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Subcutaneous testosterone pellet therapy for reversal of male osteoporosis: a review and case report

Subcutaneous testosterone pellet therapy for reversal of male osteoporosis: a review and case report THE AGING MALE 2023, VOL. 26, NO. 1, 2181953 https://doi.org/10.1080/13685538.2023.2181953 REVIEW Subcutaneous testosterone pellet therapy for reversal of male osteoporosis: a review and case report a b c Bruce Dorr , Ahmed Abdelaziz and Mickey Karram a b Obstetrics and Gynecology/Urogynecology Division, Littleton Hospital, Littleton, CO, USA; Obstetrics and Gynecology/Urogyneco logy Division, Christ Hospital, Cincinnati, OH, USA; Obstetrics and Gynecology Division, Urogynecology Chair, Christ Hospital, Cincinnati, OH, USA ABSTRACT ARTICLE HISTORY Received 12 January 2023 Purpose: To describe the effects of consistent levels of testosterone in a pellet form and it’s Revised 13 February 2023 potential to reverse osteoporosis. Accepted 13 February 2023 Methods: This is a descriptive case report of a 54 year male with a spontaneous fracture and Published online 13 March osteoporosis in the presence of what many consider a normal male testosterone level. Results: After discovering and documenting osteoporosis by DXA scan, the patient was shown to reverse the diagnosis of osteoporosis in a year on pelleted testosterone therapy. Consistent levels of KEYWORDS 943 ng/dL were achieved; the patient also experienced improvements in quality of life and sleep Testosterone; testosterone apnea. replacement therapy; Conclusion: Testosterone deficiency (TD) is a clinical syndrome and osteoporosis can be found osteoporosis; pellet therapy in levels above standard “criteria” of 300. This patient did not realize a benefit on injections both physical and clinically and both improved on pelleted testosterone. This should be further studied and considered for TD in men. Introduction desired therapeutic effect are critical in the process and clinical outcome [4]. Each year, more than 8 million men are diagnosed with We describe a case of an osteoporotic patient with osteoporosis or osteopenia [1]. Men with osteoporosis what many clinicians would consider a normal testos- are treated with lifestyle modifications, drug therapy, terone level who was successfully treated with subcuta- and hormonal therapy if they have been diagnosed with neous testosterone—(pellet) achieving higher sustained testosterone deficiency (TD). However, normal testoster- and consistent levels, resulting in almost complete one ranges remain a somewhat controversial area. recovery of osteoporosis after 1 year of treatment. Integrity of our skeletal system is maintained by a remodeling process, which is regulated by three bone cell types: bone-forming osteoblasts, bone-resorbing Case osteoclasts, and mechanically sensitive osteocytes. These A 54-year-old male triathlete had a non-fall-related tibial are under regulation by many processes, which involve plateau fracture on 1 December 2018 while stepping testosterone and androgen receptors as well as the out of his ski boot, after a normal day of snow skiing. effect of estrogen receptors that are known to be influ- Except for a back injury in a motor vehicle accident, enced by testosterone levels. Osteoporosis risk factors his medical history was non-contributory. Surgical his- are best documented in women due to the acute estro- tory included two previous wrist fractures sustained gen loss at menopause, but they also consistently lose while mountain biking and a left meniscus arthros- testosterone similar to men. Fracture risk is higher in copy to repair a meniscal tear. He had received intra- women, but men suffering from fractures carry a greater muscular testosterone supplementation in his early mortality risk over women [2,3]. Administrative therapy 40’s to improve his overall performance. He was on also plays a key role. Problems in both obtaining and maintaining effective testosterone levels to achieve the this for a year and then stopped after consulting with CONTACT Bruce Dorr bdorr@lobga.net Urogynecology Division, Littleton Hospital, Littleton, CO 80122, USA � 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. THE AGING MALE 45 a physician who expressed concern about his elevated The patient was offered traditional etidronate treat- blood count. ment by his primary care physician, but he declined Following his tibial fracture, the patient saw an treatment. Patient sought counseling on 19 March orthopedic surgeon and had casting and bracing for 2019 due to his interest in addressing his osteoporosis his left tibia for 3 months. He then underwent DEXA with hormonal treatment. His initial Testosterone (T) scan on 3 January 2019 with his results showing was 473 ng/dL, vitamin D was 39 ng/mL, Prostate- osteoporosis in the spine and femoral neck (Figure 1). Specific Antigen; 4 ng/mL, estradiol 14 ng/dL, Hga1c 4.9%, and his BMI was 26.3. Spine T 2.6, Z-2.1 osteoporosis After counseling the patient about the pros and Total hip 1.8 Z-1.4 osteopenia cons of testosterone therapy and possible side effects, Fem neck T 2.7, Z-1.8 osteoporosis. we initiated testosterone pellet therapy. He was also Figure 1. (a) Hip MRI report with patient demographics. (b) Radiography of right femoral neck and plotted t score. (c) Date of study and report. (d) T and Z score improved from 1.4 to 1.3. (e) The 6.8% improvement in 1 year data. (f) FRAX risk not calcu- lated because of normal findings. 46 B. DORR ET AL. started on 10,000 IU/day of a vitamin d3k2 nutraceut- his libido, mood, and lean body mass—all of which ical formulation and DIM (diindoyl methane) 300 mg— were issues prior to his fracture. Several systematic reviews showed conflicting data which is also nutraceutical grade formula known to regarding the effect of T on bone mineral density prevent aromatization. After 3 months, his testosterone (BMD). The Endocrine Society guideline published in level was up to 943 ng/dL, free testosterone 2010 stated that although testosterone had no effect 116 ng/dL, Hematocrit (Hct) 51%, and estradiol on vertebral, hip, and femoral BMD, it was associated 15 ng/dL. The patient was checked regularly every 3– with an increase in lumbar BMD [11]. A recent system- 4 months by physical exam and lab workup. After atic review showed that the effect of testosterone sup- 6 months, his repeat vitamin D level was 52 ng/mL plementation on BMD and the risk of falls or fracture and his estradiol was 29 ng/dL. remain inconclusive [12]. The authors acknowledged He continued testosterone therapy, and at the year that their systematic review included a very small interval, rather than the standard 2 year interval at the number of patients with osteoporosis. In contrast, recommendation of his endocrinologist, a repeated there are many previous studies suggesting the bene- DEXA scan was obtained on 3 April 2020 with ficial effect of TRT on osteoporosis/osteopenia, A results of: meta-analysis of 1083 patients from 29 randomized controlled studies showed that TRT could improve Spine T -2.2/-1.6 6% increase—osteopenia BMD at the lumbar spine by þ3.7% compared with Total hip T-1.5/.8 6.8% increase—normal placebo [13]. A recent narrative review revealed 13 Fem neck T-2.4/-1.5 7.2% increase—osteopenia studies showing the beneficial effect of TRT on osteo- porosis/osteopenia [14]. In our case, we successfully The patient, at 1 year of hormone therapy, report the use of what some would consider supra- improved his composite bone density substantially physiologic levels of T by pelleted bio-identical testos- normalizing his total hip bone density and improving terone under FDA oversight from a 503b certified his quality of life and returned to performing triath- compounding pharmacy to treat osteoporosis. Review lons in 1 year. He felt better in many ways and found of the literature did not show any published cases it easier to maintain his therapy with the pellet admin- looking at higher levels of T in enhancing bone istration. Normal assessment in our clinic would have strength except in rats [15]. even a 2 year interval for the DXA scan. Adverse effects of elevated testosterone remain controversial. Recent systematic review by Zhang did not show an increase in cardiovascular events, all- Discussion cause mortality, or prostatic events in patients with TD There is a lack of standardization of TD diagnosis [5]. treated with T [12]. However, levels of synthetic T may Generally, TD is diagnosed when patients exhibit induce vascular dysfunction, which may contribute to symptoms of TD followed by lab confirmation. The cardiac events [16]. Previous trials showed including Joint international society guidelines propose an elevated hematocrit, leg edema, and increased inci- upper limit of normal as 350 ng dL, above which treat- dence of prostatic events [17]. In our case, the patient ment is usually not beneficial [6,7]. The 2006 U.S. did not have any adverse events and a recently pub- Endocrine Society guidelines recommended a total lished 9-year study demonstrated extremely low rates serum testosterone level of 300 ng/dL as the diagnos- of complications from subcutaneous testosterone tic threshold for treatment [8]. However, there is no administration TRT [18]. Short term administration of clear T threshold that predicts patients who will and testosterone and compliance can be a limiting factor not respond to treatment [9]. Rigid interpretation of T in achieving desired results [2]. ranges should not dictate clinical decision making. A recognized complication of TRT can be aromatiza- This is further noted by the International Society for tion leading to abnormal elevation of estradiol. His the Study of the Aging Male that testosterone replace- estradiol did not appreciably change (possibly due to ment therapy (TRT) may be reasonably offered to the administration of DIM, a natural aromatase inhibi- symptomatic patients above 350 ng/d [10]. In an ideal tor) hinting that testosterone was the effective agent. setting, TRT should be based first on symptoms and Given the incidence of pre diabetes and type 2 dia- secondarily on lab values. In our case, his fracture may betes in our society, this can also negatively impact have been prevented with more appropriate therapy BMD [4]. Diabetes can lead to osteopathy and and counseling. In addition, it would have maintained decreased blood flow to the bone. In a recent study, THE AGING MALE 47 Figure 2. (a) DXA report and images of LS Spine. (b) Graph of t scores and normalization of parameters. (c) Demographic data of study. (d) Z and t scores of L1-4 and average value of 1.3. (e) 6% BMD improvement in one year. even a diagnosis of prediabetes (Hga1c of 5.7–6.4) Also, the administration of vitamin D is a confound- conferred an increased risk of osteopenia or osteopor- ing variable. Vitamin D plays a known beneficial role osis [19]. We did not observe this effect in our study in bone formation and remodeling. It is essential in as his level was normal. absorbing calcium form the gut and provides optimal Although this patient achieved both effective and circumstances for bone mineralization. This created a therapeutic total and free testosterone levels, it is better environment for the hormonal effect of testos- essential to achieve free hormone levels to activate terone [20]. receptor driven cellular processes. So, it is imperative Lastly, BMI can play a role in osteoporosis, A subset to be sure that effective free testosterone levels are of the EARTH trial (Effects of androgen replacement maintained. therapy on hypogonadal men) showed that men given 48 B. DORR ET AL. 0[3] Mendoza FA, Le Roux M, Ahmed I. Primary osteopor- testosterone enanthate injections had significant osis in men: an unmet medical need. Fertil Steril. increase in BMD [21]. It was the first study to demon- 2019;112(5):791–798. strate a beneficial effect of TRT on BMD in osteopor- 0[4] Groti Antoni� c K. Impact of testosterone therapy on otic Japanese men. They also showed that low BMI— bone turnover markers in obese males with type 2 probably due to the lower mechanical loading, was an diabetes and functional hypogonadism. Aging Male. independent risk factor for osteoporosis. Our patient 2022;25(1):269–277. 0[5] Morgentaler A, Khera M, Maggi M, et al. Commentary: had a BMI of 26.2, which, if anything, should have who is a candidate for testosterone therapy? A syn- been a deterrent in the development of osteoporosis. thesis of international expert opinions. J Sex Med. 2014;11:1636–1645. 0[6] Wang C, Nieschlag E, Swerdloff R, et al. Investigation, Conclusion treatment, and monitoring of late-onset hypogonad- This case report noted pelleted bioidentical testoster- ism in males: ISA, ISSAM, EAU, EAA, and ASA recom- one replacement using an FDA regulated 503b com- mendations. Eur Urol. 2009;55:121–130. 0[7] Buvat J, Maggi M, Gooren L, et al. Endocrine aspects of pounded pharmacy resulted in significant improvement male sexual dysfunction. J Sex Med. 2010;7:1627–1656. of bone density. This affect was related to the signifi- 0[8] Paduch DA, Brannigan RE, Fuchs EF, et al. The labora- cant elevation of what many would consider a normal tory diagnosis of testosterone deficiency. Urology testosterone level. This patient was able to strengthen 2014;83:980–988. bone, remove supportive fracture hardware in one year 0[9] Morgentaler A, Zitzmann M, Traish AM, et al. and had increased energy, recovery, and benefits to his Fundamental concepts regarding testosterone defi- ciency and treatment: International expert consensus sleep apnea without the significant side effects of resolutions. Mayo Clin Proc. 2016;91(7):881–896. standard etidronate therapy. [10] Park H, Ahn S, Moon D, et al. Evolution of guidelines for This case report raises two important questions. Is testosterone replacement therapy. JCM. 2019;8(3):410. it safe and more efficacious to administer higher than [11] Seftel AD, Kathrins M, Niederberger C. Critical update normal testosterone doses in men suffering from of the 2010 endocrine society clinical practice guide- issues related to loss of bone density and is the best lines for male hypogonadism: a systematic analysis. Mayo Clin Proc. 2015;90:1104–1115. mode of delivery in such situations as subcutaneous [12] Zhang Z, Kang D, Li H. The effects of testosterone on pellet versus transdermal or intramuscular administra- bone health in males with testosterone deficiency: a tion? There is a tremendous need for more data that systematic review and meta-analysis. BMC Endocr could address these questions, most notably a pro- Disord. 2020;20(1):12. spective randomized trial. [13] Isidori AM, Giannetta E, Greco EA, et al. Effects of tes- tosterone on body composition, bone metabolism, and serum lip profile in male-age men: meta analysis. Disclosure statement Clin Endocrinol (Oxf). 2005;63(3):280–293. [14] Shigehara K, Izumi K, Kadono Y, et al. Testoerone and Dr. Bruce Dorr is an educational consultant for BioTE. Dr. bone health for me: a narrative review. JCM. 2021; Ahmed Abel Aziz has no disclosures. Dr. Mickey Karram is a 10(3):530. research consultant for BIoTE. [15] Yarrow JF, Conover CF, Purandare AV, et al. Supraphysiological testosterone enanthate administra- Funding tion prevents bone loss and augments bone strength in gonadectomized male and female rats. Am J The author(s) reported there is no funding associated with Physiol Endocrinol Metab. 2008;295(5):E1213–E1222. the work featured in this article. [16] Alves JV, Costa R D, Pereira CA, et al. Supraphysiological levels of testosterone induce vascular dysfunction via activation of the NLRP3 inflammasome. Front Immunol. References 2020;11:1647. 0[1] Nb W, Ra A, Jp B, et al. Osteoporosis in men: an [17] Rabijewski M, Papierska L, Pia ˛tkiewicz P. An associ- endocrine society clinical practice guideline. J Clin ation between bone mineral density anabolic hor- Endocrinol Metab. 2012;97:1802–1822. mone in middle age and elderly men with pre 0[2] de Paiva Gonc ¸alves V, Cabrera-Ortega AA, Carvalho diabetes. Aging Male. 2017;20(3):205–213. JS, et al. Physiologic testosterone replacement on [18] Bhasin S, Woodhouse L, Casaburi R, et al. Older men male aged rats with orchiectomy induced osteopor- are as responsive as young men to the anabolic osis in advanced stage: a tomographic and biomech- effects of graded doses of testosterone on skeletal anics pilot study. Aging Male. 2021;24(1):139–147. muscle. J Clin Endocrinol Metab. 2005;90:678–688. THE AGING MALE 49 [19] Lips P, van Schoor NM. The effect of vitamin d on prospective randomized controlled study in Japan bone and osteoporosis. Best Pract Res Clin Endocrinol (EARTH study). Aging Male. 2017;20(3):139–145. Metab. 2011;25(4):585–591. [21] Donovitz GS. Low complication rates of testosterone [20] Shigehara K, Konaka H, Koh E, et al. Effects of testos- and estradiol implants for androgen and estrogen terone replacement therapy on hypogonadal men replacement therapy in over 1 million procedures. with osteopenia or osteoporosis: a subanalysis of a Ther Adv Endocrinol. 2021;12:204201882110152. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Aging Male Taylor & Francis

Subcutaneous testosterone pellet therapy for reversal of male osteoporosis: a review and case report

Dorr, Bruce; Abdelaziz, Ahmed; Karram, Mickey
The Aging Male , Volume 26 (1): 1 – Dec 31, 2023
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© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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10.1080/13685538.2023.2181953
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THE AGING MALE 2023, VOL. 26, NO. 1, 2181953 https://doi.org/10.1080/13685538.2023.2181953 REVIEW Subcutaneous testosterone pellet therapy for reversal of male osteoporosis: a review and case report a b c Bruce Dorr , Ahmed Abdelaziz and Mickey Karram a b Obstetrics and Gynecology/Urogynecology Division, Littleton Hospital, Littleton, CO, USA; Obstetrics and Gynecology/Urogyneco logy Division, Christ Hospital, Cincinnati, OH, USA; Obstetrics and Gynecology Division, Urogynecology Chair, Christ Hospital, Cincinnati, OH, USA ABSTRACT ARTICLE HISTORY Received 12 January 2023 Purpose: To describe the effects of consistent levels of testosterone in a pellet form and it’s Revised 13 February 2023 potential to reverse osteoporosis. Accepted 13 February 2023 Methods: This is a descriptive case report of a 54 year male with a spontaneous fracture and Published online 13 March osteoporosis in the presence of what many consider a normal male testosterone level. Results: After discovering and documenting osteoporosis by DXA scan, the patient was shown to reverse the diagnosis of osteoporosis in a year on pelleted testosterone therapy. Consistent levels of KEYWORDS 943 ng/dL were achieved; the patient also experienced improvements in quality of life and sleep Testosterone; testosterone apnea. replacement therapy; Conclusion: Testosterone deficiency (TD) is a clinical syndrome and osteoporosis can be found osteoporosis; pellet therapy in levels above standard “criteria” of 300. This patient did not realize a benefit on injections both physical and clinically and both improved on pelleted testosterone. This should be further studied and considered for TD in men. Introduction desired therapeutic effect are critical in the process and clinical outcome [4]. Each year, more than 8 million men are diagnosed with We describe a case of an osteoporotic patient with osteoporosis or osteopenia [1]. Men with osteoporosis what many clinicians would consider a normal testos- are treated with lifestyle modifications, drug therapy, terone level who was successfully treated with subcuta- and hormonal therapy if they have been diagnosed with neous testosterone—(pellet) achieving higher sustained testosterone deficiency (TD). However, normal testoster- and consistent levels, resulting in almost complete one ranges remain a somewhat controversial area. recovery of osteoporosis after 1 year of treatment. Integrity of our skeletal system is maintained by a remodeling process, which is regulated by three bone cell types: bone-forming osteoblasts, bone-resorbing Case osteoclasts, and mechanically sensitive osteocytes. These A 54-year-old male triathlete had a non-fall-related tibial are under regulation by many processes, which involve plateau fracture on 1 December 2018 while stepping testosterone and androgen receptors as well as the out of his ski boot, after a normal day of snow skiing. effect of estrogen receptors that are known to be influ- Except for a back injury in a motor vehicle accident, enced by testosterone levels. Osteoporosis risk factors his medical history was non-contributory. Surgical his- are best documented in women due to the acute estro- tory included two previous wrist fractures sustained gen loss at menopause, but they also consistently lose while mountain biking and a left meniscus arthros- testosterone similar to men. Fracture risk is higher in copy to repair a meniscal tear. He had received intra- women, but men suffering from fractures carry a greater muscular testosterone supplementation in his early mortality risk over women [2,3]. Administrative therapy 40’s to improve his overall performance. He was on also plays a key role. Problems in both obtaining and maintaining effective testosterone levels to achieve the this for a year and then stopped after consulting with CONTACT Bruce Dorr bdorr@lobga.net Urogynecology Division, Littleton Hospital, Littleton, CO 80122, USA � 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent. THE AGING MALE 45 a physician who expressed concern about his elevated The patient was offered traditional etidronate treat- blood count. ment by his primary care physician, but he declined Following his tibial fracture, the patient saw an treatment. Patient sought counseling on 19 March orthopedic surgeon and had casting and bracing for 2019 due to his interest in addressing his osteoporosis his left tibia for 3 months. He then underwent DEXA with hormonal treatment. His initial Testosterone (T) scan on 3 January 2019 with his results showing was 473 ng/dL, vitamin D was 39 ng/mL, Prostate- osteoporosis in the spine and femoral neck (Figure 1). Specific Antigen; 4 ng/mL, estradiol 14 ng/dL, Hga1c 4.9%, and his BMI was 26.3. Spine T 2.6, Z-2.1 osteoporosis After counseling the patient about the pros and Total hip 1.8 Z-1.4 osteopenia cons of testosterone therapy and possible side effects, Fem neck T 2.7, Z-1.8 osteoporosis. we initiated testosterone pellet therapy. He was also Figure 1. (a) Hip MRI report with patient demographics. (b) Radiography of right femoral neck and plotted t score. (c) Date of study and report. (d) T and Z score improved from 1.4 to 1.3. (e) The 6.8% improvement in 1 year data. (f) FRAX risk not calcu- lated because of normal findings. 46 B. DORR ET AL. started on 10,000 IU/day of a vitamin d3k2 nutraceut- his libido, mood, and lean body mass—all of which ical formulation and DIM (diindoyl methane) 300 mg— were issues prior to his fracture. Several systematic reviews showed conflicting data which is also nutraceutical grade formula known to regarding the effect of T on bone mineral density prevent aromatization. After 3 months, his testosterone (BMD). The Endocrine Society guideline published in level was up to 943 ng/dL, free testosterone 2010 stated that although testosterone had no effect 116 ng/dL, Hematocrit (Hct) 51%, and estradiol on vertebral, hip, and femoral BMD, it was associated 15 ng/dL. The patient was checked regularly every 3– with an increase in lumbar BMD [11]. A recent system- 4 months by physical exam and lab workup. After atic review showed that the effect of testosterone sup- 6 months, his repeat vitamin D level was 52 ng/mL plementation on BMD and the risk of falls or fracture and his estradiol was 29 ng/dL. remain inconclusive [12]. The authors acknowledged He continued testosterone therapy, and at the year that their systematic review included a very small interval, rather than the standard 2 year interval at the number of patients with osteoporosis. In contrast, recommendation of his endocrinologist, a repeated there are many previous studies suggesting the bene- DEXA scan was obtained on 3 April 2020 with ficial effect of TRT on osteoporosis/osteopenia, A results of: meta-analysis of 1083 patients from 29 randomized controlled studies showed that TRT could improve Spine T -2.2/-1.6 6% increase—osteopenia BMD at the lumbar spine by þ3.7% compared with Total hip T-1.5/.8 6.8% increase—normal placebo [13]. A recent narrative review revealed 13 Fem neck T-2.4/-1.5 7.2% increase—osteopenia studies showing the beneficial effect of TRT on osteo- porosis/osteopenia [14]. In our case, we successfully The patient, at 1 year of hormone therapy, report the use of what some would consider supra- improved his composite bone density substantially physiologic levels of T by pelleted bio-identical testos- normalizing his total hip bone density and improving terone under FDA oversight from a 503b certified his quality of life and returned to performing triath- compounding pharmacy to treat osteoporosis. Review lons in 1 year. He felt better in many ways and found of the literature did not show any published cases it easier to maintain his therapy with the pellet admin- looking at higher levels of T in enhancing bone istration. Normal assessment in our clinic would have strength except in rats [15]. even a 2 year interval for the DXA scan. Adverse effects of elevated testosterone remain controversial. Recent systematic review by Zhang did not show an increase in cardiovascular events, all- Discussion cause mortality, or prostatic events in patients with TD There is a lack of standardization of TD diagnosis [5]. treated with T [12]. However, levels of synthetic T may Generally, TD is diagnosed when patients exhibit induce vascular dysfunction, which may contribute to symptoms of TD followed by lab confirmation. The cardiac events [16]. Previous trials showed including Joint international society guidelines propose an elevated hematocrit, leg edema, and increased inci- upper limit of normal as 350 ng dL, above which treat- dence of prostatic events [17]. In our case, the patient ment is usually not beneficial [6,7]. The 2006 U.S. did not have any adverse events and a recently pub- Endocrine Society guidelines recommended a total lished 9-year study demonstrated extremely low rates serum testosterone level of 300 ng/dL as the diagnos- of complications from subcutaneous testosterone tic threshold for treatment [8]. However, there is no administration TRT [18]. Short term administration of clear T threshold that predicts patients who will and testosterone and compliance can be a limiting factor not respond to treatment [9]. Rigid interpretation of T in achieving desired results [2]. ranges should not dictate clinical decision making. A recognized complication of TRT can be aromatiza- This is further noted by the International Society for tion leading to abnormal elevation of estradiol. His the Study of the Aging Male that testosterone replace- estradiol did not appreciably change (possibly due to ment therapy (TRT) may be reasonably offered to the administration of DIM, a natural aromatase inhibi- symptomatic patients above 350 ng/d [10]. In an ideal tor) hinting that testosterone was the effective agent. setting, TRT should be based first on symptoms and Given the incidence of pre diabetes and type 2 dia- secondarily on lab values. In our case, his fracture may betes in our society, this can also negatively impact have been prevented with more appropriate therapy BMD [4]. Diabetes can lead to osteopathy and and counseling. In addition, it would have maintained decreased blood flow to the bone. In a recent study, THE AGING MALE 47 Figure 2. (a) DXA report and images of LS Spine. (b) Graph of t scores and normalization of parameters. (c) Demographic data of study. (d) Z and t scores of L1-4 and average value of 1.3. (e) 6% BMD improvement in one year. even a diagnosis of prediabetes (Hga1c of 5.7–6.4) Also, the administration of vitamin D is a confound- conferred an increased risk of osteopenia or osteopor- ing variable. Vitamin D plays a known beneficial role osis [19]. We did not observe this effect in our study in bone formation and remodeling. It is essential in as his level was normal. absorbing calcium form the gut and provides optimal Although this patient achieved both effective and circumstances for bone mineralization. This created a therapeutic total and free testosterone levels, it is better environment for the hormonal effect of testos- essential to achieve free hormone levels to activate terone [20]. receptor driven cellular processes. So, it is imperative Lastly, BMI can play a role in osteoporosis, A subset to be sure that effective free testosterone levels are of the EARTH trial (Effects of androgen replacement maintained. therapy on hypogonadal men) showed that men given 48 B. DORR ET AL. 0[3] Mendoza FA, Le Roux M, Ahmed I. Primary osteopor- testosterone enanthate injections had significant osis in men: an unmet medical need. Fertil Steril. increase in BMD [21]. It was the first study to demon- 2019;112(5):791–798. strate a beneficial effect of TRT on BMD in osteopor- 0[4] Groti Antoni� c K. Impact of testosterone therapy on otic Japanese men. They also showed that low BMI— bone turnover markers in obese males with type 2 probably due to the lower mechanical loading, was an diabetes and functional hypogonadism. Aging Male. independent risk factor for osteoporosis. Our patient 2022;25(1):269–277. 0[5] Morgentaler A, Khera M, Maggi M, et al. Commentary: had a BMI of 26.2, which, if anything, should have who is a candidate for testosterone therapy? A syn- been a deterrent in the development of osteoporosis. thesis of international expert opinions. J Sex Med. 2014;11:1636–1645. 0[6] Wang C, Nieschlag E, Swerdloff R, et al. Investigation, Conclusion treatment, and monitoring of late-onset hypogonad- This case report noted pelleted bioidentical testoster- ism in males: ISA, ISSAM, EAU, EAA, and ASA recom- one replacement using an FDA regulated 503b com- mendations. Eur Urol. 2009;55:121–130. 0[7] Buvat J, Maggi M, Gooren L, et al. Endocrine aspects of pounded pharmacy resulted in significant improvement male sexual dysfunction. J Sex Med. 2010;7:1627–1656. of bone density. This affect was related to the signifi- 0[8] Paduch DA, Brannigan RE, Fuchs EF, et al. The labora- cant elevation of what many would consider a normal tory diagnosis of testosterone deficiency. Urology testosterone level. This patient was able to strengthen 2014;83:980–988. bone, remove supportive fracture hardware in one year 0[9] Morgentaler A, Zitzmann M, Traish AM, et al. and had increased energy, recovery, and benefits to his Fundamental concepts regarding testosterone defi- ciency and treatment: International expert consensus sleep apnea without the significant side effects of resolutions. Mayo Clin Proc. 2016;91(7):881–896. standard etidronate therapy. [10] Park H, Ahn S, Moon D, et al. Evolution of guidelines for This case report raises two important questions. Is testosterone replacement therapy. JCM. 2019;8(3):410. it safe and more efficacious to administer higher than [11] Seftel AD, Kathrins M, Niederberger C. Critical update normal testosterone doses in men suffering from of the 2010 endocrine society clinical practice guide- issues related to loss of bone density and is the best lines for male hypogonadism: a systematic analysis. Mayo Clin Proc. 2015;90:1104–1115. mode of delivery in such situations as subcutaneous [12] Zhang Z, Kang D, Li H. The effects of testosterone on pellet versus transdermal or intramuscular administra- bone health in males with testosterone deficiency: a tion? There is a tremendous need for more data that systematic review and meta-analysis. BMC Endocr could address these questions, most notably a pro- Disord. 2020;20(1):12. spective randomized trial. [13] Isidori AM, Giannetta E, Greco EA, et al. Effects of tes- tosterone on body composition, bone metabolism, and serum lip profile in male-age men: meta analysis. Disclosure statement Clin Endocrinol (Oxf). 2005;63(3):280–293. [14] Shigehara K, Izumi K, Kadono Y, et al. Testoerone and Dr. Bruce Dorr is an educational consultant for BioTE. Dr. bone health for me: a narrative review. JCM. 2021; Ahmed Abel Aziz has no disclosures. Dr. Mickey Karram is a 10(3):530. research consultant for BIoTE. [15] Yarrow JF, Conover CF, Purandare AV, et al. Supraphysiological testosterone enanthate administra- Funding tion prevents bone loss and augments bone strength in gonadectomized male and female rats. Am J The author(s) reported there is no funding associated with Physiol Endocrinol Metab. 2008;295(5):E1213–E1222. the work featured in this article. [16] Alves JV, Costa R D, Pereira CA, et al. Supraphysiological levels of testosterone induce vascular dysfunction via activation of the NLRP3 inflammasome. Front Immunol. References 2020;11:1647. 0[1] Nb W, Ra A, Jp B, et al. Osteoporosis in men: an [17] Rabijewski M, Papierska L, Pia ˛tkiewicz P. An associ- endocrine society clinical practice guideline. J Clin ation between bone mineral density anabolic hor- Endocrinol Metab. 2012;97:1802–1822. mone in middle age and elderly men with pre 0[2] de Paiva Gonc ¸alves V, Cabrera-Ortega AA, Carvalho diabetes. Aging Male. 2017;20(3):205–213. JS, et al. Physiologic testosterone replacement on [18] Bhasin S, Woodhouse L, Casaburi R, et al. Older men male aged rats with orchiectomy induced osteopor- are as responsive as young men to the anabolic osis in advanced stage: a tomographic and biomech- effects of graded doses of testosterone on skeletal anics pilot study. Aging Male. 2021;24(1):139–147. muscle. J Clin Endocrinol Metab. 2005;90:678–688. THE AGING MALE 49 [19] Lips P, van Schoor NM. The effect of vitamin d on prospective randomized controlled study in Japan bone and osteoporosis. Best Pract Res Clin Endocrinol (EARTH study). Aging Male. 2017;20(3):139–145. Metab. 2011;25(4):585–591. [21] Donovitz GS. Low complication rates of testosterone [20] Shigehara K, Konaka H, Koh E, et al. Effects of testos- and estradiol implants for androgen and estrogen terone replacement therapy on hypogonadal men replacement therapy in over 1 million procedures. with osteopenia or osteoporosis: a subanalysis of a Ther Adv Endocrinol. 2021;12:204201882110152.

Journal

The Aging Male – Taylor & Francis

Published: Dec 31, 2023

Keywords: Testosterone; testosterone replacement therapy; osteoporosis; pellet therapy

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