From Fragile to Firm Monika Starosta MD Advocate Medical Group
Bone Remodeling 10% remodeled each year Calcium homoeostasis Maintain Mechanical strength Replace Osteocytes Release Growth Factors
Bone remodeling Osteoclasts Resorb bone mineral and collagen Resorption phase ends with osteoclast apoptosis Osteoblasts Synthesize organic matrix Have 3 fates Apoptosis Diff into osteocytes Remain on surface and diff into bone lining cells
Osteoclasts Are Terminally Differentiated Osteoblasts Embedded in Bone Osteocytes are most abundant and longest lived cell in bone Osteocytes orchestrate bone remodeling along with regulation of bone osteoclast and osteoblast activity (mechanosensors detect damage)
Figure 3 Factors that influence the development of osteoporosis Hendrickx, G. et al. (2015) A look behind the scenes: the risk and pathogenesis of primary osteoporosis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2015.48
Figure 1 Overview of BMD values during life, indicating the importance of peak bone mass and the subsequent rate of decline in BMD in the development of primary osteoporosis Hendrickx, G. et al. (2015) A look behind the scenes: the risk and pathogenesis of primary osteoporosis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2015.48
Table 2 Treatments for osteoporosis and their effects on BTM Naylor, K. & Eastell, R. (2012) Bone turnover markers: use in osteoporosis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2012.86
Bisphosphonates Beyond 5 years Analogs of pyrophosphate that bond avidly to bone mineral, are internalized by mature osteoclasts during resorption and inhibit enzyme in mevalonate pathway cell death Half life of alendronate ~10 years for elimination from skeleton
Figure 1 Uptake and release of bisphosphonates from bone Papapoulos, S. E. (2013) Bisphosphonates in osteoporosis beyond 5 years Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.57
Figure 2 Changes in bone mineral density associated with treatment with goserelin and either tamoxifen (20 mg by mouth daily) or anastrozole (1 mg by mouth daily) for 36 months, with or without concomitant zoledronic acid (4 mg by intravenous infusion every 6 months) in premenopausal women with oestrogen-receptor-positive breast cancer Coleman, R. E. et al. (2013) Management of cancer treatment-induced bone loss Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.36
Denosumab RANKL TNF superfamily that is necessary for the normal development of osteoclasts RANKL Produced by osteoblasts, T cells, keratinocytes Receptors on monocytes, macrophages and dendritic cells
Figure 2 Proposed mechanism of action for denosumab Deal C (2008) Potential new drug targets for osteoporosis Nat Clin Pract Rheumatol doi:10.1038/ncprheum0977
Denosumab vs Zolderonic Acid to delay/prevent skeletal related events Journal of Clinical Oncology 2010 A. Stopeck
Denosumab Freedom Extension
Denosumab Freedom extension
Journal of Clinical Oncology 2010 A. Stopeck Denosumab vs Zolderonic Acid to delay/prevent skeletal related events Denosumab (120 mg monthly) delayed time to first SRE by 18% compared to zoledronic acid (4 mg monthly) ONJ 2% denosumab, 1.4% zoledronic acid (75/75% receiving chemotherapy antiangiogenic agents highest risk)
Teriparatide Recombinant human PTH Phase III trial stopped after 19 mo because of dose dependent risk of osteosarcoma in rats 2004-2011 no humans affected More effective than bisphosphonate in steroid OP combined with denosumab (Tsai Lancet)
Treatment of Osteoporosis NOF treatment guidelines Hip or spine fracture BMD FRAX Treatment indefinite
Current Treatment of Osteoporosis BP stopped at 5 years Decision to change therapy No guidelines Fractures while on treatment/declining BMD
Bisphosphonate Drug Holiday Not discussed in 1995 FDA warning 2010, FLEX study FIT 3-4 years, FLEX 5 years) the optimal duration of the use has not been determined. All patients on bisphosphonate therapy should have the need for continues therapy reevaluated on a periodic basis
Long Term Bisphosphonate FLEX (daily alendronate > 5 years) continue daily alendronate vs placebo HORIZON (ZA for 3 years) ZA for 3 years vs placebo BOTH reduction in vertebral fractures (neither nonvertebral) NEJM Black DM 2012
Should drug holidays be Considered? ONLY in low risk pt (no prior Fx, T scores > - 2.0, age < 65, comorbidities)
Osteonecrosis of the Jaw Exposed bone in oral cavity despite treatment over 6-8 weeks 5% pts with cancer and high dose IV bisphosphonate (recently denosumab)
Osteonecrosis of the Jaw? Etiology Infection universal finding Soft tissue toxicity
Figure 1 Gross and radiographic appearance of osteonecrosis of the jaw Reproduced with permission from Elsevier Ltd Abu-Id, M. H. et al. J. Craniomaxillofac. Surg. 36, 95 103 (2008) Reid, I. R. & Cornish, J. (2011) Epidemiology and pathogenesis of osteonecrosis of the jaw Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2011.181
Osteonecrosis of the Jaw 67% tooth extraction No predisposing factors 26% Mean time ONJ in cancer with zolderonic acid 1.8 years 5% prevalence
Goal Directed Therapy OP Tx other chronic conditions Goals individualized
Goal Directed Therapy If started for hip/spine fracture fracture free for 5 years Hip T score BMD goal > 2.5
Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur Atypical simple transverse or oblique Fx with cortical beaking an diffuse cortical thickening Low level trauma, prodromal pain, contralateral changes, NEJM Black DM 2010
Bisphosphonates and Fractures of the Subtrochanteric or Diaphyseal Femur Pts from FLEX, FIT and HORIZON trials (total 11 pts) BP use 2.3 annual atypical fx per 10,00 pt years (up to 10 years Tx)
Fracture Prediction FRAX LS not included
Bridging Osteoporosis Treatment Gap: Fracture Liaison Service (FLS) In 2012 19-25% of Medicare women > 65 with fracture received DEXA or treatment