Osteoporosis

• Osteoporosis means “porous bone“. It is a progressive, systemic skeletal disorder characterised by reduced bone density and defects within the microstructure of bone
• Osteopenia is a precursor to osteoporosis and refers to a less severe reduction in bone density.
• Three of the most important cell types found in bone are:

  • Osteoblasts: are responsible for bone formation.
  • Osteocytes: are mature cells (derived from osteoblasts) that help to maintain bone.
  • Osteoclasts: are primarily responsible for bone breakdown.
• Osteoporosis occurs when there is a mismatch between the activity of these cells and the demand for bone remodelling, either through increased activity of osteoclasts or reduced activity of osteoblasts.
• Osteoporotic fractures are also known as “fragility fractures” because they occur from mechanical forces or trauma that would not normally cause a fracture.
• • It is most common in post-menopausal women, although there are a large number of risk factors for the disease
• General risk factors:

  • Increasing age
  • Female sex
  • Post-menopause - oestrogen deficiency causes excess bone resorption
  • Reduced mobility and activity
  • Low BMI
  • Smoking
  • Alcohol
  • Parental history of hip fracture
  • Previous fragility fracture
• Medical conditions which increase risk:

  • RA
  • Primary hyperparathyroidism
  • CKD
  • GI disease - IBD, coeliac
  • Hyperthyroidism
  • Chronic liver disease
• Medications which increase risk:

  • Corticosteroids
  • SSRIs
  • PPIs
  • Anti-epileptics
  • Anti-oestrogens
• Osteoporosis remains asymptomatic until a fracture occurs, meaning the disease can become established before it is diagnosed. 

  A fragility fracture is defined as a low-impact fracture from a standing height or less. The most common sites of fragility fracture are:

  • Vertebral: although a large number of vertebral fractures are asymptomatic
  • Hip (proximal femur)
  • Wrist (distal radius)
• Osteoporosis itself will generally not cause specific findings on clinical examination. Patients with vertebral fractures may have hyperkyphosis of the spine due to multiple vertebral body compression fractures (“Dowager’s hump”).
• There may be signs of risk factors for osteoporosis (e.g. tar staining in patients who smoke or joint swelling in patients with rheumatoid arthritis). 
• The Fracture Risk Assessment Tool (FRAX) score is used to assess the risk of fractures suspected of having osteoporosis. Calculates the 10-year fracture probability.
• NICE advises that the following patient groups should have a fracture risk assessment:

  • All women aged 65 years and over
  • All men aged 75 years and over
  • Women aged under 65 years, and men aged under 75 years with risk factors 
• FRAX score:

  • Low risk: measuring bone mineral density (BMD) is not required; give lifestyle advice and reassurance and monitor risk factors
  • Intermediate risk: offer DXA scan if close to high-risk threshold or have risk factors that may be underestimated by assessment tool
  • High risk: arrange a DXA scan to measure BMD
• BMD can be measured using a DXA scan, a specialised type of X-Ray that can indicate the density of bone depending on how much radiation is absorbed.

  Any bone in the body can be used, but the two regions typically used for osteoporosis diagnosis are the femoral neck and spine. The femoral neck BMD is generally considered the gold standard diagnostic test.
• A DXA scan produces several different scores:

  • T-score: the number of standard deviations the patient’s bone density is from the mean bone density of a 30-year-old adult
  • Z-score: the number of standard deviations the patient’s bone density is from the mean bone density of age and gender-matched control 
• Lab investigations:

  • Bone profile - usually normal
  • U&Es - screening for CKD as a cause
  • Vitamin D
  • PTH - screening for hyperparathyroidism as a cause
  • TFTs - screening for hyperthyroidism as a cause
  • Testosterone - screening for hypogonadism as a cause
• Osteoporosis can be diagnosed based on a history of a previous fragility fracture or a low BMD identified on a DXA scan
• A T score less than -2.5 from a DXA scan is diagnostic of osteoporosis

  • Osteopenia = -1 to -2.5 (lower than average bone density)
  • Normal = >-1
• All patients who undergo fracture risk assessment should be given lifestyle advice, as this may help prevent osteoporosis and fractures in low-risk patients. 

  • Exercise
  • Stop smoking
  • Reduce alcohol
  • Adequate calcium and vitamin D
• Patients with vitamin D levels. below 50nmol/L should be offered treatment:7

  • Rapid correction: 300,000 IU vitamin D3 over 6-10 weeks in divided doses, followed by maintenance vitamin D
  • Maintenance: 800-2,000 IU vitamin D3/day
• Oral bisphosphonates are generally considered the first-line treatment for patients with osteoporosis:

  • Alendronic acid 10mg daily or 70mg weekly
  • IV Zolendronic acid if patient cannot tolerate oral (once a year)
• Bisphosphonate counselling:

  • Oral bisphosphonates should always be taken on an empty stomach
  • Tablets should be swallowed whole with a whole glass of water in an upright position, and remain upright for 30 minutes after taking the medication
  • Potential side effects include gastrointestinal upset (dyspepsia, reflux), atypical fractures and osteonecrosis of the jaw (jaw pain, swelling and erythema) 
  • A dental check-up is advised before starting bisphosphonates: any dental work should be performed before or as soon as possible after starting bisphosphonates. 
• Denosumab:

  • Monoclonal antibody
  • First line in postmenopausal women who cannot take bisphosphonates
  • Calcium and vitamin D levels must be adequate before starting
• For bisphosphonates, the initial length of treatment is typically five years for oral bisphosphonates and three years for IV zoledronic acid.
• Pathogenesis:

  • When young osteoblasts are more active - reach peak bone mass in 3rd decade - osteoclast and osteoblast activity equal
  • Many factors play a role in what peak bone mass a person can achieve e.g. genetics, physical activity, nutrition, smoking, medication
  • Around 5th decade osteoclasts become more active than osteoblasts - bone mass decreases
  • Higher the peak bone mass achieved - longer it will take for above process to have a significant impact on bone density
• Risk assessment tools:

  • FRAX
  • QFracture tool
• Risk assessment tools exceptions:

  • In patients >50 with fragility fractures, or >40 with a major risk factor you don't need to do a risk assessment - proceed to DXA scan
  • In patients with vertebral fractures you can consider starting treatment without risk assessment or DXA scan
• T score and risk:

  • T score <-2.5 and intermediate/high risk - offer treatment
  • T-score >-2.5 and high risk - optimise risk factors, treat underlying conditions, repeat DXA within 2 years
• Bisphosphates side effects:

  • GI disturbance: N&V, dyspepsia/gastritis, oesophagitis, ulcers, erosions, MSK pain
  • Osteonecrosis of jaw - osteoclastic activity of bone in the jaw leading to accumulation of bisphosphonates in the jaw - prevents normal bone resorption - old bone survives beyond normal life span and has poor blood supply
  • Atypical femoral fracture - same MOA as above - old bone can fracture
• Bisphosphanates:

  • Alendronate
  • Risedronate
  • Zoledronic acid IV
  • Inhibit osteoclastic activity
  • Contraindicated in renal impairment, hypocalcaemia (bisphosphonates exacerbate) , pregnancy and breastfeeding
• Follow up:

  • Review adherence and side effects
  • if taking steroids - continue bisphosphonates until steroids stop and reassess FRAX to determine need to continue treatment
  • For all others - review after 3-5 years of treatment and do risk tool again:
  • If high risk continue treatment
  • If not high risk arrange DXA scan
  • If T score <-2.5 continue treatment and reassess every 3-5 years
  • If T score >-2.5 stop treatment and reassess in 2 years
• Referral to specialist if oral bisphosphonate not tolerated:

  • IV zoledronic acid
  • Denosumab - 1st line in post menopausal women who can't tolerate oral bisphosphonate - monoclonal antibody against RANK ligand (cytokine that activates osteoclast activity) - SC every 6 months
  • Raloxifene - post menopausal osteoporosis - binds to oestrogen receptors in bone activating oestrogen pathways - decrease in bone resorption - contraindicated in VTE and endometrial cancer
  • Strontium ranelate - stimulates osteoblasts and blocks osteoclasts
  • Teriparatide - stimulates osteoblasts