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CCR5 is a chemokine receptor that is expressed on the surface of immune cells, including T cells, monocytes, and macrophages. The HIV-1 virus uses CCR5 as a co-receptor to enter and infect immune cells. Antiretroviral drugs (maraviroc) that block the activity of CCR5 are used to treat HIV/AIDS.
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CCR5
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The NMDA (N-methyl-D-aspartate) receptor is a glutamate receptor essential for normal brain function. Dysfunction of the NMDA receptor has been implicated in several neuropsychiatric conditions (schizophrenia, Alzheimer's disease, and stroke). NMDA receptor antagonists, such as ketamine and dextromethorphan, have been used as anaesthetics and have been shown to have antidepressant effects.
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QuestionChoice
Osteoporosis is fairly common in post-menopausal women, primarily due to diminished oestrogen levels in the body, which is critical for maintaining bone homeostasis.
 - **Receptor activator of nuclear factor-kappa B (RANK)** is expressed on the surface of osteoclast precursors, which are cells responsible for bone resorption.
 - **RANK ligand (RANKL)** is expressed on the surface of osteoblast precursors, which are cells responsible for bone formation, and activates RANK on osteoclast precursors.
In normal bone homeostasis, the balance between RANKL and its inhibitor, osteoprotegerin is essential for maintaining bone mass. However, in osteoporosis, there is an imbalance in favour of RANKL, resulting in increased RANK activation and bone resorption. This leads to decreased bone density and an increased risk of fractures.
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RANK
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The acetylcholine receptor (AChR) is a protein found in the membrane of nerve cells that is responsible for the transmission of the nerve impulse across the synapse from one neuron to another. Overactivation of AChRs can lead to the development of myasthenia gravis, a chronic autoimmune disorder that causes muscle weakness and fatigue.
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AChR
QuestionChoice
CXCL13 is a B and T lymphocyte chemokine that mediates neuroinflammation through its receptor CXCR5. They are implicated in the pathogenesis of several autoimmune diseases, such as rheumatoid arthritis, myasthenia gravis, multiple sclerosis, and systemic lupus erythematosus.
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CXCR5
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This question was a bit rank lol
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# Summary 

Osteoporosis is a chronic condition characterised by low bone density and increased propensity to sustain fragility fractures. It is diagnosed with a dual-energy X-ray absorptiometry (DEXA) scan if a patient's T-score is less than -2.5. It is very common in older patients, especially post-menopausal women, with other risk factors including long-term corticosteroid use, low body weight and immobility. Other key investigations include checking calcium and vitamin D levels as these may require supplementation if low. Treatment is with bone-sparing treatment, with bisphosphonates being the first-line option in the majority of patients. Lifestyle changes such as smoking cessation, taking regular exercise and maintaining a healthy diet are important. Falls risk assessment is also key to reducing the risk of fragility fractures, especially in older patients. 

# Definition

Osteoporosis refers to a state of low bone density with structural deterioration of bones. This causes bones to weaken, increasing the risk of fragility fractures (defined as a fracture sustained due to a fall from standing or without any trauma). 

Patients are defined as having osteoporosis if their bone mineral density (BMD) is at least 2.5 standard deviations below the mean peak mass of young healthy adults. This is measured with a dual-energy X-ray absorptiometry (DEXA) scan which gives BMD for the lumbar vertebrae and the femur. 

# Epidemiology

- In the UK, around 2 million people are estimated to have osteoporosis
- Post-menopausal women are particularly at risk due to accelerated bone loss secondary to decreased oestrogen production
- Prevalence also increases significantly with age
- Almost 50% of 80 year old women have osteoporosis
- White ethnicity is also a risk factor
- There are approximately 300,000 fragility fractures per year in the UK, with osteoporosis often being undiagnosed at the time of presentation

# Aetiology

Risk of fragility fractures increases as bone density declined, however there are many other factors that increase fracture risk:

| Risk factors reducing bone density | Risk factors that do not reduce bone density |
|----------|----------|
| Low body weight | Older age |
| Menopause | Inflammatory arthritis (e.g. rheumatoid arthritis) |
| Immobility | Prolonged use of oral corticosteroids |
| Chronic disease e.g. chronic kidney disease, chronic obstructive pulmonary disease, chronic liver disease | Smoking |
| Malabsorption e.g. coeliac disease, inflammatory bowel disease, pancreatic insufficiency | Alcohol excess |
| Endocrine disease e.g. hyperparathyroidism, hyperthyroidism | History of fragility fracture |
| Certain medications (proton pump inhibitors, selective serotonin reuptake inhibitors, carbamazepine) - mixed evidence | Parental hip fracture |

# Signs and Symptoms

Osteoporosis itself is asymptomatic and so is usually diagnosed either with screening of people at high risk (e.g. those on long-term corticosteroids) or when someone presents with a fragility fracture.

The most common fragility fractures seen are:

- Vertebral body
- Neck of femur (hip)
- Distal radius
- Proximal humerus
- Pelvis

Some osteoporotic fractures (e.g. vertebral fractures) may also be asymptomatic acutely. Loss of height and kyphosis may occur due to multiple vertebral fractures, with severe kyphosis leading to reduced mobility and function.

Other common symptoms of fragility fractures include acute severe pain, difficulty weight-bearing (e.g. for a hip fracture) and mobilising. 

Signs include deformities, such as a shortened and externally rotated leg due to a hip fracture or a "dinner fork" deformity in a Colles' wrist fracture.

The area around the fracture may be bruised, swollen and tender to touch. 

# Differential Diagnosis

- **Bone metastases** may lead to pathological fractures, either in patients with known malignancies or as a first presentation of cancer (especially lung, prostate, breast, kidney and thyroid)
- **Osteomalacia** usually occurs secondary to severe vitamin D deficiency and increases fracture risk due to bone weakening; other symptoms include bone pain, muscle pain and proximal weakness with a waddling gait
- **Multiple myeloma** also is associated with pathological fractures, as well as hypercalcaemia, renal impairment, anaemia and bone pain
- **Paget's disease** increases the risk of fracture due to abnormal bone remodelling, leading to features of bone pain and bowing of the long bones
- **Osteogenesis imperfecta** is a genetic condition that commonly presents in childhood with fragility fractures, bowing of the long bones, short stature and blue sclera
- **Avascular necrosis** may mimic a spontaneous fracture with severe pain after no or minimal trauma, commonly affecting the femoral head

# Investigations

- The diagnostic investigation for osteoporosis is a **dual-energy X-ray absorptiometry scan (DEXA)**
- This measures **bone mineral density (BMD)**
- A T-score of -2.5 or less is considered diagnostic of osteoporosis
- If the T-score is between -1 and -2.5 this is referred to as osteopenia
- Z-score is also reported (this compares bone density to a age, sex and ethnicity matched population rather than healthy young adults) - below -2 is low for their age
- The following patients should be offered a DEXA scan as the initial step in assessment
- Aged over 50 presenting with a fragility fracture
- Aged under 40 with a major risk factor for fragility fracture (e.g. long-term steroids) 
- Those about to start treatment that will rapidly decrease bone density (e.g. hormone deprivation in breast cancer) - consider
- All other patients with risk factors should have their fracture risk assessed as the initial step
- **QFracture** and **FRAX** are the two online assessment tools used
- These both predict a patient's 10-year risk of hip and major osteoporotic fractures
- QFracture is interpreted based on whether the risk score is greater or less than 10%
- FRAX plots fracture risk versus age on a graph that stratifies people into low/intermediate/high risk
- With QFracture, those at approximately 10% risk or more at 10 years should have a DEXA scan 
- With FRAX, patients at intermediate or high risk of fracture should have a DEXA
- In women over the age of 75 with a history of fragility fractures, a clinical diagnosis of osteoporosis may be appropriate (if a DEXA is unfeasible)

Other investigations required in all patients include:

- **Vitamin D** to check for deficiency; this is needed prior to starting bisphosphonate treatment
- **Bone profile** to check serum calcium as this may also require supplementation
- **X-rays** or other imaging modalities (e.g. CT or MRI) may be required to diagnose and assess fragility fractures

If an underlying cause is suspected, the following investigations may be appropriate:

- **Full blood count** which may show anaemia in malabsorption or malignancy, and leukocytosis in malignancy or inflammatory disease
- **Liver function tests** for chronic liver disease
- **U&Es** for chronic kidney disease
- **ESR** or **CRP** which may be raised in inflammatory disease or malignancy
- **Thyroid function tests** if hyperthyroidism is suspected
- **Testosterone** and **sex hormone-binding globulin** if hypogonadism is suspected in men
- **Anti-TTG antibodies** for coeliac disease if there is evidence of malabsorption

# Management

**Conservative management:**

- Identification and treatment of any underlying condition contributing to osteoporosis
- Optimisation of risk factors e.g. smoking cessation, alcohol reduction
- Advise patients to take regular weight-bearing exercise to improve muscle strength, including walking, strength training and balance and flexibility training
- Advise patients to eat a balanced diet and assess their calcium intake
- Assess falls risk and consider measures to reduce this, including referral to multidisciplinary falls teams 
- Referral to specialist services for patients with very high fracture risk (e.g. T score less than -3.5, multiple vertebral fractures)

**Medical management:**

- Prescribing vitamin D supplementation for patients not exposed to adequate sunlight
- Prescribing calcium supplements to patients with an inadequate dietary calcium intake
- For patients at high risk of fragility fracture, prescribe bone-sparing treatment
- Treatment should be started promptly after a fragility fracture to reduce the risk of another fracture
- Oral bisphosphonates are the first-line treatment in the majority of patients 
- Options include alendronate and risedronate, which can be given either daily or weekly
	- These must be taken on an empty stomach, at least 30 minutes before food or other medications
	- Tablets need to be swallowed whole with a glass of water whilst the patient is upright; they should stay upright for at least 30 minutes after this
	- Common side effects include nausea, dyspepsia, gastritis, abdominal pain and musculoskeletal pains
	- Rarer side effects include oesophagitis or ulceration, stricturing or erosions, osteonecrosis of the jaw or external auditory canal and atypical stress fractures
	- To minimise risk of osteonecrosis of the jaw, patients with poor dentition or malignancy should have a dental check-up (and any work required performed) before starting bisphosphonates
	- They should also continue to have routine dental checks and maintain good oral hygiene during treatment 
	- Contraindications include severe chronic kidney disease, hypocalcaemia or vitamin D deficiency, and oesophageal abnormalities such as stricture or achalasia 
	- Patients with recent peptic ulceration, upper gastrointestinal bleeding or surgery, dysphagia, gastritis or duodenitis should be prescribed bisphosphonates with caution
- If oral bisphosphonates are not tolerated or unsuitable, options for bone-sparing treatment include:
	- Parenteral bisphosphonates (e.g. zoledronate)
	- Denosumab
	- Raloxifene hydrochloride
	- Strontium ranelate
	- Hormone replacement therapy should be considered for younger women experiencing menopausal symptoms as this will also reduce their fragility fracture risk
	- Teriparatide and romosozumab are other bone-sparing treatments that may be recommended first-line in women with severe osteoporosis - these are then followed by bisphosphonate treatment

**Surgical management:**

- Fragility fractures may require surgical fixation or joint replacement (e.g. hip arthroplasty for a fractured neck of femur)

# Complications

- Hip fractures are high-consequence injuries and lead to permanent disability in 50% and death in 20% of patients 
- Vertebral fractures may lead to disabling and painful kyphosis which may in turn cause difficulty breathing and gastrointestinal problems such as dyspepsia
- Wrist fractures can significantly affect independence and functional ability
- Many patients experience a "fracture cascade" where further fractures occur in the years following the initial one
- Pain from fractures can lead to poor sleep, low mood and reduced quality of life
- Complications of treatment may be significant (e.g. osteonecrosis of the jaw or oesophageal ulceration with bisphosphonates)

# Prognosis

- There is no cure for osteoporosis
- In general however, prognosis is good with effective treatment
- Bisphosphonate treatment should be reviewed after 3-5 years
- If patients remain at high risk of fracture it may be continued for up to 7-10 years
- Patients with previous hip or vertebral fractures, those aged 70 or older or those who sustain another fragility fracture whilst on bone protection often require longer durations of treatment
- Repeat DEXA may be appropriate to aid decision making
- If bone protection is stopped, fracture risk should be reassessed 18 months to 3 years later

# NICE Guidelines

[NICE CKS: Osteoporosis - prevention of fragility fractures](https://cks.nice.org.uk/topics/osteoporosis-prevention-of-fragility-fractures/)

[NICE - Osteoporosis: assessing the risk of fragility fracture](https://www.nice.org.uk/guidance/cg146)

# References

[National Osteoporosis Guideline Group - Prevention and Treatment of Osteoporosis](https://www.nogg.org.uk/full-guideline)

[BNF Treatment Summary - Osteoporosis](https://bnf.nice.org.uk/treatment-summaries/osteoporosis/)

[Radiopaedia - Dual-energy x-ray absorptiometry](https://radiopaedia.org/articles/dual-energy-x-ray-absorptiometry-1?lang=gb)

[WHO - Fragility fractures](https://www.who.int/news-room/fact-sheets/detail/fragility-fractures)

[International Longevity Centre UK report on Osteoporosis](https://ilcuk.org.uk/wp-content/uploads/2018/10/OsteoporosisUK.pdf)



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A 60-year-old woman has presented with severe low back pain for the past three months. She has been a chronic smoker since childhood and had premature menopause at the age of 38 years. A dual-energy x-ray absorptiometry (DXA) scan, which assesses her bone density, revealed a T-score below −2.5.

Given the likely diagnosis, what receptor is overactive at the molecular level in the patient's condition?
a