Four stages of Osteoporosis: Normal bone, Osteopenia, Osteoporosis, severe Osteoporosis

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Osteoporosis: Causes and Prevalence

 What Is Osteoporosis?

Osteoporosis is a disease that affects the bones.
The bones become brittle and unstable.

  • Bone density decreases.
  • Even small pressure can cause bone fractures.
  • Fractures often occur in the spine or hip.
  • This can cause pain and limited movement.

 How Do Our Bones Work?

Our bones are constantly renewing themselves:

  • Old bone cells are broken down by osteoclasts.
  • New bone cells are built by osteoblasts.

Normally, this is balanced.
But if more bone is broken down than built, bones become weaker.
That is typical in osteoporosis.

 Why Does This Imbalance Happen?

There are several reasons:

  • Lack of hormones (for example, after menopause)
  • Lack of exercise
  • Certain diseases
  • Some medications

Hormones, movement, and other factors affect how well the bones renew themselves.

 How Is Bone Loss Controlled?

  • RANKL is a substance in the body that promotes bone loss.
    It activates osteoclasts, the cells that break down old bone.
  • OPG is another substance that can block RANKL.
    This helps protect the bones from breaking down.

Example:
After menopause, there is less estrogen in the body.
This leads to more RANKL → more bone breakdown → osteoporosis.

 What Can Help?

A medicine like Denosumab blocks RANKL.
It can slow down or even stop bone loss.

Who Is Affected by Osteoporosis?

Osteoporosis is common around the world.

  • Most common in women over 50
  • The disease makes bones fragile.
  • Hip fractures are especially dangerous:
    • They can lead to a need for long-term care.
    • Sometimes even to early death.

Still, osteoporosis is often diagnosed too late and not treated well enough. 

Osteoporosis – Definition  Bone Remodeling 

What is Osteoporosis?

Osteoporosis is a bone disease characterized by reduced bone mass and deterioration of the bone microarchitecture.
This leads to decreased strength and stability, causing bones to fracture more easily, even under minor stress.

As the disease progresses, it often results in limited mobility and severe back pain.
Typical osteoporotic fractures, such as vertebral compression fractures and hip fractures, frequently lead to disability and long-term care dependency.

Bone Remodeling – A Continuous, Dynamic Process

Bone is not a static tissue. It is a highly active and living organ, constantly remodeling to adapt to physical stress and to repair microdamage.
This process is called bone remodeling.

 Two Main Cell Types Regulate Bone Remodeling:

  1. Osteoclasts – The Bone-Resorbing Cells
  • Specialized in breaking down old or damaged bone.
  • They dissolve the mineralized bone matrix, mainly calcium and phosphate, releasing these minerals into the bloodstream.
  • This process is called bone resorption.
  • Osteoclasts are large, multinucleated cells derived from macrophage precursor cells.
  1. Osteoblasts – The Bone-Forming Cells
  • Responsible for building new bone tissue.
  • They produce bone matrix, primarily type I collagen, and mineralize it with calcium and phosphate.
  • Some osteoblasts differentiate into osteocytes, which remain embedded in the bone and function as mechanosensors.

The Importance of Balance

  • In a healthy bone metabolism, there is a balance between osteoclast-mediated resorption and osteoblast-driven formation.
  • This balance is regulated by:
    • Hormones (e.g. estrogen, parathyroid hormone, calcitonin)
    • Cytokines
    • Mechanical load

 What Happens When Osteoclast Activity Prevails?

If osteoclasts are overactive or osteoblast function is impaired:

  • More bone is broken down than formed
  • Bone density decreases, and bone structure becomes porous
  • This leads to a higher risk of fractures – a hallmark of osteoporosis

Causes of this imbalance include:

  • Hormonal deficiency (e.g. estrogen deficiency during menopause)
  • Physical inactivity
  • Chronic diseases
  • Medications (e.g. glucocorticoids)

 Factors Affecting Bone Remodeling

Factor

Effect on Osteoclasts (Resorption)

Effect on Osteoblasts (Formation)

Estrogen

Inhibits activity

Promotes maturation and activity

Parathyroid hormone

Indirect stimulation via RANKL

Minor direct effect

Vitamin D

Indirectly increases RANKL

Stimulates bone formation

Glucocorticoids

Increase activity

Inhibit function and differentiation

Physical activity

Inhibits via mechanical signaling

Stimulates activity and differentiation

Inflammatory cytokines

Increase activity

Inhibit osteoblast maturation

Age

Increases osteoclast activity

Decreases cellular function

Bisphosphonates

Inhibit function and survival

No direct effect

Thyroid hormones

Increase activity

Indirectly inhibit

Sclerostin

Promotes RANKL, increases activity

Inhibits bone formation

Growth hormone

Indirectly inhibits osteoclasts

Promotes bone formation

IGF-1

Indirectly inhibits osteoclasts

Stimulates osteoblast proliferation and activity

 

 RANKL

RANKL – A Key Regulator in Bone Metabolism

 What does RANKL stand for?

RANKL stands for “Receptor Activator of Nuclear Factor Kappa-B Ligand.”
It is a key protein in bone metabolism and plays a central role in bone resorption by osteoclasts.

 Function of RANKL:

  • RANKL is produced by osteoblasts and osteocytes.
  • It binds to the RANK receptor, which is found on osteoclast precursor cells.
  • This binding promotes the maturation, activation, and survival of osteoclasts.
  • Result: Increased bone resorption.

 

 The RANKL–RANK–OPG System: A Delicate Balance

  • RANKL: Activates osteoclasts
  • RANK: Receptor on osteoclast precursors
  • OPG (Osteoprotegerin):
    • A natural “decoy receptor” that binds to RANKL and prevents it from attaching to RANK
    • → Protects against excessive bone resorption

The balance between RANKL and OPG determines whether bone formation or bone loss dominates.

 Clinical Relevance:

  • Postmenopausal estrogen decline → Increased RANKL, decreased OPG
    → Enhanced bone resorption → Osteoporosis
  • The drug Denosumab is a monoclonal antibody against RANKL
    → Blocks RANKL, inhibits osteoclasts
    → Reduces bone loss

Sclerostin

Sclerostin – A Key Inhibitor of Bone Formation

 What Is Sclerostin?

  • Sclerostin is a protein that plays an important role in bone metabolism, particularly by inhibiting bone formation.
  • It is primarily produced by osteocytes (mature bone cells).
  • It acts as a natural “brake” on bone growth.

 

 How Does Sclerostin Work?

  • It inhibits the activity of osteoblasts, the cells responsible for building new bone.
  • Sclerostin blocks the Wnt signaling pathway, which is crucial for bone growth.
  • As a result, less bone mass is formed, which can lead to bone loss or osteopenia/osteoporosis.
  • It also indirectly promotes osteoclast activity (bone-resorbing cells), partly by increasing RANKL levels.

 

Clinical Significance

  • Excessive sclerostin levels can contribute to the development of osteoporosis.
  • The drug Romosozumab is a monoclonal antibody against sclerostin.
    → It blocks sclerostin so that bone formation can resume.
    → Result: Increased bone mass and improved bone strength.

 

Summary:
Sclerostin inhibits bone formation and contributes to osteoporosis.
Blocking sclerostin (e.g., with Romosozumab) allows bone growth to increase again.

Epidemiology of Osteoporosis

Epidemiology of Osteoporosis

 Bone as a Living Tissue

Bone is a living tissue, built by bone-forming cells (osteoblasts) and broken down by bone-resorbing cells (osteoclasts).
Until around age 30, bone formation predominates. From age 40 onward, bone resorption outweighs formation, leading to an average annual bone loss of about 1%.

Building healthy bone depends not only on genetic factors, but also on:

  • Adequate calcium intake
  • Physical activity
  • Sex hormones

Especially in postmenopausal women, declining estrogen levels frequently lead to postmenopausal osteoporosis.

 Global Prevalence

  • Worldwide, about 20% of adults have osteoporosis and over 40% have osteopenia (low bone mass).
  • In people over 50, prevalence increases significantly:
    • Around 1 in 3 women
    • And 1 in 5 men
      suffer an osteoporotic fracture after age 50.

 International Differences in Prevalence

Prevalence of osteoporosis (selected regions):

  • Netherlands: ~4.1%
  • Turkey: up to 52.0%
  • Oceania: ~8.0% (continental average)
  • Africa: up to 26.9%

According to WHO data (2019), the countries with the highest disease burden (measured in Disability-Adjusted Life Years per 100,000 population):

Country

DALYs per 100,000

Greenland

269

India

259

Croatia

227

Slovenia

215

Solomon Islands

213

In Central Europe (Germany, Austria, Switzerland), the disease burden is about 6% of the population – significantly higher in women.

 Data from North America

  • USA: About 13% of adults aged 50+ have DXA-confirmed osteoporosis, with a much higher rate in women.
  • Canada:
    • Nearly 12% of those aged 40+ have a diagnosed osteoporosis.
    • But only about 3.6% are confirmed by DXA scans.
    • This suggests methodological differences and potential underreporting.
    • Despite lower sunlight exposure, the osteoporosis rate is not significantly higher than in the U.S., likely due to better vitamin D intake through diet and supplements.
    •  

 

Osteoporosis a life-threatening disease

Osteoporotic Fractures and Life Expectancy

Osteoporosis with fractures significantly reduces life expectancy.
The impact depends on:

  • Fracture location
  • Age
  • Health status
  • Sex

 

 1. Hip Fracture

The most severe osteoporotic fracture:

  • Mortality within 1 year after fracture:
    • Women: 15–20%
    • Men: 25–30%
  • Reduction in life expectancy (on average):
    • Women: ~1.8 years
    • Men: ~2.7 years
  • 50% of survivors remain permanently mobility-impaired

For an 80-year-old person, a hip fracture can halve the chance of surviving the next 5 years compared to peers without fracture.

 Fracture Location vs. Mortality and Life Reduction

Fracture Site

1-Year Mortality

Average Life Expectancy Reduction

Hip

15–30%

2–3 years

Vertebral

10–20%

1–2 years

Wrist/Forearm

<5%

Minimal (but indicates high risk)

 Why Does a Fracture Shorten Life?

  • Immobility → risk of thrombosis, pneumonia, muscle wasting, pressure ulcers
  • Loss of independence → increased dependency and need for care
  • Multimorbidity → osteoporosis often coexists with cardiovascular or other chronic diseases
  • Psychosocial impact → depression and social isolation after loss of mobility

 

 Conclusion: A Silent but Deadly Disease

Osteoporosis is a potentially fatal disease, reducing life expectancy similar to some cancers.
It must be diagnosed and treated appropriately.

Unfortunately, osteoporosis is still not recognized by society as a life-threatening disease and is therefore underdiagnosed and undertreated.