Case Studies in Osteoporosis

Deborah M. Kado, MD, MSAssociate Professor

Departments of Family Medicine & Public Health and Internal Medicine

UC San Diego School of Medicine

Overview

• Five cases

– Hip fracture treatment goals

– “Losing bone” despite being on therapy

– My patient has osteoporosis and won’t take a bisphosphonate

– My patient has been on a bisphosphonate for seven years

– Fracturing in spite of treatment

Case 1An 82 year old woman falls and breaks her hip

• Mrs. H tripped and broke her right hip while attempting to go to the bathroom in the middle of the night. Prior to this episode, she had been living alone and spent most of her days watching television.

• She has a history of prior wrist fracture 20 years ago when she slipped and fell on ice. She is unaware of any family history of osteoporosis.

• She last presented 6 months ago after she had had a fall at home. At that time, she had no serious injuries, weighed 115 pounds and was 5 foot 3 inches tall.

Hip fracturesEpidemiology

• One of every 6 white women will have a hip fracture during her lifetime

• Hip fracture is a major cause of disability and premature death– 1/3 remain institutionalized for at least a year– About half return home but must depend on other people or devices

for mobility– 20-25% increased risk of mortality in the first year

• Types of hip fracture– Intra-trochanteric 45%– Femoral neck 45%– Sub-trochanteric 10%

Femoral neck

Intra-trochanteric

Sub-trochanteric

Hip fracturesTreatment goals for the geriatrician

• Early surgery (within 24-48 hrs) associated with– Decreased pain– Decreased length of stay– Trend towards decreased mortality

• Peri-operative antibiotics reduce deep wound infections by 60%– Give 2 hrs pre-op and continue until 24 hrs post-op

• DVT prophylaxis– Without prophylaxis, risk of fatal pulmonary embolism 2-7%– Heparin or LMWH, compression stockings, to continue post-op until patient

ambulatory

• Rehab– Restore function, treat osteoporosis, and prevent future falls

Hip fracture case:Take home message

• Treat osteoporosis!– Not very good at starting therapy even when indicated

– What needs to be prescribed• Calcium 1,200 mg a day• Vitamin D at least 800 IU a day, up to 2,000 IU safe• Pharmacologic therapy, usually oral bisphosphonate

• Treat falls!– About 30% of persons >65 and 40% of those > 80 years fall each

year– 5-10% of falls result in fractures– Gait-training, balance, strengthening, medication adjustment, and

behaviorial instructions shown to reduce fall risk

Case 1Summary

• Mrs. H was taken to surgery and underwent a ORIF for her intra-trochanteric fracture. She did well post-op, and was discharged to a rehab facility on day 5. The physician overseeing her rehab started her on alendronate once weekly in addition to calcium and vitamin D.

• She was able to return to living at home, but now has a caregiver with her during the day to assist with her instrumental activities of daily living.

Case 2Bone density decrease despite being on bisphosphonate

• Mrs. T is a 68 year old woman who is being treated with alendronate 70mg/wk for osteoporosis. She is otherwise healthy with no previous history of fractures.

• She is a non-smoker and only occasionally has a glass of wine with dinner. She exercises regularly and has a healthy diet.

• Bone mineral testing after 1 year of alendronate reveals a T-score at the lumbar spine of –2.8 and a T-score of the total hip of – 2.9.

• Compared with her previous DXA, her bone density is 3% lower at the hip and 5% lower at the spine.

Treatment failure?“Why did my bone density decrease? I am taking the medicine.”

• Option 1: Mrs. T may have lost BMD despite prescription of an effective treatment– Caveat- she may have lost even more had she not been taking the

drug

• Option 2: Measurement imprecision– There is a measurement error of 2-3%

• Option 3: Mrs.T may be taking a bisphosphonate, but neglecting to take her calcium and vitamin D

• Option 4: Secondary cause of osteoporosis

What should you do?

• Make sure DXA readings are from the same machine– Machine calibration, particularly among different

manufacturers (i.e. Hologic vs. Lunar), can differ significantly

• Make sure patient is taking her supplemental calcium and Vitamin D as prescribed

• Consider ruling out secondary causes of osteoporosis or refer to an osteoporosis specialist

• Advise the patient to continue her medication as prescribed

When should you change therapy?Not yet.

• The observed increase in bone mineral density on bisphosphonates does not account for the magnitude of fracture risk reduction (about 50% at 1 year)

• Thus, an absence of bone mineral density increase or even an observed reduction does not necessarily indicate a treatment failure

• Only if after at least a year’s duration of medication and evidence of ongoing osteoporotic fractures, should one consider a change in therapy

– The choice of therapy should be guided by clinical expertise in the absence of RCT data refer to endocrinologist or osteoporosis expert

Case 2Summary

• Ms. T had her bone density measurements done at the same facility. She was advised to not obtain repeat measurements at more than 2 year intervals.

• She admitted to not always taking her calcium and vitamin D as prescribed. A 25-OH vitamin D level was obtained and returned at 22 ng/mL (low).

• She was prescribed Vitamin D2 gel caps 50,000 IU weekly, with the instructions to have a repeat 25-OH vitamin D level done in 3-4 months.

• She was reassured that although her bone density did appear to “decrease”, this did not signify a treatment failure.

Case 3Mrs. M has vertebral fractures, but won’t take a bisphosphonate

• Mrs. M is an 84 year old woman who presents to clinic after being rear-ended in her car. She complains of diffuse mild pain in her upper back, but otherwise feels okay. Exam is unremarkable except for some minimal tenderness over the upper back.

• She mentions a history of spine fractures in the past, but has been reluctant to take medications other than calcium and vitamin D.

• Lateral spine films reveal 3 compression fractures. Comparison with films taken 2 years ago reveal previous fractures of T8 and L1, an interval fracture at T9, not thought to be acute.

Case 3, cont.

• You counsel Mrs. M to start on an oral bisphosphonate, but she refuses stating her friend had a bad reaction

• She also mentions that she heard it causes jaw osteonecrosis and other bad side effects

• What to do you do now?

Vertebral fractures…are just not a pain in the back

• Vertebral fractures are a strong risk factor for future osteoporotic fractures– Having a single vertebral fracture is associated with a 3-fold

increased risk of future hip fracture and a 5-fold increased risk of another vertebral fracture

– Having greater than 2 vertebral fractures is associated with a 12-fold increased risk of future vertebral fracture

• With increasing numbers of vertebral fractures, there is an increasing risk of earlier mortality

Treatment for those who won’t or can’t… tolerate a bisphosphonate

• Reasons why not– Inconvenience of dosing- on empty stomach, sitting upright for ½

hour, or IV infusion– Fear of side effects (jaw osteonecrosis, heart arrhythmias,

spontaneous femur fractures)– Medical contraindication– Cost

• Alternative options in the United States– Raloxifene (in women only)– PTH 1-34 (teriparatide)– Calcitonin – Denosumab

Case 3Summary

• Mrs. M was informed that the risk of jaw osteonecrosis was far less than her risk of hip or another vertebral fracture and that the majority of reported cases have occurred in those with a history of cancer on IV bisphosphonate therapy.

• She still refused bisphosphonate therapy and was prescribed PTH 1-34 daily as an alternative agent.

• PTH 1-34 is very effective, keeping in mind the following:– FDA approved for 2 years only as associated with bone sarcoma in rats– Rapid bone loss follows discontinuation unless followed by another anti-

resorptive therapy (i.e. bisphosphonate)– Requires daily subcutaneous dosing and refrigerator storage

Mrs. L is 101 and does yoga weekly.

Case 4Mrs. M has been on a bisphosphonate for 7 years

• Mrs. M is a 72 year old woman who presents to clinic after being on risedronate for 7 years and is worried because:– her femoral neck T-score is -2.2 – she has had a minimal decline of her bone density of 1.5% despite

being compliant with the medication, calcium, and vitamin D

• She has no previous history of fractures, no family history of osteoporosis, and work up to rule out secondary causes of accelerated bone loss has been negative

• Her calculated FRAX score for major osteoporotic fracture is 12% and for hip fracture 2.7%

• She wonders what she should do now?

Bisphosphonate associated adverse events, potentially dosing and duration related

• Osteonecrosis of the jaw– 1/100,000 osteoporosis patients– 1/1,000 cancer patients receiving IV bisphosphonate

• Atrial fibrillation– Though rare, statistically significantly more occurred with IV dosing

regimen vs. placebo• Atypical femoral insufficiency fractures

– Associated with long-term use (> 5 yrs)• Esophageal cancer

– Associated with long-term use (average 5 yrs)

Alternative options for treatment are now availableWhat to do?

• Raloxifene

• PTH 1-34 (teriparatide)

• Calcitonin

• Denosumab

• Tibolone (not FDA approved, used in Europe for past 20 years)

• Strontium Ranelate (not FDA approved, used in > 30 countries)

Case 4 continued…Assessing Mrs. M’s fracture risk

• Mrs. M is 72 years old and otherwise healthy

• Mean age of hip fracture in an older woman is 81

• Aside from a FRAX score that is below treatment the treatment threshold (20% for all and 3% for hip), she also does not have a history of falls and has normal gait and balance on exam

• After 5 years of bisphosphonate treatment, she will likely continue to enjoy anti-fracture efficacy for at least another 5 years (Black et al, JAMA 2006)

Case 4Summary

• After confirming that her bone turnover markers were appropriately suppressed on therapy, Mrs. M was advised to stop her risedronate and take a “bisphosphonate holiday”

• She also was reminded to take calcium 1200 mg in diet and supplements combined along with vitamin D3 1,000IU daily

• She was encouraged to exercise regularly, including weight bearing and flexibility exercises

• Finally, she was advised to recheck her bone turnover markers at least once yearly and DXA bone mineral density scan in 2 years

Case 5Mrs. T. has fractured despite being on therapy

• Mrs. T is a 65 year old woman who presents to clinic with a newly diagnosed metatarsal fracture after being on Fosamax for 3 years:

– She reports tripping on the sidewalk & then developing pain in her foot– Her most recent femoral neck T-score is -1.9 & her spine T-score is -2.6 – She has had a decline of her bone density of about 4% despite being

compliant with the medication, calcium, and vitamin D– She has no family history of osteoporosis and no other significant

medical problems

Case 5Mrs. T. has fractured despite being on therapy-consider

secondary causes of osteoporosis• Most common secondary causes of osteoporosis

– Vitamin D deficiency (<20 ng/dL)– Hypercalciuria – Malabsorption (Celiac disease, bariatric surgery)– Hypogonadism, premature menopause

• Other secondary causes– Cushing’s disease -Rheumatoid arthritis– Hyperthyroidism -Liver impairment– Osteomalacia -COPD– Multiple myeloma -Multiple sclerosis– Hyperparathyroidism -Thalassemia– Systemic Mastocytosis -Diabetes– Kidney failure -Anorexia nervosa/bulimia– Gaucher’s disease -Organ transplantation– Hypophosphatasia -Spinal cord injury– Immobilization -Idiopathic scoliosis– Medications (steroids, lithium, barbituates, warfarin, aromatase inhibitors, Depo-provera)

Case 5Mrs. T. has fractured despite being on therapy: Further work up obtained

• No history of premature menopause or irregular menses

• Laboratory work up obtained– CBC: within normal limits– Chemistry Panel: within normal limits– Vitamin D 25-OH, serum calcium, phosphorus and intact PTH normal– 24 hour urine calcium: within normal limits– No history of malabsorption given so did not order anti-transglutaminase or

anti-endomyseal antibodies– SPEP – monoclonal spike– UPEP – no abnormal protein spikes– Serum immunofixation – positive – Serum NTX slightly elevated– Serum P1NP normal range

• Referred to hematologist – MGUS diagnosed

Case 5Summary

• Mrs T diagnosed with monoclonal gammopathy of unknown significance (MGUS), a likely contributing factor to her metatarsal fracture

• Since she displayed evidence of increased bone turnover while on alendronate, her therapy was changed to denosumab 60mg SQ every 6 months

• Once her foot fracture healed, she was advised to walk daily and begin balance exercises to decrease her risk of falls

• After 2 years of follow-up her MGUS remained stable and she experienced no further fractures

Thank you for your attention!