PCa Commentary | Volume 216 – August 2026

Posted by Edward Weber, MD | August 2026

OSTEOPOROSIS – The Stealthy Fellow Traveler with Androgen Deprivation Therapy (ADT).

“Ezekiel cried Dem Dry Bones … Dem bones, dem bones gonna walk around.” (Ezekiel 37:1-14) … osteoporosis in Biblical times well before ADT.

ADT causes a progressive decline in bone mineral density (BMD). Osteoporosis is ADT’s stealthy, silent companion, advancing without symptoms, unless diagnosed with a DEXA scan (Dual Energy X-ray Absorptiometry). The decline in BMD is greatest in the first year of ADT with “2% – 8% in the lumbar spine and 1.8% to 6.5% in the femoral neck” (Higano, CANCER 2004).  Over 2 years, the cumulative loss is up to 10% in men on ADT living 5 years: 19.4% experienced any fracture and 5.2% required hospitalization (Shahinian et al., NEJM, 2005). Lupron, Eligard, Zoladex, and Relugolix promote loss of BMD to the same extent, and adding an androgen receptor blocker (i.e., darolutamide, apalutamide) further decreases BMD and increases fracture risk.

Biology of Bone Metabolism:

Bone is in a constant cycle of remodeling: osteoblasts promote bone formation; osteoclasts break down old and damaged bone, and osteocytes are the master regulators of bone remodeling. The reduction of testosterone associated with ADT increases bone resorption alongside the reduced estradiol, which also contributes to increased bone resorption. The reduction in BMD is greatest during the first 6-12 months of ADT therapy. The significant bone loss occurs in the lumbar spine, total hip, and the femoral neck — the sites where fractures cause the greatest morbidity. The loss of BMD is associated with a fragility fracture risk of 10% – 12%. The fracture risk is twice that extent in men not taking anti-resorptive agents such as Denosumab and Zometa.

Diagnosing BMD and Assessing Fracture Risk Requires a DEXA Scan:

In interpreting a DEXA scan, the T score is the most important for men over 50 years old. The T score compares a man’s score to that of a healthy 30-year-old. (Ouch!) A T score of -1.0 to 0 or more positive is normal; -1.0 to -2.5 indicates osteopenia (low bone mass); <.5 corresponds to osteoporosis and is associated with a high risk of fragility fracture. “Fragility fractures” refer to breaks at sites not associated with prostate metastases. DEXA scans also report an estimated 10-year fracture risk (FRAX score).

A DEXA scan is recommended at the onset of ADT, but “<30% of eligible patients do not undergo DEXA screening” (Lin, Euro Urol Oncol. 2024). There is no consensus as to how frequently a DEXA evaluation should be repeated in men on ADT, but every 2 years is frequently recommended, unless clinical features suggest screening sooner.

Fractures in older men, especially those occurring at the hip or femur, cause significant morbidity, hospitalization, and death. Hip fracture in men leads to a 26.9% yearly mortality!

Bone Protective Agents Used to Treat Osteoporosis:

1. Denosumab (Xgeva and Prolia) both contain the same monoclonal antibody, which inhibits bone resorption by osteoclasts. Over 3 years of treatment, they bring about a 9% increase in BMD in the lumbar spine and a 6% increase in the hip and reduce fracture risk in the vertebra by 68% and 6% at the hip. Prolia is given 60 mg SC (subcutaneously) every 6 months to prevent or treat ADT-induced osteoporosis in men with non-metastatic prostate cancer who are at high risk for fractures. (HALT Prostate Cancer Study, Smith et al., NEJM 2009)Xgeva is given 120 mg SC every 4 weeks to delay additional bone metastases in men with metastatic castration resistant prostate cancer. Xgeva is the only agent approved by the FDA based on evidence of reducing fractures in men on ADT. Complications of Xgeva and Prolia: Decreased serum calcium is a significant risk of these agents (2.2%) and can occur in the early months of treatment. Serum calcium should be closely monitored, especially in men with bone metastases. Osteonecrosis of the jaw (ONJ) is associated with jaw fractures and dental complications. ONJ has been reported in 2.8% of men on both drugs, increasing with longer treatment. Denosumab is more effective in delaying the development of new bone metastasis than Zometa: by 20.7 months for Denosumab vs 17 for Zometa. (Smith et al., Lancet 2011) Denosumab should not be stopped abruptly, and its benefit fades quickly, so transition to a bisphosphonate is often initiated.

2. Zoledronic Acid (Zometa) is used for prevention and treatment of ADT-induced bone loss:
For prevention — 5 mg IV yearly.
For treatment of men on ADT with non-metastatic cancer, Zometa is given IV 4 mg every 3 months, yielding a 5.6% increase in BMD in the lumbar spine. (Smith et al., NEJM 2003).
Alendronate (Fosamax), an oral bisphosphonate, is used to prevent and treat osteoporosis and yields a 3.7% increase in BMD in the lumbar spine. (Greenspan, et al. Ann Int Med 2007).

3. Teriparatide (Forteo) is a parathyroid hormone analogue given SC daily and usually restricted in use to men with severe osteoporosis (i.e., T scores of -3 or greater) or those failing to respond to denosumab or bisphosphonates.

4.Transdermal estradiol patches are effective in reversing BMD loss in men receiving ADT. tE2 suppresses testosterone while maintaining physiologic estrogen levels. At 1 year, tE2 patches produce a 6-8% increase in BMD in the lumbar spine and a 2-3% increase in the total hip. (Langley, Lancet Oncology. 2013)

BOTTOM LINE:

Osteoporosis advances unannounced in men on ADT and can be associated with significant morbidity. It can only be diagnosed with a DEXA scan. Effective treatment is available, most effective if given early.

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