Osteoporosis

Normally, when bone resorption is stimulated, this is accompanied by stimulation of osteoblasts, so that bone deposition is linked to bone resorption. Factors that stimulate osteoblasts to form bone are still being identified.  One thing that is known is that when parathyroid hormone stimulates osteoblasts to activate osteoclastogenesis and bone resorption, this 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 that will affect 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 reduced secretion of estrogen.


Treatments for Osteoporosis

The goal of treatment for osteoporosis is to reduce the risk of fracture. Almost all of the approved treatments for osteoporosis are antiresorptive, meaning they work by inhibiting osteoclasts. Antiresorptive 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 Women's Health Initiative was a large study that showed 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.  Bisphosphonates 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.

Teriparatide is a peptide analog of PTH. Abaloparatide is a new peptide drug (approved by the FDA in April 2017) that also binds to the PTH receptor.  These two drugs are the only FDA-approved treatments for osteoporosis that are anabolic, meaning that they can stimulate osteoblasts to build new bone. All other therapies are antiresorptive.  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, perhaps by promoting osteoblast survival or by stimulating osteoblast proliferation.  PTH receptor agonist drugs (teriparatide and abaloparatide) are administered as a once-daily injection.


Optional

The newest approach to osteoporosis treatment is another anabolic therapy that can stimulate bone formation. Romosozumab is a sclerostin inhibitor that is presently being tested in phase III trials.

Sclerostin is a signaling molecule that is released by osteocytes and osteoclasts; its effect is to limit bone formation by blocking the signals that promote osteoblast formation. Sclerostin was discovered through studies of individuals with a rare disorder causing excessive bone formation. When sclerostin is mutant or expressed at lower levels, there is more bone formation.

Several phase III trials have shown that treatment with romosozumab increases bone density and decreases fracture risk compared to placebo.

If you are interested in reading further, check out these papers.

(2017) Romosozumab of Alendronate for Fracture Prevention in Women with Osteoporosis New England Journal of Medicine 377: 1417-1427 (link)

    [URL: http://www.nejm.org/doi/full/10.1056/NEJMoa1708322]

(2017) Romosozumab--Promising or Practice Changing? New England Journal of Medicine 377: 1479-1480 (link)

    [URL: http://www.nejm.org/doi/full/10.1056/NEJMe1711298]

(2016) Romosozumab Treatment in Postmenopausal Women with Osteoporosis New England Journal of Medicine 375: 1532-1543 (link)

    [URL: http://www.nejm.org/doi/full/10.1056/NEJMoa1607948]

(2016) Building Better Bones with Biologics--A New Approach to Osteoporosis? New England Journal of Medicine 375: 1583-1584 (link)

    [URL: http://www.nejm.org/doi/full/10.1056/NEJMe1611863]

Off-campus access: open LINK TO PROXY SERVER. Next, type in the URLs given above.


Quick Quiz: Osteoporosis


Fill-in Answer Correct False Correct Answer
1. Osteoporosis occurs when bone resorption outpaces _______.
2. The incidence of osteoporosis increases amongst post-menopausal women because of decreased secretion of _________.
3. Name the monoclonal antibody drug that mimics the action of osteoprotegerin.
4. Raloxifene is a drug that binds to the ________ receptor.
5. What cell is inhibited by bisphosphonates?
6. Name a peptide drug treatment for osteoporosis that is anabolic (acts to build new bone).


(Spelling must be correct)




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