Clinical Review

2023 Update on bone health

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Study recaps and expert perspectives on SERMs and bone effects, the microbiome’s role in bone metabolism, the added risks of frailty, and therapeutic possibilities for denosumab



I recently heard a lecture where the speaker quoted this statistic: “A 50-year-old woman who does not currently have heart disease or cancer has a life expectancy of 91.” Hopefully, anyone reading this article already is aware of the fact that as our patients age, hip fracture results in greater morbidity and mortality than early breast cancer. It should be well known to clinicians (and, ultimately, to our patients) that localized breast cancer has a survival rate of 99%,1 whereas hip fracture carries a 21% mortality in the first year after the event.2 In addition, approximately one-third of women who fracture their hip do not have osteoporosis.3 Furthermore, the role of muscle mass, strength, and performance in bone health has become well established.4

With this in mind, a recent encounter with a patient in my clinical practice illustrates what I believe is an increasing problem today. The patient had been on long-term prednisone systemically for polymyalgia rheumatica. Her dual energy x-ray absorptiometry (DXA) bone mass measurements were among the worst osteoporotic numbers I have witnessed. She related to me the “argument” that occurred between her rheumatologist and endocrinologist. One wanted her to use injectable parathyroid hormone analog daily, while the other advised yearly infusion of zoledronic acid. She chose the yearly infusion. I inquired if either physician had mentioned anything to her about using nonskid rugs in the bathroom, grab bars, being careful of black ice, a calcium-rich diet, vitamin D supplementation, good eyesight, illumination so she does not miss a step, mindful walking, and maintaining optimal balance, muscle mass, strength, and performance-enhancing exercise? She replied, “No, just which drug I should take.”

Realize that the goal for our patients should be to avoid the morbidity and mortality associated especially with hip fracture. The goal is not to have a better bone mass measurement on your DXA scan as you age. This is exactly why the name of this column, years ago, was changed from “Update on osteoporosis” to “Update on bone health.” Similarly, in 2021, the NOF (National Osteoporosis Foundation) became the BHOF (Bone Health and Osteoporosis Foundation). Thus, our understanding and interest in bone health should and must go beyond simply bone mass measurement with DXA technology. The articles highlighted in this year’s Update reflect the importance of this concept.

Know SERMs’ effects on bone health for appropriate prescribing

Goldstein SR. Selective estrogen receptor modulators and bone health. Climacteric. 2022;25:56-59.

Selective estrogen receptor modulators (SERMs) are synthetic molecules that bind to the estrogen receptor and can have agonistic activity in some tissues and antagonistic activity in others. In a recent article, I reviewed the known data regarding the effects of various SERMs on bone health.5

A rundown on 4 SERMs and their effects on bone

Tamoxifen is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of breast cancer in women with estrogen receptor–positive tumors. The only prospective study of tamoxifen versus placebo in which fracture risk was studied in women at risk for but not diagnosed with breast cancer was the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial. In this study, more than 13,000 women were randomly assigned to treatment with tamoxifen or placebo, with a primary objective of studying the incidence of invasive breast cancer in these high-risk women. With 7 years of follow-up, women receiving tamoxifen had significantly fewer fractures of the hip, radius, and spine (80 vs 116 in the placebo group), resulting in a combined relative risk (RR) of 0.68 (95% confidence interval [CI], 0.51–0.92).6

Raloxifene, another SERM, was extensively studied in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial.7 This study involved more than 7,700 postmenopausal women with osteoporosis, average age 67. The incidence of first vertebral fracture was decreased from 4.3% with placebo to 1.9% with raloxifene (RR, 0.55; 95% CI, 0.29–0.71), and subsequent vertebral fractures were decreased from 20.2% with placebo to 14.1% with raloxifene (RR, 0.70; 95% CI, 0.60–0.90). In 2007, the FDA approved raloxifene for “reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” as well as for “postmenopausal women at high risk for invasive breast cancer” based on the Study of Tamoxifen and Raloxifene (STAR) trial that involved almost 20,000 postmenopausal women deemed at high risk for breast cancer.8

The concept of combining an estrogen with a SERM, known as a TSEC (tissue selective estrogen complex) was studied and brought to market as conjugated equine estrogen (CEE) 0.45 mg and bazedoxifene (BZA) 20 mg. CEE and BZA individually have been shown to prevent vertebral fracture.9,10 The combination of BZA and CEE has been shown to improve bone density compared with placebo.11 There are, however, no fracture prevention data for this combination therapy. This was the basis on which the combination agent received regulatory approval for prevention of osteoporosis in postmenopausal women. This combination drug is also FDA approved for treating moderate to severe vasomotor symptoms of menopause.

Ospemifene is yet another SERM that is clinically available, at an oral dose of 60 mg, and is indicated for the treatment of moderate to severe dyspareunia secondary to vulvovaginal atrophy, or genitourinary syndrome of menopause (GSM). Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to estradiol and raloxifene.12 Clinical data from three phase 1 or phase 2 clinical trials revealed that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.13 While actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, there is a good correlation between biochemical markers for bone turnover and occurrence of fracture.14 Women who need treatment for osteoporosis should not be treated with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.


SERMs, unlike estrogen, have no class labeling. In fact, in the endometrium and vagina, they have variable effects. To date, however, in postmenopausal women, all SERMs have shown estrogenic activity in bone as well as being antiestrogenic in breast. Tamoxifen, well known for its use in estrogen receptor–positive breast cancer patients, demonstrates positive effects on bone and fracture reduction compared with placebo. Raloxifene is approved for prevention and treatment of osteoporosis and for breast cancer chemoprevention in high-risk patients. The TSEC combination of CEE and the SERM bazedoxifene is approved for treatment of moderate to severe vasomotor symptoms and prevention of osteoporosis. Finally, the SERM ospemifene, approved for treating moderate to severe dyspareunia or dryness due to vulvovaginal atrophy, or GSM, has demonstrated evidence of a positive effect on bone turnover and metabolism. Clinicians need to be aware of these effects when choosing medications for their patients.

Continue to: Gut microbiome constituents may influence the development of osteoporosis: A potential treatment target?...


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