Osteoporosis prevention, diagnosis and management in postmenopausal women and men over 50 years of age

Recommendations

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

Evidence statement

AI therapy

Adjuvant endocrine therapy, either with selective ER modulators such as tamoxifen or AIs, is generally given for 5–10 years. Tamoxifen has partial ER-agonistic activity in bone and is protective in postmenopausal women but leads to accelerated bone loss in premenopausal women. AIs block oestradiol production, reducing circulating oestradiol by >98%. AIs inhibit the 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.

In postmenopausal women, AIs are preferred because of modest improvements in breast cancer outcomes, compared to tamoxifen.12 While endocrine treatment in premenopausal women is evolving, the use of ovarian suppression plus AI is becoming more frequent, especially in younger (<35–40 year-old) women with high-risk breast cancer.13

In postmenopausal women, AIs are associated with a 2–3-fold accelerated BMD decline, and the magnitude of bone loss is greatest within the first two years. About 10% of untreated postmenopausal women will have a new clinical fracture within three years of AI treatment.14 In premenopausal women, bone loss is even higher; 7–9% in the first 12 months, and after five years of treatment, 13% with osteoporosis by DXA criteria.13 In randomised controlled trials (RCTs), bisphosphonates prevent AI-induced loss of bone loss, but studies are not powered for fracture endpoints. By contrast, a recent trial reported a 50% reduction in clinical fracture rates with denosumab (60 mg given six-monthly for three years) compared to placebo in postmenopausal women.14

ADT

While 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 its anabolic effects on muscle mass. Loss of muscle increases fracture risk due to higher propensity of falls.4 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 extra-testicular sex-steroid synthesis and lead to even more profound sexsteroid deprivation. 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% osteopenia.15 Sixty-one per cent 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 2–7-fold relative to the 0.5–1% bone loss occurring in ageing men.11 DXA may underestimate ADT-associated bone loss especially loss of cortical bone which can exceed 10%.16 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%.11 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.17

Multiple RCTs have shown that bisphosphonate therapy prevents ADT-associated BMD loss, but they were too small to provide fracture outcomes.11 By contrast, a large RCT in men receiving ADT showed that denosumab reduced the incidence of vertebral fractures (relative risk 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 a one-incident vertebral fracture of 42.18

Most patients with a diagnosis of early oestrogen receptor (ER)-positive breast cancer or localised prostate cancer now have good prognosis, with 10-year survival greater than 90%. 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.

Assessment includes review of clinical risk factors, basic laboratory testing (electrolytes, calcium, alkaline phosphatase and vitamin D), and hip and spine bone mineral density (BMD) measurement by dual energy X-ray absorptiometry (DXA). If reduced bone mass is present at baseline, individualised assessment is necessary to identify unrelated secondary causes of osteoporosis. In women with a T-score ≤–1.0, plain radiographs of the thoracolumbar spine should be performed to exclude subclinical vertebral fractures, defined by the Pharmaceutical Benefits Scheme (PBS) as a 20% or greater reduction in 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 clinically silent in the majority.

While risk calculators such as the Garvan Fracture Risk Calculator or Fracture Risk Assessment Tool (FRAX) may be useful, they do not take aromatase inhibitor (AI) use into account and may substantially underestimate fracture risk. The utility of bone-remodelling markers or bone imaging other than DXA requires further evaluation.

  • High prevalence of vitamin D deficiency1,2
  • Decreased physical activity3,4
  • Increased risk of falls secondary to treatment-induced neuropathy5
  • Chemotherapy-induced ovarian failure6
  • AI therapy7,8

International consensus guidelines6,9 recommend that anti-resorptive therapy should be initiated in AI-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 be considered where there is a >5–10% decrease in BMD in one year of AI treatment, or 10-year absolute risk of a major osteoporotic fracture of >20%, or of a hip fracture of >3%. However, this is outside current PBS of Australia 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 anti-resorptive treatment should be carefully individualised and discussed with the patient. Bisphosphonates can persist in the bone matrix for years after therapy is discontinued, potentially resulting in foetal exposure during pregnancy. Specialist referral may be appropriate.

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

General measures to prevent bone loss include:

  • Regular moderate physical activity (weight-bearing exercises and resistance training)
  • Smoking cessation
  • Limitation of alcohol to <2 standard drinks per day
  • Calcium intake of 1300 mg, preferably dietary
  • Vitamin D supplementation to achieve and maintain 25-OH D levels >50 nmol/L

Key recommendations for the management of bone health in men receiving androgen deprivation therapy (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.10

Risk factors for osteoporosis should be ascertained, basic laboratory testing conducted (electrolytes, calcium, alkaline phosphatase and vitamin D), and hip and spine BMD measurement determined by DXA. Absolute baseline fracture risk may be estimated using mathematical tools such as the Garvan Fracture Risk Calculator or FRAX. However, neither of these algorithms is validated for men with prostate cancer receiving ADT, and they 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.10 DXA should be repeated 12 months after commencement of ADT, with subsequent individualised monitoring frequency.

There is currently insufficient evidence to make evidence-based recommendations regarding if and when bisphosphonate therapy for primary prevention should be commenced in men with prostate cancer who are receiving ADT. Consistent with the general recommendations in this guideline, all men older than 70 years of age with a T-score of ≤–2.5 should commence anti-resorptive therapy, and therapy should be considered if there is an annual BMD loss of 5–10% or a 10-year absolute risk of a major osteoporotic fracture of >20%, or of a hip fracture of >3%.

Australian guidelines recommend that bisphosphonate therapy should be considered for primary prevention if the BMD T-score is ≤–2.0.11 However, this recommendation is outside current PBS subsidy criteria. While bisphosphonates are recommended (and subsided by the PBS) for primary fracture prevention in glucocorticoidinduced 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.

Management should also be re-evaluated after cessation of ADT, as the gonadal axis may recover in some men, with more rapid recovery reported in younger men (<65 years) or shorter (<24–30 months) duration of ADT.11

General measures to prevent bone loss should:

  • Regular moderate physical activity (weight-bearing exercises and resistance training)
  • Smoking cessation
  • Limitation of alcohol to <2 standard drinks per day
  • Calcium intake of 1000–1300 mg, preferably dietary
  • 25-OH D supplementation to achieve and maintain levels >50 nmol/L
  1. 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.
  2. 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. doi: 10.1371/journal. pone.0049312.
  3. Olsen CM, Wilson LF, Nagle CM, et al. Cancers in Australia in 2010 attributable to insufficient physical activity. Aust NZ J Public Health 2015;39(5):458–63.
  4. 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.
  5. 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.
  6. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force report: Bone health in cancer care. J Natl Compr Canc Netw 2009;11 Suppl 3:S1–S35.
  7. 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.
  8. 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.
  9. Rizzoli R, Body JJ, Brandi ML, et al. Cancer-associated bone disease. Osteoporos Int 2013;24(12):2929–53.
  10. 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.
  11. Grossmann M, Zajac J. Management of side effects of androgen deprivation therapy. Endocrinol Metab Clin North Am 2011;40(3):655–71.
  12. Dowsett M, Forbes JF, Bradley R, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 2015;386(10001):1341–52.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. Smith MR, Egerdie B, Hernandez 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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