Menopause Live - IMS Updates

Date of release: 19 June, 2017

American College of Physicians guideline: treatment to prevent fractures

An updated, new guideline from the American College of Physicians caught my eye because of two main reasons. First, it is written in a very simple, clear and didactic way, so that all health-care providers can easily understand and implement it [1]. Second, the recommendation on postmenopausal hormone therapy (HT) was somewhat unexpected. One should pay attention to the phrasing of the title of the publication, which points at a specific target aim – prevention of fractures in patients with established low bone mass or osteoporosis. The article includes 387 citations, and thus it seems that a very thorough analysis was made.

Here are the main messages in regard to women:

  • High-quality evidence showed that bisphosphonates, including alendronate, risedronate, and zoledronic acid, reduce vertebral, non-vertebral, and hip fractures compared with placebo in postmenopausal osteoporotic women.

  • High-quality evidence showed that treatment with teriparatide reduces radiographic vertebral and non-vertebral fractures compared with placebo in postmenopausal osteoporotic women.

  • High-quality evidence showed that treatment with denosumab reduces radiographic vertebral, non-vertebral, and hip fractures compared with placebo in postmenopausal osteoporotic women.

  • High-quality evidence showed that raloxifene reduces vertebral fractures in osteoporotic women; however, it did not statistically significantly decrease the risk for non-vertebral or hip fractures compared with placebo. Bazedoxifene is FDA-approved in combination with conjugated estrogens for the prevention of osteoporosis (20 mg, with 0.45 mg conjugated estrogen). The systematic review did not find any randomized controlled trials with this combination that had primary fracture outcomes.

  • Moderate-quality evidence showed that the overall effect of calcium or vitamin D alone on fracture risk is uncertain.

  • Evidence is insufficient to determine the comparative effectiveness of pharmacologic therapy or the superiority of one medication over another, within the same class or among classes, for prevention of fractures. Network meta-analyses addressing the lack of head-to-head comparisons between the drugs mostly show no statistically significant differences among the various therapies.

  • Evidence is insufficient to conclusively show the effect of physical activity on fracture risk.

As for HT, the guideline says: Moderate-quality evidence showed no difference in reduced fracture with estrogen treatment in postmenopausal women with established osteoporosis. This differs from the 2008 guideline, which reported high-quality evidence that estrogen therapy was associated with reduced risk for vertebral, non-vertebral, and hip fractures in postmenopausal women. Studies included in the 2008 guideline focused on postmenopausal women or those with low bone density as opposed to the newer data, which focused on postmenopausal women with established osteoporosis. Thus, the current claim actually favors the use of HT for primary prevention of fractures in postmenopausal women in general, but not as a strategy for secondary prevention or treatment of fractures in women with already established osteoporosis.

In another section of the guideline, the potential adverse effects of the various medications are outlined. The quote for HT was: high-quality evidence from the Women's Health Initiative showed that menopausal hormone therapy was associated with increased risk for cerebrovascular accidents and venous thromboembolic events. Another study showed that estrogen plus progestin therapy was associated with more invasive breast cancer, more node-positive tumors, and more deaths due to breast cancer than. As a result, the bottom line is: The American College of Physicians recommends against using menopausal estrogen therapy or menopausal estrogen plus progestogen therapy or raloxifene for the treatment of osteoporosis in women. (Grade: strong recommendation; moderate-quality evidence).



After the publication of these guidelines, several IMS members held active discussions through emails and expressed their opinion on their validity. The main point that was raised relates to the definition of primary vs. secondary prevention of fractures, and the relevance to hormone therapy. Here are some comments:

Margery Gass: From my perspective, the field of osteoporosis has a semantics problem. Virtually all of the osteoporosis guidelines make the case that primary prevention should consist of healthy lifestyle, exercise, adequate calcium and vitamin D (not prescription medication, which includes HT). Primary prevention measures should have no risks since most of the people will never suffer the disease outcomes. All prescription medications should be reserved for people with osteoporosis or low bone mass with high risk of fracture. Confusion stems from the fact that the FDA has a list of drugs, including HT, that have been approved for 'prevention' of osteoporosis. That does not mean that all of those drugs should be given to all postmenopausal women as primary prevention – only those at high risk of fracture.

Sue Davis: When we talk about primary prevention for cardiovascular disease, we talk about treating people at greater risk, but many of these will never have a cardiovascular event, e.g. cholesterol-lowering medication in someone who has never had a cardiac event. So menopausal hormone therapy (MHT) for fracture prevention in someone who has never had a fracture also remains primary prevention (and is FDA-approved for this purpose). Therefore I believe this new recommendation lacks consistency with the FDA-approved (evidence-based) use of MHT for primary prevention of fragility fracture in postmenopausal women.

Steven Goldstein: Although the raloxifene MORE trial did NOT show a reduction in hip fracture, after the NHANES III correction, the group was not of sufficiently high risk to show a reduction. There were less hip fractures in the placebo group in the MORE trial than in the patients treated with risendronate or alendronate in other studies. Perhaps it should be mentioned that it is hard to show a reduction in risk in a low risk group.

Ewald Boschitsch: The 'semantics problem' with osteoporosis, as mentioned by Margery Gass, is due to the lack of distinct definitions for the terms used in these guidelines, e.g. starting with the title “Treatment of low bone density or osteoporosis …'. From the osteologic point of view, low bone density per se is not something to be treated. Or 'established osteoporosis', which is characterized by a T-score less than -2.5 at the hip or spine and one or more previous fragility fractures [WHO technical report series; 843] and should primarily not be treated with MHT, so far in agreement with the guidelines. Nevertheless, there may be exceptions for conditions with increased fracture risk and a causal relationship to sex hormone deficiency such as hypogonadism or premature ovarian failure. This is not in agreement with the guidelines (Recommendation 5), neither for established nor for BMD-defined osteoporosis or osteopenia plus additional risk factors (estimated by FRAX, for example (WHO, NOF)). FRAX, by the way, is not a WHO tool, as said in the guidelines (Bull World Health Organ 2016;94:862). From my perspective, MHT has a very important place in the prevention (primary or secondary, depending on the respective definition) of osteoporosis and fragility fractures. 'MHT can be initiated in postmenopausal women at risk of fracture or osteoporosis before the age of 60 years or within 10 years after menopause and in women experiencing a spontaneous or iatrogenic menopause before the age of 45 years ….' (Climacteric 2016;19:311. IMS global consensus, endorsed by the International Osteoporosis Foundation).

Tobie de Villiers: The American College of Physicians suggests against the use of HT in osteoporotic patients but fails to supply references on which this is based. But whatever the evidence it used, the truth is that the need for HT as monotherapy in a patient with fractures or very low BMD is very small indeed, as these, for the vast majority, are older patients outside the HT window. In a younger patient below 60 years old with a T-score < -2.5, HT may be the best choice, but we have no strong evidence for or against this argument. I am convinced it will work as well as a bisphosphonate to prevent fractures but fully understand that most physicians will feel uncomfortable doing this. It is my opinion that the primary aim of 'osteoporosis treatment' is the prevention of fractures (and not chasing BMD values). All postmenopausal women and men above 50 at sufficient risk of fracture, irrespective of BMD, should consider pharmacological treatment with the aim to prevent fractures. Osteopenia, as a single risk factor for fracture, generally does not warrant anti-fracture therapy including HT. I try to avoid the semantics of prevention and treatment as they have the same aim (fracture prevention). The FDA does allow for prevention but does not define prevention. The EMEA has no prevention category. If anti-fracture treatment is indicated, the most suitable drug must be used. HT is the only drug with proven fracture-reducing capabilities in the osteopenic setting (alendronate was ineffective in FIT2; most of the newer drugs were never tested in osteopenia.


Amos Pines

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel


  1. Qaseem A, Forciea MA, McLean RM, Denberg TD; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med 2017;166:818-39