Bisphosphonates and Drug Treatment of Osteoporosis

The World Health Organisation defines osteoporosis on the basis of bone mineral density (BMD):

• BMD is usually reported as a T score.
• This is the number of standard deviations by which the patients BMD differs from the mean peak BMD for young adults of the same gender.
• For every standard deviation below the mean, the risk of fracture is approximately doubled.
• A T score of minus 2.5 or less indicates osteoporosis.
• A T score of between minus 1 and minus 2.5 indicates osteopaenia.

Bisphosphonates have an important role in the prophylaxis and treatment of osteoporosis and corticosteroid-induced osteoporosis.
Alendronic acid or risedronate sodium are considered the drugs of choice. Disodium etidronate may be considered if these drugs are unsuitable or not tolerated.
They work by being adsorbed onto hydroxyapatite crystals in bone. This slows their rate of growth and resorption. This also reduces the rate of bone turnover. Bisphosphonates are also used in the treatment of Paget's disease, hypercalcaemia of malignancy and in bone metastases in breast cancer.

• First-line treatment:²
  • Use alendronate or risedronate.
  • Note that risedronate is not recommended as a first-line treatment of osteoporosis in men as there are few data on its use in men, and this is an off-licence indication.
  • Do not give bisphosphonates to people who are unable to adhere to the dosing instructions.
• Second-line treatment:
  • Postmenopausal women with diagnosed osteoporosis: consider raloxifene, intranasal calcitonin (salmon), or cyclical etidronate. However, etidronate only prevents vertebral fractures. Studies have not demonstrated a reduced risk of hip fracture.
  • Elderly women with diagnosed osteoporosis consider cyclical etidronate or raloxifene (off-licence use).
• Adjunctive treatment: Calcium and vitamin D given as supplements in addition to bisphosphonates or raloxifene, if dietary intake is suboptimal (in the absence of conditions associated with hypercalcaemia).³

• Gastrointestinal adverse effects such as:
  • Abdominal pain
  • Dyspepsia
  • Diarrhoea
  • Constipation
  These are all common.
  A recent meta-analysis found that risedronate 5 mg daily was not associated with an increased risk of gastrointestinal adverse effects compared with placebo.⁵ This analysis included people with active dyspepsia, peptic ulcer disease, oesophagitis, or other oesophageal disorders at study entry. There was no difference in upper gastrointestinal adverse events between alendronate and placebo in two large studies, but it should be noted that women with recent peptic ulcer disease or dyspepsia requiring treatment were excluded.^6,7
• Oesophageal reactions are serious adverse events, but are uncommon. Severe oesophageal reactions (oesophagitis, oesophageal ulcers, strictures, and erosions) continue to be reported for alendronate. Oesophageal reactions may be slightly less common with risedronate, but this is not yet confirmed.⁴
  
  Oesophageal adverse effects can be avoided by taking bisphosphonates with a full glass of water while sitting upright or standing (but not lying down) and by remaining upright for at least 30 minutes afterwards.
  
  
• Reports from several hundred cases with new generation bisphosphonates (such as zolendronic acid, pamidronate and alendronic acid) have suggested that long term use increases the risk of avascular osteonecrosis of the jaw.⁸ Only 5% cases occur when they are used in osteoporosis.⁹

Alendronate: The risk of both vertebral and non-vertebral fractures is reduced by alendronate in postmenopausal women with:

• Confirmed low bone mineral density (BMD) and at least one vertebral fracture.⁶
• Confirmed low BMD but no previous vertebral fractures.⁷
• Alendronate has not been prospectively studied in women with multiple vertebral fractures, but there is no reason to suppose that it would not be effective.³
• In women with no previous vertebral fracture, the reduction in fracture risk was only significant for a T-score of less than minus 2.5; over 4.2 years one vertebral fracture was prevented for every 30 people treated, and one hip fracture was prevented for every 81 people treated.⁷
• Alendronate 70 mg once a week is therapeutically equivalent to 10 mg once a day.¹⁰

• Postmenopausal women with multiple vertebral fractures.^11,12
• Women aged between 70 and 79 years with confirmed low BMD and one vertebral fracture.¹¹
• In women with no previous fractures, the risk of hip fracture was reduced for elderly women with a T-score of less than minus 2.7, but not for those with only clinical risk factors for osteoporosis.¹³
• Risedronate 35 mg once a week is therapeutically equivalent to 5 mg once a day for the treatment of osteoporosis.¹⁴
• Analyses of studies of risedronate and etidronate found that these drugs all reduced the risk of vertebral fractures in people taking glucocorticoids.¹⁵

It is not known whether mens bones fracture at similar BMD levels to those of women. Consider referring all men to a specialist centre for investigation of underlying causes and advice on further management.
Alendronate is the only licensed bisphosphonate for the treatment of osteoporosis in men. If it is not tolerated or is contraindicated, seek specialist advice for further treatment options.