, 2011

Strontium ranelate In women with postmenopausal osteoporosis: Recent indication: Severe osteoporosis 3rd line used to be alternative to bisPO4s: elderly if potential for GI complications Beware rash (DRESS), VTE & MI Contraindication: IHD, PVD, & CVA Protelos is indicated for patients with postmenopausal osteoporosis: As a first line alternative to bisphosphonate therapy, particuarly in the elderly In those with a history or potential for upper gastrointestinal complications In women who have tried/failed (intolerance or inadequate response) treatment with other osteoporosis therapies. MHRA Drug Safety Update 2013; 6(9). 48

Denosumab (Prolia) Monoclonal Ab to RANKL which drives osteoclasts Subcut every 6/12! 60mg Dramatic and quick effect Fracture reduction similar to Zoledronate Used in renal failure

Parathyroid Hormone (PTH) Forteo (Teriparatide) 3rd line, use for 18 months Daily 20mg or 0.08ml SQ injection Intermittent antiresorptive effect Preferential osteoblast>osteoclast activity

Convenience/ patient choice PROLIA®: REAL WORLD Factors influencing treatment Efficacy Adherence Cost Convenience/ patient choice Safety/ tolerability

Osteoporosis Prevention and Treatment Hormonal Replacement SERM Treatment choice Bisphosphonates Strontium PTH Vitamin D Life Style 20 40 60 80 Age 52

Summary of Medications Bisphosphonates- First line therapy Must have GFR > 30 Denosumab, 2x/yr useful in low eGFR Strontium 3rd line C/I IHD PTH 3rd line use <2yrs Estrogen for post-menopause symptoms SERM: spine only

OP: When to refer to Specialist? Rx side effects Other complex medical conditions Inadequate response to Rx Vertebral fracture <50 years Identified secondary cause Continue to # with ‘normal’ BMD http://ebooks.adelaide.edu.au/dspace/bitstream/2440/39778/1/hdl_39778.pdf

Calcium/Vitamin D Controversies Ca/Vit D tablets –harm/benefit

Background 36, 282 postmenopausal WHI 1 G Ca + 400 IU VitD or Placebo for 7 years Baseline: 20,000 on personal Ca Baseline: 16,000 no Ca Bolland MJ et al. BMJ 2011 9;342:d2040

RESULTS NO Personal Calcium Use ANY Personal Calcium Use Event CaD N=8429 Placebo N=8289 HR 95% CI P HR 95% CI MI 209 168 1.2 (1-1.5) 0.05 180 196 0.92 (0.75-1.1) 0.44 CVA 163 (0.9-1.4) 0.14 156 189 0.8 (0.7-1) 0.08 MI/ CVA 386 326 1.16 (1-1.4) 324 370 0.9 (0.76-1) 0.09 Bolland MJ et al. BMJ 2011 9;342:d2040

Bolland MJ et al. BMJ 2011 9;342:d2040. 58

Bolland MJ et al. BMJ 2011 9;342:d2040.

Incidence of MI/CVA in Subjects on Calcium Bolland MJ et al. BMJ 2011 9;342:d2040.

Ca-VitD Incidence of Death Bolland MJ et al. BMJ. 2010;341:c3691.

Making Sense of the Results 1000 treated with Ca + Vit D for 5 years MIs 4X Stroke 4X Death 2X 3 fractures would be prevented

Calcium: Risk of Death Men vs Women Xiao Q et al. JAMA Intern Med. 2013;173(8):639-46.

Calcium: Risk of Death Men vs Women Xiao Q et al. JAMA Intern Med. 2013;173(8):639-46

Implication for Clinical Practice Recommendation for widespread use of Ca Rx no longer appropriate Calcium/vitamin D-rich diet favoured Further studies needed

Bone Health Building Blocks

Conclusion Osteoporosis is a growing epidemic Preach prevention! DEXA for all women >65, and others Treat all elderly, and patients at risk, with diet-rich Calcium and Vitamin D Don’t be afraid of bisphosphonates

Thank You