Prolia is a synthetic human monoclonal antibody that is given by injection into the arm once every 6 months. Prolia treatment prevents spine, hip, and peripheral fractures beginning as soon as the first dose. It is designed to be very specific and to bind a single protein only that promotes bone removal. This is why it is so safe and has only one side effect, a rash that occurs rarely. The drug is covered by insurance and not very expensive considered how technically advanced it is.

Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture from the Prolia Label
Prolia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.  In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, nonvertebral, and hip fractures.

Treatment to Increase Bone Mass in Men with Osteoporosis from the Prolia Label
Prolia is indicated for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.

Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer from the Prolia Label
Prolia is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients, Prolia also reduced the incidence of vertebral fractures.

Treatment of Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast Cancer from the Prolia Label
Prolia is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

Treatment of Postmenopausal Osteoporosis
In the US FDA registration study 7,800 postmenopausal women were randomized half to denosamab and half to placebo. Their average age was 72 and all had osteoporosis on bone density with a quarter also having an X-ray diagnosed spine fractures at entry.

After 3 years of therapy, the new vertebral fracture rate was 72 per 1,000 in the placebo group vs. 23 per 1,000 in the treated women for a 68% relative fracture reduction. The absolute risk reduction was 4.9%. This data shows that 20 women like those in the study would need to be treated with denosamab for 3 years to prevent 1 new spine fracture.

Hip fractures were significantly reduced after 3 years of treatment with denosamab with a statistically significant absolute risk reduction of 0.5%. This data shows that 200 women like those in the study would need to be treated with denosamab for 3 years to prevent 1 new hip fracture.

Peripheral fractures were significantly reduced after 3 years of treatment with denosamab with a statistically significant absolute risk reduction of 1.5%. This data shows that 67 women like those in the study would need to be treated with denosamab for 3 years to prevent 1 new peripheral fracture.

Bone density increased significantly at the spine and hip in women treated with denosamab. After 3 years, the difference between the denosamab and placebo groups was +8.8% in the spine, +6.4% in the total hip, and +5.2% in the femoral neck.

Warnings
Osteonecrosis of the jaw and atypical femoral fractures have occurred in patients taking denosamab but the incidence is very low. The risk is not zero but it is <10,000 or lower. There have been a few cases of atypical fracture of the femur in patients treated with Prolia but the risk extremely low.

Side Effects
There is one true side effect confirmed in the clinical trial of denosamab and that is a rash. It happens rarely. I have had one patient with what I thought was a denosamab rash despite treating hundreds of people with it.

Dermatologic Reactions from the Prolia Label
A significantly higher number of patients treated with Prolia developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the Prolia groups (p < 0.0001). Most of these events were not specific to the injection site.

Dr. Woodson’s General Comments on Prolia
Prolia is denosamab is a monoclonal antibody that binds RANK-L taking it out of play. The antibody-RANK-L complex floats around harmlessly in the blood until one of the immune system elements spots it, binds and absorbs it, then digests the complex into its constituent amino acids. These are excreted back into the blood stream where they are recycled by the body’s cell.

Denosamab is a targeted therapy aimed at a protein that causes bone to be absorbed excessively. The protein, RANK-L is an essential component of the bone remodeling cycle that becomes over produced after menopause due to sex steroid hormone deficiency. In white women, menopause triggers a genetic complex that in part expresses itself through excess RANK-L release from the osteocytes that leads to osteoporosis in many. Release of RANK-L is also promoted by several other common causes of osteoporosis. Denosamab is a monoclonal antibody the binds RANK-L inactivating it and thereby bringing stability to bone remodeling. It puts a halt to excessive bone loss while allowing for growth of new healthy bone organically.

Denosamab reduces the available RANK-L. This causes fewer osteoclasts to form and inhibits the activity of those already formed. Denosamab is not a toxin of a poison. It causes no harm to the cells it interacts with in bone. Its only action is to effectively reduce the RANK-L available for use to recruit and activate osteoclasts.

Decreasing the number of osteoclasts and their activity reduces bone absorption and the rate of absorption. It dose not completely stop absorption but it almost does just after the injection is given. Patients receive a 1 mg subcutaneous denosamab injection usually in the upper arm every 6 months.

The half-life of denosamab is 6 weeks, meaning half the original 1 mg dose of the drug has been broken down at that point. 6 weeks later after another half-life, half of what remained at 6 weeks will be left or 0.25 mg. Three months after the shot, only ¼ of the original dose remains to inhibit RANK-L and some will be bound and destroyed but most will escape.

Remodeling starts up again at that point but slowly. The osteocytes have been pumping out even more RANK-L than they would under normal postmenopause conditions because they have not gotten the feed back they expected to get from the bone absorption process. So there is a lot of RANK-L around and the osteoclasts are egger to get to work. When released from denosamab detention they vigorously peruse the signals released by dead and microfractured bone that require removal. Due to coupling, the pre-osteoblast stem cells are being called the absorption site by clouds of growth factors released into the local area around the remodeling site. The growth factors come from within the bone that is being removed. They were stored there about 7 years before when that bone was newly formed by osteoblasts just for the purpose of stimulating future bone renewal. The waiting osteoblasts are excitedly preparing to move in and fill the absorption bay left empty of bone by the osteoclasts with beautiful healthy new bone.

By using denosamab, we have slowed the activity and aggressiveness of the osteoclasts but not harmed them in any way. As the antibody level naturally wanes, the osteoclasts activity waxes and this brings the pre-osteoblast stem cells to the site and gives them time to differentiate into osteoblasts. The absorption bay is not as deep or as broad as it would be with uncontrolled remodeling and the bone remodeling cycle length is prolonged under the influence of denosamab. This permits a more balanced remodeling but one with a difference. Because the osteoclasts did not remove an excessive quantity of bone and that the process was significantly slowed down, more bone remains after the completion of the remodeling cycle than when it started. How much? Not a tremendous quantity in most people I see, my estimate is the average gain is about 1% to 2% a year. Sometimes more sometimes less and the change depends on the measurement site. What is important to understand is that the gain in bone with denosamab is not due to retention of old dead bone as is the case with all the bisphosphonates. That would be the case if denosamab had a longer half-life and suppressed born remodeling continuously. However, it does not. The increase in bone density seen in patients and in the 10 years study was a reflection of a build up of healthy newly formed normal living bone. The amount is small because this is an indirect affect not a direct effect as seen with anabolic agents like 1-34 PTH.

We know it is healthy normal bone from the results of the 10-year extension study of the registration study for denosamab. That study showed a slow but steady increase in bone density in patients treated with denosamab continually for 10 years. There was no increase in fractures in this group over the last few years of the study as was seen in the Fosamax 10 year extension study. What the denosamab 10 yr data means to me is:

  • The continuous small incremental gain in bone density is a reflection of a similar gain in healthy normal bone and that
  • There was not and increase in the fracture rate in those on denosamab continuously for 10 years means the bone formed has good mechanical properties like that seen in healthy bone and importantly
  • Denosamab can be used safely on a continuous basis in postmenopausal women with osteoporosis for at least 10 years.