Definition

Osteoporosis Most common metabolic bone disease.

Overview
March 2025
Systemic skeletal disease characterized by low
bone mass and microarchitectural deterioration
of bone tissue with a consequent increase in
bone fragility.

The disease often does not become clinically

DR LUKE BYRNE
apparent until a fracture occurs.
ST JAMES’S HOSPITAL

SLIDES WITH THANKS TO DR DONAL FITZPATRICK AND DR ROSALEEN LANNON

Impact Epidemiology
Health and economic problem around the world.
Many individuals (male and female) experience
-Pain
-Disability
-diminished quality of life
sequelae of fractures.

It is a condition that is often overlooked and undertreated, in large part because it is often
clinically silent
 “Hip fracture is all too often the final destination of a 30-year journey
fuelled by decreasing bone strength and increasing falls risk”

WHO Definition of Osteoporosis

Bone mineral density (BMD) in a patient is related to peak bone mass & subsequently,
bone loss.
T-score is the patients bone density compared with the BMD of control subjects who are
at their peak BMD.
Z-score reflects a bone density compared with that of patients matched for age and sex.

DXA
Dual energy x-ray absorptiometry
Radiation = 1/6th of a CXR
Measures BMD in g/cm2 at the spine and hip (total & NoF)
Z score = standard deviation of BMD from the mean, Compared to someone your
own age
T Score = standard deviation of BMD from the mean
Compared to young healthy female
T scores don’t apply to people < 50
• Z score < -2.0 + fracture = osteoporosis
• Z score <2.0 + no fracture = low bone mass
 • Osteoclasts - responsible for bone resorption
• Osteoblasts - responsible for bone formation
• The 2 types of cells are dependent on each other for
Normal Bone Turnover production and linked in the process of bone remodelling.
• Osteocytes = terminally differentiated osteoblasts
embedded in mineralized bone, direct the timing and
location of bone remodelling

Bone is continually remodeled throughout our lives in response to microtrauma. Bone

remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion,
and bone resorption is always followed by bone formation, a phenomenon referred to as
coupling.

Bone Turnover Markers Bone Formation markers

Biochemical products measured in the blood or urine that reflect metabolic Type 1 collagen is an important component of bone matrix and osteoblasts secrete its precursor
activity of bone but have no independent function in controlling skeletal procollagen molecule during bone formation.
metabolism. Procollagen type I N propeptide (PINP) – released when procollagen broken down to form type 1
collagen
Traditionally categorized as markers of bone formation and bone resorption.
P1NP is a measure of bone formation
CTX – best resorption marker
P1NP – best formation marker.
Bone Resorption markers Usefulness of Bone Turnover Markers
Monitoring therapeutic efficacy and compliance of OP therapy:
BTM trends reflect the biologic efficacy of anti-resorptive agents
BTMs decrease during bisphosphonate therapy. These changes are associated with increased bone mass and/or fracture rate reduction.
Denosumab rapidly suppresses bone turnover

Degradation products of type I collagen, produced from osteoclast activity – bone resorption Anabolic agents such as teriparatide initially increase bone formation followed by bone resorption. The early increase in bone formation is a result of
direct stimulation of bone formation.

C-terminal and N-terminal crosslinking telopeptides (CTX, NTX) of type I collagen released into Check before treatment and then at a certain point after treatment started
the circulation and subsequently excreted in the urine (can be measured in blood or urine) Compliance
Poor adherence with oral bisphosphonates
If BTM not suppressed on treatment, suggests that patient not taking medication, medication not absorbed or secondary cause of
osteoporosis present
Most commonly used is serum CTX

Fracture risk prediction:

High bone remodeling rates have been associated with an increased risk of fractures.

Alterations in bone formation

Limitations and resorption
Availability ◦ Osteoporosis is a reduction in skeletal mass caused by an imbalance between bone resorption and bone
formation.
Affected by ◦ Under physiologic conditions bone formation and resorption are in a fair balance.
◦ Diurnal variation and circadian rhythm ◦ A change in either, so increased bone resorption or decreased bone formation—may result in osteoporosis.
◦ Food intake ◦ Osteoporosis can be caused both by a failure to build bone and reach peak bone mass as a young adult and by
bone loss later in life
◦ Fasting samples preferable
◦ BTMs increase @ ovulation and are decreased by COCP
◦ Renal impairment Peak bone mass – achieved by age 18-25
◦ Genetic factors mostly
◦ Nutrition
◦ Endo status
◦ Physical activity
◦ Health during growth
 Secondary Osteoporosis
Post menopausal osteoporosis: Endocrine

- Hypogonadism
Metabolic

- Vitamin D deficiency

- Premature including surg menopause - Severe liver disease

Accelerated bone loss due to drop in oestrogen levels after menopause
- Cushings Medication
Most common form of osteoporosis
- Diabetes mellitus - Antiepileptics
Most clinical trials are in this cohort - Addisons disease - Steroids

- Thyrotoxicoxis or xs thyroxine replacement - Cytotoxic

- Hypercalciuria - HAART

- Hyperparathyroidism - ADT = androgen deprivation tx

GI - Heparin

- Malabsorption Radiation tx

- Inflammatory bowel disease Bone marrow transplant

- Anorexia Nervosa HIV – disease and meds

Immobilisation

History should focus on Risk Factors and

Risk of Fracture:
 Differentials:
falls
….. Presenting with fracture and low BMD
Osteomalacia
Malignancy e.g. Multiple myeloma
Pagets disease
Hyperparathyroidism
Renal osteodystrophy

All can co-exist

As well as DXA
FBC
ESR
Renal/liver/bone profile
25(OH)vitamin D
PTH
TFTs
SPEP
Testosterone
Oes/FSH/LH
Bone markers
24 hour urinary calcium
 Treatment – non pharmacological
Goal of investigations measures
-Exclude causes of low bone mass other than age and oestrogen deficiency. Lifestyle measures
-Detect potentially remediable causes/contributing factors -Exercise weightbearing exercise, muscle strengthening
-Smoking cessation
-Reduce xs alcohol
-Falls prevention
-Maintain BMI

-Adequate Ca/Vit D

Combination of Ca/Vit D supplement can reduce fracture Vitamin D:D

Supplement if not provided from diet - Plays role in calcium absorption
Calcium - NOF recommend 800-1000iu per day in >50’s
- Intake to optimise levels varies individually so levels should be checked
• Institute of Medicine (IOM) and NOF recommend
women > 50 and men > 70 – 1200mg/day Particularly at risk
- Older people
men > 50 – 1000mg/day - Intestinal malabsorption
• Excess of this doesn't confer any further benefit for bone strength - CKD
- Meds that increase breakdown of Vit D
- Limited sun exposure – house bound/institutionalised/darker skin @
And may…. higher latitudes
- Increase risk of kidney stones, cv and stroke - Obesity Adults (12-65 years) a daily vitamin D supplement containing
15 µg (600 IU) should be taken October to March FSAI 2023
Though Target level
- Literature controversial - 75 nmol/L
- Institute of Medicine guideline 2011
Pharmacological therapy
Patients at highest risk of fracture most likely to benefit from pharmacological
therapy.
Fracture risk = BMD + clinical risk factors
Recent fracture especially @ higher risk.

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Drug therapy
Anti-resorptive Not available yet in Ireland
◦ Oral bisphosphonates (mainstay of treatment) ◦ Romosuzumab
◦ Intravenous bisphosphonate ◦ Abaloparatide
◦ Denosumab (RANKL monoclonal antibody)
Anabolic
◦ Teriparitide

Others
◦ HRT – prescribed for menopause symptoms –
has beneficial effects on bone
◦ Raloxifene - SERM
◦ Strontium – off market
◦ Calcitonin – rarely used

Bisphosphonates IV Zoledronic acid

Two brands = Aclasta 5mg or Zometa 4mg once yearly.
- Occasionally patients on half dose (Mild CKD/frail).
◦
- Occasionally first dose is half does so second give at 9months and
◦ in full.
◦ - Most patients get for 3/4 years.
◦ - Some are continued longer e.g. some of long term steroid patients
◦
and some other unusual cases.
◦
Reduces risk of vrt frax by 70%, hip fractures by 41% and non vrt frax by
◦ 25% over 3 years.
◦ Ibandronate (bonviva) 150mg once month Horizon Pivotol fracture trial
◦ Reduces risk of vrt frax by 50% over 3 years. 2007
◦ JBMR 2004
Bisphosphonates Adverse effects of bisphosphonates
Inhibit osteoclast differentiation and function Oral and IV
◦ Osteonecrosis of the jaw (Greater risk with IV rather than oral)
By extension inhibit osteoblasts
◦ Atypical femoral fracture
Poor oral absorption
Expect reduction in CTX
Oral bisphosphonates
Renal excretion – avoid if creatinine cl < 30ml/min ◦ GI upset
Cheap, good safety profile, around a long time
Teratogenic IV bisphosphonate
◦ Transient hypocalcaemia
◦ Acute phase reaction

Considerations – PO bisphosphonate Considerations – iv (zoledronic acid)

Most potent bisphosphonate
GI side effects Counselling on how to take is NB Side effects/councelling:
-Same mech of action
-Flu like/acute phase reaction
-GI intolerance common -30 min before food
-10-20%
-Full glass water Severe OP
-TNF alpha action
Supplements and food may reduce absorption -Stay upright History of oesophagitis/gastritis
-Pre-hydrate & paracetamol
If compliance expected to be poor
Transient hypocalcaemia (ensure normocalcaemia
and vitamin D replete prior to infusion)
Reminders e.g. calendar/phone alarm

ONJ
AFF
Renal impairment
Osteonecrosis of the jaw Duration of Therapy
Very rare Oral Bisphosphonates:
- Review needed at 5 years
RF – cancer/chemoRx/pre-existing dental disease/certain types dental work/steroids/duration of therapy
- If bmd <-2.5 and no fractures warranted to consider
drug holiday and repeat DXA in 12-18 months.
Generally occurs after invasive dental work
Bisphosphonates persist in bone
Implant > Extraction
Not with non invasive e.g. filling, cleaning - Residual benefit of fracture reduction for up to 5 years

IV bisphosphonate
Risk = 1/10000 to <1/100000pt years Consider after 3 years
Extremely rare with oral bisphosphonates
Drug holiday applies only to bisphosphonates
More common with zoledronic acid/denosumab for malignant bone disease rather than osteoporosis
(higher does/greater cumulative exposure)

Atypical femoral fracture Incomplete AFF

Atypical femoral fracture
Under normal circumstances, stress formed microfractures are Main risk factor is duration of treatment
healed by
Bisphosphonate > 5 years
◦ callous formation followed by localized remodeling
Improvement in BMD starts to plateau at this stage
Bisphosphonates suppress bone turnover
Can occur with denosumab
◦ Rare without prior bisphosphonate exposure
Minimal or no trauma, fall from a standing height or less
Risk vs benefit
Prodromal symptoms
1 AFF for every 100 osteoporotic hip fractures prevented.
25% bilateral
Fracture line originates at the lateral cortex and is substantially transverse in its
orientation
◦ may become oblique as it progresses medially across the femur (medial spike)
 via NICE.co.uk

Receptor activator of nuclear kappa-B ligand =

RANk a member of the TNF superfamily
Denosumab (prolia)

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 Denosumab - rebound
Bisphosphonates have a prolonged residual effect
- half life in bone is years
- antiresorptive effect wears off very slowly

Denosumab
Highly potent antiresorptive that wears off rapidly when stopped
Bone turnover markedly increases
Rebound lasts 2 years
Loss of BMD gains
Risk of multiple vertebral fractures
◦ Higher with previous vertebral fractures
◦ Worse T scores
◦ Longer duration

Vertebral Fractures on stopping

Denosumab
Denosumab – duration of therapy N =797, 63.1% treated with bisphosphonates after denosumab

Freedom extension – safe for ten years

No drug holiday
We tend to use in patients with severe osteoporosis with a life
10% - vertebral fractures on stopping
expectancy <10 years
- i.e. continue denosumab for the rest of their life
Less appropriate to start denosumab for young patients
N=797

Burckhardt et al., 2021

 Effect of bisphosphonates on
stopping Denosumab Reducing rebound – transition to bisphosphonate
Oral or IV Bisphosphonate if stopping Denosumab?
Oral bisphosphonate Zoledronic acid
Ÿ Short duration (< 2 years) Ÿ Longer duration (>2 years)
Ÿ Lower risk of fracture Ÿ Higher risk of fracture
Ÿ No vertebral fractures Ÿ Hx of vertebral fractures
Ÿ T score > -2.5 Ÿ T score < -2-5
Ÿ No contraindications

Ÿ Check BTM at 3 months

Ÿ Further infusion of Zol at 6 months if BTM high, otherwise at 1 year

Burckhardt et al., 2021

Recombinant Parathyroid hormone

Stopping denosumab (Teriparatide = 1,34 PTH)
Before transitioning denosumab to zoledronic acid
Consider if denosumab should be continued
- Anabolic
if older patient – consider continuing DMAB for rest of life - Severe osteoporosis especially vertebral fractures
If still osteoporotic (t score <2.5, may be better to defer transition until improved) - Failure of other Rx – recurrent fractures/deteriorating BMD
Consider risk factors for vertebral fracture – steroids, previous vertebral fracture, severe - Well tolerated
osteoporosis - Powerful medication with significant improvement in BMD
- Daily s/c injection self administered
- Significant reduction in further vrt fractures
- Needs follow up antiresorptive
- Has not been shown to reduce risk of hip fracture
 Romosuzumab – Coming Romosuzumab
soon Indicated for osteoporosis treatment in postmenopausal women at high risk for fracture, defined as a
history of osteoporotic fracture or multiple risk factors for fracture; also indicated for patients in
Monoclonal ab against sclerostin whom other available osteoporosis therapy has failed or who are intolerant of other available
osteoporosis therapy
é bone formation; ê bone resorption

ARCH study (NEJM Sept 2017) 210 mg SC monthly x 12 months

- 12 mth romo vs Alendronate followed by alendronate for another 12 mth
- 48% lower risk new vrt frax Adequate calcium and vitamin D during treatment
- 27% lower risk of other clinical frax
- 19% lower risk of non clinical vrt frax

Thank you –
Questions?