Bone health is becoming an increasingly important issue in the management of metastatic hormone-sensitive prostate cancer, especially as patients live longer with intensified systemic treatments.
Androgen deprivation therapy has long been known to reduce bone mineral density and increase fracture risk. With androgen receptor pathway inhibitors such as enzalutamide now widely used in combination with ADT, concerns around treatment-induced skeletal fragility have become even more clinically relevant.
A new analysis from the randomized phase II BonEnza study evaluated bone health outcomes in patients receiving ADT plus enzalutamide, with or without zoledronic acid.
The study was published in Bone, Volume 209, August 2026. It was available online on April 24, 2026, and the Version of Record was published on April 28, 2026.
Title: Multiparametric assessment of bone health in metastatic hormone-sensitive prostate cancer patients receiving androgen deprivation + enzalutamide ± zoledronic acid (BonEnza study).
Authors: The study was authored by I. Caramella, A. Dalla Volta, F. Valcamonico, M. Bergamini, M. Buffoni, A. Zivi, G. Procopio, P. Sepe, N. Di Meo, S. Foti, S. Zamboni, C. Messina, A. Rizzi, E. Lucchini, M. Ravanelli, M. Zamparini, F. Zacchi, M. Laganà, D. Cosentini, R. Bresciani, N. Suardi, D. Farina, and A. Berruti.
Background
ADT remains a backbone of treatment for high-risk localized, locally advanced, and metastatic prostate cancer. In metastatic hormone-sensitive prostate cancer, the addition of androgen receptor pathway inhibitors has improved survival and changed the standard of care.
However, longer survival also means longer exposure to treatment-related adverse effects. One of the most important is cancer treatment-induced bone loss.
The authors noted that ADT alone can lead to a significant reduction in bone mineral density, while androgen receptor pathway inhibitors may further increase the risk of skeletal fragility and fractures. In previous phase 3 trials, increased fracture rates were reported with apalutamide, enzalutamide, and abiraterone compared with control arms.
Zoledronic acid is already used to prevent skeletal-related events in metastatic castration-resistant prostate cancer, but its role earlier in metastatic hormone-sensitive disease remains less clearly defined.
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Why This Study Matters
BonEnza was a multicenter, investigator-initiated, randomized phase II clinical trial. Men with histologically confirmed metastatic hormone-sensitive prostate cancer and bone metastases documented on bone scan were randomized 1:1 to receive ADT plus enzalutamide, with or without zoledronic acid. Enzalutamide was given at 160 mg once daily. Zoledronic acid was administered intravenously at 4 mg every 4 weeks for 18 cycles. Calcium and vitamin D supplementation was recommended in both arms.
The primary objective of the overall BonEnza trial was bone metastatic response assessed by whole-body diffusion-weighted MRI. This article focused on bone health outcomes, including changes in bone mineral density, trabecular bone score, bone turnover biomarkers, and vertebral fractures.
Bone mineral density and trabecular bone score were assessed by DXA at baseline and after 18 months. Vertebral fractures were assessed by whole-body diffusion-weighted MRI at baseline and after 12 months. Bone turnover markers, including alkaline phosphatase and C-terminal telopeptide of type I collagen, were evaluated in the biomarker subgroup.
Patient population
Between February 2018 and June 2021, 133 patients were screened across 8 centers in Italy. After exclusions, the intention-to-treat population included 126 patients, with 63 randomized to each treatment arm. For this bone health analysis, paired DXA evaluations were available for 89 patients:
- 45 patients in the enzalutamide-only arm
- 44 patients in the enzalutamide plus zoledronic acid arm
The median age of the overall population was 68 years. Baseline characteristics were generally balanced between the two groups, although ECOG performance status 0 was more frequent in the enzalutamide-only arm.
Key results
After 18 months, patients receiving ADT plus enzalutamide without zoledronic acid experienced a marked decline in bone mineral density. Femoral neck bone mineral density decreased by 8.6% in the enzalutamide-only arm, while it increased by 1.83% in the enzalutamide plus zoledronic acid arm. The between-arm difference was statistically significant.
A similar pattern was observed at the lumbar spine. Bone mineral density decreased by 9.26% with enzalutamide alone, while it increased by 5.47% with the addition of zoledronic acid. Trabecular bone score, a marker of bone quality, also moved in opposite directions. It worsened by 3.35% in the enzalutamide-only arm and improved by 3.01% in the enzalutamide plus zoledronic acid arm.
Bone turnover markers were evaluated in the biomarker subgroup, including ALP and CTX. ALP decreased by 35.6% in patients receiving zoledronic acid, while it remained stable in the enzalutamide-only arm, with a −0.6% change. CTX increased by 39.5% in the enzalutamide-only arm but decreased by 58.9% in the enzalutamide plus zoledronic acid arm.
These findings suggest that adding zoledronic acid was associated with improved bone mineral density, improved trabecular bone score, and reduced bone turnover markers during intensified hormonal treatment.
Vertebral fractures and safety
Vertebral fractures were assessed by whole-body diffusion-weighted MRI after 12 months, while bone mineral density and trabecular bone score were assessed by DXA after 18 months. At baseline, 4 vertebral fractures were present: 3 patients in the enzalutamide-only arm had fractures, and 1 patient in the enzalutamide plus zoledronic acid arm.
After 12 months, a total of 16 vertebral fractures were detected across both arms — 10 among 7 patients in the enzalutamide-only arm, and 6 among 5 patients in the enzalutamide plus zoledronic acid arm. Not all of these were new: the enzalutamide-only arm had 7 new fractures, and the enzalutamide plus zoledronic acid arm had 5 new fractures. In addition, one patient in each arm showed worsening of a pre-existing vertebral fracture.
The cumulative incidence of new or worsening vertebral fractures was 12.9% in the enzalutamide-only arm and 9.7% in the enzalutamide plus zoledronic acid arm. This difference was not statistically significant (Poisson rate ratio 1.33; 95% CI 0.47–3.78; p = 0.59). No correlation was found between the appearance or worsening of vertebral fractures and changes in bone mineral density, trabecular bone score, ALP, or CTX. Clinical, non-vertebral fractures were uncommon, observed in only 5 cases across the study period (4 in the enzalutamide-only arm and 1 in the enzalutamide plus zoledronic acid arm).
Regarding safety, 2 low-grade events of increased creatinine were reported in patients receiving zoledronic acid. Both resolved before the next zoledronic acid cycle and did not result in acute renal failure. No episodes of hypocalcemia or osteonecrosis of the jaw were observed.
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Interpretation
The BonEnza bone health analysis highlights an important issue in modern prostate cancer care: treatment intensification may improve oncologic outcomes, but it can also increase long-term skeletal risks.
In this study, ADT plus enzalutamide was associated with substantial bone loss at both the femoral neck and lumbar spine. The magnitude of bone loss was higher than previously reported with ADT alone, supporting the concern that androgen receptor pathway inhibitors may further worsen skeletal fragility.
The addition of zoledronic acid improved bone mineral density, trabecular bone score, and bone turnover biomarkers. The authors described these findings as the first evidence, within a randomized design, showing beneficial effects of a bone-protecting agent on both bone quantity and bone quality in prostate cancer patients.
However, the clinical impact on fractures remains uncertain. The study was not powered to demonstrate a significant reduction in fractures, and larger trials are needed to determine whether these bone health improvements translate into fewer morphometric or clinical fractures.
Conclusion
The BonEnza study showed that adding zoledronic acid to ADT plus enzalutamide improved bone mineral density, trabecular bone score, and bone turnover markers in men with metastatic hormone-sensitive prostate cancer. Although the trial was not powered to show a significant reduction in fractures, the results support further investigation of bone-protecting strategies in patients receiving hormonal doublets.
Future studies may need to explore lower doses of bone-protecting agents and use morphometric fracture reduction by DXA as a primary endpoint. For patients with metastatic hormone-sensitive prostate cancer, bone health may need to become a more central part of treatment planning as systemic therapy continues to intensify.
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