Osteoporosis - Diagnosis and Treatment

lose mass, weaken and fracture
1:3 women and 1:7 men are affected
progression is slow, silent, painless
Osteoporotic fractures- fractures due to fall from standing height or less, or without fall at all

by Age Group

? in osteoporotic fractures - 60–70% per decade and similar for first and repeat fractures
the incidence of repeat fractures was at least double the incidence of first fractures.

L. Langsetmo et al, JBMR 2009

X-rays
50 % Symptomatic (dorsalgia)
33 % Clinically diagnosed
8 % Hospitalized
2% Requiring long term care

2/3 of patients with vertebral fractures that are visible on X-rays are not diagnosed

Only 33% of Osteoporotic Vertebral Fractures are Clinically Diagnosed!

Adapted from ROSS PD: Clinical Consequences of Vertebral Fractures: AM J Med 1997;103 (2A): 30S-43S

amenorrhea (e.g., due to anorexia nervosa, hyperprolactinemia)
Drug therapy
glucocorticoids ( ≥ 7.5 mg/day for > 6 months)
antiepileptic drugs (e.g., phenytoin)
excessive substitution therapy (e.g., thyroxine)
anticoagulant drugs (e.g., heparin, warfarin)

Testosteron, Estrogen

? PTH

Osteoprotegerin ?

Muscle Srength ?

Bone Resorption ?

Oseoblast Apoptosis ?

Growth Factors ?

Bone Formation ?

celiac disease, Crohn’s disease, surgery for peptic ulcer)
chronic liver disease (primary biliary cirrhosis)

Always rule out secondary causes, especially in case of fracture or significant decrease in BMD>5% during one year on treatment

Osteoporos Int (1997)7:390-406

Definition
Normal
Osteopenia
Osteoporosis
Severe
Osteoporosis

Bone
T-Score > - 1 SD
-1 SD > T-Score > - 2.5 SD
T-Score ≤ - 2.5 SD
Osteoporosis with fracture(s)

Strategy
Prevention
Treatment

Bone mineral density is only one of risk factors for fracture.
Patient who experienced an osteoporotic fracture-definetly has osteoporosis, no matter what the BMD results are.
In case of decrease in patient’s BMD while on treatment- first re-evaluate the patient to rule out secondary causes of osteoporosis.

femoral neck

for osteoporosis, but if used for menopausal symptoms, efficient for osteoporosis)

For young people with normal gonadal status usually calcium and vitamin d replacement are sufficient

D levels for Patients with metabolic bone disorders is about 30 ng/ml=75 nmol/l

2007

M Parfitt, 1970

Treatment with vitamin D improves walking, decreases falling and risk of non vertebral fractures

bone resorption (in weeks) and formation (in months)
bone mineral density is ↑ by 3 - 8 % for the first 2-3 years then plateaus; this reduces the risk of fracture by 30 - 50% in various skeletal sites

the first vertebral fracture from 4.3% for placebo to 1.9% for Evista (relative risk reduction = 55%)
Blocks Estrogen action in brain, which can lead to increase in menopausal symptoms
Blocks Estrogen action in breast, and decreases ER+ breast cancer risk by 80%
Blocks Estrogen action in uterus, not causes epithelium hyperplasia and bleeding

skeletal retention
Side chain determines potency and side effects

lactate production
Reduce activation frequency
• inhibit recruitment of
osteoclast precursors
• inhibit differentiation of
osteoclast precursors
Increase osteoclast apoptosis

of established osteoporosis
May have benefits in many conditions characterized by increased bone remodeling (eg, Paget’s disease, hypercalcemia of malignancy)

Contraindications

Active upper GI disease (some
bisphosphonates cause esophageal
irritation)
Hypocalcemia
Renal insufficiency

In patients reated with glucocorticoids for a long time- antiresorptive treatment recommended if BMD is<-1.5

1996;348:1535. © by The Lancet Ltd 1996. Reprinted with permission.

Percent
of
patients

Clinically apparent

vertebral fractures

Hip

fractures

Wrist

fractures

5.0

2.3

2.2

1.1

4.1

2.2

*

*

**

2,027 women with low femoral neck BMD
and one or more vertebral fracture

55%

51%

48%

% reduction

SITES DURING 3 YEARS2

2. Black DM, et al.N Engl J Med. 2007; 356(18): 1809-1822. Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis.
Annually infused ACLASTA® provides a significant
and sustained fracture protection2

MORPHOMETRIC VERTEBRAL FRACTURE

NONVERTEBRAL
FRACTURE^

HIP FRACTURE
*Relative to placebo. ^ Nonvertebral fracture ia a composite endpoint excluding finger, toe and facial fractures.
ARR: Absolute Risk Reduction.

(ARR 7.6%)
P<0.001

(ARR 2.7%)
P<0.001

(ARR 1.1%)
P=0.002

AND ALL-CAUSE MORTALITY AFTER A RECENT, LOW-TRAUMA HIP FRACTURE

Lyles KW, et al. N Engl J Med. 2007; 357: 1799-1809. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture.

Hip Fracture Patients :

Hazard ratio,
0.72 (95% CI,0.56-0.93),
Zoledronic Acid (n = 1054) vs.
Placebo (n = 1057) ;P=0.01.
Death-No.(%):
Zoledronic Acid 101 (9.6) vs.
Placebo 141 (13.3)

Hazard ratio,
0.65 (95% CI,0.50-0.84).
Zoledronic Acid (n = 1065) vs. Placebo (n = 1062)
Death-No.(%):
Zoledronic Acid 92 (8.6) vs.
Placebo 139 (13.9) .

The HORIZON Recurrent Fracture Trial (RFT) :

After a recent low-trauma hip fracture3

Give vitamin D supplementation-75000-100000 IU in one dose before the Zoledronic acid infusion!!

Resorption Inhibited

Osteoclast Formation, Function, and Survival Inhibited

CFU-GM

Pre-Fusion Osteoclast

CFU-GM=colony forming unit granulocyte macrophage

Provided as an educational resource. Do not copy or distribute.

© 2007 Amgen. All rights reserved.

Osteoblasts

3: The FREEDOM Trial

Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65

40% P = 0.04

20% P = 0.01

68% P < 0.001

increase in bone density continues beyond two years

Biosynthetic PTH

C. (2011) Parathyroid hormone analogues in the treatment of osteoporosis
Nat. Rev. Endocrinol. doi:10.1038/nrendo.2011.108

65% reduction

77% reduction

90% reduction

With Nonvertebral
Fragility Fractures

*Defined as occurring with minimal trauma.
†P<.05.
N Engl J Med. 2001;344:1434-1441.

RR ↓ 53%*

637 days (approx 21 mos)
BMD Change:
⇒Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)
⇒Total Hip: +5.2% (group mean = 2.6 ± 4.9%)

Data from Jiang et al. JBMR 2003 (in press)

Baseline

Follow up

Jiang UCSF

In Israel- Forteo reimbursed as second line treatment for patient with deterioration of the disease- fractures while on therapy, or significant decrease in BMD