Treatment Options for Fragility Fractures

EMERGING TREATMENTS AND ALGORITHM FOR FRAGILITY FRACTURES

INTRODUCTION

Despite a wide range of effective anti-osteoporosis medications and a growing elderly population, the proportion of patients receiving adequate secondary fracture prevention is falling. Fragility fractures were covered in depth in with the introduction, nonpharmacologic and pharmacologic treatment options. An update will be provided here on emerging treatments within the past few years and a new algorithm will be provided.

Case Vignette

A 20 year old female cross-country runner presents to your clinic for preseason to try to maximize her performance. Her primary care order ordered a bone density test (DEXA) and asked you about the results and your recommendations. Which of the following statements and recommendations would be true?

A) Z-score -2.3; further studies warranted to rule out secondary causes

B) Z-score -2.2; normal for her age and sport

C) T-score -1.2; she has osteopenia and should start treatment with anabolic agent

D) T-score – 1.7; she has osteoporosis and should start bisphosphonate

Romosozumab-aqqg (Evenity)

Romosozumab-aqqg (Evenity) received FDA approval in April 2019. It is a monoclonal antibody that blocks the effects of the protein sclerostin and works mainly by stimulating osteoblastic activity and formation of new bone on trabecular and cortical bone surfaces. By inhibiting sclerostin, romosozumab increases bone mass and bone density and improves the structure of bone and bone strength [1]. It is an injectable medicine and one dose is two injections that are given sequentially each month. It is limited to use for 12 months due to clinical trials with bone markers and another agent should be started afterwards.
The “FRActure study in postmenopausal woMen with OstEoporosis” (FRAME) was a phase 3, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the safety and effectiveness of romosozumab in postmenopausal women with osteoporosis. One year of treatment with Evenity lowered the risk of a vertebral fracture by 73% compared to placebo (an incidence of 0.5% in romosozumab-treated patients versus 1.8% in placebo-treated patient). This benefit was maintained over the second year of the trial when Evenity was followed by one year of denosumab (Prolia) compared to placebo followed by denosumab [2].
Another phase 3, multicenter, international, randomized, double-blind “Active-ContRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk” (ARCH) was designed to evaluate the superiority of romosozumab over alendronate. The trial enrolled 4,093 ambulatory postmenopausal women and treatment with romosozumab followed by alendronate resulted in a 48% lower risk for vertebral fractures compared with alendronate only. Bone mineral density (BMD) was greater from baseline in the romosozumab treatment group at all sites throughout the study compared to alendronate alone [3].
Overall, Evenity increased the risk of cardiovascular death, heart attack and stroke in the alendronate trial, but not in the placebo trial. Therefore, Evenity contains a boxed warning on its labeling stating that it may increase the risk of heart attack, stroke and cardiovascular death and should not be used in patients who have had a heart attack or stroke within the previous year. It is also contraindicated in patients with hypocalcemia. Cost is another limiting factor and the average wholesale price is 2190 USD per dose, making a twelve month regime cost 26280 USD for one year.

Abaloparatide (Tymlos)

Abaloparatide (Tymlos) is a daily injectable parathyroid hormone–related peptide analog that is in the same class as teriparatide (Forteo). Both Forteo and Tymlos are synthetic analogues of naturally occurring parathyroid hormone (PTH). Abaloparatide is labeled for the treatment of postmenopausal osteoporosis in women at high risk of fracture because of a history of osteoporotic fracture, failure of treatment with other osteoporotic medications, smoking, excessive alcohol consumption, chronic steroid use, or a family history of fractures. It is a daily injectable with a 1.56-mL multi dose prefilled injector pen. Due to clinical studies with bone turnover markers, its use is limited to 24 months or 2 years.
The ACTIVE study showed treatment with abaloparatide increases bone mineral density (BMD) over 24 months compared with placebo at the femoral neck (4.5%), the total hip (5.5%), and the lumbar spine (12.8%), regardless of baseline BMD [4]. It also showed a reduction in new vertebral and nonvertebral fractures and a delay in the time to first incidence of nonvertebral fractures [4]. After 18 months of treatment with abaloparatide, the rate of clinical fractures of any type or at any site was 3.3% compared with 5.9% with placebo in the ACTIVE study. A follow-up study with many of the same participants occurred in which alendronate was started after 24 months which continued to show a reduction in vertebral and nonvertebral fractures when compared to placebo [5].
Tymlos + Alendronate

Image 1: A chart showing Tymlos for 18 months followed by alendronate showing continued decrease in the incidence of nonvertebral fractures up to 25 months.  Adopted from [5]

A more recent study showed a significant reduction in vertebral fractures (0.5% vs. 5.6%), major osteoporotic fractures (1.3% vs. 6.0%) and clinical fractures (3.5 % vs. 8.2%) when compared to placebo. It also showed a higher reduction in major osteoporotic fractures when compared to teriparatide( 78% reduction vs. 23%) [6].
Cost is again a barrier for abaloparatide, with a one-month supply costing approximately 1,768 USD. In comparison, a 30-day supply of teriparatide costs about $3,359. Overall, abaloparatide seems to be well tolerated in clinical studies with few adverse effects that led to discontinuation. Orthostatic hypotension can occur up to four hours following injection in as many as 31% of patients, although the clinical significance of this occurrence is not known. The most common adverse effects of abaloparatide vs. placebo include palpitations (5% vs. 0.4%), nausea (8% vs. 3%), headache (8% vs. 6%), and dizziness (10% vs. 6%).
Fragility Fx Alglorithm

Image 2. Fragility fracture treatment algorithm

Summary

In summary, there are two emerging treatments for fragility fractures within the past few years. Many high risk fractures are in need of anabolic or bone forming treatments. As with other similar treatments, there is a limited time course and cost is a barrier. An updated treatment algorithm will be provided to assist in when exactly to use these agents.

Case Conclusion

Correct answer: A. In a 20 year old female, secondary causes would need to be ruled out before starting any type of pharmacologic treatments. Any Z-score more than 2 standard deviations below expected would be considered below the expected range or age. A T-score of -1.0 to -2.4 would be considered osteopenia but further workup should be performed before treatment is started. A Z-score of -2.2 would not be considered normal, regardless of sport participation.
Antonio, Jose, et al. “Comparison of Dual-Energy X-Ray Absorptiometry (DXA) versus a Multi-frequency Bioelectrical Impedance (InBody 770) device for body composition assessment after a 4-week hypoenergetic diet.” Journal of functional morphology and kinesiology 4.2 (2019): 23.

References

  1. Li X, Niu QT, Warmington KS, et al. Progressive increases in bone mass and bone strength in an ovariectomized rat model of osteoporosis after 26 weeks of treatment with a sclerostin antibody. Endocrinology 2014;155(12):4785–4797.
  2. Cosman F, Crittenden DB, Adachi JD, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016;375(1):1532–1543.
  3. Saag KG, Petersen J, Brandi ML, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017;377(15):1417–1427
  4. Miller PD, Hattersley G, Riis BJ, Williams GC, Lau E, Russo LA, Alexandersen P, Zerbini CA, Hu MY, Harris AG, Fitzpatrick LA, Cosman F, Christiansen C; ACTIVE Study Investigators. Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial. JAMA. 2016 Aug 16;316(7):722-33
  5. Cosman F, Miller PD, Williams GC, et al. Eighteen months of treatment with subcutaneous abaloparatide followed by 6 months of treatment with alendronate in postmenopausal women with osteoporosis: results of the ACTIVExtend trial. Mayo Clin Proc. 2017;92(2):200–210.
  6. McCloskey EV, Fitzpatrick LA, Hu MY, Williams G, Kanis JA. Effect of abaloparatide on vertebral, nonvertebral, major osteoporotic, and clinical fractures in a subset of postmenopausal women at increased risk of fracture by FRAX probability. Arch Osteoporos. 2019 Feb 5;14(1):15. doi: 10.1007/s11657-019-0564-7