Focus on fracture: Gateway to evaluating osteoporosis

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With an aging population women are now spending more than 1/3 of their lives in postmenopausal years. Aging skeletons and maintenance of bone health are important midlife issues. Many women see ob/gyns for their annual comprehensive exams and have questions about their bones. In addition, women present with various risk factors for fracture (i.e. being underweight, having early menopause

(age < 45 years), use of certain medications such as glucocorticoids or aromatase inhibitors), or have sustained a prior fracture. Often, ob/gyns treat various medical and gynecologic conditions that affect bone health, and they may discover untreated fractures. It is crucial that ob/gyns are aware of screening guidelines for osteoporosis and how to evaluate women at high risk for fracture and provide appropriate treatment, when necessary. 

In the United States, 2 million osteoporotic fractures occur every year, yet the number of patients being treated for serious fractures, such as hip fractures, is decreasing.^1-3 Adding to the complexity, there is increasing diversity in the types of specialists who diagnose and treat osteoporosis. Ob/gyns are the gatekeepers of health care for many postmenopausal women and in some cases, their only contact with the health care system. The following cases will focus on identifying and treating women at high risk of first or recurrent fractures. 

Case 1  Secondary fracture prevention

Jane, a 70-year-old with a prior wrist fracture, presents for her annual gynecologic exam. Last year, her T score was -2.7 and you started her on weekly alendronate, which she reports taking consistently. The patient also tells you she has new back pain and she has lost 1 inch of height since her last exam. Dual energy X-ray absorptiometry (DXA) with vertebral fracture assessment (VFA) reveals two new vertebral fractures at T12 and L1. How do you counsel and manage this patient? 

Jane has sustained multiple osteoporotic and fragility fractures. Her diagnosis is now severe osteoporosis. Independent of bone mineral density (BMD), a prior fracture increases risk of subsequent fracture by 85%.⁴ About two-thirds of vertebral fractures go clinically undiagnosed, leading to additional fractures, chronic pain, deformity, and height loss.⁵ Therefore, it is important to recognize and intervene on these “silent” fractures to prevent future fractures at all skeletal sites. In a recent large, population-based cohort study, risk of a second major osteoporotic fracture after a first fracture was greatest 1 to 5 years following the initial event.⁶ In individuals who were examined over a 10-year period, 20% of 1311 had re-fractures within 1 year and 34% within 2 years. In addition, risk of having a second fracture was 41% higher in women than in men and risk of second fracture increased with advancing age, especially in those > 70 years.⁶

Not only is timely diagnosis important, but prompt treatment of osteoporotic fractures matters. Fracture liaison services (FLS), often housed in orthopedic departments, can help treat patients more urgently. A meta-analysis showed that perceived physician knowledge about osteoporosis (and its clinical consequences) contributes to patients feeling their educational needs are met. Understandable written literature on osteoporosis and medication are common demands from patients.⁷

Before you choose the next best therapy for Jane, she should undergo a secondary bone loss evaluation (if she did not have one previously). This includes a complete blood count (CBC), comprehensive metabolic panel (CMP, including serum calcium and phosphorus), testing for thyroid-stimulating hormone (TSH), 25 hydroxy-vitamin D level, serum protein electrophoresis (SPEP), parathyroid hormone (PTH), celiac disease (with tissue transglutaminase and IgA), and a 24-hour urine calcium and creatinine collection. If these tests were previously collected and normal, additional tests could include a 24-hour urine cortisol and single urine NTX (N-telopeptide) to determine resorption status.⁸ Conservative treatment is appropriate for acute management of Jane’s back pain, with oral analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and/or transdermal lidocaine. Opioids and possible referral to orthopedic surgery may be necessary if acute and chronic pain cannot be well managed with a conservative approach. 

In patients whose pain fails to respond to oral, intravenous (IV) or subcutaneous antiresorptive therapies (i.e. BMD decreases or they fracture while on medications), anabolic agents can be effective for reducing vertebral and nonvertebral fracture. However, these drugs should not simply be reserved for rescuing patients who have failed prior treatments. Osteoporosis specialists are starting to recommend sequential therapy in high-risk patients (i.e. those with prior fracture or multiple risk factors for fracture, such as advancing age or low BMD), starting with anabolic therapy for up to 2 cumulative years, followed by antiresorptive therapy. Treatment with anabolic therapy such as teriparatide and abaloparatide are recommended to build bone mass and lay down new bone via the bone modeling cycle 

Both teriparatide and abaloparatide are self-administered daily with small 31-gauge needles and carry a black-box warning that restricts use to 2 years due to the potential for osteosarcoma detected in rodents. However, in more than 16,000 patients who received teriparatide in controlled clinical trials and observational studies over a span of 15 years, there have been no human reports to date of osteosarcoma linked to teriparatide or abaloparatide.^9,10

Teriparatide is a recombinant PTH, requires refrigeration, and has been approved by the US Food and Drug Administration since 2002. Generic options are available in Europe and will come to US markets soon. Abaloparatide is a synthetic analog of PTH- related protein (PTHrP). It preferentially binds the RG conformational state of the PTH1R on osteoblasts, to stimulate more bone modeling (formation) than resorption. It does not require refrigeration. ACTIVE (Abaloparatide Comparator Trial In Vertebral Endpoints) was a phase 3, double-blind, randomized controlled trial to evaluate fracture reduction in 2,463 osteoporotic postmenopausal women with three treatment arms: placebo, abaloparatide, and teriparatide (open label). Although not powered to show differences in fracture efficacy between the two active therapies, there was a longer time to first major osteoporotic fracture for abaloparatide versus teriparatide (P < 0.03) and greater increases in BMD for abaloparatide versus teriparatide at femoral neck, hip, and spine sites at 6 and 12 months.¹¹

In the ACTIVExtend trial, 18 months of abaloparatide followed by 2 years of weekly alendronate (total 43 months of treatment) showed significant vertebral 84% relative risk reduction (RRR) for vertebral fractures (P < 0.001); 39% RRR for non-vertebral fractures (P < 0.038) and 50% RRR for major osteoporotic fractures (clinical spine, humerus, shoulder and hip) (P < 0.01).¹²

As described above, sequential therapy yields the largest BMD gain when an anabolic agent is followed by an antiresorptive. By contrast, when an antiresorptive such as alendronate is followed by teriparatide, hip BMD is slower to increase and BMD drops to below baseline for 12 months. When a more potent antiresorptive such as denusomab is used, there is a more attenuated rise in hip BMD while BMD drops below baseline for 24 months. Spine BMD seems to be minimally affected by the sequence. Histomorphometric and bone turnover studies have pointed to a transient increase in cortical porosity and increases in bone remodeling to explain this effect.¹³ As background, cortical bone comprises 80% of our skeletal mass, found in the long bones and vertebra.

Other ongoing trials have explored combination therapy with teriparatide and denusomab. To date, combination treatment is reserved for the highest-risk patients failing multiple single therapies and under the care of osteoporosis experts.¹⁴ In summary, the paradigm for evaluating and treating osteoporosis and its fractures is undergoing a shift. As effective therapies are being developed, more is understood about sequencing and duration of therapy.

Case 2  Use of FRAX to stratify fracture risk 

Mary is a 60-year-old postmenopausal woman with baseline
T score -2.2 at the femoral neck. Her femoral neck BMD is 0.590
g/cm² on DXA. Mary reports a final menstrual period at age 51 and eats two calcium-rich foods/day, exercises 3 days per week, and has no personal or family history of fall/fracture. She weighs 140 lb and is 5 feet 2 inches tall. How do you interpret and share the DXA results with this patient? 

Mary has low bone mass (formerly called osteopenia) on her DXA. Women with low bone mass represent the largest cohort of women who fracture.¹⁵ Therefore, it is important not to solely rely upon a T score > -2.5 as a reassurance that patients are not risk for fracture. Discussing how low BMD may contribute to fracture, in addition to advancing age, female sex, and prior fracture is more appropriate management. Annual measurement on a wall-mounted stadiometer is important. Capturing height loss > 1.5 inch since adult peak height or > 0.8 inch since last height measured may detect clinically silent vertebral fractures. 

Women with low bone mass may also need a laboratory evaluation for bone loss, and certainly counseling on lifestyle factors (smoking, exercise) and appropriate calcium and vitamin D intake. 

In addition, the FRAX tool is a free, online resource that helps risk-stratify patients and calculates their 10-year risk of hip and major osteoporotic fracture (defined as hip, forearm, spine, humerus.) Thresholds for treatment recommendations are a 10-year risk of hip fracture > 3% and of major osteoporotic fracture > 20%.¹⁶ Mary has a calculated 10-year risk of hip fracture of 1.6% and of major osteoporotic fracture of 10%. Although she does not meet criteria for treatment based on this statistical model, there are certain variables not captured in FRAX, such as falls and low spine BMD. Another risk calculator called the Garvan model does capture T scores at any skeletal sites and history of falls.¹⁷

Current recommendations by most professional organizations (National Osteoporosis Foundation, International Society of Clinical Densitometry, American College of Obstetricians and Gynecologists, and United States Preventive Services Taskforce [USPSTF]) suggest beginning DXA at age 65 or earlier in women who have risk factors for bone loss. Specifically, in its June 2018 update, the USPSTF recommended BMD testing for women aged 50 to 64 whose 10-year predicted risk of major osteoporotic fracture (calculated using the FRAX model without BMD) is ≥ 9.3 % (equivalent to that of a 65-year-old white woman with no other FRAX clinical risk factors).¹⁸ The goal of this calculation is to identify who may benefit from screening and possibly treatment to prevent a first fracture. 

A recent study addressed an alternate treatment regimen with IV zoledronate for older postmenopausal women, which may apply to the patient in this case. In the trial, 2000 older postmenopausal women (average age 71) with low bone mass (average T-score spine -1.2, femoral neck -1.6) were treated with IV zoledronate every 18 months for 6 years (4 injections). Compared to placebo, there were significant reductions in fragility fractures (composite of nonvertebral fractures and radiologically detected vertebral fractures (HR 0.63 [95% CI, 0.50-0.79; P < .001) and nonvertebral fractures (HR 0.66 95% CI, 0.51-0.85;
P < .01).¹⁹ Evidence validates treatment of low bone mass for the appropriate patient. Although treatment for every woman with low bone mass is not routinely recommended, those who meet FRAX thresholds or who lose BMD dramatically require evaluation and possible treatment. 

Case 3  Individualized therapy 

Martha is a 55-year-old postmenopausal woman who was treated with hormone therapy (HT) for 3 years (age 50-53) for bothersome vasomotor symptoms (VMS). When she chose to transition off HT at age 53 her baseline spine T score then was -2.3. Martha’s current spine T score is -2.7. She has never sustained a fracture, has maintained height, and takes supplemental calcium, vitamin D, and escitalopram for anxiety. Given Martha’s T score, you start her on denosumab, a subcutaneous antiresorptive that is given every 6 months. She would like to know how long she will remain on this medication. What do you tell this patient? 

For many postmenopausal women with symptoms of menopause, HT will alleviate symptoms and can reduce risk of osteoporotic fractures. In the Women’s Health Initiative, HT reduced observed clinical vertebral fractures (relative risk [RR], 0.65; 95% CI, 0.46- 0.92) and hip fractures (RR, 0.67; 95% CI, 0.47 -0.96) compared with placebo.²⁰

HT is FDA-approved for prevention but not treatment of osteoporosis. Although HT is effective, its anti-osteoclastic activity attenuates quickly but there does not appear to be a rebound increase in fractures after stopping HT. In fact, in the estrogen-alone arm, prior estrogen users (31.1 per 1000 person-years) had fewer fractures than placebo users (36.9 per 1000 person-years, HR, 0.85 ; 95% CI 0.73-0.98; P = 0.03).²¹

After a patient loses BMD, treatment with denusomab, a human monoclonal antibody to a receptor activator of nuclear factor kappa-B ligand (RANKL), is acceptable. The mechanisms of action and potency of bisphosphonates and denusomab differ. For that reason, drug holidays are recommended for bisphosphonates but not for denosumab. With 10 years of safety and efficacy use of denusomab, studies have shown BMD of hip and spine continue to increase without plateau and new nonvertebral and vertebral fracture rates remain low in those on treatment. In the pivotal trial, 3 years of denusomab showed reductions in vertebral (RRR 68%), non-vertebral (RRR 20%), and hip fractures (RRR 40%).^22-24 In addition, denusomab is now approved for glucocorticoid-induced osteoporosis. 

There are reports and concerns over multiple vertebral fractures following discontinuation of denusomab. In patients receiving more than two doses of the drug, the fractures have been reported as early as 7 months following the last dose (average 19 months after last dose).²⁵ Patients at highest risk are those with prior vertebral fracture as the rapid bone turnover rates following discontinuation may target trabecular bone in the spine. If denusomab therapy is halted or delayed for any reason, the patient should be transitioned to another therapy. BMD returns to baseline following 12 months off denusomab.

A newer paradigm, “treat to target,” recommends treating patients to a specific goal. The goal could be T score (usually > -2.5) and/or to an acceptable low fracture risk (i.e. 5 years from last fracture) to ensure they are out of critical fracture window.²⁶ Patients who continue to need treatment may continue or be transitioned to another therapy, and those who have met target may discontinue therapy with follow-up DXA and periodic bone health evaluation. To answer Martha’s question about duration of denusomab therapy, thus far, 10 years of continuous use of denusomab has been studied and prescribed. In the case of denusomab and the “treat to target” paradigm, if a patient’s goal BMD is met, transition to another antiresorptive for 1 to 2 years is recommended. Patients on bisphosphonates who have met target can stop treatment and continue DXA surveillance. 

In summary, the goal of any osteoporosis intervention should be to reduce fracture with informed osteoporosis education and shared decision-making to select appropriate therapy. 

Conclusion

Therapies for osteoporosis and for patients at high risk for fracture have expanded. New treatment paradigms about which ob/gyns should be aware include the following: 

• Recommending anabolic therapy first: This applies, in particular, to patients who are at highest risk for fracture, such as those who have recently fractured or who have very low T scores. 
   

• Screening based on USPSTF guidelines: DXA screening is recommended for all women > age 65. For women aged 50 to 64 who have risk factors for fracture, BMD evaluation with DXA is warranted if FRAX calculation (without BMD) is ≥ 9.3 % (equivalent to that of a 65-year-old white woman with no other FRAX clinical risk factors). However, clinical tools should not replace clinical judgment for patients who may be at high risk for fracture and may need earlier screening and/or benefit from treatment.
   

• Implementing goal-directed treatment or “treat to target”: The idea is to individualize osteoporosis treatment so that patients continue medication until goal BMD is met (i.e. T score > -2.5) and they are below acceptable fracture thresholds. For certain medications, such as denusomab, drug holidays are not recommended. 

Ob/gyns are often the gatekeepers of health care for postmenopausal women. Thus, it is essential that we play integral roles in diagnosing, evaluating, and initiating treatment for women with osteoporosis and those at high risk for fracture. 

Disclosures:

The author reports no potential conflicts of interest with regard to this article.

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