The patient Safety issues with osteoporosis treatments 78 year-old lady, retired dentist, active. Family history of osteoporosis (mother, younger sister). Humerus fracture 3 months ago. Type 2 diabetes since 1990, good glycaemic control, microalbuminuria. Creatinine clearance 40 ml/min by C-G formula. Bo Abrahamsen The patient FRAX assessment 78 year-old lady, retired dentist, active. Family history of osteoporosis (mother, younger sister). Humerus fracture 3 months ago (fall). Type 2 diabetes since 1990, good glycaemic control, microalbuminuria. Creatinine clearance 40 ml/min by C-G formula. Other biochemistry unremarkable. 25OHD 80 nmol/l. T-score -3.0 at L2-L4 spine (osteoporosis) -2.8 at femoral neck (osteoporosis) Meds Metformin, losartan, calcium + vitd 20 cigarettes daily, no alcohol UK NOGG Guidance Which drug? First choice: Weekly oral bisphosphonate (PROS: cheap, good efficacy, guidelines in favour, can be taken at home. CONS: adherence can be poor, GI tolerance issues) Fortunately I think you should be able to manage this on a tablet once a week. These drugs have been available for a long time so we have a lot of experience with them and the price is really low. 1
Patient concerns I don t want osteonecrosis of the jaw, I ve seen pictures and it is a condition that is far worse than a bone fracture. This drug has also been linked to cancer of the oesophagus. This is usually incurable. ONJ fact sheet Clinical diagnosis based on exposed visible bone in oral cavity seen by health professional, present > 8 wks. More than 95% of cases in the literature have occurred in patients with metastatic bone disease receiving long-term, high-dose, i.v. BP, in whom the estimated incidence is 1 to 12% at 36 months of exposure (annual cumulative oncology dose is about 10x the dose used for osteoporosis). Risk factors: invasive dental procedures, dental disease, poorly fitting dental appliances, tobacco/alcohol and corticosteroids or chemotherapeutic drugs. Prevalence rates in osteoporosis patients generally around 0.02% though one study reported prevalence up to 4.3%. No association with duration of use shown. Not necessary for patients (except oncology) to undergo dental evaluation or complete dental treatments prior to initiation of BP. See a dentist on a regular basis, maintain good oral hygiene. Should the need to perform an invasive dental procedure arise after therapy is initiated, there is no evidence that discontinuation of BP will improve dental outcome. Bone turnover markers non-informative. Suresh, Pazianas, Abrahamsen: Rheumatology (Oxford) 2014 53(1):19-31 Oesophageal cancer fact sheet Upper GI issues with oral BPs in general Rare disease. Associated with smoking and alcohol use which are also risk factors for osteoporosis. Men > Women. Oral BPs: Meta-analysis of seven epidemiological studies (Sun, Osteoporosis Int 2013;24:27986) Pooled RR of 1.23 (95% CI 0.79, 1.92 ns) for cohort studies Pooled RR of 1.24 (95% CI 0.98, 1.57 ns) for case control studies Oesophageal cancer has very poor survival yet no excess oesophageal cancer deaths in alendronate users (Abrahamsen, JBMR 2012): 12,000 alendronate users followed for 6 years: 0.11% died of oesophageal cancer. All cause mortality 32.1%. 48,000 control subjects followed for 6 years: 0.15% died of oesophageal cancer. All cause mortality 34%. (study also found alendronate users had half the risk of gastric cancer and gastric cancer mortality compared with background). Upper GI irritation heartburn - is the most common side effect with oral BPs and reason most commonly given by patients for stopping treatment. Although not demonstrated in clinical trials, fewer GI side effects have been noted w/ weekly or monthly BP, compared with daily BP, in post-marketing reports. Note that some patients may (inappropriately) take the drug with a small amount of yoghurt or milk to alleviate this. Not the way forward obviously. I never prescribe PPIs to help patients tolerate oral BPs; change to other drug (often zol or dmab). Suresh, Pazianas, Abrahamsen: Rheumatology (Oxford) 2014 53(1):19-31 Important safety considerations when discussing best medication for the patient Renal function Upper GI problems Dental status and planned procedures Important safety considerations when discussing best medication for the patient Renal function Upper GI problems Dental status and planned procedures 2
The patient 78 year-old lady, retired dentist, active. Family history of osteoporosis (mother, younger sister). Humerus fracture 3 months ago (fall). Type 2 diabetes since 1990, good glycaemic control, microalbuminuria. Creatinine clearance 40 ml/min by C-G formula. Other biochemistry unremarkable. 25OHD 80 nmol/l. T-score -3.0 at L2-L4 spine (osteoporosis) -2.8 at femoral neck (osteoporosis) Meds Metformin, losartan, calcium + vitd 20 cigarettes daily, no alcohol Patient agrees to start alendronate 70 mg once weekly 3 months consult with nurse, no tolerability issues Safety concerns with bisphosphonates Irrespective of duration Reflux / dyspepsia (oral) Renal toxicity (iv>oral) Hypocalcaemia (iv) Uveitis ONJ Acute phase reaction Musculoskeletal pain Atrial fibrillation (?) Liver toxicity (extremely rare) Probably unsafe in pregnancy/lactation (so absolutely avoid!) Long term use only Atypical femur fracture Reyes, J Cell Biochem. 2016 Jan;117(1):20-8 ONJ AF AFF ASBMR 2014 definition of AFF BBC 1 st of March 2017 Kim, JBMR 2016 A femur fracture located along the diaphysis from just distal to the lesser trochanter to just proximal to the supracondylar flare. With at least four of these five major criteria met: Minimal or no trauma, as in a fall from a standing height or less Fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may become oblique as it progresses medially across the femur. Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex The fracture is non-comminuted or minimally comminuted Localized periosteal or endosteal thickening of the lateral cortex is present at the fracture site ( beaking or flaring ) Minor or inconstant features: Generalized increase in cortical thickness of the femoral diaphyses Prodromal symptoms such as dull or aching pain in the groin or thigh Bilaterality Delayed fracture healing Shane E, JBMR 2014 Atypical femur fracture what should I do? Diagnosis is usually by conventional X-ray though CT or bone isotope scan often helpful. A DXA scan application has been developed (15-sec SE Femur Exam with high resolution image of the entire femur with low effective radiation dose performed at the time of a hip BMD scan). Always check opposite femur for similar lesion. Treatment surgery for all complete and most incomplete fractures (often persisting pain, delayed healing or progress to complete fractures). Teriparatide to stimulate healing? Prudent to stop antiresorptives if AFF develops. AFF, Hip Fractures and Deaths Number of fractures in One year Deaths first Excess deaths SMR Sweden 2008-2010 mortality year first year Sutroch/shaft 5,342 fractures Excluded 4,218 AFF 172 0% 0.92 None None non-aff 952 22% 1.82 209 136 Hip fractures 42,993 22% 3.4 9,458 7,309 Kharazmi JBMR 2016, Abrahamsen & Prieto-Alhambra JBMR 2016 3
Age adjusted rate per 100,000 1400 1200 1000 800 600 Fracture rate by adherence and year 522,287 female new BP users US Medicare Hip fractures (FN and IT) Harm Benefit MPR<1/3 MPR 1/3-2/3 MPR>2/3 400 Subtrochanteric and femoral shaft fractures MPR>2/3 200 MPR 1/3-2/3 MPR<1/3 0 0 1 2 3 4 5 Year of treatment Risk of ST/FS and hip fractures OR and 95%CI for OR and 95% CI for ST/FS FRACTURE HIP FRACTURE Alendronate User status a Past user ( 1 year before) Reference Reference Recent user (<1y before) 1.00(0.82 to 1.25) p=0.931 0.79(0.74 to 0.86) p<0.001 Current user 0.92(0.79 to 1.07) p=0.273 0.70(0.65 to 0.77) p<0.001 MPR b <50% Reference Reference 50-80% 1.04(0.84 to 1.27) p=0.74 0.98(0.89 to 1.08) p=0.65 >80% 0.90(0.78 to 1.03) p=0.11 0.73(0.69 to 0.79) p<0.001 Dose years c <5 Reference Reference 5-10 1.05(0.87 to 1.28) p=0.58 0.74(0.67 to 0.83) p<0.001 10 0.72 (0.45 to 1.14) p=0.16 0.74(0.55 to 0.97) p=0.027 Two (ST/FS and hip, respectively) nested case-control analyses in Danish alendronate user-only cohort, treatment start 1996-2007 (N=63,774) followed to end of 2013. Logistic regression adjusted for comorbid condition, prior fractures and comedications. Data from table 2, Wang et al, Ost Int 2014. Abrahamsen, BMJ 2016 The patient after 2 years on aln 80 year-old lady, retired dentist, active. Family history of osteoporosis (mother, younger sister). Type 2 diabetes since 1990, good glycaemic control, microalbuminuria. Creatinine clearance now 30 ml/min by C-G formula. Other biochemistry unremarkable. 25-OHD 96 nmol/l. T-score -2.9 at L2-L4 spine (osteoporosis) no sig change -2.7 at femoral neck (osteoporosis) no sig change Meds Metformin, losartan, alendronate, calcium + vitd No side effects, no new complaints, no falls or fractures No longer smokes, no alcohol Options Raloxifene (no) Zoledronic acid (no) Strontium ranelate (no) Risedronate?? Denosumab Safety concerns with denosumab Denosumab post marketing safety Irrespective of duration Infections Hypocalcaemia Cataracts? (men) ONJ Pain Flatulence Probably unsafe in pregnancy/lactation (so avoid) Long term use only Atypical femur fracture Post-marketing safety surveillance data for ProliaÒ had recorded four cases of atypical femur fracture meeting the ASBMR case definition. All patients had previously been bisphosponate users. There were also 32 reports of ONJ and eight cases of severe symptomatic hypocalcaemia; seven of the latter cases were in patients with CKD. Five cases of anaphylaxis were recorded, generally on the day of injection. There were no fatal cases of anaphylaxis. Estimated exposure with Prolia Ò was 1.2 million patient years. Suresh, Cleveland Clin J Med. 2015 Feb;82(2):105-14 Geller, abstract ECCEO 2014 4
Safety concerns with forteo/tpd Irrespective of duration Fatigue Headache Bone pain Hypercalcaemia Probably unsafe in pregnancy/lactation Long term use only Osteosarcoma?? (young rat model) Activation of dormant bone metastases?? Albumin adjusted calcium level of 1.32 mmol/l (2.1 2.6 mmol/l) Phosphate 0.66 mmol/l (0.8 1.4) Parathyroid hormone 28.0 pmol/l (1.1 6.8 pmol/l) Communicating risk in osteoporosis The challenge of selecting an appropriate scale Brown, Can Fam Physician 2014;60:324-33. Red flags in the bone clinic Red flags in the bone clinic Renal function Renal function Pregnancy Osteomalacia Osteomalacia Hypoparathyroidism 5
Key points Important to consider renal function when prescribing. Particularly critical with zoledronic acid but true for all osteoporosis drugs (all are nominally contraindicated at crea/clearance < 30 ml, alendronate and zol at <35 ml. Be mindful of a history of upper GI complaints and chronic PPI use if prescribing oral bisphosphonates. Vitamin D status, renal function and intact PTH axis important when prescribing potent parenteral antiresorptives (dmab and zol) otherwise risk of life threatening hypocalcaemia. Key points Cardiovascular concerns (stroke, deep vein thrombosis) with raloxifene and strontium ranelate make these drugs less useful in the older patient. Atypical femur fractures are very rare and survival seems to be much better than after a hip fracture. Treatment is surgery. Easy to miss incomplete fracture as thigh or hip pain may have a multitude of causes (so be vigilant). ONJ is extraordinarily rare in osteoporosis patients but if possible then wait till elective dental work including implants has been completed if already planned. Good dental hygiene recommended. Inform patients despite rarity of this AE. 6