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Intercontinental Bone Health Expert Forum - Dubai, UAE, 16-17 October 2015

Local Perspectives on Bone Health
Hassan Jaafar

1/3 women and 1/50 males develop osteoporotic fractures.
Many risk factors. Most important: Age (90% of hip fractures occur in people agede 50 and older).
Some information on osteoporosis in the Middle East.
Epidemic of Vitamin D deficiency in the Middle East, high expected osteoporosis as the population ages.
Some data on bone health in cancer
ADT causes 4.6%/year bone-loss (compared to 0.5%/year in Male).
The risk of SRE in Breast, CRPC and NSCLC is 66%, 50%, 50%, respectively (Coleman RE, Oncologist, 2004).

Living Bone
Ego Seeman

Starts by doubting the link of Vitamin D deficiency and Bone-Health abnormalities.

Heterogeneity of the skeleton is established during growth and develpment. Only around mid-life bone remodeling becomes predominant (associated with bone decay).
Bone is type-I collagen. Hidroxiapathite increases the stiffness but decreases toughness. Too much mineral increases britleness.
The extent of type-I collagen mineralization (antler vs ear ossicles).
The crystals of mineral are important in bone health but are also instrumental in its undoing.
A very detailed explanation of bone physiology that eluded me.
Brain densitometry kills brain cells
After 50, bone formation decreases and a greater decrease in bone remodeling.
Osteoporotic fractures are mostly cortical, and non-vertebral.
70% of fractures occur in non-osteoporotic patients.
The Big 3 causes of bone loss.

Some pictures

Better measure bone-remodeling markers instead of bone-densitometry.
Use CTX (C-telopeptide .cross-linked).

Skeletal Metastasis
LC Hofbauer

Breast and Prostate cancer are very frequent and have propensity for metastatic disease in the bone.
The skeletol provides a suitable microenvironmet for tmor cell survival and expansion.
Paget: Tumors provide the seed and bone the Soil (Greg Mundy).

Tumor cells activate osteoclasts. Bone resorption release tumor growth factors (Roodman, NEJM, 2004).
Anti-osteoclasts: Bisphosphonates.
Anti RANK: Denosumab

Anti-resorptive agent Denosumab is superior to (also anti-resorptive) bisphosphonates in SRE (Stopeck, JCO, 2010)

Osteolyuc; RANKL - Osteoclast - PTHrP/IL-6/TGF Beta.
Inhibition of Osteoblast (DKK1, WNT, Beta Catenin).

Osteoblastic: Increase in WNT (increase in osteoblast) and WIF / sFRP1 (increase in osteoclast) (Hofbauer, Lancet Diabetes Endocrinol, 2015).

Importance of RANKL:
If you block RANKL bone-metastasis is prevented (in preclinical models).
In humans: RANK expression is an adverse prognostic factor (Santini PlosOne, 2011).
Osteoclast differentiation factor RANK in the progesterone related breast cancer in preclinical models (Schramek D, Nature, 2010).

Targeting Wnt inhibiotors: Wnt activates osteoblasts (through B-catenin). There are 2 brakes: Dkk1 and Sclerostin.
Anti-Sclerostin antibodies improves bone mass (Hamann, J Bone Miner Res, 2013).
Anti-Dkk-1 antibodies reduce osteolytic lesions in multiple myeloma (Heath, J Bone Minr Res, 2009).
Anti-Dkk-1 may also be effective in breast-cancer metastasis.

Bone turnover markers are 3-10 times higher in metastasis compared to osteoporosis.

Assessment of bone health
Fred Saad

Prostate cancer death rate is higher in the middle-east than in north america.
At least 30% of men with prostate cancer will receive ADTs.
Prostate cancer mortality is higher with long life-expectancy and black race.
More than 90% of patients dying of prostate cancer have bone metastasis.

Risk factors for bone loss in men (the usual suspects).
ADT increases fracture rates. 4-year fractures is 19% and 9% with or without ADT in prostate cancer. After 10 years on ADT the risk of fracture is 50%.
For each bone fracture there is a decrease in life-expectancy.
Non-metastatic prostate cancer on ADT without osteoporosis and vertebral fractures doubled 3-yr mortality compared to those without vertebral fractures.

Assessment FRAX calculation tools (FRAX Calculation tool).

Who should be treated?

Denosumab (Smith MR, NEJM, 2009): 65% reduction in the risk of new fractures.

M0 metastasis
PSA doubling times less than 10 months are correlated with  clinically significant bone metastasis formation (Smith MR, JCO, 2005).
Patients at high risk should be studied with MRI because bone-scans are unreliable.
MRI is cost-effective compared to bone scans / CT scans (Lecouvet FE, Eur Urol, 2012).

Bone metastasis increase health resource utilization (Hoefeler H).

Predicting OS in CRPC (Halabi S, JCO, 2014)
Alkaline phosphatase (NTX) exhibits better correlation to OS compared to PSA in CRPC

Denosumab: Targeting RANKL in Cancer Patients
Hamdy Azim

The most peculiar feature of bone physiology is bone remodeling: interplay of osteoblasts and osteoclasts.

Osteoclasts uses MMP, H+, proteolytic enzimes (MMP, cathepsins): Bone resorption products: Ca, cytokines (TGFB, IFG), degradation of type I collagen. The cytokines are major players in bone metastasis. Osteoclast activity is the result of interplay of RANK (in onsteoclast), RANKL, and osteoprotegerin (blocks RANKL). The RANK system is the common pathway. The balance between RANKL and Osteoprotegerin establishes whether there is net bone loss. Estrogen loss during menopause boosts RANKL+ T-cells in the bone. Sex hormone deprivation casuses significant bone loss through RANKL over-expression. (Kanis JA, JCO, 2011).
Adjuvant bisphosphonates increase BMD, but there is no evidence of decreased fractured risk. Adjuvant Denosumab does dcrease risk of fractures (Gnant M, Lancet, 2015).

Vicious cycle: Cancer cells increase osteolytic factors PTHrP, RANKL, IL-11:: induces RANKL in osteoblasts:: activates Osteoclasts::Cytokines that cause tumor cell growth (vicious cycle) (Roodman GD, NEJM, 2004). Denosumab interferes with RANKL. Bisphosphonates cause apoptosis of osteoclastic cells.

Some tumor cells can hide in the bone during anti-cancer systemic therapy.

Adjuvant bisphosphonate is only helpful in postmenopausal patients, with 2.3% increase in OS
(Coleman, SABCS, 2013).

About 30% of breast cancer cells express RANK.
RANK+ BC cells decrease OS (Santini D,  PloS One, 2011)
Denosumab may be of use BEYOND bone metastasis in these cancer patients (ie, Giant Cell Tumor of the Bone).

Clinical features of metastatic bone disease
A. Brufsky

Metastatic bone disease is prevalent in patients with long survival (BC, prostate ca). It causes high tumor burden. Differences between the frequency of SRE and tumor type (more SRE in BC vs prostate patients). Pathologic fractures lead to decreased survival.
Single-dose RT is as effective a short-course RT for pain control.

NTX levels correlate with SRE and OS (Coleman RE, JCO, 2005).

All you need to know on bisphosphonates
A. Brufsky

Bisphosphonates were developed as pipe-cleaner and dishwasher detergents.
Different generations and relative potency.
Nitrogenous-containing bisphophonates inhibit FPP synthase (Geranyl PP + IPP :: Farnesyl diphosphate). Cause apoptosis on osteoclast.

Pamidronate dicreased SRE in BC. Zol vs Pamidronate: modest, but significant, superiority of Zol. Zol / Pam and Iba decrease SRE in BC. Zol also works in BC, Prostate, Solid Tumors, NSCLC.

Why we use Zol every 3-4 week (based in a trial of 12 patients). Indirect evidence appears to support the every 3-4 weeks/dose. But there is a RCT that show that Zol q12w are as effective a qMo.

How do we know is working;
NTX greater than 100: Doubles SRE and multiplies by 5 the mortality.
If you achieve NTX less than 100 you increase OS in Zol trials.
Normalization of NTX with Zol occurs in close to 80% (at 3 mo) (Lipton A, ESMO, 2006)
Persistentlty elevated NTX was associated with worse OS.
Basis of the BISMARK trial (closed due to low accrual). Other studies have shown that q3m Zol is equally effective to qMo in BC.
Toxicity: the usual (fever, myalgias, transient renal dysfunctio, and ONJ).
Perform dental procedures BEFORE initiating bone-modifying agents.
Prevention of ONJ has been very effective in decreasing its incidence.
Dr. Brufsky uses Zol for more than 2-years, ONJ in 4% (Brufsky A, Breast J, 2013)

Hypocalcemia with bone-targeted therapies
D. Santini

"Normal" serum calcium varies with age (decreases).
Always assess Calcium with Albumin.
The topic is hypocalcemia-induced drugs (bisphosphonates, denosumab, cisplatin).
Symptoms: neuromuscular excitability, arrhythmias, ectopic calcifications of basal ganglia.
Why there is higher risk of hypocalcemia with Denosumab compared to Zol? Denosumab is mor potent than Zol, causing a "hungry-bone" syndrome.
Why Vitamin-D supplementation is important in Bone-targeted therapy: Vitamin D suppresses PTH and bone-related events...

Denosumab casuses significant hypocalcemia in Prostate Cancer and NSCLC (about 20%).
Vitamin D supplementation decreases the incidence of hypocalcemia.

How to prevent hypocalcemia?
The European Clinical Guidelines: Ca 1000 mg / Vitamin D 1000-2000 U/d.

How to treat hypocalcemia?
See image.
Also correct magnesium (if applicable).
Increase Calcium and Vitamin D dose.

In very high tumor burden prostate cancer patients Denosumab should be given 1 week post initiation of systemic therapy, to decrease the risk of  "hungry-bone" syndrome.

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