REVIEW ARTICLE

Update on the Comprehensive Approach to Fragility

Fractures
Matthew R. Cohn, MD,* Arianna L. Gianakos, DO,†‡ Kirsten Grueter, RN,‡ Natalie Rosen, BA,§
Guang-Ting Cong, MD,∥ and Joseph M. Lane, MD‡

pelvis, distal radius, and proximal humerus. As a result, over

Summary: The prevention and treatment of fragility fractures 40% of osteoporotic men and 65% of osteoporotic women will
continuously evolve. Adequate fracture care should involve treating experience a fracture in their lifetime.2 This has major impli-
the fracture itself and the underlying bone disease. Although cations for the US health care system. The cumulative health
effective treatments of osteoporosis are available, a large proportion care spending on fragility fractures is projected to be $228
of patients with fragility fractures are not prescribed antiosteoporotic billion for 2016 through 2025 in the United States.3
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medications after their injury. Recent advances in diagnostic tools, Although efforts have been made in recent years to
medications, and implementation of Fracture Liaison Services allow promote primary prevention of fragility fractures through
for more effective and comprehensive treatment or fragility fractures. osteoporosis treatment, a large proportion of patients with
In the Fracture Liaison Service model, a physician and physician osteoporosis are not treated. Over 50% of patients who
extenders coordinate care. This includes a thorough medical and present with fragility fractures have previously unrecognized
surgical history, metabolic bone disease laboratory testing, dual- osteoporosis and only 15% are prescribed antiosteoporotic
energy x-ray absorptiometry screening, treatment, and long-term medications at 1 year after discharge.4,5 A fragility fracture
follow-up. Treatment options include nonpharmacologic treatment presents an opportunity for orthopedists to initiate care to
with calcium and vitamin D and antiresorptive and anabolic agents. prevent subsequent fractures. There have been important
Antiresorptive agents such as bisphosphonates and denosumab are advances in secondary fracture prevention strategies in the
first-line treatments for osteoporosis and anabolic agents such as past 5 years. More streamlined clinical care pathways, newer
teriparatide are effective in reducing bone density loss and have imaging modalities, and novel therapies have altered the
implications in fracture healing. In addition, new anabolic agents care of fragility fractures. In this review, we will discuss
including antisclerostin antibodies and parathyroid hormone-related recent developments with regard to implementation of
protein show promise as potential treatments to increase bone density. a Fracture Liaison Service (FLS), imaging and labs to diag-
Key Words: fragility fracture, osteoporosis, treatment, management nose osteoporosis, antiosteoporosis medications and their
implications on fracture healing, and new medications on
(J Orthop Trauma 2018;32:480–490) the horizon.

INTRODUCTION
Fragility fractures are low-energy events that result from FRACTURE LIAISON SERVICE
the gradual deterioration of bone microarchitecture and mass.
Fragility fractures, as sentinel events, provide opportu-
Although an array of diseases may affect bone quality and
nities for physicians to educate patients on the causes of their
result in fragility fractures, osteoporosis remains the most
bone fragility. A low-energy fracture that occurs from
common cause.1 An increase in bone resorption relative to
a standing height requires a full evaluation including bone
bone formation occurs in patients with osteoporosis, leading
mineral density (BMD) measurement, fracture risk assess-
to a decrease in bone density with aging. The thinning of bone
ment, and initiation of treatment for underlying bone fragility
cortices and loss of trabecular connectivity render bones sus-
if indicated. An FLS is a coordinated care model of providers
ceptible to fracture, particularly the vertebrae, femoral neck,
that guides patients through osteoporosis management after
Accepted for publication May 22, 2018. a fragility fracture to reduce the risk of subsequent fractures.
From the *Department of Orthopedic Surgery, Rush University Medical There are 3 critical roles in an FLS: physician
Center, Chicago, IL; †Department of Orthopedic Surgery, Jersey City Med- champion, FLS Coordinator, and Nurse Navigator. Varying
ical Center—RWJ Barnabas Health, Jersey City, NJ; ‡Hospital for Special levels of practitioners can fulfill these roles and may be
Surgery, New York, NY; §Sidney Kimmel Medical College, Philadelphia, defined based on an institution’s personnel. Our proposed
PA; and ∥Department of Orthopedic Surgery, Mount Sinai Hospital, New
York, NY. model includes a nurse practitioner or physician assistant as
J. M. Lane Serves as a consultant for the following—Bone Therapeutics, Inc; the FLS coordinator and a registered nurse as the Nurse Nav-
CollPlant, Inc; Graftys, Inc; Kuros, Inc; Radius; Merck, Inc. The remaining igator. An established physician champion within each insti-
authors report no conflict of interest. tution—an orthopedist, endocrinologist, geriatrician, primary
Reprints: Joseph M. Lane, MD, 475 East 72nd St, Ground Floor, New York,
NY 10021 (e-mail: [email protected]).
care physician, or women’s health provider—will assume
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. principal responsibility for starting treatment. Orthopedists
DOI: 10.1097/BOT.0000000000001244 tend to have more success in patient compliance with FLS

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J Orthop Trauma  Volume 32, Number 9, September 2018 Update on Fragility Fractures

programs than other providers in this role, as care for bone complications, readmissions, subsequent fractures, losses
health is already established from the acute fracture.6–8 to follow-up, and mortality. Research assistants maintain
The FLS Coordinator identifies at-risk patients, con- this registry.
ducts an assessment, and makes the appropriate referral to the Although the conventional orthopaedic care of these
physician champion. During the inpatient stay, the FLS patients will typically cease after about 1 year, the underlying
Coordinator performs an in-house Metabolic Bone Consult osteoporosis will require lifetime maintenance as a chronic
at the patient’s bedside. The assessment includes demo- disease. Referral back to the community may be appropriate
graphic information, medical and surgical history, previous once the patient has healed their fracture and the individual-
osteoporosis management, fracture history, recent fall history, ized goal for drug therapy has been met.
fall risk factors, social history including support networks,
and preoperative laboratory review. We recommend obtain-
ing certain metabolic bone laboratory test results before sur- LABORATORY TESTING
gery as further explained in a later section, as some may not Laboratory testing in the setting of osteoporotic frac-
accurately reflect the patient’s baseline if obtained postoper- tures is essential to rule out secondary causes of osteoporosis
atively. For example, if blood transfusion or large volumes of and to determine calcium and vitamin D sufficiency. Meta-
intravenous fluids are given concentrations of calcium and bolic bone laboratory testing should be performed in all
phosphate may be altered.9 These laboratory tests include patients with fragility fractures to identify the most common
a complete metabolic panel, intact parathyroid hormone treatable causes of osteoporosis (Table 1).
(PTH), thyroid stimulating hormone, and 25(OH) vitamin The goal for serum 25(OH)D in the general popula-
D. Results may alert the care team of common causes of tion is .32 ng/mL,10,11 with a ceiling of 250 ng/mL based
secondary osteoporosis, such as vitamin D deficiency, hyper- on reports of toxicity. It is recommend to maintain serum
parathyroidism, renal osteodystrophy, and hypothyroidism, 25(OH)D levels above 40 ng/mL to prevent elevations in
and act as a baseline measurement before initiating treatment. serum PTH. Vitamin D deficiency, defined as having serum
Alternatively, these laboratory tests may be conducted at a fol- 25(OH)D of less than 20 ng/mL by the Institute of Medicine
low-up appointment. The FLS Coordinator provides recom- or 30 ng/mL by the International Osteoporosis Foundation,
mendations for appropriate changes in calcium and vitamin D increases the risk of mortality and cardiovascular events,
supplementation based on laboratory results, and educational hip or other major osteoporotic fractures, and unfavorable
materials on fall prevention, muscle-strengthening exercises, functional outcomes after hip fractures.10,12 Brinker et al13
and cessation of tobacco and alcohol use. A referral is then have noted that those with fracture nonunion have a high
made for outpatient follow-up. Based on any abnormalities prevalence of vitamin D deficiency, but vitamin D defi-
from the initial laboratory results, labs may be repeated to ciency is common in the general population even in those
assess the success of any supplementation. Anti-osteoporotic who heal nonunion. Racial differences in fracture risk are
medications may also be initiated by the Fracture Liaison well documented; notably, African Americans have a lower
Service if necessary. Timing of initiation is dependent on fracture risk compared with other races despite a lower
the medication as discussed later in this review. In addition, vitamin D level.14 The influence of vitamin D–binding
C-terminal telopeptide (CTX) and bone-specific alkaline protein (DBP) on racial differences in serum vitamin D
phosphatase are followed longitudinally assess response to has recently become a point of contention. A landmark
antiosteoporotic medications. Patients also obtain an updated article suggested that although total 25(OH)D is lower in
BMD evaluation if the most recent examination was over 2 African Americans, DBP is also lower and results in similar
years prior. bioavailable 25(OH)D to whites.15 However, multiple DBP
The Nurse Navigator works as an assistant to the FLS haplotypes exist and may have skewed the results of the
Coordinator and is responsible for obviating barriers to monoclonal-based assay used in this article. Others have
follow-up. Lack of follow-up is common in this population demonstrated no racial differences in DBP concentration
for various reasons including dementia, transportation once haplotype variability is controlled.16 Because it is still
issues, financial constraints, postoperative delirium or ill- unclear whether the bound-to-unbound ratio of vitamin D is
ness, and lack of understanding of the disease. Nurse racially dependent, current management of vitamin D
navigators also assume reeducation responsibilities and insufficiency should still depend on total serum 25(OH)D as
may assist in obtaining insurance authorization for the measured by the conventional serum assay regardless of
chosen medications. Systematic documentation of compli- race.
ance and reasons for loss of follow-up is necessary to allow Although there has been controversy regarding calcium
for continuous improvements in the program. An institu- supplementation for use in primary prevention of fractures, its
tional registry is often used to record this information and use with vitamin D has been shown to reduce the risk of
operative and outcomes data for research purposes. Our nonunion and can improve overall postfracture health.17 Ini-
institutional registry includes data on demographics, body tial assessment should include the serum albumin-corrected
mass index, comorbidities, fracture and surgery character- method for calculating serum calcium concentration: cor-
istics, a number of perioperative variables, metabolic bone rected calcium = [0.8 · (normal albumin 2 patient’s albu-
laboratory test results, history of antiosteoporosis medica- min)] + serum calcium.
tions, Short Form 36 questionnaire, a modified Fried Frailty Along with 1,25-dihydroxy-vitamin D (1,25(OH)2D),
Index, functional outcome measures, major and minor PTH regulates calcium homeostasis. An important

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Cohn et al J Orthop Trauma  Volume 32, Number 9, September 2018

TABLE 1. Common Causes of Secondary Osteoporosis*

Categories Diseases/Disorders Features, Laboratory Findings
Mineralization disorders Hypophosphatemia rickets Hypophosphatemia
Renal osteodystrophy Hyperphosphatemia, increased serum creatinine, and increased serum PTH
Vitamin D deficiency Decreased serum 25(OH)D
Endocrine disorders Acromegaly High serum IGF-1 typical facies and frontal bossing
Cushings disease Cushingoid appearance and high serum cortisol with high ACTH
Diabetes mellitus (type I) Insulin deficiency and high blood glucose and HbA1C
Hyperthyroidism Low TSH
Hyperparathyroidism High PTH and hypercalcemia
Hypogonadism Low LH and FSH
Connective tissue disorders Osteogenesis imperfecta History of multiple fractures, dislocations, hearing loss, and family history
Marfan syndrome Elongated limbs, arachnodactyly, mitral prolapse, and joint laxity
Drugs Alcohol $3 units of alcohol/d
Anticonvulsants Phenytoin and carbamazepine
Chemotherapy Methotrexate and cyclophosphamide
Glucocorticoids Cushingoid appearance, greater than 5 mg/d for at least 3 mo
Excess thyroid hormone Low TSH
Loop diuretics Low serum calcium and increased urine calcium excretion
PPIs and H2-receptor antagonists Decreased calcium absorption
Nutrition deficiencies Malabsorption Stool changes, weight loss, and history of gastrointestinal intolerances
Systemic illnesses Rheumatoid arthritis Prolonged inflammatory state, characteristic joint destruction, positive RF,
ANA, and anti-CCP
Hemophilia Factor VIII/IX deficiency, recurring visceral bleeds, and hemarthrosis
Amyloidosis Renal insufficiency and bony deposits
Neoplastic Myeloma bone disease Bone pain, lytic bone erosion, anemia, and serum monoclonal proteins
Hypercalcemia of malignancy Severe hypercalcemia, hyperthyroidism, high PTHrP, especially in the
context of breast or squamous cell carcinomas.
*Table updated from Rebolledo and Lane, 2011.43
ACTH, adrenocorticotropic hormone; ANA, antibuclear antibody; CCP, cyclic citrullinated peptide; FSH, follicule-stimulating hormone; IGF, insulin-like growth factor; LH,
luteinizing sormone; RF, rheumatoid factor; TSH, thyroid stimulating hormone.

physiological effect of PTH on bone is to mobilize calcium Serum markers for bone resorption include type I cross-
from stores and to improve remodeling at the bony callus.19 linked C-telopeptide and N-telopeptide (CTX and NTX) and
Barring parathyroid disease, serum PTH should be evaluated tartrate-resistant acid phosphatase (TRAP5b). Of these, serum
along with serum calcium to accurately assess calcium and CTX is the preferred test as it offers the highest sensitivity
vitamin D adequacy. High-intact PTH (.50 ng/dL) indicates and specificity for breakdown of mature bone, while being
inadequate calcium, whereas low-intact PTH (,20 ng/dL) straightforward in clinical use. Urine NTX is a secondary
suggests a physiologic state of hypercalcemia. Increased alternative as it does not necessitate venipuncture, is not
PTH always warrants reassessment of the patient’s supple- affected by food intake, and is less sensitive to diurnal
mentation regimen. Even if serum calcium is adequate, ele- variability.22
vated PTH levels can indicate early depletion of total body The Bone Marker Standards Working Group recom-
calcium stores and suggest that the patient would benefit from mended the use of serum CTX and P1NP as standard
higher calcium supplementation. However, interindividual measures of bone turnover in the longitudinal management
variability in baseline PTH is high.20,21 Therefore, establish- of osteoporosis.23 However, bone turnover markers should be
ment of baseline PTH levels over a period of weeks to months obtained within the first few days after the fracture or should
after surgery is necessary before initiating major corrective not be obtained until 6 months after fracture in to allow time
treatment. for normalization. Several studies indicate that there is an
Bone healing can further be inferred from serum increase in markers of bone formation and resorption as early
biochemical markers. C- and N-terminal type I procollagen as the first or second week after a fracture and return to near
(C1NP and P1NP), bone-specific alkaline phosphatase, and baseline physiologic levels at approximately 6 months to 1
osteocalcin are used as markers of bone formation. P1NP is year after fracture. Changes in turnover markers after fracture
generally considered the primary biomarker for bone forma- vary by age and fracture site but generally should be taken
tion, as it has a number of biochemical advantages compared into account for 6 months after fracture.24 Bone turnover tests
with other anabolic markers. P1NP is relatively stable in can be of value, especially in tracking patient response to
serum and undergoes hepatic clearance, thereby remaining bone anabolic/antiresorptive therapy, such as during teripara-
accurate in patients with kidney disease.22 tide or denosumab use. For example, during treatment of

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J Orthop Trauma  Volume 32, Number 9, September 2018 Update on Fragility Fractures

osteoporosis with teriparatide, an increase of 10 mg/L in are termed severe fractures with deteriorated bone micro-
P1NP level from baseline, with a parallel trend in CTX lev- architecture.33 It is recommended that VFA be used con-
els, is generally considered to be a desired treatment junctively with DEXA testing as 11%–18% of patients are
response.25,26 misclassified as normal by the use of DEXA testing
alone.34

IMAGING AND RISK ASSESSMENT Hounsfield Unit Measurements

Dual-Energy X-Ray Absorptiometry Recent studies have validated the use of Hounsfield unit
(HU) measurements, derived from diagnostic computed
Dual-energy x-ray absorptiometry (DEXA) is the gold
tomography (CT) scans, to ascertain information about
standard in the clinical assessment of skeletal health. The t
regional bone quality. Such units can be measured with no
scores of a patient’s proximal femur, lumbar spine, and distal
additional cost, patient time, equipment, or radiation exposure
radius indicate a patient’s BMD compared with a young,
and can be correlated with a patient’s DEXA-derived BMD
healthy, sex, and ethnically matched reference population.
values to aid in the diagnosis and treatment of osteoporo-
According to the World Health Organization, a T-score
sis.35,36 As a majority of patients fail to undergo DEXA test-
between 21 and 22.5 is defined as osteopenic and a score
ing after sustaining a fragility fracture, HU may be used to
of 22.5 or lower is defined as osteoporotic.27 DEXA-derived
diagnose an individual’s degree of osteoporosis, predict
BMD strongly correlates biomechanically with bone strength
future fracture risk, and demonstrate a need for osteoporotic
and is an excellent predictor of a patient’s fracture risk.28
intervention.37 Normative values for HU vary by anatomical
However, degenerative changes such as lumbar osteophytes
region of interest. Studies by Pervaiz et al and Johnson et al
and aortic calcifications, common in the elderly, will falsely
have correlated proximal humerus HU and capitate HU with
elevate BMD and underestimate true fracture risk. In patients
normal, osteopenic, and osteoporotic bone quality BMD
younger than 40 years who have not reached skeletal matu-
markers.38,39 Lee et al40 further illustrated the correlation
rity, one can use Z scores to diagnose osteoporosis based on
between lumbar spine, femoral head, femoral neck, greater
bone density of age-related peers.
trochanter, distal tibia, and talus HU values and osteoporotic
cutoffs in hip BMD values. The utility of this modality to
Trabecular Bone Score identifying osteoporosis based on imaging routinely obtained
Trabecular bone score (TBS) is a gray-level textural in the workup of a fracture is promising, and further study is
index and a measure of bone distribution. Healthy bone needed to define its role in diagnosis.
trabeculae produce an image with a large number of pixel-to-
pixel variation of small amplitude. Osteoporotic trabeculae, Fracture Risk Assessment Tool
by contrast, yield high-amplitude trabecular pixels with a low
Bone density relates only partially to bone strength and
number of pixel-to-pixel gray variation. As such, dense
fracture risk. The fracture risk assessment tool was estab-
trabeculae yield a high TBS value, whereas porous, osteopo-
lished to integrate bone density with other critical elements to
rotic trabecular bone produces a low TBS value.29 TBS val-
more accurately predict fracture risk. Age, sex, height,
ues are reported for each vertebra and for the total spine.
weight, previous fracture, family history of fracture, smoking,
Although a low TBS is strongly correlated with a rise in
steroid use, rheumatoid arthritis, alcohol intake, and femoral
fragility fractures in postmenopausal women and older men,
neck BMD are used. A 3% risk of hip fracture or 20% risk of
its use is not recommended as the sole measurement in the
long bone fracture in 10 years is an indication for drug
determination of therapy.30
therapy for osteoporosis.
Vertebral Fracture Assessment
Only 30% of vertebral fractures are symptomatic and TREATMENT
come to clinical attention despite their high prevalence and
predictive capabilities of future fragility fractures.31 Thus, Nonpharmacologic Treatment
to minimize underreporting and prevent fracture risk in Calcium and vitamin D supplementation is critical in
patients, the International Society for Clinical Densitome- orthopaedic patients, especially those with fragility frac-
try recommends lateral spine imaging with densitometric tures. Coupled together, supplementation prevents falls and
vertebral fracture assessment (VFA) in all women 70 years reduces fractures among the elderly.41 Recommended daily
of age and older and all men 80 years of age and older who calcium intake is 1000 mg/d (combination of diet and sup-
display a T-score of less than 21 with 1 or more of the plements) along with a minimum of 2000 IU/d of vitamin
following risk factors: historical height loss greater than 1.5 D3. Many over-the-counter supplements contain both cal-
inches, previous vertebral fracture, and a 3-month history cium and vitamin D, often with 400 mg and 500 IU
of glucocorticoid therapy.32 Vertebrae T7-L5, with a $20% amounts, respectively. Monthly supplementation may be
visually estimated loss in vertebral body height relative to purchased for less than $20.00. The 2 major forms of cal-
a normal looking adjacent vertebra are classified as frac- cium supplementation are calcium carbonate and calcium
tures and are thus assessed using the Genant grading system citrate. Calcium carbonate contains a high composition of
and via automated vertebral morphometric analysis. Verte- elemental calcium and is low cost. However, calcium citrate
brae with more than a 40% reduction in height and/or area is often preferred as it is better absorbed in patients with low

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Cohn et al J Orthop Trauma  Volume 32, Number 9, September 2018

gastric acidity, such as those taking proton pump inhibitors. Figure 1. These medications are classified as either antiresorp-
Orthopedists may recommend these supplements to patients tive or anabolic agents.
and instruct them to seek regular monitoring of serum cal-
cium, 25(OH)D, and PTH levels with one of their medical Bisphosphonates
providers. Calcium supplementation should be used with Bisphosphonates are powerful antiresorptive agents that
caution in patients with a history of kidney stones or renal are still the most widely used pharmacologic treatment for
failure and may also lead to constipation. Although some osteoporosis. Bisphosphonates bind the surface of hydroxy-
epidemiological evidence suggested that calcium and vita- apatite crystals and decrease osteoclastic activity by inhibiting
min D supplementation may increase the risk of myocardial farnesyl pyrophosphate synthase, a protein in the mevalonate/
infarction, recent research has found no correlation between HMB co-A reductase pathway, and inducing early apopto-
calcium and vitamin D intake and ischemic and nonische- sis.44 These medications has proven effective in reducing the
mic cardiovascular events.18,42 Weightbearing activities and risk of fractures, improving BMD, and normalizing elevated
exercise are also mainstays of preventive care and must be serum bone turnover markers.45
tailored to the individual patient’s physical capabilities. When initiating bisphosphonate treatment after a recent
Risk of falling should also be evaluated in each patient, fracture, several factors must be considered. Previous studies
and prevention strategies such as hip protectors and assis- have demonstrated that administration of zoledronic acid at
tive devices within the household should be considered.43 least 6 weeks after surgical repair for hip fracture causes an
In addition, tobacco and alcohol consumption can hinder increase in BMD, as well as a reduction of clinical vertebral
fracture healing and have consequential effects on bone fractures, nonvertebral fractures, and all-cause mortality.46
health.43 In studies conducted by Lyles et al,47 Zoledronic acid
decreased the risk of any new clinical fracture by 35% and
Pharmacologic Treatment decreased the risk of myocardial infarction. The patient
Initiation of a pharmacologic treatment should be should be considered for one of the following treatments
considered in patients based on the criteria presented in at 2- to 3-year follow-up1: continuation of bisphosphonate

FIGURE 1. A flow chart illustrating the

assessment of a patient with a fragility
fracture. CTX serum cross-linked C-telo-
peptide of type I collagen; DEXA, dual-
energy x-ray absorptiometry; FLS,
Fracture Liaison Service; FRAX, fracture
risk assessment tool; PTH, parathyroid
hormone.

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J Orthop Trauma  Volume 32, Number 9, September 2018 Update on Fragility Fractures

treatment,2 initiation of drug holiday, or3 change in pharma- factor-kB ligand (RANKL), a cytokine that is essential for
cologic treatment.45 the formation, function, and survival of osteoclasts.60 Its
Bisphosphonates have no contraindications, but poten- mechanism is similar to the soluble decoy receptor osteo-
tial side effects include stomach pain, esophagus irritation, protegerin, which is a physiologic regulator of osteoclast
and muscle aches. In addition, long-term use of bisphosph- differentiation and function. The antibody prevents
onates can lead to adynamic bone metabolism, which can osteoblast-produced RANKL from reaching receptor activa-
paradoxically result in skeletal fragility and rarely atypical tor of nuclear factor-kB receptors on the surface of osteo-
femoral fractures.43 Therefore, a drug holiday should be con- clasts and their precursors. Reduced osteoclastic activity
sidered if bone density and bone markers are stable after 3 to leads to higher bone density and decreased bone
5 years of treatment.45 resorption.49,61
Although there is ongoing debate about the effects of Subcutaneous administration of 60 mg of denosumab
bisphosphonates on fracture union during bone repair, every 6 months increases a patient’s BMD.55,62 Several
recent experimental evidence has demonstrated that net clinical studies have demonstrated a reduction in the risk
osteoblast function does not seem to be impaired and rather of osteoporotic fractures of greater than 50% in high-risk
that there is an increase in callus size and mineralization.48 postmenopausal women.30 A large RCT indicated a 68%
Several studies have demonstrated that for fractures healing decrease in risk of vertebral fractures and a 40% decrease
by endochondral ossification, bisphosphonates preferen- in nonvertebral fragility fractures compared with pla-
tially deposit at the acute fracture site and are able to cebo.61 These affects can be achieved without disrupting
increase callus and trabecular bone volume, as well as bone fracture healing. The FREEDOM trial, a double-blind, pla-
mineral content during the reparative phase of bone heal- cebo-controlled analysis, tested the effects of denosumab
ing.49 Clinically, data from a double-blind randomized con- on fracture healing in patients with incident nonvertebral
trolled trial (RCT) evaluating the impact of bisphosphonate fractures and found that denosumab was not associated
treatment on hip fracture healing indicated no significant with delayed healing or any complications after fracture
delay in healing when treated with bisphosphonate ther- or surgical management.63 Although denosumab is dosed
apy.47,50 Several reports have shown there to be no clini- every 6 months, if it is not administered for 9 months,
cally significant difference in healing times through there is a rebound phenomenon where there is a temporary
endochondral fracture repair.49 The literature has demon- rise in the risk of developing vertebral compression
strated that treatment with bisphosphonates for distal radius fractures.
fractures led to increased BMD at the fracture site compared Denosumab is a novel and effective antiresorptive
with the placebo and that there was no delay in healing agent used in the treatment of osteoporosis and the pre-
based on radiographic union compared with a control pop- vention of fragility fractures. The evidence from trials
ulation.51,52 By contrast, animal studies have shown that suggests that denosumab may be as effective as bisphosph-
although bisphosphonates do not delay endochondral repair, onate therapy in preventing fractures and possibly more
they can delay osteoclast-mediated callus remodeling.53 effective than bisphosphonates in slowing decay of cortical
Based on these data, we recommend that bisphosphonates and trabecular microarchitecture.64 There are several char-
be initiated 6 weeks after fracture, but further study is acteristics that separate denosumab from bisphosphonates
needed to determine the optimal timing of bisphosphonate including1: its reversibility through its action of targeting
initiation in the setting of a recent fracture. RANKL without being incorporated into the bone mineral,2
There is also evidence that bisphosphonates may its lack of gastrointestinal side effects, convenient biannual
improve implant fixation, implant contact, periimplant bone subcutaneous administration, and3 its potential use in
volume, and implant fixation strength, resulting in an impaired renal function as it is not eliminated by the
overall increased implant stability.49 Specifically, bishosph- kidneys.
onates may significantly reduce periprosthetic bone loss
after total joint arthroplasty and improve pin fixation of Teriparatide
pertrochanteric fractures.54–56 Other studies have reported Teriparatide is a recombinant form of human PTH
that both systemic and local perioperative treatment with that contains the N-terminal fragments from the 1 through
bisphosphonates can improve the fixation of total knee pros- 34 positions of the 84 amino acid native hormone. It is one
theses.57–59 of two anabolic agents approved by the Food and Drug
Overall, RCT evidence has shown that bisphosphonate Administration for postmenopausal osteoporosis. Contin-
treatment after fracture does not delay fracture healing and uous PTH exposure, as in hyperparathyroidism, stimulates
that application of bisphosphonates may improve osseointe- osteoclasts to resorb bone. However, intermittent, low-
gration.50 Bisphosphonates are important in the prevention of dose PTH promotes osteoblast differentiation from its
fractures, and routine DEXA measurements and laboratory precursors and decreases osteoblast apoptosis. As such,
values can help prevent potential complications with their PTH can be a potent stimulator of bone formation in
use. patients with osteoporosis. Clinically, intermittent low-
dose exposure is achieved by administering 20 mg subcu-
Denosumab taneously each day.
Denosumab is a high-affinity, high-specificity mono- Use of teriparatide leads to an 8.1% increase in bone
clonal antibody against the receptor activator of nuclear mass in the vertebrae and a 2.5% increase in the hip. This

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Cohn et al J Orthop Trauma  Volume 32, Number 9, September 2018

confers a 70% reduction in risk of vertebral fractures and oncogenic potential related to observations from preclinical
a 38% risk reduction in nonvertebral fractures.65 Recent rat studies. However, results from a 7-year surveillance
research on combination therapy with teriparatide and deno- study of adults with osteosarcoma have not indicated a link
sumab has yielded promising results. Combination therapy between osteosarcoma and teriparatide.74 Nevertheless, ter-
leads to greater increases in BMD in the lumbar spine, fem- iparatide should not be used in patients younger than 18
oral neck, and total hip compared with teriparatide or deno- years, patients with Paget disease, or patients who have
sumab alone at 2-year follow-up.66 Given the effect at these received high-dose radiation for cancer.
varying sites of bone architecture, combination therapy may
lead to increased bone formation in trabecular bone and Abaloparatide
mixed cortical and trabecular bone. PTH-related protein (PTHrP) is a cytokine that
Although there is no clear consensus on indications for was initially discovered as the cause of humoral hypercal-
teriparatide in the treatment of postmenopausal osteoporosis, cemia of malignancy. Further study revealed that it is
we recommend its use in the following patient populations: a multifunctional signaling protein produced by osteocytes
those who continue to have a steady decline in bone density that regulates endochondral bone formation. PTHrP shares 8
and/or suffer a fragility fracture despite antiresorptive use, of 13 residues of the N-terminal region in common with
experience upper gastrointestinal irritation from bisphospho- PTH and therefore acts similarly as an agonist of the PTH
nates, or have a severely low bone density (ie, BMD t-score , receptor type 1. Evidence shows that it may also have
3.5). In patients with a history of bisphosphonate use, the receptor-independent actions that stimulate bone formation
clinician may switch to teriparatide or add it to the bisphosph- in a paracrine and autocrine manner.75 Although teriparatide
onate regimen. Patients with the major risk of fracture being in is an effective anabolic agent, it exhibits simultaneous
the spine (markedly low BMD in this region or history of resorptive properties and may lead to hypercalcemia. In
vertebral fractures), switching to or adding teriparatide confers addition, teriparatide has shown less efficacy in preventing
equal benefit.67 However, if very low bone density is observed nonvertebral fractures, particularly before 9 months of treat-
in the hip or if the patient suffered a hip fracture while on ment.76–78 Abaloparatide, a peptide with 41% homology to
bisphosphonates, adding teriparatide may be most beneficial. PTH and 76% homology with PTHrP, differs from teripara-
Last, combination therapy with denosumab may be considered tide by selectively binding PTH receptor type 1 in the G
in patients who meet the above criteria and fail to respond to protein–dependent (GTPgS-sensitive) receptor conforma-
teriparatide alone or in combination with bisphosphonates. tion, called RG.79 It is hypothesized that by binding in the
Given the anabolic effects of teriparatide, there is RG conformation, in contrast to the G protein–independent
great interest in its potential to augment fragility fracture high-affinity conformation, called R0 abaloparatide leads to
healing. In vitro and in vivo studies indicate that teripara- transient cAMP production compared with teriparatide and
tide may enhance callus formation in the healing process. therefore leads to less catabolic and resorptive activity.79
Teriparatide at the 20 mg dose significantly shortened time Abaloparatide (Tymlos) was recently approved by the
to cortical continuity and callus formation after distal Food and Drug Administration for treatment of severe
radius fracture.68 Daily injection of PTH 1–84, a similar osteoporosis after rigorous study. It is to be administered as
medication used in Europe, accelerated fracture healing, an 80-mg daily subcutaneous injection. A phase 3 double-
reduced pain, and improved functional outcomes in osteo- blind randomized control trial titled Abaloparatide Compara-
porotic patients with pelvic fractures compared to controls. tor Trial In Vertebral Endpoints (ACTIVE) revealed that
At 8 weeks, 100% of fractures in the treatment group had abaloparatide was superior to teriparatide and placebo in pre-
healed compared with 9% of controls.69 Studies also indi- venting new major osteoporotic fractures, defined as fractures
cate that teriparatide is beneficial after instrumented lumbar of the wrist, upper arm, hip, and clinical spine. At 18 months,
posterolateral fusion. It has been shown to reduce the inci- major osteoporotic fractures occurred in 1.5%, 3.1%, and 6.2%
dence of pedicle screw loosening by about 50% and may of patients in the abaloparatide, teriparatide, and placebo
accelerate bone union compared with risedronate and con- groups, respectively. Abaloparatide was found to decrease
trol.70,71 Teriparatide may also be beneficial in treating the rate of new morphometric vertebral fractures compared
bisphosphonate-associated atypical femoral fracture.72 with placebo, but was underpowered to detect a difference
However, positive effects have not been observed at all compared with teriparatide. Abaloparatide was found to
fracture sites. A recent small, randomized placebo-controlled decrease the rate of nonvertebral fracture compared with pla-
trial showed that patients undergoing internal fixation for cebo, whereas teriparatide was not.80 In further analysis, aba-
femoral neck fractures did not show improved radiographic loparatide was found to increase BMD and protect against
healing, decreased pain, or lesser need for revision surgery vertebral and nonvertebral fractures across a wide variety of
with teriparatide.73 ages and baseline risks, including those with and without pre-
The most common side effects of teriparatide include vious fractures.81
lightheadedness, palpitations, and elevations in calcium that In a study comparing 3 doses of abaloparatide (20, 40,
can potentially lead to kidney stones. Therefore, calcium and 80 mg), teriparatide, and placebo, abaloparatide led to
supplementation should be decreased after starting teripara- a dose-dependent increase in BMD of the lumbar spine, fem-
tide and serum levels should be monitored regularly. oral neck, and total hip.77 The 80-mg dose led to a 12.9%
Patients often express concern about the risk of osteosar- BMD increase in the spine compared with 8.6% in patients
coma as the US product label contains a warning of treated with teriparatide. Preliminary results from a phase III

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J Orthop Trauma  Volume 32, Number 9, September 2018 Update on Fragility Fractures

TABLE 2. Summary of Route, Dosing, Mechanism, Indications, Contraindications, and Side Effects of Osteoporosis Medications
Average
Wholesale
Osteoporosis Price per
Medication Route/Dose Mechanism Indications Contraindications Side Effects Month*
Bisphosphonates
Alendronate Oral, 70 mg Inhibits osteoclast Prevention Delayed esophageal GI: esophagitis, $47
weekly farnesyl emptying, inability to heartburn, difficulty
pyrophosphate sit or stand upright for swallowing.
synthase enzyme, 30 min, hypocalcemia, Headache, fever,
required in mevalonate creatinine clearancer joint pain
(cholesterol pathway); ,35 mL per minute,
inhibits GTPase hypersensitivity
formation
Ibandronate Oral, 150 mg Prevention and Oral: see above, IV: $41
monthly; treatment renal toxicity,
intravenous injection site
3 mg every reaction, ocular
3 mo inflammation,
osteonecrosis of
jaw
Risedronate Oral 35 mg Prevention and See above $67
weekly or 150 treatment (alendronate)
mg monthly
RANKL inhibitor
Denosumab Subcutaneous, Monoclonal antibody Treatment Hypocalcemia, Arthralgia, $1121
60 mg every against the receptor immunosuppression, nasopharyngitis,
6 mo activator of nuclear creatinine ,30 mL per back pain
factor-kB ligand minute
(RANKL)
SERMs
Raloxifene Oral, 60 mg Agonist on estrogen Prevention and Past or current history of Hot flashes, leg $44
daily receptors in bone treatment venous cramps
(reduce osteoclast thromboembolic
resorption) events, pregnancy,
hypersensitivity
Parathyroid
hormone analog
Abaloparatide Subcutaneous Interacts with parathyroid Treatment Orthostatic $1666
80 mcg/40 receptor 1 and exhibits hypotension,
mcL anabolic actions to hypercalcemia,
(available as regulate the bone arthralgia,
a prefilled pen formation dyspepsia, upper
that delivers respiratory
30 daily doses infection, urinary
of 80 mcg) tract infection and
bone pain
Teriparatide Subcutaneous, Receptors on osteoblast Treatment Risk of osteosarcoma, Transient $3367
20 mcg daily (activates osteoblasts) hypersensitivity, Paget hypercalcemia,
for ,2 y and renal tubule cells, disease dizziness, nausea,
stimulates intestinal headache
absorption Ca and PO4
Anti-sclerostin
antibody
Romosozumab, 210 mg monthly Humanized monoclonal Treatment History of Reaction at injection NA
blosozumab, injection antibody targeting hypersensitivity site
BPS804 sclerostin
*Updated Wholesale Prices Taken from goodrx.com.

trial shows that both abaloparatide and teriparatide reduced Similar to teriparatide, adverse effects included back pain,
vertebral fractures compared with placebo, whereas only aba- hypercalciuria, and arthralgias. Hypercalcemia was observed,
loparatide led to a significant reduction in nonvertebral frac- but occurred less commonly compared with teriparatide.
tures.80 Increases in BMD were also significantly greater in These early results suggest that abaloparatide can be used
the abaloparatide-treated group compared with teriparatide. as an effective and well-tolerated alternative to teriparatide.

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Cohn et al J Orthop Trauma  Volume 32, Number 9, September 2018

FIGURE 2. Illustration of mechanisms of anti-osteoporosis medications. Editor’s Note: A color image accompanies the online
version of this article.

Medications in Development ongoing. Although further study is needed to evaluate the

Antisclerostin Antibodies effect on fracture incidence, long-term tolerability, and
adverse effects, early results suggest that sclerostin inhibitors
The canonical Wnt signaling pathway increases bone may shift the treatment paradigm for osteoporosis treatment.
mass by several mechanisms including renewal of stem Route, dosing, mechanism, indications, contraindications, and
cells, stimulation of osteoblast precursor replication, and side effects of osteoporosis medications are briefly summa-
inhibition of osteoblast and osteocyte apoptosis.82 Sclerostin rized in Table 2. Mechanisms of the anti-osteoporosis medi-
is a native protein expressed by osteocytes that inhibits the cations are illustrated in Figure 2.
canonical Wnt signaling pathway. It acts by inhibiting the
LRP5/6 receptor and by increasing RANKL expression.
These effects of sclerostin significantly reduce bone forma-
tion. Antisclerostin monoclonal humanized antibodies have CONCLUSIONS
been developed to block this pathway and show potential as The traumatologist should recognize patients at risk of
potent anabolic agents.83 osteoporosis and low-energy fractures. Failure to address
Three sclerostin inhibitors are currently being investi- osteoporosis begets additional fragility fractures. Drug therapy
gated: romosozumab (Amgen and UCB), blosozumab (Eli with anticatabolic or anabolic agents will lower fracture risk by
Lilly), and BPS804 (Novartis). Early results of clinical trials 50%–70%. Anabolic medications not only lower fracture risk
are promising. In a phase II clinical trial of romosozumab but also may enhance fracture healing. Thus, the orthopedist
given as a once monthly injection, a positive response in should take an active role in identifying patients with declining
BMD and bone turnover markers was observed. Patients were bone health who warrant further evaluation and care. They may
randomized to receive romosozumab, alendronate, teripara- initiate treatment themselves and/or refer appropriately to a pro-
tide, or placebo. At 1 year, BMD increased in the spine vider who can treat osteoporosis in the long term.
(11.3%), the total hip (4.1%), and the femoral neck (3.7%),
which were significantly higher than the other treatment
groups.84 Even greater increases (19.4% in the spine and TAKE-HOME POINTS FROM THIS UPDATE
7.1% in the hip) were observed at 2 years. Adverse events • Greater efforts must be made to initiate osteoporosis treat-
were minimal, with some patients reporting a mild reaction at ment after a fragility fracture to prevent subsequent frac-
the injection site. In the first 3 months of treatment, P1NP tures. Implementation of an FLS creates an efficient system
levels increased significantly as CTX levels fell, further indi- to initiate treatment before referral for long-term treatment.
cating bone formation. Improvements in trabecular and corti- • It is recommended that metabolic bone laboratory test re-
cal bone mass as analyzed by high-resolution quantitative CT sults of calcium, intact PTH, vitamin D, thyroid-stimulating
were also observed. Phase II studies of blosozumab yielded hormone, bone-specific alkaline phosphatase, and CTX be
similar findings, with dose-dependent increases in lumbar obtained in the acute fracture setting to detect secondary
spine, total hip, and femoral neck BMD.85 Phase III trials causes of osteoporosis and to establish baseline measure-
of these medications and a phase II study of BPS804 are ments. Alternatively, these laboratory test results can be

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J Orthop Trauma  Volume 32, Number 9, September 2018 Update on Fragility Fractures

obtained at follow-up, and markers of bone turnover may 20. Gardham C, Stevens PE, Delaney MP, et al. Variability of parathyroid
be obtained 6 months after fracture. hormone and other markers of bone mineral metabolism in patients
receiving hemodialysis. Clin J Am Soc Nephrol.2010;5:1261–1267.
• DEXA remains the mainstay of osteoporosis screening. 21. Sellmeyer DE, Black DM, Palermo L, et al. Hetereogeneity in skeletal
Additional imaging modalities that are being used or inves- response to full-length parathyroid hormone in the treatment of oste-
tigated include TBS, VFA, and Hounsfield unit measure- oporosis. Osteoporosis international. Osteoporos Int. 2007;18:973–
ments from CT scans. 979.
22. Wheater G, Elshahaly M, Tuck SP, et al. The clinical utility of bone
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agents, bisphosphonates and denosumab, and the anabolic 23. Vasikaran S, Eastell R, Bruyere O, et al. Markers of bone turnover for the
agents abaloparatide and teriparatide. prediction of fracture risk and monitoring of osteoporosis treatment:
• Antisclerostin antibody is a potent anabolic agent that has a need for international reference standards. Osteoporos Int. 2011;22:
shown great promise in phase 3 clinical trials with potential 391–420.
24. Hannon R, Eastell R. Preanalytical variability of biochemical markers of
to shift the paradigm of osteoporosis treatment. bone turnover. Osteoporos Int. 2000;11:S30–S44.
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