A Phase 1/2 interventional study of Denosumab (Prolia) and Letrozole (Aromatase Inhibitors) in Infertility, Male, sponsored by Martin Blomberg Jensen. Completed at 1 site in Denmark. Open to male participants aged 18 Years to 60 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-10-21.
Sponsored by Martin Blomberg Jensen · Phase 1/2, Interventional, and Treatment
This clinical interventional study aims to assess whether treatment with denosumab in combination with letrozole can improve sperm production in infertile men with non-obstructive azoospermia selected by serum anti-mullerian hormone (AMH) as a positive predictive biomarker.
Infertility is a health issue worldwide with more than 15% of couples experiencing infertility. Male factors contribute in 50% of all cases and is the sole cause in 30% of all infertile couples . Treatment options for the male infertility are limited and only specific conditions like varicocele and hypogonadotropic hypogonadism can be effectively treated with surgery and hormonal stimulation, respectively. However, for the remaining 90% of infertile men, no treatment options exist. Instead, their female partners must undergo fertility treatment.
Men with the most pronounced impairment of semen quality, men with azoospermia, have no sperm in the ejaculate and are classically divided into obstructive azoospermia (OA) and non-obstructive azoospermia (NOA), with the ladder being the most common. These men needs to have surgery performed for sperm retrieval with either testicular sperm aspiration (TESA), testicular sperm extraction (TESE) or micro testicular sperm extraction (microTESE) in order to have a chance of becoming biological fathers. The chance of successful sperm retrieval in men with OA is close to 100%, whereas men with NOA have a significantly lower chance with only around 10-40% being successful. This is due to the vast difference in etiology between men with OA and NOA. Even with a successful surgical intervention only half of the cases will result in a live birth, leaving the majority of men with NOA no chance of becoming biological fathers. Therefore, novel treatment options for even a minor sub-group of these men are warranted.
RANKL is a ligand for the receptor activator of nuclear factor kappa beta (RANK), and their pathway plays a prominent role in the regulation of bone metabolism. The binding of RANKL to RANK on osteoclast precursors induces osteoclast maturation and activation, thereby stimulating bone resorption, and regulates cell cycle i.e., proliferation, differentiation, and apoptosis. Osteoprotegerin (OPG) is a secreted decoy receptor that controls RANKL-RANK interaction by binding RANKL and inhibits activation of RANK and preventing osteoclast differentiation and activation.
Denosumab, a drug used in millions of patients worldwide under trade names Prolia® and Xgeva®, inhibits the RANKL pathway and is used to treat osteoporosis and bone metastases. The drug's mechanism of action inhibits RANKL and thus inhibits bone resorption through reduced osteoclast activation. This reduces the loss of bone mineral density (BMD), which reduces the risk of bone loss and thereby the risk of fracture and osteoporosis. Denosumab has been shown in several clinical studies to be a safe and effective drug in both women and men and has been in clinical use in both sexes for many years. As Denosumab has a teratogenic effect, pharmacokinetic studies in both monkeys and healthy men were performed before approval of the drug as a treatment for osteoporosis in men. These studies showed that Denosumab concentration in semen does not pose a risk to the fetus during sexual intercourse with the pregnant woman and therefore is safe to use for the suggested infertility indication as there is no risk of fetal transmission.
The investigators have also shown that RANKL also influences germ cell apoptosis, differentiation, and proliferation in mice and humans. This indicates that the RANKL system could be a potential direct regulator of spermatogenesis, and thus highlighting that the drug Denosumab, a RANKL inhibitor, commonly used to treat osteoporosis, may be used for medical treatment of men with decreased sperm production. The effects of denosumab in vitro were supported by a pilot intervention study in 12 infertile men, which showed that denosumab either had a highly beneficial or detrimental effect on sperm production. This implies that only a sub-group of infertile men should be offered this treatment and these men should be identified by, preferably, a simple and accessible biomarker.
Therefore, the investigators are currently conducting two randomized clinical trials "First In Treating Infertility (FITMI)" and "Novel Approach for Oligospermia (NAPO) to explore whether denosumab can improve semen quality in infertile men selected by serum AMH, but already have sperm concentration between 2 mio/mL - 20 mio/mL (FITMI) and 0.01 mio/mL - 2 mio/mL (NAPO). These are both important studies, but still leaves out men with no sperm in the ejaculate, azoospermic patients. Therefore, there is a need for a trial adressing these patients for a potential novel treatment option.
NT-NOA is a single-center, sponsor-investigator-initiated, interventional trial, Following successful completion of screening procedures, subjects will all receive denosumab 60 mg s.c. and Letrozole oral tablet 2.5 mg once daily. Participants will all initiate letrozole treatment 14 days prior to the denosumab injection and will continue until the TESE procedure. The study will be carried out at the Division of Translational Endocrinology, Copenhagen University Hospital, Herlev, Copenhagen, Denmark.
The investigators believe it is of clinical relevance to treat 10 patients with denosumab in combination with letrozole for 1 of them to achieve sperm production, however, it is difficult to estimate. Ideally 50% of the treated participants will have sperm suitable for ART post intervention. By including 16 patients, there will be sufficient power to determine if combination therapy with denosumab and letrozole induces a clinically relevant effect on spermatogenesis.
282 studies on the registry are indexed under Infertility, Male; 65 are open to participants now.
This study's enrollment of 16 is below the median of 80 across 187 interventional studies indexed under Infertility, Male.
Browse Infertility, Male studies →Martin Blomberg Jensen is the lead sponsor of 13 studies on the registry; 4 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Cancer (malignancy)
Malignancy means cancer. Criteria about another or earlier malignancy ask whether you have had a different cancer, usually within a set number of years.
Some are commonly allowed, such as treated skin cancers other than melanoma and early cancers removed completely — check the exceptions this study lists.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Subcutaneous injection with 60 mg Denosumab once
Drug: Denosumab (Prolia) · Drug: Letrozole (Aromatase Inhibitors)
Subcutaneous injection with 60 mg Denosumab once
Letrozole oral tablet 2.5 mg once daily
Sperm in the semen sample or TESE on day 90
Finding of sperm in the semen sample (day 80) or TESE (day 90), that subsequently will be compared with prior TESE if available.
Time frame: Day 80 (semen sample) and 90 (TESE) after inclusion
The change in expression of proliferation (KI-67, PCNA) and apoptosis (cPARP, TUNEL assay) markers in TESE tissue at day 90 compared to prior TESE if available
TESE
Time frame: Day 90 after inclusion
The number of participants with sperm in the ejaculate (sperm pr. milliliter) assessed by semen samples delivered on day 14
Semen sample
Time frame: Day 14 after inclusion
The number of participants with sperm in the ejaculate (sperm pr. milliliter) assessed by semen samples delivered on day 80
Semen sample
Time frame: Day 80 after inclusion
The number of pregnancies achieved by sperm from the ejaculate or by TESE
Survey
Time frame: Day 180 after inclusion
The change in serum levels of reproductive hormones (FSH, LH, AMH, Inhibin B og INSL3) on day 14
Serum sample
Time frame: Day 14 after inclusion
The change in serum levels of reproductive hormones (FSH, LH, AMH, Inhibin B og INSL3) on day 80
Serum sample
Time frame: Day 80 after inclusion
The change in serum levels of sex steroids (Testosterone, Estradiol and SHBG) on day 14
Serum sample
Time frame: Day 14 after inclusion
The change in serum levels of sex steroids (Testosterone, Estradiol and SHBG) on day 80
Serum sample
Time frame: Day 80 after inclusion
The change in seminal fluid levels of reproductive hormones (AMH, Inhibin B, INSL3) on day 14
Seminal fluid
Time frame: Day 14 after inclusion
The change in seminal fluid levels of reproductive hormones (AMH, Inhibin B, INSL3) on day 80
Seminal fluid
Time frame: Day 80 after inclusion
The change in the endocrine gonadal function (Inhibin B/FSH ratio, Testosterone/LH ratio and AMH/testosterone ratio) on day 14
Serum sample
Time frame: Day 14 after inclusion
The change in the endocrine gonadal function (Inhibin B/FSH ratio, Testosterone/LH ratio and AMH/testosterone ratio) on day 80
Serum sample
Time frame: Day 80 after inclusion
The change in seminal fluid levels of RANKL, OPG, AMH and Inhibin B on day 14
Seminal fluid
Time frame: Day 14 after inclusion
The change in seminal fluid levels of RANKL, OPG, AMH and Inhibin B on day 80
Seminal fluid
Time frame: Day 80 after inclusion
The change in serum levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 14
Serum
Time frame: Day 14 after inclusion
The change in serum levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 80
Serum
Time frame: Day 80 after inclusion
The change in seminal fluid levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 14
Seminal fluid
Time frame: Day 14 after inclusion
The change in seminal fluid levels of minerals (calcium, phosphate, magnesium, zink, bikarbonate, citrate) on day 80
Seminal fluid
Time frame: Day 80 after inclusion
Plan to share: No
Ran from Mar 2025 to primary completion in Apr 2026, 13 months.
Primary completion moved once since we started tracking on Sep 25, 2026: Aug 2026 → Apr 2026, on Oct 21, 2026.
Earlier changes are on the record history on ClinicalTrials.gov ↗
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
This study is completed, as verified in Oct 2026. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Studies of the drugs tested here: Denosumab · Letrozole
Martin Blomberg Jensen