15.03.1 Drugs used to treat osteoporosis

For the prevention of osteoporosis, and to prevent fractures, calcium supplements and vitamin D are used. For the treatment of osteoporosis, drugs that decrease the loss of bone (raloxifene, bisphosphonates, denosumab) or increase acquisition of bone (strontium, teriparatide).

Calcium supplements of 1,000/1,500 mg/day are recommended to prevent osteoporosis, and this is often combined with Vitamin D. Vitamin D is a mixture of cholecalciferol and ergocalciferol, hormones synthesized in skin requiring UV irradiation. Their primary active metabolite is calcitriol (1,25-dihydroxycholecalciferol). Calcitriol has a receptor-mediated role in calcium homeostasis whereby it facilitates the absorption of Ca²⁺ and phosphate from intestine, and decreases their excretion from kidney. The standard dose of cilcitriol is 400-600 IU for adults.

Hormone replacement therapy (HRT), which is a mixture of progesterone and oestrogens, or oestrogen were previously used in the treatment of osteoporosis. This seems like a rationale treatment, as the problem underlying osteoporosis is often low levels of oestrogens. However, there is some evidence that long-term treatment with HRT or oestrogens can increase the risk of breast and endometrial (uterine) cancer. Thus, these agents are no longer used long-term in osteoporosis.

Raloxifene is a partial agonist at oestrogen receptors. On bone, this decreases the reabsorption of bone, to help maintain bone density. Thus, raloxifene is used to prevent or treat postmenopausal osteoporosis. Raloxifene acts to antagonize the effects of oestrogens on oestrogen receptors in the breast and endometrium. Thus, raloxifene reduces the risk of breast cancer, and is used for this in women who are at high risk of breast cancer.

Presently, the most commonly used agents to prevent and treat osteoporosis are the bisphosphonates, such as alendronate and zoledronic acid. The bisphosphonates inhibit the reabsorption of bone. They have long half-lives, so that alendronate is effective when administered once-weekly and zoledronic acid can be administered intravenously once a year in subjects with severe osteoporosis. Alendronate is used orally, but due to irritating the gastrointestinal tract, subjects need to remain upright for 30 minutes after taking. Bisphosphonates are also useful in the treatment of Paget’s disease, where there are enlarged and misshapen bones.

Strontium is similar in structure to calcium, and can substitute for calcium in bone formation. Thus, strontium increases bone mineral density and reduces the risk of fractures in subjects with osteoporosis.

Parathyroid hormone has a major role in calcium homeostasis. It increases calcium absorption from the gut, it increases calcium reabsorption from the kidney, and it stimulation of bone formation. Thus, it is not surprising that teriparatide, the active fragment of parathyroid hormone is used in the treatment of osteoporosis, especially when there is a high risk of fractures and other agents are unsuitable. Teriparatide is used subcutaneously. In order for teriparatide to be effective, calcium is needed. Thus, teriparatide is used in subjects who are also receiving calcium supplements and Vitamin D.

The newest agent available to treat osteoporosis is denosumab. Denosumab binds to the RANKL ligand, which is involved in bone reabsorption. By binding to the RANKL ligand, denosumab inhibits bone reabsorption. Denosumab only needs to given subcutaneously every 6 months to be effective in the treatment of postmenopausal osteoporosis.