Acute Effects of Kisspeptin Administration on Bone Metabolism in Healthy Men

Alexander N. Comninos; Morten S. Hansen; Alan Courtney; Sirazum Choudhury; Lisa Yang; Edouard G. Mills; Maria Phylactou; Mark Busbridge; Muaza Khir; Thilipan Thaventhiran; Paul Bech; Tricia Tan; Ali Abbara; Morten Frost; Waljit S. Dhillo

Disclosures

J Clin Endocrinol Metab. 2022;107(6):1529-1540. 

In This Article

Abstract and Introduction

Abstract

Context: Osteoporosis results from disturbances in bone formation and resorption. Recent nonhuman data suggest that the reproductive hormone kisspeptin directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown.

Objective: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo.

Methods: In vitro study: of Mono- and cocultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, 2-way crossover clinical study in 26 men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. Cells for the in vitro study were from 12 male blood donors and 8 patients undergoing hip replacement surgery. Twenty-six healthy eugonadal men (age 26.8 ± 5.8 years) were included in the clinical study. The intervention was Kisspeptin (vs placebo) administration. The main outcome measures were changes in bone parameters and turnover markers.

Results: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P = .0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P < .0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P = .021) and 24.3% maximal increase in carboxylated osteocalcin levels (P = .014).

Conclusion: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex steroid levels. Kisspeptin could therefore have clinical therapeutic application in the treatment of osteoporosis.

Introduction

Osteoporosis is an escalating global health challenge, with 1 in 2 women and 1 in 5 men over the age of 50 years predicted to suffer an osteoporotic fracture.[1,2] In the United States, approximately 10 million Americans over the age of 50 years suffer from osteoporosis, resulting in 1.5 million osteoporotic fractures and an annual economic cost of over $17 billion,[3] with a similar heavy burden in Europe.[4] Furthermore, the detrimental impacts on the patient sustaining a fracture are considerable, amounting to the fourth leading cause of chronic disease morbidity in Europe.[4] These concerning figures are broadly echoed throughout the world with dramatic future increases in osteoporotic fractures anticipated due to an ageing population.[5–7]

Current osteoporosis treatments are generally effective in most, but not all, patients. In addition, they have contraindications and rare but significant much-publicized adverse effects, that limit their recommended duration of use.[8–10] Unfortunately, there are no new osteoporosis treatments in late-stage clinical development currently.[11] Taken together, there is an urgent need to better understand the regulation of bone remodeling, in order to identify new safe and effective therapeutic targets.

Osteoporosis results from disturbances in the fine balance between bone formation and bone resorption, performed by osteoblasts and osteoclasts, respectively. The most common cause of this disturbance is sex steroid deficiency (predominantly estrogen), although there exist a plethora of alternative secondary causes and risk factors.[12] The net result is thinner and disordered bone architecture, which is prone to fracturing. Therefore, improving this bone formation/resorption balance forms the cornerstone for the development of novel therapeutic agents for the prevention and treatment of osteoporosis.

Kisspeptin is a naturally occurring hormone critical for reproduction in men and women.[13–17] Furthermore, kisspeptin-based medicines are in clinical development for a range of common reproductive disorders.[18–23] It is therefore timely that recent data in rodents demonstrate that kisspeptin administration directly promotes osteoblast differentiation in vitro via the kisspeptin receptor (Kiss1r) expressed on rodent osteoblasts.[24] This suggests that kisspeptin may have direct beneficial effects on skeletal homeostasis, independent of its ability to stimulate downstream sex steroid levels via its more established action on the hypothalamic–pituitary–gonadal axis.[25] However, there are no data on the direct effects of kisspeptin on human bone metabolism as yet, and so we aimed to investigate this.

We employed RNA sequencing to identify KISS1R expression on human osteoclast precursors and human mature osteoclasts, adding to the previously reported identification of Kiss1r expression on rodent osteoblasts and monocyte-derived osteoclasts.[24,26] We then performed a series of multimodal kisspeptin administration studies both in vitro and clinically (in vivo) to assess the effects of kisspeptin on anabolic and resorptive parameters of bone metabolism, as well as on bone biochemistry in humans, for the first time.

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