Drug Intervals (Holidays) with Oral Bisphosphonates Rizwan Rajak Consultant Rheumatologist & Lead for Osteoporosis GP Postgraduate Meeting April 2018
Contents Case presentation Pathway for Bisphosphonate Intervals Holidays Calcium & Vitamin D supplementation
Case Presentation
Case 82 year old female Low impact fracture to the left radius and ulna in India early Dec 2016 Internal fixation with a volar radial plate & intramedullary ulnar nail (in India) Returned to UK in Jan 2017 referred to fracture clinic Repeat X-ray
X-ray Left Wrist 7 weeks post op (late Jan 2017)
Transverse, comminuted fracture, fracture has not united, no callus demonstrated
X-ray Left Wrist 6 months post op (early June 2017) X-ray Left Wrist 4 months post op (early April 2017)
Case Low impact fracture / delayed healing On Alendronic Acid Referred to Osteoporosis clinic July 2017
Case Osteoporosis risk factors: BMI is 20.9 Age of menarche 10 years Hysterectomy at 37 but is unsure if she had bilateral salpingo-oophorectomy. She did not go onto HRT Not nulliparous, having had two children No chronic conditions that could lead to bone loss No medications that can lead to bone loss No family history of osteoporosis or parental hip fracture Previous fractures to right elbow 5 years ago and left shoulder 8 years ago all of these fractures occurred due to low trauma Prone to recurrent falls (reviewed by the Falls Team) Remains very active, trying to walk as much as possible. Non-smoker No alcohol Good calcium intake in her diet Noticed loss of height over the last few years.
Case PMH fit and well Medications: Alendronic Acid 70mg weekly Calcium & Vitamin D supplements Multivitamins Intermittent Ranitidine
Case DEXA scan Mar 2017 Mean L spine T-score of -2.9 osteoporotic range Mean total hip T-score of -2.3 osteopenic range No previous bone density scans for comparison
Case Longest Alendronic Acid use? She has been on Alendronic Acid 70 mg for approximately 30 years No other treatment for her osteoporosis Only recently started calcium and vitamin D supplementation since the recent wrist fracture Prior to this, she was not taking supplementation
Case OP Secondary markers: FBC, ESR, U&Es, egfr, CRP, LFTs, ferritin, B12, folate, bone profile, TFTs, myeloma screen, coeliac screen and HbA1c all normal. Vitamin D was found to be significantly deficient at 23 Plan: Stop Alendronic Acid!!!! Vitamin D loading followed by Calcium and Vitamin D supplements and additional Vitamin D at 1000 units daily Xray T/L Spine Forearm DEXA CT scan of her forearm
CT Lt Forearm 7 months post op (July 2017)
Case X-ray thoracolumbar spine - no vertebral fractures DEXA forearm - T score - 5.0 (severe osteoporosis) CT Forearm - ulnar non-union, no callous formation Plan: Treat with Teriparatide (anabolic agent) Ortho opinion regarding further surgery +/- bone biopsy
Case Discussion atypical wrist fracture? Alendronic Acid for almost 30 years Low impact fracture mid-shaft ulnar / radius fracture with issues of prolonged delayed / no bone healing Cortex does look unusual, not a typical site for osteoporotic wrist fractures, significant Bisphosphonate exposure May be equivalent of an atypical fracture in the wrist phenomenon has never been previously reported
Case Key learning points / issues of the case: No pre-treatment DEXA scan Need for Bone Health assessment for early menapause patients (37 years) Not given supplementation during treatment with ALN 2 fractures during course of ALN treatment not reviewed 3 decades of ALN use!!
Bisphosphonate Therapeutic Intervals (Drug Holidays)
Pathway for Bisphosphonate Drug Holidays Developed by Bone Health Committee CHS Approved by CPC, CHS stakeholders Based on NOS guidelines, collaboration with St George s Osteoporosis team Available on CHS intranet, awaiting inclusion on to DXS
How Long to Treatment be Given? Teriparatide or PTH: 24 months For the remaining drugs it is not clear Few RCTs assessing this: ALN: 5 yrs v 10 yrs (FLEX study) ZOL: 3 yrs v 6 yrs (HORIZON study) Watts and Diab; JCEM, 2010 95:1555
How Long to Treatment be Given?
FLEX study Continuing ALN for 10 years reduced the risk of nonvertebral fractures in women with a fem neck T score of <-2.5 at 5 yrs 1 After discontinuation of ALN, 22% had clinical fracture: age and low hip BMD were risk factors 2 1. Schwartz et al; JBMR 2010 2. Bauer et al; JAMA 2014
How Long to Treatment be Given?
How Long to Treatment be Given? BMD & BTMs are stable after stopping BP: ALN ~ 2yrs ZOL ~ 3 yrs Shorter for RIS & IBN Long term use of other meds: PTH (2 yrs), RLX (8 yrs), Denosumab (8 yrs), Strontium (10 yrs) Loss of benefits after stopping treatment
Effect of discontinuation
How Long to Treatment be Given? Patients who did not need treatment in the first place Discontinue Treatment Lower risk patients, if DXA is stable/increasing Consider a drug holiday after 3-5 years of treatment Higher risk patients (fractures, corticosteroid Rx, very low BMD) Consider a drug holiday after 10 years of therapy May use teriparatide or raloxifene (but not another potent antiresorptive agent ie. denosumab) during the holiday from bisphosphonates Watts and Diab; JCEM, 2010 95:1555
What to do after Discontinuation
Inadequate response to treatment 2 fragility fractures 1 fracture + no significant change in BTMs and/or significant decrease in BMD Significant decrease in BMD Diez-Perez A et al; Osteoporosis Int 2012
Inadequate response to treatment Consider other factors 1 Compliance with treatment Not Calcium & Vitamin D replete Treatment period Control of secondary causes Probability of inadequate response to BP was 4x higher in patients with 25OHD <30ng/ml 2 1. Diez-Perez A et al; Osteopoosis Int 2012 2. Peris PA et al; Bone 2013
A systematic review of persistence and compliance with bisphosphonates for osteoporosis Percentages of daily and weekly bisphosphonate users persistent with therapy after 1 year based on prior bisphosphonate usage Osteoporos Int (2007) 18:1023 1031
Possibilities of treatment Change to another anti-resorptive with greater potency Change administrative route: oral to parental Change potent anti-resorptive to anabolic agent Diez-Perez A et al; Osteopoosis Int 2012
Osteonecrosis of the Jaw Exposed necrotic bone in the maxillo-facial region Over 90% of reported cases in cancer patients receiving BP doses 10X higher than used to treat osteoporosis Estimated incidence in OP: 1:10,000-1:100,000 Khosla et al; ASBMR Rask Force, JBMR 2008;23:159 Woo S-B et al; Ann Intern Med 2006;144:753-761
Atypical Femoral Fractures Odvina et al in 2005 reported series of 9 patients with spontaneous, atypical fractures, all on bisphosphonate therapy for a period of time ranging from 3-8 yrs Mainly in the subtrochanteric region Characterized by delayed or absent healing during management Histology revealed over suppression of bone turnover, possibly linked to bisphosphonate usage Odvina et al; JCEM; 2005
Calcium & Vitamin D supplementation
Calcium Most trials reported an approximate 30% fracture risk reduction with an intake of approximately 1000 mg/day of elemental calcium
Vitamin D Seneca Study: Vitamin D levels in EU; 47% women & 36% men had 25OH D levels of <12ng/ml At risk groups: Significant Vitamin D deficiency Fragility fractures, osteoporosis or high risk of fractures On osteoporosis treatment Parathyroid disease On medications such as steroids or anti-epileptics Malabsorption disorders Vitamin D Status (nmol/l) Osteoporosis Int. 2014 Low <50 20.6 Intermediate 50-75 9.9 High >75 6.9 10 year hip fracture incidence rates % Meta-analyses of 5 clinical trials (> 60 yrs) showed significant reduction in risk for falling in those taking vitamin D vs placebo
Calcium & Vitamin D Meta-analysis (29 studies, 63,000 individuals) looked at calcium + vitamin D trials for use in prevention of fracture & BMD loss 1 Supplementation associated with12% risk reduction in fractures of all types Trials with higher compliance revealed significant risk reduction compared to studies with lower compliance In the 8 studies with greater than 80% compliance, 24% risk reduction for all fractures was identified Calcium + Vitamin D, Calcium alone, Vitamin D alone vs placebo 2 Combination therapy provided best BMD improvements and response to anti-resorptive agents 1. Tang BM et al; Lancet; 2007 2. Boonen S et a; J Clin Endocrinol Metab 2007
Calcium & Vitamin D An effective tool that can be used to help patients understand the importance of calcium and vitamin D brick and mortar analogy: without both brick and mortar, the structure (healthy bone) could not be achieved. Sunyecz JA; Ther Clin Risk Manag; 2008
Key learning points Important to review patients on bisphosphonates be preventative and reactive Use Bisphosphonate therapeutic interval (drug holiday) pathway Ensure adequate calcium & vitamin D supplementation
Thank you