Hormones, the skeleton and HRT Flashcards
Which hormone is replaced in hormone replacement therapy?
Oestrogen
Name some systemic hormones with skeletal effects
- Oestrogen
- Parathyroid hormone (PTH)
- Vitamin D
- Calcitonin
What is the macrostructure of bone?
- Cortical (compact) bone - around outside of bone and composes main part of shaft
- Trabecular (spongy) bone - tends to be in head of bone
What are osteoblasts?
- Differentiate from mesenchymal stem cells
- Bone forming cells - lay down osteoid + promote mineralisation of osteoid
- Life cycle determined by control of differentiation and apoptosis
What are osteoclasts?
- Derived from haematopoietic stem cells
- Resorption of bone - secrete acid to dissolve + release mineral, enzymes to degrade osteoid/matrix
- Life cycle determined by control of differentiation + apoptosis
What are osteocytes?
- Terminally differentiated, post-mitotic osteoblasts
- Entombed within lacuae in bone matrix
- Communicate with each other + bone surface via dendrites which run along canaliculi
- Lacunar-canalicular network
- May live for decades
What actually is the function of osteocytes?
- Regulate bone remodelling in response to mechanical + endocrine stimuli
- Function as endocrine cells
What is the lacunar-canalicular network?
- Lacunar = holes (where cells are)
- Canalicular = networks (between cells)
- Allows communication between osteocytes and from osteocytes to surface cells + systemic circulation
Control of remodelling: What are factors favouring resorption?
- Unloading
- Eg. bedrest, zero-gravity
- Ie. lack of mechanical stress
Control of remodelling: What are factors favouring formation?
- Load bearing exercise
- Osteocytes involved in sensing mechanical stress for this
Bone turnover serves homeostasis of serum calcium and phosphate, in conjunction with which hormones?
- PTH
- Vit D (calcitriol)
- Calcitonin
What is the role of PTH (parathyroid hormone)?
- Control plasma calcium (2.2-2.6 mmol/L)
- Released in response to decreased Ca
- Stimulates 1-a hydroxylase -> forms active vitamin D in kidney
- Increases Ca reabsorption in kidney
- Promotes bone remodelling (anabolic + catabolic)
- Prevents osteoblast + osteocyte apoptosis
What are the actions of Vitamin D?
- Increases Ca absorption from gut
- Promotes differentiation of osteoclast + osteoblast lineages
- Inhibits PTH release
- Inhibits 1-alpha hydroxylase
- Necessary for bone mineralisation
Vitamin D is synergistic with PTH
What are actions of calcitonin?
- Released from C-cells of thyroid gland
- Neg feedback reg of serum Ca -> released in response to inc Ca
- Lowers serum calcium
- Importance in human Ca homeostasis is doubtful
- Inhibits osteoclast function (preventing resorption -> lowering serum Ca)
How does oestrogen act on osteoblasts and osteoclasts?
- Oestrogen receptors present on both osteoclasts and osteoblasts
- Regulates life cycle of them both
- Osteoclasts -> promote apoptosis -> shorten life cycle
- Osteoblasts -> protect from apoptosis -> lengthen life cycle
- Indirectly inhibit osteoclast differentation
- May be necessary for new bone formation in response to mech stress
What is RANK?
- Receptor activator of nuclear factor kappa-B
- It’s a surface receptor on pre-osteoclasts, when activated it stimulates osteoclast differentiation
What is RANK-ligand?
- RANK ligand prod by pre-osteoblasts, osteoblasts + osteocytes
- Binds to RANK (receptor) + stimulates osteoclast differentation
What is OPG (osteoprotogerin)?
- Decoy receptor prod by osteocytes
- Binds to RANK-L, preventing activation of RANK
- Preventing osteoclast differentation
Ratio between RANK ligand and OPG is critical in controlling rate of bone resorption
What is sclerostin?
- Produced by osteocytes
- Inhibits osteoblast differentiation
- Essential negative feedback on bone formation
- Absence -> excessive bone formation
- It’s a brake on bone formation + mechanical stress can take this brake off
What is osteoporosis?
- Loss of bone mass
- Affects cortical and trabecular bone
What is osteomalacia?
Loss of bone mineralization
What are the causes for osteoporosis?
- Endocrine
- Malignancy
- Drug-induced
- Renal disease
- Nutritional
What are the endocrine causes of osteoporosis?
- Hypogonadism - notably any cause of ostrogen deficiency
- XS glucocorticoids - endogenous or exogenous
- Hyperparathyroidism
- Hyperthyroidism
How do you diagnose osteoporosis?
- Measurement of bone mineral density (BMD)
- By DEXA scan (dual-energy x-ray absorptiometry)
- Result = T score (# of SDs below average for young adult at peak bone density)
- Z score = matched to age and/or group
What is the T score diagnosis for osteoporosis?
Can oestrogen be a given as treatment for osteoporosis?
Yes - Effects well established but safety of long term treatment has been questioned
What is the usual first line treatment for osteoporosis?
- Bisphosphonates
- Inhibit function of osteoclasts
- Risedronate, alendronate
PTH analogues can be used to treat osteoporosis, what is important about this?
- PTH can be anabolic and catabolic
- Must be dose-time dependent therapy
What is the name of the (drug) antibody used against RANK ligand, in order to treat osteoporosis?
Denosumab - for postmenopausal as well
What are lifestyle treatments for osteoporosis?
- Adequate calcium + vitamin D intake
- Appropriate exercise
What are clinical features of the menopause?
- Most common early manifestation: vasomotor symptoms (hot flushes)
- Later: accelerated bone loss, osteoporosis
With oestrogen and progesterone therapy (HRT), how is the relative risk of getting breast cancer 27%?
- Placebo relative risk = 0.30
- oestrogen + progesterone relative risk = 0.38
- 38-30 = 8
- 8/30 x 100 = 27%
- Therefore 27% increase in terms of relative risk
- AKA 1.27 more times likely to develop breast cancer if you go for HRT
What is the NICE guidance for HRT?
- HRT most effective treatment for relief of vasomotor symptoms although other options are available
- For most symptomatic, menopausal women, the benefits of HRT outweigh the risks
- Inc in risk of breast cancer exp with some HRT preparations disappears once HRT is stopped
