1. Management of Vitamin D Deficiency and
Osteoporosis in Clinical Practice
M. Ali Karamat
MBBS MRCP MD FRCP
Consultant Physician and Honorary Senior Lecturer
2. Overview of calcium homeostasis
Ca2+
Ca2+ reabsorption
&
1,25DHD
PTH
bone resorption
Ca2+ availability
Ca2+ absorption
3. 1. National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013.
Available at: http://www.nos.org.uk/document.doc?id=1352
2. Adapted from Fraser WD and Milan AM. Calcified Tissue Intl 2013; 92(2): 118-127.
Vitamin D metabolism1,2
Metabolism of vitamin D
There are two basic types of vitamin D:
Ergosterol is the basic building block of
vitamin D
in plants.
2.17-dehydro-cholesterol is the basic
building block
of vitamin D in humans.
4. Renal and extrarenal 1,25(OH)2D3 production serves endocrine,
autocrine and paracrine functions
1. Adapted from Dusso AS et al. Am J Physiol Renal Physiol 2005; 298(1): F8-28.
Vitamin D is a multifunctional prohormone1
5. 1. National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013.
Available at: http://www.nos.org.uk/document.doc?id=1352
Manifestations and symptoms of vitamin D deficiency1
Manifestations
Deficiency Osteomalacia in
adults
Rickets in children
Insufficiency Secondary
hyperparathyroidism
Bone loss
Muscle weakness
Falls and fragility
fractures in older
people
Symptoms
Bone pain (ostealgia)
Joint pain (arthralgia)
Muscle pain (myalgia)
Muscle weakness
6. 1. Adapted from IOM (Institute of Medicine). Dietary reference intakes for calcium and vitamin D. Washington; DTNAP; 2011.
2. Adapted from Krall EA et al. N Engl J Med 1998; 321(26): 1777-83.
3. Adapted from Arabi A et al. Bone 2010; 47(2): 408-12.
Relationships between vitamin D and musculoskeletal
health……..
Calcium absorption, bone
mineral density (BMD) and
osteomalacia1
Parathyroid hormone (PTH)2,3
7. 1. Adapted. from Bischoff-Ferrari HA et al. NEJM 2012; 367(1): 40-49
2. Adapted from Wang L et al. Circ Cardiovasc Qual Outcomes 2012; 5: 819-29.
Relationships between vitamin D and…
Fractures1 Cardiovascular risk2
8. Persistently low Vitamin D status predisposes >75
year old women to fractures
Vitamin D Status (nmol/l) 10 year hip fracture incidence rates
%
Low <50 20.6
Intermediate 50-75 9.9
High >75 6.9
Swedish population based prospective study on BMD, falls, fractures
N = 987, final report available for 640 women (>75 years old)
Osteoporosis Int. 2014;25(Suppl 2). Abstract OC19
9. 1. Adapted from Hélard L et al. Dis Markers 2013; 35(5): 525-9.
Relationship between vitamin D and length of hospital stay
in the elderly1
• Vitamin D insufficiency
(≤50nmol/L) was associated
with a 3-day longer hospital
stay in elderly inpatients
(15.2±8.2 vs. 12.1±7.0 days,
p=0.017)
• 25OHD concentration
inversely correlated (r=-0.14,
p=0.028) and was inversely
associated with length of
stay (adjusted β=-0.07, 95% CI
-0.14 to -0.02, p=0.043)
10. 1. Hyppönen E and Power C. Am J Clin Nutr 2007; 85(3): 860-8.
2. Pearce SHS and Cheetham TD. BMJ 2010 Jan 11; 340: b5664. doi:10.1136/bmj.b5664.
During the winter months there is inadequate sunlight
in the UK to synthesise vitamin D1
Vitamin D insufficiency is common in the UK population2
Up to 50% of adult population in the UK will be
vitamin D insufficient in winter and spring, with
16% having severe deficiency2
There is a significant north-south gradient in the prevalence of vitamin D insufficiency/deficiency1
In summer and autumn, 28% of adult population
in Scotland will be vitamin D insufficient, with
8% having severe deficiency1
11. 1. National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013.
Available at: http://www.nos.org.uk/document.doc?id=1352
2. https://www.gov.uk/government/publications/vitamin-d-advice-on-supplements-for-at-risk-groups
3. http://www.nice.org.uk/nicemedia/live/13795/67630/67630.pdf
The Chief Medical Officers defined at risk groups of vitamin
D deficiency in clinical practice in February 20122
Adult at risk groups1,2,3
People over 65 years of age Thinning of the skin reduces the efficiency of vitamin D synthesis
People not exposed to a great deal of sunlight E.g. those who cover their skin for medical, social, cultural or religious reasons, who are
housebound or confined indoors for long periods
People with darker skin E.g. people of African, African-Caribbean or South Asian origin
Darker skin pigments interfere with UV light reaching the appropriate skin layer
Pregnant and breast feeding women, Especially teenagers and young women
12. Recommended thresholds for treatment
National Osteoporosis Society thresholds for treatment1
Serum 25OHD
<30nmol/L*
Deficiency Treatment recommended
Serum 25OHD
30–50nmol/L*
Insufficient in some
people
Treatment is advised in patients with the following:
• Symptoms suggestive of vitamin D deficiency
• Increased risk of developing vitamin D deficiency because
of reduced exposure to sunlight, religious/cultural dress
code, dark skin, etc.
• Fragility fracture, osteoporosis or high fracture risk
• Treatment with antiresorptive medication for bone disease
• Raised PTH
• Medication with antiepileptic drugs or oral glucocorticoids
• Conditions associated with malabsorption
Serum 25OHD
>50nmol/L
Sufficient for almost
the whole population
Provide reassurance and give advise on maintaining adequate
vitamin D levels through safe sunlight exposure and diet
1. National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013.
Available at: http://www.nos.org.uk/document.doc?id=1352
2. Turpeinen U et al. Clin Chem 2003; 49(9): 1521-24.
3. Janssen MJW et al. Clin Lab 2014; 60: Available at: http://www.clin-lab-publications.com/files/eaop/2014_01+02/130223-Janssen.pdf
4. Knudsen CS et al. Clin Chem Lab Med 2012; 50(11): 1965-8.
However, reliable routine serum 25OHD measurement tests may not be accurate below
30nmol/L. Evidence suggests tests have a limit of quantification ranging from 10–22.5nmol/L2-4
*Reference levels may differ in this range.
13. 1. EFSA Panel on Dietetic Products NaAN. Scientific opinion on the tolerable upper intake
level of vitamin D. EFSA Journal 2012; 10(7): 2813.
2. National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical
Clinical Guideline for Patient Management. April 2013. Available at: http://www.nos.org.uk/document.doc?id=1352
Recommended dosing strategy
National Osteoporosis Society dosing strategy2
Where rapid correction of vitamin D deficiency is required, the recommended
treatment regimen is based on fixed loading doses followed by regular
maintenance therapy:
• Loading regimen to provide a total of approx. 300 000 IU vitamin D, given
either as separate weekly or daily doses over 6 to 10 weeks
• Maintenance therapy comprising vitamin D in doses equivalent to 800–2000 IU
daily (occasionally up to 4000 IU daily), given either daily or intermittently at
higher doses
Where correction of vitamin D deficiency is less urgent maintenance therapy may
be started without the use of loading doses*
* European Food Safety Authority
*In primary care, where rapid correction may often not be required, maintenance therapy may be
started without the use of loading doses
EFSA advises an upper limit of 4000 IU/day is safe for adults
and children >11 years of age1
14. 1. Gallagher JC et al. Ann Intern Med 2012; 156: 425-37.
3200 IU/day is sufficient for restoring daily vitamin D
concentrations no need for 20KIU when rapid repletion is not
required
• Dose response to
vitamin D3 treatment
in healthy
postmenopausal
women was
curvilinear and
tended to plateau at
approx. 112 nmol/L in
patients receiving
more than 3200
IU/day1
15. CMOs’ letter February 2012*
- The following groups of people are at risk of vitamin D deficiency:
• All pregnant and breastfeeding women, especially teenagers
and young women.
Recommendations
All UK Health Departments recommend:
• All pregnant and breastfeeding women should take a daily supplement
containing 10μg of vitamin D, to ensure the mother’s requirements for vitamin
D are met and to build adequate foetal stores for early infancy.
*specific to pregnancy and lactation
Pregnancy & Lactation
16. Vitamin D: increasing supplement use among at-risk groups NICE public
health guidance 56
11 key recommendations
• Recommendation 1 Increase access to vitamin D supplements
• Recommendation 2 Clarify existing guidance
• Recommendation 3 Develop national activities to increase awareness about vitamin D
• Recommendation 4 Ensure a consistent multiagency approach
• Recommendation 5 Increase local availability of vitamin D supplements for at-risk groups
• Recommendation 6 Improve access to Healthy Start supplements
• Recommendation 7 Only test vitamin D status if someone has symptoms of deficiency or is at very
• high risk
• Recommendation 8 Ensure health professionals recommend vitamin D supplements
• Recommendation 9 Raise awareness among health, social care and other relevant practitioners of
• the importance of vitamin D
• Recommendation 10 Raise awareness of the importance of vitamin D supplements among the local
• population
• Recommendation 11 Monitor and evaluate the provision and uptake of vitamin D supplements
NICE November 2014
17. Vitamin D3 vs. calcium/vitamin D3 combination
– Not all patients need the added calcium the combination provides
– Guidelines state calcium/vitamin D3 should not be used as sources
of vitamin D, given the high doses of calcium required if treating
deficiency in combination1,2
Unlicensed
– The Advice from the Royal Pharmaceutical Society, the National
Pharmacy Association and the MHRA is that wherever possible, a
licensed medicine should be supplied against a prescription3
– Recent publications have shown unlicensed preparations can have
significant variances between actual content and label strength.
One analysis showed variances in label claim versus actual from 8+
2% to 210+ 29%4.
Treatment of choice in vitamin D deficiency1
1. National Osteoporosis Society Practical Guidelines. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. April 2013.
Available at: http://www.nos.org.uk/document.doc?id=1352
2. Data on file Internis Pharmaceuticals Ltd D2.
3. http://www.gmc-uk.org/guidance/ethical_guidance.asp. Accessed October 2014
4. http://www.ncbi.nlm.nih.gov/pubmed/23364495
.
*NOS – National Osteoporosis Society
18. • Variable content
– 14.3–171% of label content leading to poor control1
– 8–201% of label content2
– 3 cases of hypervitaminosis D, hypercalcaemia and renal insufficiency in patients
taking oral vitamin D supplement3
• Declared vitamin D3 content 600 IU per capsule vs. actual content approx. 880
times higher3
• No medical information or pharmacovigilance
• No yellow card adverse event reporting
• Unregulated excipients
• No TSE certification
Challenges with unlicensed unregulated supplements
1. Data on file. Internis Pharmaceuticals Ltd.
2. Garg S et al. J Nutr Health Aging 2013; 17(2): 158-61.
3. Benemel S et al. Brit J Clin Pharmacol 2013; 76(5): 825-6.
Evidence suggests vitamin D intoxication due to use of unlicensed supplements
is not rare.3 Vitamin D supplements do not undergo quality control and may be
dangerous to consumers’ health. Given preparations labeled ‘food’ are commonly
used without medical prescription, their contents should be strictly regulated3
*TSE – transmissible spongiform encephalopathy
19. • Vitamin D is well known and has been widely used in clinical practice
for many years1
1. Data on file. Internis Pharmaceuticals Ltd.
2. IOM (Institute of Medicine). Dietary reference intakes for calcium and vitamin D. Washington; DTNAP; 2011.
3. Adapted from Vieth R. Ann Epidemiol 2009; 19(7): 441-5.
4. EFSA Panel on Dietetic Products NaAN. Scientific opinion on the tolerable upper intake level of vitamin D. EFSA Journal 2012; 10(7): 2813.
Safety of vitamin D treatment in the licensed form
• Toxicity is most likely to occur in
chronic overdosage where
hypercalcaemia could result2
– Doses above 10,000 IU/day are
associated with toxicity2
– Doses ≥50,000 IU/day for several
weeks or months are frequently
associated with toxicity, including
documented hypercalcaemia2
20. 2.129. Incidences of High to Toxic 25-Hydroxy Vitamin D Levels
amongst Users of a Direct-to-the-Public Blood Spot Vitamin D Testing
Service Direct to Public Blood Spot Testing Service DBS
Shea & Berg
• 69 users (1.5%) had 25OHD >220 nmol/l
• Only 2 under medical supervision
• 6 patients had 25OHD >500 nmol/l and were taking 11,000-100k IU/day
• Yet, 55% of users with 25OHD >220 nmol/l were taking 10KIU/day or less
Conclusion: Highlights the fact that it is vital that public awareness is
increased on the risks of self-administration and over-treatment.
Asks: How many people are over supplementing unknowingly as
they have not had their levels checked?
Queen Mary University
23-25th April 2014
21. Vitamin D2
• Vitamin D2 as a lower tissue bioavailability especially after intermittent bolus
dosing1
• Vitamin D3 is the NOS recommended treatment of choice1
Metabolised Vitamin D treatment such as Alfacalcidol, one alpha and
Calcitriol
• Restricted for use only in renal impairment2
• Additional twice weekly serum calcium levels monitoring required
• Variable cost depending on dose response, other costs are calcium testing and
HCP time as weekly testing is required
Vitamin D2 & metabolised vitamin D treatments
1.http://www.nos.org.uk/page.aspx?pid=183&srcid=325- accessed Oct 2013
2. https://www.medicines.org.uk/emc/medicine/2449
23. Causes of hypercalcaemia
Common
• Malignancy (metastatic via cytokines & humoral via PTH-rp)
• Primary and secondary hyperparathyroidism
Rare
• Hyperthyroidism
• Thiazide diuretics
24. Treatment of severe symptomatic hypercalcaemia
Almost inevitably occurs in malignancy
• Volume expansion
– Saline (care with CCF/RF)
– Furosemide
• Administer iv bisphosphonate (pamidronate)
• In very rare and severe cases of hypercalcaemia
(Ca2+ 4.5 – 5 mmol/L), haemodialysis may be used
25. Overview of approved osteoporosis treatments in the UK1-3
Class Molecule Brands Dose and method of administration
Bisphosphonate
Alendronate
Binosto Weekly 70 mg effervescent tablet for oral solution
Fosamax Daily 10 mg tablet
Fosamax Once Weekly Weekly 70 mg tablet
Fosavance
Weekly tablet containing 70 mg alendronate
and 2800 IU vitamin D3
Alendronic Acid Oral Solution Weekly oral solution (drink) containing 70 mg alendronate
Alendronic acid (generic) Weekly 70 mg tablet
Etidronate Didronel PMO
Daily 400 mg etidronate tablet for 14 days followed by daily
1.25 g calcium carbonate tablet for 76 days (90-day cycle)
Risedronate
Actonel Daily 5 mg tablet
Actonel Once a Week Weekly 35 mg tablet
Actonel Combi
Weekly 35 mg risedronate tablet and daily sachet providing
1000 mg calcium and 800 IU vitamin D3
Risedronate sodium (generic) Weekly 35 mg tablet
Ibandronate
Bonviva Monthly 150 mg tablet
Bonviva Injection 3-monthly 3 mg IV injection
Ibandronic acid (generic) Monthly 150 mg tablet or 3-monthly 3 mg IV injection
Zolendronate
Aclasta Annual 5 mg IV infusion
Zoledronic acid (generic) Annual 5 mg IV infusion
IV, intravenous.
All product SmPCs can be found at https://www.google.co.uk/?gfe_rd=cr&ei=jPzGVqnHEuPW8geKvq-IAg&gws_rd=ssl#q=emc
Trademarks registered to companies as stated on trademark registry
26. Overview of approved osteoporosis treatments in the UK1-3
1.National Osteoporosis Society website. Drug treatments for
osteoporosis. Available at: https://www.nos.org.uk/
scans-tests-drugs/drug-treatments.
mAb, monoclonal antibody; PTH, parathyroid hormone; rh, recombinant human; SERM, selective estrogen receptor modulator.
Class Molecule Brands Dose and method of administration
– Strontium ranelate Protelos Daily 2 g sachet of granules, mixed with water
SERM
Raloxifene
Evista Daily 60 mg tablet
Raloxifene hydrochloride
(generic)
Daily 60 mg tablet
Bazedoxifine acetate Conbriza Daily 20 mg tablet
rhPTH Teriparatide Forsteo Daily 20 mcg self-administered injection
Anti-PTH Calcitonin Miacalcic
Daily 100 IU or twice daily 50 IU SC or IM injection
(maximum treatment duration 4 weeks)
Human mAb Denosumab Prolia Twice-yearly 60 mg injection given under the skin
All product SmPCs can be found at
https://www.google.co.uk/?gfe_rd=cr&ei=jPzGVqnHEuPW8geKvq-IAg&gws_rd=ssl#q=emc
Trademarks registered to companies as stated on trademark registry
27. Anti-fracture efficacy of approved treatments for
postmenopausal women with osteoporosis*1
Vertebral fracture Non-vertebral fracture Hip fracture
Alendronate A A A
Etidronate A B nae
Ibandronate A A# nae
Risedronate A A A
Zolendronic acid A A A
Denosumab A A A
Calcitriol A B nae
Raloxifene A nae nae
Strontium ranelate A A A#
Teriparatide A A nae
rhPTH (1-84) A nae nae
1.National Osteoporosis Guideline Group. Osteoporosis: Clinical
Guideline for Prevention and Treatment. July 2010. Available at:
https://www.shef.ac.uk/NOGG/NOGG_Executive_Summary.pdf.
*When given with calcium and vitamin D. A=Recommendation based on meta-analysis of randomised controlled trials (RCT) or
at least one RCT, nae, not adequately evaluated; rhPTH, recombinant human parathyroid hormone;
# in subsets of patients only (post-hoc analysis).
28. Bisphosphonates have been shown to prevent both
vertebral and non-vertebral fractures1
• Meta-analysis for alendronate relative to placebo resulted in a:
– RR of vertebral fracture of 0.56 (95% CI 0.46–0.68, 4 RCTs, n=7,039)
– RR of hip fracture of 0.62 (95% CI 0.40–0.98, 3 RCTs, n=7,455)
– RR of wrist fracture of 0.67 (95% CI 0.34–1.31, 4 RCTs, n=7,931)
– RR for other non-vertebral fractures of 0.81 (95% CI 0.68–0.97, 6 RCTs, n=9,973)
• Meta-analysis for etidronate relative to placebo resulted in a:
– RR of vertebral fracture of 0.40 (95% CI 0.20–0.83, 3 RCTs, n=341)
– RR of hip fracture of 0.50 (95% CI 0.05–5.34, 2 RCTs, n=180)
– RR for other non-vertebral fractures of 1.04 (95% CI 0.64–1.69; 4 RCTs, n=410)
– There were no data for wrist fracture
• Meta-analysis for risedronate relative to placebo resulted in a:
– RR of vertebral fracture of 0.61 (95% CI 0.50–0.75, 3 RCTs, n=2301)
– RR of hip fracture of 0.74 (95% CI 0.59–0.93, 3 RCTs, n=11,770)
– RR of wrist fracture of 0.68 (95% CI 0.43–1.08, 2 RCTs, n=2439)
– RR for other non-vertebral fractures of 0.76 (95% CI 0.64–0.91, 5 RCTs, n=12,399)
1.NICE technology appraisal guidance TA160. October 2008.
Available at: https://www.nice.org.uk/guidance/ta160.
29. Bisphosphonates are considered first line treatment for the
primary prevention of osteoporotic fragility fractures1
1.NICE technology appraisal guidance TA160. October 2008.
Available at: https://www.nice.org.uk/guidance/ta160.
Initial treatment offered is alendronate
Alternative treatment option 1 –
risedronate or etidronate when women:
• are unable to comply with administration
of, or have a contraindication to or are
intolerant of alendronate and
• have a combination of T-score, age
and number of clinical risk factors.
Alternative treatment option 2 –
strontium ranelate when women:
• are unable to comply with administration
of, or have a contraindication to or are
intolerant of alendronate and either
risedronate or etidronate and
• have a combination of T-score,
age and number of clinical risk factors.
Postmenopausal women
30. Bisphosphonates are considered first line treatment for
secondary prevention of osteoporotic fragility fractures1
1.NICE technology appraisal guidance TA161. October 2008.
Available at: https://www.nice.org.uk/guidance/ta161.
Alternative treatment option 1
– risedronate or etidronate
when women:
are unable to comply with
administration of, or have a
contraindication to or are intolerant
of alendronate and
have a combination of
T-score, age and number of
clinical risk factors.
Alternative treatment option 2
– strontium ranelate
when women:
are unable to comply with
administration of, or have a
contraindication to or are intolerant
of alendronate and either risedronate
or etidronate and
have a combination of T-score, age
and number of clinical risk factors.
Alternative treatment option 3
– teriparatide
when women:
are unable to take, have a
contraindication to or are intolerant
of alendronate and either risedronate
or etidronate, or
have a contraindication to, or are
intolerant of strontium ranelate or
have had an unsatisfactory response
to treatment with alendronate,
risedronate or etidronate and
have a combination of T-score,
age and number of fractures.
Initial treatment offered is alendronate
Postmenopausal women
31. Bisphosphonate therapy is associated with poor adherence
in the treatment of osteoporosis1
• Both compliance and persistence are suboptimal for postmenopausal
women undergoing bisphosphonate therapy for the treatment of
osteoporosis
• 80% of patients are non-compliant within one year of bisphosphonate
treatment initiation2
1.Imaz I et al. Osteoporosis Int 2010; 21: 1943–1951.
2.Data on File. Internis Pharmaceuticals Ltd. D1
+
The consistency and
accuracy with which a
prescribed regimen is
followed
The length of time from
beginning to completion
or discontinuation
of therapy
Adherence
Compliance Persistence
Few strategies attempting to improve adherence have demonstrated
clinical outcomes – the design and development of new programmes
or treatments to improve adherence to these drugs is needed
32. At least one third of new bisphosphonate patients treated
with tablets will not receive a further prescription1
1.Data on file. Internis Pharmaceuticals. 2015.
40%
60%
% of patients initiated with
risedronate sodium (n=4,952)
Receive no further prescription
Receive a subsequent prescription
35%
65%
% of patients initiated with
alendronate sodium (n=54,916)
Receive no further prescription
Receive a subsequent prescription
33. GI side effects are the main reason for stopping oral
bisphosphonate therapy1
• Difficulty or discomfort in swallowing (dysphagia) is common, especially
among elderly people, and the perceived potential for upper GI problems
is a barrier to good long-term adherence
• In a normal clinical setting, GI adverse events are among the most
common reasons for giving up oral bisphosphonate therapy
• Generic bisphosphonate formulations have been shown to be associated
with an increase in upper GI adverse events, leading to therapy
discontinuation
1. Brandi M and Black D. Clin Cases Miner Bone Metab 2013; 120(3): 187–190.
Length of
contact of the
tablet
Reflux
Gastric acid
conditions
Multiple factors contribute to the development
of clinical GI effects and should be considered:
The chemical
formula of the
molecule
Lack of
education on
expected side
effects
34. Managing GI tolerability could be the key for your patients
who discontinue alendronate therapy1,2
• GI side effects are the most common reason for alendronate discontinuation2
• Alendronate tablets can contribute to gastric irritability in a number of ways2,3
1. Brandi M and Black D. Clin Cases Miner Bone Metab 2013; 120(3): 187–190.
2. Invernizzi M et al. Aging Clin Exp Res 2015; 27: 107–113.
3. Accoto CG et al. Calcif Tissue Int 2012; 91: 325–334.
Dyspepsia Dysphagia Oesophagitis Oesophageal ulcers
Early tablet dissolution
Slow transit time
Acid reflux
Hazardous reflux Less acidic
More acidic
