Normally, when bone resorption is stimulated, this is accompanied by stimulation of osteoblasts, so that bone deposition occurs subsequently. Factors that stimulate osteoblasts to form bone are still largely unknown, however, it is known that parathyroid hormone stimulation of osteoblasts ultimately leads to bone deposition (see below). When bone resorption outpaces bone deposition, there will be a net loss of bone. Partial reduction of bone mass is referred to as osteopenia. Osteoporosis is a severe reduction in bone mass that substantially increases the risk of bone fracture. Osteoporosis is diagnosed by measuring bone density (bone mass per unit volume) at different sites around the body.
Everyone experiences bone loss as they age, but not everyone develops osteoporosis. A critical factor for determining bone health as one ages is peak bone mass. The skeleton reaches full size at the end of puberty, but bone mass continues to increase until the mid-30's. Someone with a low peak bone mass is more likely to develop osteoporosis later in life. The development of a high peak bone mass will be a function of genetics, but is also influenced by good nutrition and exercise. Prevention of osteoporosis is focused on ensuring adequate dietary levels of calcium and vitamin D along with a healthy exercise regimen during the bone building years.
Hormones are very important for skeletal health. Inadequate levels of vitamin D can lead to poor mineralization of bone. Hypersecretion of PTH, thyroid hormone, and cortisol all promote bone loss. The gonadal steroids (estrogen and testosterone) have a key role in maintaining skeletal mass. They work by suppressing the production of signals that promote osteoclastogenesis. Osteoporosis is a disease of the elderly, and particularly of post-menopausal women, because of a loss of the action of gonadal steroids.
The goal of treatment for osteoporosis is to reduce the risk of
fracture. Almost all of the approved treatments for osteoporosis
are anti-resorptive, meaning they work by inhibiting
osteoclasts. These treatments are able to reduce bone loss, but
they do not work to build new bone. This is one reason why
preventive measures such as good nutrition and exercise are so
important.
Until recently, the mainstay of osteoporosis treatment in post-menopausal women was hormone replacement therapy (HRT) with estrogen and progesterone. The results of the Women's Health Initiative have shown that HRT can reduce the risk of fractures. However, this study also showed that HRT causes a greater risk of adverse cardiovascular events, as well as an increased risk of breast cancer. For this reason, there has been a large drop in prescriptions for HRT, and now mainly other drug treatments are used.
Bisphosphonates are now the first line of therapy for osteoporosis. Bisphosphonates are a non-hormonal drug therapy for osteoporosis; they are chemically related to pyrophosphate. They concentrate in bone and work by inhibiting osteoclast activity and inducing osteoclast apoptosis. Examples of bisphosphonates are alendronate and risedronate.
SERM stands for Selective Estrogen Receptor Modulator. These drugs bind to estrogen receptors, acting as estrogen agonists in some tissues, while acting as estrogen antagonists in other tissues. The goal is to avoid the adverse effects of administering estrogen (such as increased risk of breast cancer) while at the same time gaining the beneficial effect of estrogen on bone health. A SERM that has been approved for treatment of osteoporosis in the U.S. is raloxifene.
Denosumab is a monoclonal antibody that binds to RANKL to inhibit osteoclastogenesis. Denosumab mimics the effect of the endogenous protein osteoprotegerin.
Calcitonin is a hormone that acts oppositely to PTH: calcitonin secretion is stimulated by hypercalcemia and it acts to reduce calcium in the ECF. Calcitonin binds to receptors on the osteoclast and inhibits bone resorption. Calcitonin is a peptide hormone, and is administered either by injection or as a nasal spray.
Teriparatide is a peptide analog of PTH. Teriparatide is the only FDA-approved treatment for osteoporosis that is not anti-resorptive, but instead stimulates osteoblasts to build new bone. Although PTH leads to excessive bone resorption if it is present chronically (as in hyperparathyroidism), it has been found that intermittent treatment with PTH actually stimulates bone deposition. Recall that PTH receptors are located on osteoblasts. It appears that PTH stimulates bone deposition, either by promoting osteoblast survival, or by stimulating osteoblast proliferation. Teriparatide is administered in a once-daily injection.