THE MANAGEMENT OF BONE STRESS INJURIES WITH ANTIFRACTURE AGENTS
Dr Greg Lovell
AIS Dept of Sports Medicine
CASE STUDY
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Athlete has consented to this presentation
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41 yr old Paralympic triathlete
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presented with 3 weeks of vague right sided posterior chest wall pain late Feb 2016
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Spect CT – posterior rib stress fracture
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Due to compete in Rio
CLINICAL APPROACH
Bone stress
injury
Fracture risk
stratification
Bone health risk
factors
Management
Bone Health checklist
Genetics
Training history
Nutrition history
Calcium, Vit D
Endocrine history
Bone disease
Bone
quality
Bone
Health
Modifiable
factors
Inhibitors
Hughes J 2015
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Risk stratification
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Bone quality
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Osteopenia
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Endocrine history
Modifiable factors
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Low risk, high grade
TSB, load
Bone inhibitors
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Psychological stress
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Energy availability
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Failed to respond to rest and low load over 4 weeks
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Repeat - CT and US rib stress fracture line present and callus identified
MANAGEMENT DECISIONS
1. Pain
2. Load
what and when
NWB/brace/ plaster
PWB
FWB
Sport
Diagnosis
3. Fitness
muscle strength
CVS fitness
biomechanics
Return to sport
Additional treatments 4. Nutrition
5. Fracture enhancement drugs - Bisphosphonates/PTH/oestr
6. Other - LIPUS/TENS/Vibration/HBO
FRACTURE HEALING ENHANCEMENT
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Large number of fractures – long bone fractures
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Complications - Non union
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Co-existing risk factors eg diabetes, osteoporosis, smoking, alcohol, NSAIDs
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Impairment - loss of function
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Demand for early function
HOW MIGHT THIS BE RELEVANT IN SPORTS MEDICINE?
Bone stress injury
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close to major competition
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high grade - likely long rehabilitation times
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high risk – complications
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bone quality problems
BONE ENHANCEMENT PRINCIPLES
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Increase osteoblastic activity
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Recruit osteoprogenitor cells
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Inhibit osteoclasts
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Stimulate vascularisation
FRACTURE HEALING ENHANCEMENT
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Bone regeneration – BMP, FGF, VEGF; EPO
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CVS system – statins, ACE inhibitors, vasodilators
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Others –
• melatonin, botox, vit E, lithium, sildenafil
• Insulin, IGF1, GH, vanadium
• Proteasome inhibitors
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Anti-osteoporotic drugs
ANTI-OSTEOPOROTIC DRUGS
Antiresorptive
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Bisphosphonates
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Denosumab
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Strontium
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Cathepsin K inhibitors
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Estrogens, SERMs
Anabolic
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PTH
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Strontium
Biologicals
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Sclerostin antibody, Wnt signalling proteins
Others – Vit K2, Calcitonin, Calcium sensing antagonists
BISPHOSPHONATES
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Structural analogues of inorganic pyrophosphate
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Bind to hydroxyapatite crystals
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Inhibit osteoclast resorption
• Effects on- Osteoclast recruitment, differentiation, resorptive activity, apoptosis
FRACTURE MODELS
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Short term - increased callus and bone mineral content
• only has the potential to maximise a system’s intrinsic bone forming potential Yu 2012
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Delay in remodelling from woven to lamellar bone - Kates 2016
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Single dose 1-2 weeks after fracture -> increased bone mineral content and strength
[Little 2005, Amanat 2007]
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Closed fractures - incr callus size and strength, single bolus
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HORIZON trial – hip fracture – zolendonic acid no effect
ANIMAL BONE STRESS DATA
Sloan 2010 rat ulna stress model – daily alendronate
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suppressed bone formation by 44% at 4 weeks cf control, decreased strength at 8 weeks
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microcrack repair reduced at 4 weeks
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periosteal woven bone no change
Kidd 2011 – rat bone stress model - daily risedronate – delayed healing but dose
dependent
Savaridas 2013 - rat direct fracture model
ibandronate had inhibitory effect on healing
HUMAN BONE STRESS
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Stewart 2005 - Case report 5 tibial stress reactions – reduced pain and
improved RTS
IV pamid weekly x4
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Chambers 2011 – case report 5 lumbar pars stress #; reduced pain,
radiological healing IV monthly x3
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Milgrom 2004 prophylactic risedronate no benefit
DENOSUMAB - PROLIA
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Antiresorptive agent
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Monoclonal antibody that selectively blocks RANKL
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Blocks formation of osteoclasts,increases apoptosis
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In osteoporosis improved BMD and bone strength, reduced fractures
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Disturbs ‘targeted remodelling’ - blocks RANKL released by osteocytes
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Animal studies on fracture healing - no significant effect (Bukata 2011)
PTH - PARATHYROID HORMONE
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Amino acid peptide secreted by parathyroid glands
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Function is to maintain calcium homeostasis
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Effect on GI, renal, bone
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Intermittent PTH is anabolic - increases osteoblastic activity
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Continuous PTH is catabolic – promotes osteoclast activity
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Teriparatide – synthetic polypeptide, recombinant form of the active component of human PTH
Babu 2015
PTH
PTH
Animal data ++
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Improved bone healing in normal conditions AND in impaired
bone healing – age, oestrogen deficiency, malnutrition
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Improved callus volume, mineralisation, bone mineral
content, union rates and fracture site strength
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Intermittent treatment leads to increased osteoblastic activity
-> incr Bone mass and strength (anabolic effect)
Piechl 2011 Ellegaard 2010; Barnes 2008; Andreassen
1999, 2004
PTH HUMAN REPORTS
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Neer 2001 - in osteoporosis stimulates cancellous bone formation ->incr BMD and decr frac risk
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> 10 case reports on fracture healing
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Delayed union/ non-union
• Rubery and Bukata 2010 – 3 odontoid fractures all united
• Others – sternal, trochanteric, humeral, femoral #
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Number of reports of atypical femoral fractures healing with PTH treatment
Campbell 2015
PTH HUMAN TRIALS
Aspenberg 2009
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102 postmenopausal women RCT radial frac
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Teriparatide 20ug for 8 weeks improved healing by 1.7 wks (7.4 v 9.1 wks),
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no functional outcome difference
Peichl 2011
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65 osteoporotic elderly patients RCT pelvic frac + vit D 800IU, Ca++ 1000mg +/- PTH
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Healing 8 wks 100% v 10%; 12 wks 70%
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Mean healing time 7.8 wks PTH group, 12.6 control
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Significant clinical improvements in PTH group
Johansson 2016
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No effect in RCT on 40 proximal humerus fractures
PTH AND STRESS FRACTURES
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Ballieul 2016
• Bilat sacral stress # in a 36yr old endurance athlete – 6 months of treatment
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Raghavan 2012
• Two metatarsal stress fractures healed after delayed healing
• 4 weeks daily forteo + vit D 50,000IU daily and calcium 2,000mg daily
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Malhotra 2013
• Tensile femoral neck stress #, 3 months of forteo + vit D 50,000 wkly and Calcium 500mg bd
5. FRACTURE ENHANCEMENT DRUGS
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Antiresorptive agents
• Bisphosphonates
• Denosumab
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Anabolic
• PTH - most promising fracture enhancement drug
PTH
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Teriparatide (Forteo)
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Daily subcutaneous injection – 20ug
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Cost ~$500 per 28d course
Do not use
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if open physes, PH osteosarcoma
Common adverse effects –
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include nausea, arthralgia, headache, dizziness and injection-site reactions
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Consider measuring baseline serum levels of calcium, vitamin D, creatinine, uric acid and parathyroid hormone
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Check se Ca++ after one month
FORTEO – BLACK BOX WARNING
BLACK BOX WARNING
• original study was treatment in rats predisposed to tumours over a 2 year period –
(equivalent to human dosing for > 30 years and dose 3-10x)
• repeat study showed no tumours in these rats if used < 6 months and dose dependent
• similar study in monkeys over 18 months found no tumours
• US Cancer Survey 2012 -in approx. 600 cases of osteosarcoma over a 7 year period, no
patient had prior treatment with PTH
• no case reports of osteosarcoma in thousands of patients worldwide on teriparatide
• menopausal osteoporosis patients are being advised to limit the use of PTH to 2 years
over their lifetime
Vahle 2002, 2004, Jerome 2001, Watanabe 2012, Andrews 2012
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Athlete consented to use of PTH
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Started on daily subcut Forteo, vit D 1,000 IU bd, caltrate 600mg tds
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Pain improved over next 2 weeks
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Started to train again after 2 weeks
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Still some minimal discomfort at 4 weeks ->
• so due to poor bone quality 2 nd course of Forteo given
• Asymptomatic at 6 wks and fully training
AIS EXPERIENCE
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Over last 2 years
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Athletes with stress reaction/fracture close to competition
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Daily injections for one month
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Supplemented with calcium and vitamin D
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Blood screen before start of therapy
AIS EXPERIENCE
15 athletes – 11 positive response
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Sacral stress fracture
1/1
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Lumbar pars stress fracture
1/3
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Lumbar pedicle stress fracture
1/2
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Femoral stress reaction
3/3
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Femoral neck stress reaction
1/1
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Metatarsal stress fracture
2/3
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Rib stress fracture – delayed union
1/1
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Rib fracture
1/1
June 30
FORTEO AIS APPROACH
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Right patient at the right time
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Daily injections
• Length of course will depend on the bone stress injury
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Supplement with
• Vit D 1,000 IU bd - check vit D level if < 50 stat dose 50-100,000 IU
• Caltrate 600mg bd – check dietary intake
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ABSTRACT
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Title: Management of bone stress injury with anti-fracture agents
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Author: Dr Greg Lovell
Institution: Australian Institute of Sport
Bone stress injury is common in elite sport, often occurring when an athlete is in intensive training or prior to an important event.
Rehabilitation times can be prolonged. Currently there is interest and research in the possible role of anti-fracture osteoporosis
drugs in the treatment of fractures. In particular bisphosphonates and parathyroid hormone (PTH) have both been reported to be
considered useful in fracture management and there are now case reports of their use for bone stress injury management in
athletes. After due consideration of an athlete’s injury and need to compete, review of possible drug side effects and with
appropriate loading management advice, fifteen elite athletes were treated at the AIS with PTH. Eleven had a good response to
treatment and were able to successfully return to training and competition. This presentation will consider the actions of these
drugs on bone and how they may be a useful adjunct for sports physicians when treating bone stress injuries.
Biography
Dr Greg Lovell is a senior sports physician at the Australian Institute of Sport and a fellow of ACSEP. His particular sports medicine
interests include bone stress injuries and groin injury management.