Metabolic Bone Disease Flashcards
Mrs Roberts, a 65 year old postmenopausal woman, develops acute severe back pain while picking up her 4 year old grandchild
No PHx of back pain
Current height 168cm, but was 173cm tall when married 42 years previously
Weight is 72kg and BMI 25.5
Caucasian
DDx?
Acute onset of severe back pain: acute disc disruption +/- nerve root compression, acute vertebral fracture, or pathological cause (e.g. bony mets, multiple myeloma)
Height loss: likely due to loss of height of vertebra(e) or intervertebral disc spaces (≥3cm of height loss is significant)
List 10 RFs for OP
Low exercise levels
Smoking
Co-morbidities (e.g. RA)
Poor nutrition (low Ca2+ intake)
Risk of vit D insufficiency (e.g. no sun exposure, poor diet)
Prolonged amenorrhoea in younger years
Early menopause
PHx of #
FHx of #/OP
Lack of previous/current therapies for postmenopausal OP
Mrs Roberts, a 65 year old postmenopausal woman, develops acute severe back pain while picking up her 4 year old grandchild
PHx: T2DM complicated by microalbuminaemia and mild peripheral neuropathy
Rx: mixed insulin
Widowed, lives alone, doesn’t like to cook
O/E: well-looking, slightly overweight, no Cushingoid features, afebrile, RR 14, HR 80 regular, BP 135/90, signs of hyperinflation with some scattered wheeze, moderate kyphosis with tenderness over mid-thoracic spine, normal breast examination
Most likely Dx? Ix?
Osteoporotic crush #
Ix: XR thoracolumbar spine to confirm
Mrs Roberts, a 65 year old postmenopausal woman, develops acute severe back pain while picking up her 4 year old grandchild
An XR thoracolumbar spine was performed
Interpret the plain film
Anterior wedge compression #
Full series showed 30% anterior wedge compression # at T8 and 20% anterior wedge compression # at L2
Describe the WHO criteria for Dx of OP
Normal: T-score ≥ -1 (reference standard for “normal” BMD is healthy 30 year old woman)
Osteopaenia: -1 to -2.4
OP: ≤ -2.5
Severe OP: ≤ -2.5 and ≥1 #
NB For every 1 SD decreased from normal, RR of # increases 1.5-2.5 fold
Distinguish between the Z- and T-score of a DXA
Z-score: number of SDs above or below the mean for the patient’s age, sex and ethnicity
T-score: number of SDs above or below the mean of a healthy 30 year old adult of the same sex and ethnicity as the patient
What does the DXA measure?
Area density in g/cm^2
What does a Z-score less than -2 indicate?
May be useful in identifying those with underlying accelerated causes of bone loss
How is OP usually diagnosed?
Presence of fragility or minimal trauma #
BMD of spine and proximal femur by DXA
Mrs Roberts, a 65 year old postmenopausal woman, develops acute severe back pain while picking up her 4 year old grandchild
Ix: FBG elevated (consistent with T2DM), HbA1c 7.3% (above goal of 7%), UEC indicates some renal insufficiency with eGFR of 40mL/min, LFTs reveal ALP of 140IU/L, 25-OH vit D 25nmol/L, PTH 14pmol/L, CMP normal, TSH normal, CRP normal
BMD T-score for lumbar spine is -2.35 and femoral neck is -2.98
How are bone resorption and formation measured?
Resorption: serum B-CTX (C-terminal telopeptide)
Formation: P1NP (N-terminal propeptide of type 1 procollagen)
Mrs Roberts, a 65 year old postmenopausal woman, develops acute severe back pain while picking up her 4 year old grandchild
Ix: FBG elevated (consistent with T2DM), HbA1c 7.3% (above goal of 7%), UEC indicates some renal insufficiency with Cr of 0.190mmol/L and eGFR of 40mL/min, LFTs reveal ALP of 140IU/L, 25-OH vit D 25nmol/L, PTH 14pmol/L, CMP normal, TSH normal, CRP normal
DXA: T-score for lumbar spine is -2.35 and femoral neck is -2.98
Bone turnover markers: serum B-CTX 0.52ng/mL, P1NP 108ug/L
What are the normal parameters for all these Ix?
FBG: 3.0-5.4mmol/L
Cr: 0.05-0.10mmol/L
eGFR: 40mL/min
GGT: less than 35IU/L
ALP: 30-120IU/L
25-OH vit D: optimal target is >50nmol/L
PTH: 1.2-6.5pmol/L
Ca2+ (corrected): 2.1-2.6mmol/L
Phosphate: 0.87-1.45mmol/L
TSH: 0.5-5mIU/L
CRP: <10mg/L
T-score: ≥1
B-CTX: >30 years premenopausal women should be less than 0.45ng/mL
P1NP: premenopausal women should be less than 70ug/L
What is P1NP?
Marker of bone formation
Procollagen type 1 propeptides
Cleared by liver endothelial cells
What is CTX? Briefly describe its pharmacokinetics
Marker of bone resorption (cleaved during bone resorption)
Diurnal variation (peak at 8-9.30am)
Must be measured fasting
Cleared by kidneys
List 5 common secondary causes of OP which are correctable
Cushing’s syndrome or use of exogeous corticosteroids (>5mg/day for >3/12)
Excessive alcohol use (>2 units or 18g/day)
Smoking
Malabsorption (e.g. coeliac disease, IBD)
Primary or secondary hypogonadism (including Rx-associated, e.g. corticosteroids, opioids, androgen deprivation therapy for prostate Ca, aromatase therapy for breast Ca)
List 13 less common secondary causes of OP
Low BMI (below 20) and associated eating disorders
Lack of or excessive exercise
Thyrotoxicosis or thyroxine over-replacement
Primary hyperPTH
Chronic liver or kidney disease
Hypercalciuria
RA or ankylosing spondylitis
DM
MM
HIV or its treatment with protease inhibitors
Mastocytosis
Organ transplant or immunosuppressive (e.g. cyclosporin/cyclophosphamide, tacrolimus)
Osteogenesis imperfecta
Give 2 examples of tools developed to calculate # risk in patients with OP
FRAX (WHO # Risk Assessment Tool)
Garvan Tool
What factors must be taken into account when deciding on appropriate treatment for OP?
Patient/family’s wishes
Benefit/risk ratio for each treatment
Severity of disease
Prior treatment
Presence of co-morbidities that might influence choice of medication (e.g. dysphagia, achalasia)
What are the goals of OP Mx?
risk reduction
Reduction in mortality through hip # avoidance
Improve QoL with preserved mobility and independence
List 6 therapies available for OP
HRT (mostly women only)
Raloxifene (women only)
Bisphosphonates: alendronate, risedronate, zoledronate
Teriparatide
Denosumab
Strontium
Outline the mechanism of HRT and SERMs as treatment for OP
Outline the mechanism of bisphosphonates as treatment for OP
Outline the mechanism of denosumab as treatment for OP
Outline the mechanism of teriparatide as treatment for OP
Outline the mechanism of strontium as treatment for OP
SEs of bisphosphonates
GIT
ONJ
Atypical #
Progression of stage 4 CKD
SEs of denosumab
ONJ
Atypical #
Hypocalcaemia
Infection
Allergy
SEs of raloxifene
GIT
Thrombosis
Progression of stage 4 CKD
Teriparatide SEs
Hypercalcaemia
?osteosarcoma (rodent studies)
Progression of stage 4 CKD
What is the relationship between strontium and CVD? What are the clinical implications of this?
Pooled data from RCT studies showed that women using strontium ranelate were at increased risk of MI compared with placebo; however, mortality was not increased
Strontium is contraindicated in patients with a Hx of IHD, PVD or CVD, and patients with HTN with SBP ≥160mmHg or DBP ≥90mmHg
Relative contraindications include patients with significant RFs for CV events (e.g. HTN, hyperlipidaemia, DM, smoking)
What criteria must be met for patients to qualify for PBS reimbursement for teriparatide?
Severe OP
T score less than -3.0
2 minimal trauma #s
One fracture occurring despite at least 12/12 of anti-resorptive drug treatment
OR intolerance to oral and IV bisphosphonates
I.e. must have had a trial of anti-resorptive treatment, including bisphosphonates
List 5 contributing factors to #s in CKD
OP
Osteomalacia
HyperPTH
Adynamic bone disease
Post-transplantation (steroid, calcineurin inhibitors)
Describe the mechanism of hyperPTH in CKD. What are some other causes of secondary hyperPTH?
Failing kidneys do not convert enough vitamin D to its active form, and they do not adequately excrete phosphate. When this happens, insoluble calcium phosphate forms in the body and removes calcium from the circulation. Both processes lead to hypocalcemia and hence secondary hyperparathyroidism.
Secondary hyperparathyroidism can also result from malabsorption (chronic pancreatitis, small bowel disease, malabsorption-dependent bariatric surgery) in that the fat-soluble vitamin D can not get reabsorbed.
What is adynamic bone disease? Are there any important considerations for ABD as a cause of OP?
Adynamic bone disease (ABD) is a variety of renal osteodystrophy characterized by reduced osteblasts and osteoclasts, no accumulation of osteoid and markedly low bone turnover
Seen in CKD, esp in dialysis patients
Note that in ABD, anti-resorptive therapy increases #
How should the dose of bisphosphonates be altered in CKD patients? Give an example of a drug regimen that may be recommended
Bisphosphonates are renally excreted and although there is no therapeutic drug monitoring (consider monitoring with ALP?), dose reduction by 50% may be indicated
Risedronate 35mg fortnightly to monthly
Describe the current recommendations for OP Mx in CKD patients
1-3a: same as patients without CKD
3b: caution with IV bisphosphonates, dose reduction with oral bisphosphonates
4: and 4d: bisphosphonates with hypocalcaemia precaution
5: no data
What renal AEs have been seen in case reports with IV bisphosphonates?
Glomerulosclerosis or ATN
What is the most probable cause of # in patients with stage 1-3 CKD? How should these patients be managed?
OP, rather than CKD-MBD once other metabolic/biochemical abnormalities are corrected (e.g. hyperphosphataemia, secondary hyperPTH)
Consider treatment with antiresorptives once secondary causes of OP are excluded, and ensure adequate Ca2+ and vit D (particularly is deficiency is present)
What are the 4 main options for OP Mx in patients with CKD?
Raloxifene: vertebral # risk protection only
Oral alendronate: weekly tablet
Oral risedronate: weekly or monthly tablet
6/12ly SC denosumab injections
What are the 3 stages of ONJ?
1) Asymptomatic
2) Pain + inflammation/infection
3) Pain + inflammation/infection + osteolysis
What is ONJ?
Exposed necrotic bone >8 weeks
List 6 RFs for ONJ
IV bisphosphonates (malignancy) 0.8-12%
Prolonged bisphosphonates
Steroids
Smoker
Poor oral hygiene
Also reported in denosumab
What is the rate of ONJ for patients on oral bisphosphonates?
1 in 100,000 patient years
Oral bisphosphonates calculated ONJ rate was 0.01-0.04%, which increased to 0.09-0.34% if extraction performed
What is one of the limitations of bisphosphonates, illustrated in the attached radiograph?
Plain film shows an incomplete atypical femoral # (lateral break, suggestive of stress #) with periosteal thickening
Risk of atypical # (including atypical femoral #) increases with prolonged bisphosphonate use and decreases rapidly with cessation
BUT uncommon
When should a “drug holiday” in OP be considered?
If BMD increased to >T = -.25 at femoral neck after 3-5 years (but drug holiday can only be considered if patient is monitored for any subsequent bone loss)
