See also: VitaminD |

Guidelines

Osteoporosis

• NOGG guidelines: http://www.ncbi.nlm.nih.gov/pubmed/19135323
• NOGG Executive summary: http://www.shef.ac.uk/NOGG/NOGG_Executive_Summary.pdf
• NOGG Pocket Guide: http://www.shef.ac.uk/NOGG/NOGG_Pocket_Guide_for_Healthcare_Professionals.pdf
• Diagnosis:
• Osteoporosis = BMD via DXA at femoral neck >=2.5 SD below young adult female (T<=-2.5)
• Investigations: Hx, Exam, Ix to
• Aim
• exclude mimics: osteomalacia, myeloma
• identify cause and contributory factors
• assess risk of subsequent fractures
• select most appropriate form of Tx
• Routine
• Hx & Exam
• FBC, ESR/CRP, Ca, Alb, Crea, PO4, AP, ALT/AST
• TFT
• Bone densitometry (DXA)
• Other procedures, if indicated
• Lateral radiographs of LS/TS or DXA-based vertebral imaging
• Protein immunoelectrophoresis and urinary BJP
• Testo, FSH, LH (in men)
• Prolactin
• 24h-urinary cortisol/DST
• Endomyseal/Tissue transglutaminase antibodies
• Isotope bone scan
• Markers of bone turnover, when available
• Urinary calcium excretion
• Clinical RF used for the assessment of fracture probability
• Age
• Sex
• BMI<=19kg/m2
• Previous fragility fracture, particularly of the hip, wrist and spine incl morphometric vertebral fracture
• Parental Hx of hip fracture
• Current glucocorticoid treatment (any dose, by mouth for three months or more)
• Current smoking
• Alcohol intake of >=3units/day
• Secondary causes of osteoporosis, including
• RA
• Untreated hypogonadism
• Prolonged immobility
• Organ transplantation
• T1DM
• Hyperthyroidism
• GI disease
• CLD
• COPD
• Falls [not currently in FRAX]
• Case finding
• Women with prior fragility fracture: consider treatment (w/o further risk assessment, except younger)
• In presence of other clin RFs: determine 10y probability of major osteoporotic fracture (FRAX)
• In patients requiring BMD measurement, fracture probability should be recalculated
• Intervention thresholds [aj] 10% major osteoporotic fracture risk vs age
• 40y>5%; 50y>7%, 60y>12%, 70y>80%, 80y>28%
• Treatment
• General management
• assessment of risk of falls and prevention
• maintenance of mobility
• correction of nutritional deficiencies, esp Ca>1000mg/d, VitD>=800 IU/d, Protein>1g/kg body weight/d
• Pharmacological interventions (effective for V=vertebral / H=hip fractures, also licensed for M=Men, G=Glucocorticoid-induced osteoporosis)
• Bisphosphonates
• esp generic Alendronate (VHMG)
• Ibandronate (V)
• Risedronate (VH)
• Zoledronate (VH)
• Raloxifene (V,H)
• Strontium ranelate (VH)
• Teriparatide (VM)
• PTH (1-84) (V)
• Other approved interventions: Calcitonin, Calcitriol, Etidronate, HRT

Teaching Diab/Endo 22-Oct-2009

Osteoporosis Guidelines

Caroline Jagger, Osteoporosis Specialist Nurse, MRI

• severe osteoporosis = T<-2.5 & associated fractures
• primary osteoporosis = senile = postmenopausal
• NICE guidelines: only postmenopausal women
• 1st choice: Alendronate weekly (cheap, but GI SE - check after 4 weeks)
• NOGG (National Osteoporosis Guideline Group): guidance for men & women, use of FRAX tool (predicts 10y fracture risk)
• eg: 75y women with fracture: may treat without DEXA
• DEXA T=-2.5 may equate T=-3.5 on qCT
• Strontium: ?; a/w DVT, DRESS
• Zolendronic acid: 5mg annual infusion as iv alternative (SE: flu-like sy for 3d, occas. bone pain for 6wks, rarely AF, very rarely osteonecrosis of jaw [1:100k at standard doses, 1:1k in oncology eg 4mg q1mth]
• BMD: 80% genetic + 20% environmental
• NB: lumbar BMD may icr with age due to degenerative disease
  

Vitamin D and metabolic bone disease

Dr Michael Davis, MRI

• colecalciferol=VitD3=sunshine; synthesis affected by
• sunlight angle: shadow should be less than height (in temperate climates: only sufficient during May-Sept)
  
• skin phototype (see Fitzpatrick'75): minimal erythemal dose: x2 causes sunburn, x0.5 enough for VitD synthesis
• icrd age: dcrd skin thickness: dcrd VitD synthesis
• UVB 290-320: responsible for VitD synthesis in skin
• almost all diets are insufficient in VitD to comply with current recommendations of optimal VitD levels: therefore either supplementation or sunshine
• D2=Ergocalciferol: food/supplements, D3=Colecalciferol: additives/sunshine?#, 1,25OHD=Calcitriol
• 25OHD=storage form of VitD=measured in assays
• hypercalcaemia: dcrs 1-hydroxylation
• 1,25OHD: icrs intestinal Ca absorption
• PTH: on bone; on kidneys: icrs 1-hydroxylation: icrs gut Ca absorption
• Metabolic bone disease
• Osteomalacia/Rickets: soft bendy bones, painful, proximal muscle weakness if due to dcrd VitD
  
• Osteoporosis: asymptomatic until fracture
  
• Paget's disease
• Bone remodelling units: 4 stage cycle (80% of bone formed during 9mth cycle length)
  
• Osteoclast activity: bone resorption
• Osteoblast precursor activity: putting down [mainly T1] collagen (Osteoid)
  
• Osteoblast activity: bone formation (if problems with this step: osteomalacia)
• Resting phase
• 1780s: cod liver oil for 'rheumatism' at MRI (Percival); Rickets: English disease; 1822: sunshine cures Rickets; 1932: VitD isolated
• Development of VitD deficiency from VitD insufficiency:
• VitD insuff: dcrd Ca: icrd PTH: icrd conversion of 25OHD to 1,25OHD: icrd gut Ca reabsorption: restored Ca levels at expense of icrd PTH: ultimately leads to 25OHD depletion: =VitD deficiency
• Current Recommended Daily Dose: 10mcg (400iu) VitD where diet is the only source: only to prevent severe VDD, i.e. osteomalacia/rickets
• VDD: associations
• malabsorption, chron liver dis, gastric bypass, PHPT, AED, etidronate, vegetarian (NB: meat protects ?how), immigrants (clothing, eg Hindus: veget+clothing)
• renal, hypophosphataemia (XLH, acquired tumoral), Cadmium
• Ix: Corr Ca [lo / lo-nl], PO4 [lo / lo-nl], AP, Crea [nl], PTH [hi], +-VitD
• NB: occas'ly: pseudohypoparathyroidism of VDD: vlo Ca, hi PO4, (hi) PTH - eg in young adults
• Xrays: occasly Looser zones
• Rx Osteomalacia: (long-term treatment)
  
• 800iu od; or
• 50k iu od for 5-10d; or
• 300k iu IM q 1-3mth (if malabsorption)
• Rx VDD
• 800iu VD od; or
• 40k D3 / 50k D2 mthly [CAUTION: NOT DAILY!! else TOXIC]; or
• 300k iu VD 3mthly: check Ca q3-4mth
• Rx with Calcitriol: only if VDDR or renal dis; need to be assessed q3mth
  
• VDD: icrd PTH: exacerbates osteoporosis (esp cortical bone, eg DEXA forearm)
• 25OHD:
• <5ng/mL: hi risk of osteomalacia (esp if lo meat diet)
• <10ng/mL: moderate risk of osteomalacia
  
• <20ng/mL: moderate risk of icrd PTH drive
• <30ng/mL: small risk of icrd PTH drive
• Prevention: exercise, casual sunshine 20-30min/d
• Symptoms of osteomalcia: hip pain, waddling gait, proximal myopathy, Looser's zones: sy usu only if VD<5ng/mL
  
• always check for coeliac (eg W Ireland)

Bone markers in osteoporosis

Prof Bill Fraser, Liverpool University

• Markers of bone resorption
  
• [Type 1] collagen crosslinks: PYD/DPD
• Telopeptide NTX/CTX ***
• crosslinked C-terminal telopeptide 1CTP
• Acid phosphatase (TRAP5b)
• [Hydroxyproline: NB: reutilised]
• [Ca: NB: reutilised]
• Markers of bone formation
• Alkaline phosphatase (Bone-[specific]=B[S]AP) *
  
• Osteocalcin: [NB: difficult in transport]
• Pro-collagen peptide
• P1CP/P1NP (Procollagen Type 1 N-propeptide#?) **
  
• Preferred:
• EDTA-Plasma-CTX [£12] and
• P1NP [any sample]: esp. in Teriparatide therapy
  
• Other tests available: FGF23
• Clinical use of bone turnover markers
• baseline: if very hi, consider alternative causes (Paget's, tu, HCM, toxicosis, osteopotegrin Ab, ...)
• marker of compliance: bisphosphonate dcr markers by at least 50%;
  
• may help with fracture risk prediction in future
• Marker targets: aim lower quartile
• BMD change after bisphosphonate treatment only accounts for 4-40% risk reduction, whereas:
  
• Bone marker change accounts for 25-60% risk reduction
• eg the greater the BAP dcr the greater hip fracture risk reduction
• Alendronate absorption: 40% at 30min, 90%+ at 1hr (before ingestion of any food or tablets)
• Clowes JCEM'04 on compliance and response to bisphosphonate therapy
• "Non-response" to bisphosphonates: usu due to wrongly/not taking them
• Teriparatide: PTH(1-34): BMD icr 2.6-13.7%, vertebr # dcr 65% (20mcg=licensed dose), 69% (40mcg)
• NB: different effect on cortical vs trabecular bone; ? icrd wrist fractures
• NB: tachyphylaxis if used in hypoparathyroidism [less if PTH(1-84) used]
• transverse midshaft femoral fractures: ? relationship to bisphosphonates: causality uncertain (if used in correct patients)
• Alendronate plus Ca-VitD better than Alendronate alone

Interventional radiology for osteoporosis

Dr Richard Whitehouse, MRI

• vertebral fractures very underreported (both XRays and CT): ask for sagittal image reconstruction or review
• vertebral fractures: {wedge | biconcave | crush}: usu if >25% depression
• Swiss cheese analogy of errors and possible harm: only if happen to be aligned
  
• vertebroplasty: injection of cement
• kyphoplasty: = vertebroplasty with prior balloon inflation

Journal Club

• Seleena Farook: Denosumab NEJM'09Aug: 60mg s.c. q6mth; NB: FDA ? icr in tumours (breast cancer subgroup)
• Simeen Akhtar: Vertebroplasty NEJM'09Aug: no better than sham procedure / facet joint injection; NB: Charlson comorbidity index for 10y mort risk
  

Case presentation: Oncogenic osteomalacia

Claire Higham

• oncogenic osteomalacia = hypophosphataemic osteomalacia
• due to FGF23 (fibroblast growth factor 23)
• acting via FGF-receptor (and affected by KLOTHO protein) in proximal tubule
• FGF23 pathway: revealed molecular basis of AR-hypophosphataemia, XL-H, AD-H