Update: Osteoporosis

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  • Country specific
  • NOF clinicians guide : Endorsed by: AA clinical endocrinologists ACOG AC radiology AC rheumatology American Geriatric Society American orthopedic assn
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  • RISK Factors : weighted.
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  • Medicare coverage : Including but not limited to. ≥ 5mg daily for 3 months.
  • Update: Osteoporosis

    1. 1. Update in Osteoporosis Teresa Bryan, M.D. General Medicine Noon Conference February 24, 2009
    2. 2. Objectives <ul><li>WHO Task Force Fracture Risk Assessment Tool (FRAX) </li></ul><ul><li>NOF Guidelines for pharmacologic intervention in postmenopausal women and men ≥ age 50 </li></ul><ul><li>ACP Practice Guidelines for Screening in Men </li></ul><ul><li>ACP Practice Guidelines for Pharmacologic Therapy </li></ul><ul><li>Association of Atrial fibrillation with bisphosphonates </li></ul><ul><li>Bisphosphonate associated osteonecrosis of the jaw </li></ul>
    3. 3. Background <ul><li>Estimated 44 million Americans </li></ul><ul><li>55% people 50 years of age or older </li></ul><ul><li>1 out of every 2 Caucasian women will experience osteoporotic fracture and 1 out of every 5 men. </li></ul><ul><li>Hip fractures result in 10-20% excess mortality in 1 year. </li></ul><ul><li>20% hip fracture patients require long-term nursing home care. </li></ul>
    4. 4. US Preventive Services Task Force Recommendations Ann Int Med. 2002;137:526-528 <ul><li>Routinely screen women 65 years of age and older. </li></ul><ul><li>Screen women at increased risk beginning at 60 years of age. </li></ul><ul><li>No recommendation for or against routine screening in women younger than 60 years of age. </li></ul>
    5. 5. Definitions <ul><li>Osteoporosis : a skeletal disorder characterized by compromised bone strength predisposing to an increased risk for fracture. Diagnosed by: </li></ul><ul><ul><li>Occurrence of fragility fracture </li></ul></ul><ul><ul><li>Osteoporosis by DXA criteria </li></ul></ul><ul><li>Osteoporotic fracture : (fragility fracture) those occurring from a fall from a standing height or less without major trauma such as a MVA. </li></ul>
    6. 6. Dexa Interpretation <ul><li>T score : Difference in SDs compared to value of young adults same sex. </li></ul><ul><li>Z score : Difference in SDs compared to value of individuals same age and sex. </li></ul><ul><li>Osteoporosis : T score ≤-2.5 </li></ul><ul><li>Osteopenia : T score between -1 and -2.5 </li></ul><ul><ul><ul><li>SD=Standard Deviation </li></ul></ul></ul>
    7. 7. Osteoporotic Risk Assessment <ul><li>Majority of fracture occur in those with low bone mass rather than osteoporosis </li></ul><ul><li>WHO Fracture Risk Assessment Tool (FRAX) </li></ul><ul><li>Considers 9 clinical risk factors for osteoporosis </li></ul>
    8. 8. FRAX Risk Factors <ul><li>Age </li></ul><ul><li>Previous Fracture </li></ul><ul><li>Parent with h/o hip fracture </li></ul><ul><li>Current smoking </li></ul><ul><li>Glucocorticoids > 3 months </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Secondary osteoporosis </li></ul><ul><li>Alcohol 3 or more units daily </li></ul><ul><li>Bone Mineral Density </li></ul>
    9. 9. WHO Fracture Risk Assessment Tool (FRAX) http://www.shef.ac.uk/FRAX/
    10. 10. WHO Fracture Assessment Tool http://www.shef.ac.uk/FRAX/
    11. 11. Applications of FRAX in US <ul><li>Not intended for young adults or children </li></ul><ul><li>Only applies to previously untreated patients </li></ul><ul><li>Total hip density may be substituted for femoral neck BMD </li></ul><ul><li>Convert T score based on reference standard used in FRAX </li></ul>
    12. 12. Cost-effectiveness <ul><li>Intervention threshold: 10 year fracture probability 2.5 to 4.9% </li></ul><ul><li>Assumes annual treatment cost of $600 </li></ul><ul><li>“Willingness to pay” threshold of $60,000 per QALY gained </li></ul>Osteoporosis International Dec 2007 http://www.nof.org/professionals/Cost-effective_osteoporosis_%20treatment_US.pdf
    13. 13. http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf
    14. 14. National Osteoporosis Foundation Screening Recommendations <ul><li>Women 65 and older </li></ul><ul><li>Men 70 and older </li></ul><ul><li>Postmenopausal and perimenopausal women with increased risk factor profile (low body wt, prior fx, meds) </li></ul><ul><li>Men 50-70 with increased risk factor profile </li></ul><ul><li>Fracture after age 50 </li></ul><ul><li>Consider in postmenopausal women discontinuing estrogen. </li></ul>
    15. 15. Risk Factors NEJM 2008;358:1474-82.
    16. 16. Secondary Osteoporosis <ul><li>Type 1 DM </li></ul><ul><li>Osteogenesis imperfecta </li></ul><ul><li>Untreated, longstanding hyperthyroidism </li></ul><ul><li>Hypogonadism </li></ul><ul><li>Premature menopause <45 year. </li></ul><ul><li>Chronic malnutrition </li></ul><ul><li>Malabsorption </li></ul><ul><li>Chronic liver disease </li></ul><ul><li>Meds: anticonvulsants, heparin, glucocorticoids </li></ul>
    17. 17. Clinical Assessment of Osteoporosis in Postmenopausal Women and Men >50 <ul><li>History and physical exam </li></ul><ul><li>Consider laboratory tests: (esp if Z<2.0) </li></ul><ul><ul><li>Ca, phos, Cr, LFTs, TSH, CBC, VIt D level </li></ul></ul><ul><ul><li>Testosterone level in men </li></ul></ul><ul><li>If clinically indicated: </li></ul><ul><ul><li>SPEP, Urine cortisol, Urine calcium, anti-tissue transglutaminase antibodies (Celiac sprue) </li></ul></ul>
    18. 18. Pharmacologic Therapy (NOF Recommendations for Postmenopausal Women and Men >50) <ul><li>Hip or vertebral fracture </li></ul><ul><li>T score ≤ -2.5 femoral neck, total hip or spine </li></ul><ul><li>T score -1 to -2.5 hip or spine: </li></ul><ul><ul><li>10 year hip fx probability ≥ 3%* </li></ul></ul><ul><ul><li>10 year all major osteoporosis related fx probability ≥ 20% * </li></ul></ul>*WHO absolute fracture risk model
    19. 19. Case <ul><li>57 year old woman. Healthy. </li></ul><ul><li>FH: 80 year old mother with mult vertebral fx and “hump” in her back </li></ul><ul><li>Prior fx: cervical spine when fell off bed playing with grandson </li></ul><ul><li>No smoking, no ETOH, no prior prednisone, no RA or secondary causes </li></ul><ul><li>Weight: 155 lb Height 5ft 6 in </li></ul>
    20. 20. Case (cont) <ul><li>T score -2.4 </li></ul><ul><li>Frax assessment tool : 10 year probability of fx </li></ul><ul><ul><li>Major osteoporotic : 21% </li></ul></ul><ul><ul><li>Hip : 4.9 </li></ul></ul>
    21. 21. Universal Recommendations <ul><li>Adequate intake of calcium and vitamin D: </li></ul><ul><ul><li>Adults > 50: 1200 mg elemental calcium /day </li></ul></ul><ul><ul><li>All adults > 50: 800-1000 IU/day </li></ul></ul><ul><li>Regular Weight Bearing Exercise: </li></ul><ul><ul><li>At least 30 min 3x weekly </li></ul></ul><ul><li>Fall prevention strategies: </li></ul><ul><ul><li>Correct vision and hearing problems </li></ul></ul><ul><ul><li>Evaluate neuro problems </li></ul></ul><ul><ul><li>Review meds for Side effects </li></ul></ul><ul><li>Avoid tobacco and alcohol </li></ul>
    22. 22. Treatment Options FDA Approved <ul><li>Bisphosphonates </li></ul><ul><li>Estrogen </li></ul><ul><li>SERMS (Selective Estrogen Receptor Modulators) </li></ul><ul><li>Calcitonin </li></ul><ul><li>Forteo (parathyroid hormone) </li></ul>
    23. 23. Bisphosphonates <ul><li>Alendronate (fosamax): 10 mg qd or 70 q week </li></ul><ul><li>Risedronate (actonel): 5 mg qd or 35mg q week </li></ul><ul><li>Ibandronate (Boniva): 2.5mg qd, 150 mg q month, 3mg IV q3 months </li></ul><ul><li>Zolendronic acid (Reclast): 5mg IV yearly </li></ul><ul><li>Treatment efficacy: </li></ul><ul><ul><ul><li>Bisphosphonates decrease risk vertebral fracture by approx 50% </li></ul></ul></ul><ul><ul><ul><li>Risk of hip fracture decreased by 37% </li></ul></ul></ul>
    24. 24. Estrogen Agonists/Antagonists (Formerly SERMS) <ul><li>Raloxifene (Evista) </li></ul><ul><li>Decreased vertebral fx 30%-55% </li></ul><ul><li>60 mg qd </li></ul><ul><li>Increase risk DVT </li></ul><ul><li>No effect on endometrium </li></ul><ul><li>Decreases risk of breast cancer </li></ul><ul><li>Causes hot flashes (6%) </li></ul>
    25. 25. Calcitonin <ul><li>Miacalcin: nasal, SQ or IM </li></ul><ul><li>200 IU intranasally qd </li></ul><ul><li>25-39% reduction vertebral </li></ul><ul><li>Possible analgesic action for acute osteoporotic fracture </li></ul>
    26. 26. PTH (Teriparatide) <ul><li>Forteo 20 ug SQ daily </li></ul><ul><li>Previous failed therapy </li></ul><ul><li>Decrease vertebral fx 65% </li></ul><ul><li>Osteosarcoma in rats </li></ul><ul><li>Expensive </li></ul>
    27. 27. Estrogen <ul><li>FDA approved </li></ul><ul><ul><li>Osteoporosis prevention </li></ul></ul><ul><ul><li>Vasomotor symptoms </li></ul></ul><ul><ul><li>Vulvovaginal atrophy </li></ul></ul><ul><li>Progesterone combination if no hysterectomy </li></ul><ul><li>Risk MI/Stroke/Breast CA </li></ul><ul><li>Consider non-estrogen treatment first </li></ul>
    28. 28. Monitoring Effectiveness <ul><li>Monitor and encourage compliance </li></ul><ul><li>Review risk factor modification </li></ul><ul><li>Calcium and vitamin D intake </li></ul><ul><li>Repeat BMD q 2 years (medicare guidelines) </li></ul>
    29. 29. Osteoporosis in Men <ul><li>1.5 million men over age 65 in US have osteoporosis </li></ul><ul><li>Mortality with hip fractures higher in men up to 37.5% </li></ul><ul><li>Absolute BMD in men who fracture hip is higher than in women. </li></ul><ul><li>Prevalence: </li></ul><ul><ul><li>7% white men </li></ul></ul><ul><ul><li>5% black men </li></ul></ul><ul><ul><li>3% Hispanic men </li></ul></ul>
    30. 30. Case <ul><li>68 year old WM </li></ul><ul><li>COPD </li></ul><ul><li>Stopped smoking 9 years ago </li></ul><ul><li>2 prior pred tapers x 2 weeks </li></ul><ul><li>Wt 180 lb, Ht 5 ft 8in </li></ul><ul><li>No alcohol, RA </li></ul><ul><li>FH negative </li></ul><ul><li>Frequent yard work </li></ul>
    31. 31. ACP Guidelines for Screening in Men Risk Factors <ul><li>Age >70 years </li></ul><ul><li>Low body weight (BMI<20-25 kg/m 2) </li></ul><ul><li>Weight loss > 10% </li></ul><ul><li>Physical inactivity </li></ul><ul><li>Use of oral corticosteroids </li></ul><ul><li>Previous fragility fracture </li></ul>Ann Intern Med 2008;148:680-684.
    32. 32. Common Secondary Causes in Men <ul><li>Cushing’s or steroid therapy </li></ul><ul><li>Excessive alcohol use </li></ul><ul><li>Hypogonadism </li></ul><ul><li>Low calcium intake of Vit D insufficiency </li></ul><ul><li>Smoking </li></ul><ul><li>Family history of minimal trauma fracture </li></ul>Ann Intern Med 2008;148:680-684
    33. 33. ACP Guidelines in Men Recommendations <ul><li>1- Perform individualized assessment of risk factors for osteoporosis in older men (Strong recommendation; high-quality evidence) </li></ul><ul><li>2- Obtain DXA for men who are at increased risk for osteoporosis and are candidates for drug therapy (Strong recommendation; moderate-quality evidence) </li></ul><ul><li>3- Further research to evaluate osteoporosis screening tests in men </li></ul>Ann Intern Med 2008;148:680-684
    34. 34. Treatment in Men <ul><li>Treat secondary causes </li></ul><ul><li>Bisphosphonates reasonable first line </li></ul><ul><li>Teriparatide </li></ul><ul><li>Calcitonin </li></ul><ul><li>Raloxifene not well studied in men </li></ul>
    35. 35. Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the ACP (Ann Intern Med 2008;149:404-415.) <ul><li>What are the comparative benefits in fracture reduction among treatments for low bone density? </li></ul><ul><li>How does fracture reduction resulting from treatments vary among individuals with different fracture risks? </li></ul><ul><li>What are the short and long-term adverse effects and do these vary by specific subpopulations? </li></ul>
    36. 36. Effect of Bisphosphonates on Fracture Risk Reduction Annals 2008;149:404-415 ↓ ↓ ↓ Risedronate ↓ ↓ ↓ Zoledronic acid Not studied ↔ ↓ Ibandronate ↓ ↓ ↓ Alendronate Hip Nonvertebral Vertebral
    37. 37. Copyright restrictions may apply. Black, D. M. et al. JAMA 2006;296:2927-2938. BMD Change in FLEX Participants
    38. 38. Copyright restrictions may apply. Black, D. M. et al. JAMA 2006;296:2927-2938. Incidence of Fracture by Treatment Group
    39. 39. Effect on Fracture Risk Reduction Annals 2008;149:404-415 ↔ Not studied ↔ Tamoxifene ↔ ↔ ↓ Raloxifene modest ↓ modest ↓ modest ↓ Calcium +Vit D Not studied ↓ ↓ Teriparatide ↓ ↓ ↓ Estrogen Not studied ↔ ↓ Calcitonin Hip Nonvertebral Vertebral
    40. 40. MacLean, C. et. al. Ann Intern Med 2008;148:197-213 Risk for hip fractures relative to placebo for participants who are at high risk for fracture, by agent
    41. 41. MacLean, C. et. al. Ann Intern Med 2008;148:197-213 Risk for hip fracture relative to placebo for participants who are not at high risk for fracture, by agent
    42. 42. ACP Recommendations <ul><li>1- Offer pharmacologic treatment to men and women who have known osteoporosis and to those with h/o fragility fractures. (Strong recommendation; high-quality evidence) </li></ul><ul><li>2- Consider treatment for men and women at risk for developing osteoporosis. (weak recommendation; moderate-quality evidence) </li></ul><ul><li>3- Choose treatment options based on assessment of risk and benefit to individual patients. (Strong recommendation; moderate-quality evidence) </li></ul><ul><li>4- ACP recommends further research to evaluate treatment of osteoporosis in men and women. </li></ul>Ann Intern Med 2008;149:404-415
    43. 43. Risk of Afib with Bisphosphonates <ul><li>Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly -Pivotal Fracture Trial (HORIZON)* </li></ul><ul><li>RCCT: 7765 postmenopausal women with osteoporosis yearly zoledronic acid vs placebo x 3 yrs. </li></ul><ul><li>Significant reduction in hip and vertebral fractures </li></ul><ul><li>Increased incidence of Afib classified as serious adverse event ( 1.3% vs 0.4%) P<0.001 </li></ul><ul><li>Overall freq of AF no different in 2 groups (2.4 vs 1.9%) </li></ul><ul><li>Subsequent HORIZON-Recurrent Fracture Trial failed to find increased AF in treatment group. </li></ul>
    44. 44. Rate of AF serious adverse events Horizon-Pivotal Fracture Trial .09% 0.51% Year 3 .17% 0.53% Year 2 .29% 0.47% Year 1 Placebo Zoledronic Acid
    45. 45. Association of other Bisphosphonates with AF Risk <ul><li>Fracture Intervention Trial (FIT): RCCT of alendronate in 6459 postmenopausal women. Serious adverse AF events alendronate (1.5%) vs placebo (1.0%) P=.07 NEJM 2007;356:1895-1896. </li></ul><ul><li>Case control study : More AF patients (719) than controls(966) had ever used alendronate (6.5% vs 4.2%, P=.03) Arch Int Med. 2008;168(8):826-31. </li></ul><ul><li>Larger case control study in Denmark : No assn of bisphosphonate use with AF in 13,586 patients w/AF and 68,054 controls. (3.2% vs 2.9%) BMJ 2008;336:813-16. </li></ul>
    46. 46. Summary <ul><li>Some suggestion of increased AF serious adverse events with bisphosphonate therapy </li></ul><ul><li>Not a consistent finding </li></ul><ul><li>Prior RCCT were not designed to examine the occurrence of Afib. </li></ul><ul><li>Unlikely that there is causal relation between AF and bisphosphonates. </li></ul>
    47. 47. Case <ul><li>68 year old WF calls you saying that her dentist wants to extract a tooth, but he is very concerned because she is on alendronate 70mg weekly. She wants to know your opinion regarding her risk for ONJ. </li></ul><ul><li>PMH: 2 prior fragility fractures, T score <2.5 </li></ul><ul><li>MEDS: alendronate 70 mg x 8 years </li></ul>
    48. 48. ONJ
    49. 49. Bisphosphonate Associated ONJ: Definition <ul><li>Current or previous treatment with a bisphosphonate </li></ul><ul><li>Exposed, necrotic bone in the maxillofacial region > 8 weeks </li></ul><ul><li>No history of radiation therapy to the jaws </li></ul>American Academy of Oral and Maxillofacial Surgeons
    50. 50. Case Series 119 patients . J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75
    51. 51. Case Series 119 patients J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75
    52. 52. Epidemiology <ul><li>Annals systematic review: 368 ONJ patients </li></ul><ul><ul><li>84% with multiple myeloma or breast cancer </li></ul></ul><ul><ul><li>4% with osteoporosis </li></ul></ul><ul><ul><li>60% after dentoalveolar surgery </li></ul></ul><ul><ul><li>Remaining 40% probably related to infection, denture trauma or other trauma </li></ul></ul><ul><ul><li>Prevalence of ONJ in cancer patients 6-10% </li></ul></ul><ul><ul><li>Prevalence in osteoporosis patients unknown </li></ul></ul>Ann Intern Med 2006;144:753-761.
    53. 53. Epidemiology <ul><li>ASBMR task force review of case reports estimated risk as 1 in 10,000 to 1 in 100,000 patient years of treatment. </li></ul><ul><li>Post-marketing surveillance </li></ul><ul><ul><li>Merk: 170 cases/20 million patient years (0.7/100,000patient years) </li></ul></ul><ul><ul><li>Proctor and Gamble: 1/10,000 patient years </li></ul></ul><ul><li>RCCTs : </li></ul><ul><ul><li>No cases of ONJ reported alendronate, risedronate, ibandronate </li></ul></ul><ul><ul><li>HORIZON: 2 cases (control, and placebo equal) </li></ul></ul><ul><li>Population based prevalence studies : </li></ul><ul><ul><li>3 cases in 780,000 patients receiving bisphosphonates for osteoporosis. </li></ul></ul><ul><ul><li><1 in 100,000 patient-years </li></ul></ul>
    54. 54. Case <ul><li>Patient later informed you that she underwent procedure without incident. The dentist had drawn “blood-work” which indicated that her risk for ONJ was very low. </li></ul>
    55. 55. Bone Turnover Markers as Predictors of Risk? <ul><li>Serum levels of morning fasting C terminal telopeptide (CTX) </li></ul><ul><li>Based on data from 17 ONJ patients receiving bisphosphonates </li></ul><ul><ul><li><100 low risk </li></ul></ul><ul><ul><li>100-150 moderate risk </li></ul></ul><ul><ul><li>>150 high risk </li></ul></ul><ul><li>Limitations: </li></ul><ul><ul><li>No controls </li></ul></ul><ul><ul><li>Reduced markers of resorption expected in patients receiving bisphosphonates </li></ul></ul><ul><ul><li>Low normal range in healthy women falls within range proposed as high risk. </li></ul></ul>J Oral Maxillofac Surgery 2007;65:2397-2410
    56. 56. Clinical Application <ul><li>Risk of ONJ <1 in 100,00 patient years in non-cancer patients using bisphosphonate treatment suggests a positive benefit-risk profile. </li></ul><ul><li>All patients taking bisphosphonates should be informed of the benefits and risks of treatment. </li></ul><ul><li>Patients taking bisphosphonates should be encouraged to maintain good oral hygeine. </li></ul>
    57. 57. Summary <ul><li>Consider screening postmenopausal women and men over 50 at increased risk for osteoporosis </li></ul><ul><li>Educate patients on universal recommendations </li></ul><ul><li>Consider treating patients with: </li></ul><ul><ul><li>Prior fragility fracture </li></ul></ul><ul><ul><li>T<-2.5 </li></ul></ul><ul><ul><li>Osteopenic patients with elevated risk profile </li></ul></ul><ul><li>Review risk/benefit profile with all patients </li></ul>
    58. 58. Medicare Coverage for BMD Testing <ul><li>Estrogen deficient women at clinical risk </li></ul><ul><li>Individuals with vertebral abnormalities </li></ul><ul><li>Individuals receiving or planning to receive long term glucocorticoid therapy </li></ul><ul><li>Primary hyperparathyroidism </li></ul><ul><li>To assess response to therapy </li></ul>
    59. 59. Screening: Pros and Cons <ul><li>Pros: </li></ul><ul><ul><li>Common disease with significant morbidity </li></ul></ul><ul><ul><li>Screening methods available </li></ul></ul><ul><ul><li>Interventions available to reduce risk </li></ul></ul><ul><ul><li>Knowledge of risk could improve compliance </li></ul></ul><ul><li>Cons: </li></ul><ul><ul><li>Little direct evidence that screening improves outcome. </li></ul></ul><ul><ul><li>No cutoff value for BMD that delineates fracture risk. </li></ul></ul><ul><ul><li>Other risk factors may be more important than BMD </li></ul></ul><ul><ul><li>Cost efficiency issues </li></ul></ul><ul><ul><li>Knowledge of normal value may hinder compliance </li></ul></ul>
    60. 60. Non-FDA Approved Drugs <ul><li>Calcitriol </li></ul><ul><li>Other bisphosphonates: (etidronate, pamidronate, tiludronate) </li></ul><ul><li>Parathyroid Hormone (PTH-84) </li></ul><ul><li>Sodium Flouride </li></ul><ul><li>Strontium renelate </li></ul><ul><li>Tibolone </li></ul>
    61. 61. Adverse Effects of Drugs <ul><li>Bisphosphonates: </li></ul><ul><ul><li>Gastrointestinal: </li></ul></ul><ul><ul><ul><li>Esophageal ulcerations </li></ul></ul></ul><ul><ul><ul><li>Mild upper GI events (reflux, nausea) </li></ul></ul></ul><ul><ul><li>Osteonecrosis of the jaw: </li></ul></ul><ul><ul><li>Atrial fibrillation: </li></ul></ul><ul><ul><ul><li>Alendronate and zolendronic acid </li></ul></ul></ul>
    62. 62. Adverse Effects <ul><li>Estrogen </li></ul><ul><ul><li>Thromboembolic events </li></ul></ul><ul><ul><li>Breast cancer (estrogen + progesterone) </li></ul></ul><ul><li>Teripartide </li></ul><ul><ul><li>RCCTS  no evidence of serious adverse events </li></ul></ul><ul><li>SERMs </li></ul><ul><ul><li>Pulmonary embolism </li></ul></ul><ul><ul><li>Thromboembolic </li></ul></ul><ul><li>Calcium and vitamin D </li></ul><ul><ul><li>RCCTs no clinically important serious adverse events. </li></ul></ul>

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