Romosozumab-aqqg (Evenity) [Medicare]

Number: 0954m

Commercial CPB  |  Medicare CPB

 

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Medicare Part B Step Therapy Criteria

For Medicare Advantage Plans That Do Not Offer Prescription Drug Coverage (MA)

Evenity, for the indication listed below:

• Treatment of osteoporosis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Prolia (denosumab) or IV zoledronic acid
  2. Intolerable adverse event with Prolia (denosumab) or IV zoledronic acid
  3. Prolia (denosumab) or IV zoledronic acid is contraindicated for the member.

For Medicare Advantage Plans That Offer Prescription Drug Coverage (MAPD)

Evenity, for the indication listed below:

• Osteoporosis

  Is not covered for new starts, unless the member meets ANY of the following:

  1. Inadequate response to a trial of Forteo 
  2. Intolerable adverse event to Forteo
  3. Forteo is contraindicated for the member
  4. Two-year treatment with parathyroid hormone has been reached for the member.

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Policy

Note: Requires Precertification:

Medicare Part B plans: Precertification of romosozumab-aqqg (Evenity) is required of participating providers and members in applicable Medicare Part B plan designs. For precertification of romosozumab-aqqg (Evenity), call (866) 503-0857 or fax (844) 268-7263.

1. Criteria for Initial Approval

   Aetna considers romosozumab-aqqg (Evenity) medically necessary for postmenopausal osteoporosis treatment when any of the following criteria are met:

   1. Member has a history of fragility fractures; or
   2. Member has a pre-treatment T-score less than or equal to -2.5 or member has osteopenia (i.e., pre-treatment T-score greater than -2.5 and less than -1) with a high pre-treatment FRAX fracture probability (see Appendix B) and meets any of the following criteria:
      
      
      1. Member has indicators of very high fracture risk (e.g., advanced age, frailty, glucocorticoid use, very low T-scores [less than or equal to -3], or increased fall risk); or
      2. Member has failed prior treatment with or is intolerant to previous injectable osteoporosis therapy (e.g., zoledronic acid [Reclast], teriparatide [Forteo, Bonsity], denosumab [Prolia], abaloparatide [Tymlos])); or
      3. Member has had an oral bisphosphonate trial of at least 1-year duration or there is a clinical reason to avoid treatment with an oral bisphosphonate (see Appendix A).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational or Not Medically Necessary and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of romosozumab-aqqg (Evenity) therapy medically necessary for all members (including new members) who meet all initial selection criteria and have received less than 12 monthly doses of Evenity.

Dosage and Administration

Evenity (romosozumab-aqqg) is available as 105 mg/1.17 mL solution in a single-use prefilled syringe. A full dose of Evenity requires two single-use prefilled syringes. Evenity should be administered by a healthcare provider. 

The recommended dose of Evenity is 210 mg administered monthly via subcutaneous injection (injecting two 105 mg/1.17 mL prefilled syringes, one after the other) in the abdomen, thigh or upper arm. Treatment duration for Evenity is 12 monthly doses, as the anabolic effect of Evenity wanes after 12 monthly doses of therapy. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered.

Adequately supplement calcium and vitamin D during treatment.

Source: Amgen, 2020

Experimental and Investigational or Not Medically Necessary

Aetna considers monthly injection of romosozumab-aqqg (Evenity) contraindicated and not medically necessary for members who have had a myocardial infarction or stroke within the preceding year. 

Aetna considers romosozumab experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established: 

• Glucocorticoid-induced osteoporosis
• Osteoporosis related to maintenance hemodialysis
• Osteoporosis related to osteogenesis imperfecta
• Treatment of renal osteodystrophy
• Treatment of tibial diaphyseal fracture or hip fracture not related to postmenopause osteoporosis.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J3111	Injection, romosozumab-aqqg, 1 mg
Other HCPCS codes related to the CPB:
Abaloparatide [Tymlos] - No Specific code:
J0897	Injection, denosumab, 1 mg
J3110	Injection, teriparatide, 10 mcg
J3489	Injection, zoledronic acid, 1 mg
ICD-10 codes covered if selection criteria are met:
M80.00xA - M80.08xS	Age-related osteoporosis with current pathological fracture
M81.0	Age-related osteoporosis without current pathological fracture
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
M81.8	Other osteoporosis without current pathological fracture [not covered for Glucocorticoid-induced osteoporosis] [related to hemodialysis and osteogenesis imperfecta]
N25.0	Renal osteodystrophy
Q78.0	Osteogenesis imperfecta
S72.001A - S72.92XS	Fracture of femur
S82.101A - S82.199S	Fracture of upper end of tibia
S82.201A - S82.299S	Fracture of lower end of tibia
S82.301A - S82.399S	Fracture of lower end of tibia
S82.401A - S82.499S	Fracture of shaft of fibula
Z99.2	Dependence on renal dialysis

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Evenity is indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.
• Limitations of Use: Limit duration of use to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered.

Romosozumab-aqqg is available as Evenity (Amgen Inc.). Romosozumab-aqqg inhibits the action of sclerostin, a regulatory factor in bone metabolism, and increases bone formation and, to a lesser extent, decreases bone resorption. Animal studies showed that romosozumab-aqqg stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength (Amgen, 2020).

Evenity carries a black box warning for potential risk of myocardial infarction, stroke and cardiovascular death. In a randomized controlled trial in postmenopausal women, there was a higher rate of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, in patients treated with Evenity compared to those treated with alendronate. Per the label, Evenity should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits outweigh the risks in patients with other cardiovascular risk factors. If a patient experiences a myocardial infarction or stroke during therapy, Evenity should be discontinued (Amgen, 2020).

Labeled warnings and precautions also include hypersensitivity reactions (including angioedema, erythema multiforme, dermatitis, rash, and urticaria), hypocalcemia (severe renal impairment or receiving dialysis increases risk), osteonecrosis of the jaw, and atypical femoral fracture. Evenity is contraindicated in patients with hypocalcemia. The most common adverse reactions (5% or more) reported with Evenity in clinical trials were arthralgia and headache.

Postmenopausal Osteoporosis

Approximately 10 million Americans (80 % of them women) suffer from osteoporosis, which may lead to an increased risk of spine, wrist, and hip fractures. For postmenopausal women, age, personal or family history of fracture, Asian or Hispanic heritage, smoking, and cortisone use have been associated with significantly increased likelihood of osteoporosis; while higher body mass index (BMI), African American heritage, estrogen or diuretic use, and exercise have been associated with significantly decreased likelihood of osteoporosis (Siris et al, 2001). Furthermore, Wu and colleagues (2002) reported that any fracture (unrelated to motor vehicle accidents) sustained between the ages of 20 and 50 years is associated with increased risk of fractures after the age of 50 years in women. Although osteoporosis is usually considered a disease of women, up to 20 % of vertebral fractures and 30 % of hip fractures occur in men. Risk factors for osteoporotic fractures in men include low BMI, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, and diseases that predispose to low bone mass (Eastell et al, 1998). However, the exact mechanism of bone loss remains unknown in primary male osteoporosis (Legrand et al, 2001). 

Bone mineral density (BMD) is useful in the diagnosis of osteoporosis. It is usually provided as the T score -- the number of standard deviations (SDs) the BMD falls below or above the mean value in a reference population (young, healthy adults). The World Health Organization (WHO) osteoporosis diagnostic classification assessment (1994) defines osteoporosis as a T score of 2.5 or more SDs below the mean (i.e., less than -2.5). Osteopenia is defined as a T score of -1.0 to -2.5 and a T score of -1.0 or higher is considered normal. It should be noted that a male database should be used for diagnosing osteoporosis in men.

In 2008, a World Health Organization (WHO) task force introduced the Fracture Risk Assessment Tool (FRAX), which provides a fracture risk assessment by estimating the 10-year probability of hip fracture or major osteoporotic fractures combined (hip, sine, shoulder, or wrist) for an untreated patient using femoral neck BMD and easily obtainable clinical risk factors for fracture.

Past guidelines have recommended non-pharmacologic interventions to reduce bone loss in postmenopausal women include lifestyle measures such as adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol prior to pharmacologic interventions. In general, 1200 mg of elemental calcium daily, total diet plus supplement, and 800 international units of vitamin D daily are advised (Rosen 2019). In addition to lifestyle measures, patients at high risk for fracture should receive pharmacologic therapy. Oral bisphosphonates are considered as first-line pharmacologic therapy in postmenopausal women with a history of fragility fracture or with osteoporosis based upon bone mineral density (BMD) measurement (T-score ≤-2.5). Alendronate (Fosamax) and risedronate (Actonel) have been the most extensively studied bisphosphonates under clinical trials conditions. Both drugs can lower the risk of vertebral and hip fractures by 25 to 50 %. However, there may be clinical reasons to avoid oral bisphosphonate therapy, which may include esophageal disorders, an inability to follow the dosing requirements (e.g., stay upright for at least 30 to 60 minutes), or chronic kidney disease (CKD) (estimated glomerular filtration [eGFR] rate <30 mL/min). Oral bisphosphonates should also be avoided after certain types of bariatric surgery in which surgical anastomoses are present in the GI tract (e.g., Roux-en-Y gastric bypass). Alternatives for initial therapy in patients with contraindications or intolerance to oral bisphosphonates include intravenous (IV) bisphosphonates (unless the contraindication is CKD), denosumab (Prolia), teriparatide (Forteo)/abaloparatide (Tymlos) (except in CKD), and raloxifene (Evista), a selective estrogen receptor modulator (SERM).

The 2010 guidelines from the American Association of Clinical Endocrinologists (Watts 2010) recommended teriparatide for patients with very high fracture risk or patients in whom bisphosphonate therapy has failed. They state that teriparatide is contraindicated in patients at increased risk of osteosarcoma (those with Paget disease of bone, open epiphyses, a history of irradiation involving the skeleton, or an unexplained elevation of alkaline phosphatase level of skeletal origin). Teriparatide should also not be administered to patients with primary or any form of secondary untreated or unresolved hyperparathyroidism. 

In the 2016 update of the American Association of Clinical Endocrinologists and American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis (Camacho 2016), the document states approved agents with efficacy to reduce hip, nonvertebral, and spine fractures including alendronate, risedronate, zoledronic acid, and denosumab are appropriate as initial therapy for most patients at high risk of fracture. Teriparatide, denosumab, or zoledronic acid should be considered for patients unable to use oral therapy and as initial therapy for patients at especially high fracture risk. Also, raloxifene or ibandronate may be appropriate initial therapy in some cases where patients requiring drugs with spine-specific efficacy.

In 2019, the Endocrine Society released guidelines on the pharmacologic treatment of osteoporosis in postmenopausal women, which were cosponsored by the European Society of Endocrinology. The document provides recommendations for the treatment and management of osteoporosis in postmenopausal women and emphasizes assessment after being on treatments to see if further treatment is necessary. The guidelines continue to recommend starting with lifestyle and nutritional optimization for bone health, especially calcium and vitamin D, for all postmenopausal women, along with an assessment of 10-year fracture risk according to country-specific guidelines. As before, bisphosphonates and denosumab are still advised as first-line therapies. For women who have been on bisphosphonates for 3 to 5 years, fracture risk should be assessed and women with a low-to-moderate risk of fracture should be prescribed a "bisphosphonate holiday". However, in patients with very severe osteoporosis, multiple fractures, and/or very low bone density, the Endocrine Society recommends anabolic treatments (e.g., teriparatide (Forteo) or abaloparatide (Tymlos) as first-line therapy.

On April 09, 2019, the U.S. Food and Drug Administration (FDA) approved Evenity (romosozumab-aqqg) subcutaneous injection, a sclerostin inhibitor for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. Evenity is a monoclonal antibody that increases bone formation and, to a lesser extent, decreases bone resorption. Sclerostin is produced by osteocytes and inhibits bone formation. In animal models and a phase I trial in healthy adults, inhibiting sclerostin through the administration of a sclerostin monoclonal antibody increased bone mass (Padhi 2011; Ominsky 2010; Li 2009). One dose of Evenity consists of two injections, one immediately following the other, given once a month by a health care professional. The bone forming effect of Evenity wanes after 12 doses so more than 12 doses should not be used. If osteoporosis therapy is needed after the 12 doses, patients should begin an osteoporosis treatment that reduces bone breakdown.

The safety and efficacy of Evenity were demonstrated in two clinical trials involving a total of more than 11,000 women with postmenopausal osteoporosis. In the first trial, one year of treatment with Evenity lowered the risk of a new fracture in the spine (vertebral fracture) by 73% compared to placebo. This benefit was maintained over the second year of the trial when Evenity was followed by one year of denosumab (another osteoporosis therapy) compared to placebo followed by denosumab. In the second trial, one year of treatment with Evenity followed by one year of alendronate (another osteoporosis therapy) reduced the risk of a new vertebral fracture by 50% compared to two years of alendronate alone. Evenity followed by alendronate also reduced the risk of fractures in other bones (non-vertebral fractures) compared to alendronate alone.

In the first trial (FRActure study in postmenopausal woMen with ostEoporosis (FRAME) Clinical Trial; NCT01575834), Cosman et al 2016 state romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. The author enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of 210 mg romosozumab or placebo monthly for 12 months; thereafter, patients in each group received denosumab 60 mg for 12 months, administered subcutaneously every 6 months. The co-primary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of non-vertebral and symptomatic vertebral) and non-vertebral fractures. At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). The reduction in non-vertebral fractures was not significantly different between romosozumab (56 of 3589 patients or 1.6% of patients) and the placebo group (75 of 3591 or 2.1% of patients), P=0.10. At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. The authors concluded that in postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year.

In the FRAME trial, one year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Two years after the publication of the FRAME study, Cosman et al (2018) further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T-score changes from baseline over the 2-year study and contrast these results with the long-term BMD gains seen with denosumab during Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (n = 3591 placebo, n = 3589 romosozumab), most romosozumab-treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T-score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo-to-denosumab: 0.38 and 0.17), with the 2-year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p < 0.001), with fewer fractures consistently observed across other fracture categories. The data support the clinical benefit of rebuilding the skeletal foundation with romosozumab before transitioning to anti-resorptive therapy.

Subsequent to the initial FRAME trial, Cosman et al (2018) conducted a post-hoc analysis for the role of regional background fracture risk on non-vertebral outcome. In the initial FRAME study, 1 year of the bone-forming agent romosozumab significantly reduced new vertebral and clinical fracture risk versus placebo. Non-vertebral fracture risk was not significantly reduced in the overall population, influenced by a low placebo-group fracture rate, observed particularly in the highest-enrolling region of Latin America. In year 1 of FRAME, postmenopausal women with a T-score of -2.5 to -3.5 at the total hip or femoral neck were randomized to subcutaneous romosozumab 210 mg or placebo once monthly for 12 months. Of 7180 randomized women, 43% were from Latin America, largely Colombia and Brazil. Pre-specified analyses assessed fracture risk reductions by geographic regions. A significant treatment-by-geographic region interaction for the clinical (p = 0.029) and non-vertebral fracture (p = 0.042) endpoints led to further characterization of the Latin American population and comparison with the remaining study population, grouped post hoc as rest-of-world. Non-vertebral fracture efficacy in the overall population was also assessed by baseline fracture risk using the Fracture Risk Assessment Tool (FRAX). Romosozumab significantly and consistently reduced new vertebral fracture risk in Latin America (70% reduction; p = 0.014) and rest-of-world (74% reduction; p < 0.001). For non-vertebral fracture, risk reductions were observed in rest-of-world (42% reduction; p = 0.012), with no treatment effect observed in Latin America, where background non-vertebral fracture risk was low (1.2% in the placebo group). Consistent with this finding, in the overall population, greater reductions in non-vertebral fracture risk were observed among women with higher FRAX scores. These findings suggest that fracture risk assessment should consider regional factors in addition to classical risk factors, such as bone mineral density. In women at high risk for fracture, romosozumab reduced non-vertebral fracture risk within 1 year.

In the second trial submitted for FDA approval (Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH); NCT01631214), Saag et al (2017) enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open-label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (non-vertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of non-vertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab-to-alendronate group (6.2% [127 of 2046 patients]) than in the alendronate-to-alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab-to-alendronate group versus 266 of 2047 patients (13.0%) in the alendronate-to-alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of non-vertebral fractures was lower by 19% in the romosozumab-to-alendronate group than in the alendronate-to-alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open-label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab-to-alendronate and alendronate-to-alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. The authors concluded that in postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone.

The skeletal effects of romosozumab have also been compared with teriparatide in a randomized, open label phase 3 study by Langdahl et al (2017; NCT01796301). The authors state previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. The authors compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. This randomized, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. Women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an area BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture were enrolled. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 μg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomized patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. The authors concluded that transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture.

Glucocorticoid-Induced Osteoporosis

Taylor and Saag (2019) noted that glucocorticoid-induced osteoporosis is an under-recognized complication of chronic glucocorticoid therapy characterized by a decrease in new bone formation.  Anabolic therapies, such as teriparatide, combat the disease by promoting new bone growth.  These researchers outlined the pathophysiology of glucocorticoid-induced osteoporosis and detailed the evidence of safety, efficacy, and patterns of use of teriparatide and other future anabolic therapies.  In multiple clinical trials, teriparatide has been shown to significantly increase lumbar spine BMD in patients with glucocorticoid-induced osteoporosis when compared with placebo, alendronate, and risedronate.  When compared with alendronate, significantly fewer vertebral fractures were noted in the teriparatide group.  Adverse effects noted in clinical trials include nausea, insomnia, flushing, myalgias, and mild hypercalcemia/hyperuricemia.  Early studies in rats noted an increased incidence of osteosarcoma; however, an increased rate beyond levels observed in general populations has not been reported in human studies or with long-term pharmaco-vigilance.  Abaloparatide and romosozumab are newer anabolic therapies that have shown some benefit in post-menopausal osteoporosis; but have not yet been studied in the chronic glucocorticoid population.  The authors concluded that major specialty organizations continue to recommend bisphosphonates as 1st-line therapy in glucocorticoid-induced osteoporosis due to the proven benefit and relative affordability.  However, the use of anabolics shows promise to improve outcomes by increasing BMD and reducing fracture-associated morbidity and mortality and has a role for selected populations at high fracture risk.

Hip Fracture and Tibial Diaphyseal Fracture

In a randomized, double-blinded, dose-finding, phase-II clinical trial, Schemitsch and colleagues (2020) examined the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of inter-trochanteric or femoral neck hip fractures.  Subjects (age of 55 to 94 years) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo post-operatively on day 1 and weeks 2, 6, and 12.  The primary end-point was the difference in the mean timed "Up & Go" (TUG) score over weeks 6 to 20 for romosozumab versus placebo.  Additional end-points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH).  A total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo.  Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198).  The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups.  The RUSH scores improved over time across treatment groups; but did not differ significantly between the romosozumab and placebo groups.  The overall safety and tolerability profile of romosozumab was comparable with that of the placebo.  The authors concluded that romosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population.  Level of evidence = I.

In a randomized, double-blinded, dose-finding, phase-II clinical trial, Bhandari and colleagues (2020) examined the effect of romosozumab on the radiographic and clinical outcomes of surgical fixation of tibial diaphyseal fractures.  Subjects (18 to 82 years old) were randomized 3:1:1:1:1:1:1:1:1:1 to a placebo or 1 of 9 romosozumab treatment groups.  Participants received subcutaneous injections of romosozumab or the placebo post-operatively on day 1 and weeks 2, 6, and 12.  The primary outcome was the time to radiographic evidence of healing ("radiographic healing") analyzed after the week-24 assessments had been completed for all patients.  A total of 402 patients were randomized: 299 to the romosozumab group and 103 to the placebo group . The median time to radiographic healing (the primary outcome) ranged from 14.4 to 18.6 weeks in the romosozumab groups and was 16.4 weeks (95 % CI: 14.6 to 18.0 weeks) in the placebo group, which was not a significant difference.  There was also no significant difference in the median time to clinical healing, no relationship between romosozumab dose/frequency and unplanned revision surgery, and no apparent treatment benefit in terms of physical function.  The safety and tolerability profile of romosozumab was comparable with that of the placebo.  The authors concluded that romosozumab did not accelerate tibial fracture-healing in this patient population.  Moreover, these researchers stated that additional studies of patients at higher risk for delayed healing are needed to examine the potential of romosozumab to accelerate tibial fracture-healing.  Level of evidence = I.

Osteoporosis in Individuals with Chronic Kidney Disease Stages 3 to 5D

Hara et al (2021) stated that chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among individuals with CKD than among individuals who do not have CKD.  Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear if they are also safe and effective for patients with CKD, who have altered systemic mineral and bone metabolism.  In a Cochrane review, these investigators examined the safety and effectiveness of pharmacotherapies for the treatment of osteoporosis in patients with CKD stages 3 to 5, and those undergoing dialysis (5D).  They searched the Cochrane Kidney and Transplant Register of Studies up to January 25, 2021 via contact with the Information Specialist using search terms relevant to this review.  Studies in the Register were identified through searches of Central, Medline, and Embase, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.  Randomized controlled trials (RCTs) comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included.  A total of 2 review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data.  The main outcomes were the incidence of fracture at any sites; mean change in the BMD (measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events (AEs); and quality of life (QOL).  Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95 % confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes.  Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.  A total of 7 studies involving 9,164 randomized participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were post-menopausal women; 5 studies included patients with CKD stages 3 to 4, and 2 studies included patients with CKD stages 5 or 5D.  A total of 5 pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide).  All studies were judged to be at an overall high risk of bias.  Among patients with CKD stages 3 to 4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95 % CI: 0.39 to 0.69; low certainty evidence).  Anti-osteoporotic drugs probably make little or no difference to the risk of clinical fracture (RR 0.91, 95 % CI: 0.79 to 1.05; moderate certainty evidence) and AEs (RR 0.99, 95 % CI: 0.98 to 1.00; moderate certainty evidence).  These investigators were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group.  Among patients with severe CKD stages 5 or 5D, it was unclear if anti-osteoporotic drug reduced the risk of clinical fracture (RR 0.33, 95 % CI: 0.01 to 7.87; very low certainty evidence).  It was uncertain whether anti-osteoporotic drug improved the BMD at the femoral neck because the certainty of this evidence was very low (MD 0.01, 95 % CI: 0.00 to 0.02).  Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95 % CI: 0.03 to 0.04, low certainty evidence).  No AEs were reported in the included studies.  It was unclear if anti-osteoporotic drug reduced the risk of death (RR 1.00, 95 % CI: 0.22 to 4.56; very low certainty evidence).  The authors concluded that among patients with CKD stages 3 to 4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence.  Anti-osteoporotic drugs made little or no difference to the risk of clinical fracture and AEs in moderate certainty evidence.  Among patients with CKD stages 5 and 5D, it was unclear if anti-osteoporotic drug reduced the risk of clinical fracture and death because the certainty of this evidence was very low.  Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence.  It was uncertain whether anti-osteoporotic drug improved the BMD at the femoral neck because the certainty of this evidence was very low.  These researchers stated that larger studies including men, pediatric patients or individuals with unstable CKD-mineral and bone disorder are needed to examine the effect of each anti-osteoporotic drug at each stage of CKD. 

These investigators noted that this review could not evaluate the safety or effectiveness of anti‐osteoporotic drugs in patients with unstable CKD‐mineral and bone disorder (MBD).  This review could not evaluate the safety or effectiveness of anti‐osteoporotic drugs in men or pediatric patients.  These researchers could not sufficiently examine the safety or effectiveness of anti‐osteoporotic drugs in patients with each CKD stage.  They could not sufficiently examine the effect of each anti‐osteoporotic drug.  These investigators stated that future studies should compare the subtypes of anti‐osteoporotic drugs to provide clinicians with information on the comparative effectiveness of available therapies. 

Miller et al (2022) noted that patients with osteoporosis and CKD are at increased risk of fracture and associated negative outcomes, including increased mortality.  The present post-hoc analysis of 2 randomized, multi-center, phase-III clinical trials -- Fracture Study in Postmenopausal Women with Osteoporosis (FRAME) and Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk (ARCH) -- examined the safety and effectiveness of romosozumab in post-menopausal women with osteoporosis and mild-to-moderate CKD.  The analysis included data from 7,147 patients from FRAME and 4,077 from ARCH; 81 % of patients from FRAME and 85 % from ARCH had mild or moderate reduction in estimated glomerular filtration rate (eGFR) at baseline, and part of this reduction was likely age-related.  During the 1-year, double-blind phases of the trials, patients received romosozumab 210 mg subcutaneously (SC) or placebo monthly in FRAME and romosozumab 210 mg SC monthly or alendronate 70 mg po (oral) weekly in ARCH.  BMD at the lumbar spine, total hip, and femoral neck and vertebral and non-vertebral fractures were assessed at baseline and month 12.  In both trials, the least-square mean (LSM) percent change from baseline BMD was significantly greater in the romosozumab groups versus controls across all kidney function categories at month 12.  Romosozumab reduced the relative risk of new vertebral fractures at month 12 among patients with eGFR of 30 to 59, 60 to 89, and 90 or higher ml/min by 72 % (95 % CI: 14 to 91; p = 0.017), 70 % (40 to 85; p < 0.001), and 84 % (30 to 96; p = 0.005), respectively, in FRAME versus placebo, and by 51 % (5 to 75; p = 0.04), 19 % (-28 to 49; p = 0.39), and 57 % (1 to 81, p = 0.04), respectively, in ARCH versus alendronate.  Incidences of AEs, asymptomatic decreases in serum calcium, and evolution of kidney function during the studies were similar across all baseline kidney function groups.  The authors concluded that romosozumab is an effective therapeutic option for post-menopausal women with osteoporosis and mild-to-moderate reduction in kidney function, with a similar safety profile across different levels of kidney function.  Moreover, these researchers stated that additional studies are needed to examine the effectiveness of romosozumab in patients with severe reduction of kidney function. 

These investigators carried out a preliminary sub-analysis of ARCH and FRAME patients in the CKD stage 3a and 3b subgroups.  The median eGFR values at baseline for ARCH CKD stage 3a and 3b patients, respectively, were 40.3 and 53.8 ml/min/1.73 m2 for the alendronate treatment group and 40.0 and 53.9 ml/min/1.73 m2 for the romosozumab treatment group.  The median eGFR values at baseline for FRAME CKD stage 3a and 3b patients, respectively, were 40.6 and 53.8 ml/min/1.73 m2 for the placebo treatment group and 41.1 and 53.5 ml/min/1.73 m2 for the romosozumab treatment group.  The 95 % CIs for LSM difference in BMD between treatment groups overlapped for the FRAME and ARCH stage 3a and 3b subgroups at the lumbar spine, total hip, and femoral neck.  Safety profiles were overall similar between treatment groups for both the stage 3a and 3b subgroups in both studies.  In ARCH, the treatment-emergent serious AE and fatal AE percentages were numerically greater for the stage 3b subgroup compared with stage 3a for both the alendronate and romosozumab treatment groups.  Similarly, in FRAME, the treatment-emergent serious AE and fatal AE percentages were numerically greater for patients with stage 3b versus stage 3a for both the placebo and romosozumab treatment groups.  These researchers stated that in clinical practice, it has been suggested eGFR be complemented with other objective findings (e.g., urinary albumin) to improve kidney function assessment and better predict the risk for progression to end-stage renal disease (ESRD).  There were too few patients enrolled in FRAME and ARCH with a severe reduction in kidney function to allow assessment in this subgroup.  Finally, the limitations of subgroup and post-hoc analyses have been well described and should be taken into consideration.

Osteoporosis Related To Maintenance Hemodialysis

Sato and colleagues (2021) stated that romosozumab reportedly increases BMD potently but might adversely affect cardiovascular disease (CVD).  In an observational, single-center study, these researchers examined the effectiveness of romosozumab in osteoporotic hemodialysis (HD) patients with a high-risk of fracture.  Among 96 HD romosozumab-treated HD patients with high-risk of fracture, 76 HD patients completed 1 year of subcutaneous administration of romosozumab (210 mg/4 weeks) for 1 year.  Romosozumab-untreated HD patients (n = 55) were also included.  Changes in BMD and serum markers, together with fracture occurrence, and CVD events, were monitored.  During romosozumab treatment of 76 HD patients, BMD time-dependently increased significantly by 15.3 % ± 12.9 % at the lumbar spine (L1 to L4), and 7.2 % ± 8.3 % at the femoral neck at 1 year.  Serum BAP and total P1NP increased significantly and serum TRACP-5b decreased at 4 weeks; fragility fractures occurred in 3 (3.8 %) patients.  Hypocalcemia occurred at 4 to 48 weeks despite the increased dosing of active vitamin-D derivatives, but without any symptom.  New CVD events occurred in 5.2 % of romosozumab-treated HD patients and 10.9 % in romosozumab-untreated HD patients.  The authors concluded that BMD was increased significantly during romosozumab treatment at the lumbar spine, and the femoral neck, respectively, at 1 year in HD patients.  Hypocalcemia occurred but without any intolerable event.  There was no apparent increase in CVD events during 1 year of study, suggesting romosozumab as a promising agent for HD patients with severe osteoporosis.

Osteoporosis Related To Osteogenesis Imperfecta

Uehara and colleagues (2022) noted that the efficacy of romosozumab for severe osteoporosis is uncertain in patients with osteogenesis imperfecta (OI).  These investigators examined the effect of romosozumab on bone fragility in a severe osteoporotic case of OI.  A 64-year-old man with OI was referred to the authors’ department for determining the cause of his repeated fractures.  He was medicated with alendronate for only 1 year, 8 years ago, but it did not prevent repeated fractures, and thus he had not received any treatments for osteoporosis since then.  However, recently, the frequency of fractures had increased.  At presentation, his lumbar and bilateral total hip BMD values were severely decreased at 0.546 and 0.209 g/cm2, respectively.  Because of his severe osteoporosis, these investigators started romosozumab treatment with eldecalcitol; romosozumab (210 mg) was injected subcutaneously every month.  At 12 months following drug initiation, his lumbar and total hip BMD increased by 22.0 % and 136.4 % versus pre-treatment levels, respectively.  Bone formation markers increased, and bone resorption markers decreased at 12 months of the therapy.  Neither hypocalcemia nor any other severe adverse effects were observed in this severe osteoporotic case.  The authors concluded that the findings of this study revealed good responses of BMD and bone turnover markers to romosozumab treatment, which can be considered as an effective therapeutic option for osteoporotic OI patients.  Moreover, these researchers stated that the mechanism of fracture prevention by romosozumab needs to be further examined. 

The authors stated that the drawbacks of this study included the lack of a control group, small sample size (n = 1), and the retrospective design.  Since OI is a very rare disease, it is difficult to carry out an analysis using large samples.  Furthermore, multiple fractures before romosozumab treatment may have affected the data of BMD and bone metabolism markers in this case.  These investigators could not rule out the possibility that his low BMI was also causing osteoporosis.

Patients with Osteoporosis Undergoing Spinal Surgery

Bryant et al (2021) noted that osteoporosis represents the most common metabolic disease of the bone, with an estimated 10 % of adults aged 50 years or older affected in the U.S.  This patient population is at increased risk for spine fracture and instrumentation-related complications following spinal surgery.  Surgeon knowledge of the available treatments for patients with low BMD and how they impact biology of fusion may aid in mitigating negative effects in the post-operative period.  Recombinant parathyroid hormone (teriparatide) is the most extensively studied bone-protecting agent in humans.  Furthermore, the success of the monoclonal antibody denosumab has led to further clinical investigations of human patients undergoing spinal surgery.  Another monoclonal antibody, romosozumab, was recently approved by the FDA for human use in patients with osteoporosis.  Although studies of romosozumab in patients undergoing spinal surgery have not been carried out, this is a promising potential therapeutic agent based on its early success in pre-clinical and clinical trials.  In a systematic review, these investigators examined the mechanisms of action and evidence of use of anti-resorptive and anabolic agents in patients with osteoporosis undergoing spinal surgery.  In accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review was carried out to examine the anti-resorptive and anabolic agents used in the peri-operative period in patients with osteoporosis undergoing spinal surgery.  The search was carried out by using the PubMed, Embase, and Cochrane Library databases.  Titles and abstracts were screened and subsequently selected for full review.  The initial search retrieved 330 articles.  Of these articles, 23 final articles were included and reviewed.  Many of these articles reported that use of adjuvant agents in the peri-operative period improved radiographic evidence of bony fusion and bone fusion rates.  These agents tended to improve BMD post-operatively.  The authors concluded that although anti-osteoporosis agents are effective to varying degrees as treatments of patients with low BMD, teriparatide and bisphosphonates have been the most extensively studied with respect to spinal instrumentation.  The advent of newer agents represents an area for further investigations, especially due to the current paucity of controlled studies.  It is imperative for spine surgeons to understand the mechanisms of action of these drugs and their effects on biology of fusion.

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Appendix

Appendix A: Clinical Reasons to Avoid Oral Bisphosphonate Therapy

• Presence of anatomic or functional esophageal abnormalities that might delay transit of the tablet (e.g. achalasia, stricture, or dysmotility)
• Active upper gastrointestinal problem (e.g., dysphagia, gastritis, duodenitis, erosive esophagitis, ulcers)
• Presence of documented or potential gastrointestinal malabsorption (e.g. gastric bypass procedures, celiac disease, Crohn’s disease, infiltrative disorders, etc.)
• Inability to stand or sit upright for at least 30 to 60 minutes
• Inability to take oral bisphosphonate at least 30 to 60 minutes before first food, drink, or medication of the day
• Renal insufficiency (creatinine clearance <35 mL/min)
• History of intolerance to an oral bisphosphonate.

Appendix B: WHO Fracture Risk Assessment Tool

• High FRAX fracture probability: 10 year major osteoporotic fracture risk ≥ 20% or hip fracture risk ≥ 3%.
• 10-year probability; calculation tool available at: FRAX Fracture Risk Assessment Tool
• The estimated risk score generated with FRAX should be multiplied by 1.15 for major osteoporotic fracture (including fractures of the spine (clinical), hip, wrist, or humerus) and 1.2 for hip fracture if glucocorticoid treatment is greater than 7.5 mg (prednisone equivalent) per day.

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References