Dr Debasis Mukherjee

IPGME&R, KOLKATA

Dept. of Orthopaedics

Older patients have frequent admissions and increased length of stay, increasing possible points of contact

Patients from nursing facilities, those at greatest risk, may have little continuity

Discharge medications for patients going to skilled nursing facilities can have LARGE impact

Study: Only 6% of patients admitted with hip fracture to a tertiary care hospital were adequately treated for osteoporosis at discharge, only 12% at 5 years!

Another study: only 21% medicare beneficiaries with hip fracture had any prescription treatment; patients older than 74 and those with other comorbidities were least likely to receive treatment

"A disease characterised by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk".

WHO: utilizes Bone Mineral Density as definition (T score <-2.5); surrogate marker

Cortical Bone Dense and compact Runs the length of the long bones, forming a

hollow cylinder Trabecular bone

Has a light, honeycomb structure Trabeculae are arranged in the directions of

tension and compression Occurs in the heads of the long bones Also makes up most of the bone in the vertebrae

Principal organizing feature of compact bone Haversian canal – place for the nerve blood

and lymphatic vessels Lamellae – collagen deposition pattern Lacunae – holes for osteocytes Canaliculi – place of communication between

osteocytes

Osteocytes - derived from osteoprogenitor cells Osteoblasts Osteoclasts

Trapped osteoblasts In lacunae

Keep bone matrix in good condition and can release calcium ions from bone matrix when calcium demands increase Osteocytic osteolysis

Make collagen Activate nucleation of hydroxyapatite

crystallization onto the collagen matrix, forming new bone

As they become enveloped by the collagenous matrix they produce, they transform into osteocytes

Stimulate osteoclast resorptive activity

Resorb bone matrix from sites where it is deteriorating or not needed

Digest bone matrix components Focal decalcification and extracellular

digestion by acid hydrolases and uptake of digested material

Disappear after resorption Assist with mineral homeostasis

MatrixMineral

Collagen type I and IV Layers of various orientations (add to the

strength of the matrix) Other proteins 10% of the bone protein

Direct formation of fibers Enhance mineralization Provide signals for remodeling

A calcium phosphate/carbonate compound resembling the mineral hydroxyapatite Ca10(PO4)6(OH)2

Hydroxyapatite crystals Imperfect Contain Mg, Na, K

Calcification occurs by extracellular deposition of hydroxyapatite crystals Trapping of calcium and phosphate ions in

concentrations that would initiate deposition of calcium phosphate in the solid phase, followed by its conversion to crystalline hydroxyapatite

Mechanisms exist to both initiate and inhibit calcification

Proceeds in cycles – first resorption than bone formation

The calcium content of bone turns over with a half-life of 1-5 years

Phase I Signal from osteoblasts Stimulation of osteoblastic precursor cells to

become osteoclasts Process takes 10 days

Phase II Osteoclast resorb bone creating cavity Macrophages clean up

Phase III New bone laid down by osteoblasts Takes 3 months

Vitamin D Parathyroid Hormone Calcitonin Estrogen Androgen

Osteoblast have receptors for (1,25-(OH)2-D) Increases activity of both osteoblasts and

osteoclasts Increases osteocytic osteolysis (remodeling) Increases mineralization through increased

intestinal calcium absorption Feedback action of (1,25-(OH)2-D) represses

gene for PTH synthesis

Accelerates removal of calcium from bone to increase Ca levels in blood

PTH receptors present on both osteoblasts and osteoclasts

Osteoblasts respond to PTH by Change of shape and cytoskeletal arrangement Inhibition of collagen synthesis Stimulation of IL-6, macrophage colony-stimulating

factor secretion Chronic stimulation of the PTH causes

hypocalcemia and leads to resorptive effects of PTH on bone

C cells of thyroid gland secrete calcitonin Straight chain peptide - 32 aa Synthesized from a large preprohormone Rise in plasma calcium is major stimulus of

calcitonin secretion Plasma concentration is 10-20 pg/ml and half

life is 5 min

Osteoclasts are target cells for calcitonin Major effect of clacitonin is rapid fall of

plasma calcium concentration caused by inhibition of bone resorption

Magnitude of decrease is proportional to the baseline rate of bone turnover

Estrogens Increase bone remodeling

Androgens Increase bone formation

Growth hormone Increases bone remodeling

Glucocorticoids Inhibit bone formation

Thyroid hormones Increase bone resorption Increase bone formation

Cytokines IL-6 IL-1

Prostaglandins Growth factors

IGF-I TGF-β

A disease characterized by: low bone mass microarchitectural deterioration of the bone

tissue Leading to:

enhanced bone fragility increase in fracture risk

Normal: Not less than 1 SD below the avg. for young adults

Osteopenia: -1 to -2.5 SD below the mean Osteoporosis: More than 2.5 SD below the

young adult average 70% of women over 80 with no estrogen

replacement therapy qualify Severe osteoporosis

More than 2.5 SD below with fractures

Although exact numbers are not available, based on available data and clinical experience, on estimated 25 million Indians may be affected. [Indian J Med Res. 2008 Mar;127(3):263-8.]

Increase in the incidence related to decreasing physical activity

1 of 3 women are affected with osteoporosis 1 of 5 men are affected with osteoporosis

Mechanisms causing osteoporosis Imbalance between rate of resorption and

formation Failure to complete 3 stages of remodeling

Types of osteoporosis Type I Type II Secondary

1. Genetics / family Hx..

2. Race /Asians

3. Gender /( F-estrogen, M-androgen )

4. Age / intake,absorption, Ca loss↓ ↑

5. Nutrition / Ca,Vit-D intake↓

6. Physical exercise /sedentary occupation ,immobility

7. Physical build / small frames,undreweights

8. Habits/life style / Smoking,Alcohol,carb.Bevereges ,/ Sunlight?↓9. Medication /Heparin,Corticosteroids

10. Underlying pathologies /ESRD,Hyperthyroidism,04/25/15 2973 NRS P&P-1 /ziad.khaled@iat.ac.ae/FCHS 35

All women 65 years and older Postmenopausal women <65 years of age:

If result might influence decisions about intervention

One or more risk factors History of fracture

Healthy premenopausal women Healthy children and adolescents Women initiating ET/HT for menopausal

symptom relief (other osteoporosis therapies should not be initiated without BMD measurement)

Outcome of interest: Fracture Risk! Outcome measured (surrogate): BMD

Key: Older women at higher risk of fracture than younger women with SAME BMD!

Other factors: risk of falling, bone fragility not all related to BMD

Osteoporosis: disease of bone that increases risk of fracture; more than BMD goes into causing a fracture; BMD is important, but in reducing fractures must also consider falls risk, age and other factors!!!

Laboratory Data Limited value in diagnosis Markers of bone turnover (telopeptide) more useful in

monitoring effects of treatment than in diagnosis Helpful to exclude secondary causes ▪ Hyperthyroidism▪ Hyperparathyroidism▪ Estrogen or testosterone deficiency▪ Malignancy▪ Multiple myeloma▪ Calcium/Vitamin D deficiency

Quantitative Ultrasonography Quantitative computed tomography Dual Energy X-ray Absorptiometry (DEXA)

?”gold standard” Measurements vary by site Heel and forearm: easy but less reliable (outcome of

interest is fracture of vertebra or hip!) Hip site: best correlation with future risk hip fracture Vertebral spine: predict vertebral fractures; risk of falsely

HIGH scores if underlying OA/osteophytes

Relative Risk of Fracture per SD Decrease in BMD

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DXA-assessed content is a proven effective method for assessing osteoporosis related fracture risk.Population surveys and research studies demonstrate a decrease in bone density measured by DXA predicts fracture at specific sites.

Marshall, D, et al: Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. British Medical Journal. 312:1254-1259, 1996.

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Hans, D, et al: Ultrasonographic heel measurements to predict hip fracture in elderly women: the EPIDOS prospective study. Lancet. 348:511-514, 1996.

Bauer, DC, et al: Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women. Archives of Internal Medicine. 157:629-634, 1997.

Frost, ML, et al: A comparison of fracture discrimination using calcaneal quantitative ultrasound and dual x-ray absorptiometry in women with a history of fracture at sites other than the spine and hip. Calcified Tissue International. 71:207-211, 2002.

T score: standard deviation of the BMD from the average sex matched 35-year-old

Z score: less used; standard deviation score compared to age matched controls

WHO: Osteoporosis: T score <-2.5 Osteopenia: T score -1 - -2.5 For every 1 decrease in T score, double risk of fracture 1 SD decrease in BMD = 14 year increase in age for predicting

hip fracture risk Regardless of BMD, patients with prior osteoporotic fracture

have up to 5 times risk of future fracture!

Postmenopausal women with T-score below –2.0 with no risk factors

Postmenopausal women with T-score below –1.5 with one or more risk factors

Goal: prevent fracture, not just treat BMD Osteoporosis treatment options

Calcium and vitamin D Calcitonin Bisphosphonates Estrogen replacement Selective Estrogen Receptor Modulators Parathyroid Hormone

Fewer than half adults take recommended amounts Higher risk: malabsorption, renal disease, liver

disease Calcium and vit D supplementation shown to

decrease risk of hip fracture in older adults 1000 mg/day standard; 1500 mg/day in

postmenopausal women/osteoporosis Vitamin D (25 and 1,25): 400 IU day at least;

Frail older patients with limited sun exposure may need up to 800 IU/day

Likely not as effective as bisphosphonates 200 IU nasally/day (alternating nares) Decrease pain with acute vertebral

compression fracture

Decrease bone resorption Multiple studies demonstrate decrease in hip and

vertebral fractures Alendronate, risodronate IV: pamidronate, zolendronate (usually used for

hypercalcemia of malignancy, malignancy related fractures, and multiple myeloma related osteopenia)

Ibandronate (boniva): once/month Those at highest risk of fracture (pre-existing

vertebral fractures) had greatest benefit with treatment

Jaw osteonecrosis Underlying significant dental disease Usually associated with IV formulations Case reports associated with oral

formulations

Renal failure Esophageal erosions

GERD, benign strictures, most benign GI problems are NOT a contraindication

Concern for esophageal irritation/erosions from direct irritation, recommendations to drink water after and not lie down at least 30 minutes

Reality: no increased GI side effects compared to placebo group in multiple studies

Reduction in bone resorption Proven benefits in treatment FDA approval, now limited because of recent

concerns from HERS trial and other data suggesting possible increased total risks with HRT (?increased cardiac risk, increased risk VTE, increased risk cancer)

Raloxifene FDA recommended Decrease bone resorption like estrogen No increased risk cancer (decrease risk breast

cancer) Increase in vasomotor symptoms associated

with menopause

Teriparatide Why PTH when well known association with

hyperparathyroidism and osteoporosis??? INTERMITTENT PTH: overall improvement in bone

density Optimal bone strength relies upon balance between bone

breakdown and bone build up; studies with increased density but increased fracture risk/fragility with flouride show that just building up bone is not enough!!!

Studies suggest improved BMD and decreased fractures

?risk osteosarcoma with prolonged use (over 2 years): studies with rats

SQ, expensive Option for severe osteoporosis, those on

bisphophonates for 7-10 years, those who can not tolerate oral bisphosphonate

Optimal effect requires bone uptake Not for use in combination with Bisphosphonate!

May need to stop bisphosphonate up to 1 year prior

First Line Therapies with Evidence for Fracture Prevention in Postmenopausal Women

1. Decrease osteoporosis/improve BMD 2. Decrease risk of break: hip protectors 3. Decrease risk of fall

Padding that fits under clothing Multiple studies demonstrate effectiveness at

preventing hip fractures Likely cost effective Problem: adherence!

Falls are a marker of frailty Hip fracture is a marker of frailty

Mortality after hip fracture:?due to hip fracture or hip fracture as marker for those who are declining?

Increased risk of falls: Prior fall (fear of falling) Cognitive decline Loss of vision Peripheral neuropathy Weakness Stroke Medications: anticholinergics, tcas, benzos… ETOH

US Preventive Task Force Test Bone Mineral Density in all women over age

65, younger postmenopausal women with at least one risk factor, and postmenopausal women with a history of fracture

Treat patients with T score <-2 and no risk factors, T score <1.5 if any risk factors, and anyone with prior vertebral/hip fracture

Older men Not included in recommendations Screening not recommended or paid for Significant problem, risk of osteoporosis, risk of

fracture, especially after age 70, even more so after age 80

Significant evidence that men with osteoporosis benefit from treatment

•Osteoporosis is characterized by low bone mass with micro-architectural deterioration of bone tissue leading to enhance bone fragility, thus increasing susceptibility to fracture.

•The management of osteoporosis should be guided by an assessment of the patient’s absolute risk of osteoporosis related fractures.

•Fragility fracture increases the risk of further fractures and should be considered in the assessment.

•Lifestyle modification and pharmacologic therapy should be individualized to enhance adherence to the treatment plan.

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