Can testosterone therapy increase alkaline phosphatase (ALP) levels?

Testosterone Therapy Can Increase Alkaline Phosphatase (ALP) Levels

Testosterone therapy can cause an increase in alkaline phosphatase (ALP) levels, particularly in the bone-specific alkaline phosphatase (B-ALP) isoenzyme, which reflects increased bone turnover during testosterone treatment. 1, 2

Mechanism and Evidence

• Testosterone stimulates bone metabolism, which can lead to increased levels of bone-specific alkaline phosphatase (B-ALP), a marker of bone turnover 1
• In hypogonadal men with testosterone levels <250 ng/dL, there is a negative correlation between testosterone and ALP levels, suggesting that very low testosterone is associated with higher ALP 2
• When testosterone therapy is initiated, studies show that B-ALP levels can increase significantly, particularly with injectable testosterone preparations 3
• A study comparing oral testosterone undecanoate and intramuscular testosterone depot showed that both formulations increased bone alkaline phosphatase, with injectable testosterone causing a more pronounced effect 3

Clinical Significance and Monitoring

• Elevated ALP during testosterone therapy generally reflects increased bone turnover rather than liver toxicity 2
• In hypogonadal men receiving testosterone replacement therapy, ALP levels typically decrease over time as bone metabolism normalizes, with studies showing significant reductions at 6,12, and 24 months of treatment 2
• This decrease in ALP with continued testosterone therapy is associated with an increase in bone mineral density (BMD) on DEXA testing 2
• Monitoring ALP can be used as a marker of response to testosterone therapy in hypogonadal men 2

Important Considerations

• When evaluating elevated ALP in patients on testosterone therapy, it's important to distinguish between bone-specific ALP and liver-derived ALP 1
• Intramuscular injections and transdermal testosterone preparations do not appear to be associated with hepatic dysfunction, making liver-related ALP elevation less likely 1
• Oral testosterone preparations (except undecanoate, which is not available in the US) can cause hepatotoxicity and should be avoided 1
• Laboratory interference can occur with certain medications; a case report showed discordant testosterone results in a patient taking synthetic alkaline phosphatase (asfotase alfa) 4

Monitoring Recommendations

• Prior to initiating testosterone therapy, baseline liver function tests should be performed 1
• For patients on testosterone therapy with elevated ALP, consider:
  • Checking bone-specific ALP (B-ALP) to determine if the elevation is bone-related 1
  • Evaluating other liver function tests to rule out hepatotoxicity 1
  • Monitoring ALP trends over time, as levels typically normalize with continued therapy 2
• Routine monitoring of liver function tests is not necessary for men receiving intramuscular injections or transdermal preparations of testosterone 1

Clinical Implications

• Transient elevation of ALP, particularly B-ALP, during testosterone therapy should not necessarily prompt discontinuation of treatment 2
• The increase in B-ALP may actually indicate a positive bone response to testosterone therapy 3, 2
• In postmenopausal women, elevated ALP is mainly caused by high bone turnover, which may be similar to the mechanism in hypogonadal men receiving testosterone therapy 5
• For patients with significantly elevated ALP levels, consider evaluating for other potential causes, including bone metastases in patients with risk factors 1, 6