Testosterone treatment for prostate cancer significantly affects bone density, with androgen deprivation therapy (ADT) causing accelerated bone loss and increased fracture risk. Men receiving ADT typically experience bone mineral density reductions of 2–4% annually, substantially higher than age-related decline. This occurs because testosterone suppression disrupts normal bone remodelling, increasing bone breakdown whilst reducing bone formation. Understanding this relationship is crucial for men undergoing prostate cancer treatment, as proactive monitoring and bone-protective interventions can substantially reduce the risk of osteoporosis and fragility fractures. This article examines the mechanisms, clinical consequences, and evidence-based strategies for protecting skeletal health during testosterone-suppressing treatment.

Understanding Testosterone and Bone Health

Testosterone plays a crucial role in maintaining bone health throughout a man's life, though this relationship is often underappreciated compared to the well-established link between oestrogen and bone density in women. Testosterone contributes to bone strength through both direct and indirect mechanisms. The hormone binds to androgen receptors present on bone cells, stimulating bone formation and inhibiting bone resorption—the process by which bone tissue is broken down. Additionally, testosterone can be converted to oestradiol (a form of oestrogen) through the enzyme aromatase, and this oestrogen also supports bone mineralisation in men.

Healthy testosterone levels help maintain the delicate balance between osteoblasts (cells that build bone) and osteoclasts (cells that break down bone). When testosterone levels are adequate, this balance favours bone formation and preservation of bone mineral density (BMD). Research has consistently demonstrated that men with low testosterone levels face an increased risk of osteoporosis and fragility fractures, particularly of the hip, spine, and wrist.

Peak bone mass is typically achieved in early adulthood, after which bone density gradually declines with age. In men, this decline accelerates when testosterone levels drop significantly below the normal range. Reference ranges for testosterone vary between laboratories and assay methods, and morning samples are recommended for accurate interpretation. The relationship between testosterone and bone health becomes particularly significant in the context of prostate cancer treatment, where therapeutic interventions deliberately suppress testosterone production to slow cancer progression. Understanding this fundamental connection is essential for both patients and healthcare professionals when considering the broader implications of androgen deprivation therapy.

How Prostate Cancer Treatment Affects Testosterone Levels

Prostate cancer cells are typically androgen-sensitive, meaning they require testosterone and other androgens to grow and proliferate. Androgen deprivation therapy (ADT), also known as hormone therapy, exploits this dependency by dramatically reducing testosterone levels in the body. This treatment approach has become a cornerstone of management for advanced prostate cancer and is increasingly used in combination with other therapies for localised disease.

ADT can be achieved through several mechanisms. Luteinising hormone-releasing hormone (LHRH) agonists such as goserelin and leuprorelin work by initially stimulating, then suppressing, the pituitary gland's production of luteinising hormone, which in turn reduces testicular testosterone production. After an initial temporary surge, testosterone levels fall to castration levels (typically below 1.7 nmol/L) within 2–4 weeks. In UK practice, this initial 'flare' is typically managed with a short course of an anti-androgen. LHRH antagonists like degarelix achieve testosterone suppression more rapidly without the initial surge. Alternatively, anti-androgens such as bicalutamide block testosterone from binding to androgen receptors on cancer cells, though they don't reduce testosterone production itself.

Surgical castration (bilateral orchidectomy) provides permanent testosterone suppression but is less commonly performed today given the availability of medical alternatives. The degree and duration of testosterone suppression varies depending on the specific treatment regimen. Some men receive continuous ADT for advanced disease, whilst others may have intermittent therapy, allowing testosterone levels to recover partially between treatment cycles.

The profound reduction in testosterone levels achieved by ADT—often to less than 5% of normal levels—creates a state of medically-induced hypogonadism. Whilst this is therapeutically beneficial for controlling prostate cancer, it inevitably affects all tissues and organs that depend on testosterone, including bone. The extent of bone density loss correlates with both the duration of treatment and the degree of testosterone suppression achieved.

Impact of Testosterone Suppression on Bone Density

The skeletal consequences of ADT are both significant and well-documented in clinical research. Men receiving ADT experience accelerated bone loss at rates substantially higher than age-related decline. Studies have shown that bone mineral density typically decreases by 2–4% annually during the first years of treatment, with losses of 3–5% in the lumbar spine and 2–6% in the hip being commonly observed. This rate of bone loss is comparable to that seen in women during the early postmenopausal period.

The mechanism underlying this rapid bone loss involves disruption of normal bone remodelling. With testosterone suppression, osteoclast activity (bone breakdown) increases whilst osteoblast activity (bone formation) decreases, tipping the balance decisively towards net bone loss. The trabecular bone of the spine is particularly vulnerable, being more metabolically active than cortical bone. However, all skeletal sites are affected to varying degrees.

Clinical consequences of this bone loss are substantial. Men on long-term ADT face a significantly elevated fracture risk, with studies indicating approximately 20–30% increased risk of fracture compared to men not receiving ADT. Fractures most commonly occur in the spine, hip, and wrist—sites typical of osteoporotic fractures. These fragility fractures can occur with minimal trauma and carry serious implications for quality of life, independence, and mortality, particularly in older men.

The risk of osteoporosis and fractures increases with treatment duration. Men receiving ADT for more than 12 months face particularly high risks, though significant bone loss can occur within the first 6–12 months of treatment. Additional risk factors—including older age, low baseline bone density, previous fractures, smoking, excessive alcohol consumption, low body weight, and corticosteroid use—further compound the skeletal risks associated with testosterone suppression. Importantly, ADT is recognised as a secondary cause of osteoporosis in fracture risk assessment tools such as FRAX.

Monitoring and Managing Bone Health During Treatment

Given the substantial skeletal risks associated with ADT, NICE guidance recommends proactive assessment and monitoring of bone health in men receiving or about to commence androgen deprivation therapy. Before starting ADT, clinicians should conduct a comprehensive fracture risk assessment using validated tools such as FRAX (Fracture Risk Assessment Tool) or QFracture, considering both treatment-related and patient-specific risk factors. This assessment should include evaluation of previous fractures, family history of osteoporosis, lifestyle factors (smoking, alcohol intake, physical activity), and concurrent medications that may affect bone health.

Dual-energy X-ray absorptiometry (DEXA) scanning is the gold standard investigation for measuring bone mineral density. NICE recommends arranging DEXA scans for men with intermediate fracture risk (to refine risk assessment) or for those likely to receive long-term ADT. The scan measures BMD at the lumbar spine and hip, generating a T-score that compares the patient's bone density to that of a healthy young adult. A T-score of -1.0 or above is considered normal, -1.0 to -2.5 indicates osteopenia (low bone mass), and -2.5 or below indicates osteoporosis.

Ongoing monitoring is essential throughout treatment. The frequency of repeat DEXA scans should be individualised based on baseline findings, fracture risk, and treatment. Men at higher risk or on bone-protective therapy often require monitoring every 1–2 years. Blood tests to assess calcium, vitamin D, and renal function provide important information for safe management.

Lifestyle modifications form the foundation of bone health management. All men on ADT should receive advice about:

• Weight-bearing exercise: Regular walking, jogging, or resistance training helps maintain bone density and muscle strength, reducing fall risk

• Adequate calcium intake: Aim for 1,000–1,200 mg daily through diet (dairy products, fortified foods, leafy greens) or supplements if needed

• Vitamin D supplementation: The general UK recommendation is 10 micrograms (400 IU) daily; higher doses (20 micrograms/800 IU daily) are typically recommended for those with osteoporosis or vitamin D deficiency

• Smoking cessation: Smoking accelerates bone loss and impairs bone healing

• Alcohol moderation: Limit intake to within recommended guidelines (14 units weekly)

• Falls prevention: Home safety assessment, vision checks, and review of medications that may increase fall risk

Patients should be advised to contact their healthcare team urgently if they experience new severe back pain, limb weakness or numbness, or bladder/bowel dysfunction, as these may indicate spinal cord compression requiring emergency assessment. They should also report any unexplained bone pain, height loss, or fractures, as these may indicate significant bone loss requiring urgent assessment and treatment intensification.

Treatment Options to Protect Bone Density

When lifestyle measures alone are insufficient, or when bone density is already compromised, pharmacological interventions can significantly reduce fracture risk in men receiving ADT. The choice of treatment depends on baseline bone density, fracture risk assessment, and individual patient factors.

Bisphosphonates are the most commonly prescribed bone-protective agents in this setting. These medications work by inhibiting osteoclast activity, thereby reducing bone resorption. Alendronic acid (70 mg weekly) and risedronate sodium (35 mg weekly) are oral bisphosphonates frequently used for osteoporosis prevention and treatment in men. For men who cannot tolerate oral bisphosphonates due to gastrointestinal side effects, or who have difficulty with the administration requirements (remaining upright for 30 minutes after dosing), intravenous options are available. Zoledronic acid (5 mg annually) offers the convenience of once-yearly administration and has demonstrated efficacy in preventing bone loss in men on ADT.

Clinical trials have shown that bisphosphonates can prevent or even reverse bone loss during ADT, with increases in BMD of 2–5% typically observed over 12 months of treatment. However, whilst bisphosphonates effectively improve bone density, evidence for fracture reduction specifically in men on ADT is less robust than in postmenopausal women, partly because fracture trials require very large numbers of participants and long follow-up periods.

Denosumab represents an alternative mechanism of bone protection. This monoclonal antibody inhibits RANKL (receptor activator of nuclear factor kappa-B ligand), a protein essential for osteoclast formation and function. Administered as a subcutaneous injection (60 mg every six months), denosumab (Prolia) is licensed in the UK for bone loss associated with hormone ablation in men with prostate cancer at increased fracture risk. The HALT Prostate Cancer study showed that denosumab reduced the incidence of new vertebral fractures by 62% compared to placebo in men receiving ADT. Denosumab does not require dose adjustment for kidney function, unlike bisphosphonates, though monitoring is still required in severe renal impairment.

Before starting any bone-protective treatment, calcium and vitamin D status should be assessed and deficiencies corrected. This is particularly important with denosumab, which carries a risk of hypocalcaemia, especially in those with impaired renal function.

Both bisphosphonates and denosumab are generally well-tolerated, though potential adverse effects require consideration. Common side effects include flu-like symptoms (particularly with intravenous bisphosphonates), gastrointestinal upset (with oral bisphosphonates), and musculoskeletal pain. Rare but serious complications include osteonecrosis of the jaw (particularly in those undergoing dental procedures) and atypical femoral fractures with long-term use. Patients should maintain good dental hygiene and inform their dentist about bone-protective medication before invasive dental work. Any suspected side effects should be reported to the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or via the Yellow Card app).

The decision to initiate bone-protective medication should follow NICE guidance and consider the individual's absolute fracture risk. Generally, treatment is recommended for men with:

• Confirmed osteoporosis (T-score ≤ -2.5)

• Osteopenia (T-score -1.0 to -2.5) plus additional risk factors

• Previous fragility fracture

• High 10-year fracture probability

For severe osteoporosis with multiple vertebral fractures, teriparatide (a parathyroid hormone analogue) may be considered, though evidence specifically in ADT-related bone loss is limited.

Regular review of bone-protective treatment is essential. Healthcare professionals should reassess fracture risk periodically, monitor treatment adherence and tolerability, and consider treatment duration. Current evidence suggests that bisphosphonates can be used safely for 3–5 years, after which a 'drug holiday' may be considered in lower-risk patients, though men on continuing ADT may require ongoing bone protection. Denosumab should not be stopped abruptly due to risk of rebound bone loss and vertebral fractures; if discontinuation is necessary, transition to a bisphosphonate is typically recommended to maintain bone protection.

Frequently Asked Questions