Bone resorption inhibitors

Bone resorption inhibitors


Bisphosphonates are a class of drugs used to prevent loss of bone mass in conditions characterised by excessive bone resorption which causes bone fragility, such as osteoporosis, Paget's disease of bone, bone metastasis and primary hyperparathyroidism. Mechanistically bisphosphonates bind to hydroxyapatite on bony surfaces, and are taken in to osteoclasts during bone resorption. Bisphosphonates act to disrupt osteoclast function and number (via apoptosis).

As bisphosphonates are poorly absorbed orally they should be taken on an empty stomach (with water) at least 30 minutes before food is ingested.

Safety information for all bisphosphonates includes being alert to the risk of bisphosphonate-induced atypical femoral fractures, with patients advised to report any thigh, hip, or groin pain whilst taking bisphosphonates. With intravenous bisphosphonates there is a very low risk of developing osteonecrosis of the jaw. Risk factors to consider include potency of the bisphosphonate, cumulative dose, duration and type of malignant disease, concomitant treatment, smoking, comorbid conditions, and history of dental disease. Patients should be advised to maintain good oral hygiene, attend routine dental check-ups, and report any dental mobility, or oral pain, swelling, non-healing sores or discharge during treatment. Benign idiopathic osteonecrosis of the external auditory canal has also been reported, primarily in patients receiving bisphosphonate therapy for >2 years. Risk factors for developing osteonecrosis of the external auditory canal include steroid use, chemotherapy, infection or ear operations.

There are two groups of bisphosphonate drugs:

Non-nitrogenous (simple) bisphosphonates are absorbed by osteoclasts and are broken down to metabolites that lead to the formation of inactive ATP molecules that cannot be used as a source of energy. Energy depletion then leads to osteoclast apoptosis. This sub-family of drugs cause more adverse effects than the nitrogenous bisphosphonates, so are prescribed less frequently.

  • Etidronate (etidronic acid- not available in the UK) is administered orally, being used to treat Paget's disease of bone and irregular bone growth due to hip fracture or spinal cord injury. Continuous use will lead to osteomalacia as etidronate prevents bone calcification. In light of this etidronate should be used infrequently and only for a short time and alternative bisphosphonates should be considered for treating osteoporosis.
  • Tiludronate (tiludronic acid- not available in the UK, discontinued in the US) is administered orally, being used to treat Paget's disease of bone.
  • Sodium clodronate (not available in the US) is delivered orally to treat osteolytic lesions and hypercalcaemia and bone pain associated with skeletal metastases in patients with breast cancer or multiple myeloma

Nitrogenous bisphosphonates bind to and inhibit farnesyl diphosphate synthase, an enzyme of the HMG-CoA reductase (mevalonate) pathway. Once absorbed by osteoclasts nitrogenous bisphosphonates inhibit production of isoprenoid precursors, leading to apoptosis.

Pamidronate (pamidronate sodium, pamidronic acid, ~100 times more potent than etidronate) is administered i.v. to treat hypercalcaemia of malignancy,  osteolytic lesions and bone pain in bone metastases associated with breast cancer or multiple myeloma and  Paget's disease of bone.

Alendronate (alendronic acid, ~500 times more potent than etidronate) is administered orally for the treatment of postmenopausal osteoporosis, osteoporosis in men and for prevention and treatment of corticosteroid-induced osteoporosis in postmenopausal women not receiving hormone replacement therapy. Sometimes prescribed in combination with colecalciferol (vitamin D3).

Ibandronate (ibandronic acid, ~1000 times more potent than etidronate) is administered i.v. for the treatment of hypercalcaemia of malignancy, or orally to reduce bone damage in bone metastases in breast cancer and to treat postmenopausal osteoporosis.

Risedronate (risedronate sodium, ~2000 times more potent than etidronate) is delivered orally for the treatment of osteoporosis in men at high risk of fractures, postmenopausal osteoporosis to reduce risk of vertebral or hip fractures, Paget's disease of bone and for the prevention of postmenopausal osteoporosis (including corticosteroid-induced osteoporosis). Sometimes prescribed in combination with calcium and colecalciferol (vitamin D3).

Zoledronic acid (~10000 times more potent than etidronate) is delivered by i.v. infusion for the treatment of Paget's disease of bone, postmenopausal osteoporosis and osteoporosis in men (including corticosteroid-induced osteoporosis), hypercalcaemia of malignancy and to reduce bone damage in advanced malignancies involving bone.



In normal physiology calcitonin is involved in calcium (Ca2+) and phosphorus metabolism, acting to lower blood Ca2+ levels and increase calcium and phosphate deposition in bone. Calcitonin protects against skeletal calcium depletion during periods of calcium mobilization (e.g. during pregnancy and lactation).

In the clinic calcitonin salmon (peptide produced by recombinant technology or peptide synthesis) is used to treat hypercalcaemia of malignancy, osteitis deformans (Paget's disease of bone), for prevention of acute bone loss due to sudden immobility, and is used to treat postmenopausal osteoporosis in some countries.



Cinacalcet is a positive allosteric activator of the calcium-sensing receptor (CaSR) which potentiates the action of extracellular calcium by lowering the threshold for CaSR activation and leads to inhibition of parathyroid hormone (PTH) secretion and production. Decreased levels of PTH results in diminished osteoclast-driven bone resorption. Cinacalcet is prescribed for the treatment of secondary hyperparathyroidism in patients with end-stage renal disease on dialysis, primary hyperparathyroidism in patients where parathyroidectomy is inappropriate and hypercalcaemia in parathyroid carcinoma.


Raloxifene hydrochloride

Raloxifene is a selective estrogen receptor modulator (SERM) with estrogen-like effects on bone which reduce bone resorption and increase bone mineral density in postmenopausal women. Raloxifene is prescribed for the prevention and treatment of osteoporosis in postmenopausal women.



Denosumab is a monoclonal antibody which suppresses the activity of RANK ligand (RANKL), which normally promotes bone removal and resorption, but which becomes over active in many bone loss diseases. The drug is delivered by s.c. injection for the treatment of postmenopausal osteoporosis and men at increased risk of fractures, bone loss associated with hormone ablation in patients with prostate cancer at increased risk of fractures, giant cell tumour of bone that is unresectable and prevention of skeletal related events in patients with bone metastases from solid tumours.

Like the bisphosphonates, denosumab poses a risk of atypical femoral fractures, osteonecrosis of the jaw and hypocalcaemia.


Strontium ranelate

Strontium ranelate is a strontium(II) salt of ranelic acid, which acts as a "dual action bone agent" (DABA) which both increases new bone deposition by osteoblasts and reduces resorption by osteoclasts. Due to the reported risk of myocardial infarction, strontium ranelate is only recommended for treatment of severe osteoporosis in postmenopausal women or men at high risk for fracture in cases where other treatments are contra-indicated or not tolerated.