Accepted: 26 January 2017

DOI: 10.1111/jocd.12326

REVIEW ARTICLE

Calcium hydroxylapatite: A review on safety and

complications

J.A. Kadouch MD, PhD

Mohs Klinieken Amsterdam, Amsterdam,

The Netherlands
Correspondence
Jonathan A. Kadouch, Mohs Klinieken
Amsterdam, Amsterdam, The Netherlands.
Email: jonathan.kadouch@gmail.com
Summary
Background: Radiesseâ, or calcium hydroxylapatite (CaHA), is a biodegradable, bios-
timulatory soft tissue filler suitable for deeper folds and wrinkles. In the literature,
good results have been documented with the use of CaHA and patient satisfaction
scores are high. This study reviews the current literature on safety and complica-
tions of CaHA.
Methods: A literature search in MEDLINE/PubMed electronic database was con-
ducted. A total of 21 articles were included and screened for reports of adverse
events (AEs).
Results: Twenty-one peer-reviewed articles, published between 2004 and 2015,
were included. A total of 5081 treatments with CaHA were performed on 2779
patients. A total of 173 (3%) AEs were reported. The assessed types of AEs con-
sisted of nodules (n=166, 96%), persistent inflammation/swelling (n=4, 2%), persis-
tent erythema (n=2, 1%), and overcorrection (n=1, 1%).
Conclusion: Based on the results in this study, CaHA appears to have a good safety
profile. Nodules are by far the most common AE. Of the reported nodules, 49%
occurred in “dynamic” areas currently known for having a higher tendency for nod-
ules. Several treatment approaches exist for managing CaHA nodules; however, in
most cases, CaHA nodules are not visible and resolve without intervention.

KEYWORDS
calcium hydroxylapatite, complications, radiesse, safety, soft tissue fillers

1 | INTRODUCTION
â
Radiesse (Calcium Hydroxylapatite, CaHA; Merz Pharmaceuticals
GmbH, Frankfurt, Germany) is a biodegradable, volumizing wrinkle

Europe
filler (in short, “filler”) which received Conformite
enne (CE)
certification in 2003 for dermal and subdermal application in the
face and has been marketed since then. In 2006, CaHA was
approved by the American Food and Drug Administration (FDA) for
the correction of moderate-to-severe wrinkles and folds in the face,
and/or as a corrective measure in the treatment of facial fat loss in
individuals infected with HIV. CaHA consists 30% of calcium hydrox-
ylapatite microspheres and 70% of sodium carboxy-methylcellulose
(CMC) gel. The CaHA microspheres are composed of a synthetic
form of a natural substance found in the bones and teeth.1 CMC is a
derivative of cellulose and acetic acid, and is soluble in water.2 The
substance is frequently applied as a thickening agent and stabilizer
of emulsions in certain foods and nonfood products, and to increase
the viscosity in liquid pharmacological preparations. After injection,
the CMC gel is rapidly broken down while the CaHA microspheres
act as a sort of platform for newly synthesised collagen.3 This means
the filler is slowly replaced by autologous connective tissue, or neo-
collagen. For this reason, CaHA is also called a biostimulatory filler.
Animal studies have shown that this neocollagenesis already occurs
in the fourth week and continues until at least 12 months after
injection.4 The filling effect after CaHA injections remains visible for
12-18 months on average. CaHA is a volumizing filler and is in

152 | © 2017 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/jocd J Cosmet Dermatol. 2017;16:152–161.

KADOUCH | 153

principle unsuitable for fine and thin lines and wrinkles. CaHA is suit- T A B L E 1 Common classification of adverse events (AEs) after
able for deeper folds and wrinkles and should be injected deeply filler injections5,21
dermally, subdermally, or supraperiostally. It is used in the face for Early-type AEs (onset<2 wk) Late-type AEs (onset<2 wk)
mid-deep to deep wrinkles and folds and to correct volume loss and Technical mishap: Infection (Biofilm):
contours.3,5 Experience with CaHA has shown that it is also suitable • Noninflammatory nodule • Erythema
for creating angled contours, which makes it a popular filler for • Asymmetry • Edema
men.6 “Rejuvenation” of the hands and treatment of vocal cord insuf- • Contour irregularity • Pain

ficiency are also known indications for the use of CaHA.7,8

Infection:
• Erythema
Microscopically, CaHA is easily recognizable as 25- to 45-lm • Edema
blue-gray, round-oval particles, surrounded by fibrin.9 In general, lit- • Tenderness or pain
tle infiltrate is seen histologically around the microspheres with • Inflammatory nodule
• Inflammatory nodule
• Ulceration
(Granulomatous) Type IV
hypersensitivity reaction:
• Erythema

CaHA, except for a few macrophages. The size and the flat/smooth • Abscess • Edema
Type I hypersensitivity reaction: • Pain
aspect of the particles certainly contribute to the mild immune
• Erythema • Inflammatory nodule
response.10-12 Some data suggest that the CaHA particles are not • Edema/Angioedema • Ulceration
dissolved through phagocytosis, but through enzymatic breakdown.9 Type IV hypersensitivity reaction: (Granulomatous) Foreign body
The calcium makes CaHA microspheres radio-opaque. However, in a • Erythema reaction:

study from 2008, Carruthers showed that CaHA is not consistently

• Edema • (Non-) inflammatory nodule
• Tenderness or pain • Erythema
• •
13
and reliably reproduced on radiographs. The same study showed Inflammatory nodule Edema
that CaHA is easily recognizable on CT, and 100% of the CaHA • Ulceration • Pain
depots were identified on CT directly after injection. An important Vascular occlusion: • Ulceration

additional aspect is that in only 0.6% of cases (1/160), the CaHA
depots blocked the view of underlying structures. The authors con-
cluded that it is unlikely that CaHA depots would be confused in
practice with standard abnormalities and aberrant radiographic find-
ings.13 Echographic studies showed a higher density of the tissue
surrounding the CaHA depots (neocollagenesis?) and the image of
reflection and shadow artefacts, probably due to the presence of cal-
cium.14 A study by van Rozelaar et al.15 examined the relationship
between the visible treatment effect of L-poly lactic acid (PLLA) and
CaHA on MRI on the one hand, and the quality of life of the study
participants on the other. A total of 82 patients were included, one
half being treated with CaHA and the other half with PLLA. Both
products are invisible on MRI, but the treatment effect (neocollagen-
esis) after 1 year was visibly evident for both fillers as a clearly
defined, pleomorphic, hypointense subcutaneous tissue.15 Another
study showed that immediately after injection, the CaHA depots
were recognizable on MRI as a low-to-intermediate intensity
signal.16 That signal was no longer visible 2.5 years after injection,
but there was still an evident increase in subcutaneous volume,
suggesting neocollagenesis.
In the literature, good results have been documented with the
17-19
use of CaHA. Patient satisfaction scores are high (87%-
89%).3,19,20 Transient adverse effects like ecchymosis, edema, ery-
thema, pain, and itching have been noted to varying extents.3,17-20
They are what are referred to as “injection site reactions” (ISRs) and
are a consequence of the trauma to the skin during injection. These
type of adverse effects are intrinsic to the treatment and should
therefore not be classified as adverse events (AEs).5 In addition,
these reactions are not filler specific, they may occur regardless of
which filler was used. Real complications, or AEs, are usually classi-
fied into early (onset within 2 weeks after injection) and late (onset
later than 2 weeks after injection, Table 1).5,21 Examples of early
AEs are technical mishaps occurring during the injection (eg,
• Tissue necrosis (Pseudo) abscess:
• Blindness • Fluctuating inflammatory
Skin discoloration: swelling
• Tyndall effect Migration (dislocation) of filler
• Hyperpigmentation material:
• Erythema • Noninflammatory nodule
Persisting skin discoloration:
• Hyperpigmentation
• Erythema/Teleangie €ctasis
overfilling, injection too superficially, contour irregularities), early
infections, vascular occlusions, discolorations of the skin, and hyper-
sensitivity reactions. Aside from the hypersensitivity reactions, such
early complications can be considered as being not filler specific, but
rather a doctor-related factor resulting from incorrect injection or
inadequate sterility.5,22 As for possible hypersensitivity reactions to
CaHA, none have ever been recorded. In order to obtain an impres-
sion of the safety profile of CaHA as a product, it therefore seems
more interesting and relevant to investigate the late AEs. Examples
of late AEs include nodules/granulomas, migration, and late infec-
tions/biofilms.5,23 This study reviews the currently available literature
on AEs after facial injection with CaHA to evaluate its safety profile.
2 | METHODS
An extensive literature search in MEDLINE/PubMed electronic data-
base was conducted, using the keywords “Radiesse filler” and “Cal-
cium hydroxylapatite filler.” A total of 165 original articles were
found. Only peer-reviewed cohort studies with >10 patients included
were selected. Case reports, reviews, and animal studies were dis-
carded, as well as articles in which adverse events were not assessed
and cases in which patients had been concurrently treated with a
second soft tissue filler at the same location. Only articles describing
 154
|

T A B L E 2 Results from the literature search: included studies

Author Sklar et al. Tzikas et al. Goldberg et al. Jacovella et al. Jansen et al. Roy et al. Silvers et al. Godin et al. Moers-Carpi et al.
Year of publication 2004 2004 2006 2006 2006 2006 2006 2007 2007
Prospective vs Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective Prospective
retrospective cohort study
Number of patients treated 64 90 10 40 609 82 100 46 70
Number of treatments 119 103 NS, 10 55 1348 NS, 82 100 107 70
Injection sites:
Glabellar area 19 12 106
Tear trough, infraorbital 15 2 4 8
Cheeks/zygoma 4 6 14 100
Nasolabial folds 52 60 24 395 39 70
Lips 15 29 10 338 29
Perioral area 12 13 288 27
Marionette lines 56 75
Chin, mental crease 2 4 5
Prejowl sulcus 10
Nose 5 6
Other or not specified 8 10 118 82 7
Number of AEs:
Nodules (of which excised) 3 (-) 43 (4) 1 (1) 48 (?) 6 (?) 15 (2)
Overcorrection 1
Persistent erythema 2
Persistent inflammation/edema

(Continues)
KADOUCH
 KADOUCH

TABLE 2 (Continued)
Author Stupak et al. Smith et al. Sadick et al. Moers-Carpi et al. Carruthers et al. Rokhsar et al. Tzikas et al. Marmur et al.
Year of publication 2007 2007 2007 2008 2008 2008 2008 2009
Prospective vs Prospective Prospective Prospective Prospective Prospective Prospective Retrospective Prospective
retrospective cohort study
Number of patients treated 13 117 113 60 30 14 1000 100
Number of treatments 17 117 151 NS, 60 30 NS, 14 2381 100
Injection sites:
Glabella area 235
Tear trough, infraorbital 5 21
Cheeks/zygoma 15 30 123
Nose 17 14 11
Nasolabial folds 117 86 60 760 100
Perioral area 26 3
Lips 14 349
Marionette lines 684
Prejowl sulcus 5 48
Chin, mental crease 107
Other or not specified 40
Number of AEs:
Nodules (of which excised) 1 (-) 2 (-) 1 (-) 1 (-) 40 (-)
Overcorrection
Persistent erythema
Persistent inflammation/edema 2

(Continues)
|
155
 156
|

TABLE 2 (Continued)
Author Bass et al. Marmur et al. Rauso et al. Van Rozelaar et al. Total
Year of publication 2010 2010 2013 2014 -
Prospective vs retrospective cohort study Prospective Prospective Prospective Prospective -
Number of patients treated 117 50 26 41 2779
Number of treatments 117 50 NS, 26 NS, 41 5081
Injection sites:
Glabella area 372
Tear trough, infraorbital 55
Cheeks/zygoma 292
Nose 36
Nasolabial folds 117 50 1930
Perioral area 369
Lips 784
Marionette lines 815
Prejowl sulcus 63
Chin, mental crease 118
Other or not specified 26 41 332
Number of AEs:
Nodules (of which excised) 1 (-) 1 (-) 3 (3) 166 (>10)
Overcorrection 1
Persistent erythema 2
Persistent inflammation/edema 2 4

AEs, adverse events; NS, not specified.

Two articles do not precise how many nodules were excised.20,28
KADOUCH
KADOUCH | 157

injections of CaHA in the face were included. The relevant results

were cross-referenced. Finally, a total of 21 articles could be
included (Table 2).
The reported injection sites were categorized as: glabellar area,
tear trough/infraorbital area, cheeks, nose, nasolabial folds, perioral
area, lips, marionette lines, prejowl sulcus, chin/mental crease, and as
other or not specified location. CaHA is regarded as not suitable for
the lips and the periorbital area.6 These areas are also referred to as
the “dynamic” areas of the face, as they are characterized by fre-
quent muscle movements and little subcutaneous fat.
ISRs such as ecchymosis or hematoma, edema, erythema, pain,
and itching were not included. As in most articles no clear distinction
was made between early and late AEs, both were included (Table 3).
If possible, the reported AEs were classified according to the classifi-
cation depicted in Table 1. In cases where a lumpiness was
described, instead of a nodule or an overcorrection (technical mis-
hap), it was categorized as a nodule when it had been (successfully)
treated with intralesional corticosteroids. For publications in which
only the cohort size was specified and not the number of treat-
ments, the amount of patients was also used as treatment number.
3 | RESULTS
A total of 21 peer-reviewed articles, published between 2004 and
2015, could be included. Twenty articles were based on prospec-
tively performed cohort studies,13,15,20,24-40 and one article consisted
of a large retrospective study.19 All together, 5081 treatments with
CaHA performed on 2779 patients were included.
The preferred injections sites for the CaHA treatments were the
nasolabial folds (38%, 1930 of 5081), marionette lines (16%, 815 of
5081), lips (15%, 784 of 5081), glabellar area (7%, 372 of 5081), and
the perioral area (7%, 369 of 5081). In 332 cases (7%, 332 of 5081),
Nodules (n = 166)
OvercorrecƟon (n = 1)
Persisten erythema (n = 2)
Persistent
inflammaƟon/edema (n =
4)
F I G U R E 1 Reported AEs in 5081 treatments with CaHA
performed on 2779 patients
the injection site was not among the regular injection sites or not
specified. A total of 173 (3%, 173 of 5081) AEs were reported. The
assessed types of AEs could be categorized as nodules (96%, 166 of
173), persistent inflammation/swelling (2%, 4 of 173), persistent ery-
thema (1%, 2 of 173), and overcorrection (technical mishap; 1%, 1 of
173; Figure 1). When specified per injection site, the incidence of
AEs for lip treatments was 9.4% (74 of 784), followed by the tear
trough/infraorbital area 1.8% (1 of 55), perioral area 1.6% (6 of 369),
cheeks 0.8% (1 of 123), and nasolabial folds 0.3% (5 of 1930). No
infections/biofilms, abscesses, hypersensitivity reactions, migrations/
dislocations, calcifications, granulomas, or other (serious) AEs were
documented in the included studies.
When looking further at the significant number of reported nod-
ules (n=166), the majority occurred at the lips (45%, 74 of 166), fol-
lowed by the perioral area (4%, 6 of 166) and the nasolabial fold
(3%, 5 of 166). In 80 cases (48%), the exact location of the docu-
mented nodules could not be assessed from the information in the
article. Based on the total number of treatments, the incidence of

T A B L E 3 Reported AEs in relation to the injection sites

Nodules (of which Persistent Persistent
Type of AEs injection sites excised) Overcorrection erythema inflammation/edema Total
Glabella area
Tear trough, infraorbital 1 1
Cheeks/zygoma 1 (-) 1
Nose
Nasolabial folds 5 (-) 5
Perioral area 6 (?) 6
Lips 74 (>1) 74
Marionette lines
Prejowl sulcus
Chin, mental crease
Other or not specified 80 (9) 2 4 86
Total 166 1 2 4 173

AEs, adverse events.

No granulomas, infections, abscesses, allergic reactions, migrations, or calcifications were reported.
158 | KADOUCH
nodules was 3% (166 of 5081), with a predilection for the lips. Most
nodules could be treated with massaging or intralesional corticos-
teroids. However, in at least 10 cases (6%, 10 of 166), excision of
the nodule was deemed necessary. As two articles do not precise
how many nodules were excised,20,28 the exact number of excised
nodules could not be assessed.
4 | DISCUSSION
CaHA is currently the second most popular soft tissue filler, after
the hyaluronic acid-based fillers.41 Other known temporary fillers are
poly-L-lactic acid (PLLA) and polycaprolactone. Polycaprolactone has
only recently been brought on the market, and little literature is
available on the safety and AEs of this product. Several studies have
been published that give an impression of the safety profile of
CaHA. In this article, we reviewed the currently available literature
on reported CaHA AEs. Twenty-one studies describing 5081 CaHA
injections in 2779 patients were included. The onset of nodules is
the most common reported AE (96%, 166 of 173), and its incidence
in this cohort is 3% (166 of 5081). In comparison, for PLLA, the inci-
dence of nodules and papules is believed to be around 10-16%.17
Similarly to CaHA, the PLLA studies describe no serious late AEs
aside from the nodules. Interestingly, hyaluronic acid fillers seem to
F I G U R E 2 Classification of
granulomatous foreign body reactions by
Duranti50
generate different types of late complications, such as infections,
migrations, abscess formation, and hypersensitivity reactions.17 This
phenomenon could result from the different chemical and physical
properties between these soft tissue fillers, as CaHA and PLLA both
consist of particles, whereas (cross-linked) hyaluronic acid fillers
mostly consist of gels. Several studies have shown that such filler
properties can influence the onset, type, and histological aspect of
complications.9,10,23,42,43
4.1 | Nodules or granulomas
When interpreting the above results, it is important to be clear
about the difference between granulomas and early/late nodules.
A granuloma is a purely histological diagnosis that cannot be made
with the naked eye.43,44 A nodule is a clinical description of what
a doctor sees and feels. The term nodule does not suggest any-
thing about the cause. Nodules can be caused by incorrect posi-
tioning of filler material, muscle- or gravity-induced displacement
or accumulation, capsular contraction, infection, hypersensitivity
reaction, or result from a foreign body reaction to the filler mate-
rial.10,23 Interestingly, infections or biofilms, type IV hypersensitivity
reactions, and foreign body reactions are all believed to be capable
of inducing granulomatous immune reactions histologically.45-48 All
fillers, being corpora aliena, induce some level of granulomatous
KADOUCH
foreign body reactions (GFBRs). Granulomatous immune reactions
can be classified according to a severity grading system ranging
from grade I, a slight reaction with few inflammatory cells com-
posed predominantly of histiocytes, lymphocytes, and plasma cells,
to grade IV, a pronounced GFBR with multiple granulomas con-
taining multinucleated giant cells and totally encapsulating the
implants (Figure 2).43,49-51 Granuloma-induced nodules are believed
to be able to present themselves clinically both as inflammatory
43,44
and noninflammatory lesions. However, not all fillers seem to
be capable of producing a grade IV granulomatous reaction.43 The
implant size may play a crucial role. A histological study on perma-
nent fillers showed that for fillers consisting of particles, such as
polymethylmethacrylate and hydroxyethylmethacrylate/ethyl-
methacrylate, the immune response was capable of encapsulating
the particles, whereas for the nonparticulated fillers, such as
polyalkylimide gel and polyacrylamide gel, this phenomenon was
43
not seen. Also for CaHA, which consists of 25-45-lm particles,
grade IV granulomas encapsulating the filler material have been
demonstrated histologically.9,44,51,52 Based on the results in this
study, infections and hypersensitivity reactions do not seem to
play a major role in CaHA complications, reducing the probable
etiologies of a histological granulomatous immune response to
CaHA to a foreign body reaction.
4.2 | Etiology of CaHA nodules
In the management of CaHA nodules, it may be useful to deter-
mine in what time frame the nodule arose. Similarly to the classifi-
cation of AEs, CaHA nodules can be divided into “early” (onset
within 2 weeks after injection) or “late” (onset later than 2 weeks
after injection) nodules. An early nodule is likely to result from
technical mishaps (overfilling, injection too superficially, contour
irregularities), whereas late nodules could arise due to dislocated/
accumulated material from muscle contractions or gravity, capsule
formation, or a foreign body reaction.23 In this study, it was not
possible to differentiate the reported nodules into these etiological
subsets. Unfortunately, the terminology of filler AEs is not always
used consistently or correctly, and the moment of onset of the
nodules not always specified properly. However, nodules arising in
“dynamic” facial areas, such as the lips or the periorbital area, are
likely to be the result of muscle contractions. On the other hand, if
a good effect of intralesional corticosteroid injections is reported,
we can assume that the nodules are not the result of an inade-
quate injection technique or muscle contractions but of a GFBR.
Although no infections were reported in this review, in case of an
inflammatory nodule, an infection should still be considered. In this
study, 45% (74 of 166) of the reported nodules occurred in
dynamic areas, while these areas represent only 17% (839 of 5081)
of the total treatments. Although in 48% (80 of 166) of cases the
exact location of the documented nodules could not be assessed
from the information in the article, the current data suggest that if
dynamic areas were avoided, the incidence of CaHA nodules would
be substantially lower than the 3% reported in this study.
| 159
For example, if we would maintain the nodule-ratio of the
dynamic versus non-dynamic facial areas for the nodules that could
not be allocated to a location (n = 80), then avoiding injections in
the dynamic facial areas would result in an incidence of CaHA
nodules of 0.61% (21 of 3437).
4.3 | Management of CaHA nodules
In the management of nodules, it can be useful to differentiate them
by the time of onset. As described above, early (noninflammatory)
nodules arising <2 weeks are likely to be due to incorrect injection/
positioning of filler material. In such cases, massaging, aspiration, or
intralesional injection of sterile water might be helpful. For late-
occurring nodules, intralesional injections with corticosteroids could
also be an option and has been shown to be effective in some
cases.20,28,34 In cases of inflammatory nodules, whether arising early
or late, an infection and antibiotic treatment should always be con-
sidered. Clarithromycin, tetracyclines, and fluoroquinolones are often
advised. Excision should always be the last option and tried to be
avoided. This study showed that in at least 10 cases (6%, 10 of
166), the reported nodule was excised. However, in most cases,
CaHA nodules are not visible and resolve without intervention.25
5 | CONCLUSION
Based on the results in this study, CaHA appears to have a good
safety profile. Nodules are by far the most common AE, and no seri-
ous adverse events, infections, or hypersensitivity reactions were
reported in the investigated articles. Furthermore, the assessed data
quite unambiguously reveal that if the dynamic areas of the face (ie,
lips and the periorbital area) are avoided, this would significantly
reduce the incidence of nodules. Etiologically, infection and hyper-
sensitivity appear to play little or no role in the onset of CaHA nod-
ules. Their onset is more probably related to incorrect positioning of
filler material, muscle- or gravity-induced displacement, capsular con-
traction, or a GFBR. When treating CaHA nodules, one should not
overlook the temporary character of the product and that the nod-
ules normally resolve without intervention.
REFERENCES
1. Havlik RJPDC. Hydroxylapatite. Plast Reconstr Surg. 2002;110:1176-
1179.
2. Baker C. Methylcellulose & Sodium Carboxymethylcellulose: Uses in
Paper Conservation. The American Institute for Conservation. Vol-
ume one, 1982. http://cool.conservation-us.org/coolaic/sg/bpg/
annual/v01/bp01-04.html. Accessed February 28, 2016.
3. Jacovella PF. Calcium hydroxylapatite facial filler (Radiesse): indica-
tions, technique, and results. Clin Plast Surg. 2006;33:511-523.
4. Coleman KM, Voigts R, DeVore DP, Termin P, Coleman WP 3rd.
Neocollagenesis after injection of calcium hydroxylapatite composi-
tion in a canine model. Dermatol Surg. 2008;34(Suppl 1):S53-S55.
5. Kadouch JA. Werking en bijwerking van fillers. Ned Tijdschr Dermatol
Venereol. 2014;24:599-607.
160 | KADOUCH
6. van Loghem JY, Yutskovskaya A, Werschler P. Calcium hydroxylap-
atite over a decade of clinical experience. J Clin Aesthet Dermatol.
2015;8:38-49.
7. Bank DE. A novel approach to treatment of the aging hand with
Radiesse. J Drugs Dermatol. 2009;8:1122-1126.
8. Sadick NS. A 52-week study of safety and efficacy of calcium
hydroxylapatite for rejuvenation of the aging hand. J Drugs Dermatol.
2011;10:47-51.
9. Requena L, Requena C, Christensen L, Zimmermann US, Kutzner H,
Cerroni L. Adverse reactions to injectable soft tissue fillers. J Am
Acad Dermatol. 2011;64:1-34; quiz 5-6.
10. Nicolau PJ. Long-lasting and permanent fillers: biomaterial influence
over host tissue response. Plast Reconstr Surg. 2007;119:2271-2286.
11. Lemperle G, Morhenn VB, Pestonjamasp V, Gallo RL. Migration
Studies and Histology of Injectable Microspheres of Different Sizes
in Mice. Plast Reconstr Surg. 2004;113:1380-1390.
12. Yutskovskaya Y, Kogan E, Leshunov E. A randomized, split-face, his-
tomorphologic study comparing a volumetric calcium hydroxylapatite
and a hyaluronic acid-based dermal filler. J Drugs Dermatol.
2014;13:47-52.
13. Carruthers A, Carruthers J. Evaluation of injectable calcium
hydroxylapatite for the treatment of facial lipoatrophy associated
with human immunodeficiency virus. Dermatol Surg. 2008;34:1486-
1499.
14. Schelke LW, Van Den Elzen HJ, Erkamp PP, Neumann HA. Use of
ultrasound to provide overall information on facial fillers and sur-
rounding tissue. Dermatol Surg. 2010;36(Suppl 3):1843-1851.
15. van Rozelaar L, Kadouch JA, Duyndam DA, Nieuwkerk PT, Lutgen-
dorff F, Karim RB. Semipermanent filler treatment of HIV-positive
patients with facial lipoatrophy: long-term follow-up evaluating MR
imaging and quality of life. Aesthet Surg J. 2014;34:118-132.
16. Pavicic T. Complete biodegradable nature of calcium hydroxylapatite
after injection for malar enhancement: an MRI study. Clin Cosmet
Investig Dermatol. 2015;8:19-25.
17. De Vries CG, Geertsma RE. Clinical data on injectable tissue fillers: a
review. Expert Rev Med Devices. 2013;10:835-853.
18. Hanke CW. Evolution of filler materials in dermatology. J Am Acad
Dermatol. 2013;68:858-859.
19. Tzikas TL. A 52-month summary of results using calcium hydroxylap-
atite for facial soft tissue augmentation. Dermatol Surg. 2008;34
(Suppl 1):S9-S15.
20. Jansen DA, Graivier MH. Evaluation of a calcium hydroxylapatite-
based implant (Radiesse) for facial soft-tissue augmentation. Plast
Reconstr Surg. 2006;118(3 Suppl):22S-30S, discussion 1S-3S.
21. Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to dermal fillers:
review. Dermatol Surg. 2005;31(11 Pt 2):1616-1625.
22. Daines SM, Williams EF. Complications associated with injectable
soft-tissue fillers: a 5-year retrospective review. JAMA Facial Plast
Surg. 2013;15:226-231.
23. Kadouch JA, Kadouch DJ, Fortuin S, van Rozelaar L, Karim RB,
Hoekzema R. Delayed-onset complications of facial soft tissue aug-
mentation with permanent fillers in 85 patients. Dermatol Surg.
2013;39:1474-1485.
24. Sklar JA, White SM. Radiance FN: a new soft tissue filler. Dermatol
Surg. 2004;30:764-768.
25. Tzikas TL. Evaluation of the radiance FN soft tissue filler for facial
soft tissue augmentation. Arch Facial Plast Surg. 2004;6:234-239.
26. Goldberg DJ, Amin S, Hussain M. Acne scar correction using calcium
hydroxylapatite in a carrier-based gel. J Cosmet Laser Ther.
2006;8:134-136.
27. Jacovella PF, Peiretti CB, Cunille D, Salzamendi M, Schechtel SA.
Long-lasting results with hydroxylapatite (Radiesse) facial filler. Plast
Reconstr Surg. 2006;118(3 Suppl):15S-21S.
28. Roy D, Sadick N, Mangat D. Clinical trial of a novel filler mate-
rial for soft tissue augmentation of the face containing synthetic
calcium hydroxylapatite microspheres. Dermatol Surg. 2006;32:
1134-1139.
29. Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-
label, 18-month trial of calcium hydroxylapatite (Radiesse) for facial
soft-tissue augmentation in patients with human immunodeficiency
virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg.
2006;118(3 Suppl):34S-45S.
30. Godin MS, Majmundar MV, Chrzanowski DS, Dodson KM. Use of
radiesse in combination with restylane for facial augmentation. Arch
Facial Plast Surg. 2006;8:92-97.
31. Moers-Carpi M, Vogt S, Santos BM, Planas J, Vallve SR, Howell DJ.
A multicenter, randomized trial comparing calcium hydroxylapatite to
two hyaluronic acids for treatment of nasolabial folds. Dermatol Surg.
2007;33(Suppl 2):S144-S151.
32. Stupak HDM, Moulthrop THM, Wheatley P, Tauman AV, Johnson
CM Jr. Calcium hydroxylapatite gel (Radiesse) injection for the cor-
rection of postrhinoplasty contour deficiencies and asymmetries.
Arch Facial Plast Surg. 2007;9:130-136.
33. Smith S, Busso M, McClaren M, Bass LS. A randomized, bilateral,
prospective comparison of calcium hydroxylapatite microspheres
versus human-based collagen for the correction of nasolabial folds.
Dermatol Surg. 2007;33(Suppl 2):S112-S121; discussion S21.
34. Sadick NS, Katz BE, Roy D. A multicenter, 47-month study of safety
and efficacy of calcium hydroxylapatite for soft tissue augmentation
of nasolabial folds and other areas of the face. Dermatol Surg.
2007;33(Suppl 2):S122-S126; discussion S6-7.
35. Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite versus nonani-
mal stabilized hyaluronic acid for the correction of nasolabial folds: a
12-month, multicenter, prospective, randomized, controlled, split-
face trial. Dermatol Surg. 2008;34:210-215.
36. Rokhsar C, Ciocon DH. Nonsurgical rhinoplasty: an evaluation of
injectable calcium hydroxylapatite filler for nasal contouring. Derma-
tol Surg. 2008;34:944-946.
37. Bass LS, Smith S, Busso M, McClaren M. Calcium hydroxylapatite
(Radiesse) for treatment of nasolabial folds: long-term safety and
efficacy results. Aesthet Surg J. 2010;30:235-238.
38. Marmur ES, Taylor SC, Grimes PE, Boyd CM, Porter JP, Yoo JY. Six-
month safety results of calcium hydroxylapatite for treatment of
nasolabial folds in Fitzpatrick skin types IV to VI. Dermatol Surg.
2009;35:1641-1645.
39. Marmur E, Green L, Busso M. Controlled, randomized study of pain
levels in subjects treated with calcium hydroxylapatite premixed with
lidocaine for correction of nasolabial folds. Dermatol Surg.
2010;36:309-315.
40. Rauso R, Curinga G, Rusciani A, Colella G, Amore R, Tartaro G.
Safety and efficacy of one-step rehabilitation of human immuno-
deficiency virus-related facial lipoatrophy using an injectable
calcium hydroxylapatite dermal filler. Dermatol Surg. 2013;39:1887-
1894.
41. Cosmetic surgery National Data Bank: Statistics 2013. http://
www.surgery.org/media/statistics. Accessed February 28, 2016.
42. Kadouch JA, Tutein Nolthenius C, Kadouch DJ, van der Woude HJ,
Karim RB, Hoekzema R. Complications after facial injections with
permanent filler; important limitations and considerations of MRI
evaluation. Aesthet Surg J. 2014;34:913-923.
43. Kadouch JA, Vos W, Nijhuis EW, Hoekzema R. Granulomatous
foreign-body reactions to permanent fillers: detection of CD123+
plasmacytoid dendritic cells. Am J Dermatopathol. 2015;37:107-
114.
44. Daley T, Damm DD, Haden JA, Kolodychak MT. Oral lesions associ-
ated with injected hydroxyapatite cosmetic filler. Oral Surg Oral Med
Oral Pathol Oral Radiol. 2012;114:107-111.
45. Alijotas-Reig J, Fernandez-Figueras MT, Puig L. Late-onset inflamma-
tory adverse reactions related to soft tissue filler injections. Clin Rev
Allergy Immunol. 2013;45:97-108.
KADOUCH | 161

46. Alijotas-Reig J, Fernandez-Figueras MT, Puig L. Inflammatory, 51. Shahrabi-Farahani S, Lerman MA, Noonan V, Kabani S, Woo SB.
immune-mediated adverse reactions related to soft tissue dermal fil- Granulomatous foreign body reaction to dermal cosmetic fillers with
lers. Semin Arthritis Rheum. 2013;43:241-258. intraoral migration. Oral Surg Oral Med Oral Pathol Oral Radiol.
47. Alijotas-Reig J, Garcia-Gimenez V, Miro-Mur F, Vilardell-Tarres M. 2014;117:105-110.
Delayed immune-mediated adverse effects related to polyacrylamide 52. Moulonguet I, Arnaud E, Bui P, Plantier F. Foreign body reaction to
dermal fillers: clinical findings, management, and follow-up. Dermatol radiesse: 2 cases. Am J Dermatopathol. 2013;35:e37-e40.
Surg. 2009;35(Suppl 1):360-366.
48. Christensen L, Breiting V, Janssen M, Vuust J, Hogdall E. Adverse
reactions to injectable soft tissue permanent fillers. Aesthetic Plast
Surg. 2005;29:34-48. How to cite this article: Kadouch JA. Calcium
49. Lemperle G, Morhenn V, Charrier U. Human histology and persis- hydroxylapatite: A review on safety and complications.
tence of various injectable filler substances for soft tissue augmenta-
J Cosmet Dermatol. 2017;16:152–161.
tion. Aesthetic Plast Surg. 2003;27:354-366; discussion 67.
50. Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. Injectable hya-
luronic acid gel for soft tissue augmentation. A clinical and histologi-
cal study. Dermatol Surg. 1998;24:1317-1325.