Prolia (Denosumab); Prolia Uses, Warnings & Prolia Side Effects

Skeletal system

Our skeletal system was thought to be constant after puberty and that our bony structure remains the same after we reach our adult height and size. This was, however, wrong and we now know that our bones are continuously undergoing destruction and new bone formation in a process known as bone remodeling. This process is the result of the action of 2 main cells found in our bones, the osteoblasts and osteoclasts.

Osteoblasts lay down new bony matrix which is formed of protein and then new mineral crystals formed of calcium and phosphate called hydroxyapatite are laid on the formed protein matrix. The calcium phosphate crystals are what give the bone its strength and ability to withstand stress.

Osteoclasts, on the other hand, destroy that bony matrix gradually releasing calcium into the circulation. This process is kept in balance in adults by the effect of several hormones and regulatory mechanisms. It is important to understand that the level of blood calcium greatly depends on that balance as well as the effect of hormones like parathyroid hormone and vitamin D on calcium absorption and excretion.

What is Prolia and how does it work?

Prolia

Prolia was developed in the early 21st century and was approved by the FDA between 2009 and 2010 first for the treatment of women with postmenopausal osteoporosis then for the treatment of a subtype of bone cancer in 2013. Other uses have been approved and suggested since then as will be mentioned in the “uses” section in the article.

Prolia or denosumab is a monoclonal antibody, which means that it is a protein that binds to other protein or non-protein structures to trigger an action or block one. The term monoclonal means that it is targeted towards a specific protein, mostly a receptor on the surface of cells. The receptor that denosumab binds to is called RANK-L which is found on the surface of osteoblasts. In normal situations, RANKL binds to another receptor called RANK which is found on the mother cells of osteoclasts to push their maturation. This balance between osteoblasts and osteoclasts is what keeps bone remodeling a constant and balanced process. When denosumab binds to RANKL, it inhibits it from binding to RANK and thus, prevents the maturation of osteoclasts. This in turn makes the balance towards new bone formation via osteoblasts.

Uses

Prolia uses

Generally speaking, Prolia can be used for any condition in which there is bone loss. It helps keep the bone density high and thwart any destruction regardless of the cause as long as it is done via osteoclasts. Uses of Prolia include:

1) Postmenopausal osteoporosis:

Postmenopausal osteoporosis

Osteoporosis is a disease of bone loss. The mineral as well as the protein content of bones is greatly reduced, putting bones at risk of pathological fractures. In females, after menopause, the ovarian reserve burns out and the level of estrogen begins to drop. Estrogen is responsible for many functions in the female body including increasing the activity of osteoblasts and maintaining bone mineral density. The severity of affection differs between women but as many as 25% of women suffer from osteoporosis after the age of 70.

Osteoporosis is, unfortunately, asymptomatic for most cases and is discovered after a pathological fracture occurs -pathological fractures are those which occur in an already diseased bone-. Several medications can be used to prevent or manage osteoporosis since the development of a fracture at such an age can become debilitating since most patients suffer from either vertebral or neck of femur fractures. Prolia is usually given to cases which either can’t tolerate traditional medications or in whom traditional medications are ineffective. It is given alone via subcutaneous injections.

2) Giant cell tumor of the bone:

Giant cell tumor of the bone

One of the types of bone cancer involves the uncontrolled division of osteoclasts which causes widespread destruction of bone. Prolia both controls such proliferation and prevent the development of fractures in those patients. Giant cell tumors are usually managed by surgery through various removal methods of the tumor with bone preservation. Prolia is used in cases when surgery is not feasible usually because of the patient’s poor general health. It is used alone in the form of subcutaneous injections.

3) Male osteoporosis:

Male osteoporosis

Although males don’t suffer from osteoporosis as frequently as females, testosterone levels also wane as age progresses and up to 10% of males can have osteoporosis at the age of 80. Prolia has shown conflicting evidence in clinical trials regarding male osteoporosis, but it can be used in cases unresponsive to other medications.

4) Cases of hypercalcemia due to cancer:

Hypercalcemia

Some types of cancer secrete hormones that can cause a rapid increase in the level of serum calcium. This can be countered by several drugs such as those of osteoporosis especially bisphosphonates, and although denosumab isn’t considered as a first-line drug in such cases, it can be used in select resistant cases.

5) With anti-androgen therapy:

With anti-androgen therapy

Some anti testosterone medications may be used in patients with prostatic enlargement or prostatic cancer especially advanced cases. They come with the side effect of depriving the male of the hormone keeping his bone density high, triggering a male “menopause”.

Several medications can be used to treat it including the same medications used for women with postmenopausal osteoporosis as well as denosumab.

6) Steroid induced osteoporosis:

Steroid induced osteoporosis

Prolonged corticosteroid therapy can cause osteoporosis through increasing the osteoclastic activity and inhibiting osteoblastic function. Traditional osteoporosis medications are also used with calcium and vitamin D. Denosumab can be used form the start in patients at high risk of fractures.

Mode of administration

Mode of administration

Denosumab is given via a subcutaneous injection.

Adverse effects

Prolia side effects

The most common side effects associated with Prolia are related to joint and muscle pain especially at the back. Most side effects are related to the alteration of blood calcium levels. Other side effects include:

  • Generalized fatigue and weakness
  • Sore throat, nausea and diarrhea
  • Headache
  • Cough
  • Breathlessness
  • Sleeping disturbances
  • Dermatological side effects like eczema
  • Increased risk of infections: One of the commonly noticed side effects of Prolia is the increased incidence of infections among patients who take it. The reason behind this is that RANKL, the receptor that it blocks is also found on the surface of some white blood cells and its blockage can negatively affect immunity.
  • Hypersensitivity: A group of patients were found to be allergic to the subcutaneous injection of Prolia. Manifestations range from mild redness and itchiness at the site of injection to face edema and even severe anaphylactic shock. This is why Prolia should always be administered in a hospital setting by healthcare professionals. Such reactions can be easily managed in hospitals but can be fatal if the drug is given at home.
  • Alopecia: Hair loss has been reported in a minority of patients receiving denosumab. Most patients were males, but the condition was irreversible. It is believed that it resulted from an induced autoimmune reaction by the drug.
  • Hypocalcemia: Calcium is one of the most important minerals in our blood and is essential for the functioning of the heart and muscular contraction in general. A disturbance of calcium level especially hypocalcemia can be fatal if not treated properly. Calcium level is controlled by several hormones and most of which function on the bones, gastrointestinal system and the kidney. Most hormones also act on osteoclasts to stimulate or inhibit their functioning which directly affects the release of calcium from bones. Hypocalcemia resulting from denosumab is either subclinical or mild and can be managed with relative ease, but in rare cases, ICU admission may be necessary since hypocalcemia can cause death by suffocation due to spasm of the vocal cords.
  • Rebound osteoporosis: Many drugs have to be stopped gradually since their sudden withdrawal can cause severe side effects. Although Prolia is mainly used to control and prevent osteoporosis, its sudden withdrawal can cause rebound osteoporosis severe enough to cause multiple vertebral fractures. Therefore, its gradual withdrawal is always advised for patients who have used it for a long time.

Can Prolia be used in pregnancy?

Can Prolia be used in pregnancy?

Prolia has been proven to cause fetal harm and loss and is contraindicated in pregnancy unless absolutely necessary. Fertile women are advised to use a safe method of contraception throughout the duration of therapy by Prolia plus 5 months after discontinuation.