- Email: [email protected]
Large-particle calcium hydroxylapatite injection for correction of facial wrinkles and depressions
DERMATOLOGIC
SURGERY
Large-particle calcium hydroxylapatite injection for correction of facial wrinkles and depressions Murad Alam, MD,a,b,c Jillian Havey, MD,a Natalie Pace, BS,a Marisa Pongprutthipan, MD,a and Simon Yoo, MDa,b,c Chicago, Illinois Background: Small-particle calcium hydroxylapatite (Radiesse, Merz, Frankfurt, Germany) is safe and effective for facial wrinkle reduction, and has medium-term persistence for this indication. There is patient demand for similar fillers that may be longer lasting. Objective: We sought to assess the safety and persistence of effect in vivo associated with use of largeparticle calcium hydroxylapatite (Coaptite, Merz) for facial augmentation and wrinkle reduction. Methods: This was a case series of 3 patients injected with large-particle calcium hydroxylapatite. Results: Large-particle calcium hydroxylapatite appears to be effective and well tolerated for correction of facial depressions, including upper mid-cheek atrophy, nasolabial creases, and HIV-associated lipoatrophy. Adverse events included erythema and edema, and transient visibility of the injection sites. Treated patients, all of whom had received small-particle calcium hydroxylapatite correction before, noted improved persistence at 6 and 15 months with the large-particle injections as compared with prior small-particle injections. Limitations: This is a small case series, and there was no direct control to compare the persistence of small-particle versus large-particle correction. Conclusions: For facial wrinkle correction, large-particle calcium hydroxylapatite has a safety profile comparable with that of small-particle calcium hydroxylapatite. The large-particle variant may have longer persistence that may be useful in selected clinical circumstances. ( J Am Acad Dermatol 2011;65:92-6.) Key words: calcium hydroxylapatite; cheek augmentation; Coaptite; facial augmentation; fillers; HIV lipoatrophy; soft-tissue augmentation; wrinkle reduction.
S
mall-particle (25-45 micrometer) calcium hydroxylapatite (Radiesse, Merz, Frankurt, Germany) is a commonly used prepackaged, injectable soft-tissue augmentation that was Food and Drug Administration (FDA) approved for correction of moderate to severe facial wrinkles and folds in 2006.1-4 Before that, this material was approved for dental, orthopedic, and From the Departments of Dermatology,a Otolaryngology-Head and Neck Surgery,b and Surgery,c Northwestern University, Feinberg School of Medicine. Supported by Department of Dermatology, Northwestern University. Conflicts of interest: None declared. Reprint requests: Murad Alam, MD, Department of Dermatology, Northwestern University, 676 N St Clair, Suite 1600, Chicago, IL 60611. E-mail: [email protected]. Published online April 19, 2011. 0190-9622/$36.00 Ó 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.12.018
92
vocal-cord augmentation applications, and used off-label for facial augmentation. In the realm of facial filling, small-particle calcium hydroxylapatite is one of two FDA-approved medium-term filler materials, the other being poly-L-lactate (Sculptra, Sanofi-Aventis, Malvern, PA), that provide correction for 1 to 2 years rather than for 6 to 9 months as many other temporary injectable fillers.5 Significantly, in the United States, there are no temporary fillers that last longer than poly-L-lactic acid or small-particle calcium hydroxylapatite. And permanent fillers have not become popular, possibly because of reports of troublesome adverse events after their use elsewhere in the world. In this context, it is interesting that a large-particle version of calcium hydroxylapatite (Coaptite, Merz; distributed by Boston Scientific) has already been FDA approved for use in urinary incontinence.6,7 For facial filling, large-particle calcium hydroxylapatite offers the theoretic promise of a better and
Alam et al 93
J AM ACAD DERMATOL VOLUME 65, NUMBER 1
longer-lasting correction than small-particle calcium hydroxylapatite. We report 3 cases of facial augmentation using large-particle calcium hydroxylapatite. We believe these are the first reported applications of this material for this off-label indication. We document the safety and effectiveness of our experience, and provide pilot data for future larger-scale studies.
total of 2 3 1 mL syringes of large-particle calcium hydroxylapatite injection to her bilateral nasolabial folds. In all, 1.1 and 0.9 mL were placed into the right and left nasolabial folds, respectively (Fig 1).
Case 2 A 46-year-old woman with upper mid-face atrophy and Fitzpatrick skin type II to III received a total CAPSULE SUMMARY of 2 3 1 mL syringes of largeMETHODS particle calcium hydroxylapInjection of large-particle calcium Injection material and atite injection to her bilateral hydroxylapatite for correction of midapparatus mid cheeks for augmentation face subcutaneous atrophy appears to Material used was calcium of these. In all, 0.9 and 1.1 mL be safe and effective. hydroxylapatite injectable were placed into the right In vivo persistence of large-particle implant (Coaptite, Merz), and left cheeks, respectively calcium hydroxylapatite may be greater with particle size 75 to 125 (Fig 2). than that of small-particle calcium micrometer, in an aqueous hydroxylapatite, but controlled trials are gel carrier (sodium carboxyCase 3 needed to establish this. methylcellulose, glycerin, A 57-year-old man with sterile water). Syringe size severe mid-facial HIVwas 1 mL. Needle size was 21-gauge, .5 and 1.25 in. associated lipoatrophy and Fitzpatrick skin type III received a total of 4 x 1 mL syringes of large-particle Anesthesia calcium hydroxylapatite injection into his bilateral Infraorbital nerve block was via intraoral apmid cheeks. In all, 1.7 and 2.3 mL, respectively, were proach with 1 to 2 mL total of 1% lidocaine without placed into the right and left sides (Fig 3). epinephrine. Additional anesthesia was via fanning All patients tolerated the injections well, and method with 1% lidocaine with 1:200,000 epinephcompared with prior injections with small-particle rine and 10% sodium bicarbonate (8.4% solution). calcium hydroxylapatite filler (ie, Radiesse, Merz) (last treatment 24, 21, and 45 months before largeImplantation technique particle injection, respectively, for patients 1, 2, and After marking with a permanent marker (Sharpie, 3), each self-reported greater persistence of results at Sanford Corp, Oakbrook, IL) of wrinkles and skin 6 and 15 months follow-ups. Specifically, patients depressions on the nasolabial folds and medial 1 and 2 reported greater than 50% persistence of the cheeks, and application of anesthesia, correction filler correction at 15 months, and patient 3 reported was begun with bevel-down needle insertion. The 25% to 50% persistence at this time point. Injector clinical assessment was consistent with these patient needle was advanced until the middle to deep subassessments, with the primary injector noting greater cutis, aspiration was performed to ensure that the tip was not within a blood vessel, and injection was then than 75% persistence of filler by palpation and live commenced slowly as the needle was withdrawn. visual assessment at 6 months after treatment in all 3 Injection rate was at all times less than 0.3 mL/min. patients. Adverse events were minor and similar to Retrograde linear threading technique was then conthose with small-particle calcium hydroxylapatite tinued until the defect was corrected. Additional filler, with all 3 patients experiencing mild injection injections on the same side of the face were placed discomfort, along with posttreatment transient edema, erythema, and focal ecchymoses. All patients through the same entry point, and longer needles reported that the needle entry sites were visible for were used, as appropriate, to reach portions of the defect farther from the entry site. Each linear thread 1 to 2 days after injection. comprised no more than 0.1 mL. Firm massage, with DISCUSSION index finger inside the mouth and thumb outside, was Based on our limited experience of 3 cases, largethen used to remove any unevenness. particle calcium hydroxylapatite filler appears to be RESULTS safe for injection into wrinkles and depressions in the Case 1 mid face. No persistent bruising, contour abnormalA 44-year-old woman with prominent nasolabial ity, vascular occlusion, neuropathic pain, or implant fold creases and Fitzpatrick skin type II received a migration was detected in any of the patients. d
d
94 Alam et al
J AM ACAD DERMATOL
JULY 2011
Fig 1. Case 1. View of right (A) and left (B) nasolabial folds before injection, and right (C) and left (D) after injection.
There were some technique differences in how we injected large-particle calcium hydroxylapatite, as compared with our routine technique with smallparticle filler. For one, a larger bore 21-gauge needle was used. This could be quite painful on injection if nerve blocks or intralesional anesthetic were not used, and we highly recommend the use of such effective anesthesia. In addition, the locus of injection was the middle to deep subcutis rather than the superficial subcutis; we selected this to avoid the risk of superficial injection, which could potentially pose a risk of vascular occlusion and of visible intradermal implant. The thicker, larger particle size elevated the importance of avoiding a superficial implant, which would likely be more visible with larger than smaller
particles. Finally, injection rate was scrupulously kept below 0.3 mL/min to minimize the probability of intravascular injection. Although no such occlusion with this material has been observed by us or others, we deemed it prudent to actively prevent this outcome, as the larger particle size would pose a theoretic occlusion risk to small-bore vessels if injected with great force. Adverse events in all 3 of our cases were extremely minimal, and indistinguishable from those with small-particle treatment. The only exception was that the needle entry sites were faintly visible as round red spots on the skin for 1 to 2 days after injection before resolving completely. To minimize marking, we used only one entry site per side of the
J AM ACAD DERMATOL VOLUME 65, NUMBER 1
Alam et al 95
Fig 2. Case 2. Front view of patient before (A) and after (B) injection of bilateral mid-cheek area.
Fig 3. Case 3. Front view before treatment (A); after marking of areas to be treated (B); and after treatment (C) of patient receiving injections for HIV-associated facial atrophy.
face, and used needles of different lengths, aimed at varying angles, to access all portions of each defect. Very large or diffuse defects may require multiple entry sites. Fifteen months after injection, all patients report that some of the implanted material remains in place. They also report that, compared with prior injections with small-particle calcium hydroxylapatite, the correction appeared to be more persistent, with more gradual drop-off in the apparent degree of correction.
Clearly, these 3 case reports cannot definitively establish the safety of large-particle calcium hydroxylapatite for facial wrinkle correction, nor can they demonstrate with any certainty that this material has improved longevity. However, to the degree that biodegradation of calcium hydroxylapatite is by macrophage engulfment, beginning from the outside of each spherule and continuing to the center, it does seem plausible that the larger particle size may pose an obstacle to the rapidity of this process. Specifically, for larger particles, the ratio of surface
96 Alam et al
area to volume is proportionately lower, and hence the area per unit volume of mineral that is vulnerable to macrophages is relatively less. In addition, the safety of injection of large-particle calcium hydroxylapatite is supported by its relative similarity to small-particle material in all characteristics except particle diameter; and small-particle calcium hydroxylapatite is FDA approved for soft-tissue augmentation and has an excellent safety record in phase IV studies. In conclusion, these 3 preliminary case reports demonstrate the efficacy and tolerability of the offlabel use of large-particle calcium hydroxylapatite filler for correction of facial wrinkles and depressions. Further studies enrolling more patients are needed to confirm these findings. Such additional studies may also clarify the clinical circumstances in which use of large-particle calcium hydroxylapatite filler is preferable to the use of small-particle filler.
J AM ACAD DERMATOL
JULY 2011
2.
3.
4.
5.
6.
7. REFERENCES 1. Graivier MH, Bass LS, Busso M, Jasin ME, Narins RS, Tzikas TL. Calcium hydroxylapatite (Radiesse) for correction of the mid-
and lower face: consensus recommendations. Plast Reconstr Surg 2007;120(Suppl):55-66S. 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):S112-21. Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite versus nonanimal stabilized hyaluronic acid for the correction of nasolabial folds: a 12-month, multicenter, prospective, randomized, controlled, split-face trial. Dermatol Surg 2008;34: 210-5. Alam M, Yoo SS. Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions. J Am Acad Dermatol 2007;56:285-9. Alam M, Gladstone H, Kramer EM, Murphy JP Jr, Nouri K, Neuhaus IM, et al. American Society for Dermatologic Surgery. ASDS guidelines of care: injectable fillers. Dermatol Surg 2008; 34(Suppl):S115-48. Mayer RD, Dmochowski RR, Appell RA, Sand PK, Klimberg IW, Jacoby K, et al. Multicenter prospective randomized 52-week trial of calcium hydroxylapatite versus bovine dermal collagen for treatment of stress urinary incontinence. Urology 2007;69: 876-80. Coaptite P040047. Approval order and physician labeling. Bioform Inc, San Mateo (CA). U.S. Department of Heath and Human Services, Food and Drug Administration, Center for Devices and Radiologic Health, 2005.
SURGERY
Large-particle calcium hydroxylapatite injection for correction of facial wrinkles and depressions Murad Alam, MD,a,b,c Jillian Havey, MD,a Natalie Pace, BS,a Marisa Pongprutthipan, MD,a and Simon Yoo, MDa,b,c Chicago, Illinois Background: Small-particle calcium hydroxylapatite (Radiesse, Merz, Frankfurt, Germany) is safe and effective for facial wrinkle reduction, and has medium-term persistence for this indication. There is patient demand for similar fillers that may be longer lasting. Objective: We sought to assess the safety and persistence of effect in vivo associated with use of largeparticle calcium hydroxylapatite (Coaptite, Merz) for facial augmentation and wrinkle reduction. Methods: This was a case series of 3 patients injected with large-particle calcium hydroxylapatite. Results: Large-particle calcium hydroxylapatite appears to be effective and well tolerated for correction of facial depressions, including upper mid-cheek atrophy, nasolabial creases, and HIV-associated lipoatrophy. Adverse events included erythema and edema, and transient visibility of the injection sites. Treated patients, all of whom had received small-particle calcium hydroxylapatite correction before, noted improved persistence at 6 and 15 months with the large-particle injections as compared with prior small-particle injections. Limitations: This is a small case series, and there was no direct control to compare the persistence of small-particle versus large-particle correction. Conclusions: For facial wrinkle correction, large-particle calcium hydroxylapatite has a safety profile comparable with that of small-particle calcium hydroxylapatite. The large-particle variant may have longer persistence that may be useful in selected clinical circumstances. ( J Am Acad Dermatol 2011;65:92-6.) Key words: calcium hydroxylapatite; cheek augmentation; Coaptite; facial augmentation; fillers; HIV lipoatrophy; soft-tissue augmentation; wrinkle reduction.
S
mall-particle (25-45 micrometer) calcium hydroxylapatite (Radiesse, Merz, Frankurt, Germany) is a commonly used prepackaged, injectable soft-tissue augmentation that was Food and Drug Administration (FDA) approved for correction of moderate to severe facial wrinkles and folds in 2006.1-4 Before that, this material was approved for dental, orthopedic, and From the Departments of Dermatology,a Otolaryngology-Head and Neck Surgery,b and Surgery,c Northwestern University, Feinberg School of Medicine. Supported by Department of Dermatology, Northwestern University. Conflicts of interest: None declared. Reprint requests: Murad Alam, MD, Department of Dermatology, Northwestern University, 676 N St Clair, Suite 1600, Chicago, IL 60611. E-mail: [email protected]. Published online April 19, 2011. 0190-9622/$36.00 Ó 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.12.018
92
vocal-cord augmentation applications, and used off-label for facial augmentation. In the realm of facial filling, small-particle calcium hydroxylapatite is one of two FDA-approved medium-term filler materials, the other being poly-L-lactate (Sculptra, Sanofi-Aventis, Malvern, PA), that provide correction for 1 to 2 years rather than for 6 to 9 months as many other temporary injectable fillers.5 Significantly, in the United States, there are no temporary fillers that last longer than poly-L-lactic acid or small-particle calcium hydroxylapatite. And permanent fillers have not become popular, possibly because of reports of troublesome adverse events after their use elsewhere in the world. In this context, it is interesting that a large-particle version of calcium hydroxylapatite (Coaptite, Merz; distributed by Boston Scientific) has already been FDA approved for use in urinary incontinence.6,7 For facial filling, large-particle calcium hydroxylapatite offers the theoretic promise of a better and
Alam et al 93
J AM ACAD DERMATOL VOLUME 65, NUMBER 1
longer-lasting correction than small-particle calcium hydroxylapatite. We report 3 cases of facial augmentation using large-particle calcium hydroxylapatite. We believe these are the first reported applications of this material for this off-label indication. We document the safety and effectiveness of our experience, and provide pilot data for future larger-scale studies.
total of 2 3 1 mL syringes of large-particle calcium hydroxylapatite injection to her bilateral nasolabial folds. In all, 1.1 and 0.9 mL were placed into the right and left nasolabial folds, respectively (Fig 1).
Case 2 A 46-year-old woman with upper mid-face atrophy and Fitzpatrick skin type II to III received a total CAPSULE SUMMARY of 2 3 1 mL syringes of largeMETHODS particle calcium hydroxylapInjection of large-particle calcium Injection material and atite injection to her bilateral hydroxylapatite for correction of midapparatus mid cheeks for augmentation face subcutaneous atrophy appears to Material used was calcium of these. In all, 0.9 and 1.1 mL be safe and effective. hydroxylapatite injectable were placed into the right In vivo persistence of large-particle implant (Coaptite, Merz), and left cheeks, respectively calcium hydroxylapatite may be greater with particle size 75 to 125 (Fig 2). than that of small-particle calcium micrometer, in an aqueous hydroxylapatite, but controlled trials are gel carrier (sodium carboxyCase 3 needed to establish this. methylcellulose, glycerin, A 57-year-old man with sterile water). Syringe size severe mid-facial HIVwas 1 mL. Needle size was 21-gauge, .5 and 1.25 in. associated lipoatrophy and Fitzpatrick skin type III received a total of 4 x 1 mL syringes of large-particle Anesthesia calcium hydroxylapatite injection into his bilateral Infraorbital nerve block was via intraoral apmid cheeks. In all, 1.7 and 2.3 mL, respectively, were proach with 1 to 2 mL total of 1% lidocaine without placed into the right and left sides (Fig 3). epinephrine. Additional anesthesia was via fanning All patients tolerated the injections well, and method with 1% lidocaine with 1:200,000 epinephcompared with prior injections with small-particle rine and 10% sodium bicarbonate (8.4% solution). calcium hydroxylapatite filler (ie, Radiesse, Merz) (last treatment 24, 21, and 45 months before largeImplantation technique particle injection, respectively, for patients 1, 2, and After marking with a permanent marker (Sharpie, 3), each self-reported greater persistence of results at Sanford Corp, Oakbrook, IL) of wrinkles and skin 6 and 15 months follow-ups. Specifically, patients depressions on the nasolabial folds and medial 1 and 2 reported greater than 50% persistence of the cheeks, and application of anesthesia, correction filler correction at 15 months, and patient 3 reported was begun with bevel-down needle insertion. The 25% to 50% persistence at this time point. Injector clinical assessment was consistent with these patient needle was advanced until the middle to deep subassessments, with the primary injector noting greater cutis, aspiration was performed to ensure that the tip was not within a blood vessel, and injection was then than 75% persistence of filler by palpation and live commenced slowly as the needle was withdrawn. visual assessment at 6 months after treatment in all 3 Injection rate was at all times less than 0.3 mL/min. patients. Adverse events were minor and similar to Retrograde linear threading technique was then conthose with small-particle calcium hydroxylapatite tinued until the defect was corrected. Additional filler, with all 3 patients experiencing mild injection injections on the same side of the face were placed discomfort, along with posttreatment transient edema, erythema, and focal ecchymoses. All patients through the same entry point, and longer needles reported that the needle entry sites were visible for were used, as appropriate, to reach portions of the defect farther from the entry site. Each linear thread 1 to 2 days after injection. comprised no more than 0.1 mL. Firm massage, with DISCUSSION index finger inside the mouth and thumb outside, was Based on our limited experience of 3 cases, largethen used to remove any unevenness. particle calcium hydroxylapatite filler appears to be RESULTS safe for injection into wrinkles and depressions in the Case 1 mid face. No persistent bruising, contour abnormalA 44-year-old woman with prominent nasolabial ity, vascular occlusion, neuropathic pain, or implant fold creases and Fitzpatrick skin type II received a migration was detected in any of the patients. d
d
94 Alam et al
J AM ACAD DERMATOL
JULY 2011
Fig 1. Case 1. View of right (A) and left (B) nasolabial folds before injection, and right (C) and left (D) after injection.
There were some technique differences in how we injected large-particle calcium hydroxylapatite, as compared with our routine technique with smallparticle filler. For one, a larger bore 21-gauge needle was used. This could be quite painful on injection if nerve blocks or intralesional anesthetic were not used, and we highly recommend the use of such effective anesthesia. In addition, the locus of injection was the middle to deep subcutis rather than the superficial subcutis; we selected this to avoid the risk of superficial injection, which could potentially pose a risk of vascular occlusion and of visible intradermal implant. The thicker, larger particle size elevated the importance of avoiding a superficial implant, which would likely be more visible with larger than smaller
particles. Finally, injection rate was scrupulously kept below 0.3 mL/min to minimize the probability of intravascular injection. Although no such occlusion with this material has been observed by us or others, we deemed it prudent to actively prevent this outcome, as the larger particle size would pose a theoretic occlusion risk to small-bore vessels if injected with great force. Adverse events in all 3 of our cases were extremely minimal, and indistinguishable from those with small-particle treatment. The only exception was that the needle entry sites were faintly visible as round red spots on the skin for 1 to 2 days after injection before resolving completely. To minimize marking, we used only one entry site per side of the
J AM ACAD DERMATOL VOLUME 65, NUMBER 1
Alam et al 95
Fig 2. Case 2. Front view of patient before (A) and after (B) injection of bilateral mid-cheek area.
Fig 3. Case 3. Front view before treatment (A); after marking of areas to be treated (B); and after treatment (C) of patient receiving injections for HIV-associated facial atrophy.
face, and used needles of different lengths, aimed at varying angles, to access all portions of each defect. Very large or diffuse defects may require multiple entry sites. Fifteen months after injection, all patients report that some of the implanted material remains in place. They also report that, compared with prior injections with small-particle calcium hydroxylapatite, the correction appeared to be more persistent, with more gradual drop-off in the apparent degree of correction.
Clearly, these 3 case reports cannot definitively establish the safety of large-particle calcium hydroxylapatite for facial wrinkle correction, nor can they demonstrate with any certainty that this material has improved longevity. However, to the degree that biodegradation of calcium hydroxylapatite is by macrophage engulfment, beginning from the outside of each spherule and continuing to the center, it does seem plausible that the larger particle size may pose an obstacle to the rapidity of this process. Specifically, for larger particles, the ratio of surface
96 Alam et al
area to volume is proportionately lower, and hence the area per unit volume of mineral that is vulnerable to macrophages is relatively less. In addition, the safety of injection of large-particle calcium hydroxylapatite is supported by its relative similarity to small-particle material in all characteristics except particle diameter; and small-particle calcium hydroxylapatite is FDA approved for soft-tissue augmentation and has an excellent safety record in phase IV studies. In conclusion, these 3 preliminary case reports demonstrate the efficacy and tolerability of the offlabel use of large-particle calcium hydroxylapatite filler for correction of facial wrinkles and depressions. Further studies enrolling more patients are needed to confirm these findings. Such additional studies may also clarify the clinical circumstances in which use of large-particle calcium hydroxylapatite filler is preferable to the use of small-particle filler.
J AM ACAD DERMATOL
JULY 2011
2.
3.
4.
5.
6.
7. REFERENCES 1. Graivier MH, Bass LS, Busso M, Jasin ME, Narins RS, Tzikas TL. Calcium hydroxylapatite (Radiesse) for correction of the mid-
and lower face: consensus recommendations. Plast Reconstr Surg 2007;120(Suppl):55-66S. 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):S112-21. Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite versus nonanimal stabilized hyaluronic acid for the correction of nasolabial folds: a 12-month, multicenter, prospective, randomized, controlled, split-face trial. Dermatol Surg 2008;34: 210-5. Alam M, Yoo SS. Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions. J Am Acad Dermatol 2007;56:285-9. Alam M, Gladstone H, Kramer EM, Murphy JP Jr, Nouri K, Neuhaus IM, et al. American Society for Dermatologic Surgery. ASDS guidelines of care: injectable fillers. Dermatol Surg 2008; 34(Suppl):S115-48. Mayer RD, Dmochowski RR, Appell RA, Sand PK, Klimberg IW, Jacoby K, et al. Multicenter prospective randomized 52-week trial of calcium hydroxylapatite versus bovine dermal collagen for treatment of stress urinary incontinence. Urology 2007;69: 876-80. Coaptite P040047. Approval order and physician labeling. Bioform Inc, San Mateo (CA). U.S. Department of Heath and Human Services, Food and Drug Administration, Center for Devices and Radiologic Health, 2005.