Dr Anna Fenton. Gynaecological Endocrinologist Christchurch

Transcription

1 Dr Anna Fenton Gynaecological Endocrinologist Christchurch 16:30-17:25 WS #46: Management Options for Osteoporosis 17:35-18:30 WS #56: Management Options for Osteoporosis (Repeated)

2 Osteoporosis Update 2017 Anna Fenton Endocrinologist Burwood Hospital Bone Clinic, Clinical Lead CDHB Bone Density Service and Women s Southern Cross

3 Disclosures Advisory Board Pfizer PTAC Endocrine sub-committee

4 Important facts 56% of women and 29% of men will suffer a fracture after the age of 60 because of osteoporosis. Nearly 4,000 New Zealanders break a hip each year. This figure is expected to rise to 5,000 in ten years time as our population ages. Young people can suffer from osteoporosis too.

5 Important facts Nearly 20% of people with hip fractures die from fracture-related complications within a year. Men fare worse than women. In addition to the 20% of people who die within a year of their hip fracture, one third never return home, and those that do lose their mobility and independence. More women are hospitalized with a hip fracture due to osteoporosis than through breast cancer. Spinal fractures amongst the elderly are associated with substantial morbidity and mortality: only 50% are alive at 3 years, 30% at 5 years and 10% at 7 years. The estimated cost to New Zealand is $1.1billion each year.

6 Who do we treat? The aim is to treat those at high risk Low trauma hip or vertebral fracture T-score <-2.5 at the femoral neck, spine or radius 33% Low bone mass with FRAX/Garvan calculator 10 yr fracture risk of >20% or hip fracture risk >3% Wrist fracture with elevated FRAX score Individualize intervention threshold for each patient

7 Case Study Ms A, a 54yr old, presents to your clinic after a bone density test that has confirmed osteoporosis. There is a positive family hx of hip fracture and she has been a smoker in the past. Her LMP was 3 years ago and she stills has frequent hot flushes. She fractured her wrist after slipping over 2 years ago. T-score L1-4 = -3.2, T Hip She wants to discuss the treatment options. She has been online and is fearful of using prescription medication.

8 Management options Would you treat her? What with?

9 Management options Would you treat her? Calcium Vitamin D Hormone therapy Duavive Bisphosphonate therapy Denosumab Teriparatide (not for her)

10 Calcium to use or not to use

11 Calcium supplementation This is controversial and by no means an area with universal agreement!

12 Number with verified MI (%) Effect of calcium on MI 6 Calcium n=732 Placebo n= NNT: fracture, 50; CVS event, Time to First MI (months) Bolland MJ et al. BMJ2008;336:262-6.

13 Study Baron 1999 Grant 2005 Grant 2005 Vit D Prince 2006 Reid 2006 Lappe 2007 Reid 2008 Total Relative Risk Risk of Myocardial of Myocardial Infarction [95% Confidence InfarctionInterval] Test for heterogeneity: I² = 0%, P = 0.96 Weight (%) [ ] P= S R Ba G Grant 2 Pri R Bonn La Test for Favors calcium Favors placebo

14 Comments Vitriolic chat forum in response to the original publication in BMJ In conclusion, we like the editorialists remain to be convinced as to whether calcium supplements alone or in conjunction with vitamin D cause cardiovascular disease R Prince The concern here is that Bolland et al's paper is going to dissuade our local patient population from taking their calcium supplements - when it doesn't apply to 96.5% of them, as they would have been excluded from the meta-analysis. M Grove The relevance of any putative effect of calcium alone on CVD might be questioned B Dawson Hughes

15 Summary of Auckland Calcium Study results * Verified + unreported events * Bolland et al., doi: /bmj be Daly et al., Nutrients 2010, 2, ; doi: /nu

16 WHI CACS Study Manson et al., Menopause 2010;17(4):683

17 WHI Calcium/Vitamin D study RCT of 36,282 women Calcium 1000mg daily + Vitamin D 400iU daily Average intervention period 7 yrs Designed to assess effect on hip fracture, total fractures and colorectal cancer Few clear clinical effects seen. Hip fracture RR 0.62( ) after 5yrs of use if no additional personal supplements. Magnified effect of HRT on hip fracture reduction No effect on MI, CAD, total heart disease, CVA, colorectal cancer, total mortality. Suggestion of breast cancer risk reduction Prentice et al., Osteoporosis Int (2):567

18 WHI Calcium/Vitamin D study Calcium/D Placebo Haz ratio Participants <70yrs Annualized % Annualized % HR + 95% CI Total Mortality ( ) CVD Death ( ) CAD Death ( ) Participants >70yrs Total Mortality ( ) CVD Death ( ) CAD Death ( )

19 Effect of calcium and vitamin D on total fracture risk NOF meta-analysis Weaver at al., 2016 Osteoporosis International. 27(1);367

20 Effect of calcium and vitamin D on hip fracture risk NOF meta-analysis Weaver at al., 2016 Osteoporosis International. 27(1);367

21 Calcium and vitamin D supplementation Advise on adequate amounts of calcium (at least 1,200 mg per day) and vitamin D (800-1,000 IU per day) including supplements if necessary for individuals age 50 and older. NOF Clinicians Guide to Prevention and Treatment of Osteoporosis If we wish to be cautious then perhaps restrict use of calcium supplementation in those with CAD or over 70 yrs of age. Diet is always best. Vitamin D may be more efficacious if given daily rather than in a monthly bolus.

22 Benefit vs Risk of Bisphosphonates The good, the bad and the ugly

23 The good.. More than halve fracture risk Increase bone density Given infrequently so don t add to polypharmacy Excellent compliance 8 out of 10 get no side effects at all Risedronate available without a Special Authority!

24 % Change From Baseline Mean Percentage Change in Lumbar Spine BMD Over Time Placebo ZOL 5 mg %* N = Months

25 % Patients With New Vertebral Fracture Morphometric Vertebral Fracture Results (Stratum I) Placebo ZOL 5 mg 71%* (61%, 78%) 12.8% 70%* (62%, 76%) 5 60%* (43%, 72%) 7.7% 0 3.7% 1.5% 2.2% Years 3.8% Relative risk reductions (95% confidence intervals) vs placebo *P <.0001, based on logistic regression with treatment and baseline fracture status in the model using log-likelihood type approach

26 The effect of treatment of osteoporosis on mortality in eight studies included in the primary analysis. Bolland M J et al. JCEM 2010;95:

27 Oral alendronate/risedronate vs IV zoledronate Perhaps 50% of patients persist with oral treatment Patients who do not adhere do not get fracture benefits The oral regime can pose problems. Fasting(only 0.65% absorbed) GI side effects. Patient preference

28 The bad. 15% acute phase reaction Make sure they are not unwell Panadol after infusion, keep up fluids Be aware of renal issues GFR >35 Make sure they are replete with D/calcium Consider steroid cover if previous severe APR

29 Incidence (%) Common ( 5% in ZOL) Post-Dose Symptoms Occurring Within 3 Days After Infusion 16 15% Pyrexia 14 Placebo values cross-hatched % Myalgia Flu-like illness 7% Headache Arthralgia 6% 5% % 1% 2% 1% 2% 1% 2% 1% 2% 1% Annual Infusion

30 The Ugly. ONJ Atypical Fractures

31 Osteonecrosis of the jaw

32 Patient Risk Factors Drugs Corticosteroids Diabetes Old age Smoking Immunosuppression

33 Christchurch Experience BRONJ Total 14 cases Sex Reason for Bisphos Rx Trigger Site Management of BRONJ Resolution 6 M 7 malignancy 3 spontaneous 10 mandible 5 conservative 12 complete reepithelialization 8 F 7 osteoporosis 11 extraction 4 maxillae 5 LA debride 1 chronic sinus 4 GA debride 1 improved in 6/12 but patient deceased

34 Patient Features Bisphosphonates prescribed for osteoporosis. Sex Age Medical Features Trigger Resolution 7 female 5 > 75 (69, 79, 85, 86,75, 78, 53*) 3 = Very elderly (Ages 79,85,86) 1=Post renal transplant 1=Diabetes 1=RA and corticosteroids 6 extractions 1 spontaneous 7 resolved 3 = Immunosuppressed (renal transplant, diabetes, RA with prednisone++) 1 = 56 spontaneous/ RA/ Coeliacs?/ Zometa/ Alendronate ad Pamidronate

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36 The Bottom Line No patient should ever be discouraged from going on bisphosphonates by fear of ONJ. No patient should ever be denied dental care because they have been on bisphosphonates. Juliet Gray, CDHB Specialist Dentist

37 Atypical femoral shaft fractures

38 Atypical femoral fractures Multiple case reports Often bilateral stress reactions Often prodromal pain Most long-term alendronate (case-finding) Characteristic fractures Transverse Thickened cortex Medial spike Patient characteristics similar to those with ONJ NEJM 2008;358 (12): J Orthop Trauma 2008;22(5): Injury 2008;39(2): J Bone Joint Surg Am Nov;91(11):

39 Subtrocanteric fractures in FIT, FLEX and Horizon trials If we treat 1000 patients for 3 years: Prevent: 71 vertebral, 11 hip, 16 other #s Cause: 0.3 subtrochanteric #s (if RR 1.5) D Black, NEJM 2010

40 Atypical femoral fractures on alendronate Abrahamsen et al., BMJ 2016

41 Drug Holidays

42 Why consider a drug holiday No real evidence that this is the right approach Aim is to balance the risks of longer term bisphosphonate therapy and the advantages of ongoing therapy Side effects may be related to cumulative dose so minimise drug exposure AND maximise the benefits in fracture risk reduction

43 Current best practice Assess each patient as an individual after 3 yrs of zoledronate and 5 yrs of alendronate There is consistent evidence of reduced vertebral fracture risk in prolonging treatment beyond 3-5 years but the data with non-vertebral fractures is inconsistent and often not statistically significant. Risedronate may not be a good option for a drug holiday

44 Current best practice Continue therapy if: T-score of -2.5 or less at the femoral neck Existing vertebral fracture and T-score of -2.0 or less Stop therapy if: T-score at femoral neck better than -2.0 AND no new fractures in the past 2 yrs Patients with risk factors for fracture such as those using steroid therapy will require separate consideration.

45 Current best practice After discontinuation of therapy there are no data to guide us in determining when and whether to re-start therapy. The role of BMD and bone turn-over measurements is currently under study

46 Menopause Hormone Therapy

47 Menopause Hormone Therapy The original treatment for osteoporosis Similar efficacy to the bisphosphonates but also improves bone micro-architecture In young women at menopause, no significant increase in stroke, DVT or CAD. These are age- and progestin-related issues The adverse impact of HRT on breast cancer is seen with combined hormone therapy particularly those containing medroxyprogesterone acetate or norethisterone A good option for women in their 50s or early 60s especially if they have menopausal sx The benefits appear to remain for 2yrs+ after cessation of therapy

48 The way forward Duavive Conjugated estrogens plus bazedoxifene Clear benefits on BMD Denosumab (Prolia) Given sc q 6/12 ~$400 per dose Effective reduction in vertebral, hip and non-vertebral fractures Similar issues with ONJ Possibly the preferred option after Forteo Fracture liaison service Case finding with appropriate screening and management

49 The Ideal Menopause Therapy Requires a Balance of Effects in a Tissue- Dependent Manner Positive Effects Without Negative Effects Central nervous system vasomotor effects Skeleton Stabilization of bone loss BMD Vagina Dryness, irritation, or dyspareunia Uterus Breast Neutral endometrial stimulation Neutral effect on breakthrough bleeding Neutral preclinical effect at ERs of breast No increase in breast density No increase in breast pain Cardiovascular No increase in risk of cardiovascular disease Komm BS. Reprod. Sci. 2008;15:

50 Achieving Balance Requires Tissue Specific Effects on the Estrogen Receptors Estrogens and SERMs have unique chemical structures and each bind to estrogen receptors α and β, which vary in proportion from tissue to tissue 1 A Composite Effect That Is Agonist in Some Tissues, Antagonist in Others COMPETITIVE BINDING AT THE ESTROGEN RECEPTOR 1 Once bound to the estrogen receptor, the complex undergoes change in shape; affecting the interaction of other proteins with the receptor Achieving Balance Requires Tissue Specific Effects on the Estrogen Receptors (eg, those that regulate gene expression), and may impact associated physiologic responses 1 These responses vary according to the tissue type and ER-binding compound, leading to an agonist or antagonist effect 2 Tailoring their effects by combining them at a specific ratio produces a composite series of agonist and antagonist responses; with effects specific to each target tissue 1,3 1. Green KA et al. Nat Rev Cancer. 2007;7: ; 2. Niccolini A, et al. Front Biosci. 2006;11: ; 3. Thomas C, et al. Nat Rev Cancer. 2011;11:

51 Adjusted mean change Significant Reduction vs Placebo in Average Daily Severity Score of Hot flushes Reduction in average daily severity score of hot flushes primary end point Week 4 Week 12 from baseline 0.5 Treatment difference -0.9[ Treatment difference DUAVEE (n=122) Placebo (n=63) * P<.001 vs. placebo. Based on data analysis using ANCOVA model: Change from baseline = Treatment + Baseline + Site. FDA. Guidance for Industry. Estrogen and estrogen / progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms recommendations for clinical evaluation. UCM pdf. Accessed March 26, Pinkerton JV, et al. Menopause. 2009;16(6):

52 BLEEDING Duavive use is associated with higher rates of amenorrhoea and lower rates of bleeding than CE/medroxyprogesterone acetate in 2 clinical trials Palacios et al., Maturitas 2015.

53 % Mean change from baseline Duavive Significantly Increased Lumbar Spine BMD vs Placebo at 24 Months Lumbar spine BMD results at 24 months >5 years Postmenopausal 1 5 Years Postmenopausal 3.11% Treatment difference 3.62% Treatment difference * P<0.001 vs. placebo. Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-us) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried. forward. Study 1 excluded those subjects with missing source documentation. Adapted from Lindsay Fertility and Sterility 2009 and Data on File.

54 % Mean change from baseline Duavive Significantly Increased Total Hip BMD vs Placebo at 24 Months Total Hip BMD results at 24 months >5 years 1 5 Years Postmenopausal Postmenopausal 1.07* 0.55* 1.73% Treatment difference % Treatment difference 1.42 Duavive (n=96) Placebo (n=95) Duavive (n=155) Placebo (n=150) * P<0.001 vs. placebo. Adjusted mean changes and P-values based on an ANCOVA model with treatment and region (US or non-us) as factors and baseline BMD value and years since menopause as covariates using the modified intention to treat population with last observation carried forward. Study 1 excluded those subjects with missing source documentation. Adapted from Lindsay Fertility and Sterility 2009 and Data on File.

55 Questions