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Guideline

Special issues

Bone loss associated with aromatase inhibitor therapy for breast cancer and androgen deprivation therapy for prostate cancer

Bone loss associated with aromatase inhibitor therapy for breast cancer and androgen deprivation therapy for prostate cancer

Most patients with a diagnosis of early oestrogen receptor (ER)-positive breast cancer or localised prostate cancer now have a good prognosis, with 10-year survival rates greater than 90% (pbs.gov.au). Survivorship issues such as unfavourable cancer treatment effects on bone health are of paramount importance. Endocrine treatments improve cancer-specific outcomes, but lead to severe hypogonadism, and therefore accelerated bone loss.

Recommendation 37

Grade

All women commencing aromatase inhibitor therapy should have baseline assessment of fracture risk prior to commencing therapy, including clinical risk factors, biochemistry and BMD (DXA) measurement, with ongoing monitoring based on risk factors.

A

Baseline assessment includes review of clinical risk factors, blood and urine laboratory testing (electrolytes, calcium, alkaline phosphatase and 25(OH)D) and DXA BMD measurements.1 If reduced bone mass is present at baseline, individualised assessment is necessary to identify unrelated secondary causes of osteoporosis.

In all postmenopausal women, and in premenopausal women with a Z-score of ≤–1.5, subclinical vertebral fractures should be excluded either by vertebral fracture assessment as part of DXA or by plain radiographs of the thoracolumbar spine. Vertebral fractures are defined by the PBS as a 20% or greater reduction in the height of the anterior or mid-portion of a vertebral body relative to the posterior height of that body. This is important because evidence suggests that spinal fractures are often the first fracture to occur in osteoporosis, increase the risk of future fragility fractures, and are mostly clinically silent.2

Although risk calculators such as FRAX® may be useful, they do not consider aromatase inhibitor use and may substantially underestimate fracture risk.

  • High prevalence of vitamin D deficiency3–5
  • Decreased physical activity6,7
  • Increased risk of falls secondary to treatment-induced neuropathy8
  • Chemotherapy-induced ovarian failure9
  • Aromatase inhibitor therapy10,11

Recommendation 38

Grade

Women commencing aromatase inhibitor therapy who fall within one of the following two categories should commence antiresorptive therapy unless contraindicated:

  • age ≥70 years with BMD T-score ≤–2.0
  • age >50 years with a minimal trauma fracture (including radiological vertebral fracture) or a high estimated 10-year fracture risk.

There is limited evidence specific to women receiving aromatase inhibitors to guide firm recommendations outside these criteria, especially in premenopausal women.

A

Australasian1,3 and international consensus guidelines9,12 recommend antiresorptive therapy should be initiated in aromatase inhibitor-treated women not fulfilling the above criteria if the lowest BMD T-score is ≤–2.0 or if more than two fracture risk factors are present, and that it should be considered where there is a greater than 5–10% decrease in BMD after one year of aromatase inhibitor treatment or if the 10-year absolute risk of a major osteoporotic fracture is ≥20% or that of a hip fracture is ≥3%. However, this is outside current Australian PBS subsidy criteria.

Premenopausal women commonly have normal baseline BMD with low short-term fracture risk, yet lose bone more rapidly than older postmenopausal women. Decisions regarding antiresorptive treatment should be individualised and discussed with the patient. Bisphosphonates can persist in the bone matrix for years after therapy is discontinued, potentially resulting in fetal exposure during pregnancy. Specialist referral may be appropriate.

Recommendation 39

Grade

The duration of antiresorptive treatment in women undergoing or who have completed aromatase inhibitor therapy should be individualised and based on absolute fracture risk.

D

Bone loss in women is most marked in the 12–24 months after initiation of aromatase inhibitor treatment. Limited data suggest partial BMD recovery after cessation of aromatase inhibitor treatment. DXA should be repeated 12 months after commencement of aromatase inhibitor therapy, with subsequent individualised monitoring frequency.

Recommendation 40

Grade

General measures to prevent bone loss should be implemented in all women commencing aromatase inhibitor therapy.

C

Recommendation 41

Grade

All men commencing ADT should have a baseline assessment of fracture risk, including BMD assessment by DXA.

A

Key recommendations for the management of bone health in men receiving ADT are adapted from previously published management guidelines of the Endocrine Society of Australia, the Australian and New Zealand Bone and Mineral Society, and the Urological Society of Australia and New Zealand.13

Risk factors for osteoporosis should be ascertained, basic laboratory testing should be conducted (electrolytes, calcium, alkaline phosphatase, and vitamin D) and hip and spine BMD measurements should be determined by DXA. Linkage of deidentified Australian MBS and PBS databases recently showed that approximately 80% of Australian men commencing ADT for prostate cancer were not referred for a DXA scan.13 Absolute baseline fracture risk may be estimated using mathematical tools such as FRAX® or Garvan Fracture Risk Calculator. However, neither of these algorithms is validated in men with prostate cancer receiving ADT, and the tools may underestimate true fracture risk. In men with a T-score ≤–1.0, thoracolumbar spine X-rays should be performed to exclude clinically silent vertebral fractures.14 DXA should be repeated 12 months after commencement of ADT, with subsequent individualized monitoring frequency.

Recommendation 42

Grade

All men receiving ADT with a history of minimal trauma fracture should be commenced on antiresorptive therapy, unless contraindicated.

A

There is currently insufficient evidence to make evidence-based recommendations regarding if, and when, antiresorptive therapy for primary prevention should be commenced in men with prostate cancer receiving ADT. Consistent with general recommendations in this guide, all men aged ≥70 years with a T-score ≤–2.5 should commence antiresorptive therapy, and therapy should be considered if there is an annual BMD loss of 5–10% or a 10-year absolute risk of major osteoporotic fracture ≥20% or that of hip fracture ≥3%.

Australian guidelines recommend that antiresorptive therapy should be considered for primary prevention if the BMD T-score is ≤–2.0.15 However, this recommendation is outside current PBS subsidy criteria. Although antiresorptive therapy is recommended (and subsidised by the PBS) for primary fracture prevention in glucocorticoid-induced osteoporosis when the T-score is ≤–1.5, current evidence is insufficient to recommend the same or similar T-score cut-off for men receiving ADT.

Recommendation 43

Grade

Bone health should be reviewed 1–2 yearly in men on continuous ADT.

C

Management should also be re-evaluated after cessation of ADT, because the gonadal axis may recover in some men, with more rapid recovery reported in younger men (<65 years) or in those with a shorter (<24–30 months) duration of ADT.15

Recommendation 44

Grade

General measures to prevent bone loss should be implemented in all men commencing ADT.

C

For both women and men commencing and during aromatase inhibitor therapy or ADT, skeletal health should be considered in the decision-making process regarding the choice and duration of endocrine therapy. Skeletal health should be assessed regularly and non-pharmacological intervention optimised.1

Evidence Statement

Aromatase inhibitor therapy

Adjuvant endocrine therapy, either with SERMS, such as tamoxifen or aromatase inhibitors, is generally given for 5–10 years. Tamoxifen has partial ER agonist activity in bone and is protective in postmenopausal women, but leads to accelerated bone loss in premenopausal women. Aromatase inhibitors block oestradiol production, reducing circulating oestradiol by >98%. Aromatase inhibitors inhibit oestradiol-mediated negative feedback on gonadotropin production. They cannot be used in premenopausal women unless ovarian function is suppressed, typically by pharmacological or surgical means.16–18

In postmenopausal women, aromatase inhibitors are preferred because of modest improvements in breast cancer outcomes compared with tamoxifen.19 Although endocrine treatment in premenopausal women is evolving, the use of ovarian suppression plus an aromatase inhibitor is becoming more frequent, especially in younger women (<35–40 years) with high-risk breast cancer.20

In postmenopausal women, aromatase inhibitors are associated with a two- to threefold accelerated decline in BMD and bone loss is greatest within the first two years. Approximately 10% of untreated postmenopausal women will have a new clinical fracture within three years of aromatase inhibitor treatment.21 In premenopausal women, bone loss is even higher, with rates of 7–9% in the first 12 months; after five years of treatment, 13% of women have osteoporosis by DXA criteria.20 In RCTs, bisphosphonates prevented aromatase inhibitor-induced bone loss, but the studies were not powered for fracture end points.22–25 In contrast, a large trial reported a 50% reduction in clinical fracture rates with denosumab (60 mg given six-monthly for three years) compared with placebo in postmenopausal women.21

Of note, given the rapid offset of denosumab action and risk of rebound vertebral fractures, delays in the six-monthly administration should be avoided and, according to current evidence, a course of denosumab treatment needs to be followed by a bisphosphonate (refer to Section 3.2). Women should be informed about this prior to starting treatment.

Androgen deprivation therapy

Although testosterone is important for bone health due to direct effects on the male skeleton, a large proportion of its bone-protective actions are indirect, via aromatisation to oestradiol. In addition, testosterone improves bone strength through anabolic effects on muscle mass. Loss of muscle increases fracture risk due to a higher propensity for falls.7 ADT usually involves depot preparations of gonadotropin-releasing hormone (GnRH) analogues and reduces sex steroids to castrate levels. Newer treatment modalities, such as abiraterone, also inhibit extratesticular sex steroid synthesis and lead to even more profound sex steroid deprivation.26,27

Low BMD is highly prevalent among men even prior to commencement of ADT, and under-recognised. A study among 236 Australian men (mean age 70 years) with prostate cancer newly commencing ADT showed that, at baseline, 11% had osteoporosis and 40% had osteopenia.28 Sixty-one percent of the men with osteoporosis were unaware of the diagnosis. Even in the absence of ADT, bone health is a concern in older men with prostate cancer.

During the first year of ADT, BMD loss is accelerated by two- to sevenfold relative to the 0.5–1% bone loss occurring in ageing men.12 DXA may underestimate ADT-associated bone loss, especially the loss of cortical bone, which can exceed 10%.29 BMD continues to decline with long-term ADT, albeit at a lower rate. Large registry studies have shown that ADT increases relative fracture risk by 30–60%.15 In a cohort study of more than 50,000 men who survived for at least five years after prostate cancer diagnosis, fracture incidence approached 20%, and the number needed to harm for the occurrence of any fracture was 28 for GnRH agonist use and 16 for orchidectomy.30

Multiple RCTs have shown bisphosphonate therapy prevents ADT-associated BMD loss, but they were too small to provide fracture outcomes.15 In contrast, a large RCT in men receiving ADT showed that denosumab reduced the incidence of vertebral fractures (RR at three years 0.38 versus placebo; P=0.006) in men receiving ADT with a median T-score of –1.5 at randomisation, with a number needed to treat to prevent one incident vertebral fracture of 42.31

  1. Grossmann M, Ramchand SK, Milat F, et al. Assessment and management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: Position statement summary. Med J Aust 2019;211(5):224–29.
  2. Hasserius R, Karlsson MK, Nilsson BE, Redlund-Johnell I, Johnell O; European Vertebral Osteoporosis Study. Prevalent vertebral deformities predict increased mortality and increased fracture rate in both men and women: A 10-year population-based study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study. Osteoporos Int 2003;14(1):61–68.
  3. Grossmann M, Ramchand SK, Milat F, et al. Assessment and management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: Position statement of the Endocrine Society of Australia, the Australian and New Zealand Bone & Mineral Society, the Australasian Menopause Society and the Clinical Oncology Society of Australia. Clin Endocrinol (Oxf) 2018;89(3):280–96.
  4. Acevedo F, Pérez V, Pérez-Sepúlveda A, et al. High prevalence of vitamin D deficiency in women with breast cancer: The first Chilean study. Breast 2016;29:39–43.
  5. Chen P, Li M, Gu X, et al. Higher blood 25(OH)D level may reduce the breast cancer risk: Evidence from a Chinese population based case-control study and meta-analysis of the observational studies. PLoS One 2013;8(1):e49312.
  6. Olsen CM, Wilson LF, Nagle CM, et al. Cancers in Australia in 2010 attributable to insufficient physical activity. Aust N Z J Public Health 2015;39(5):458–63.
  7. Pizot C, Boniol M, Mullie P, et al. Physical activity, hormone replacement therapy and breast cancer risk: A meta-analysis of prospective studies. Eur J Cancer 2016;52:138–54.
  8. Kolb NA, Smith AG, Singleton JR, et al. The association of chemotherapy-induced peripheral neuropathy symptoms and the risk of falling. JAMA Neurol 2016;73(7):860–66.
  9. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force report: Bone health in cancer care. J Natl Compr Canc Netw 2009;7(Suppl 3):S1–32.
  10. Becker T, Lipscombe L, Narod S, Simmons C, Anderson GM, Rochon PA. Systematic review of bone health in older women treated with aromatase inhibitors for early-stage breast cancer. J Am Geriatr Soc 2012;60(9):1761–67.
  11. Edwards BJ, Raisch DW, Shankaran V, et al. Cancer therapy associated bone loss: Implications for hip fractures in mid-life women with breast cancer. Clin Cancer Res 2011;17(3):560–68.
  12. Rizzoli R, Body JJ, Brandi ML, et al. Cancer-associated bone disease. Osteoporos Int 2013;24(12):2929–53.
  13. Hamid M, Hayden A, Moujaber T, et al. Dual-energy X-ray absorptiometry assessment of bone health in Australian men with prostate cancer commencing androgen deprivation therapy. Med J Aust 2023;218(3):126–30.
  14. Grossmann M, Hamilton EJ, Gilfillan C, Bolton D, Joon DL, Zajac JD. Bone and metabolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy. Med J Aust 2011;194(6):301–06.
  15. Grossmann M, Zajac JD. Management of side effects of androgen deprivation therapy. Endocrinol Metab Clin North Am 2011;40(3):655-71, x.
  16. Chlebowski RT, Col N, Winer EP, et al. American Society of Clinical Oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 2002;20(15):3328–43.
  17. Ramchand SK, Cheung YM, Yeo B, Grossmann M. The effects of adjuvant endocrine therapy on bone health in women with breast cancer. J Endocrinol 2019;241(3):R111–24.
  18. Kerr AJ, Dodwell D, McGale P, et al. Adjuvant and neoadjuvant breast cancer treatments: A systematic review of their effects on mortality. Cancer Treat Rev 2022;105:102375.
  19. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 2015;386(10001):1341–52.
  20. Pagani O, Regan MM, Walley BA, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 2014;371(2):107–18.
  21. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2015;386(9992):433–43.
  22. Brufsky AM, Bosserman LD, Caradonna RR, et al. Zoledronic acid effectively prevents aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer 2009;9(2):77–85.
  23. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol 2008;9(9):840–9.
  24. Majithia N, Atherton PJ, Lafky JM, et al. Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy: A 5-year follow-up. Support Care Cancer 2016;24(3):1219–26.
  25. de Sire A, Lippi L, Venetis K, et al. Efficacy of antiresorptive drugs on bone mineral density in post-menopausal women with early breast cancer receiving adjuvant aromatase inhibitors: A systematic review of randomized controlled trials. Front Oncol 2022;11:829875.
  26. Barata PC, Sartor AO. Metastatic castration-sensitive prostate cancer: Abiraterone, docetaxel, or… Cancer 2019;125(11):1777–88.
  27. Manceau C, Mourey L, Pouessel D, Ploussard G. Abiraterone acetate in combination with prednisone in the treatment of prostate cancer: Safety and efficacy. Expert Rev Anticancer Ther 2020;20(8):629–38.
  28. Cheung AS, Pattison D, Bretherton I, et al. Cardiovascular risk and bone loss in men undergoing androgen deprivation therapy for non-metastatic prostate cancer: Implementation of standardized management guidelines. Andrology 2013;1(4):583–89.
  29. Hamilton EJ, Ghasem-Zadeh A, Gianatti E, et al. Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy. J Clin Endocrinol Metab 2010;95(12):E456–63.
  30. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352(2):154–64.
  31. Smith MREB, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361(8):745–55.
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