Update on Osteoporosis 2016

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1 WELCOME!

2 Update on Osteoporosis 2016 Jennifer J. Kelly, D.O., F.A.C.E. Associate Professor of Medicine Division of Endocrinology, Diabetes and Metabolism Upstate Medical University Director of the Clinical Densitometry Unit Joslin Diabetes Center Syracuse NY

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7 Issues with FRAX Only hip BMD in calculations (no spine) FRAX does not take into account other factors (falls) Doses not considered (steroids, # of cigarettes or fractures) Patient treatment decisions should be a judgment FRAX cannot be used for patients already on treatment

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9 Fewer Than 35% of Hip Fracture Patients Received Pharmacologic Treatment Within 6 Months

10 Vertebral Fracture Assessment

11 Assessment using a DXA System Identify many (~30%) of missed patients based on BMD alone Improve targeting of therapy and patient understanding Improve acceptance and compliance Reduce osteoporotic fractures Steroid use is an ISCD reason for ordering test

12 TBS Trabecular Bone Score

13 Tests to evaluate for secondary causes of Osteoporosis CMP, phosphorus, PTH, 25OH D level. Testosterone in men. 24 hour urine collection for calcium and creatinine. Depending upon the patient, may consider other tests such as screening for Cushings, SPEP. Consider bone turnover markers (P1NP, CTX)

14 Case #1 50 year old woman has a baseline DXA after menopause. No family history of osteoporosis. She is healthy, takes no medications. Her lumbar spine T-score is -2.0, total hip -1.6, femoral neck Should she be treated?

15 Osteopenia, when to treat? Need to assess all risk factors (with FRAX or on own). If a person has had a non-traumatic fracture, they have osteoporosis regardless of their T- score and are at high risk for future fracture. Weigh and discuss with patient risks and benefits of treating vs. not treating.

16 Osteopenia T-score closer to -2.5, may warrant treatment more so than one closer to -1. For instance in a patient with diabetes or RA, may be more likely to treat with osteopenia. Can use osteopenic doses of bisphosphonates.

17 When to treat Osteopenia? In this patient, could emphasize calcium and vitamin D intake, weight bearing exercise, don t smoke, limit alcohol. If she had other risk factors, could consider risks and benefits.

18 New diagnosis of Osteoporosis Case #2 60 year old woman (or man) has a routine DXA. T-score of the lumbar spine -2.6, hip -2.3, femoral neck No other family history, associated meds or risk factors. Should she be treated, and if so with which med?

19 Treatments for Osteoporosis: Bisphosphonates Anti-resorptive medications. Alendronate (Fosamax), risedronate (Actonel) and ibandronate (Boniva). Main concern for side effects related to local GI irritation at the esophagus. Need to take correctly. IV Ibandronate is available every 3 months, IV Zoledronate is available as a once a year infusion (can have acute phase reaction symptoms).

20 Zoledronic Acid (Reclast) Approved to be given yearly for PMO in women, glucocorticoid induced osteoporosis and in men. Given every 2 years for osteopenia. Covered under Medicare part B rather than part D as it is given in an office (does not have an impact on donut hole).

21 Treatments for osteoporosis: SERMs Selective Estrogen Receptor Modulators are approved for use in postmenopausal women. Protects against breast cancer. Raloxifene (Evista) 60 mg oral daily, side effects can include hot flashes and increased risk of DVT. Two other SERMs (basedoxifene and lasofoxifene) are currently under clinical development.

22 Denosumab (Prolia) RANKL inhibitor, anti-resorptive. Given SQ 60 mg every 6 months in office. FDA approved in 2010 but Amgen has 10 years of data. DXAs improve well, generally well tolerated. Can be given at lower GFR (make sure no renal osteodystrophy present first if GFR<30)-may need metabolic bone biopsy. Side effects: skin rashes (seen first 3 yrs of study, not seen in later years), ONJ possible.

23 Treatments for osteoporosis: Calcitonin A 32 amino acid peptide secreted by the C-cells in the thyroid, it inhibits osteoclast resorption. A nasal preparation, salmon calcitonin (Miacalcin) is approved for use in osteoporosis, given 200 IU daily in alternating nostrils. Recently recommended by FDA to no longer be used.

24 Treatments for osteoporosis: Teriparatide The only current FDA approved anabolic agent for osteoporosis, it is a PTH analog. Reserved for patients at high risk of fracture or who could not tolerate or have failed other therapies. Given as a daily SC injection for up to 2 years. Side effects may include dizziness, palpitations, transient hypercalcemia. Black box warning on osteosarcoma in rats. JBMR article in 2013 revealed 10 year safety data.

25 Which med to choose? Most patients do well with oral bisphosphonates, may need to try generic choice first by insurance. If the patient cannot tolerate orals, could try an injectable (or if failed orals previously) If initial T-score quite low (-3), teriparatide may be a good choice. Comes down to patient preference, insurance and any other contraindications, T-score.

26 Questions we ask ourselves before starting an osteoporosis medication? How long do I plan to treat? Do I want to choose something else down the road?

27 Examples: If Teriparatide first, obviously something later. Bisphosphonate may provide chance for a later drug holiday. Denosumab (potent antiresorptive) not amenable to a drug holiday. Can pick Raloxifene in the appropriate pts. Other choices likely in future in pipelines.

28 Treatment Questions? Denosumab works well, how long to give? We really cannot utilize a drug holiday with Denosumab. Future options??

29 Longevity of effect

30 How Long to Treat with Denosumab? This topic was addressed in recent article: How Long to Treat with Denosumab Costa AG, Bilezikian JP Curr Osteoporos Rep Dec 13(6) PMID

31 Use of Denosumab One of the most vexing questions facing a clinician today is how long to treat, which may seem odd for a chronic disease such as osteoporosis, considering most other chronic diseases, including heart disease, diabetes, hypertension and hyperlipidemia, have no limits with regard to duration of therapy.

32 Denosumab Effect Powerful, rapid effect. Good safety profile. Rare ONJ, AFF At discontinuation, rapid increase in BTMs, declines in BMD (5-6%) in 12 months. BTMs and BMDs returned near baseline after 24 months off treatment. Effect reversible, no immediate fracture risk increase, responsiveness demonstrated by retreatment.

33 How long to treat? Rapid reversibility raises concerns. High risk patients might warrant longer-term use. Concern over AFF/ONJ: small increment at nadir of BTM is short and does not persist the whole 6 months. Increase at end, is greater/earlier. At this point, more in favor of continuing long term therapy with Denosumab than bisphosphonates. Need more long term data.

34 Case #3 62 year old woman, on Fosamax for 6 years. She takes it correctly and tolerates it well. Never had a fracture, recent DXA shows T-score of the lumbar spine -2.3, total hip -2.2, femoral neck Could a drug holiday be considered? What if she had a T-score currently of -3 or had previous fractures (or on steroids, etc.) Would that change opinion?

35 Drug Holidays Bisphosphonates have a long retention time in bone. After a bone loading period, it appears the amount of bisphosphonate released back into the circulation can maintain BMD and BTM for a period of time, possibly years. There has been a wider discussion evolving concerning a drug holiday in postmenopausal women after 5-7 years of med use. There is no standard of care on this, but numerous opinions.

36 Drug holidays New Task force paper published in JBMR January 2016 issue. Main data for alendronate up to 10 years (FIT/FLEX study) Main data for zoledronate up to 6 years (HORIZON extension study)

37 Drug holiday? That meant something different in the 1960 s.

38 Drug Holidays Hence, if a drug holiday is considered in low risk person, a minimum duration of 5 years of alendronate use seems reasonable or 3 years of zolendronic acid. Drug holidays not feasible for teriparatide or denosumab as drug effect wears off. T-scores, any previous fractures, high risk medication use, other risk factors should be considered in determining a drug holiday. Could test DXA and/or BTMs one year later to see if stable.

39 Length of treatment There is no expiration date as to when to stop therapy. Need to reassess periodically if still indicated Some patients on therapy over 10 years but if they are high risk for fracture, the benefit outweighs rare risks. Need to individualize.

40 Things people like to ask about Alkaline diet More exercise, other modalities Strontium Other vitamins

41 Strontium Approved for use in many European countries. Ranelate used elsewhere, nutrition shops here have citrate Cannot promise same efficacy/safety CV concerns in Europe with med use.

42 Approved Strontium

43 Strontium ranelate promotes bone formation by osteoblasts, inhibit bone resorption by osteoclast and leads to incorporation of Sr into mineralized matrix formed during treatment

44 Another type of patient Patient on Fosamax 5 years and has decreased T-score (5%) at any site, and/or fracture. Is this a failure? Should a different medication be selected and if so which one?

45 Questionable med failure First assess if they actually were taking the medication and taking it correctly. Look for underlying secondary causes (low Vitamin D, etc) Could consider an injectable (Reclast, Prolia or Forteo) Again need to assess all individual aspects of patient (if concern for oversuppression, an anabolic choice may be better).

46 Long term therapy Experts in the field agree that risk of osteoporotic fracture much higher than rare potential side effects. Can leave patients on long term bisphosphonates if indicated (10 years). Atypical femoral fractures may be another variant of an osteoporotic fracture. ONJ extremely rare, encourage regular dental exams, can hold med if oral surgery to be done. Important to reassess therapy periodically to see if warranted to continue.

47 Combination Therapy Data does not suggest benefit to adding teriparatide to bisphosphonates (perhaps after several months, anabolic window). Some data on small study combining teriparatide to raloxifene Newer data on denosumab and teriparatide shows potential benefit. Concern for decreased bone turnover with 2 anti-resorptives given together (incl. HRT)

48 Take home points Osteoporosis is very common and fractures can be devastating. Most therapies are safe and effective, ask about dental issues, thigh or hip pain at visits. Patients on bisphosphonates over 3-5 years, reassess periodically to see if a drug holiday or change in therapy is appropriate. Treat patients after non traumatic hip fractures. Denosumab (Prolia) good alternative to bisphosphonates, teriparatide (Forteo) to be considered as anabolic therapy. Always ask if patients actually taking meds (correctly) along with calcium and vitamin D.

49 New Medications on the Horizon Sclerostin inhibitor (Romosozumab) monoclonal Ab against Sclerostin (produced by osteocytes & inhibits bone formation). Abaloparatide (is a peptide that selectively binds to the RG conformation of the parathyroid hormone type 1 receptor)

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51 Crisis in the Treatment of Osteoporosis June 2016 JBMR month in JBMR) We as a physicians who care deeply about the treatment of patients with osteoporosis, find ourselves in a dire situation. Tools to prevent sufferings and mortality, but for osteoporosis we may well be coming back full circle: the downward spiral of vertebral fracture, hip fracture, immobility, loss of independence, and premature death that we thought we had conquered may soon become the accepted norm again.

52 New York Times June 1, 2016 Fearing Drugs Rare Side Effects, Millions Take Their Chances With Osteoporosis

53 It s erroneous to think it s a lady s disease.

54 Conclusion I would like to end with an excerpt from an editorial: Increasing Options for the Treatment of Osteoporosis Sundeep Khosla, MD N Engl J Med 2009; 361:

55 Khosla NEJM 2009 Beyond the science driving new drug development, however, will remain the art of being a physician. Specifically, our success or failure in combating osteoporosis increasingly depends not so much on the drugs available to us but rather on our ability to engage our patients and ensure that they take the medications we prescribe.

56 Thank you!! Questions??