Hormone Replacement Therapy in Postmenopausal Women: Urinary N-Telopeptide of Type I Collagen Monitors Therapeutic Effect and Predicts Response of Bone Mineral Density

doi:10.1016/S0002-9343(96)00387-7

The American Journal of Medicine

Volume 102, Issue 1, January 1997, Pages 29-37

https://doi.org/10.1016/S0002-9343(96)00387-7 Get rights and content

Abstract

PURPOSE: To assess the ability of the urinary N-telopeptide of type I collagen (NTx) to monitor and predict therapeutic effects of hormone replacement therapy (HRT) in postmenopausal women.

PATIENTS AND METHODS: To assess the relationship between baseline or change in NTx (predictive variable), and change in lumbar and hip bone mineral density (BMD; outcome variable), we conducted a 2-year randomized controlled study at academic university and private practice medical centers in 236 healthy women 1 to 3 years postmenopausal; 227 women completed the study. Women received estrogen plus progesterone plus calcium (treated group) or calcium alone (control group).

RESULTS: In the treated group NTx significantly (P <0.0001) decreased, and spine and hip BMD significantly (P <0.00001 and P <0.005, respectively) increased; in the control group NTx did not change but BMD decreased significantly (P <0.01). Subjects in the highest quartiles for baseline NTx (67 to 188 units) or decreasing NTx (−66% to −87%) through 6 months demonstrated the greatest gain in BMD in response to HRT (P <0.05 and P <0.005). For every increase of 30 units in baseline NTx, the odds of gain in BMD in response to HRT increased by a factor of 5.0 (95% confidence interval [CI] 1.9 to 13.3); for every 30% decrease in NTx through 6 months, the odds of gaining BMD in response to HRT increased by a factor of 2.6 (95% CI 1.6 to 4.4). In the control group an increase of 30 units in mean NTx across the study indicated a higher odds of losing BMD by a factor of 3.2 (95% CI 1.6 to 6.5). A high baseline NTx (>67 units) indicated a 17.3 times higher risk of BMD loss if not treated with HRT.

CONCLUSION: These data support the clinical utility of NTx to monitor the antiresorptive effect of HRT in recently postmenopausal women, and to predict changes in BMD in response to HRT.

Section snippets

Subjects

A total of 236 women, aged 40 to 58 years, and 6 months to 3 years naturally postmenopausal, were enrolled and met the inclusion criteria in the 8-site study. Women were excluded who were over 30% of their ideal body weight as indicated by the Metropolitan Life Insurance Company table, had taken any medication within the last 2 months, had disorders that might influence bone or mineral metabolism, or had ever been treated with bisphosphonates or sodium fluoride. Women with recent fractures,

Results

Baseline clinical and laboratory characteristics are presented in Table 1. Mean baseline values were not significantly different between the treated and control groups. In all, 227 women completed the study; the dropout rate was 2% in the HRT group and 6% in the control group, and was not significantly different between the two groups. Only results for women completing the study are included. No significant site difference was found in the percent change L1-L4 outcome using the Kruskall-Wallis

Discussion

In the present study, recently postmenopausal healthy women receiving hormone replacement therapy plus calcium over 1 year demonstrated a significant decrease in the urinary excretion of the N-telopeptide of type I collagen (indicating a decrease in bone resorption); a significant increase in bone mineral density at spine and hip was subsequently observed. These results are not unexpected; such effects of HRT on bone markers of resorption17, 19have been described in short-term studies with

Acknowledgements

We wish to thank Ted Clay, MS, Mary Pettinger, MS, and Charles Slemenda, PhD, for their expertise in statistical analysis, SmithKline Beecham for supplying the calcium supplements for the study, and the clinical coordinators whose persistence and careful guidance were invaluable to the study.

Ostex International, Seattle, Washington, provided financial grants to each investigative site for conduct of the study.

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Cited by (245)

Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines
2022, Maturitas
The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after natural menopause) covering all aspects of lifestyle and therapeutic management, with or without menopause hormone therapy (MHT).
Literature review and consensus of French expert opinion. Recommendations were graded according to the HAS methodology and levels of evidence derived from the international literature, except when there was no good-quality evidence.
The beginning of menopause is an ideal time for each woman to evaluate her health status by assessing her bone, cardiovascular, and cancer-related risk factors that may be amplified by postmenopausal estrogen deficiency and by reviewing her lifestyle habits. Improving lifestyle, including nutrition and physical activity, and avoiding risk factors (notably smoking), should be recommended to all women. MHT remains the most effective treatment for vasomotor symptoms but it could be also recommended as first-line treatment for the prevention of osteoporosis in early postmenopausal women at low to moderate risk for fracture. The risks of MHT differ depending on its type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. There is reasonable evidence that using transdermal estradiol in association with micronized progesterone or dydrogesterone may limit both the venous thromboembolic risk associated with oral estrogens and the risk of breast cancer associated with synthetic progestins. Treatment should be individualized to each woman, by using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of its benefit–risk balance. For bothersome genitourinary syndrome of menopause (GSM) symptoms, vaginal treatment with lubricants and moisturizers is recommended as first-line treatment together with low-dose vaginal estrogen therapy, depending on the clinical course. No recommendation of an optimal duration of MHT can be made, but it must take into consideration the initial indication for MHT as well as each woman's benefit–risk balance. Management of gynecological side-effects of MHT is also examined.
These recommendations are endorsed by the Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVI) and the Collège National des Gynécologues-Obstétriciens Français (CNGOF).
Menopause, menopause hormone therapy and osteoporosis. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines
2021, Gynecologie Obstetrique Fertilite et Senologie
L’ostéoporose post-ménopausique est une pathologie fréquente qui touche près d’1 femme sur 3. La carence estrogénique de la ménopause entraîne en effet un phénomène de perte osseuse rapide, maximale les premières années de post-ménopause, qui peut être prévenue par un traitement hormonal (THM). L’évaluation du risque individuel d’ostéoporose repose avant tout sur la mesure de la densité minérale osseuse (DMO) au rachis et au fémur par DXA. Les facteurs de risque cliniques (FRC) pris isolément ou combinés dans le score FRAX ne permettent pas de prédire de manière fiable les fractures et/ou une ostéoporose densitométrique (T-score < −2,5) chez les femmes en début de ménopause. La mesure densitométrique est de fait indiquée chez toutes les femmes ayant des FRC d’ostéoporose et au cas par cas, lorsque la connaissance de la DMO est susceptible de conditionner la prise en charge de la femme en début de ménopause, notamment la balance bénéfices-risques du THM. Le THM prévient la perte osseuse et les anomalies de la micro-architecture osseuse du début de la ménopause. Il diminue de 20 à 40 % le risque de fracture à tous les sites osseux indépendamment du niveau basal de risque avec un effet–dose dépendant des estrogènes. Compte tenu d’une variabilité inter-individuelle de la réponse osseuse, un suivi individuel de l’effet osseux du THM est justifié lorsqu’il est prescrit pour la prévention de l’ostéoporose. Ce suivi repose sur la mesure de la DMO lombaire et fémorale (sur le même système de mesure de DXA) après 2 ans de THM avec comme critère de réponse, l’absence de perte osseuse significative. L’arrêt du traitement est associé à la reprise d’une perte osseuse transitoire d’intensité variable selon les femmes, et au retour dans les 2 à 5 ans suivants, à un niveau de risque fracturaire comparable à celui d’une femme de même âge n’ayant jamais été traitée. Quand le THM est prescrit pour la prévention du risque fracturaire chez une femme à risque majoré, il est donc conseillé de faire une mesure de DMO à l’arrêt du THM en vue d’une prise en charge adaptée (relais possible par un autre traitement de l’ostéoporose).
Postmenopausal osteoporosis is a frequent clinical condition, which affects nearly 1 in 3 women. Estrogen deficiency leads to rapid bone loss, which is maximal within the first years after the menopause transition and can be prevented by menopause hormone therapy (MHT). Assessment of the individual risk of osteoporosis is primarily based on the measurement of bone mineral density (BMD) at the spine and femur by DXA. Clinical risk factors (CRFs) for fractures taken either alone or in combination in the FRAX score were shown not to reliably predict fractures and/or osteoporosis (as defined by a T-score <−2.5) in early postmenopausal women. If DXA measurement is indicated in all women with CRFs for fractures, it can be proposed on a case-by-case basis, when knowledge of BMD is likely to condition the management of women at the beginning of menopause, particularly the benefit-risk balance of MHT. MHT prevents both bone loss and degradation of the bone microarchitecture in early menopause. It significantly reduces the risk of fracture at all bone sites by 20 to 40% regardless of basal level of risk with an estrogen-dependent dose–effect. Given the inter-individual variability in bone response, individual monitoring of the bone effect of MHT is warranted when prescribed for the prevention of osteoporosis. This monitoring is based on repeated measurement of lumbar and femoral BMD (on the same DXA measurement system) after 2 years of MHT, the response criterion being no significant bone loss. Discontinuation of treatment is associated with a resumption of transient bone loss although there is a large variability in the rate of bone loss among women. Basically, there is a return to the level of fracture risk comparable to that of in untreated woman of the same age within 2 to 5 years. Therefore, when MHT is prescribed for the prevention of osteoporosis in women with an increased risk at the beginning of menopause, measurement of BMD is recommended when MHT is stopped in order to consider further management of the risk of fracture whenever necessary (with possibly another anti-osteoporotic treatment).
American association of clinical endocrinologists/American college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update
2020, Endocrine Practice
Citation Excerpt :
Bone turnover markers (BTMs) provide a dynamic assessment of skeletal activity and are useful modalities for skeletal assessment. Although they cannot be used to diagnose osteoporosis, elevated levels can predict more rapid rates of bone loss (71-73) and are associated with increased fracture risk independent of BMD in some studies (74-76). One recent study without data for BMD failed to verify prediction of hip fractures with BTMs (77).
The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs).
Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.
The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high -risk features, a new dual-action therapy option, and transitions from therapeutic options.
This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of postmenopausal osteoporosis. (Endocr Pract. 2020;26 (Suppl 1):1-44)
Biochemical markers of bone turnover in osteoporosis
2020, Marcus and Feldman’s Osteoporosis
Bone turnover markers (BTMs) are divided into the markers of bone formation and those of bone resorption. N-terminal collagen type I extension propeptide and serum C-terminal cross-linking telopeptide of type I collagen have been selected as the reference markers of bone formation and resorption, respectively. BTM levels are influenced by numerous factors. BTM cannot be used for the diagnosis of osteoporosis or to predict accelerated bone loss. The utility of BTMs for fracture prediction in postmenopausal women requires further studies. Bone resorption inhibitors decrease BTM levels. Changes in BTMs after their withdrawal vary according to their mechanisms of action. Bone formation–stimulating drugs increase the concentrations of bone formation markers. BTM may be used for dose-finding studies, bridging studies, and, hopefully, for monitoring the antiosteoporotic treatment. Sequential therapy trials, head-to-head comparisons, and combination therapy studies improve our understanding of the mechanisms of action of antiosteoporotic drugs on bone metabolism.
Emerging concepts in the epidemiology, pathophysiology, and clinical care of osteoporosis across the menopausal transition
2018, Matrix Biology
Citation Excerpt :
Similarly, elevated osteocalcin levels predicted severe and diffuse bone loss in premenopausal women [94]. Indeed, elevated baseline NTX level indicated a 17.3 times greater risk of BMD loss in early postmenopausal women if left untreated [95]. An increase of 1 SD in NTX and osteocalcin levels increased the odds of losing spinal BMD, the most affected site during early menopause, by 2.1 and 1.6%, respectively [96].
Bone loss in women accelerates during perimenopause, and continues into old age. To-date, there has been little progress made in stratifying for fracture risk in premenopausal and early postmenopausal women. Epidemiologic data suggests that changes in serum FSH could predict decrements in bone mass during peri- and postmenopause. In bone, FSH stimulates osteoclast formation by releasing osteoclastogenic cytokines. Here, we address the evidence for bone loss across the menopausal transition, discuss strategies for detection and treatment of early postmenopausal osteoporosis, and describe the role FSH plays in physiology and likely in pathophysiology of early postmenopausal bone loss.
Brazilian guidelines for the diagnosis and treatment of postmenopausal osteoporosis
2017, Revista Brasileira de Reumatologia
A osteoporose é a principal causa de fraturas na população acima de 50 anos. É uma doença silenciosa que afeta especialmente as mulheres na pós‐menopausa e idosos e tem elevada taxa de morbimortalidade. O principal objetivo do tratamento da osteoporose é a prevenção das fraturas. A identificação dessa população de risco através do diagnóstico e tratamento precoces é de fundamental importância. A última diretriz brasileira para tratamento da osteoporose em mulheres na pós‐menopausa foi elaborada em 2002. Desde então foram desenvolvidas novas estratégias de diagnóstico da osteoporose, bem como fármacos com novos mecanismos de ação foram adicionados ao arsenal terapêutico. A Comissão de Osteoporose e Doenças Osteometabólicas da Sociedade Brasileira de Reumatologia em conjunto com a Associação Médica Brasileira e sociedades afins desenvolveu esta atualização da diretriz do tratamento da osteoporose em mulheres na pós‐menopausa de acordo com as melhores evidências científicas disponíveis. Esta atualização é destinada aos profissionais das várias especialidades médicas e da área da saúde envolvidos no tratamento da osteoporose, médicos em geral e organizações relacionadas à saúde.
Osteoporosis is the leading cause of fractures in the population older than 50 years. This silent disease affects primarily postmenopausal women and the elderly, and the morbidity and mortality rates are high. The main goal of treating osteoporosis is the prevention of fractures. The identification of populations at risk through early diagnosis and treatment is essential. The last Brazilian guideline for the treatment of postmenopausal osteoporosis was elaborated in 2002. Since then, new strategies for diagnosis and risk stratification have been developed, and drugs with novel action mechanisms have been added to the therapeutic arsenal. The Osteoporosis and Osteometabolic Diseases Committee of the Brazilian Society of Rheumatology, in conjunction with the Brazilian Medical Association and other Societies, has developed this update of the guidelines for the treatment of postmenopausal osteoporosis according to the best scientific evidence available. This update is intended for professionals in many medical and health specialties involved in the treatment of osteoporosis, for physicians in general and for health‐related organizations.

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Clinical StudiesHormone Replacement Therapy in Postmenopausal Women: Urinary N-Telopeptide of Type I Collagen Monitors Therapeutic Effect and Predicts Response of Bone Mineral Density

Abstract

Section snippets

Subjects

Results

Discussion

Acknowledgements

Phys Med Rehab Clin North Am.

Obstet Gynecol.

Lancet

Am J Med.

Bone

Involutional osteoporosis

NEJM

Lifetime risks of hip, Colles, or vertebral fracture and coronary heart disease among white postmenopausal women

Arch Intern Med.

The prevention and treatment of osteoporosis

NEJM

Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogen

NEJM

Long-term estrogen replacement prevents bone loss and fractures

Ann Intern Med.

Hip fracture and the use of estrogens in postmenopausal women: the Framingham study

NEJM

Clinical indications for bone mass measurements: a report from the Scientific Advisory Board of the National Osteoporosis Foundation

J Bone Miner Res.

A specific immunoassay for monitoring bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine

J Bone Miner Res.

Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment

J Clin Endocrinol Metab.

Monitoring bone resorption in early postmenopausal women by an immunoassay for cross-linked collagen peptides in urine

J Bone Miner Res.

Osteocalcin: isolation, characterization and detection

Methods Enzymol.

Improved method for determination of serum alkaline phosphatase of skeletal origin

Clin Chem.

Clinical Studies
Hormone Replacement Therapy in Postmenopausal Women: Urinary N-Telopeptide of Type I Collagen Monitors Therapeutic Effect and Predicts Response of Bone Mineral Density