Focusing on the Patient: Diagnosis and Management of Osteoporosis

Focusing on the Patient: Diagnosis and Management of Osteoporosis Learning Objectives After participating in this educational activity, participants should be able to: 1. Apply updated guidelines to assess patients for risk and properly diagnose osteoporosis in the clinic 2. Integrate measures into patient s treatment plans to prevent osteoporosis and osteoporosis-related fractures 3. Assess the benefits and risks of current treatment options for osteoporosis and understand the importance of monitoring patients after the initiation of treatment 4. Apply knowledge gained from this program to optimize patient adherence to treatment plans

Introduction Osteoporosis, characterized by low bone mass, deterioration of bone tissue, compromised bone strength, and susceptibility to fractures, is a common condition affecting almost 10 million adults in the United States. An additional 43 million individuals have low bone density.[1,2] One of every two Caucasian women in the United States will have an osteoporotic fracture in their lifetime; one out of every 5 men in the United States will have an osteoporotic facture in their lifetime.[1] The economic burden of osteoporosis is huge with costs of over $19 billion in the year 2012 attributed to osteoporosis-related fractures.[3] As the population ages, the economic burden of this disease is expected to rise to $25 billion by 2025.[3] In addition to the economic burden, there can be substantial chronic pain and disability for the affected individual. For many, this disease can rob them of the golden years and negatively impact the ability to travel, to exercise, and to fully enjoy their retirement years. As health care providers, we can make a huge difference in the quality of life of patients in our practice who are either at risk for osteoporosis or have already been diagnosed. New guidelines have been established for screening and diagnosing osteoporosis. Many providers are not familiar with these guidelines. This article will review current guidelines which can then be implemented in the care of our patients. Proper education with patients about ways to prevent osteoporosis will also be discussed. New treatment options including new formulations of existing treatments and novel non-oral treatment options are available and will be reviewed to help the provider be aware of all options when discussing treatment with patients. Lastly, the issue of patient compliance with current treatment regimens will be discussed with recommendations on how to address this issue. Case Study: Sue Sue, a 56 year old female, comes in for her Annual Well-Woman Exam. She asks if she should get a Dexa Scan (DXA) to screen for osteoporosis. She has been menopausal for 4 years, took hormonal treatment for 2 years, and then stopped as she felt fine and was no longer having vasomotor symptoms. However, she is now concerned if she is putting herself at risk for osteoporosis by not being on hormone treatment. According to current National Osteoporosis Foundation (NOF) guidelines, the next appropriate step would be: A. Order a Dexa Scan to screen for osteoporosis B. Encourage Sue to resume her Hormonal Regimen C. Begin Alendronate 35 mg weekly for osteoporosis prevention D. Advise Calcium 1000 mg per day E. Calculate her 10 year risk of an osteoporotic fracture with the Fracture Risk Algorithm (FRAX) Current Guidelines for Screening for Osteoporosis The National Osteoporosis Foundation recommends screening all postmenopausal women and all men 50 and older for the risk of osteoporosis. In addition, all women should have their bone mineral density (BMD) measured by the age of 65 and men by the age of 70.[4] Similar recommendations have been made by the North American Menopause Association, the

American College of Obstetricians and Gynecologist, and the United States Prevention Services Task Force.[5-7] Risk factors for osteoporosis include prior fractures, long-term glucocorticoid use, rheumatoid arthritis, tobacco use, excessive alcohol (> 2 drinks a day), lack of calcium/vitamin D, lack of exercise including weight-bearing and weight-lifting, family history, and age. The World Health Organization (WHO) developed the Fracture Risk Algorithm (FRAX) as a tool for calculating the 10-year probability of a major osteoporotic fracture.[8] FRAX takes into account the following: 1. Age 2. Sex 3. Weight 4. Height 5. Previous fractures 6. Family history of fractures 7. Tobacco use 8. Long-term glucocorticoid use 9. Rheumatoid arthritis 10. Causes of secondary osteoporosis 11. Alcohol use 12. BMD of femoral neck if available The FRAX can be accessed at http://www.shef.ac.uk/frax/ The NOF has calibrated FRAX for use in the United States. It is computer-driven, but paper versions are available. FRAX provides two calculations; it gives the 10-year probability for an individual s risk for a major osteoporotic fracture of the spine, forearm, hip or shoulder and separately, the 10-year probability of a hip fracture. Treatment should be considered if the 10- year probability of a major osteoporotic fracture is 20% or higher and if the probability of a hip fracture is 3% of greater.[4] The FRAX can be an important tool in clinical practice and can guide treatment decisions in our patients. Back to Sue She does not meet the guidelines for ordering a DXA based on her age of 56. Her hormonal regimen should not be resumed solely to prevent or treat osteoporosis as non-hormonal treatment options such as the bisphosphonates may be more appropriate if indicated. Her calcium intake should be 1200 mg or greater since she is over the age of 50. Appropriate screening for osteoporosis would be to utilize the FRAX. Additional clinical information about Sue is as follows: her height is 66 inches, weight is 130 lbs., no prior history of fractures, no family history of fractures, non-smoker, alcohol use is 0-1 glass of wine per evening, no rheumatoid arthritis, no history of long-term glucocorticoid use, and no secondary osteoporosis conditions. Her clinical information is put into the FRAX algorithm. Results show her 10-year probability of a major osteoporotic fracture to be 6.3% and of a hip fracture to be.7%. These numbers would indicate treatment with a bisphosphonate is not appropriate at this time. Reassessing her risk in 1 year

with the FRAX is reasonable. Instructions on self-scoring with the FRAX in between risks may be beneficial for Sue. Bone Mineral Density Measuring the bone mineral density can be very useful in diagnosing and screening for osteoporosis. The gold standard for measuring BMD is dual-energy x-ray absorptiometry (DXA).[4] It is commonly referred to as the Dexa Scan. According to the WHO, the DXA should measure the BMD at both the femoral neck of the hip and the lumbar spine. BMD is calculated as the quantity of mineral in grams per square centimeter of bone (g/cm2). In clinical use, BMD is more commonly assessed as the relationship between the measured BMD compared to the average BMD of a normal young adult of the same sex (T-score). In addition, the Z-score is reported and is the relationship between the measured BMD and the expected BMD for the patient s age and sex. Both measurements are expressed as standard deviation (SD) units. T-scores between -1 and -2.5 indicate low bone mass or osteopenia. T-scores -2.5 or below indicate osteoporosis. These guidelines and scoring apply to postmenopausal women and men 50 and older. They do not apply to children, premenopausal women, or men under the age of 50. The diagnosis of osteoporosis can be made by measuring the bone mineral density or by the occurrence of an adulthood hip or vertebral fracture in the absence of major trauma.[4] In a recent study of over 600 postmenopausal women who had received BMD screening, 41.3% did not meet the criteria for screening.[9] In addition to ordering BMD screening inappropriately, clinicians may not be routinely referring all men in their practice for a BMD by the age of 70. BMD testing should be performed in women 65 and older and in men 70 and older. Measuring BMD in postmenopausal women younger than 65 and in men between the ages of 50-69 should be based on individual risk factors and prior history of fracture.[4] Other conditions associated with a low BMD include hyperparathyroidism and osteomalacia. Therefore, a thorough physical exam is important in interpretation of BMD scores. According to the NOF 2013 guidelines, vertebral imaging should be performed in all women 70 and older and all men 80 and older if BMD T-score is <1.0 at the spine, hip or femoral neck.[4] Also, it should be performed in women age 65-69 and men 75-79 if BMD T-score is <1.5 at the spine, hip or femoral neck. Lastly, it should be ordered in postmenopausal women age 50-64 and men 50-69 with specific risk factors including low trauma fracture, historical height loss of 1.5 inches or more, prospective height loss of.8 inches or more or recent or ongoing long term glucocorticoid treatment.[4] Patient Education The NOF recommends that clinicians counsel all postmenopausal women and men age 50 and older on ways to prevent osteoporosis and to reduce the risk of osteoporosis-related fractures. Appropriate advice for Sue, our 56 year old patient, who is worried about her risk of osteoporosis, would include all of the following EXCEPT:

A. Diet rich in fruit and vegetables B. Aerobic, weight-bearing, and weight-lifting exercise at least 3 times per week C. Limit alcohol to no more than 2 drinks per day D. Calcium intake of 600 mg per day with Vitamin D 200 IU a day E. Calcium intake of 1200 mg per day with Vitamin D 800 IU a day Sufficient calcium intake is defined as >1200 mg/day or more for women age 51 and older and for men age 71 and older. For women younger 51 and for men age 50-70, sufficient calcium intake is defined as >1000 mg/day. Vitamin D helps with intestinal absorption of calcium. The Institute of Medicine recommends that all individuals age 50 and older receive 800-1000 international units (IU) of vitamin D per day.[10] Most calcium supplements include Vitamin D. Since Sue is 56 years old, she should have a calcium intake of >1200 mg per day with >Vitamin D 800 IU per day. Smoking is associated with an increased risk of osteoporosis-related fractures and lower BMD in women. Excessive alcohol use increases the risk of falls and hip fractures. All patients should be advised to quit smoking and to limit alcohol to no more than 2 drinks per day. Exercise can improve BMD especially if done at least 3 times per week. Aerobic, weight-bearing, and weight-lifting exercise improves BMD in postmenopausal women. A recent survey of over 600 postmenopausal women who had been assessed with DXA showed that 25.5% were not taking calcium supplementation; 31.1% were not taking Vitamin D supplementation; and 59.8% were not exercising at least 30 minutes per week.[9] This highlights the importance of patient education. Scheduling patients for a follow-up visit after a DXA is done to review all treatment recommendations including dietary and life-style is advised to increase compliance. For larger medical clinics, a patient care coordinator to follow these patients could be instrumental in treatment and prevention of future fractures. A nurse or physician extender such as a Physician s Assistant (PA) or a Nurse Practitioner (NP) could serve in this role as patient care coordinator for this population at risk of osteoporotic fractures. Treatment Pharmacologic treatment should be initiated in patients with hip or vertebral (clinical or asymptomatic) fractures. It should also be initiated in patients with T-scores <2.5 at the femoral neck, total hip or lumbar spine as measured by DXA after appropriate evaluation.[4] Treatment options vary with the class of medication used and in dosing regimens and route of delivery. For this article, treatment categories will be divided into the following groups: 1. Bisphosphonates 2. RANKL Inhibitor 3. Hormone Therapy (HT) 4. Selective Estrogen Receptor Modulators (SERMs) 5. Calcitonin 6. Parathyroid Hormone (Teriparatide)

Bisphosphonates This class of FDA-approved medication for the treatment and prevention of osteoporosis is the most widely used with an estimated 4 million women in the US using this class of drugs in 2008.[11] It includes Alendronate (Fosamax ), Risedronate (Actonel ), Ibrandronate (Boniva ), and Zoledronic acid (Reclast ). Bisphosphonates inhibit the activity of osteoclasts and reduce the rate of bone resorption. Short term side-effects include gastrointestinal discomfort and musculoskeletal pain. Long-term side-effects include osteonecrosis of the jaw and atypical femur fractures if thigh or groin pain develop. The risk of jaw osteonecrosis appears to be highest in patients immunocompromised such as cancer patients receiving IV bisphosphonates at higher dosages than most patients take. Mouth trauma and major dental work increase the risk of jaw osteonecrosis; therefore, discontinuing bisphosphonate therapy prior to and during major dental work is a consideration.[12] In most patients, bisphosphonates are discontinued after 5 years due to uncertainty of the long-term safety and necessity of treatment beyond 5 years. Numerous studies show the effectiveness of the bisphosphonates reducing the risk of both vertebral and hip fractures. The Fracture Intervention Trials (FIT and FIT 2) of thousands of women with vertebral and/or hip fractures showed that daily use of Alendronate reduced the risk of a subsequent vertebral or hip fracture by approximately 50%.[12,13] The 3 year Vertebral Efficacy with Risedronate Therapy (VERT) studies showed a reduction in vertebral fractures by 41-49% and non-vertebral fractures by approximately 36% with risedronate therapy.[14] A recent review of published clinical trials of ibandronate conclude that ibandronate is effective in reducing both vertebral and non-vertebral fractures.[15] Lastly, the 3 year Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study showed a reduction in the risk of vertebral fracture by 70%, risk of hip fracture by 41%, and non-vertebral fracture by 25% with zoledronic acid treatment.[16] Case Study: Mary Mary, a 65 year old female, has come in to review the results of her recent BMD. Her T-score at her femoral neck is -2.0 and is -2.2 at her lumbar spine. She is not on hormone therapy as there is strong family history of breast cancer. She does not want to lose height and get hunched over as she has seen some of her older women friends. She asks about treatment options. She takes Calcium 1200 mg a day, Vitamin D 1600 IU a day, and exercises regularly. Her exercise regimen includes walking 3-4 times a week, water aerobics, and golfing. She is a non-smoker and drinks no more than 1 glass of wine per evening. She has never had a fracture and there is no family history of osteoporotic fractures that she is aware of. Appropriate management at this time includes (choose the best answer): A. No pharmacologic intervention needed B. Initiate treatment with Alendronate 35 mg weekly C. Initiate treatment with Alendronate 70 mg weekly D. Initiate treatment with Teriparatide daily injection E. Initiate treatment with Denosumab (RANKL Inhibitor) 2 times/year injection F. Both A and B are acceptable treatment options

Discussion: Mary s BMD score is consistent with osteopenia; she does not meet the criteria for osteoporosis. She is a candidate for prevention of osteoporosis and may be offered treatment with weekly Alendronate. After reviewing the side-effect profile, she may elect to forego pharmacologic treatment and continue her life-style of weight-bearing exercise and calcium & Vitamin D supplementation. She should have a repeat BMD in 2 years. Treatment options C, D, and E are for the treatment of osteoporosis and not for prevention of osteoporosis. The bisphosphonates vary in dosing regimens and available formulations. It can be very helpful in knowing specific options for each medication so we can provide greater choices for our patients. Each of the four bisphosphonates will now be listed with dosing options: 1. Alendronate (Fosamax )-available as a 5, 10, 35, 70 mg tablet and a relatively new buffered solution of 70 mg; also available with Vitamin D as 70 mg/2800 IU or 70 mg/5600 IU. Dosage is 10 mg daily or 70 mg weekly for treatment of osteoporosis; 5 mg daily or 35 mg weekly for prevention of osteoporosis. Alendronate is generic and cost-effective for most patients. All tablets taken with minimum 6-8 ounces of plain water on an empty stomach and should not lie down for at least 30 minutes and until after the first food of the day. Most common side-effects: abdominal pain, heartburn, dyspepsia, nausea, back pain, and arthralgia; less common esophageal ulcer, jaw osteonecrosis, atypical femur fracture.[12] 2. Risedronate (Actonel )-available as a 5, 30, 35, 75, 150 mg tablet. Also, a new delayedrelease once a week tablet is now available that can be taken after breakfast. Dosage is 5 mg daily, 35 mg weekly, 75 mg for 2 consecutive days a month, or 150 mg once a month. No dosage difference between prevention versus treatment of osteoporosis. Same dosage instructions and side-effect profile as Alendronate. May be generic by June 2014.[18] 3. Ibandronate (Boniva )-available as an oral 150 mg tablet to be taken monthly 60 minutes before first meal; a daily 2.5 mg tablet rarely used; and a quarterly 3 mg/3 ml IV injection. All preparations FDA-approved for the treatment of osteoporosis; only the oral preparations FDA-approved for prevention of osteoporosis. Same side-effect profile as other bisphosphonates. Generic is available.[19] 4. Zoledronic acid (Reclast ) available as a 5 mg/100 ml vial and delivered as an IV infusion over no less than 15 minutes and should be followed by a 10 ml normal saline flush. Administered yearly for treatment of osteoporosis and every 2 years for prevention of osteoporosis. Can be expensive. Renal function and calcium level should be checked before each treatment and 2 weeks later.[20] RANKL Inhibitor This class of medication targets and binds to the RANK Ligand and inhibits osteoclast formation, thereby decreases bone resorption. In lower estrogen states, such as menopause, there is an increase in RANK Ligand activity. Denosumab (Prolia ) is an FDA-approved RANKL Inhibitor for the treatment of postmenopausal osteoporosis, for prevention of osteoporosis in those at high risk for fracture, for patients intolerant to other therapy (such as bisphosphonates) and for men at high risk for fracture including men receiving androgen deprivation therapy for prostate

cancer.[21] The 3-year Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 months (FREEDOM) trial examined denosumab for the prevention of fractures in over 7,800 postmenopausal women. Denosumab reduced the risk of vertebral fracture by 68%, hip fracture by 40%, and nonvertebral fracture by 20%.[22] Denosumab is available as a 60 mg subcutaneous injection that is given twice a year in the arm, thigh, or abdomen. Can be administered in out-patient clinic setting. Can be expensive so may be necessary to work with a specialty pharmacy for approval and shipment. Side-effects include back and extremity pain. Calcium level should be checked before administering. Important to make sure a patient is not on other Denosumab-containing products such as those used to treat giant cell tumor of the bone (Xgeva ). Hormone Therapy Estrogen hormone therapy (HT) is FDA-approved for the treatment of osteoporosis in women. A study from the Women s Health Initiative Study of over 10,000 postmenopausal women found that estrogen therapy significantly reduced the risk of vertebral and hip fractures.[23] However, there are many side-effects of estrogen therapy including increased risk of cardiovascular disease, stroke, breast cancer, and thromboembolic events. Therefore, estrogen is not considered first-line therapy for the treatment or prevention of osteoporosis. It may be considered if women cannot tolerate standard treatments like the bisphosphonates or Denosumab. Estrogen comes in many dosage forms including transdermal patches, oral tablets, vaginal rings, and topical gels. To prevent uterine cancer, it should be given with progesterone in women with an intact uterus. The main reason to prescribe HT in menopausal women is to treat moderate to severe vasomotor symptoms and to relieve vaginal dryness when topical preparations are not adequate. Alternative treatment should be considered first if treating osteoporosis. Men s risk of osteoporosis increases with declining levels of testosterone which is common after the age of 45-50. Testosterone slows bone thinning, reduces calcium loss, and may improve bone thickness in vertebral bone. Testosterone in gel or patch form may help off label to prevent osteoporosis select in men; it is not used for osteoporosis prevention in women.[24] SERMs Raloxifene (Evista ) is a selective estrogen receptor modulator medication (SERM) and is FDAapproved for the prevention and treatment of osteoporosis in women. It acts as an estrogen receptor agonist in bone to increase BMD of the lumbar spine, hip, and total body in postmenopausal women. In breast tissue, raloxifene acts an estrogen antagonist and is FDA approved for the reduction in risk of invasive breast cancer. In the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) trial of over 7,700 women with osteoporosis, women receiving Raloxifene experienced a 30% reduction in the risk of vertebral fractures in women with previous vertebral fracture and a 55% reduction in women with no prior vertebral fractures.[25] However, there is no data to indicate a decrease in the risk of hip or non-vertebral fractures.

Raloxifene is dosed as a 60 mg tablet once a day. Side-effects include hot flashes, leg pain, and an increased risk of deep vein thrombosis.[26] Calcitonin Calcitonin is FDA-approved to treat osteoporosis in women at least five years past menopause. It slows bone loss and increases bone density. A randomized trial of 1,100 postmenopausal women showed a modest increase in BMD and a 33% reduction in the risk of new vertebral fractures with at least 3 years of calcitonin treatment.[27] There is no data showing a reduction in the risk of non-vertebral fractures with calcitonin. Currently it is available as a 200 unit/spray and is dosed as 1 spray in nostril daily, alternate nostrils. In addition, can be given as a 200 unit/ml subcutaneous or intramuscular dose every other day. Side-effects include rhinitis.[28] Calcitonin can also be used to treat the bone destruction caused by cancer and has been shown to reduce both bone and nerve pain caused by cancer.[29] Parathyroid Hormone Teriparatide (Forteo ) is FDA approved for the treatment of osteoporosis in postmenopausal women and in men with a high risk for fracture. It is made from human parathyroid hormone and increases the rate of bone formation; it is therefore considered anabolic and as a result, unique from the other medications used to treat osteoporosis. It is given as a daily 20 mcg subcutaneous injection and is dispensed with a pre-loaded pen containing a 1 month supply. Maximum duration of treatment is 2 years and its use should be restricted to patients with osteoporosis who are at high risk for fracture. Can be expensive. Side-effects include leg cramps, dizziness, nausea, and headache.[30] A retrospective analysis of the Fracture Prevention Trial and the MORE trial indicated that teriparatide treatment in postmenopausal women reduced the risk of any new fractures by 72%, new adjacent fractures by 75%, and new nonadjacent fractures by 70%.[31] Patient Adherence to Osteoporosis Treatment Plans In a recent study of women who were prescribed osteoporosis medication, nearly 30% had not filled their prescriptions within 60 days of the order date.[32] Another study showed poor compliance with daily bisphosphonate treatment compared to weekly treatment with a bisphosphonate.[33] Patient surveys have consistently indicated a preference for less frequent treatment options. Current options now include a once yearly Zoledronic acid infusion, twice yearly Denosumab injections in the doctor s office, quarterly Ibandronate infusions, and monthly as well as weekly oral bisphosphonate regimens. Side-effect tolerability can be a barrier to continued compliance with treatment. Nausea and heartburn experienced with the bisphosphonates is a common complaint. Non-oral and nonbisphosphonate options for treatment can address this issue. Case Study: Linda Linda is a 68 year old female with osteoporosis of the hip and lumbar spine per her DXA and is on Alendronate 70 mg weekly. She has been experiencing a lot of nausea and heartburn after taking the Alendronate and would like to address other treatment options. Appropriate treatment options include all of the following EXCEPT:

A. Yearly Zoledronic acid infusion B. Twice yearly Denosumab injections C. Quarterly Ibandronate Infusions D. Raloxifene 60 mg daily E. Delayed release Risedronate tablet Discussion: All listed options would be appropriate except Raloxifene. This patient has osteoporosis of her hip based on DXA and there is no data to suggest a reduction in hip fractures with Raloxifene. In summary, Osteoporosis is very common and is often underdiagnosed and undertreated. Appropriate screening in the primary care setting includes identifying risk factors for osteoporosis in our patients, patient education, application of the FRAX, and appropriate ordering of DXA to measure BMD. Treatment includes being aware of all current FDA approved drugs for osteoporosis, knowing the various dosing and formulations options and then individualizing treatment to match the patient s preference for treatment. Partnering with our patients and employing shared decision making can increase compliance and patient satisfaction. Ultimately, to prevent future fractures in our patients can be both rewarding and attainable. References 1. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services; 2004. 2. The 2010 Burden of Osteoporosis and Low Bone Mass Among Residents of the U.S. Age 50 and Older. National Osteoporosis Foundation news release; November 1, 2013. http://nof.org/news/1648. Accessed March 17, 2014. 3. National Osteoporosis Foundation. What is Osteoporosis? http://nof.org/articles/7. Accessed March 17, 2014. 4. National Osteoporosis Foundation. Clinicians Guide to Prevention and Treatment of Osteoporosis. Revised 2013. http://nof.org/files/nof/public/content/file/2237/upload/878.pdf Accessed February 17, 2014. 5. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010 Jan-Feb; 17(1):25-54. 6. Committee on Practice Bulletins-Gynecology. The American College of Obstetricians and Gynecologists. ACOG Practice Bulletin N. 129. Osteoporosis. Obstet Gynecol. 2012 Sep;120(3):718-734. 7. U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. preventive services task force recommendation statement. Ann Intern Med. 2011 Mar 1;154(5):356-364. 8. Kanis FA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008 Apr; 19(4): 385-397. 9. Schnatz PF, Marakovits KA, Dubois M, et al. Osteoporosis screening and treatment guidelines: are they being followed? Menopause. 2011; 18:1072-1078. 10. National Research Council. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press, 2011.

11. Siris ES, Pasquale MK, Wang Y, et al. Estimating bisphosphonate use and fracture reduction among US women aged 45 years and older, 2001-2008. J Bone Miner Res. 2011; 26:3-11. 12. Fosamax (alendronate sodium) prescribing information. https://www.merck.com/product/usa/pi_circulars/f/fosamax/fosamax_pi.pdf 13. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of Alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet. 1996: 348: 1535-15341. 14. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077-2082. 15. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999; 282: 1344-1352. 16. Adami S, Idolazzi L, Rossini M. Evidence of sustained vertebral and nonvertebral antifracture efficacy with ibandronate therapy: a systematic review. Ther Adv Musculoskelet Dis. 2011 Apr: 3 (2): 67-79. 17. Black DM, Delmas PD, Eastell R, et al. Once-yearly Zoledronic acid for treatment of postmenopausal osteoporosis. N Eng J Med. 2007; 356: 1809-1822. 18. Actonel (risedronate sodium) tablets prescribing information. http://www.actonel.com/global/prescribing_information.pdf 19. Boniva Tablets (ibandronate sodium) prescribing information. http://www.gene.com/download/pdf/boniva_tablets_prescribing.pdf 20. Reclast (zoledronic acid) Injection prescribing information. http://www.pharma.us.novartis.com/cs/www.pharma.us.novartis.com/product/pi/pdf/re clast.pdf 21. Prolia (denosumab) Injection prescribing information. http://pi.amgen.com/united_states/prolia/prolia_pi.pdf 22. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fracture in postmenopausal women with osteoporosis. N Eng J Med. 2009; 361: 756-765. 23. Anderson GL, Limacher M, Assf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women s Health Initiative randomized trial. JAMA 2004; 291: 1701-1712. 24. Ebeling P (2008). Osteoporosis in men. New England Journal of Medicine 358 (14):1474-1482. 25. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Eng J Med. 1997; 337:1641-1647. 26. Evista (raloxifene) prescribing information. pi.lilly.com/us/evista-pi.pdf 27. Chesnut CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000; 109:267-276.

28. Miacalcin (calcitonin-salmon) nasal spray prescribing information. http://www.pharma.us.novartis.com/cs/www.pharma.us.novartis.com/product/pi/pdf/m iacal in_nasal.pdf 29. Foley KM, Abernathy A (2008). Management of cancer pain. DeVita, Hellman, and Rosenberg s Cancer: Principles and Practice of Oncology, 8 th ed., Vol 2, pp 2757-2790. Philadelphia.: Lippincott, Williams, and Wilkens. 30. Forteo (teriparatide) prescribing information. pi.lilly.com/us/forteo-pi.pdf 31. Bouxsein ML, Chen P, Glass EV, et al. Teriparatide and raloxifene reduce the risk of new adjacent vertebral fractures in postmenopausal women with osteoporosis. Results from 2 randomized controlled trials. J Bone Joint Surg Am. 2009 Jun; 91(6):1329-1338. 32. Reynolds K, Munter P, Cheetham TC, et al. Primary non-adherence to bisphosphonates in an integrated healthcare setting. Osteoporos Int. 2013 Sep;24(9):2509-2517. 33. Ettinger MP, Gallagher R, MacCosbe PE. Medication persistence with weekly versus daily doses of orally administered bisphosphonates. Endocr Pract. 2006 Sep-Oct; 12 (5): 522-528.