Musculoskeletal Clinical Correlates: Osseous Conditions in Dental Patients
Learning Objectives Define osteoporosis and explain how it is diagnosed. Describe the main risk factors for developing osteoporosis. Explain how different rates of bone resorption and formation during remodeling can either increase or decrease bone mass. For the major pharmaceuticals used to treat osteoporosis (bisphosphonates, denosumab, teriparitide, raloxifen and other SERMs), identify the main sites of action. Outline the major factors to be considered for implant placement in an osteoporotic patient.
Osteoporosis 80% of affected patients are women. 1/2 women and 1/8 men over 50 will have an osteoporosis-related fracture in their lifetime. risk of hip fracture = risk of breast, uterine and ovarian cancer combined. 1/4 hip fracture patients over 50 die in the year following their fracture.
2-4%/yr 0.5-1%/yr Life expectancy from 50 to 81.7 yrs Up to 30% of bone mass can be lost during 5-10yrs postmenopause
Number of cases (X106) 2.0 Future Considerations Comparative incidences: Women in the United States 2004-2008 1.5 1,420,000 1.0 0.5 373,000 345,000 213,000 0 Osteoporotic Fractures Stroke Heart Attack Breast Cancer Adapted from Watts et al, AACE Guidelines 2010 (data from Burge et al, Rosamond et al, and ACS) https://www.aace.com/files/osteo-guidelines-2010.pdf
Osteoporotic Fractures Number (X106) Future Impact of Osteoporosis 8.0 6.0 6,260,000 4.0 2.0 1,660,000 0 1990 2050 (estimate) Harvey et al 2010
Osteoporosis Porous bone Definition: Loss of bone mass beyond a critical density Localized or diffuse Secondary or primary Osteoporosis typically refers to the primary agerelated condition Very common (15 million annually in U.S.) Increased risk of fractures
Osteoporosis A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture Trabecular bone Normal Osteoporosis
Osteoporosis Porous bone Definition: Loss of bone mass beyond a critical density Localized or diffuse Secondary or primary Osteoporosis typically refers to the primary agerelated condition Very common (15 million annually in U.S.) Increased risk of fractures
DEXA Normal Osteopenia Osteoporosis Severe Osteoporosis BMD>-1.0 SD below the young adult reference BMD 1.0 to 2.5 SD below young adult reference BMD <-2.5 SD below the young adult reference BMD <2.5 SD below the young adult reference and fracture
Osteoporosis
All bones are not equal! Dense high proportion of cortical bone High proportion of trabecular bone
Bone formation has two distinct processes Intramembranous Ossification E12.5 E14.5 E12.5 E14.5 Endochondral Ossification E15.5 E15.5 E18.5 E18.5
Why the Jaw? Origin of bone Composition of bone Metabolic bone disease & the jaw Bone turnover Microflora Vascularity/lymphangiogenesis Hematopoiesis/marrow elements
Peak Bone Mass
Needs to be coupled: amount and location
Bone Remodeling Cycle
Bone Remodeling
Vital Statistics of adult bone remodeling Lifespan of BMU ~6-9 mos Speed ~25um/d Bone replaced by a BMU ~ 0.025 mm 3 Lifespan of osteoclasts ~2 weeks Lifespan of osteoblasts (active) ~3 months Rate of turnover of whole skeleton~10%/yr (BMU = bone multicellular unit) Manolagas; Endo Rev 21:115-137, 2000
Why is the coupling so important? Bone mass & Bone quality Bone Formation <----> Bone Resorption Bone mass normal, but Dr. Yuji Mishina
Post-menopausal Osteoporosis
Post-menopausal bone loss is the result of imbalance between bone formation and resorption within a BMU. Bone Mass % Resorption Bone Turnover Formation 50 60 70 80 Age (years)
Treatments for osteoporosis target either resorption of formation Calcium? exercise vitamin D? estrogen bisphosphonates calcitonin denosumab (Prolia) strontium ranelate fluoride androgens PTH (Teriparatide) RGD peptides SERMs Antiresorptive vs. Anabolic osteoclast transport inhibitors outside US Experimental
Anti-resorptives vs. anabolic agents for treating bone disease Anti-resorptives (e.g. estrogen, SERMs, bisphosphonates, Denosumab) Anabolic agents (e.g. PTH, growth factors, exercise) Osteoblasts Osteoclasts Small and slow increases in bone Large and rapid increases in bone
Therapeutic targets Denosumab Teriparatide Teriparatide Teriparatide Bisphosphonate
Antiresorptives Bisphosphonates Reduce remodeling ~70% Inhibit membrane ruffling Inhibit osteoclast differentiation Induce osteoclast apoptosis H O O O ll l ll HO-P-C-P-OH l l l O R O H H Denosumab Resting bone surface 85% - low BP affinity Resorbing surface 2% - 8x higher affinity Forming surface 10-12% - 4x higher affinity Strong affinity for calcium Adapted from McCauley & Nohutcu 2002
Bisphosphonate: Mechanisms Dimethylallyl diphosphate X HMG-CoA Mevalonate Phosphomevalonate Mevalonate disphosphate Isopentenyl diphosphate (IPP) FPP Synthase Farnesyl diphosphate (FPP) Geranylgeranyl diphosphate (GGPP) Small GTPases Ras, Rab, Rho, Rac Prenylated proteins Loss of actin rings Loss of survival signals
Bisphosphonates Mechanism of Action Normal protein prenylation Loss of protein prenylation Membrane ruffling Actin ring formation Loss of ruffling Loss of actin ring apoptosis Normal Osteoclast Osteoclast on bisphosphonates
Why is the coupling so important? mechanisms to increase bone mass Examples Bone Formation <---> Bone Resorption Bone mass BMP treatment BMP receptor KO Anti-resorptives Anabolic agents Romosozumab (Anti-sclerostin Ab) Dr. Yuji Mishina
Implant Challenge 63 yo female Smoking history: pkg/d quit 1980 Alcohol: seldom Hx: Osteoporosis, hip fracture Hx: Arthritis Meds: Fosamax 10 yrs. Caltrate D Allergy: Penicillin
63 year old female Right hip fracture age 60 with diagnosis of osteoporosis T scores of -1.6 to -1.9 for the vertebrae and -1.8 to -3.0 at the femur over past 3 yrs Taking alendronate for 3 years Wants to replace posterior teeth
What information is needed to answer this patient s question? Knowledge of osteoporosis Knowledge of the medications Knowledge of local factors/disorders in the oral cavity
Initial Exam PANX
Implant integration compromise
Implant Integration
Summary Osteoporosis: population, definition Diagnosis Etiology Medications: Mechanisms of action Impact of therapeutics on the oral cavity & implant placement
Osteoporosis & Oral Bone loss Relationship: low BMD & residual ridge reduction in the edentulous mouth -Due to reduced biomechanical loading Osteoporosis: risk for minor accentuation of alveolar bone loss in cases of periodontitis but overruled by local factors.