Osteoporosis in practice Katie Moss Rheumatology Consultant St George s Hospital London
Disclosures Lilly Educational grant and advisory board Prostrakan Educational grant
Osteoporosis Case history 66 year old women Presents with new thoracic back pain PMH Rheumatoid arthritis 2010 DH Methotrexate Prednisolone 5mg daily (intermittent for flare ups)
OP case - lateral thoracic spine xray Can you spot the abnormalities?
OP case - lateral thoracic spine xray Vertebral fractures T9 and T12 Wedge fractures
>50% are painless Vertebral fractures Xray reports often don t mention the word fracture If vertebral fracture is found, often not investigated for osteoporosis If family history of kyphosis high risk - beware!
Classification of vertebral fractures
Fragility fractures cause significant morbidity Additional morbidity due to fragility fracture event Morbidity attributable to ageing alone Hip fracture is all too often the final destination of a 30 year journey fuelled by decreasing bone strength and increasing falls risk 2 1. J Endocrinol Invest 1999;30:583-588 Kanis JA & Johnell O 2. Osteoporosis Review. 2009;17(1):14-16 Mitchell PJ
Osteoporotic vertebral fracture morbidity Signs Kyphosis Loss of height Tummy bulges loss of space below ribs Symptoms Neck pain and head falls forward Back pain Breathing difficulties Indigestion & GO reflux Stress incontinence Poor mobility Falling forwards
Differential diagnosis of low trauma Vertebral fractures Exclude bone metastases if: Systemic symptoms GI or respiratory symptoms Neurological symptoms Osteoporosis Consider osteoporosis in anyone age >50 years presenting with a low trauma fracture at any site History of cancer By Requesting: MRI scan or NM bone scan (does not show myeloma though)
How do you diagnose osteoporosis?
Diagnosis of osteoporosis In the past a DXA scan was the primary investigation Now Fracture Risk Assessment +/- DXA is recommended
Components of bone strength Bone turnover Mineralisation BMD Cortical thickness and porosity Bone mineral density (BMD) is only one component of bone strength Geometry Trabecular architecture Healthy Bones/ St George s University Hospitals NHS Foundation Trust Other factors also contribute to bone strength
NICE Clinical Guideline 146 Do not routinely measure BMD to assess fracture risk without prior assessment using FRAX or QFracture.
Diagnosis of osteoporosis using Fracture Risk Assessment first Clinical Risk factors FRAX fracture probability High Treat Intermediate BMD Reassess probability Low High Low Treat
Case history what risk factors for osteoporosis does she have? 66 year old women Presents with new thoracic back pain PMH Rheumatoid arthritis 2010 DH Methotrexate Prednisolone 5mg daily (intermittent for flare ups)
Osteoporosis Case Risk factors 66 year old women Presents with new thoracic back pain PMH Rheumatoid arthritis 2010 DH Methotrexate Prednisolone 5mg daily (intermittent for flare ups)
Risk factors for osteoporosis Other risk factors: Major risk factors for osteoporotic fracture included in FRAX Untreated premature menopause/hypogonadism Aromatase inhibitor/antiandrogens Primary hyperparathyroidism/cushings/ thyrotoxicosis Liver cirrhosis/severe cholestasis Malabsorption Immobility Previous fragility fracture Glucocorticoids Family history of hip fracture Secondary OP RA Low BMI Smoker High alcohol
Osteoporosis case Fracture risk assessment FRAX www.shef.ac.uk/frax/ NOGG Treatment thresholds in UK
Limitations of fracture risk assessment tools Some Risk factors not yet included you need to consider them too eg Aromatase inhibitors falls risk not included in FRAX Included in QFRACTURE Risk score applies only to treatment naïve patients BMD input for hip only in FRAX May underestimate risk in those with low spine BMD only
Investigations for Osteoporosis Essential in all patients Vit D Bone profile U+E Why? Selected patients Exclude malignancy ESR/myeloma screen/psa Imaging Diagnosing secondary OP PTH TFT LFT Testosterone Coeliac Assessing for asymptomatic fractures if height loss/kyphosis Thoracic/Lumbar spine xrays
Treatment of vitamin D deficiency Treatment of severe vitamin D deficiency <30nmol/L loading dose to replenish vitamin D stores first 60 000 Units weekly for 5 weeks total 300 000 units Then repeat vitamin D/bone profile 1 month later Then maintenance treatment Treatment of vitamin D insufficiency/maintenance therapy 800-2000 units daily All people age >65 should take vitamin D 400 units daily National Osteoporosis Society vitamin D guidelines 2013
Osteoporosis treatments 2 types Antiresorptives reduce osteoclast number/function Anabolics increase Osteoblast activity
Osteoporosis Treatment 2 types Antiresorptives Bisphosphonates RANKL inhibitors SERM - Selective Oestrogen Reuptake modulators (Dual action agents Strontium ranelate) (oestrogens if premature menopause) Anabolics Synthetic PTH (Dual action agents - Strontium ranelate)
Osteoporosis drugs are highly efficacy Clinical endpoint is low trauma fracture Relative Risk reduction- Vertebral fracture 70% Hip fracture 40% Drug trial efficacy at all sites - hip, spine & major osteoporotic fracture sites Alendronate/Risedronate Denosumab Zoledronate Strontium ranelate
1 st Line Treatment Oral bisphosphonates - alendronate Consider switching if: Contraindication to bisphosphonates Intolerant Poor compliance due to eg dementia Treatment failure
Oral bisphosphonates- Cautions/Contraindications Oesophageal Severe Indigestion/Strictures/Barretts oesophagus Renal GFR <30 Very poor dentition Exclude metabolic derangement - vit D, Calcium Risk of hypocalcaemia and inefficacy
What constitutes 1 st line treatment failure? Patient sustaining a low trauma fracture after >1 year of treatment? Exclude non-adherence and secondary causes Or not? Licensed drugs are not 100% effective Fracture risk reduction: vertebral/hip/non-vertebral 60/40/20%
What constitutes 1 st line treatment failure? IOF criteria: 2 or more fragility fractures 1 fragility # + either: significant drop in BMD >4-5%, no significant drop in BTM >20-30% Both significant drop in BMD >4-5% + no significant reduction in BTM Exclude non-adherence and secondary causes Diez-Perez A, Compston JE - Osteoporosis International 2012
2 nd line treatment Zoledronate Bisphosphonate annual IV Denosumab - RANKL inhibitor 6 monthly subcut For severe osteoporosis Teriparatide synthetic PTH subcutaneous daily Expensive NICE criteria Less commonly used treatments Raloxifene - SERM mild efficacy Strontium ranelate Dual action agent CVD risk
Is Zoledronate more effective than alendronate? Significant reduction in bone turnover markers in zoledronate group
2 nd line treatment Zoledronate Bisphosphonate IV Denosumab - RANKL inhibitor subcutaneous For severe osteoporosis Teriparatide synthetic PTH subcutaneous Expensive NICE criteria Less commonly used treatments Raloxifene - SERM mild efficacy Strontium ranelate Dual action agent CVD risk
Denosumab RANKL inhibitor
Denosumab - Prolia Subcut injection 6 monthly Compliance 100% Community administration Caution GFR < 30ml/min SE infection cellulitis Hypocalcaemia especially if low GFR 34
Is Denosumab more effective than alendronate? Switching from alendronate to denosumab leads to: Larger BMD gains More suppression of bone turnover But no fracture data Brown JP, Bone HG 2009 Kendler DL, JBMR 2010
Is Denosumab more effective? Meta-analysis 142 RCTs, 113 000 women* At 3 yrs Denosumab showed greater gains in Lumbar Spine & Total Hip BMD than oral bisphoshonates, zoledronate, raloxifene Teriparatide showed greater gain in Lumbar Spine BMD than denosumab Denosumab better at preventing vertebral # than oral bisphosphonates, strontium ranelate or raloxifene** * Mandema JW, JCEM 2014 **Freemantle N, OI 2013
Osteoporosis Practical point Hospital discharge summaries - should include date of giving parenteral treatment and plans for future injections GPs - Include parenteral treatments in patient s usual drug list to prevent duplicate prescribing
2 nd line treatment Zoledronate Bisphosphonate IV Denosumab - RANKL inhibitor subcutaneous For severe osteoporosis Teriparatide synthetic PTH subcutaneous Expensive NICE criteria Less commonly used treatments Raloxifene - SERM mild efficacy Strontium ranelate Dual action agent CVD risk
Parathyroid hormone peptides eg Teriparatide Efficacy Reduces vertebral and non-vertebral fractures Increases spine BMD more than alendronate 1 Less back pain and improved quality of life 2 Disadvantages Cost Daily subcutaneous injection License limited to 2 years NICE - for 18 mths 1. Body J-J et al J Clin Endocrinol Metab 2002, 87: 4528-4535 2. Crans GC et al Arthritis & Rheumatism Dec 2004. Vol 50,12: 4028-4034 39
Saag KG Arthritis Rheumatism 2009
Comparison of 3 parenteral drugs Safety Tolerability Additional Denosumab Can increase Infection ONJ Hypocalcaemia (especially in CKD) good Fast onset/offset Consider in CKD Community nurse can give it zoledronate Renal ONJ hypocalcaemia Flu-like symptoms Cheaper Fast onset, slow offset Mortality benefit after hip # License for GIOP teriparatide No ONJ No atypical femoral # Daily injection Fast onset/offset License for GIOP Reduces back pain Increases QoL NICE restricted - expensive Only licensed anabolic drug
In practice. Zoledronate is usually given 2 nd line due to cost Unless specific reason to give denosumab instead: Frail/elderly/housebound CKD with GFR around 30 (specialist clinic)
Rare side effects of bisphosphonates Atypical femoral fractures Osteonecrosis of the jaw Rare in OP pts <1:10 000 Prevention better than cure See Dentist before and during treatment Atypical Femoral fractures Association with bisphosphonates But???causative Rare Prodrome of unusual thigh pain Can be bilateral
Management of atypical femoral fractures Stop bisphosphonate Request urgent xray of whole femur Periosteal reaction Insufficiency fracture Consider MRI Xray the other femur Refer to osteoporosis clinic/orthopaedics
Bisphosphonates - Risk of atypical fractures vs benefit Treatment with bisphosphonates for 10 yrs: Age adjusted incidence of Atypical femoral fractures = 1.1/1000 pt yrs Non-vertebral fractures prevented = 37 per 1000 pt yrs Vertebral fractures prevented = 62.7 per 1000 pt yrs Black DM, Cummings SR, Karpf DB. Lancet 1996 Ringe JD, Doherty JG. Rheumatol Int 2010 Dell RM, Adams AL, Greene DF. J Bone Miner Res 2012 Liberman UA, Weiss SR, Broll J. N Engl J Med 1995
Osteoporosis Case - Treatment Commence alendronate + Adcal D3 Also remember non-drug treatment Analgesia and specialist physiotherapy for vertebral fracture Falls risk assessment Increase protein and BMI if low Specialised osteoporosis exercise program Kyphoplasty/vertebroplasty if severe back pain at 8 weeks
Calcium supplements and CVD Increased CVD risk seen in: Bollard MJ 2010 metanalysis calcium alone Bolland MJ 2011 metanalysis Ca/D3 No increased CVD risk seen in: Wang L 2010 metanalysis Lewis J 2013 metanalysis Lewis JR 2014 - Ancillary of placebo control study Harvey N 2016 Observ Biobank study n=500 000 No known mechanism
The jury is still out so My advice: Women age <70 yrs on osteoporosis treatment could have vitamin D + dietary calcium Use the calcium calculator
But - It is very important that certain patients have Calcium/Vitamin D Low calcium intake/vegans Elderly reduced dietary calcium absorption Glucocorticoid patients Steroids cause a negative calcium balance USA guidelines Ca 1200-1500mg Patients given parenteral antiresorptives Net positive flux of Ca to skeleton Risk of hypocalcaemia if Ca/D3 supplements not given
Drug holiday from bisphosphonates Why? Possible risk of long term bone suppression Anti fracture efficacy may persist after stopping bisphosphonates Applies to bisphosphonates with longest skeletal half life zoledronate and alendronate Drug holiday to maintain benefit while reducing the risk Suresh E, Pazianas M, Abrahamsen B. Rheumatol Jan 2014
Review patients on bisphosphonates after 5 years (or 3 years for zoledronate) High risk patients continue treatment T<-2.5 hip Previous hip or vertebral fracture Recurrent fractures (consider spine xrays) Ongoing Glucocorticoid treatment Moderate/low risk 2 year drug holiday then reassess T>-2.5 hip and no previous hip or vertebral fractures FDA expert panel McClung M, Harris ST, Miller PD et al. Bisphosphonate therapy for osteoporosis: benefits, risks and drug holiday. Am J Med 2013;126:13 20
Denosumab has a fast offset It is not retained in bone beyond 6 months Therefore drug holiday concept does not apply
Remember your hospital Fracture Liaison Service (FLS) nurse Identifies all patients age >50y with low trauma (fragility) fractures fracture sustained from a fall from standing height Assessment of osteoporosis risk Osteoporosis treatment initiated
Osteoporosis Key learning points 1 Consider osteoporosis in all pts age >50 yrs presenting with fragility fracture Diagnosis of osteoporosis should include fracture risk assessment Don t miss vertebral fractures Osteonecrosis of jaw is rare in osteoporosis patients
Osteoporosis Key learning points 2 Fragility fracture despite OP treatment escalate to parenteral treatment Calcium/vitamin D supplements are probably safe regarding cardiovascular disease Review osteoporosis treatment after 5 years and consider drug holiday from bisphosphonates if not high risk
Thank you