Osteoporosis

Osteoporosis refers to low bone mineral density (BMD) and destruction of bone that results in increased risk of fragility and fractures. It is defined by the World Health Organisation (WHO) as a BMD that is less than 2.5 standard deviations below the average BMD in young, healthy adults. Osteoporosis represents a more advanced stage of osteopenia.

BMD refers to the mass of minerals per volume of bone volume (this is measured as optical density of bone per square centimetre using imaging). The minerals in question are calcium, magnesium, sodium and carbonate. The main component of bone is hydroxyapatite (calcium hydroxide phosphate). The other components of bone that make up its integrity include collagen matrices and cells.

It is a common condition affecting the elderly population, especially in women. The BMD in women sharply declines in the post-menopausal stage. In England and Wales alone it affects >2 million women, and 180,000 of the fractures are due to osteoporotic fragility fractures. As such it is ubiquitous and should be treated accordingly to prevent severe morbidity and mortality that may arise from the complications of osteoporosis.

🏃‍♀️ Physiology

Bone, although a seemingly dormant tissue, is actually highly dynamic and serves multiple functions. Some of these include: structural support, facilitating movement, protection of vital organs, and very importantly serving as a reservoir of calcium and phosphate (along with other minerals).

As mentioned earlier, bone is made up of calcium phosphate crystals known as hydroxyapatite, but also is made up of cells which coordinate bone homeostasis in an organised manner.

The cells of bone are:

1. Osteoblasts - these are the bone-forming cells. They derive from mesenchymal stem cells (MSCs). The produce type I collagen which is the primary component of the bone matrix. They also secrete alkaline phosphatase (ALP) which promotes deposition of calcium and phosphate into the matrix. Osteoblastic activity may be regulated with through parathyroid hormone, and various cytokines/receptors. Once inactive they are known as bone lining cells.
2. Osteoclasts - these are the cells responsible for bone resorption. They are much larger and are multinucleated. They derive from the same lineage of macrophages (haematopoeitic stem cells). They attach to the bone surface and secrete hydrogen ions and proteolytic enzymes (such as cathepsin K) to dissolve the bone matrix. RANKL (receptor activator of nuclear factor kappa-ß ligand) produced by osteoblasts and osteocytes promotes osteoclastic differentiation (osteoclastogenesis) when bound to the RANK receptor. Osteoprotegrin (OPG) is a decoy receptor that may intercept RANKL to prevent it binding to the RANK receptor thus inhibiting osteoclastogenesis and osteoclast activity.
3. Osteocytes - osteocytes are mature bone cells that from osteoblasts that have become completely surrounded by the very own matrix they have deposited. They have dendritic processes that communicate with other bone cells. By doing so they are able to orchestrate bone deposition and resorption (remodelling) in response to mechanical load. This is known as mechanotransduction. They also inhibit osteoblast activity through the release of sclerostin.

Bone remodelling itself is an ongoing process which has 4 distinct phases. The purpose of bone remodelling is to allow the skeleton to adapt to mechanical stress, repair damage, regulate calcium and phosphate levels.

The four phases of bone remodelling are:

1. Activation phase

Osteocytes respond to microdamage and mechanical stress to produce RANKL and reduce OPG secretion. This process activates osteoclast precursors and initiates osteoclastogenesis.

2. Resorption phase

Osteoclasts fully mature and attach to the bone surface with what is known as the ruffled border. The ruffled border is the site of the osteoclast that interacts with the resorption bay of the bone. Here they secrete proteolytic enzymes and create an acidic environment which breaks down the bone matrix.

3. Reversal phase

Osteoblast precursors are recruited to the previous resorption site to prepare the surface for new bone deposition.

4. Formation phase

Osteoblasts begin to synthesise new bone matrix by laying down an unmineralised scaffolding known as osteoid. Osteoid subsequently becomes mineralised with hydroxyapatite. Some of these osteoblasts become completely embedded in the matrix surrounding them and differentiate into osteocytes. Others will become inactive and form bone-lining cells, while others will simply undergo apoptosis.



So what regulates bone physiology?

1. Parathyroid hormone (PTH) - this is the main regulator of calcium homeostasis. It acts to increase serum calcium levels by stimulating osteoclast activity and increasing renal absorption of calcium.
2. Calcitonin - the antagonist to PTH, it serves to decrease serum calcium levels by inhibiting osteoclstogenesis.
3. Vitamin D - vitamin D promotes calcium absorption from the gut and thus promotes bone matrix mineralisation.
4. Oestrogen - inhibits bone resorption by inhibiting osteoclastogenesis and osteoclast activity.
5. RANKL - promotes osteoclastogenesis when bound to the RANK receptor.
6. Osteoprotogerin - intercepts RANKL binding to the RANK receptor and as such inhibits osteoclastogenesis.
7. Bone morphogenetic proteins (BMPs) - these are a group of growth factors that promote osteoblast differentiation from MSCs.
8. Wnt proteins - a group of 19 glycoproteins involved in a complex cellular pathway that ultimately results in osteoblast formation.
9. Sclerostin - a glycoprotein produced by osteocytes that inhibits the Wnt pathway and ultimately prevents osteoblast formation.

Pathophysiology

Osteoporosis occurs due to a shift from normal, balanced bone remodelling into an imbalance of relatively increased osteoclastic activity. This results in decreased BMD and alterations to bone composition and architecture. Typically we reach peak bone mass in the third decade. It begins to decline in the fifth decade. This is much more rapid for women in the 5-10 years after menopause.

So what causes this shift?

• Hormonal changes - as mentioned above, oestrogen has a protective effect on bone by inhibiting osteoclast activity. With reduced oestrogen comes an increase in cytokines such as IL-1, IL-6 and TNF-alpha which all promote osteoclastogenesis. In men, oestrogen is derived from aromatization of testosterone. Therefore a decrease in testosterone in elderly men also is associated with osteoporosis.
• Ageing - ageing is associated with decreased differentiation of MSCs and reduced osteoblast formation. Oxidative stress that occurs leads to reactive oxygen species forming which also impairs bone formation. Sclerostin is increased in elderly individuals which prevents the Wnt pathway, as such prevents osteoblast formation.
• Genetic predisposition - certain genes may influence bone metabolism, especially those for the vitamin D receptor and oestrogen receptor.
• Endocrine disorders - hyperthyroidism, hyperparathyroidism, Cushing’s syndrome all lead to increased bone resorption.
• Gastrointestinal issues - such as coeliac disease, IBD, chronic liver disease, chronic pancreatitis may all affect absorption of nutrients which causes deficiencies in calcium and vitamin D.
• Medications - steroid-induced osteoporosis (SIOP) is a well known side effect of long-term glucocorticoid use.

This leads to cortical bone thinning and trabecular bone loss. Cortical bone is the hard, outer layer of bones. When thinning it increases bone fragility. Trabecular bone is highly metabolically active bone found in the spine, hip and long bones. It is more susceptible to resorption and gets lost with osteoporosis.

This multi-factorial interplay leads to a decrease in bone quantity and quality. This predisposes individuals to fragility fractures.

⚠️ Risk factors

NICE separates the risk factors by those that affect bone strength but do not reduce BMD and those that affect bone strength as well as reduce BMD:

😷 Presentation

⭐️ Osteoporosis itself is asymptomatic. It presents clinically as fragility fracture. This is defined as a fracture caused by a fall from a standing height or less or from low energy trauma.

🔍 Investigations

When assessing an individual for fragility fracture risk, we should do the following in a step-wise manner:

1. Exclude non-osteoporotic causes of fragility fracture
1. This may include metastatic cancer, multiple myeloma, osteomalacia, Paget’s disease.
2. Exclude secondary causes of osteoporosis
1. This may include endocrine conditions, rheumatological conditions, malabsorptive disorders, chronic liver disease, COPD.
3. Calculate the 10-year fragility fracture risk using QFracture or FRAX
1. QFracture is the preferred tool.
2. FRAX may underestimate the risk of fragility fractures in patients on regular corticosteroids, patients with a history of multiple fragility fractures, patients who drink heavily and patients who smoke heavily.
3. Patients are categorised as following by the aforementioned tools:

Risk	QFracture	FRAX
High risk	>10%	Red zone on chart
Intermediate risk	Close to 10% but below 10%	Orange zone on chart
Low risk	<10%	Green zone on chart

4. Assess BMD using DEXA scan
1. Dual-energy X-ray absorptiometry (DEXA) is a means of measuring BMD. It works by sending two X-ray beams of differing energy levels through the bone and surrounding soft tissues. Bones and soft tissues absorb X-rays differently (bones absorb more X-rays). A detector on the opposite side measures the amount of X-rays passing through the body and can distinguish between bone and soft tissue. The DEXA machine uses this absorption data to calculate the BMD in grams per square centimetre. This is then compared to reference standards called T-scores (references use young adult mean) or Z-scores (references use age-matched mean).
2. DEXA is offered to high risk patients or patients at intermediate risk.
3. It may also be offered to the following 2 groups without calculating the fragility fracture risk:
1. >50 years of age + history of fragility fracture
2. <40 years of age + risk factor (as mentioned above)
💯

T-score and Z-score

The T-score and Z-score are used to interpret BMD results from the DEXA scan. They usually compare BMD at the hip and/or spine.

The T-score compares the BMD to an average peak BMD of a healthy young adult and indicates the number of standard deviations the BMD is away from this.

The Z-score compares the BMD to an average BMD of an individual of the same age, sex and size and indicates the number of standard deviations the BMD is way from this.

T-score at the hip	Result
Normal	≥ -1
Osteopenia	-1 to -2.5
Osteoporosis	< -2.5
Severe osteoporosis	< -2.5 + fracture

Other investigations that should be done to determine an underlying cause of osteoporosis include:

• Vitamin D levels
• Testosterone level
• Thyroid function tests
• Parathyroid hormone
• Urinary free cortisol
• Calcium and phosphate levels
• Alkaline phosphatase (ALP)
• Serum/urine protein electrophoresis

🧰 Management

🚨 Complications

• Osteoporotic hip fracture - this is a huge cause of morbidity and mortality (in 20% of cases). It almost always requires hospitalisation and can lead to permanent disability in 50% of patients. It carries a 10x increased relative mortality risk in the year after the fracture.

More can be read on hip fractures here:

Pelvic and hip fracture
• Osteoporotic vertebral fracture - around 50-70% are silent. However, they may cause back pain loss of height, kyphosis and localised pain on palpation of the spinous process.
• Osteoporotic forearm fracture - may cause significant impact on activities of daily living and the quality of life of a patient.