Osteoporosis

1. Osteoporosis Clinical cases and literature review Catherine Bakewell, MD

2. Quick overview • Definition—(per WHO) normal bone density is a value within one standard deviation of the mean value in young adults of the same sex and race. • BMD btw 1 and 2.5 standard deviations below the mean is defined as osteopenia, • BMD > or = 2.5 standard deviations below the mean is defined as osteoporosis (and is associated with skeletal fragility)

3. Risk Factors • History of fragility fracture in a first-degree relative • Low body weight (less than 58 kg [127 lb]) • Current cigarette smoking • Female sex • Estrogen deficiency at an early age (menopause before age 45 years or bilateral ovariectomy, prolonged premenopausal amenorrhea [greater than one year]) • White race • Advanced age • Lifelong low calcium intake • Alcoholism • Inadequate physical activity • Recurrent falls • Dementia • Impaired eyesight despite adequate correction • Poor health/frailty • Medical conditions: chronic obstructive pulmonary disease, gastrectomy, hyperparathyroidism, hypogonadism, multiple myeloma, celiac disease • Glucocorticoid therapy for more than three months • Other drugs: anticonvulsants, GnRH agonists, lithium, excessivedoses of thyroid hormone

4. Screening • BMD should be measured in all postmenopausal women < 65 y.o. who have one or more risk factors for osteoporosis. • Measurement of BMD is also recommended for all women 65 years and older.

5. Mrs. T • A 53 year old woman presents to your clinic with concerns about osteoporosis, and she is requesting screening. • What do you want to know?

6. Mrs T. (cont) • You decide to get a DXA scan, which shows: • A total T score of –2.0 at the hip, and –1.7 at the spine. • She complains of some height loss, but a chest X-ray is negative for compression fractures.

7. Treatment of Osteopenia • You tell her she should take calcium and vitamin D supplementation. • She asks “didn’t they just do a study that showed that that didn’t work? I thought I read something about that in the paper.”

8. EBM • Jackson et al, N Engl J Med. 2006. “Calcium plus Vitamin D supplementation and the risk of fractures.” • Design: Randomized, placebo-controlled trial, 36K women at 40 different sites, healthy, postmenopausal aged 50 – 70 years (of note, corticosteriod use was an exclusion criteria). Mean follow up period: 7 years. • Intervention: CaCO3 1000mg plus Vitamin D 400 IU daily. Personal use of calcium, vitamin D, bisphosphonates, and calcitonin was allowed. 52% of women were taking HT at baseline. • Outcomes: no difference in number of hip, wrist, vertebral, or total fractures. At year 6, Calcium plus vitamin D did increase BMD by 0.9% at the hip but not at the spine. • Conclusions: No significant benefit, slight increase in risk of kidney stones

9. Problems? Flaws?

10. Study limitations • Although not statistically significant, treated women did have 12% fewer hip fractures, the type of fracture associated with the largest morbidity and mortality. Plus bone density at the hip increased slightly. • Women in this trial were also at low risk; many had already had the benefits of taking large amounts of calcium and vitamin D, and more than half were taking hormone therapy. • Vitamin D dosing was potentially inadequate (further discussion to follow) • 40% of women in the intervention group did not take the supplements

11. What doses do you recommend?

12. Vitamin D • Bishoff-Ferrari et al. performed meta-analysis (JAMA 2005) • 12 studies included: examined efficacy of different doses of Vitamin D • Conlusion: oral Vit D btw 700-800 IU/d reduces risk of non-vertebral fractures; 400 IU/d is not sufficient.

13. Calcium • To maintain neutral calcium balance: • 1,000mg/d for premenopausal women • 1,500 mg/d for postmenopausal women

14. Counselling • Mrs. T needs to be counselled re:

15. Bisphosphonates for Osteopenia • Should Mrs. T be started on Fosamax?

16. Physiologic effects • * Decreased bone resorption * Decreased bone formation by 70-95% * Increased mineralization density * Slight increase in bone volume * Increase bone strength first 5 years * Decreased fracture rate first 5 years,compared to placebo * Half-life in bone greater than 10 years * Long-term effects on bone unknown

18. Guidelines • National Osteoporosis Foundation recommends tx for women with T < -2.0 or < -1.5 with risk factors.

19. Schousboe et al, 2005 • Modeled cost-effectiveness of treating osteopenic women with alendronate for 5 years. • Compared cost per quality-adjusted life-year (QALY) of tx vs not tx women aged 55 - 75, femoral neck scores of – 1.5 to – 2.4. • Costs ranged from 74 K to 322K per QALY gained.

20. Conclusions • Therapy only deemed cost effective in women who had risk factors unrelated to BMD, such as dementia, visual impairment, or frequent falls. • Current recommendation is to reserve bisphosphonates for women with T scores of –2.5, or those with osteopenia and pathologic fracture.

21. Mrs T. Goes Home • So you decide that Mrs. T should start with supplementation and lifestyle modification, and undergo repeat DEXA scan in 2 years time.

22. What about other therapies? • Calcitonin • SERMs • Estrogen • Intermittant PTH

23. Calcitonin • produced by cells in the thyroid gland • acts directly on osteoclasts to stop bone resorption • Taken as a nasal spray (Miacalcin), dose 200 units per spray (per day) • More expensive than bisphosphonate • Very safe, moderately effective

24. Estrogen • Reasonable to start under age 60 (or for first ten post-menopausal years). • Most physicians only recommend for treatment of post menopausal symptoms. • Excellent at maintaining bone mineral density. • Consider switching to SERM after 5 – 10 years.

25. Selective Estrogen Receptor Modulators (ex:Raloxifene) • Prevents vertebral osteoporotic fractures in women with osteoporosis, and stabilizes bone density. • Physiological substitute for estrogen at the bone. • Increased risk of thrombosis. • Can worsen menopausal symptoms.

26. Ms. B • Ms B is a 67 yr old woman with a T-score of –3. You have had her on Ca, Vit D, and Boniva(due to her awful GERD) for 2 years now. She develops the acute onset of thoracic back pain, and CXR reveals a new compression fracture. • What are you going to do?!

27. Intermittent PTH • Recombinant (1-34) variant FDA approved in 2002, stimulates both osteoclasts and osteoblasts. • Intermittent spikes of PTH stimulate more bone formation than resorption. • Administered at a dose of 20 mcg/day SC for 18 to 24 months. • After discontinuation,patients should be treated for the next two years with an anti-resorping medication; otherwise the bone density will decrease. • Other doses, durations are being experimented with, but not officially approved.

28. Mrs. S • Mrs. S is a 78 year old woman with osteoporosis (T score –2.6 at the hip by DEXA 2 years ago) on Fosamax 70 mg weekly. • She is concerned because she has heard about reports of dead jaw bone in people on this medication. • What do you say to her?

29. Woo et al, Annals, 2006 • Systematic review– Bisphosphonates and Osteonecrosis of the Jaws • 368 patient cases • Strongly assoc with use of aminobisphosphonates (IV preparation), for people with malignancy, related to severe suppression of bone turnover • 94% of pts tx with pamidronate or zoledronic acid or both

30. Osteonecrosis, cont • 85% of affected patients have metatstatic breast cancer or multiple myeloma. Only 4% have osteoporosis. • For pts with cancer receiving IV bisphosphonate, prevalence 6 – 10%. • In pts on alendronate for osteoporosis, prevalence unknown. • 60% of all cases occur after dental surgery (such as tooth extraction), the remaining 40% are assoc with denture or physical trauma.

31. Osteonecrosis, cont

32. Osteonecrosis, cont

33. Osteonecrosis, cont

34. Mrs S. • You can reassure Mrs. S that her chances of osteonecrosis are very, very low. • However, (for other patients) it is reasonable to hold off on initation of bisphosphonate until after necessary dental procedures.

35. Ms. W • Ms W is a charming 45 year old woman with rheumatoid arthritis, who has been on low dose prednisone (5mg/day) for 10 years now. • What is her risk of osteoporosis?

36. Glucocorticoid induced bone loss • Unlike other agents that increase bone loss (thyroxine, sustained PTH), glucocorticoids accelerate resorption while inhibiting bone formation. • Patients beginning on high dose prednisone (mean 21mg/day) lost a mean of 27% of their L-spine in one year (Reid et al, 1990). • Luckily, the decline in BMD slows thereafter.

37. Mechanisms for glucocorticoid induced osteoporosis

38. General guidelines • Keep duration of therapy as short as possible • Consider high dose pulse therapy rather than tx for weeks or months • Don’t forget the basics (weight bearing exercise, smoking cessation, minimize alcohol)

39. Screening • Measure baseline BMD if it is anticipated that a patient will be on glucocorticoids for > 3 mo. • DEXA repeated yearly if on preventative therapy.

40. Supplementation • Adequate Calcium and vitamin D supplementation appear to largely negate the effects of low dose (up to 10mg/day) steroid administration. (Buckley et al, 1996; Saag et al, 1998). • Recommended supplemenation doses that for postmenopausal women: 1500mg Calcium plus 800IU of Vitamin D.

41. HRT • For premenopausal women with oligo or amenorrhea on steroids, the ACR recommends addition of oral contraceptive. • For men with testosterone deficiency (decreased libido, fatigue) consider testosterone supplementation.

42. Bisphosphonates • Should be initiated on essentially everyone initiating long-term glucocorticoid therapy (>5mg/day for >3 months) except those on HRT (unless pt has fxr on HRT) or premenopausal women who may become pregnant. • ACR Recommendations (2001 Update)

43. What would Schousboe say? • Given the high costs of bisphosphonate for prevention, perhaps a better strategy would be: • DEXA at baseline and yearly • Start bisphosphonate tx only if BMD is abnormal (T score < -1.0). • Alendronate 35mg weekly for prevention, and 70mg weekly for treatment.

44. Calcitonin • Consider calcitonin if bisphosphonate contraindicated or not tolerated. • May also reduce pain from prior fractures.

45. Thiazides • Measure urinary calcium excretion. • Thiazide diuretics (and salt restriction) shown to decrease calcium excretion. • Enthusiasm tempered by lack of evidence that thiazides increase BMD in pts on corticosteriods.

46. Ms W. • Should have a DEXA scan at the hip and lumbar spine. • Should be on Calcium and Vit D. • Add bisphosphonate if T score < -1.0. • Consider addition of thiazide, especially if hypertensive or she has elevated urinary calcium excretion. • Evaluate for estrogen deficiency.

47. References • Bischoff-Ferrari HA, Wellet WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randonized controlled trials. JAMA 2005; 293:2257-64. • Buckley LM, Leib ES, Cartularo KS, et al. Calcium and Vitamin D3 supplementation prevents loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. Ann Intern Med. 1996; 125: 961. • Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-83. • Laan, RF, Van Riel, PL, Van de Putte, LB, et al. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. Ann Intern Med 1993; 119:963 • Ott S. Osteoporosis and bone physiology: description, diagnosis, treatment, and explanation of underlying physiology. Retrieved on September 26th, 2006 from University of Washington Web Site: http://courses.washington.edu/bonephys/ • Primer on the Rheumatic Diseases. 12th Ed. Atlanta, GA: Arthritis Foundation; 2001: 511-27; 596. • Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum 2001; 44:1496. • Reid, IR, Heap, SW. Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy. Arch Intern Med 1990; 150:2545. • Saag KG, Emkey R, Schnitzer TJ et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. N Engl J Med. 1998; 339: 292. • Schousboe JT, Nyman JA, Kane RL, et al. Cost-effectiveness of aldenronate therapy for osteopenic postmenopausal women. Ann Intern Med. 2005;142: 734 – 41. • Woo SB, Hellstein JW, Kalmar JR. Systematic review: Bisphosphonates and Osteonecrosis of the Jaws. Ann Intern Med. 2006;144:753-761.