Reversibility in male idiopathic osteoporosis possible

in Endocrinology, Diabetes & Metabolism Case Reports
Authors:
Ijaz S Jamall Risk-Based Decisions, Inc. 1540 River Park Drive, Suite 203, Sacramento, California, USA
Theodor-Billroth-Academy®, Munich – Sacramento, CA, Germany, USA
INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®, Germany, USA

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https://orcid.org/0000-0002-1437-2281
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Michael C Ullery Primary Care Physician, Heart and Vascular Medical Associates, 500 University Avenue, Sacramento, California, USA

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Massimiliano Rocchietti March Internal Medicine Unit, Faculty of Medicine and Psychology, University of Rome "Sapienza", Sant'Andrea Hospital, Rome, Italy

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Elisa Pignatti Department of Surgery, Medicine Dentistry and Morphological Sciences with Interest in Transplant, University of Modena and Reggio Emilia, Modena, Italy

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Vincenzo Rochira Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
UOC of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, Modena, Italy

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Björn L D M Brücher Theodor-Billroth-Academy®, Munich – Sacramento, CA, Germany, USA
INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®, Germany, USA
Department of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany

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Correspondence should be addressed to I S Jamall or V Rochira; Email: ijamall@riskbaseddecisions.com or rochira.vincenzo@unimore.it
Open access

Summary

A 44-year-old athletic man presented in 2009 with severe low back pain. Dual-energy x-ray absorptiometry revealed severe osteoporosis; serum testosterone was 189 ng/dL while serum estradiol (E2) measured by liquid chromatography/mass spectrometry was 8 pg/mL. DNA was extracted and sequenced from a blood sample from the patient since his maternal first cousin also had low bone mass and both patients were screened for aromatase dysfunction by PCR analysis for the CYP19A1 gene, which encodes aromatase. No known pathologic mutations were observed in the coding exons, but novel single nucleotide polymorphisms were detected both in the proband and in his cousin. Treatment with topical testosterone started in August 2010. Over the next 8 years, testosterone dosage was varied and switched from topical gel to injections and maintained on depo-injections of testosterone at about 60 mg once per week. Re-examination in March 2012 included a brain MRI to exclude pituitary lesions; hyperparathyroidism was ruled out (normal serum parathyroid hormone, calcium, and calcium to phosphorous ratio) and celiac disease was excluded (negative transglutaminase antibodies). Follow-up in October 2018 showed improved bone mineral density of the lumbar spine by 29% and of the left femoral hip by 15% compared to baseline measurements. This reveals the importance of measuring serum E2 for making the correct diagnosis, as well as for monitoring a therapeutic effect. Herein, we propose treatment of male osteoporosis where serum E2 levels are below about 20 pg/mL with testosterone to reverse osteoporosis.

Learning points

  • Estrogen deficiency in the diagnosis of male idiopathic osteoporosis.

  • Importance of serum estradiol in male osteoporosis.

  • Role of polymorphisms in aromatase gene on bone health.

  • Reversal of osteoporosis.

  • Tailored testosterone treatment for bone health.

Abstract

Summary

A 44-year-old athletic man presented in 2009 with severe low back pain. Dual-energy x-ray absorptiometry revealed severe osteoporosis; serum testosterone was 189 ng/dL while serum estradiol (E2) measured by liquid chromatography/mass spectrometry was 8 pg/mL. DNA was extracted and sequenced from a blood sample from the patient since his maternal first cousin also had low bone mass and both patients were screened for aromatase dysfunction by PCR analysis for the CYP19A1 gene, which encodes aromatase. No known pathologic mutations were observed in the coding exons, but novel single nucleotide polymorphisms were detected both in the proband and in his cousin. Treatment with topical testosterone started in August 2010. Over the next 8 years, testosterone dosage was varied and switched from topical gel to injections and maintained on depo-injections of testosterone at about 60 mg once per week. Re-examination in March 2012 included a brain MRI to exclude pituitary lesions; hyperparathyroidism was ruled out (normal serum parathyroid hormone, calcium, and calcium to phosphorous ratio) and celiac disease was excluded (negative transglutaminase antibodies). Follow-up in October 2018 showed improved bone mineral density of the lumbar spine by 29% and of the left femoral hip by 15% compared to baseline measurements. This reveals the importance of measuring serum E2 for making the correct diagnosis, as well as for monitoring a therapeutic effect. Herein, we propose treatment of male osteoporosis where serum E2 levels are below about 20 pg/mL with testosterone to reverse osteoporosis.

Learning points

  • Estrogen deficiency in the diagnosis of male idiopathic osteoporosis.

  • Importance of serum estradiol in male osteoporosis.

  • Role of polymorphisms in aromatase gene on bone health.

  • Reversal of osteoporosis.

  • Tailored testosterone treatment for bone health.

Background

Primary and secondary hypogonadism with serum total testosterone concentrations <200 ng/dL is a well-recognized cause of osteoporosis in men of all ages (1, 2, 3, 4). In men with low or low-normal serum testosterone levels, however, such as patients with Klinefelter syndrome, bone mineral density (BMD) may be preserved without testosterone replacement (5). In contrast, loss-of-function mutations in the CYP19A1 gene, which encodes for aromatase, the enzyme responsible for converting testosterone to estradiol (E2), is a rare syndrome characterized by the presence of unfused epiphyses, osteopenia or osteoporosis, eunuchoid skeletal proportions, and, importantly, undetectable serum E2 levels which requires lifelong estrogen replacement therapy (6, 7).

In clinical settings different from congenital estrogen deficiency, BMD decrease is inversely correlated with low serum E2, but not with serum T, as noted in several population studies (8, 9), suggesting that in cases of low T, BMD is impaired only when serum E2 is low as in hypogonadal men (3, 9). Similarly, low serum E2 due to mild estrogen deficiency may theoretically cause osteopenia or osteoporosis in eugonadal men (10, 11).

Case presentation

The patient, a 44-year-old 6-foot 2-inch (1.87 m), 178 pounds (81 kg), BMI of 22.9, non-smoker, with minimal alcohol consumption complaining of chronic low back pain was first seen by Dr Michael C. Ullery in January 2009. A complete physical examination showed a healthy athletic male who exercised aerobically and with weights for approximately 60 min a day, ruling out RED-S. No blue discoloration of his sclera was observed ruling out osteogenesis imperfecta. Multiple myeloma and marfanoid syndrome were also excluded. Initial x-rays and CT scans suggested degenerative disc disease and the patient was conservatively treated with chiropractic and physiotherapy but with no lasting relief. The first dual-energy x-ray absorptiometric (DEXA) scan done in January 2009 showed a BMD of the lumbar spine of 0.784 g/cm2 with a T score of −2.8 and a Z score of −2.6 and left femoral neck value of 0.718 g/cm2 with a T score of −2.1 and a Z score of −1.8, respectively, indicative of severe osteoporosis of the lumbar spine and osteopenia of the left hip. A blood test revealed low serum testosterone (189 ng/dL) and a low E2 of 8 pg/mL. Repeated blood tests were performed in order to obtain a diagnosis between January 2009 and August 2010 (pre-treatment) and showed low to normal testosterone levels with consistently low serum E2 levels of 8–17 pg/mL (Table 1). Serum E2 was measured by an ultrasensitive E2 test based on liquid chromatography/mass spectrometry (LC/MS) (Quest Diagnostics Nichols Institute San Juan Capistrano, CA, USA) with a sensitivity of 4 pg/mL. In February 2009, the patient underwent a thorough examination at the Mayo Clinic (Scottsdale, Arizona, USA) and a repeat DEXA scan there confirmed osteoporosis/osteopenia. The patient was put on calcium (1200 mg/daily) and Vitamin D3 (800 IU/daily) supplementation with bisphosphonate therapy. The latter consisted of alendronate (Fosamax®) 10 mg/daily p.o. from 16 to 23 February 2009 (7 days) when the drug was stopped as the patient developed diarrhea and abdominal cramps. He was next treated with risedronate (Actonel®) at 5 mg/daily p.o. from 2 to 19 March 2009 (18 days). The patient developed jaw pain and this drug was also discontinued.

Table 1

Serum testosterone and estradiol in patient 1.

Pre-treatment Post-treatment
January 2009 February 2009 August 2009 August 2010 December 2010 August 2011 April 2012 February 2013 December 2013 August 2015 July 2016 November 2017 September 2018
Testosterone
 Total (ng/dL) 189 353 336 275 296 422 435 309 869 557 472 1006 626
 Free (pg/mL) 7.5 66.8 67.9 50.8 62.5 112 NA NA NA 118.7 NA NA 148.5
Estradiol-E2 (pg/mL) 8 17 15 8 21 43 37 22 36 43 40 41 31

Investigation

In an effort to uncover the cause of the osteoporosis, the patient was next seen in August 2009 by an endocrinologist at the University of California San Francisco Medical Center (San Francisco, CA, USA). Differential diagnoses included marfanoid syndrome and hypogonadism but were each excluded by physical examination and laboratory tests.

In October 2009, the patient was seen by an endocrinologist, Dr Massimiliano Rochietti March at the Ospedale S. Andrea in Rome, Italy.

Back in the USA, laboratory tests in August 2010 showed serum testosterone of 275 ng/dL in the low-normal range, and serum E2 of 8 pg/mL, the latter well below the reference range for adult males (10–35 pg/mL) and below the threshold of 20 pg/mL below which bone health is not protected.

In October 2010, the patient (patient 1) reported that his then-48 years old maternal first cousin (patient 2), born of the twin of the patient’s mother, had documented osteopenia, normal serum testosterone (300 ng/dL), and still low serum E2 (17 pg/mL).

DNA was extracted and sequenced from a blood sample from patient 1 and from his maternal first cousin (patient 2) and analyzed by PCR for the CYP19A1 gene, which encodes aromatase, in Modena, Italy. No known pathologic mutations were observed in the coding exons, but novel single nucleotide polymorphisms (SNPs) were detected in both the proband (patient 1) and his cousin (patient 2) which might explain the consistently low serum E2.

Treatment

Patient 1 was first treated with topical testosterone (AndroGel® 1.62%, 5 g/day) beginning in August 2010 in an attempt to force testosterone conversion to E2 by increasing the concentrations of the androgenic substrate thereby increasing the patient’s serum E2. By December 2010, serum testosterone was 296 ng/dL, but serum E2 had increased to 21 pg/mL and remained stable above 20 pg/mL over time during testosterone treatment (Table 1). Over the next decade, testosterone dosing was varied and switched from topical gel to injections and maintained on depo-injections at about 60 mg testosterone once per week.

Pituitary lesions (brain MRI), hyperparathyroidism (laboratory investigations), and celiac disease (negative antibodies) were excluded.

Table 1 shows the changes in testosterone and E2 over time in patient 1, and Table 2 shows the changes in BMD of the lumbar spine and left femoral neck in patient 1. Figure 1 is a plot of serum E2 vs lumbar spine BMD indicating that serum E2 above about 20 pg/mL is associated with consistent increases in BMD in patient 1.

Figure 1
Figure 1

Changes in serum E2 vs BMD in patient 1.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0407

Table 2

Changes in bone mineral density (g/cm2) over time in patient 1.

January 2009 January 2011 October 2011 January 2013 August 2014 April 2017 October 2018
Lumbar spine 0.784 0.754 0.796 0.830 0.862 0.802 0.975
 T score −2.8 −3.1 −2.7 −2.4 −2.1 −2.6 −2.1
 Z score −2.6 −2.8 −2.4 −2.1 −1.7 −2.2 −1.9
Left femoral neck 0.718 0.740 0.731 0.749 0.791 0.778 0.825
 T score −2.1 −1.9 −2.0 −1.9 −1.6 −1.7 −1.9
 Z score −1.8 −1.7 −1.7 −1.6 −1.3 −1.3 −1.2

The patient (patient 1), 57 in 2018, is doing well and his BMD at the lumbar spine appears to have peaked as of October 2018 (Table 2). Overall, his lumbar spine BMD improved by 29% from the lowest measured value baseline in 2010 while BMD in the left femoral hip improved by 15% over this period.

His maternal first cousin (patient 2), now 60 years of age, opted not to undergo any treatment and showed normal testosterone (337 ng/dL) with low E2 (17 pg/mL) in October 2009. A summary of his blood work is presented in Table 3. As of January 2016, he continued to have osteopenia of his lumbar spine. BMD changes are given in Table 4. The genetic analyses of the aromatase gene for both the proband (patient 1) and his first cousin (patient 2) are given in Table 5.

Table 3

Serum testosterone and estradiol in patient 2.

October 2009 May 2016
Testosterone
 Total (ng/dL) 300 353
 Free (pg/mL) 66.1 66.8
Estradiol (pg/mL) 17 16.7
Table 4

Changes in bone mineral density (g/cm2) over time in patient 2.

January 2009 October 2014 October 2016
Lumbar spine 0.966 0.958 0.958
 T score −1.1 −1.2 −1.2
 Z score −0.9 −0.8 −0.7
Left femoral neck 0.794 0.774 0.661
 T score −1.6 −1.7 −2
 Z score −1.3 −1.4 −1.1
Table 5

Results of the genetic analysis of the CYP19A1 gene (encoding for the enzyme aromatase) of patient 1 and of his first cousin patient 2. The two cousins showed the same identical pattern of polymorphisms of the aromatase gene. Underlined, the intron 4 tetranucleotide repeat polymorphism associated with estrogen levels (23).

Patient 1 Patient 2
Wildtype Wildtype
g.106531A>G in homozygosity (SNP, rs3759811) g.106531A>G in homozygosity (SNP, rs3759811)
g.106684A>G (Val80Val) in homozygosity (SNP, rs700518) g.106684A>G (Val80Val) in homozygosity (SNP, rs700518)
IVS4 TTTA repeat 7/7 (STR polymorphism, rs60271534) IVS4 TTTA repeat 10/10 (STR polymorphism, rs60271534)
g.124928T>G in homozygosity (SNP, rs4324076) g.124928T>G in homozygosity (SNP, rs4324076)
g.125094A>T in homozygosity (SNP, rs1143704) g.125094A>T in homozygosity (SNP, rs1143704)
Wildtype Wildtype
Wildtype Wildtype
Wildtype Wildtype
g.132810C>T in homozygosity (SNP, rs10046) g.132810C>T in homozygosity (SNP, rs10046)
g.132952T>G in homozygosity (SNP, rs4646) g.132952T>G in homozygosity (SNP, rs4646)

Outcome and follow-up

The patient was doing well at follow-up in 2018 and to date (2023).

Discussion

The increase of serum E2 from under 20 pg/mL due to testosterone treatment improved BMD markedly over a period of about 10 years. This is in line with experimental data coming from rare cases of men with aromatase deficiency (6) showing that the increase of serum E2 leads to a parallel increase in BMD in a dose-dependent fashion (7). Furthermore, the data reported here confirm that BMD in men requires serum E2 levels to be consistently above 20 pg/mL (9, 11), as already demonstrated in different settings such as aromatase-deficient men (12) and in population studies (13, 14). As a matter of fact, the same concept was introduced by Nethander et al. who demonstrated that a 1 s.d. (9.6 pg/mL) decrease in serum E2 is associated with a 0.38 s.d. decrease of BMD and to an increase in fracture risk (15). Caution about the assay used for serum E2 measurement (LC/MS method used in this study) is mandatory since many commercially available assays have poor accuracy for the measurement of E2 in the low range in males (10, 16). For this reason, the routine measurement of serum E2 is not recommended in men with or without impaired BMD (10, 17), except in cases where an endocrinologist is aware of an accurate and sensitive method for E2 assay used by the referral laboratory (10). Accordingly, the rapid diffusion of the LC-tandem mass spectrometry in clinical laboratories together with the availability of immunoassays for E2 that are the most accurate and sensitive for serum E2 in the range of 10 to 30 pg/mL (18, 19) may be of value in clinical practice in order to ruling in/ruling out relative estrogen deficiency in men with hypogonadism or with low to normal serum testosterone (10, 11), such as in the case here described. Accordingly, when ultrasensitive assays are used, serum E2 changes may be monitored to check if testosterone treatment is able to ensure values above 20 pg/mL and to optimize the dose of testosterone treatment looking also at bone health (10, 11).

Patient 1 described here showed a peculiar pattern of various genetic polymorphisms of the aromatase gene and this pattern was shared with his first cousin (patient 2) (their mothers were maternal twins) who both presented with low serum E2 and osteopenia/osteoporosis. The result of the genetic analysis raises the question of the possible causal effect of these polymorphisms in lowering aromatase function and, consequently, serum E2. Recently, several genetic studies have demonstrated an association between some aromatase polymorphisms and lower levels of serum E2 in men (20, 21, 22). Even though none of the SNPs and/or polymorphisms found in our patient and his cousin are known to be related to aromatase dysfunction, it is possible that one or more of them may be at the basis of their observed low serum E2.

In conclusion, this case demonstrates the importance of measuring serum E2 in male patients with idiopathic osteoporosis and low or low to normal serum T. In this case, the pivotal role of serum E2 in improving BMD over 8 years in a male patient with consistently low serum E2 (<20 pg/mL) and low to normal serum testosterone and a peculiar SNP pattern in his aromatase gene similar to that of his first cousin with osteopenia/osteoporosis. At present, serum E2 is rarely checked in men in clinical practice but should be considered if an ultrasensitive method for E2 assay is available (10, 16).

It is indisputable that the physiological concept that only serum E2 above a certain value can ensure optimal bone health. With this in view, these two cases of male first cousins add new insights to this issue. We propose that testosterone treatment of male osteoporosis patients where serum E2 levels are consistently below about 20 pg/mL and low or low to normal testosterone may help reverse osteoporosis. In order to exert beneficial effects on BMD, testosterone replacement treatment of hypogonadal men must ensure serum E2 levels above 20 pg/mL.

Declaration of interest

The authors declare there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details was obtained from the patient.

Author contribution statement

All authors contributed to the diagnosis and treatment of the patients in this study, in the evaluation of the data presented and the drafting of this manuscript.

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  • 1

    Stahl F, Dörner G, Knappe G, & Schnorr D. Total and free testosterone in plasma of hypo- and agonadal men. Endokrinologie 1975 66 152157.

  • 2

    Fink HA, Ewing SK, Ensrud KE, Barrett-Connor E, Taylor BC, Cauley JA, & Orwoll ES. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. Journal of Clinical Endocrinology and Metabolism 2006 91 39083915. (https://doi.org/10.1210/jc.2006-0173)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Rochira V, Balestrieri A, Madeo B, Zirilli L, Granata AR, & Carani C. Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology. European Journal of Endocrinology 2006 154 175185. (https://doi.org/10.1530/eje.1.02088)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Finkelstein JS, Lee H, Leder BZ, Burnett-Bowie SA, Goldstein DW, Hahn CW, Hirsch SC, Linker A, Perros N, Servais AB, et al.Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. Journal of Clinical Investigation 2016 126 11141125. (https://doi.org/10.1172/JCI84137)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Bonomi M, Rochira V, Pasquali D, Balercia G, Jannini EA, & Ferlin A. Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism. Journal of Endocrinological Investigation 2016 40 123134. (https://doi.org/10.1007/s40618-016-0541-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Rochira V, & Carani C. Aromatase deficiency in men: a clinical perspective. Nature Reviews. Endocrinology 2009 5 559568. (https://doi.org/10.1038/nrendo.2009.176)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Rochira V, Faustini-Fustini M, Balestrieri A, & Carani C. Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters. Journal of Clinical Endocrinology and Metabolism 2000 85 18411845. (https://doi.org/10.1210/jcem.85.5.6583)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Vandenput L, & Ohlsson C. Estrogens as regulators of bone health in men. Nature Reviews. Endocrinology 2009 5 437443. (https://doi.org/10.1038/nrendo.2009.112)

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