OSTEOPOROSIS

1. OSTEOPOROSIS Dr. Edward Warren Chair, Geriatrics Carolinas Campus May 2012

2. Objectives • Define osteoporosis. • Apply knowledge of risk factorsof osteoporosis to patient evaluation and management. • Discuss diagnosis of osteoporosis. • Discuss fractures associated with osteoporosis. • Treat osteoporosis optimally. • Prevent osteoporosis effectively.

3. Osteoporosis • A reduction in bone mass with an increased risk and ease of fractures • Loss of bone tissue results in a deterioration of skeletal microarchitecture

4. Osteoporosis • Increased “porosity” of bone • Prevalence = 10,000,000 in the US only a minority of these are diagnosed and treated

5. Osteopenia • Osteopenia=low bone density • “penia” from Greek “penes”, related to “penury” meaning “poor”. • Osteopenic women have more than 50% of the fractures postmenopause. • Prevalence = 18,000,000 in the US

6. PrevalenceUnderdiagnosed & Undertreated in ALL! • Osteopenia in Caucasians & Asians • Women 52% • Men 35% • Osteoporosis in Caucasians & Asians • Women 20% • Men 7% • Hispanic women are catching up fast! • Blacks have 40% less fractures, but more fatalities!

7. Bone Remodeling • Bone repairs itself by constant, active remodeling • bone reabsorption (osteoclasts) • bone formation (osteoblasts) • The remodeling cycle may become unbalanced • after menopause • with aging in both men and women • bone reabsorption rate exceeds bone formation rate: weeks vs months • net bone loss is predominantly cancellous (trabecular) bone.

8. Lifetime Changes in Bone Mass

9. Risk Factors • Personal fracture • 1° relative fracture • Female gender • Advanced age • Caucasian/Asian • Low Ca intake • Vitamin D deficiency • Low hormone levels • Tobacco abuse • Alcohol Abuse • Sedentary Lifestyle • Frailty • Ectomorphic • Certain medications • Certain diseases

10. Risk Factors: Medications • Anticonvulsants • Warfarin • Glucocorticoids • Lithium • Neuroleptics • Medroxyprogesterone • Excess levothyroxine • Excess Vitamin A • Excess Vitamin D • PO4 binding antacids: Aluminum hydroxide • Aromatase Inhibitors & GnRH Antagonists (for CA prostate) • Immunosuppressants& Cytotoxins (i.e. MTX)

11. Risk Factors: Diseases • Cushing’s Disease • Addison’s Disease • 1° Hyperparathyroidism • Hyperthyroidism • Hypogonadism • Multiple myeloma • Leukemias • Sickle Cell • Osteomalacia • Paget’s Disease • COPD • Vitamin D deficiency • Malabsorption syndromes • Malnutrition • RA, Lupus • Diabetes Mellitus • Renal Failure

12. Risk Factors: Ca & Vitamin D • Calcium, vitamin D & parathyroid hormone maintain bone homeostasis. • Low Ca in diet or malabsorption of it leads to 2° hyperparathyroidism. • PTH is excreted when serum Ca is low, leading to increased bone resorption, decreased renal Ca excretion, and increased renal production of 1,25 dihydroxy-vitamin D. • Vitamin D increases absorption of Ca and P from the gut, and inhibits PTH synthesis.

13. Clinical Manifestations • Hip fractures • Vertebral and other Osteoporotic Fractures • Wrist fractures • Most any fracture you can think of • pelvis, head of the humerus, etc. • 1,500,000 fractures yearly in the US

14. HIP Fractures • Incidence doubles q5 years after age 70. • 300,000 hip fractures yearly in the US • Likelihood for a 50 year old Caucasian to fracture a hip is: 14% women, 5% men • African Americans are half as likely. • Only ⅓ have a full recovery. • 20% live in a nursing home lifelong.

15. HIP Fractures Complications: • Deep venous thrombosis • Pulmonary embolism • 5 – 20% mortality rate • 66% suffer permanent mobility loss • Doubles risk of future fractures.

16. Vertebral Compression Fractures • 700,000 yearly in the US • Many are asymptomatic • Height loss • Kyphosis • Back pain

18. Vertebral Compression Fractures • Thoracic compression fractures • Restrictive lung disease • Lumbar compression fractures • abdominal distention • early satiety • constipation

19. PEARL THE MOST IMPORTANT PART OF TREATMENT IS DIAGNOSIS.

20. Evaluation • Comprehensive H&PE as ALWAYS! • Measure bone mineral density: BMD • Assess for secondary causes of bone loss: UGH!

21. H&PE • FH: fractures, especially at early age • SH: tobacco, ethanol, activity, diet • PMH: prior fractures, risk factors, fragility fractures (with minimal force), vitamin D & calcium use • Elderly fall risk: balance, orthostatic hypotension, debility, poor vision, poor hearing, poor cognition

22. H&PE • BMI < 20 • kyphoscoliosis • vertebral point tenderness • height loss

23. Bone Mineral Density • Dual-energy X-ray Absorptiometry (DEXA, DXA) • highly accurate, standard in most centers • Single-energy X-ray Absorptiometry (SEXA, SXA, SEX?) • less accurate, less available • Quantitative CT • expensive, more radiation, less reproducible • gives true density • Ultrasound • cheap and mobile

24. Bone Mineral Density: DXA • Preferred method of measurement • Can measure hip, anterior-posterior spine, lateral spine, and wrist • Cost = $200 to $300 • Covered by Medicare and Medicaid at 24 month intervals on anyone

25. Bone Mineral Density: DXA • Two dimensional technique. • Two x-ray energies are used to measure the mineralization in an area. The mineral content is divided by this area. • Small people are rated spuriously low. • Machines vary from each other = problem

26. Bone Mineral Density: DXA • STASTICS TO THE RESCUE • A Bell-shaped curve is formed for each population by age, gender, and race. • T-score compares one to 30 year olds matched for gender and race. • Z-score compares one to age, gender, and race matched controls.

27. T-score graph The WHO has defined the following categories based on bone density in white women: Normal bone: T-score > -1 Osteopenia: -1 > T-score > -2.5 Osteoporosis: T-score < -2.5

28. National Osteoporosis Foundation Recommendations for DXA • Women > age 65 & Men > age 70 • Estrogen-deficient women with clinical risks • Osteopenia or vertebral fracture on x-ray • Fragility fractures • Patients with illness or medication that imparts risk > age 50 • Glucocorticoid treatment ≥7.5 mg of prednisone duration of therapy > 3 months • Primary hyperparathyroidism • Monitoring response to an FDA-approved medication for osteoporosis

29. Monitoring with DXA • Repeat BMD evaluations at > 2 year intervals since years are needed for any changes • Significant changes are 4% in spine and 6% in hips • Treatments do not often produce changes large enough to detect reliably • In those below age 50, use Z-scores. If < -2.0, then they are “below expected range”, and would need additional clinical criteria for a diagnosis.

30. FRAX • This is the WHO fracture risk algorithm • www.shef.uk/FRAX/ • Enter clinical data and get a fracture risk. • The National Osteoporosis Foundation advises treatment for 3% risk of hip fracture or 20% risk of osteoporotic fractures.

31. FRAX

32. Screening for Secondary Causes

33. Screening for Secondary Causes • ↑ Ca  hyperparathyroidism or malignancy • ↑ iPTH  hyperparathyroidism • ↓ iPTH  malignancy (↑ PTHrP suggests humoral hypercalemia of malignancy) • ↓ Ca  osteomalacia, malnutrition, or malabsorption

34. Screening for Secondary Causes • Cushing’s suspected  dexamethasone suppression test • Malnutrition suspected  albumen, prealbumen, cholesterol, CBC, vitamin B12, folic acid, Fe, TIBC  if low, then further evaluation needed • Myeloma suspected  serum protein electrophoresis, urine electrophoresis for light chains, and bone marrow exam • X-rays are for fracture documentation only.

35. Preventing and Treating Osteoporosis • Weight-bearing exercise: lifelong • Smoking cessation: lifelong • Ethanol moderation: lifelong • Calcium and vitamin D: dietary, sunlight, lifelong • Estrogen replacement • Bisphosphonates • Selective estrogen receptor modulators • Calcitonin • Others

36. Treatment Criteria • T-score < -2.5 • Any postmenopausal woman with risk factors regardless of T-score

37. Risk Factor Reduction • Glucocorticoids can be titrated to minimal effective doses. • Thyroid hormone doses need to be as low as needed to normalize TSH. • Smoking cessation. • Ethanol moderation.

38. Fall Risk Factor Reduction • Ethanol avoidance. • Reduce or eliminate sedating medications. • Protect against orthostatic hypotension. • Address nocturia. • Fix environmental hazards: wires, rugs, furniture, socks • Vision correction

39. Exercise • Decrease in physical activity or immobilization decline in bone mass • Walking, a weight-bearing exercise, can be recommended for all adults • Exercise  2% bone mass increase at best. NNT = 1600 • Start slowly and gradually increase the number of days and time spent walking each day (at least 3 days weekly) • Improves coordination, balance, and strength.

40. DOE’s vs POE’s • DOE = disease oriented evidence • 2% increase in bone mineral density • POE = patient oriented evidence • how many fractures are prevented

41. NNT • Alendronate reduces vertebral compression fractures 44%: relative risk. • Shun, reject, ignore relative risk. • Liars figure and figures lie. • At worst relative risk is used to fool you into believing something is better than it really is. • At best it is being presented by someone who does not know any better.

42. NNT • Alendronate reduces vertebral compression fractures 44% in 3 years • Placebo 3.9% fractures: alendronate 2.2% • Number Needed to Treat • 1.7% absolute reduction • 1.7/100 patients  reciprocal • NNT of 59 patients to prevent 1 fracture/3 years

43. NNT • “NNT” is well ensconced in the medical parlance and can be searched for on the internet with a drug name to find the value easily. • Bisphosphonates reduce hip fractures about 40%, relative risk. • About 1% of people over 65 have hip fractures yearly • Absolute reduction is thus 0.4% or 4/1000 • The reciprocal of 0.004 is NNT = 250 • Is it worth $250,000 to prevent one hip fracture a year?

44. Calcium & Vitamin D • Calcium and vitamin D maintain or increase bone density in postmenopausal women & help prevent hip and nonvertebral fractures in all older adults. • Calcium has no benefit on fracture rate used alone. • Vitamin D: NNT = 45 to prevent a hip fracture over 3 years. • 1200 mg / day of calcium: men 65 years and older & postmenopausal women. • 1000 IU / day of vitamin D3: regardless of sunlight exposure to offset skin changes that  efficient use of UV light to synthesize vitamin D precursors. (I start with 4000 units qd.) • Calcium has no harmful cardiac effects.

45. Estrogen Replacement • Estrogen produces bone loss protection. • All benefit is lost in 10 years if stopped. • 10,000 treated women in 1 year • 8 extra MI’s 18 extra DVT’s • 8 extra CVA’s 6 fewer CA colon • 5 fewer hip fractures 44 fewer fractures • neutral death rate (voided by progesterone) • NNT 385 for hip fractures over 3 years

46. Estrogen Replacement • SERMS (selective estrogen response modulators) • Tamoxifen reduces bone turnover and CA breast, but it increases uterine CA. • Raloxifene reduces vertebral collapse as well as CA breast. NNT is 22 in 4 years for a vertebral fracture.

47. Bisphosphonates • Structurally related to pyrophosphates which are incorporated into bone matrices where resorption is active. • Impair osteoclast function. • Poorly absorbed: bioavailability only 5%. • Reduce osteoclast number by apoptosis • NNT for hip fracture 77 – 91 in 3 years • NNT for vertebral fracture 13 – 20 in 3 years • Side effects: dyspepsia & esophageal perforation • Incapacitating bone pain, arthralgia, and myalgia can occur any time.

48. Bisphosphonates: Alendronate • In comparison with placebo: •  bone density of spine (8%) & hip (3.5%) – DOE’s •  vertebral & hip fracture rate by 50% at 2 years • NNT 37 for vertebral fractures in 3 years – POE • Dosing for Prevention: Once-weekly 70 mg po: $102/month • Side effects • GI: abdominal pain, dyspepsia, esophagitis, nausea, vomiting, diarrhea • Musculoskeletal pain

49. Bisphosphonates: Zoledronic Acid • Most potent. Given by yearly IV infusion. • In comparison with placebo: •  bone density of spine (5.1%) & hip (3.5%) – DOE’s •  vertebral & hip fracture rate by 70% and 41% respectively at 3 years • NNT 107 for vertebral fractures in 3 years – POE • NNH (number needed to harm) = 100 • Cost $1250/year • Side effects • GI: abdominal pain, dyspepsia, esophagitis, nausea, vomiting, diarrhea • Musculoskeletal pain

50. Other Bisphosphonates • Risedronate • Approved for osteoporosis: 35 mg po weekly: $130/month • In comparison with placebo: •  bone density of spine (5.4%) & hip (1.6%) – DOE’s •  new vertebral & hip fracture rate of 50% – relative risk • GI side effects • Ibandronate: similar: $470/3 months • Benefits lost 1 year after stopping • NNT = 13 – 20 over 3 years for vertebral fracture • Death rates equal in drug and placebo groups