Osteoporosis: Pathophysiology and Management Dr. Frank Waldron-Lynch M.D Ph D MRCPI MRCP(UK), Section of Endocrinology, Yale University School of Medicine.
Jan 21, 2015
Osteoporosis: Pathophysiology and ManagementDr. Frank Waldron-Lynch M.D Ph D MRCPI MRCP(UK),
Section of Endocrinology, Yale University School of Medicine.
Outline
• Definition of osteoporosis• Pathogenesis• Diagnosis• Therapy• Future development
http://www.med.yale.edu/intmed/endocrin/patient/bonecenter.html
Classic presentation
Definition
• Clinical– Loss of bone mass sufficient to significantly
increase the risk of fracture
• Diagnostic– T score – number of standard deviations above or
below the mean for a similar healthy 30 year old• Normal BMD = T: 0 to -1• Osteopenia BMD = T: -1 to -2.5• Osteoporosis BMD = T: less than -2.5
– Z score – number of standard deviations above or below the mean for the patients age, sex and ethnicity
Epidemiology
• United States– 10 million individuals with osteoporosis– 34 million individuals with osteopenia
• Fracture Risks over age 50– 50% of women will have an osteoporosis related
fracture– 25 % of men will have an osteoporosis related
fracture
• Estimated costs– Direct health care $14 billion each year
http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/default.asp
Pathogenesis
• Peak bone mass
• Etiology Bone loss
• Age
• Secondary causes
Peak Bone Mass
• Genetically determined– 70-75%– Driven by sex hormones during puberty– Depends on site measured – spine, femur, radius
• Ethnicity– Chinese American later than Caucasians
• Women– Peak accrual ages 11-15– 95 per cent achieved by late teens
• Men– Peak accrual later teens– Maximum spine age 20– Radius and femur by mid twenties
Factors Affecting Peak Bone Mass
• Delay or Failure of puberty– Primary Hypogonadism
• Turners syndrome• Klinefelter syndrome• Absent cervix, uterus, cervix and/or vagina • Cryptorchidism • Chemotherapy, Radiotherapy• Chronic systemic diseases
– Secondary Hypogonadism• Kallmann syndrome• CNS tumors, infiltrative disorders• Malnutrition • Chronic systemic illness
Etiology of Bone loss in Osteoporosis
OSTEOCLAST - RESORPTIONOSTEOBLAST - FORMATION
Primary cause is estrogen deficiency+
Estrogen Deficiency
• Women – Occurs earlier– At menopause bone loss rates to increase by 2
to 6 fold– For subsequent 6-8 years– Impairs calcium absorption from gut
• Men– Testosterone declines age– Estrogen declines age– Both androgens and estrogen contribute
Riggs B. N Engl J Med 1986;314:1676 Age (years)
Ann
ual F
ract
ure
Inci
denc
e,
per 1
00,0
00
0
1000
2000
3000
4000
35 45 55 65 75 85+
Vertebrae
Hip
Colles'
Fracture Risk with Aging
Caucasian women
Hip Fracture Risk for a Given T-score Depends on Age
10 year risk of fracture in Swedish women
Secondary causes of accelerated bone loss• Inherited disorders
– Osteogenesis imperfecta tarda– Thallasemia
• Amenorrhea – Eating disorders– Low weight– Excess Exercise– Female athlete triad
• Energy deficiency• Low bone mineral density• Amenorrhea
– Premature ovarian failure
Secondary causes of accelerated bone loss• Respiratory
– Cystic fibrosis• Gastrointestinal
– Celiac sprue– Post Gastric by pass– Inflammatory bowel disease
• Renal– Idiopathic hypercalciuria– Chronic renal failure
• Post organ transplant– Immunosuppressive therapy
Secondary causes of accelerated bone loss• Endocrine
– Hyperthyroidism– Hyperparathyroidism– Cushing’s syndrome– Hypogonadism– Vitamin D deficiency
• Rheumatology– Rheumatoid arthritis– Seronegative athropathies
• Lifestyle– Smoking– Alcohol
Secondary causes of accelerated bone loss• Drugs
– Glucocorticoids– Cyclosporine– Anti seizure medications
• Phenobarbital• Phenytoin
– Heparin– Chemotherapy
• Aromatase inhibitors
– Thyroxine• Over replacement
Diagnosis
• Approach to patient
• Investigations– Bloods– Urine– Imaging
• FRAX use
• Calcium and Vitamin D
Approach to patient with suspected osteoporosis – guide investigations• Focused history
– Fracture history– Loss of height– Exercise– Menstrual history– Hypogonadism men– Diet– Smoking– Alcohol
• Past medical history– Secondary causes
Focused history
• Medications– Any drugs effect BMD– Any drug affect calcium absorption
• Family history– History osteoporosis
• Systems review– Gastrointestinal system
• GERD• Esophageal stricture• Malabsorption
Examination – Key points
• Weight– Calculate body mass index
• Height– Measure and follow– Loss greater than 1 inch may indicate spinal
fracture• Muscular skeletal
– Spine• Deformity• Tenderness• Mobility
– Muscle strength• Proximal muscle weakness
Investigations
• Bloods -Basic– CBC– Electrolytes and eGFR– Serum calcium and phosphate– TSH– Testosterone (Men)– Serum protein electrophoresis – Bone markers (consider)
• Urine– 24 hour urine– Volume– Creatinine and calcium
OSTEOCLAST - RESORPTIONOSTEOBLAST - FORMATION
Intact Osteocalcin (OCI) Mineralization
Bone Alkaline phosphatase (Bone AP) MaturationDeoxypyridinoline (fDPD/Cr)
N-Terminal cross-linking telopeptide
(NTx/Cr)
Procollagen Type 1N Propeptide (PINP) Synthesis
Bone re modelling – Bone markers
Bone markers - Use
• Diagnosis– Identification high bone turnover states– Not as well validated as DXA
• Monitor therapy– Commencing– During treatment– Urinary Ntx
• Should decrease on bisphosphates
Direct measurement of BMD by DXA and as well as CT allows us to diagnose osteopenia
• Bone mineral density testing – Important means of assessing fracture risk– Not stand alone test
• Other risk factors have impact on fracture risk – occasionally more significant impact than bone
density results alone– Glucorticoids
• All known risk factors should be considered when deciding to treat patients– Mostly treating patients based on risk– No overt disease
• We need better tools for assessing fracture risk
Bone mineral density testing
FRAX - Fracture Risk Assessment Tool
WHO has recently released FRAX, the WHO Fracture Risk Assessment Tool. Patients and clinicians can access this tool at:
http://www.shef.ac.uk/FRAXhttp://www.shef.ac.uk/FRAX
– Data from 9 cohorts around the world– Validated in 11 independent cohorts with similar
geographic distribution
FRAX - Use
FRAX variables
Treatment recommended
• Consider FDA-approved medical therapies in postmenopausal women and men aged 50 years and older, based on the following:– A hip or vertebral fracture – T-score ≤ -2.5 at the femoral neck or spine after
appropriate evaluation to exclude secondary causes
– Low bone mass (T-score between -1.0 and -2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture ≥ 3% or a 10-year probability of a major osteoporosis-related fracture ≥ 20%
– Clinicians judgment and/or patient preferences may indicate treatment for people with 10-year fracture probabilities above or below these levels
Caveats regarding FRAX
• Prospective data on the efficacy of FRAX in making pharmacologic treatment decisions are lacking
– Can osteoporosis medication help equally well with all risk factors? (likely not!)
– That is, not everyone with a high FRAX should be treated with a medication
– We need intervention trials with FRAX as an outcome
• It does not capture spinal osteoporosis
Non Pharmacologic Treatment
• Essential – Are as important as any medication
• Nutritional– Calcium– Vitamin D– Vitamin A
• Lifestyle– Smoking– Exercise
• Falls risk reduction
Calcium and Vitamin D
• Calcium– Total sufficient to prevent calcium
malabsorption and secondary hyperprathyroidism
– Test adequate by 24 hour urine if eGFR > 60cc/min
– Total daily intake 1500 mg/day
• Vitamin D– Aim serum 25(OH) vitamin D > 25 ng/dl (ideally
25-35)– Total daily intake 800 IU– Higher if malabsorption
Effects of Vitamin D supplementation
• Double-blind community-based RCT in the UK
• 2686 individuals (2037 men; 649 women)– Over age 65
• 100,000 U of vitamin D3 orally every 4 months for 5 years
• mailed to the study subjects so compliance not confirmed
Trivedi et al. BMJ;326:469
Drug Therapy for Low Bone Mass
Prior to drug therapy treat any secondary causes
Drug Therapy for Low Bone Drug Therapy for Low Bone MassMass
• Bisphosphates
• Parathyroid hormone
• Selective Estrogen Receptor Modulators
• Denosumab
Targeting the bone resorption side of thebone remodeling cycle
ETIDRONATEETIDRONATE
PAMIDRONATE
ALENDRONATE
IBANDRONATE
RISEDRONATE
TILUDRONATE
CLODRONATECLODRONATE
ZOLEDRONATE
Bisphosphonates
Bisphosphonates are the most effective antiresorptive agents available for the
prevention and treatment of bone loss.
Anti-fracture efficacy of bisphosphonates in osteoporotic women
Vertebralfracture
Hip fracture
Non-vertebral fracture
Alendronate (Fosamax®)
√√ √√ √√
Risedronate (Actonel®)
√√ √√ √√
Zolendronate (Reclast®)
√√ √√ √√
Ibandronate(Boniva®
√√ ?? √√
When can the patient have a drug holidayfrom bisphosphonates?
The Flex Trial
1. Time to non vertebral fracture2. Time to vertebral fracture after 5 years
JAMA 296:2927
Management of patients taking bisphosphates
• Dental examination prior to treatment• Repeat BMD 1-2 years of treatment
– Demonstrate efficacy• Check BMD 1-2 years later
– Improve patient compliance• 5 years
– Stop drug individuals with a good response– No longer osteoporotic
• 10 years– Stable BMD– No recent fractures
Raloxifene
• Selective Estrogen Receptor Modulators (SERMs)
• Raloxifene– Reduces vertebral fracture– No reduction in hip fracture
• Reserve use with women without hip involvement
• Other beneficial actions– Reduces risk invasive breast cancer– No increase on cardiovascular motality of
mobidity
Denosumab: therapy targeted atthe RANKL/OPG system
Not approved by FDA yet
Osteoclast precursorRANKRANK
OPGOPG
RANKRANK -Ligand-Ligand
Osteoblast
DenosumabDenosumab
Humanized anti-RANK-Ligand
Mechanism of action Denosumab
Denosumab: The FREEDOM trial
• 7,868 women ages 60 to 90• Mean L-spine T-score -2.8• 23% of had prevalent vertebral fractures at
baseline• 60 mg of denosumab subQ every six months or
placebo for 3 years• 68% reduction in vertebral fractures p<0.0001.• 20% reduction in non-vertebral fractures p=0.011.• 40% reduction in hip fracture at p=0.036.• No increased incidence of malignancy • Some increase in erysipelas
Targeting the bone formation side of thebone remodeling cycle
Parathyroid Hormone
PTH - Mechanism of Action
PTH binds to cell surface
G protein-coupled receptor
Decreased apoptosis andstimulation of osteoblasts
Stimulation of differentiationof proosteoblasts to osteoblasts
Net increase in number andaction of bone forming
osteoblasts
Effect of rhPTH(1-34) on the Risk of New Effect of rhPTH(1-34) on the Risk of New Vertebral FracturesVertebral Fractures
*p <0.001 vs. Placebo
Ris
k R
edu
ctio
n (
RR
)
Placebo(n=448)
rhPTH 20(n=444)
rhPTH 40(n=434)
64 22 19100%
75%
50%
0%
25%
% o
f Wo
men
8
0
246
101214
RR 0.31 (95% CI, 0.19 to 0.50)*
RR 0.35 (95% CI, 0.22 to 0.55)*
65% 69%
No. of women who had > 1 fracture
PTH plus ALENDRONTE may not be better than PTH alone
PTH
• Advantages– First anabolic therapy– Good efficacy data
• Use first prior to bisphosphate• 18 months – 2 years treatment
PTH
• Disadvantages– Must be given by subcutaneous injection– Risk Osteosacroma– Cost
• Monitoring– Hypercalcemia and hypercalciuria– Check one week and then six months after
initiation treatment
• Not use in patients with calcium oxalate renal stone disease
Summary
• Osteoporosis is an important public health problem
• Accurate diagnosis and treatment requires the use of bone densitometry.
• Radiologists play a central role in the diagnosis and management– of this disease:– measuring bone density– diagnosing fractures– pointing out secondary causes of bone loss
• There needs to be greater attention paid to fall risk-reduction and other modifiable environmental factors.
Summary
• A variety or antiresorptive agents are available for the prevention and treatment of osteoporosis of which the bisphosphonates are the most efficacious.
• Parathyroid hormone is the 1st truly anabolic therapy for the treatment of osteoporosis and is an important addition to our therapeutic regimen.
• Additional anabolic therapies are on the horizon
Thank you for your attention