Evaluation of Osteoporosis in Hemophilic Arthropathy Patients: Correlation with Disease Severity and Serum Trace Minerals

Sahar Fathi
Assistant Professor of Rheumatology , physical Medicine and Rehabilitation Ain Shams University

Journal of osteoporosis
August 2011

Hemophilia

Hemophilia A - Factor VIII deficiency Hemophilia B Factor IX deficiency

Hemophilia

Hemophilia is a coagulation disorder characterized by acute hemorrhages into the musculoskeletal system leading to arthropathy and disability. Hemoarthrosis occurs in 75%90% of patients with hemophilia. The most common target joints are knees, ankles, and elbows. About 50% of patients with hemophilia develop permanent joint deformities.

Blood-induced joint disease

Consequences of blood in a joint:

Pain and spasm that lead

of movement. Hypertrophy of synovial membrane with reactive blood vessels. Iron uptake by macrophages. Damage to articular cartilage.

to decrease range

Blood-induced joint disease

Recurrent bleeding: Large amounts of hemosiderin deposited into synovial membrane. Iron stimulates synovial cell proliferation, and cytokine activity.
Inflammatory response

occurs to plasma enzymes, cytokines, chemokines (IL-1,IL-6, RANKL,TNF) and growth factors (PDGF, VEGF)

Pathogenesis of Joint Destruction

Blood-induced-Joint-Disease begins with inflammatory synovitis that progresses to cartilage and bone destruction. Angiogenesis of the synovium occurs that exacerbates bleeding. Neutrophils also express RANK and RANKL, which favors osteoclast differentiation and bone resorption.

Clinical Classification of Hemophilia

Severity Factor VIII Clinical Features (or IX ) level Severe Moderate <1 unit/ dl Spontaneous bleeding 1-5 unit/dl Severe bleeding after minor trauma or surgery >5 unit/dl bleeding after significant trauma or surgery

Mild

Hemophilia and Osteoporosis

Patients with severe hemophilia may be at risk for developing reduced bone density as arthropathy and joint deformities result in prolonged immobilization and reduced physical activity which predisposes to osteoporosis. This can lead to increase tendency of bone fragility and fractures in patients after trivial trauma

Hemophilia and Osteoporosis

Blood loss creating developmental pressure on hematopoietic system, so enhances the production of hematopoietic growth factors which increases proliferation of hematopoietic progenitor cells, increasing the number of osteoclasts.

Osteoporosis and trace minerals

Osteoporosis is a multifactorial disease with particular considerations to calcium, magnesium (Mg), and other trace elements as copper (Cu) and zinc (Zn). These trace elements are essential in bone metabolism as cofactors for specific enzymes for optimal bone matrix development and bone density integrity.

Osteoporosis and trace minerals

Zinc inhibits the differentiation of osteoclasts and promotes osteoblast activity. Zinc increases bone growth factors and bone matrix proteins. Magnesium is important in bone cell activity, it is mitogenic for osteoblasts. Copper is a cofactor for lysl oxidase which is required in cross linking of collagen and elastin.

Aim of the Study

we aimed to assess the presence and severity of osteoporosis in patients with hemophilic arthropathy by determining dual energy X-ray absorptiometry (DEXA) and to correlate these findings with the extent of joint disease and serum levels of trace minerals as magnesium, copper, and zinc.

Patients & Methods

This study included 20 male patients with hemophilic arthropathy (type A) and 20 healthy, age- and sex-matched controls.

Their age ranged from 7 to 40 years. The diagnosis of hemophilia was made clinically, and classified according to measured factor VIII activity in the plasma.

Exclusion Criteria

Cigarette smoking or alcohol abuse. Patients with history of any chronic medical illness producing osteopenia/ osteoporosis, thyroid or parathyroid disorders, and history of chronic renal or hepatic diseases. Patients with prolonged intake of steroids, antiepileptic medication, iron for anemia, Ca or Vit D supplementation.

Clinical Assessment
All patients were subjected to the following: (1)- Joint Evaluation:

Lower limb joints (ankles and knees) were assessed by using the clinical evaluation score of the world Federation of Hemophilia (WFH) which includes seven criteria and a total possible score of 12. Each joint was ascribed a score. Normal joints were scored as 0, the highest possible score for knees and ankles was 48.

(2)Juvenile Arthritis Functional Assessment Report (JAFAR):

It is a single dimension scale based on 23 items used as a disability score to evaluate the functional status and daily living activities for each patient. The response to each activity was scored between 0 and 2 as follows:

0 = indicating that the activity could be done alone without any difficulty during the previous week 1 = indicating that it could be done some of time 2 = indicating that it was almost never done alone.

The sum of all items, assuming a range between 0 and 46 with lower score indicating better function.

Radiological Assessment

Plain X ray: anteroposterior projection and lateral views of both knee joints. Total x ray score: the maximum possible score of a given joint was 13. The total score for both knee joints was 26

DEXA

Bone densitometry: in all subjects, bone mineral density (BMD) was measured at the femoral neck and lumbar spine using DEXA. Results were recorded for each patient as Z score (difference in SD from the mean of a healthy age- and gender-matched sample).

Laboratory Investigations

Serum magnesium level was measured. Normal range for serum magnesium is 1.92.5mg/dl. Determination of copper and zinc in serum was done. Normal levels for copper and zinc ranged from 0.71.0g/mL and 0.8 1.2g/mL, respectively.

Results

Results

The patients age ranged from 7 to 40 years, with a mean of 21.7 11.2 years. According to the factor level, 8 patients (40%) diagnosed as mild grade and 12 patients (60%) diagnosed as moderate grade of hemophilia.

Demographic, clinical, laboratory and radiological data of hemophilic arthropathy patients.

Patients (n = 20) Range Disease duration (years) Factor level units/ml Total joint score Functional assessment score Total x ray score 2-33 2-10 4-21 0-9 6-19 Mean SD 14.7 10.5 5.05 3.3 13.5 6.2 2.8 3.4 12.5 4.8

Radiographic Changes
Soft tissue swelling Osteopenia Overgrowth of epiphysis Erosions Cysts

DEXA Results
Patients (n = 20) Range Controls (n = 20) Mean SD Sig. P Mean Range SD

Z score -2.7(-0.9) -2.1 0.6-0.2 1.3 lumbar Z score -3.0(-0.5) -1.8 0.8 -0.4 1.4 femur

0.7 0.5 0.7 0.6

0.001 0.001

HS HS

Serum levels of Ca, Mg, Cu and Zn

Patients (n = 20) Controls (n = 20) P Sig. Range Mean SD Range Mean SD
Calcium (mg/dl) Magnesium 1.5 1.8 1.6 0.09 (mg/dl) Copper (mg/ml) 0.40 0.66 0.55 0.08 0.65 0.05 0.7 1.0 0.8 1.2 0.84 0.12 1.0 0.13 0.001 0.001 HS HS 1.9 2.5 2.2 0.21 0.001 HS 9.1 9.6 9.3 0.18 9 9.5 9.2 0.18 0.26 NS

Zinc (mg/ml) 0.53 0.72

Both TJS and total x ray score correlated positively with disease duration and functional assessment score and correlated negatively with serum factor level of hemophilia and serum levels of Zn. Z score of neck of femur correlated negatively with total joint score, functional assessment score and total X-ray score.

The positive correlation between serum cupper level and Z score of neck of femur among all patients.

The positive correlation between serum zinc level and Z score of neck of femur among all patients.

Conclusion

In hemophilic arthropathy patients, osteoporosis represents a frequent concomitant observation which may complicate the future treatment of these patients. Extensive joint disease is an important risk factor for the severity of osteoporosis. Screening of young hemophilics for reduced bone density is recommended with measuring the levels of Mg, Cu and Zn for better assessment and management of the disease.

THANK YOU

JAFAR

In the past week, was Patient able to: time Sometimes never 1 Take shirt off hanger ___ ___ ___ 2 Button shirt ___ ___ ___ 3 Pull on sweater over head ___ ___ ___ 4 Turn on water faucet ___ ___ ___ 5 Sit on floor, then stand up ___ ___ ___ 6 Dry back with towel ___ ___ ___ 7 Wash face with wash cloth ___ ___ ___ 8 Tie shoelaces ___ ___ ___ 9 Pull on socks ___ ___ ___ 10 Brush teeth ___ ___ ___ 11 Stand up from chair without using arms ___ ___ ___

JAFAR

12 Get into bed ___ ___ ___ 13 Cut food with knife and fork ___ ___ ___ 14 Lift empty glass to mouth ___ ___ ___ 15 Reopen previously opened food jar ___ ___ ___ 16 Walk 50 feet without help ___ ___ ___ 17 Walk up 5 steps ___ ___ ___ 18 Stand on tiptoes ___ ___ ___ 19 Reach above head ___ ___ ___ 20 Get out of bed ___ ___ ___ 21 Pick up something from floor from standing position ___ ___ ___ 22 Push open door after turning knob ___ ___ ___ 23 Turn head and look over shoulder ___ ___ ___

In all subjects, BMD was measured at the femoral neck and axially at the lumbar spine (L1L4) in the anterior and posterior projection using DEXA; results were recorded for each patient as Z score (difference in SD from the mean of a healthy age- and gender-matched sample) and T score (difference in SD from the mean of a healthy young adult). Osteoporosis and osteopenia were defined as T score less than 2.5 and T score between 1 and 2.5, respectively