Androgen Deprivation Therapy, (ADT) for Treatment of Prostate Cancer can lead to an unseen liability, loss of bone density or osteoporosis. Prostate cancer suppression with Lupron and other testosterone lowering agents (ADT) has been long-recognized and widely employed, but the downside consequences of testosterone and estradiol (E2) suppression are loss of bone mineral density (BMD) and strength and an increase in fractures — an unseen liability. “Unseen” because without an evaluation with a DEXA scan a man can be completely unaware of his liability until he falls, sustains a fragility fracture leading to morbidity, hospitalization and possible death.
Testosterone and its steroid cousin estradiol (E2) are essential for development and maintenance of bone structural health. This Commentary will discuss the physiology of these agents and how their diminishment affects bone health. It will stress the importance of monitoring with periodic DEXA (Dual Emission X-Ray Absorptiometry) scans, the consequences of loss of bone density and strength, and measures to combat this deterioration.
Testosterone and Estradiol Biology Relative to Bone Health:
- Serum testosterone (T) is released from the testes upon stimulation by luteinizing hormone from the pituitary gland, penetrates the PC cell, joins the androgen receptor and together activate hundreds of response elements in the cell’s DNA (one of which is PSA) to, among other programs, promote bone health. In cancer cells, however, T also promotes malignant proliferation. Therapeutic suppression of T by Lupron, Xtandi, etc., deprive cancer cells of T resulting in rapid cell death. This is a welcome result but comes with the heavy price of multiple adverse effects diminishing a man’s quality of life.
- The normal range of serum T in males is wide, between 300 – 1000 ng/dL, diminishing with age. Lupron alone lowers T to < 50ng/Dl. The desired level is <20 ng/dL. The addition of an androgen receptor pathway inhibitor (ARPI), such a Xtandi or Nubeqa drops T levels to nearly undetectable. However, the addition of an ARPI to Lupron significantly increases the risk of fractures by .5 – 2.4 times compared with Lupron alone. (Saporita. Prostate Cancer. Prostatic Diseases. 2026) Adding prednisone, which usually accompanies Zytiga (abiraterone), further impairs bone formation.
- In males, serum estrogen (E2) and T combine to promote bone formation. E2 maintains bone mineral density and strength by retarding on-going bone remodeling, an essential part of bone physiology. In males, serum E2 is nearly entirely derived from enzymatic conversion of serum testosterone into serum estrogen, with the consequence that when T is vastly lowered by ADT, E2 also is much lower.
- The normal range of E2 in men is between 10-40 pg/mL; with +/- 60 pg/mL required for bone formation. With ADT, E2 decreases dramatically to 2-3 pg/mL in 6+ weeks. Transdermal estrogen patches elevate serum E2 to 43-90 pg/mL.
The Consequences of Low Testosterone and Low Estrogen:
- Bone mineral density (BMD) deteriorates rapidly when both of these steroids are low — about 3% – 5% yearly. In 12 months, there is a cumulative BMD loss of 2% – 8% in the lumbar spine and 2% – 6.5% in the hip. BMD loss continues as ADT continues. This loss goes unnoticed until a fall results in an osteoporotic fracture with its adverse consequences.
The DEXA Scan:
- A DEXA scan evaluates bone density and is best targeted at the hip region. It reports a man’s BMD in two categories: Z, comparing a man to age matched controls; and T, the comparison relevant to older men, which compares a man’s BMD to that of a healthy young adult (Ouch !) The analysis is reported on a scale ranging from a favorable +3, through 0 to -1 (normal) to -1 to -2.5, osteopenia, and > -2.5, osteoporosis.
The National Cancer Cooperative Network recommends having a DEXA scan at the initial diagnosis of prostate cancer (rarely done); but a DEXA is clearly indicated at the start of ADT and should be repeated periodically.
What Can be Done to Maintain or Improve a Low BMD?
- Exercise: Recommended are aerobic exercise for cardiovascular health and balance; and walking, jogging, resistance training, weightlifting, and yoga. The Mayo Clinic has suggestions: click on “Exercising with Osteoporosis: Stay active the safe way.”
- Nutrients: Calcium 1200 mg. and Vitamin D3 800 -1000 mg. daily.
- Addressing BMD loss with agents that inhibit bone resorption: Zometa, Recast, Xgeva and Prolix (denosumab). Daily injected teriparatide (brand name Forteo) is an agent that promotes new bone formation.
- Withholding androgen suppression until the diagnosis of metastases with PSMA PET/CT avoids the adverse effects of continuous ADT over a duration of possibly years without a significant shortening of overall survival [visit link to PCa Commentary Vol. 197 below] https://www.prostatecancerfree.org/pca-commentary-197
- Transdermal Estradiol PATCHES can be used alone or in combination with ADT to control prostate cancer and lessen adverse effects of ADT by both lowering serum testosterone and raising serum estrogen [visit link to PCa Commentary Vol. 201 below] https://www.prostatecancerfree.org/pca-commentary-201
BOTTOM LINE:
Osteoporosis is associated with ADT and proceeds unrecognized without a diagnostic DEXA scan. It is associated with a heightened fracture risk – increasing as ADT continues.