(I start with Lecture 3 — the one I like most, followed by 4,1 and 2 ;))

Lecture 3: Diagnosis & Intervention Thresholds of Osteoporosis (Eugene McCloskey)

**Eugene McCloskey is THE person behind the FRAX tool

He started off the lecture by discussing the difference between diagnosis and definition of osteoporosis.

Definition is but an epidemiological tool. (WHO BMD tool to classify osteoporosis & osteopenia) —> identify osteopenic women who will then become osteoporotic without treatment.

What’s most important though, is, identifying patients at risk, not worrying about diagnosis.

The aims in managing osteoporosis

1. To make the diagnosis of osteoporosis?

2. TO REDUCE INCIDENCE OF FRACTURES

3. To identify patients at increased risk of fractures

4. To be able to assess that risk accurately

5. To give advice to aid understanding of the disease, the aims of therapy and the choice of therapy

6. Treatment: lifestyle advice & therapeutic agents

BMD T-score threshold doesn’t capture all elements of fracture risk

Same T-score but older, means higher fracture risk (Kanis et al. (2001)

Treatment advice in clinical guidelines

Should I treat or not? What should I treat with?

Approaches to intervention thresholds:

• T-score

• Prior fracture

• Absolute fracture risk (age independent - fixed threshold, or age dependent)

(!) Not just to treat, but to tailor the treatment to what is best

BMD - Treatment threshold or Risk factor?

In some guidelines — BMD is the gatekeeper for treatment (and hence, reimbursement for insurance)

FRAX tool — uses BMD as a risk factor

BMD T-score and prior fracture are age-dependent risk thresholds

Differs between guidelines — require/don’t require BMD and differs according to # site. Hence affects drug equity.

Considering therapeutic options in postmenopausal women across the spectrum of fracture risk

• Low risk —> Hormone therapy, SERMs

• High risk—> Oral/IV bisphosphonates, denosumab, strontium ranelate

• Very high risk —> anabolic followed by antiresorptives

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Lecture 4: Long-term Strategies for Osteoporosis (Eugene McCloskey)

Advice & Education

1. Diet: increase Ca and Vit D intake

2. Exercise:

   1. Leading a more sedentary lifestyle leads to further loss of bone density and muscle

   2. Weight bearing and resistance exercises can build and maintain BMD

   3. Improving balance, flexibility and strength reduces risk of falls

3. Healthy BMI: low BMI is a risk factor for future fracture

4. Moderate alcohol intake & cease smoking: excess of both lead to low BMD

Treatment choice: why not just start with the most effective treatment?

1. Physician considerations:

• fracture risk/probability

• prescribing restrictions/contraindications

• reimbursement (e.g NICE in UK)

• past experience (‘habit’)

• until recently — lack of direct head-to-head studies to prove superiority

• many ‘more potent’ treatments have potentially limited exposure times

2. Patient considerations:

• preference/choice

• problems with adherence

All osteoporosis drugs are not made equal

Majority of osteoporosis drugs work only as long as treatment continues to be administered.

Bisphosphonates — keep on working after it’s stopped. Intermittent treatment complements their mechanism of action. Even zolendronate every 18 months prevents fractures in women with osteopenia (Reid et al., NEJM 2016)

Summary

1. Bisphosphonate-free strategies for long-term care of osteoporosis require continuity of exposure to treatment for many years

2. Discontinuation of and/or transitioning from denosumab requires early antiresorptive therapy to minimize bone loss

3. Best to avoid transitioning to teriparatide (and most likely abaloparatide)

4. Following bone-forming agents with an antiresorptive is required to maintain BMD gains and fracture reductions

5. In patients at very high risk of fracture, the greatest gain in bone mass are achieved with first line bone-forming agents followed by an antiresorptive

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Lecture 1: Pharmacological Treatment for Fracture Prevention: What is the role of MHT? (Bronwyn Stuckey)

“Bone Drugs” (antiresorptive & osteo-anabolic drugs for osteoporosis) target elements of bone turnover.

Antiresorptives:

1. Bisphosphonates

   1. bind to bone matrix

   2. osteoclast apoptosis

2. Denosumab

   1. RANKL inhibition

3. Romosozumab

   1. sclerostin inhibition

   2. inhibits the inhibitor

The ‘weapons-grade’ bone drugs are a result of innovative pharmacological development.

Their target and mechanism of action are therefore known.

Their long-term side effects are not always evident at first.

Estrogen is a gift of nature.

1. the effect of its withdrawal is known

2. the long-term side effects of its use in menopause have been documented ad nauseum

Efficacy of MHT for vertebral # prevention is similar to anti-resorptives.

(Eastell R, JCEM 2019)

Also worth noting that: Calcium + Vit D, or Vit D alone, or Ca alone… are useless when it comes to vertebral # prevention.

Other references: Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis

Bisphosphonates, denosumab and estrogen all have efficacy in prevention of fracture. Why is estrogen not first line?

? concern about breast cancer incidence with MHT

? waiting until fracture risk is high before Rx

? perception that the bone specific medication is better

? ease of administration of bone specific medication

? marketing

? patient preference

? uncertainty about its mechanism of action

Conveying risk of MHT

Using data from WHI:

Increased risk estimated <0.1% per annum or incidence of <1.0 per 1000 women per year of use

Similar or lower than the risk associated with:

• reduced physical activity

• obesity

• alcohol consumption

How does MHT work?

MHT has pleiotrophic effects on bone turnover pathways.

• reduce RANKL production

• increase osteoprotegenin production to reduce RANKL signal

• (+) osteoclast apoptosis

• reduce cytokines involved in clast recruitment

• action on bone formation

Risks of continuing ‘bone drugs’

Bisphosphonates: atypical femoral #, osteonecrosis of the jaw (dentist may ask the patient to stop)

The speaker shared an anecdote of a patient who is high-risk of fracture and on bisphosphonate, who was asked to go on a ‘drug holiday’ of 6 months by her dentist prior to a dental procedure… and as a result, sustained multiple vertebral fractures.

Drug Holidays

Drug holidays only apply to bisphosphonates to avoid excessive suppression of bone turnover and risks of AFF and ONJ.

Drug holidays DO NOT apply to denosumab even when requested by the dentist.

Can you have an estrogen drug holiday? (You don’t need one)

References:

• Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo-Controlled FREEDOM Trial and Its Extension

• No Increase in Fractures After Stopping Hormone Therapy: Results From the Women’s Health Initiative

Prevention & management of osteoporosis is a continuum starting in childhood

• Childhood & adolescence: nutrition, exercise, adequate vitamin D

• Premenopause: nutrition, exercise, adequate vitamin D, avoid hypoestrogenism

• Early postmenopause: MHT + exercise + nutrition, check BMD*, assess for secondary causes of osteoporosis

• Later menopause: MHT + Vitamin D

• When MHT contraindicated: BPs, denosumab

• Fracture while on Rx, T-score < -3.0: romosozumab, teriparatide

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Lecture 2: Anabolic Treatment Fracture Prevention: New perspectives (Santiago Palacios)

**disclaimer: this lecture felt way out of my league simply because I am not at all familiar with anabolics.

His lecture discussed comparisons between Triparetide, Abaloparetide & Romosozumab.

Osteoanabolic Drugs

Also known as bone forming agents, are group of drugs that share in common the following actions on bones:

• new bone formation stimulation, large BMD increases, and both trabecular and cortical microarchitecture improvement

• compared to antiresorptive agents, osteoanabolic drugs have demonstrated to be superior in fracture risk reduction, especially regarding vertebral fracture risk.

• most current guidelines for postmenopausal osteoporosis management recommend the use of osteoanabolic drugs as first line pharmacologic treatment options in patients at very high risk of fracture.

1. Teriparatide: first stimulates bone formation followed by a later increase in bone resorption

2. Abaloparatide: compared with teriparatide, shows a lower rate of bone formation and bone resorption, but a higher net anabolic effect

3. Romosozumab: fast increase in bone formation and antiresorption, followed by a fast decrease in both actions

Patients considered at high risk of osteoporotic fracture who may be candidates for osteoanabolic treatment (typically include):

• Patients with multiple fragility fractures

• Patients with very low BMD: specifically those with a T-score of -3.0 or lower

• Patients who have failed or not responded adequately to previous antiresorptive therapy

• Patients with extremely high fracture risk: based on fracture risk assessment tools like FRAX, especially when the 10-year probability of hip fracture exceeds 3% or major osteoporotic fracture exceeds 20%

• Patients with rapid bone loss

• Patients with severe vertebral fractures

• Postmenopausal women or men with 2’ causes of osteoporosis

• Patients with conditions severely affecting bone metabolism

A question was asked by audience: How about patients who have osteopenia/low T-score but high CV risk? (anabolic drugs —> CV risk)

The answer was to individualize. Perhaps for this patient, it is wise to start with antiresorptive first.

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